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Molecular Aspects of Medicine 32 (2011) 170

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Molecular Aspects of Medicine


journal homepage: www.elsevier.com/locate/mam

Review

Nutrition and human health from a sexgender perspective


Maria Marino a, Roberta Masella b, Pamela Bulzomi a, Ilaria Campesi c,f, Walter Malorni d,e,
Flavia Franconi c,f,
a

Department of Biology, University Roma Tre, Viale Guglielmo Marconi 446, I-00146 Roma, Italy
Department of Veterinary Public Health and Food Safety, Italian National Institute of Health, Rome, Viale Regina Elena 299, I-00161 Rome, Italy
c
Center for Biotechnology Development and Biodiversity Research, Via Vienna 2, I-07100 Sassari, Italy
d
Department of Therapeutic Research and Medicine Evaluation, Italian National Institute of Health, Viale Regina Elena 299, I-00161 Rome, Italy
e
San Raffaele Institute Sulmona, Viale dellAgricoltura 1, LAquila, Italy
f
Department of Pharmacology, University of Sassari and National Laboratory, INBB Osilo-Sassari, Via Muroni 23, I-07100 Sassari, Italy
b

a r t i c l e
Keywords:
Nutrition
Health
Sex
Gender
Food
Beverage

i n f o

a b s t r a c t
Nutrition exerts a life-long impact on human health, and the interaction between nutrition
and health has been known for centuries. The recent literature has suggested that nutrition
could differently inuence the health of male and female individuals. Until the last decade
of the 20th century, research on women has been neglected, and the results obtained in
men have been directly translated to women in both the medicine and nutrition elds.
Consequently, most modern guidelines are based on studies predominantly conducted
on men. However, there are many sexgender differences that are the result of multifactorial inputs, including gene repertoires, sex steroid hormones, and environmental factors
(e.g., food components). The effects of these different inputs in male and female physiology
will be different in different periods of ontogenetic development as well as during pregnancy and the ovarian cycle in females, which are also age dependent. As a result, different
strategies have evolved to maintain male and female body homeostasis, which, in turn,
implies that there are important differences in the bioavailability, metabolism, distribution, and elimination of foods and beverages in males and females. This article will review
some of these differences underlying the impact of food components on the risk of developing diseases from a sexgender perspective.
2011 Elsevier Ltd. All rights reserved.

Abbreviations: c-GCS, c-glutamylcysteine synthetase; 11b-HSD-2, 11b-hydroxysteroid dehydrogenase; 19- and 20-HETE, 19- and 20-hydroxyeicosatetraenoic acids; 5,6-, 8,9-, 11,12-, and 14,15-EET, 5,6-, 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acids; AAG, a-1 acid glycoprotein; AgRP, agouti-related
protein; AR, androgen receptor; ARE, androgen response element; ArKO, aromatase knockout mouse; ASK, apoptosis signal-regulating kinase; ATP,
adenosine triphosphate; BMI, body mass index; CART, cocaine- and amphetamine-regulated transcript; COX, cyclo-oxygenase; CYP, cytochrome P450
enzyme; DHA, docosahexaenoic acid; DPA, docosapentaenoic acid; EE, energy expenditure; EPA, eicosapentaenoic acid; ER, estrogen receptor; ERE, estrogen
response element; ERK, extracellular signal-regulated kinases; FFA, free fatty acid; FM, fat mass; GPx, glutathione peroxidase; GR, glutathione reductase;
GSH, glutathione; GSSG, glutathione disulde; GST, glutathione-S-transferase; HDL, high density lipoprotein; HMGR, 3-hydroxyl-3-methyl glutaryl CoA
reductase; IGF- I, insulin-like growth factor-I; IGF-II, insulin-like growth factor-II; JNK, c-Jun-terminal kinase; LBD, ligand-binding domain; LBM, lean body
mass; LDL, low density lipoprotein; LOX, lypo-oxygenase; LT, leukotrienes; MAPKs, mitogen-activated protein kinases; MI, myocardial infarction; NO, nitric
oxide; NOS, nitric oxide synthase; NPY, neuropeptide Y; Nrf, nuclear-related factor; OC, oral contraceptives; OGTT, oral glucose tolerance test; PCA,
protocatechuic acid; PI3K, phosphatidylinositol 3 kinase; PLA2, phospholipase A2; POMC, pro-opiomelanocortin; PPAR-a, peroxisome proliferator activated
receptor-a; PPAR-c, peroxisome proliferator activated receptor-c; PUFA, n-3 polyunsaturated fatty acids; RDA, recommended dietary allowance; RONS,
reactive nitrogen oxygen species; ROS, reactive oxygen species; TNF, tumor necrosis factor; TRAIL, TNF-related apoptosis-inducing ligand; UV, ultraviolet;
VLDL, very low-density lipoproteins; VSMC, vascular smooth muscle cell; WHO, World Health Organization.
Corresponding author at: Department of Pharmacology, University of Sassari, Via Muroni 23, I-07100 Sassari, Italy. Tel.: +39 079228717.
E-mail address: franconi@uniss.it (F. Franconi).
0098-2997/$ - see front matter 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.mam.2011.02.001

M. Marino et al. / Molecular Aspects of Medicine 32 (2011) 170

Contents
1.

2.

3.

4.

5.

6.

7.

8.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
1.1.
Historical accounts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
1.2.
Gender blindness and gender bias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
1.3.
Sexgender and nutrition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
Physiology of organs and apparatus involved in nutrition from a sexgender perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
2.1.
Sexgender differences in the brain region involved in regulation of food consumpion . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
2.2.
Sexgender related differences in the nutrient bioavailability and metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
2.2.1.
Nutrient bioavailability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
2.2.2.
Metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
2.3.
Body weight and composition in male and female . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
2.3.1.
Bone mass . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
2.3.2.
Skeletal muscle mass . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
2.3.3.
Adipose tissue mass and metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
2.4.
Sexgender related differences in the cardiovascular system and nutrient distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
2.5.
Energy balance from a sexgender perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
2.6.
How do gender physiology differences arise? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
2.6.1.
Genetic mechanisms. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
2.6.2.
Epigenetic mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
2.6.3.
Hormonal mechanism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
Nutrients and food components in health and disease in a sex-gender perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
3.1.
The role of food in health . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
3.1.1.
Proteins and amino acids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
3.1.2.
Fat quality and quantity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
3.1.3.
Micronutrients: vitamins and minerals. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
3.2.
Plant-derived flavonoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
3.3.
A debate: alcoholic beverages in women and men . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
Special cases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
4.1.
Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
4.2.
Obesity, diabetes mellitus and cardiovascular disease prevention in women and men . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
Conditions specific to women . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
5.1.
Influence of oral contraceptives and hormonal replacement therapy on nutrition. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
5.2.
Pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
Sexgender specific nutritional requirements in early life: timing and the critical window . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
6.1.
Is the placenta sexually dimorphic?. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
6.2.
Timing and critical windows . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38
6.3.
Early events and developmental plasticity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38
6.4.
Infant feeding and weaning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
Influence of foods on cell fate from a sexgender perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
7.1.
Sexgender, antioxidants and cell fate. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
7.2.
Cytology and cytopathology in male and female cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
7.2.1.
Oxidative stress . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
7.2.2.
Oxidative stress and cell injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42
7.3.
The antioxidant defense systems in XX and XY cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44
7.3.1.
Endogenous defense systems. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44
7.3.2.
Exogenous antioxidants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
7.4.
Nutrients as modulators of XX and XY cell fate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46
7.4.1.
Necrosis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
7.4.2.
Apoptosis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
7.4.3.
Autophagy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48
7.4.4.
Cross-talk between apoptosis and autophagy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50

M. Marino et al. / Molecular Aspects of Medicine 32 (2011) 170

1. Introduction
1.1. Historical accounts
The term gender comes from the Latin genus (descent, family, type), cognate with Greek cemo1 (race, stock, kin). Until
about the 14th century, this term indicated things that have to be treated differently because of their inherent differences.
Only after the 14th century has the term gender been used as a synonym for sex. The distinction between the terms sex
and gender was rst made between the 1950s and 1960s by medical personnel working with intersex and transsexual patients (Stoller, 1968). Since then, gender has been increasingly used to distinguish between sex as biological and gender as
socially and culturally constructed. Feminists have used this terminology to argue against the deterministic concept biology
is destiny. An example of a biological deterministic view is that of Geddes and Thomson (1889), who dened women as
anabolic and men as catabolic. Following their ideas, anabolic women conserve energy, and they are passive, conservative, sluggish, stable, and uninterested in politics; on the other hand, the energy surplus of catabolic men makes them eager,
energetic, passionate, variable, and, thereby, interested in political and social matters. In the 1970s, such a sex difference was
used to argue that women should not become airline pilots because they will be hormonally unstable once a month and,
therefore, unable to perform their duties as well as men (Rogers, 1999). Because of this biological determinism, people perceived the word woman not as a sex term but as a gender term that depended on social and cultural factors (such as social
position), thus distinguishing sex (being female or male) from gender (being a woman or a man). In contrast, Gayle Rubin
used the sex/gender system to describe a set of arrangements by which the biological raw material of human sex and
procreation is shaped by human, social intervention (Rubin, 1975).
Currently, there are at least three denitions of gender. The rst one is social, cultural and psychological aspects that pertain to the traits, norms, stereotypes and roles for those whom society has designated as male or female (Doyle, 1985). The
second denition limits gender to [. . .] use when referring to men and women as social groups (American Psychological
Association, 2001). The third denition states that gender is self-representation as male or female and how the individual
is responded to by social institutions (Institute of Medicine and America, 2001). The latter denition includes selfrepresentation, which also includes biological aspects. The World Health Organization (WHO), for example, uses gender
to refer to the socially constructed roles, behaviors, activities, and attributes that a given society considers appropriate for
men and women (WHO, 2009). However, it is also difcult to dene sex. The rare ambiguous cases, such as trans-sexualism,
are relevant for denition and use. Indeed, Grumbach et al. (2003) wrote that Sex determination and differentiation are
sequential processes that involve successive establishment of chromosomal (and genetic) sex in the zygote at the moment
of conception, determination of gonadal (primary) sex by the genetic sex, and regulation by the gonadal sex of the differentiation of the genital apparatus and, hence, the phenotypic sex. Clearly, this denition includes chromosomal, genetic and
gonadal sex and describes how the complexity of each phenomenon can occur in different intermediary outcomes.
Thus, gender and sex are both complex issues. In recent years, sex and gender have been considered dichotomic concepts
(Argyrous and Stilwell, 2003). In short, physical differences were called sex, inuenced by genes and hormones; psychological differences were called gender, in which environment, cultural, and psychosocial factors played a prominent role. However, Fausto-Sterling rejected the discourse of biological versus social determinism and advocated a deeper analysis of how
interactions between the biological being and the social environment inuence individual capacities (Fausto-Sterling,
1992). Nevertheless, many people have ordinarily taken sex ascriptions to be solely a matter of biology with no social or cultural dimensions. However, secondary sex characteristics, or the physiological and biological features that are commonly
associated with males and females, are affected by social practices. In some societies, females who have a lower social status
are fed less, and the lack of nutrition results in making them smaller in size ( Jaggar, 1983). Uniformity in muscular shape,
size and strength within sex categories may not entirely be caused by biological factors; it may also depend on exercise: if
males and females are allowed the same opportunities to exercise and equal encouragement to exercise, the body dimorphism could diminish (Fausto-Sterling, 1992). A number of pathological phenomena involving bones (e.g., osteoporosis) have
social causes directly related to expectations about gender, womens diet and their opportunity to exercise (Fausto-Sterling,
2005). This example suggests that physiological features, which are thought to be sex-specic traits not affected by social
and cultural factors, are, after all, to some extent the product of social conditioning. Hence, social conditioning shapes our
biological features. Epigenetic changes in the nervous system are emerging as critical components of enduring effects induced by early life experience (Collins et al., 2009). Sex differences in the brain are largely determined by steroid hormone
exposure during a sensitive perinatal period that alters subsequent hormonal and nonhormonal responses throughout the
lifespan (McCarthy et al., 2009). Steroid hormones are uniquely poised to exert epigenetic changes such as acetylation
and methylation on the developing nervous system to dictate adult sex differences in brain and behavior (McCarthy
et al., 2009). Many steroid-induced epigenetic changes are opportunistic and restricted to a single lifespan, but new evidence
suggests that endocrine-disrupting compounds can exert multigenerational effects (McCarthy et al., 2009). Similarly, maternal diet also induces transgenerational effects, but the impact is sex specic (Jimenez-Chillaron et al., 2009). In this scenario,
the distinction between sex and gender (i.e., whether the difference between males and females are biologically or socially
determined) could have potentially deleterious effects on scientic progress. In line with this approach, the terms gender
and sex are linked in the present paper. In our opinion, these two terms emphasize the interaction between sex and gender
in terms of differences and similarities.

M. Marino et al. / Molecular Aspects of Medicine 32 (2011) 170

1.2. Gender blindness and gender bias


Gender-blindness refers to a failure to identify or acknowledge differences on the basis of gender where they are significant. Gender-blindness occurs at all levels of medical practice and education and is often perpetuated by the convention of
using gender neutral language. In this regard, it is signicant that in 1991, Bernadine Healy, the rst woman director of the
US National Institutes of Health, summarized two studies in the July issue of the prestigious New England Journal of
Medicine that demonstrated sex bias in the management of coronary heart disease (Healy, 1991). To better illustrate the situation, she spoke of Yentl syndrome: Yentl was the young heroine in Nobel prize recipient Isaac Singers short story from
the Lublin Jewish community. Yentl had to dress and act like a boy to be able to attend school and be educated in the Talmud
(Singer, 1983).
Sex and gender differences are the results of multifactorial inputs that are inuenced by gene repertoires, sex and other
hormones as well as environmental factors (e.g., food components). The effects of these different inputs will be different in
different periods of the ontogenetic development, during aging, and during the menstrual cycle in females. However, these
individual phases are often difcult to consider in experimental studies (Leinwand, 2003). Thus, women have historically
been excluded from research studies. Consequently, most modern guidelines are based on studies predominantly conducted
on middle-aged men (Wenger, 2006). Lack of evidence about the effectiveness of medical interventions in women can result
in both withholding treatment that could be benecial and exposing patients to treatments that are harmful (Rogers, 2004).
In line with the above insights, the WHO recently stated that the increased knowledge and evidence of the impact of
gender inequalities on specic health problems and health services and of successful responses, and developing tools to promote and expand health sector policies, interventions and programs that systematically address gender concerns represents
a key issue in human health. Nonetheless, the pervasiveness of gender-blindness in medical practice and institutions is so
extensive that many care operators, researchers and policy makers were or are not aware of its existence. Gender blindness
and stereotyped preconceptions about men and women lead to gender bias. However, the exaggeration of observed sex and
gender differences can also lead to a further illustrative but simplistic bias (Hamberg, 2008).
1.3. Sexgender and nutrition
Although nutrition has classically been perceived as a means to provide energy and building material to the body, the
ability of some food components to prevent and protect against diseases is becoming better recognized. In particular, research over the past 15 years has provided exciting evidence for the biological activity of dietary factors that can inuence
specic molecular systems and mechanisms that maintain body functions.
Although high-quality nutrition during gestation and after delivery is critical to the healthy development of the child, and
the womb environment plays a role in the later development of obesity, type 2 diabetes, high blood pressure and heart disease in childhood and adulthood (Collins et al., 2009), the impact of diet constituents on male and female physiopathology
throughout life has received little attention. Furthermore, the paucity of ndings and the low quality of some of these studies
demand a systematic review of the literature. In this review, we summarize some important aspects of the possible implications of nutrition and diet constituents in sexgender disparity.
2. Physiology of organs and apparatus involved in nutrition from a sexgender perspective
There are marked differences between men and women in the incidence and expression of many major diseases. These
sexgender based differences in the pathophysiology of disease imply, in turn, that there are important underlying differences in physiological functions. Despite the importance of this topic, sexgender differences in physiology are not systematically addressed either in physiology textbooks or in the medical physiology curriculum, with the obvious exception of
reproductive physiology.
The functional differences between men and women as well as their similarities are of the utmost importance because they
provide fundamental insight into the mechanisms regulating the integrated functions of the intact organism. Much of the human data found in medical texts represent the environment in which the testing was conducted. Medical schools and military
institutions located largely in Europe and North America have provided the largest number of healthy individuals in which
to make measures of function. Consequently, most of the data present in physiology textbooks represent young (1822 year),
healthy, 70-kg Caucasian males. Similarly, when physiological adaptations to exercise, altitude, or space have been studied,
young, Caucasian, male trained athletes again populated the data set (Blair, 2007,and literature cited therein).
The actual distribution of human population is broader than that represented by these subsets, and the distribution of females likely overlaps but does not coincide with the distribution for males. While the data obtained from these subjects have
greatly increased our knowledge of physiology and pathophysiology, this information has been used to represent the behavior
of humans as a collective rather than individually. The consequences, as we will see, have led to a limited view of the mechanisms controlling organ and tissue function and to limitations in the diagnosis and care of humans with disease (Huxley, 2007).
Far from being exhaustive, this chapter will explore a new eld of interest, sex-based biology, identifying physiological
and pathophysiological differences between women and men in the body systems principally involved in food uptake
and utilization (e.g., nervous system, gastrointestinal apparatus, cardiovascular system, adipose tissue, and skeletal muscle).

M. Marino et al. / Molecular Aspects of Medicine 32 (2011) 170

Finally, the mechanisms by which sex steroid hormones act as potential modulators of integrated physiological responses in
women and men will also be reported.
2.1. Sexgender differences in the brain region involved in regulation of food consumpion
There are well-dened differences in brain structure that result from fetal exposure to gonadal steroid hormones. Brain
weight is sexually dimorphic from 2 years postnatally onwards, taking differences in body size between boys and girls into
account (Swaab and Hofman, 1995). Increasingly, we are learning of sex-related differences in the size, shape, and activation
of many brain regions. Immunolocalization and, more recently, functional magnetic resonance imaging has demonstrated in
men a greater size and activation of some portions of the amygdala, a brain region involved in emotional arousal, and the
hypothalamus, a brain region central for maintaining homeostasis in several functions (e.g., reproduction, thermoregulation,
stress response, food uptake) (Swaab and Hofman, 1995).
One major difference between the sexes is the size of the amygdala (Hamann, 2005). In the adult human brain, the male
amygdala is signicantly larger than the female amygdala, even when total brain size is taken into account (Goldstein et al.,
2001). Although the specic consequences of this sex difference in amygdala size are not known, structural differences in
brain anatomy are often associated with differences in brain function and response. For example, one recent study found
a relation between the size of the amygdala in patients with epilepsy and sexual drive; patients with a great residual amygdala size after undergoing neurosurgery reported greater sexual drive and motivation than other patients with less amygdala
size (Baird et al., 2004). Consistent with this idea, neuroimaging studies revealed that women, on average, retain stronger
and more vivid memories of emotional events than men.
Another prominent human sex difference is the substantially greater role that visual stimuli play in male sexual behavior.
In contrast, compared with men, women have signicantly greater activation to calorie-rich foods within the dorsolateral,
ventrolateral, and ventromedial prefrontal cortexes; the middle/posterior cingulate; and the insula. Men failed to show
greater activation in any cortical region compared with women, although amygdala responses were greater in men at a more
liberal threshold (Killgore and Yurgelun-Todd, 2010). Interestingly, the amygdala, like other brain regions that differ in size
between men and women, contains relatively high concentrations of sex steroid hormone receptors (Hamann, 2005).
The sexually dimorphic nucleus of the preoptic area of the hypothalamus, as rst described in the rat by Gorski et al.
(1978), is still the most conspicuous morphological sex difference in the mammalian brain. The cytoarchitectonic sex difference of this cell group, which is three to eight times larger in male rats than in female rats, is so evident that it can even be
observed with the naked eye in Nissl-stained sections. Two other cell groups in the preoptic-anterior hypothalamic area of
humans that were more numerouses in the male brain than in the female brain have been described (Allen et al., 1989;
Swaab and Hofman, 1995).
Other regions of the brain that exhibit sex-related differences include the prefrontal cortex, auditory cortex, and both
Brocas and Wernicke areas (Allen and Gorski, 1990; Cahill, 2003).
These morphological differences, in concert with the effects of sex steroid hormones on neuronal function, support the enormous programming inuence of the intrauterine period on sexgender as opposed to the idea that children born as a tabula rasa,
as postulated in the 1960s and 1970s (Money, 1975). The reported differences in brain structures are currently hypothesized to
be the basis of sexgender differences in the structure of the brain and, thus, for behavior; gender identity (the feeling of being
either a man or a woman); gender role (behaving as a man or a woman in society); sexual orientation (heterosexuality, homosexuality or trans-sexuality); and sexgender differences regarding cognition, aggressive behavior, memory, and emotion. Furthermore, the morphological differences in the hypothalamus are proposed to support diverse non-reproductive differences
between males and females, such as differences in pain threshold and cognitive style and the greater glucocorticoid response
to stressors exhibited by females compared with males (McCarthy and Konkle, 2005). Environmental factors (e.g., food components and other exogenous substances classied as endocrine disruptors) that interfere with sex steroid hormone activity in the
developing brain may permanently inuence later behavior (Bulzomi and Marino, 2011).
Energy balance requires that an organism match caloric intake relatively precisely with caloric expenditure. For heterotrophic organisms, like human beings, the only way to increase or decrease caloric intake to fulll caloric expenditure needs
is to regulate food intake through diet.
Hunger, appetite, and satiety were often regarded as problems in the physiology of digestion. In recent years, however,
they have been studied more and more commonly as functions of the brain. The critical forebrain regulation of food intake
behavior occurs in the hypothalamus, which, as reported above, is the brain region in which sex-related differences are most
pronounced (Benoit et al., 2008).
Lesions of the ventromedial hypothalamus result in dramatically increased food intake and obesity, whereas lateral hypothalamic area lesions yield hypophagia and reduced growth. These ndings led to the hypothesis that the hypothalamus nuclei control food intake by acting as the satiety and feeding centers (Fig. 1) (Stellar, 1954). In particular, the arcuate
nucleus of the hypothalamus contains two populations of neurons that seem to be the rst-order relay neurons in responding
to adiposity signals from the periphery. One population co-expresses neuropeptide Y (NPY) and the melanocortin receptor
antagonist agouti-related protein (AgRP), whereas the other population contains pro-opiomelanocortin (POMC), the precursor to the melanocortin receptor agonist a-melanocyte-stimulating hormone and cocaine- and amphetamine-regulated
transcript (CART). A central infusion of NPY or AgRP potently stimulates food intake (Rossi et al., 1998), whereas the intracerebroventricular administration of a-melanocyte-stimulating hormone or CART inhibits food intake (McMinn et al., 2000),

M. Marino et al. / Molecular Aspects of Medicine 32 (2011) 170

Fig. 1. The arcuate nucleus (ARC) of hypothalamus, localized close to the III ventricle (III Ven) contains two populations of neurons. One population coexpresses the neuropeptide Y (NPY) and agouti-related protein (AgRP) which, in turn, potently stimulate food intake by stimulating orexigenic pathways in
the paraventricular nucleus (PVN) of hypothalamus. Another neuronal population present in the ARC contains pro-opiomelanocortin (POMC) which inhibits
food intake by inhibiting the orexigenic pathways in the PVN and acting as an anorexigenic neuropeptide. The neurons present in the ARC respond to
adiposity signals (e.g., leptin) from the periphery. For details see the text.

suggesting that these two populations represent primary orexigenic and anorexigenic pathways, respectively. In further
support of this function, food deprivation increases the expression of AgRP and NPY mRNA and decreases POMC and CART
gene expression (Brady et al., 1990). Overexpression of agouti or AgRP yields hyperphagia and obesity, and the disruption
of the genes encoding the melanocortin receptor-4R, POMC, or CART have the same effect (Graham et al., 1997). Ablation
of these neurons in adult mice yields dramatic reductions in food intake and body weight, whereas the reverse occurs with
ablation of POMC neurons (Luquet et al., 2005). Importantly, receptors for the adipocyte hormone leptin and pancreatic b-cell
hormone insulin are expressed on both of these types of neurons, moreover, either leptin and insulin cross the blood-brain
barrier, suggesting that neurons are responsive to circulating levels of these hormonal signals acting as effectors for altering
food intake in response to alterations in energy balance as indicated by body adiposity (Benoit et al., 2008).
There are few overt sex differences in food intake (Asarian and Geary, 2006; Geary, 2004). Meal size and meal frequency are
similar between males and females and in both humans and rats, and total food intake appears to vary roughly in proportion to
body size to match energy expenditure. The one clear phenotypic sex difference in eating in humans, rats and mice is that cycling
females eat less during the peri-ovulatory phase of the ovarian cycle (Asarian and Geary, 2006; Geary, 2004). Rats and mice have
45 d ovarian cycles, and food intake is up to 25% less during the night following the luteinizing hormone surge (the night of
ovulation and estrus) in comparison to the other nights of the cycle (about 8090% of food intake occurs nocturnally in rats
and mice). Eating also varies during the menstrual cycle in women. Daily food intake in women is lowest during the periovulatory period, which is usually dened as the four days surrounding the luteinizing hormone (LH) surge (Asarian and Geary,
2006; Buffenstein et al., 1995; Lissner et al., 1988). Plasma estradiol levels are maximal during this phase of the menstrual cycle.
Some studies also demonstrated that average daily food intake is lower in the follicular phase, during which estradiol secretion
increases, than in the luteal phase (Asarian and Geary, 2006; Pelkman et al., 2001). Meal size is a function of signals that act to
maintain eating during a meal, and signals that act to terminate eating (i.e., produce satiation). Neither endogenous nor exogenous estradiol affects the positive feedback signal provided by sweet tastes, which sustains eating (Geary, 2001).
The cyclic change in eating apparently does not occur during anovulatory cycles. Gonadectomy unveils further sex
gender differences in the control of eating in rats and mice: gonadectomized females eat more, whereas gonadectomized
males eat less. Gonadectomy also eliminates the cyclic eating decrease in females. The effects of gonadectomy on eating
in rats and mice are apparently due to testosterone in males and estradiol in females (Asarian and Geary, 2002; Butera,
2010) demonstrated that a four-day cyclic regimen of estradiol could produce apparently normal cyclic patterns of spontaneous meal size and number and daily food intake in rats. Prospective studies indicate that the menopausal transition is
associated with a 12 kg increase in body adiposity without any change in body weight, which is reduced or absent in
women receiving estrogen replacement therapy (Asarian and Geary, 2002; Butera, 2010).
Cyclic changes in food intake do not appear attributable to differing food selection. Women appear to eat more sweets
during the luteal phase of the cycle than other phases, possibly due to simultaneous increases in estradiol and progesterone.
One report that macronutrient selection varied during the estrous cycle in rats (Bartness and Waldbillig, 1984) has not been
conrmed in other studies (Heisler et al., 1999).

M. Marino et al. / Molecular Aspects of Medicine 32 (2011) 170

Both estradiol and progesterone are elevated throughout much of the luteal phase. However, progesterone has no effect
on eating except in pharmacological doses in female rats (Wade, 1975), and even a pharmacological dose has no effect on
eating in women (Pelkman et al., 2001). Pharmacological doses of progesterone can reverse the inhibitory effect of estradiol
on eating in rats (Wade, 1975). If the same is true of women, it may explain the lack of effect of mixed hormonal contraceptive treatments on eating (Asarian and Geary, 2006; Rosenberg, 1998).
The most fruitful investigations of the mechanisms of the estradiol-induced inhibitory effect on eating are based on the
hypothesis that estradiol acts in the brain to alter the neural processing of peripheral feedback signals that control eating
(Asarian and Geary, 2006). These signals include orosensory signals that increase or decrease food reward and control meal
size by affecting the maintenance of eating during the meal. Estradiol does not appear to inhibit eating by reducing the potency of orosensory stimuli in either rats or women (Asarian and Geary, 2006). Ghrelin, a recently discovered peptide hormone, is synthesized and released by gastric endocrine cells; this hormone decreases the latency between meals and
increases meal size (Azzara et al., 2005). At present, it is not clear whether estradiol and ghrelin interact to control meal size
in physiological conditions.
Satiation signals are other peripheral feedback signals that control eating (Geary, 2001). These signals, arising from postingestive actions of food in the stomach, intestines or post-absorptive sites, are initiated during the meal and decrease meal size
(Geary, 2001). Estradiol appears to increase the potency of several signals that control meal termination, especially the satiating
action of cholecystokinin. Cholecystokinin, which is released from the small intestines during meals, controls meal size (i.e.,
satiation) via physiological negative feedback signals. The interaction of estradiol and cholecystokinin is the only mechanism
discovered so far that can be linked to both the endogenous feedback control signal and endogenous estradiol (Geary, 2001).
Increased adiposity produces a number of negative feedback control signals that provide tonic restraints limiting meal
size (e.g., insulin and leptin) (Asarian and Geary, 2006; Cummings et al., 2002; Lutz, 2005). Exogenous leptin and insulin have
markedly different inhibitory potencies in male and female rat eating patterns (Davis et al., 2009). Comparing age- and
weight-matched male and female rats, the acute intracerebroventricular administration of leptin reduced eating more potently in females, whereas 1 mU insulin given intracerebroventricularly decreased 24-h food intake and body weight in male
rats but not in female rats, male rats given estradiol or ovariectomized female rats (Clegg et al., 2006). Furthermore, the
inhibitory effect of insulin on eating in ovariectomized rats was decreased by estradiol. Low serum estradiol levels appear
to enhance insulin sensitivity, but they are not necessarily sufcient for the anorexigenic effects of insulin. In contrast, in
the case of leptin, the potency of the inhibition of eating of centrally administered leptin appears to be increased by estradiol.
Leptin also has other effects that make it an attractive candidate for the sexually differentiated control of eating: it plays
crucial physiological roles in the control of pubertal development in both sexes (Chan and Mantzoros, 2001; Chehab
et al., 2002) and in the control of gonadotropin-releasing hormone secretion and ovulation in women (Welt et al., 2004).
There are interesting data available concerning sexgender differences in the role of serotonin in eating. Serotonin in the
central nervous system inhibits eating by reducing meal size (Blundell, 1992). Evidence of sex differences suggests that the
inhibitory effect of estradiol on eating during estrus, but not the tonic inhibitory effect of estradiol on eating, may be mediated by increased serotonin synaptic activity. Furthermore, these data are consistent with a critical role for cholecystokinin
in the peri-ovulatory decrease in eating because hypothalamic serotonin appears to be involved in the central processing of
the cholecystokinin satiation signal (Poeschla et al., 1992).
As a whole, these data indicate that estradiol affects the potency of several, but not all, peripheral feedback controls of
meal size. However, the possibility that these feedback controls operate differently in men and women has received very
little attention (Kissileff et al., 2003). How testosterone interacts with peripheral feedback control mechanism of eating in
rats or mice has been much less extensively examined than that of estradiol in part because of testosterone selectively increases meal number, not meal size, in rats, and very few physiological controls of spontaneous meal frequency are known.
Finally, these data indicate that women may eat about 10% less during one-third to one-half of the estrous cycle, an amount
that is more than sufcient to affect energy balance (Asarian and Geary, 2006).
Besides sexgender differences in food uptake and utilization, several studies have described remarkable differences
between men and women at the end point of the food chain: food consumption. Consistently, women are reported to have
higher intakes of fruit and vegetables, higher intakes of dietary bers and lower intakes of fat (Wardle et al., 2004;
Westenhoefer, 2005), whereas men eat more beef than women (Baghurst, 1999; Cosgrove et al., 2005; Linseisen et al.,
2002; McAfee et al., 2010). These sexgender differences in food choice are reported both in young and old ages (Bates
et al., 1999; Caine-Bish and Scheule, 2009; Cooke and Wardle, 2005). Food choice is dependent on a wide spectrum of factors,
and, notably, the choices that people make in food selection determine which and how much of each nutrient enters into the
body. At least in developed Western countries, people choose food not only on the basis of their biological needs but also on
the basis of many psychological and/or emotional, economic and social issues (Armitage et al., 2004).
2.2. Sexgender related differences in the nutrient bioavailability and metabolism
Data on sex-based differences in digestive system functions have accumulated in the literature (Table 1). These data point
to four major factors that contribute to inter-individual variability in this system: food bioavailability, food distribution, food
metabolism, and food elimination. Studies that reveal sexgender variability in gut functions are attributable to one or more
of these four processes. Here, sexgender related differences in nutrient bioavailability and metabolism will be thoroughly
discussed.

M. Marino et al. / Molecular Aspects of Medicine 32 (2011) 170


Table 1
Sexgender differences in digestive system functions.
Parameters

Physiologica differences

References

Gastric pH
Gastric uid ow
Intestinal motility
Gastric emptying

Acidity M > F
M>F
M>F
M>F

Gandhi
Gandhi
Gandhi
Gandhi

et
et
et
et

al.
al.
al.
al.

(2004)
(2004)
(2004)
(2004)

F, females; M, males.

2.2.1. Nutrient bioavailability


Nutrient bioavailability is assessed by the rate and extent of their absorption. Factors that inuence nutrient absorption
include gastric acid secretion, gastric emptying time, gastrointestinal blood ow, and surface area (Martinez and Amidon,
2002), along with the effects of pre-systemic hepatic and gut metabolism and transport. Some of these factors have been
investigated for sex disparities. Characteristics of stomach and proximal jejunal uids, including osmolality, electrolyte concentrations, and levels of bile acids and proteins, do not seem to vary signicantly by gender in controlled experiments
(Dressman et al., 1990; Lindahl et al., 1997), although conicting reports exist (Collen et al., 1994).
However, a pivotal role for estrogens in the organization and architectural maintenance of the colon epithelial barrier has
been reported (Wada-Hiraike et al., 2006a; Wada-Hiraike et al., 2006b). Additionally, several sexgender related differences
in colorectal cancer are reported in Section 4.1. Estrogens inhibit gastric emptying (Coskun et al., 1995; Wu et al., 2002),
whereas the effects of progesterone vary depending on concentration: low concentrations increase gastric emptying in rats
while high concentrations inhibit emptying (Chen et al., 1995; Liu et al., 2002). Preclinical ndings have implicated gonadal
hormones in the motor activity of the gastrointestinal tract (Bond et al., 1994; Ryan and Bhojwani, 1986). Sex-related differences in gastrointestinal transit have also been described in animal models, with reduced transit in ovariectomized rats treated with estrogen as compared to ovariectomized females and male controls (Bond et al., 1994). Early studies have found
that progesterone and estrogen inhibit intestinal contractility and transit (Wald et al., 1981). Recent reports suggest that progesterone may inuence contractile elements of the gut. The acute administration of progesterone in guinea pig colon muscle cells produce a transient blocking of calcium release from storage sites. In a study of colonic muscle cells from women
with chronic constipation and slow colonic transit, an impaired contractile response to G protein-dependent agonists has
been detected (Xiao et al., 2006). The authors suggested that this impairment may be due to the overexpression of progesterone receptors, a well-known estrogen effect. Gonenne and coworkers (Gonenne et al., 2006) showed that micronized progesterone treatment in post-menopausal women is associated with looser stool consistency as compared to women
receiving a placebo. Moreover, they nd that progesterone treatment accelerated colonic transit, measured as the rate of
emptying of the ascending colon, and overall colonic transit at 48 hr. The link between gonadal hormones and gastrointestinal motor activity is likely direct as well as indirect. Cong et al. (2007) have found abnormal levels of prostaglandins and
cyclo-oxigenases (COX) enzymes in women with slow transit constipation. They hypothesized that these alterations are the
result of over-expression of colonic muscle progesterone receptors.
The sympathetic and parasympathetic branches of the autonomic nervous system modulate gastrointestinal function.
The autonomic nervous system provides the major linkage between the gut and the brain. Sexgender differences in autonomic nervous system function markers such as heart rate variability have been described in healthy, age-matched controls
(Cowan et al., 1994). Tillisch et al. (2005) found greater sympathetic modulation in men as compared to women. Reduced
vagal tone is noted in women who report severe constipation (Cain et al., 2007) as well as in healthy women who have a
history of depression and/or anxiety, suggesting that additional factors need to be considered when examining peripheral
markers of autonomic nervous function between sexes (Jarrett et al., 2003). These differences seem to be related to gonadal
hormones, although limited data suggest that there are menstrual cycle-linked differences in autonomic nervous system
tone, particularly in symptomatic women (Heitkemper and Jarrett, 2008; Matsumoto et al., 2006).
Variability in the intestinal expression of proteins that modulate the gut transport of nutrients, such as the intestinal cholesterol transport mediator P-glycoprotein (Levy et al., 2007b), may result in sex-based variability in plasma nutrient concentrations, although sexgender-specic variation in the expression of intestinal P-glycoprotein has not been demonstrated.
More information is available on sex-related differences in drug absorption and bioavailability. For example, orally administered verapamil is cleared faster in men than women, a difference that is not observed after intravenous administration of this
drug, suggesting that intestinal processes modulate sex-specic differences in verapamil pharmacokinetics (Krecic-Shepard
et al., 2000). Ferrous sulfate absorption, measured with the aid of radioisotope labeling, is higher in prepubertal girls than
boys (Woodhead et al., 1991), suggesting that hormonal differences may contribute to sex-based pharmacokinetic variability
for this mineral salt (see also Section 3.1.3.6). Based on these variabilities in drug and mineral absorption, differences in other
food component bioavailabilities should also exists, but studies that examine this topic are generally few.
2.2.2. Metabolism
Sex-based differences in metabolism seem to play a greater role in inter-gender variability of the gastrointestinal system
than any of the other parameters. There are sexgender differences in protein metabolism between males and females.

M. Marino et al. / Molecular Aspects of Medicine 32 (2011) 170

Studies utilizing stable isotope-labeled amino acids show little indication that whole body protein synthesis or breakdown is
different between genders. There is evidence that leucine oxidation may be different between sexes, both at rest and during
exercise, but this evidence is not unequivocal, and additional properly controlled studies must be undertaken to clarify this
controversy (Tipton, 2001) (see also Section 3.1.1).
The gastrointestinal and liver enzymes responsible for food metabolism also vary by sex. For example, gastric alcohol
dehydrogenase activity is higher in males than in females in both humans (Frezza et al., 1990) and animals (Lee et al.,
2001), resulting in higher blood concentrations of ethanol in females compared to males following an equivalent ingestion
of alcohol (see also Section 3.4).
More information is available on sexgender-related differences in drug metabolism. Hepatic clearance of drugs is a function of liver blood ow (see below) and hepatic enzyme activity. Although cardiac output and hepatic blood ow are lower in
women than men, sexgender differences in hepatic enzymes seem to play the major role in determining drug pharmacokinetic variability by sex (Wang et al., 2008).
Lipophylic food components, such as fatty acids, retinoic acids, and avonoids, bind to an orphan receptor member
of the nuclear receptor superfamily (i.e., constitutive androstane receptor and the pregnane X receptor) and represent
xenobiotic sensors that regulate drug clearance in the liver and intestine via induction of genes involved in drug and
xenobiotic metabolism. These xenosensors coordinate the expression of several genes encoding cytochrome P450
superfamily (CYP) expression (di Masi et al., 2009; Wang et al., 2008). The expression of some CYPs is clearly sexdependent, for example, CYP3A4 is more expressed in females, whereas CYP2D6 is more expressed in males (Franconi
et al., 2007).
Steroid sex hormones regulate constitutive androstane receptor activity, which may explain the sexual dimorphism in
phenobarbital-induced target genes (Agrawal and Shapiro, 1996; Chang et al., 1997; di Masi et al., 2009); moreover, important sexgender differences in some of the key CYP enzymes have been demonstrated (Gandhi et al., 2004). At present, it is
unknown if these sex-related differences are present after liphophylic nutrient (i.e., vitamins, plant-derived polyphenols)
metabolism; however, it is important to note that all retinoic acids can auto-induce pregnane X receptors (Wang et al.,
2008) and, thus, may modify the metabolism of many compounds.
Regarding fatty acid metabolism, there are pronounced tissue-specic differences between men and women (see
Sections 2.3.3; 3.1.2, 3.2 and 3.3). Catecholamines, in vivo, mediate less leg free fatty acid release in women than
in men, whereas the levels of free fatty acids (FFA) released from the upper body deposit are comparable. These data
correspond to in vitro adipose tissue biopsy data, which indicate a more pronounced difference in catecholaminemediated lipolysis between upper body and lower body fat deposit in women than in men. In addition, FFA release
by the upper body subcutaneous fat deposit is higher in men than in women, indicating a higher resistance to the
antilipolytic effect of meal ingestion in the upper body fat deposit in men. Moreover, basal fat oxidation (adjusted
for fat free mass) seems to be lower in females as compared to males, thereby contributing to a higher fat storage
in women. Finally, postprandial fat storage may be higher in subcutaneous adipose tissue in women than in men,
whereas storage in visceral adipose tissue has been hypothesized to be higher in men (Blaak, 2001). All of the above
differences may play a role in the variation in net regional fat storage between men and women, but the number of
in vivo studies on sex-related differences in fatty acid metabolism is very limited, and most ndings require
conrmation.
The possibility that estrogen may play an important role in regulating cholesterol homeostasis has been suggested by the
evidence that the oral administration of estrogen in post-menopausal women results in lowered levels of LDL (Farhat et al.,
1996). Models of estrogen deciency have been used to gain insight into the mechanisms of this regulation. These models
include the aromatase knockout (ArKO) mouse (Fisher et al., 1998a). ArKO mice present an age-progressive obesity and hepatic steatosis. By 1 year of age, both male and female ArKO mice developed hypercholesterolemia and elevated triglycerides
(Jones et al., 2000), suggesting that the absence of estrogen impairs lipid homeostasis. Hewitt et al. (2003) observed that
although cholesterol feeding did not result in an increase in serum cholesterol levels, there was a 3-fold increase in hepatic
cholesterol levels in ArKO mice in comparison to wild-type female mice. The cholesterol that enters the liver would then
inhibit the de novo synthesis of cholesterol. Several studies have examined the role of estrogens in the regulation of 3-hydroxyl-3-methyl glutaryl CoA reductase (HMGR) transcripts and protein with variable results (Marino et al., 2001; Messa et al.,
2005). More recent data suggest that HMGR levels and activity are lower in adult females compared to males (De Marinis
et al., 2008).
There is abundant evidence that the proportion of energy derived from fat during exercise is higher in women than in
men (Blaak, 2001). During exercise, women oxidize more lipids and fewer carbohydrates as metabolic substrates than
men. This different metabolism is reected in lower glycogen utilization in skeletal muscle and lower hepatic glucose production for women compared with men. These latter observations may explain the lower leucine oxidation observed during
endurance exercise in women (see also Section 3.1.1). Animal and preliminary human study evidence suggests that 17bestradiol may be a major determinant of the sex dimorphic response in carbohydrate metabolism during exercise
(Tarnopolsky and Ruby, 2001). From a practical standpoint, women may need to increase their dietary energy intake (and
percentage derived from carbohydrates) for four days before a sporting event in order to compensate muscle glycogen
concentrations (Tarnopolsky and Ruby, 2001).

10

M. Marino et al. / Molecular Aspects of Medicine 32 (2011) 170

2.3. Body weight and composition in male and female


Among the well-recognized morphological sex differences between males and females, the most obvious is that men are
taller and heavier than women (Table 2). The body mass is usually considered as comprising two compartments: lean body
mass (LBM), which is principally determined by the mass of bone and muscles, and fat body mass (FM), which is principally
determined by the mass of the adipose tissue. The major difference between the two body compartments is that LBM contains a small percentage of essential lipids (about 35%), whereas FM contains metabolically active lipids and is virtually
water free. LBM and FM describe body composition; in addition, this partition renders it possible to dene the minimal body
weight achievable without compromising LBM. The differences between the sexes in LBM/FM ratio are well known: males
typically have proportionately more muscle mass, more bone mass, and a lower percentage of body fat than women. These
differences are largely the consequence of the well-documented effects of gonadal steroid hormones on skeletal muscle and
bone homeostasis and are reviewed below.
2.3.1. Bone mass
The differences between the sexes in the structural components of bone strength (e.g., skeletal dimensions, cortical thickness), biomechanical responses, mineral mass and turnover, and even trabecular microstructure, are obvious. Sexual dimorphism in skeletal dimensions and shape is well known and constitutes the basis of sex evaluation for archeological and
forensic applications. For example, in the Framingham cohorts, adult men have longer femora, with more obtuse neck-shaft
angles; longer and wider femoral necks; and higher bone mineral density. Thus, the greater prevalence of fragility fractures
with advancing age in women, compared to men, may largely be explained by the smaller skeletal size and bone mass of
women even after adjustment for body size. Although women and men both lose bone mineral density and bone microstructure with age, these effects are more pronounced in women. In particular, women exhibit a decrease in cortical thickness, a
decrease in the number of trabeculae, and an increase in spacing between trabeculae compared to men (Glatt et al., 2007;
Karasik and Ferrari, 2008; Khosla et al., 2006), and these changes notably accelerate after menopause with the decline in
estrogen levels. Adaptation by periosteal apposition may also be reduced in women compared to men, further contributing
to a structural instability of bones that occurs at an earlier point in the life of a woman than a man (Karasik and Ferrari,
2008). Despite this pronounced sexual dimorphism in mass, structure and shape, there is no strictly gender-limited phenotype (i.e., distinctive features of the male and female skeleton that result from quantitative and qualitative variations of bone
modeling and remodeling as opposed to completely different mechanisms of regulation). Even estrogen may be as important
for attaining peak bone mass in males as in females, as demonstrated by the lower bone mineral density in young females
with late menarche as well as in men with loss-of-function mutations in the estrogen receptor a gene and aromatase gene.
Age-related declines in bone mineral density in men are also directly related to declining levels of estradiol, which may be
even more prominent than the decline of testosterone in aging men (Karasik and Ferrari, 2008).
2.3.2. Skeletal muscle mass
Human skeletal muscle tissue comprises 4045% of total body weight and is one of the most metabolically active tissues
in the body. Besides its obvious importance for human locomotion, skeletal muscle serves as a seemingly endless repository
of protein and free amino acids in addition to providing precursors for glucose via gluconeogenesis. Human skeletal muscle
protein undergoes continuous remodeling, which results in a delicate balance between muscle protein synthesis and breakdown during growth, health, disease, and aging. The homeostatic balance of muscle is affected by fasting, feeding, exercise,
aging, and disease (Shefeld-Moore and Urban, 2004). The sexgender differences on muscle protein metabolism have been
recently reviewed in Burd et al. (2009). Sex steroid hormones, growth hormone, and glucocorticoids strongly inuence the
metabolic exibility of skeletal muscle and its substrate storage capacity, which are important regulators of the skeletal
muscle protein remodeling process. Testosterone, like other anabolic hormones, stimulates muscle growth in humans by
increasing protein synthesis and/or decreasing protein breakdown. Hypogonadal elderly men receiving testosterone replacement therapy show decreases in muscle protein breakdown and increases in protein synthesis, LBM, and muscular strength.
To date, several testosterone replacement studies have shown a disproportionate response between increases in muscle
strength and muscle mass, with muscle mass more often increasing without proportional increases in muscle strength
(Shefeld-Moore and Urban, 2004).

Table 2
Anatomical differences between men and women.

Parameters

Male

Female

References

Body weigth (kg)a


Height (cm)a
Body surface area (cm)a
Total body water (L)
Extracellular water (L)
Intracellular water (L)

78
176
18,000
42
18.2
23.8

68
162
16,000
29
11.6
17.4

Soldin
Soldin
Soldin
Soldin
Soldin
Soldin

Normalized for body surface area.

and
and
and
and
and
and

Mattison
Mattison
Mattison
Mattison
Mattison
Mattison

(2009)
(2009)
(2009)
(2009)
(2009)
(2009)

M. Marino et al. / Molecular Aspects of Medicine 32 (2011) 170

11

The depletion of ovarian hormones due to ovariectomy induces an anabolic environment characterized by increased circulating growth factor levels and a positive energy balance (Fisher et al., 1998b). Variations in skeletal muscle strength have
been described during the human menstrual cycle, and muscle mass and strength diminish during the post-menopausal
years, leading to sarcopenia (Dionne et al., 2000). Female rat muscles show fewer histopathological and biochemical changes
after repeated eccentric contractions than male muscles, including the release of creatine kinase into the bloodstream and
activity of the intramuscular lysosomal acid hydrolase, b-glucuronidase (Enns and Tiidus, 2010). As a consequence, female
muscles are more fatigue-resistant and recover faster than male muscles after intense aerobic exercise (Glenmark et al.,
2004). Male and ovariectomized female rats exhibit higher indexes of exercise-induced muscle membrane damage, which
disappear in ovariectomized female rats after estradiol treatment (Glenmark et al., 2004; McCormick et al., 2004). Estrogen
also plays a signicant role in stimulating muscle repair and regenerative processes, including the activation of differentiation process in myoblasts (Galluzzo et al., 2009).
2.3.3. Adipose tissue mass and metabolism
The sex-related differences in adipose tissue begin early in life and are further strengthened during puberty. These differences stem from metabolic and hormonal differences between the sexes and contribute to differences between women and
men in obesity-related health risks. Women of all races and cultures have greater adipose stores than men, even after correcting for body mass index (BMI). Indeed, the mean percentage of body fat for normal-weight women (BMI = 1825 kg/m2) is
similar to the percentage body fat of men who are classied as obese (BMI = 30 kg/m2) (Nielsen et al., 2004; Power and
Schulkin, 2008). This sex difference in adiposity is present at birth. Female babies have more subcutaneous fat than male
babies at all gestational ages (Rodriguez et al., 2005). Prepubertal girls have more fat in their legs and pelvis than prepubertal
boys (He et al., 2004).
Body fat is distributed differently between men and women. Women have greater adipose stores in the thighs and buttocks; men tend to be more likely to have signicant amounts of abdominal fat and be more susceptible to abdominal adiposity (Power and Schulkin, 2008). Women have larger stores of subcutaneous fat, whereas men are more likely to have
visceral fat (Lemieux et al., 1993). Obese women will have large amounts of visceral fat; obese men will have a large amount
of subcutaneous fat in their legs.
A key to understanding these key biological differences is determining the underlying reasons that males and females
store excess calories in different places. These differences are presumably due to differential evolutionary and sexual selection pressures (Hoyenga and Hoyenga, 1982; Power and Schulkin, 2008; Shi et al., 2009). Visceral fat can be mobilized more
rapidly to respond to shorter thermo-energetic challenges. Consequently, one reason to store fat in the visceral depot is to
make it more accessible for specic, intermittent activities. If males are more responsible for hunting, gathering or immediate protection, it would make sense to put stored calories in fat with greater lipolytic activity where it can be mobilized over
the short time frame required for these activities (Shi et al., 2009).
Given the lower lipolytic rates in subcutaneous adipose tissue, this type of fat is much better suited to respond to chronic
metabolic challenges, such as gestation and lactation in females. Consistent with this hypothesis, female rats gain weight
during the early part of gestation, and that weight gain is disproportionately subcutaneous adipose tissue. Such a buildup of subcutaneous fat would facilitate the females ability to counteract the enormous and chronic metabolic challenge
associated with gestation and lactation. This is a period of high energetic demand with a relatively low level of ability for
the organism to effectively hunt and/or gather calories from its environment. In rats, this means that subcutaneous fat
increases until day 12 of gestation and declines progressively until lactation, when it is utilized to provide energy; visceral
fat deposits, including lumbar and mesenteric adipose tissues, progressively increase until the 19th day of gestation
(Lopez-Luna et al., 1991; Shi et al., 2009). This indicates that subcutaneous, but not visceral, adipose tissue becomes the preferred energy source and is utilized during the last stage of gestation in female rats. In women, subcutaneous fat deposits
become more lipolytically active than visceral fat deposits during lactation; thus, subcutaneous adipose tissue is utilized
as an important source of energy supply during lactation (Rebuffe-Scrive et al., 1985). In contrast to what occurs in nonpregnant woman in which lipolysis in the gluteal/femoral subcutaneous adipose tissue is signicantly less (Rebuffe-Scrive
et al., 1985).
The well-recognized sex differences in body fat distribution are associated with different diseases. Visceral fat has been
associated with increased cardiometabolic risk in numerous studies (Despres et al., 2008); thus, men and post-menopausal
women typically have increased cardiometabolic risk relative to pre-menopausal women. What is less well recognized is
mounting evidence suggesting that larger gluteo-femoral fat stores are protective against cardiometabolic risk.
Several epidemiological studies suggest that a high waist-to-hip ratio is a better predictor of all-cause and cardiovascular
disease mortality than a large waist circumference alone (Canoy et al., 2007; Yusuf et al., 2005). Moreover, a larger hip circumference has been shown to be protective against both cardiovascular disease and metabolic risk in multiple ethnic
groups, independent of waist circumference or abdominal fat (Peverill et al., 2007; Snijder et al., 2004). Intriguingly, transplantation of subcutaneous fat from the inguinal region of male donor mice into the intra-abdominal compartment of male
recipient mice on a high-fat diet resulted in signicantly protective effects on adiposity, insulin sensitivity and glucose
tolerance (Hocking et al., 2008). It would be interesting to see if similar or even greater protective effects could be conferred
from transplanting female subcutaneous (inguinal) fat because the protective effect of a large hip circumference with regard
to cardiovascular morbidity and mortality is signicant only in women, with only a borderline signicant effect on total
mortality in men (Heitmann et al., 2004).

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The question of sex differences in fat distribution can be examined in animal models. Several animal species, including
pigs and some rodents, show sex-specic differences in fat distribution, with males having more intra-abdominal fat and
less subcutaneous fat than females. As in humans, estrogen appears to be instrumental in maintaining the sex-specic fat
distribution pattern. In rats, ovariectomy leads to an increase in visceral fat and a loss of subcutaneous fat in females, and
estrogen treatment reverses this effect (Asarian and Geary, 2006; Clegg et al., 2006).
How can estrogen regulate deposit mass and, consequently, determine fat distribution? For years, estrogen was thought
to indirectly affect adipose tissue metabolism by changes in enzyme substrate availability or a permissive effect on other
hormone effects (Bjorntorp, 1996). However, estrogen receptors exist in human adipose tissue (Crandall et al., 1998;
Pallottini et al., 2008), indicating that estrogens could directly act on adipose tissue metabolism. Estrogens may control
fat distribution by changing the lipolytic response into the two main fats differently, thereby favoring fat accumulation in
the subcutaneous depot at the expense of the visceral depot. In particular, in the visceral adipose depot, estradiol lowers
the activity of lipoprotein lipase, the enzyme responsible for FFA re-esterication (which is the major determinant of lipogenesis) (Iverius and Brunzell, 1988). Noteworthy is the proposal that estrogen promotes a selective reduction in visceral
adiposity, partially by promoting the use of lipid as fuel. Estrogen-promoted fat oxidation in muscle inhibits lipogenesis
in adipose deposits, liver, and muscle (DEon et al., 2005; Pallottini et al., 2008).
Other studies in ovariectomized rodents have elucidated possible mechanisms by which changes in estrogen levels may
impact body weight. In rodents, an ovariectomy induces an increase in food intake and a concomitant increase in body
weight (Lovejoy and Sainsbury, 2009). These effects of estrogen deciency may be mediated by increases in the hypothalamic expression of the orexigenic peptides (i.e., NPY and AgRP) (Pelletier et al., 2007). The effects of estrogen deciency
may also be mediated by the decreased expression of anorexigenic peptides (POMC) (see below). Menopause or estrogen
deciency may also contribute to weight gain via mechanisms related to energy expenditure (EE). Estrogen receptor a
knockout mice show perturbations in physical activity (Ogawa et al., 2003). Additionally, on the night of estrous, female rats
and mice show a dramatic increase in physical activity, which is abolished by the removal of estrogens (e.g., ovariectomy)
(Ogawa et al., 2003). In humans, Lovejoy et al. (2008) recently showed that the onset of menopause is associated with a signicant reduction in 24-h physical activity and EE, although dietary intake did not change. The relatively sudden drop in
physical activity at the onset of menopause may be related to the effects of a lack of estrogen on the hypothalamus nuclei,
which are important regulators of physical activity (Lovejoy and Sainsbury, 2009).
The differences in body composition between males and females could have profound consequences on the distribution
of nutrients and their metabolites, as occurs for drugs (Franconi et al., 2007). Moreover, the sex and gender differences in the
metabolic machine of skeletal muscle and adipose tissue could affect the fate of nutrients in females and males.
2.4. Sexgender related differences in the cardiovascular system and nutrient distribution
Because nutrients reach the organ through the cardiovascular system, the blood ow fraction destined to each organ
determines the relative rate and amount of nutrients that will be in contact with tissue. The nutrient distribution is affected
by multiple factors, including BMI, body composition, plasma volume, organ blood ow, and the extent of tissue and plasma
protein binding of the nutrient. Sexgender differences in the cardiovascular system could affect nutrient distribution, and,
conversely, the sex and gender differences as well as difference in physical activity could also contribute to the differential
effects of nutrients on the cardiovascular system. As reported above, women have a higher body fat percentage, a lower average body weight, a smaller average plasma volume, and a lower average organ blood ow than men, with obvious implications for disparities in the rate and extent of nutrient distribution.
There are multiple differences between women and men in terms of their normal cardiovascular function. It comes as
little surprise to learn that the size of the heart and major blood vessels of women are smaller than those of men of the same
race (Huxley, 2007; Luczak and Leinwand, 2009). In humans, left ventricular mass is not signicantly different in boys and
girls during infancy and childhood (de Simone et al., 1995). Increased absolute and relative heart weight in males becomes
evident at puberty, when sex-specic hormonal inuences are imposed on the original anatomical pattern; this gender difference in absolute values results in adulthood with male hearts being 1530% bigger than female hearts. Because the initial
number of cardiac myocytes is likely to be similar in both sexes, hypertrophic growth must be enhanced in males as opposed
to females. Aging is associated with a preservation of cardiac muscle mass in women and a reduction in the left and right
ventricular weights in men (Olivetti et al., 1995).
In addition to size, the anatomic location of the major vessels in the heart, lung, and most organs are also indistinguishable among the sexes. Although healthy men and women are in homeostasis and possess the same structural elements, how
those components function to achieve homeostasis with respect to the cardiovascular system differs (from subtly to profoundly) (Hammond et al., 1988; Levy et al., 1987). In the steady state, the differences between male and female heart
dimensions translate into a smaller stroke volume and thus a lower cardiac output in female. Less evident is that the heart
rate is faster in females than in males (Umetani et al., 1998). In a large population-based study, the average heart rate for
women was 35 beats faster per min than that of men (Geelen et al., 2002). Contrary to common belief, though, the heart
rate of male and female fetuses do not differ in utero (Papanek et al., 1998).
Sexual dimorphism appears also in arterial blood pressure during adolescence and persists through adulthood. In men
less than 60-year old, the average systolic and diastolic pressure is higher than in age-matched women by 67 mm Hg
and 35 mm Hg, respectively. After menopause, blood pressure (particularly systolic) in women increases, so hypertension

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13

becomes more prevalent than or at least as prevalent as in men (Huxley, 2007). Under conditions of cardiovascular stress
(e.g., exercise, loud noises, or psychological stress), men respond by increasing mainly vascular resistance, which is manifested as a further increase in mean blood pressure (Barnett et al., 1999), whereas women predominantly increase heart rate,
thereby increasing cardiac output. In both cases, there is an appropriate cardiovascular response, but there are potentially
different outcomes.
Recall further that the control of blood pressure involves actions of the autonomic nervous system. In the periphery,
increases in sympathetic activity result in resistance vessel constriction with an increase in vascular resistance. The reduction or withdrawal of sympathetic activity reduces systolic volume, cardiac output, and vascular resistance. In contrast, the
parasympathetic (vagal) system slows the heart, and the withdrawal of parasympathetic activity unmasks the sympathetic
drive (Huxley, 2007; Luczak and Leinwand, 2009). Recent studies of blood pressure control and cardiac function in healthy
men and women have demonstrated that women and men use the two arms of the baroreex system differently. At all
ages, women have reduced sympathetic activity (reected by lower vascular resistance and blood pressure) and enhanced
parasympathetic activity relative to men. Similarly, men have higher plasma norepinephrine levels than women (Geelen
et al., 2002), which could inuence lipolysis (see below). The consequence, though, is that in response to changes in body
position (e.g., in response to uid shifts), women are more vulnerable to orthostatic hypotension and fainting (Barnett
et al., 1999).
The composition of the circulating blood also displays sexgender specic differences in the levels of the formed elements, the most obvious being that women have fewer circulating red blood cells per unit volume of plasma than males
(Huxley, 2007). This is manifested as lower hematocrit levels in women than in men. Both lipid and plasma protein compositions demonstrate sexual dimorphisms. With respect to lipids, the high-density lipoprotein (HDL) level is higher and the
cholesterol level is lower in pre-menopausal females than in males; this antiatherogenic blood lipid prole is also associated with a lower incidence of cardiovascular disease. Following menopause, the lipid prole of females becomes more athrogenic and is correlated with the higher incidence of heart disease in that population (Huxley, 2007).
The major protein groups responsible for binding drugs in human plasma are inuenced by concentrations of sex hormones, so plasma-nutrient binding can clearly be inuenced by sexgender. Owing to differences in body fat percentage,
lipophilic agents (e.g., fatty acids, lipophylic vitamins, plant polyphenols) may have a relatively greater volume of distribution, and water-soluble compounds (e.g., carbohydrates, proteins, B complex vitamins) may exhibit a relatively lower volume of distribution, in females compared to males. As far as we know, no information is available on the effect of these
sex-related physical differences in nutrient distribution to tissues.
With respect to hemodynamic responses, although most studies have been conducted on males, re-examination appears
to be underway in several areas. One example is the response of the cardiovascular system to the ingestion of a meal. After
the intake of a meal, the digested nutrients will be taken up by the epithelial cells of the gut. After absorption, the tissues of
the body take up the nutrients from the blood for immediate utilization or storage for later use. In order to efciently absorb
nutrients from the gut epithelial cells, rapidly deliver them to the various storage tissues in the body (liver, skeletal muscle,
adipose tissue), and provide the tissues with the extra oxygen that is required for the associated metabolic processes, the
blood ow is redistributed postprandially, and energy expenditure increases (van Baak, 2008).
After a meal, the blood ow to the splanchnic area is increased by vasodilation induced by the presence of chyme in the
gastrointestinal tract. The mechanisms involved in this postprandial hyperemia are direct effects of the absorbed nutrients,
enteric nervous system effects and reexes, gastrointestinal hormones and peptides, and local non-metabolic or metabolic
vasoactive mediators. Lipid/bile mixtures are the most potent vasodilators, with proteins and their digestive products being
the least potent vasodilators. The increase in blood ow is more prolonged after a high-fat meal than after an isoenergetic
high-carbohydrate meal (van Baak, 2008). Blood ow into the superior mesenteric artery is faster in females than in males;
following a meal, it increases to a similar extent in both sexes, thereby maintaining the difference. In the portal venous system, no apparent differences exist for males and females, and for both sexes, venous ow increases to a similar extent in
males and females. Although the control of blood ow within the splanchnic circulation for males was reected in the systemic circulation by a drop in peripheral resistance, the same was not true in females (van Baak, 2008).
To compensate for the postprandial fall in total peripheral resistance, cardiac output and blood pressure should be modied accordingly. Whereas mean arterial pressure is lower in females than in males, the ingestion of a meal results in no
change in females and a fall (reduced diastolic pressure) in males.
There are also lower plasma protein levels in females than in males (Huxley, 2007). The outcome is that there is a lower
absorbing force (low plasma oncotic pressure) in the exchange vessels in females than in males. This lower plasma oncotic
pressure in females is offset by a lower ltering force (low capillary hydrostatic pressure). In both cases, assuming that the
conductivities and surface areas of the vasculatures are equal, volume balance is maintained. Sex differences in plasma protein-binding can theoretically lead to differences in distribution parameters for certain nutrients and drugs (Huxley, 2007).
Albumin, a-1 acid glycoprotein (AAG) and a-globulins are the main binding proteins for various substances in plasma (i.e.,
fatty acids, vitamins, steroid hormones, drugs). Albumin concentrations do not consistently vary by sex, but AAG levels and
AAG-glycosylation states vary in association with endogenous and exogenous estrogens (Brinkman-Van der Linden et al.,
1996; Succari et al., 1990; Walle et al., 1994), which both decrease levels of AAG in the plasma and induce hepatic glycosylation of these proteins (Brinkman-Van der Linden et al., 1996). In addition, exogenous estrogens increase the levels of the
serum-binding globulins, which include sex hormone-binding globulins, corticosteroid-binding globulin, and thyroxinebinding globulin (Wiegratz et al., 2003).

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During pregnancy, the effects on binding proteins are complex. As pregnancy progresses, the concentrations of albumin
and other plasma proteins decrease (Haram et al., 1983). However, the effects of pregnancy on the concentration of AAG are
under debate. Two studies report an overall decrease in AAG concentration over the course of pregnancy (Aquirre et al.,
1988; Wood and Wood, 1981), one study reports no change (Chu et al., 1981), whereas another reports a reduction in
AAG levels throughout pregnancy (Haram et al., 1983). Some researchers report that there is a steady increase in the production of endogenous ligands, such as FFA, during pregnancy; these ligands compete for other substances binding sites that
are distinct from their own on albumin (Hill and Abramson, 1988; Notarianni, 1990). Furthermore, protein-binding capacity
may be reduced secondary to intrinsic alterations in protein structure during pregnancy (Perucca and Crema, 1982).
2.5. Energy balance from a sexgender perspective
As describe above, in addition to the effect on FM, sex steroid hormones promote the differentiation of LBM. In fact, the
drop in estrogen that occurs with menopause and the gradual decline in androgens that occurs in older men are associated
with a decline in muscle and bone mass. This is likely due to a combination of direct effects of sex hormones on muscle and
bone as well as indirect effects via the hypothalamus. For instance, the sudden drop in estrogens after an ovariectomy in
rodents increases hypothalamic expression of NPY, which reduces lean mass via inhibiting the growth hormone axis and circulating insulin-like growth factor-I (IGF-I) levels (Aubert et al., 1998). In contrast, orchiectomy in male rodents decreases
NPY expression in the arcuate nucleus of the hypothalamus and reduces adiposity. These effects can be abolished by testosterone replacement (Sohn et al., 2002). In addition to the negative effects of reductions in estrogens or androgens on muscle
mass, circulating levels of IGF-I decrease with age, and this further contributes to the gradual loss of lean body mass in aging
women and men (Kamel et al., 2002). These reductions in lean body mass may not only promote weight gain by reducing 24h energy expenditure, but they may also promote the development of insulin resistance through the loss of insulin-sensitive
muscle mass.
Body size and LBM are strong determinants of energy expenditure; it is therefore not surprising that, in absolute terms,
women have lower energy expenditure than men (Lovejoy and Sainsbury, 2009). The average aerobic tness, expressed as
the maximal oxygen uptake (VO2 max), of adult women is 2.0 l/min, compared with 3.5 l/min for men. When adjusted for
differences in body weight, the average VO2 max for women is 40 ml  kg1  min1 vs. 50 ml  kg1  min1 for men
(McKardle et al., 1986). These differences can be reduced still further (to 54 ml  kg1  min1 vs. 59 ml  kg1  min1)
when the results are normalized for lean body mass and disappear completely when results are normalized for lean body
mass and gender differences in total body hemoglobin (Harm et al., 2001).
Thus, for any task requiring a given absolute oxygen uptake, the average woman is working at a higher percentage of
her exercise capacity than the average man. This would result in a higher heart rate, higher body temperature, greater
stress, and a quicker onset of fatigue during the exercise (Harm et al., 2001). These more severe exercise responses may result in a greater number of injuries and less tolerance for a stressful environment. For example, in a study of 124 men and
186 women during basic combat training, the women had a 51% injury rate compared with 27% for the men (Jones et al.,
1988). However, studies with animals have demonstrated that female muscles are more fatigue-resistant and recover faster
than male muscles and that estrogens increase skeletal muscle force production. Female rat muscles show fewer histopathological changes after repeated eccentric contractions than male muscles; male and ovariectomized female rats exhibit
higher indexes of exercise-induced muscle membrane damage, which disappear in ovariectomized female rats after estradiol
treatment. Variations in skeletal muscle strength have been described during the human menstrual cycle, and muscle mass
and strength diminish during the post-menopausal years, leading to sarcopenia. Altogether, these data indicate that estrogens are an important regulator of skeletal muscle mass and the muscle protein remodeling process (Fulco et al., 1999;
Galluzzo et al., 2009; Glenmark et al., 2004; Lemoine et al., 2003; McCormick et al., 2004).
The average woman is less active and less t than the average man. Therefore, when exercise data are normalized for
tness, the gender differences are often greatly reduced. If allowed to work at a similar percentage of their maximal exercise
capacity, men and women would have similar cardiovascular and thermoregulatory responses (Harm et al., 2001). However,
men tend to be faster than women during aerobic events due to their greater muscle strength and the mechanical advantage
of their longer arms and legs (Harm et al., 2001). Women, on the other hand, tend to have a greater endurance capacity due
to a greater reliance on fat metabolism during exercise; thus, a glycogen-sparing effect may delay fatigue during longduration events (Tarnopolsky et al., 1995).
It is less clear whether there are sex differences in basal metabolic rate or total daily EE independent of body composition.
A number of studies have failed to nd any sex difference in EE after adjustment for body composition differences (Buchholz
et al., 2001). However, several studies have found that, even after adjusting for differences in fat-free mass, women have lower daily EE than men (Carpenter et al., 1998; Morio et al., 1997). Furthermore, the decline in resting EE with age is greater in
women (80.3 kJ d1 year1) than men (46.9 kJ d1 year1) (Roubenoff et al., 2000), suggesting that women may be at
greater risk for obesity with aging. Because sex differences in EE have also been found in pre-pubertal children matched
for body composition (Lovejoy and Sainsbury, 2009), the difference may be due to sex chromosome gene effects or the in
utero organizational effects of gonadal hormones.
More consistent sex differences have been observed in response to physical activity and EE. In men, higher levels of physical activity are associated with a reduced percent of body fat, but this relationship is not observed in women (Paul et al.,
2004; Westerterp and Goran, 1997). Moreover, physical training programs result in smaller reductions in body weight

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15

and fat loss in women than in men (Westerterp et al., 1992). The relative lack of impact of exercise on body weight or body
fat in women may be due to sex differences in metabolic response to exercise training as well as dietary compensation because energy intake increases in women but not in men after exercise (Westerterp et al., 1992). Meijer et al. (1991) compared
men and women training for a half-marathon event for 5 months and found that men increased their total daily EE by the
end of training because of increases in both exercise and non-exercise (habitual) activities. Women, on the other hand, did
not signicantly increase their total EE after endurance training because, unlike the men, they did not experience increases in
non-exercise-associated or dietary thermogenesis (Lovejoy and Sainsbury, 2009).
Stress hormones, adrenaline (epinephrine) and noradrenaline (norepinephrine), are responsible for many adaptations
both at rest and during exercise. Since their discovery, thousands of studies have focused on these two catecholamines
and their importance in many adaptive processes to different stressors, such as exercise, hypoglycemia, hypoxia and heat
exposure, and these studies are now well acknowledged (Zouhal et al., 2008). In fact, because adrenaline and noradrenaline
are the main hormones whose concentrations increase markedly during exercise, many researchers have worked on the effect of exercise on these amines and reported variation in their basal concentrations from 1.5- to >20-fold increases depending on exercise characteristics (e.g., duration and intensity). Similarly, several studies have shown that adrenaline and
noradrenaline are involved in cardiovascular and respiratory adjustments and substrate mobilization and utilization. Previous studies conducted in men have used different types of exercise to compare trained and untrained subjects in response to
exercise at the same absolute or relative intensity. Their results were conicting. Parameters such as age, nutritional and
emotional state inuence catecholamine concentrations (Zouhal et al., 2008). Most ndings then reported a higher adrenaline response to exercise in endurance-trained compared with untrained subjects in response to intense exercise at the same
relative intensity as all-out exercise. This phenomenon is referred to as the sports adrenal medulla. This higher capacity to
secrete adrenaline is observed both in response to physical exercise and to other stimuli such as hypoglycemia and hypoxia.
For some authors, this phenomenon can partly explain the higher physical performance observed in trained compared with
untrained subjects. In women, studies remain scarce; the results are more conicting than in men, and the physical training
type (aerobic or anaerobic) effects on catecholamine response remain unknown (Zouhal et al., 2008).
2.6. How do gender physiology differences arise?
2.6.1. Genetic mechanisms
Sex-based differences in normal physiology, or in predisposition to a specic disease, can be due to genetic differences,
the actions of the sex steroid hormones, an interaction between these factors and/or an epigenetic mechanism.
The obvious genetic basis for sex-based differences lies in the fact that females have two X chromosomes but no Y chromosome, whereas males have a Y chromosome but only one X chromosome. There are genes on the Y chromosome that have
no counterpart on X chromosomes, and, conversely, genes located on the X chromosome can, in some cases, be expressed at
higher levels in females than in males. The Sry gene, which normally initiates development of the testes, is located on the Y
chromosome and is also implicated in the development of arterial blood pressure by modulating the synthesis of norepinephrine, the major neurotransmitter of the peripheral sympathetic nervous system (Turner et al., 2009). Indeed, genes present on the Y chromosome may be responsible for the considerable differences reported in blood pressure and stress
responses between men and women and may also affect the response to dietary salt through a modied Na+ and K+ excretion
in the kidney (Dumas et al., 2002).
Regarding the X chromosome, genes found on the pseudoautosomal region of the X chromosome include those genes that
code for enzymes affecting oxidative stress, cell survival, apoptosis and fat distribution (Bhuiyan and Fukunaga, 2008; Price
et al., 2002; Resch et al., 2008). These ndings indicate that the sex chromosomes regulate a wide range of cellular responses
that inuence the effect of feeding on health and cell fate. However, as discussed below, sex physiology differences are inuenced not only by the genetic sex of the animal (cell) but also by the hormonal environment. The gene for the androgen
receptor is located on the X chromosome. Some androgen receptor polymorphisms, such as the CAG repeat polymorphism
on exon 1 of the gene, which encodes the transcriptional regulatory domain of the androgen receptor, are negatively associated with transcriptional activity. Shorter repeated segment that are associated with gene high activity levels are associated with low levels of HDL, high levels of visceral fat, and low estrogen levels in adolescent and adult males. Sexually
dimorphic gene expression is also present on genes located on autosomes; dimorphisms in genes that are important in
the liver and adipose tissue affect steroid and lipid metabolism (Yang et al., 2006).
2.6.2. Epigenetic mechanisms
Gene expression can be altered by sex steroid hormones through epigenetic modication. Epigenetic modications are
heritable and reversible biochemical changes of the chromatin structure. Unlike mutations that involve an alteration in
the DNA sequence, epigenetic modications can regulate gene expression via chromatin remodeling. The most studied epigenetic modication is DNA methylation (i.e., transfer of a methyl group from a methyl donor), which is critical during
embryogenesis and in processes like imprinting and X-chromosome inactivation (Chiam et al., 2009). Although epigenetic
modications were originally thought to be highly regulated and stable, there is emerging evidence suggesting that they
are much more dynamic than previously thought. Recent studies have demonstrated some exciting and novel mechanisms
of dynamic epigenetic regulation associated with hormones and hormone receptor activities. For instance, following the
administration of estrogens, DNA methylation at specic estrogen-responsive/ERa-regulated gene promoters undergoes

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time- and DNA strand-specic cyclical uctuations. Moreover, these dynamic DNA methylation changes are essential for
estrogen-induced and ERa-dependent gene transcription (Chiam et al., 2009). Recently, the hypothesis that a change in environmental factors, such as hormonal perturbations and nutrition, may permanently alter the epigenome of cancer stem cells
and predispose these cells to cancer development in adulthood has emerged (Cheng et al., 2008; Hilakivi-Clarke, 2007). Furthermore, the idea that sex hormone receptors may play a pivotal role in mediating the relationship between hormones, epigenetic modications, and sex-related differences provides a new and exciting area of research.
In addition to the contribution of genetic and gonadal steroid hormone effects to the pathophysiology of disease, societal
factors can also play a marked role in the incidence and expression of diseases. Gender differences in lifestyle, daily environment, and healthcare can all make signicant contributions to physical and mental health. These differences are present in
all societies but play a particularly substantial role in certain cultures in developing nations. Although this topic is beyond
the scope of this review, it is nonetheless an important contributing variable to the expression of gender-based differences in
pathophysiology.
2.6.3. Hormonal mechanism
2.6.3.1. Sex steroid hormone synthesis. The sex steroid hormones include androgens, estrogens, and progestins. Receptors for
the sex steroid hormones are present in numerous non-reproductive tissues, including the heart, bone, skeletal muscle, vasculature, liver, immune system, and brain. Both males and females produce estrogens, progestins, and androgens, although
circulating androgen levels are higher in males than in females, and circulating estrogen/progestin levels are higher in premenopausal females than in males. The biosynthesis of gonadal steroids is well understood and clearly explained in textbooks (Greenspan and Gardner, 2004; Loose-Mitchell and Stancel, 2001; Norman and Litwack, 1997). Only a few key points
relevant to the current discussion of the mechanisms of sex steroid hormones merit mention here. Testosterone is a key
intermediate in both women and men and is converted to estrogen by the action of aromatase and to the more potent
androgen, dihydrotestosterone, by 5-a reductase. In women, estradiol (i.e., 17b-estradiol) is the main form of circulating
estrogen, and circulating levels of testosterone are relatively low. In men, testosterone is the principal circulating androgen,
and circulating estrogen levels are much lower than in women. A key point, though, is that circulating levels of hormones
may not reect hormone concentrations at the tissue level because both aromatase and 5-a reductase can be found in a
number of tissues (Gonzales et al., 2007). For example, in bone, testosterone is converted to estradiol by aromatase; estradiol then acts locally to promote mineralization and prevent osteoporosis. In fact, mutations of genes encoding either aromatase or estrogen receptor a result in altered bone phenotype in men (Carani et al., 1997). 5-a Reductase in the prostate
converts testosterone to the more potent androgen, dihydrotestosterone, which is a critical step for the effective promotion
of prostate growth and function (Steimer, 2003). Administration of an aromatase inhibitor to young men decreases endothelial vasodilator function, as assessed by ow-mediated dilation of the brachial artery (Lew et al., 2003), providing evidence that the conversion of testosterone to estradiol may contribute to the regulation of the peripheral circulation in
men (Mendelsohn and Karas, 2005). In women, evidence suggests that the relationship among circulating concentrations
of free estradiol, free testosterone, and sex hormone-binding globulin may be more predictive of changes in carotid intimal
thickening than concentrations of any of these hormones alone (Karim et al., 2008). Despite these few examples, the complexities of gonadal steroid hormone metabolism and local variation are still not well understood, particularly with respect
to the non-reproductive effects of gonadal steroids. More information is needed to illuminate how local balances between
levels of androgens and estrogens inuence male and female physiology and how imbalances may contribute to sex differences in pathophysiology.
One of the complexities of unraveling the contribution of steroid hormones to either normal physiology or disease is the
changing role of these hormones across development.
2.6.3.2. Effects of sex-steroid hormones during sexual differentiation. Few data are available on the onset of sex-dependent differentiation of human tissues. The testicles and ovaries develop in the sixth week of pregnancy. This happens under the inuence of a cascade of genes, such as the sex-determining gene on the Y chromosome (Sry). The production of the testosterone
and its peripheral conversion into dihydrotestosterone by a boys testes is necessary for the sexual differentiation of the sexual organs between weeks 6 and 12 of pregnancy. However, once the differentiation of the sexual organs into male is settled
(determined by the presence of the Y chromosome of the father), the next organ to differentiate is the brain due to the inuence of sex steroid hormones on the developing brain cells. From the earliest stages of fetal brain development onwards,
many neurons throughout the entire nervous system already have receptors for these hormones. This involves (permanent)
organizational changes, whereas during puberty, the brain circuits that developed in the womb are activated by sex hormones (Blecher and Erickson, 2007; Piprek, 2009; Swaab and Hofman, 1995).
Several brain regions possess the enzymes that transform testosterone into the compounds that amplify (dihydrotestosterone) or differentiate (estrogens) its action (Negri-Cesi et al., 2004). In rats, this conversion is the most important mechanism for the virilization of the brain (Gorski, 1984), but in human beings, the sexual differentiation of the brain is not only
caused by hormones, even though they are very important for sexgender identity and sexual orientation (Lopes et al.,
2006). The presence of aromatase in the developing male brain explains the extraordinary ability of estrogens to contribute
to the organizing actions of androgens. In addition, both estrogen receptors and testosterone receptors have been observed in
the mammalian brain; therefore, male differentiation of some brain regions might be under the direct control of testosterone
(Blecher and Erickson, 2007; Piprek, 2009; Swaab and Hofman, 1995).

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17

The stages of development at which sex steroids determine sexual differentiation of the human brain are most probably
the three periods during which sexually dimorphic peaks in gonadal hormone levels are found, namely, during the rst half
of gestation (when the genitalia are formed), during the peri-natal period, and during puberty. In human neonates of
3441 weeks of gestation, the level of testosterone is 10-fold higher in males than in females (Swaab, 2007).
The development of the female sexual organs in the womb is primarily based on the absence of androgens (Swaab, 2007).
A girls brain is protected against the effect of circulating estrogens from the mother by the protein a-fetoprotein, which is
produced by the fetus and binds strongly to estrogens but not to testosterone (Bakker et al., 2006).
At the end of the pregnancy, when a-fetoprotein declines, the fetus is more exposed to estrogens from the placenta, which
inhibits the hypothalamuspituitarygonadal axis of the child. This inhibition is lost once the child is born, which causes a
peak in testosterone in boys and a peak in estrogens in girls. The circulating testosterone level in boys at this time is as high
as it will be during adulthood, although a large part of it is bound to proteins in the circulation. In addition, at this time, the
testosterone level is higher in boys than in girls. During these two periods, there are no high levels of testosterone in girls.
These two peaks of testosterone are said to x the development of structures and circuits in the brain for the rest of a persons (de Zegher et al., 1992; Quigley, 2002).
After the juvenile pause, which lasts until 813 year of age, neuronal cell bodies of female hypothalamus start to release
gonadotropin-releasing hormone in a pulsatile pattern into the pituitary portal circulation. As a consequence, in the rodents,
the plasma concentration of estradiol uctuates and is highest just before the gonadotropins surge and is very low during
estrus (Greenspan and Gardner, 2004; Loose-Mitchell and Stancel, 2001). In women, both estrogen and progesterone secretion are increased during most of the luteal phase, which lasts about 10 days, and as described previously, eating behavior
may change during the luteal phase. There is no close counterpart to this in rats and mice. Rather, the corpora lutea are
formed at various points in the cycle and last across cycles (Greenspan and Gardner, 2004; Loose-Mitchell and Stancel,
2001; Miller, 1988; Norman and Litwack, 1997).
In the male, testosterone secretion is viewed as relatively constant. In fact, serum testosterone levels rise to 20% above
mean levels (500 ng/dl), peaking at 8:00 p.m., and fall to 35% below mean levels, at 7:00 a.m., in healthy men (Greenspan
and Gardner, 2004; Miller, 1988; Norman and Litwack, 1997).
Sex steroid hormone levels rise during puberty, which activates circuits that were built during development, and
behavioral patterns and/or disorders that originated much earlier in the development begin being expressed.
As a whole, in utero, sex hormones are critical for sex determination and differentiation, and gonadal steroid hormone
levels and their contributions to physiological function undergo marked changes in the transition from childhood to adolescence to adulthood. In women, there are the additional variables of the menstrual cycle, pregnancy, and menopause, and, in
both women and men, testosterone levels decline with age.
2.6.3.3. Mechanisms of sex steroid hormones. To further complicate this picture, the receptor for the sex steroid hormones
mediates their target tissue effects through different but synergistic mechanisms.
The androgen receptor (AR), a 110-kDa phospho-protein, is a member of the nuclear receptor superfamily and functions
as a ligand-activated transcription factor. AR is localized at the plasma membrane, in the cytoplasm (where it is associated
with heat shock proteins while in the resting state), and in the nucleus of androgen-target cells. Like other nuclear receptors,
the AR structure is composed of ve functional domains (Setlur and Rubin, 2005). The binding of androgen induces a conformational change, receptor dimerization, and nuclear translocation of the hormonereceptor complex (Fig. 2) (Setlur and
Rubin, 2005). This complex binds to specic androgen response elements (ARE) in the upstream promoter of target genes
and, along with several co-regulator proteins (co-activators and co-repressors), leads to the transcriptional activation of
androgen-regulated genes (Berry et al., 2008; Massie et al., 2007; Shang et al., 2002; Wang et al., 2007). In addition to this
slow genomic mode of action, increasing evidence suggests that androgens, as well as other steroid hormones, exert rapid
extra-nuclear effects (Michels and Hoppe, 2008). As a whole, the pleiotropic effects elicited by androgens are obtained by
different signal transduction pathways (i.e., genomic and extranuclear), and signal activation depend on the cellular context
of the target cell, the receptor location within cells (i.e., membrane, cytosol, nucleus), and the ligand itself (i.e., testosterone
versus dihydrotestosterone) (Michels and Hoppe, 2008).

Fig. 2. Testosterone (T) binds to its cognate receptor, (AR), which, in turn, dimerize, translocate into the nucleus and bind to specic DNA sequences (i.e.,
ARE) present in the promoter region of target genes (direct). However, after T binding, AR can interact with other transcriptional factors (Sp1 or AP-1)
increasing the gene transcription (indirect). In both cases, ARs should interact with co-regulatory proteins (co-activators or co-repressors) necessary to
recruit the component of transcription machinery. Besides these genomic mechanisms, T induces rapid effects that have been attributed to a plasma
membrane localized AR. For details see the text.

18

M. Marino et al. / Molecular Aspects of Medicine 32 (2011) 170

Fig. 3. Estradiol (E2) binds to its cognate receptors, (ERa and ERb), which, in turn, dimerize, translocate into the nucleus and bind to specic DNA sequences
(i.e., ERE) present in the promoter region of target genes (direct). However, after E2 binding, ERs can interact with other transcriptional factors (Sp1 or AP-1)
increasing the gene transcription (indirect). In both cases, ERs should interact with co-regulatory proteins (co-activators or co-repressors) necessary to
recruit the component of transcription machinery. Besides these genomic mechanisms, E2 induces rapid effects that have been attributed to a plasma
membrane localized ERs. For details see the text.

Like androgens, estrogens effects in living cells are mediated by various pathways rather than by a single uniform mechanism (Fig. 3). Estradiol (the most potent estrogen) binds to estrogen receptors, ERa and ERb, which are the products of separate genes present on distinct chromosomes (Ascenzi et al., 2006). The pioneering work of OMalley and colleagues
(OMalley, 2005) demonstrated that ERs function as ligand-activated transcription factors. In fact, the biological effects of
ERs result from modications in the pattern of expression of specic target genes. These transcriptional regulations are
achieved through the recruitment of ERs to the promoter region of the target gene, either directly through interaction with
cognate DNA sequences (i.e., ERE) or through ER interaction with other transcriptional factors (Klein-Hitpass et al., 1986). In
both cases, ERs interact with co-regulatory proteins (co-activators or co-repressors) to activate transcription machinery
(McKenna and OMalley, 2002; Smith and OMalley, 2004) (Ascenzi et al., 2006; OLone et al., 2004).
The genomic action of steroid hormones occurs after a time-lag of at least 2 h after estradiol stimulation and explains
some hormone functions in physiological and pathological situations. Only seconds are required for rapid estradiol-induced
signals (Morley et al., 1992; Marino et al., 2001; Marino et al., 1998; Dang and Lowik, 2005; Levin, 2005). These rapid pathways are insensitive to inhibitors of transcription (e.g., actinomycin D) and translation (e.g., cycloheximide) (Losel et al.,
2003) and have been attributed in most cells to a population of ERs present on the plasma membranes (Acconcia et al.,
2005a; Galluzzo et al., 2007; Marino and Ascenzi, 2008).
The physiological signicance of rapid ER-dependent pathways is quite clear, at least for some estradiol target tissues.
Estradiol actions on proliferation have been assumed to be exclusively mediated by ERa-induced rapid membrane-starting
actions (Ascenzi et al., 2006; Marino et al., 2005), whereas estradiol induces cancer cell death through ERb-dependent nongenomic signaling (Acconcia et al., 2005b; Strom et al., 2004; Weihua et al., 2003; Galluzzo et al., 2007). Estradiol affects
neural functions in both male and female brains, in part, by inducing such rapid responses (Farach-Carson and Davis,
2003; Losel et al., 2003). In the skeleton, the rapid ERa-dependent pathway transmits survival signals and prolongs the life
span of osteoblasts (Kousteni et al., 2003; Kousteni et al., 2002; Kousteni et al., 2003; Manolagas et al., 2002). In the liver,
rapid 17b-estradiol-induced signals are strongly linked to the increased expression of the LDL receptor, which leads to a
decreased level of LDL in the plasma (Distefano et al., 2002; Marino et al., 2001). The 17b-estradiol-activated rapid pathways
are responsible for 17b-estradiol-induced survival signals (Acconcia et al., 2005b) and the activation of nitric oxide synthase
(NOS), which may be at the root of 17b-estradiol vascular protection in ischemia/reperfusion injury in vivo (Chambliss and
Shaul, 2002; Simoncini et al., 2000). ERa-dependent rapid signals are also essential for 17b-estradiol-induced skeletal
myoblast differentiation (Galluzzo et al., 2009).
Remarkably, AR potentially inhibits ERa, but not ERb, activities, via a direct interaction between AR and ERa, which decreases mRNA and protein ERa expression in breast cancer cells. Thus, androgens may oppose estrogen signaling in breast
tissue to control cellular proliferation and maintain tissue homeostasis (Birrell et al., 2007).
Despite the increased awareness of sexgender differences in physiology, this area is far from being resolved. The focus of
this chapter has meant to provide an awareness of the major issues in the eld of physiology of nutrition, so future studies
can further explore these differences and ultimately provide sexgender specic recommendations based upon the results of
careful research.
3. Nutrients and food components in health and disease in a sex-gender perspective
Please test your servants for ten days: Give us nothing but vegetables to eat and water to drink. Then compare our appearance
with that of the young men who eat the royal food, and treat your servants in accordance with what you see. Bible: Book of
Daniel
Hippocrates, the Father of Western medicine wrote his famous dictum Let food be thy medicine and medicine thy
food (Lucock, 2004) and started the philosophy of food as medicine. Nutrition in the 20th century has greatly changed
due to changes in the economy and evolution from an agrarian to an industrialized society. In the 1920s through the early
1930s, dietary deciencies were a major focus of public health. Identifying the causes of these human nutritional deciencies
prompted signicant research into basic chemical research and clinical trials to assess the role of vitamins, minerals,

M. Marino et al. / Molecular Aspects of Medicine 32 (2011) 170

19

proteins, lipids, carbohydrates, and nutrients for improving human health and nutrition. Consequentially, in the last 50
60 years, numerous changes have been observed in diets and lifestyles. The improvements in living standards, food and
available services have increased health probabilities because a variety of diseases are linked to poor and/or unbalanced
nutrition. Paradoxically, changes in diets and lifestyles have also yielded signicant negative consequences in terms of inappropriate dietary patterns. As examples, the increased consumption of energy-dense diets high in fat, particularly saturated
fat, and the low intake of unrened carbohydrates together with the lack of exercise leads to obesity, which is becoming an
increasingly signicant cause of disability and premature death (WHO, 2009). Additionally, population-based epidemiological evidence has helped clarify the role of diet in preventing and controlling morbidity and premature mortality resulting
from non-communicable diseases (WHO, 2009), suggesting that together with good nutrients, some specic dietary components that increase the probability of occurrence of diseases in individuals exist (WHO, 2009).
Most importantly, dietary adjustments may not only inuence present health, but it may also determine whether an individual will develop diseases such as cancer, cardiovascular diseases and diabetes much later in life (WHO, 2009). One example is provided by a Finnish study showing that the age-adjusted mortality rates of coronary heart disease drop dramatically
between the early 1970s and 1995 (Puska et al., 1998), and this change mainly occurs through dietary reductions in plasma
cholesterol levels. On the other hand, epidemiological data from cross-sectional, casecontrol, and prospective studies have
shown a strong relationship between the intake of foods rich in antioxidant vitamins and minerals, or the actual intake of
these nutrients, and the risk of cancer and ischemic cardiovascular diseases (Block et al., 1992; Byers and Guerrero, 1995;
Hercberg et al., 1998; Kohlmeier and Hastings, 1995; Stampfer and Rimm, 1993; Stampfer and Rimm, 1995). However, these
results have been not conrmed by intervention trials (see below).
Sufcient, safe and varied food supplies may not only prevent malnutrition but also reduce the risk of chronic diseases.
Nutritional deciency increases the risk of common infectious diseases, notably those of childhood (Scrimshaw et al., 1968).
Malnutrition is generally associated with poverty and inequity, and women are poorer than men. Eliminating these causes
requires political and social actions, and nutritional programs can be only one aspect.
In the last 20 years, the importance of sexgender in health issues has become apparent (Fiscella et al., 2000; Institute of
Medicine and America, 2001; Institute of Medicine, 2002, 2004; WHO, 2009), and nutrition appears to be an area where
sexgender relevance is enormous, especially in the context of cardiovascular diseases (Legato, 2004). Men and women also
differ in the prevalence of eating disorders, with women being more affected than men, and the sexgender differences in
lifetime prevalence in adults could be less substantial than the values that are quoted in standard texts (Treasure et al.,
2010).
Traditionally, considerable attention has been focused on nutrient adequacy when investigating relationships between diet
and health. The health and nutritional needs of females differ from those of males not only because of physiological sexdifferences but also because of gender differences. As already mentioned, culturally dened roles and opportunities differ between males and females, leading to signicant differences in their knowledge of health and nutrition, their exposure to health
and nutrition risks, their access to care, and the social consequences they experience as a result of poor health and nutrition.
In Western countries, in the absence of specic predisposing conditions, a normal diet is sufcient to prevent overt vitamin deciency diseases such as scurvy, pellagra, and beriberi. However, insufcient vitamin intake is apparently a cause of
chronic diseases. Recent evidence has shown that suboptimal levels of vitamins, even when well above levels causing deciency syndromes, are risk factors for chronic diseases such as cardiovascular disease, cancer, and osteoporosis. The risk of
undernutrition is prevalent among older patients and is sexgender-related. Female in-patients are at a markedly increased
(by more than 3-fold) risk for undernutrition when compared to men (Castel et al., 2006). These ndings are in contrast with
previous publications reporting similar prevalence rates in elderly men and women (Perissinotto et al., 2002; Rea et al.,
1997) or higher rates in men (Ritchie et al., 1997).
Importantly, dietary amount recommended by many Istitutions have been issued (Allender et al., 2008). However, gender
determinant has actually been neglected. In the last edition of Dietary Guidelines for the Americans (2005), terms such as
sex and gender appear two and seventeen times, respectively. In the majority of cases, sexgender is associated with
caloric intake, pregnant women. The above observations and the numerous metabolic sexgender differences described in
the previous chapters clearly indicate that nutrition represents a key determinant that should be viewed through gender
glasses. In many cultures, women have traditionally functioned as the primary preparers of food within the family, and women consistently show more interest in nutrition, healthy eating, dieting, body-image, and weight control (Davy et al., 2006;
Wardle et al., 2004).
3.1. The role of food in health
Every human being is the author of his own health or disease. Buddha
All humans have the following nutritional needs: carbohydrates, protein, lipids, and micronutrients (vitamins and minerals). More recently, a new class of food or food components has attracted interest: functional foods or nutraceuticals, a
term combining the words nutrition and pharmaceutical. Functional foods could improve health and provide medical benets, including the prevention and treatment of disease. Such products may range from isolated nutrients, dietary supplements, herbal products, and beverages. In this section, the impact of food components on human health will be described
from a sexgender perspective.

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M. Marino et al. / Molecular Aspects of Medicine 32 (2011) 170

3.1.1. Proteins and amino acids


As reported above, the adult male in any species is generally recognized as being a larger and heavier animal than the
adult female and having more muscle than the female. The metabolism of the male is also different from that of the female
(see Chapter 2). Despite this, many nutrition workers use only one sex for their experiments, and there are no available data
giving the separate requirements of each sex. Generally, sexgender-based differences in protein metabolism are small when
compared with those often observed in lipid and carbohydrate metabolism, and importantly, the menstrual cycle induces
relatively small changes in protein kinetics (Lamont et al., 1987; Miller et al., 2006).
The sexgender-based differences in protein metabolism have recently been reviewed by Burd et al. (Burd et al., 2009).
Briey, in the basal state, when protein kinetic rates are normalized to lean mass, men and women have virtually identical
turnover rates of muscle protein; however, women rely less on protein as a substrate during aerobic exercise than their age
matched male counterparts (Burd et al., 2009; Fujita et al., 2007). Chronic adaptations to resistance exercise suggest quantitative differences in hypertrophic responses (Burd et al., 2009).
Sexgender differences have been described during treatment with b-blocker drugs, which antagonize the action of catecholamine induced by activating adrenergic b-receptors that are also involved in the control of lipolysis (see Section 2.2.2).
In men, but not in women, the b-blockers increase leucine oxidation and lysine rate of appearance (Lamont et al., 2003). This
is important because individual nutritional needs may be varied by pharmacological treatments, and this can occur in a
sexgender-specic manner.
In middle-aged women and men, no signicant sexgender differences have been described in muscle protein metabolism (Smith et al., 2009). However, a sexual dimorphism in response to mixed meal ingestion has been observed, with a more
pronounced anabolic response in men than in women in terms of both muscle protein metabolism and anabolic signaling
(Smith et al., 2008).
Older men and women have basal differences in muscle protein synthesis (Burd et al., 2009). Indeed, the doseresponse
relationship between myobrillar protein synthesis and the availability of essential amino acids is shifted down and to the
right, and consumption of extra amino acids cannot overcome this shift. Older women also have a reduced capacity for
hypertrophy in response to resistance exercise compared to men (Burd et al., 2009).
In conclusion, there is no sexgender difference in basal or fed muscle protein metabolism in the young, but post-menopausal women have a greater anabolic resistance than older men (Rennie, 2009), and some sexgender-related differences
are probably related to sex hormones (Kumar and Kalyankar, 1984; Tipton, 2001; Volpi et al., 1998). Thus, age should be
considered in association with sexgender aspects: the total nutrient intake of energy, protein, alcohol, water, sodium
and ber decreases signicantly with age and includes the concentration of total amino acids, essential amino acids, nonessential amino acids and branched-chain amino acids (Pitkanen et al., 2003). All aminoacids are generally lower in the plasma of females (Table 3) with the exception of citrulline, cysteine, aspartate, glycine, serine and taurine, which are higher in
women (Pitkanen et al., 2003).
Because of the bodys inability to synthesize approximately half of the biologically crucial amino acids, a deciency of
dietary protein or an imbalance of essential amino acids activates the so-called amino acid response signal transduction
pathway (Klaassen and Aleksunes, 2010). The amino acid response pathway in mammalian cells, which has been designed

Table 3
Plasma and serum level of some amino acids in women and in men.
Amino acids

Young M

Young F

Arginine
Aspartic acid
Cysteine
Glutamate
Glycine
Homocysteine



=/
=

++
=a

++
++
=/
=
++

+++
++
+++



Hystidine
Leucine
Isoleucine
Lysine
Phenylalanine
Serine
Methionine
Taurine
Threonine
Tryptophan
Tyrosine
Valine

+

=

+

+++

Old M

Old F

++



++

+
=

=
=
+
=
=



=
=
=

=
=
+

+
=
=


=
=

=aa



++
=
+
++

+


References
Forte et al. (1998)
Pitkanen et al. (2003)
Bates et al. (2002), Fukagawa et al. (2000), Pitkanen et al. (2003)
(Fukagawa et al., 2000)
Fukagawa et al. (2000), Pitkanen et al. (2003)
Lussier-Cacan et al. (1996), Sassi et al. (2002)
Bates et al. (2002)
Polge et al. (1997)
Caballero et al. (1991)
Fukagawa et al. (2000)
Caballero et al. (1991)
Polge et al. (1997)
Pitkanen et al. (2003)
Armstrong and Stave (1973), Fukagawa et al. (2000), Pitkanen et al. (2003)
Fukagawa et al. (2000), Pitkanen et al. (2003)
Pitkanen et al. (2003)
Armstrong and Stave (1973)
Pitkanen et al. (2003)
de Lange et al. (1972), Pitkanen et al. (2003), Polge et al. (1997)
Caballero et al. (1991)

M, male; F, female; +, sufcient elevation; ++, modest eleventation; +++, large elevation; , sufcient reduction; ++, modest eleventation; +++, large
reduction; =, no signicant differences.
a
418 years.

M. Marino et al. / Molecular Aspects of Medicine 32 (2011) 170

21

to detect and respond to amino acid deciency, can initiate a signaling cascade that leads to increased translation of a main
regulator: activating transcription factor 4 (Kilberg et al., 2009) and ultimately regulating many steps that lead to protein
synthesis (Brasse-Lagnel et al., 2009). Proteins that increase their expression as targets of the amino acid response pathway
include membrane transporters, transcription factors from the basic region/leucine zipper superfamily, growth factors, and
metabolic enzymes (Kilberg et al., 2005). Signicant progress has been achieved in understanding the molecular mechanisms
by which amino acids control the synthesis and turnover of mRNA and protein. However, it is not known whether this is
sexgender specic. Researchers have begun to report sexgender differences in amino acid transporters expression in animals. Future emphasis should be placed on quantifying sexgender differences in humans (Klaassen and Aleksunes, 2010).
Indeed, some sexgender differences have been described in signaling pathways that are activated by amino acids. For example, leucine metabolism varies during the menstrual cycles and is more active in the luteal phase, suggesting the importance
of sex hormones in the metabolism of this amino acid (Lariviere et al., 1994). sexgender-related differences in leucine oxidation, non-oxidative leucine disposal, and protein catabolism during moderate-intensity exercise have been described,
whereas sexgender-related differences in lysine kinetics have not been found (Lamont et al., 2001). Importantly, leucine
and lysine kinetics are similar between genders in resting conditions (Lamont et al., 2001). Leucine activates the mTOR
signaling pathway, which turns on the translational machinery necessary for muscle protein synthesis in both rodent and
human models (Anthony et al., 2000; Kimball and Jefferson, 2006) through a very specic mechanism (Byeld et al.,
2005; Nobukuni et al., 2005).
Sexgender differences in arginine metabolism have been also reported. Arginine is a precursor of NO, a free radical that it
is involved in many fundamental functions, such as neurotransmission, immunity, and the control of vascular tone, and arginine appears to be 25% higher in women plasma than in men (Forte et al., 1998). This is probably due to estrogens (Weiner
et al., 1994). Moreover, testosterone seems to increase the activity of arginase, the enzyme that breaks down arginine into
urea and ornithine, when administered to rats (Kumar and Kalyankar, 1984; Volpi et al., 1998). Sexgender differences have
also been seen in the conversion of arginine to nitrate, being higher in women than in men (Forte et al., 1998).
Sulfuric amino acids exert many functions, and some of them are illustrated in Fig. 4. Insufcient intake of sulfuric amino
acids is clearly detrimental; however, the negative effects of methionine or cysteine excess have also been reported (Garlick,
2006; Stipanuk et al., 2006; van de Poll et al., 2006), and sexgender differences have been reported in methionine toxicity in
the liver (Dever and Elfarra, 2009). In fact, methionine (30 mM) causes toxicity in male but not female hepatocytes. The toxicity is prevented by the addition of aminooxyacetic acid, an inhibitor of methionine transamination (Dever and Elfarra,
2009). This is consistent with the fact that 17b-estradiol inhibits the activity of methionine transport systems in some cells
(Hissin and Hilf, 1979), indicating the importance of this sexual hormone in methionine homeostasis. At high concentrations,
methionine is also hepatotoxic in humans; methionine toxicity has been linked with infant cholestasis and total parenteral
nutrition (Moss et al., 1999) and has been found in patients with chronic liver disease who often develop hypermethioninemia, which may, in turn, exacerbate hepatocellular necrosis and brogenesis (Finkelstein, 2003).
A deeper understanding of the interaction between sulfuric amino acid metabolism and nutritional demand is required to
optimize sulfuric amino acid nutrition while considering the different roles of these amino acids in many aspects of ones life
stage. They are precursors to essential molecules such as glutathione and taurine, which play a crucial role in oxidative stress

Fig. 4. Methionine-cysteine metabolic pathways. 1, transmethylation; 2, trans-sulfuration; 3, folate depedent remethylation; 4, folate independent
remethylation; BHMT, betaine homocysteine methyltransferase; 5-CH3THF, 5-methyltetrahydrofolate; DMG, dimethylglicine; MS, methionine synthase;
MT, methyltransferase; 5,10-MTHF, 5,10 methyl tetrahydrofolate; MTFHFR, methyltetrahydrofolate reductase, SAM, S-adenosyl-L-methionine; SAH,
S-adenosyl-L-homocysteine. For details see the text.

22

M. Marino et al. / Molecular Aspects of Medicine 32 (2011) 170

conditions because they can affect cellular redox status (Franconi et al., 2006b). Some mechanisms through which sulfuric
amino acids control oxidative status are described in Chapter 7 (Section 7.2.1). Additionally, sulfuric amino acids, particularly
cysteine, may also act as precursors of hydrogen sulde (H2S) (Stipanuk, 2004). While originally considered a toxic gas, H2S is
now recognized for its physiological function as the third (with NO and CO) gaseous transmitter in the body.
Finally, sulfuric amino acids may also be involved in the regulation of gene transcription and participate in methyl group
metabolism (Tesseraud et al., 2009). Methyl group and one-carbon metabolism are instrumental in human health processes
because they ultimately affect cell division and homeostasis of methylation reactions, also participating in epigenetic processes. The regulation of gene transcription and participation in methyl group metabolism are interdependent. Thus, modulating one pathway can have a signicant effect on the development of adverse conditions Tetrahydrofolate serves as a
coenzyme to accept or donate one-carbon units for metabolic pathways, such as the synthesis of DNA and methionine
(Wagner, 1995). For de novo methionine synthesis, the folate coenzyme 5-methyl-tetrahydrofolate remethylates homocysteine to yield methionine and regenerate tetrahydrofolate. Methionine may subsequently be activated to S-adenosylmethionine. Alternatively, homocysteine can be catabolized to compounds such as cysteine and glutathione through the
transsulfuration pathway. Alterations in the supply of methyl groups and, subsequently, of S-adenosylmethionine levels
may compromise transmethylation reactions. Glycine N-methyltransferase is a key protein in the liver that regulates Sadenosylmethionine and the S-adenosylmethionine/S-adenosylhomocysteine ratio; its activity is increased more by retinoid
treatment in males than in females, indicating that retinoid-modulated methyl group metabolism is tissue- and sexgender
specic (McMullen et al., 2002).
In conclusion, sexgender effects on amino acid metabolism and function are not clearly dened and are often controversial. Considering the relevance of these molecules to human health, the research on the inuence of sexgender on amino
acid metabolism and functioning should be improved in the near future. Special consideration should be given to foods
as an important regulator of epigenomes because many dietary food components are involved in one-carbon metabolism
(e.g., choline, betaine, folate), providing compelling evidence for the interaction of nutrients with the epigenome (Davis
and Uthus, 2004).
3.1.2. Fat quality and quantity
Dietary fat is classied as saturated, monounsaturated, or polyunsaturated based on the number of double bonds that
exist in the molecular structure. Within each class exists many different chemical variations or isomers. There is considerable support among the nutritional communities for the diet-heart (lipid) hypothesis, i.e., the idea that an imbalance of
dietary cholesterol and fats are the primary cause of atherosclerosis and cardiovascular disease (Kris-Etherton et al.,
2007). A reduction in the overall consumption of saturated fatty acids, trans-fatty acids and cholesterol is recommended
along with the need to increase intake of n-3 polyunsaturated fatty acids (n-3 PUFA) (Kris-Etherton et al., 2007). These nutritional recommendations are widely due to epidemiologic studies showing strong positive correlations between the intake of
saturated fatty acids and the incidence of cardiovascular diseases, which seem to result from the concomitant rise in serum
LDL (Hu et al., 1997; Posner et al., 1991).
Americans (both men and women) have widely reduced all types of fat consumption, and the amount of fat in their diet
has decreased from 45% in 1965 to 34% in 1995 (Department of Agriculture and Center for Nutrition Policy, 1995). Dietary
guidelines recommend that fat intake should be less than 30% of total daily energy intake, that daily saturated fat intake
should supply no more than 10% of energy, that trans-fat should be no more than 1% of the daily energy intake, and that
dietary cholesterol intake should not exceed 300 mg/d (Krauss et al., 2000; Mosca et al., 2007). However, Weggemans
et al. (1999) did not observe a different lipid response for men and women after modications in trans-fat intake.
In recent years, an anti-saturated fatty acid campaign has been widely promoted (Putnam et al., 2002), but not all saturated fatty acids have the same impact on serum cholesterol (Kris-Etherton and Yu, 1997), which should be considered when
making dietary recommendations to prevent cardiovascular diseases.
Despite the efforts to reduce fat intake, body weight can increase. In fact, the decrease in fat calories has resulted in an
increase in carbohydrate calories, primarily in the form of simple sugars (Willett, 1998), and high-carbohydrate low-fat diets
can produce high triglycerides and LDL levels and elevate weight gain (Lammert et al., 2000). Hypertriglyceridemia is of special importance in women as a cardiovascular risk factor (Collins et al., 2009; Mosca et al., 2007), and the triglyceride levels in
women continue to increase with age. Conversely, in men, triglyceridemia increases up to 45 years of age and then decreases
slightly (Cullen et al., 1997). Notably, specic female conditions, such as pregnancy (with a triglyceride peak by the third
trimester that returns to normal by the sixth week postpartum) (Montes et al., 1984), hormone replacement therapy (ESHRE,
1998), and oral contraceptives OC (Godsland et al., 1990) lead to an increased level of triglycerides in the blood. The previous
data suggest that the control of triglycerides is of particular interest to women.
As usual, most of the evidence on the relation between dietary fat, blood lipids and cardiovascular risk is from studies
performed on men (Freedman et al., 2004; Kris-Etherton et al., 1999). Importantly, the Womens Health Initiative Dietary
Modication trial showed that a reduction in total fat intake and an increased intake of vegetables, fruits and grains did not
signicantly reduce cardiovascular risk in post-menopausal women (Howard et al., 2006).
These sexgender differences are not surprising because fat distribution and lipid metabolism between men and women
are very different (see Chapter 2), suggesting that the quality of dietary fat could have different effects between genders
(Erkkila et al., 2008; Lapointe et al., 2006). The response of total cholesterol to a decrease in the intake of saturated fat is
greater in men than in women, whereas responses to trans fat and to dietary cholesterol did not differ between men and

M. Marino et al. / Molecular Aspects of Medicine 32 (2011) 170

23

women (Weggemans et al., 1999). On the other hand, the postprandial lipid response is lower in women than in men because
women have a higher clearance capacity, which is related to an increase in lipoprotein lipase activity (Lopez-Miranda et al.,
2007). In addition, estradiol likely promotes a rapid clearance of chylomicron remnants (Lopez-Miranda et al., 2007). After
menopause, the postprandial lipid response changes, indicating that interventions should consider the phase of the womans
life. Altogether, these observations provide clear evidence of how diet can inuence risk factors for cardiovascular diseases,
and additional pieces of data also suggest that this can occur in a sexgender-dependent way.
However, limiting fat cannot be considered as a general rule because the consensus today is that not all fats have a deleterious effect. In fact, some fats appear to exert a benecial effect on human health, such as x-3 fatty acids. A diet that is
rich in x-3 fatty acids is garnering appreciation for supporting cognitive processes in humans and upregulating genes that
are important for maintaining synaptic function and plasticity in rodents. In turn, diets that are high in saturated fat are
becoming notorious for reducing molecular substrates that support cognitive processing and increasing the risk of neurological dysfunction in both humans and animals. Although these studies suggest an important effect of fat on the brain, further
work is necessary to determine the mechanisms of action and the conditions for therapeutic applications in males and females (Gomez-Pinilla, 2008).
Observational ndings suggest that in populations that consume low levels of highly unsaturated fatty acids, women have
higher blood levels of docosahexaenoic acid (DHA) as compared with men and that this difference is independent of dietary
intake (Bakewell et al., 2006; Crowe et al., 2008; Giltay et al., 2004; Nikkari et al., 1995); women have also higher levels of
a-linolenic acid in comparison with men (Bakewell et al., 2006; Burdge et al., 2002; Burdge et al., 2008; Burdge and Wootton,
2002; Crowe et al., 2008; Giltay et al., 2004; Metherel et al., 2009). However, two of these studies indicate that eicosapentaenoic acid (EPA) and docosapentaenoic acid (DPA) are found in lower circulating concentrations in women compared with
men, which may indicate either a greater rate of conversion of these fatty acids into DHA or their displacement from lipids.
The difference could be ascribed to differences in b-oxidation, adipose tissue composition and mobilization, and possible
inuences of sex hormones on the desaturase and elongase enzymes involved in the synthesis of LC n-3 PUFA. In fact,
desaturases and elongases are more elevated in females (Bakewell et al., 2006; Burdge and Wootton, 2002). A role for sex
hormones in mediating the sex differences is conrmed from studies on women using OC or hormone-replacement therapy
(Childs et al., 2008). In particular, OC and hormone-replacement therapy are associated with higher plasma concentrations of
x-3 fatty acids (Childs et al., 2008), suggesting that female sex hormones may up-regulate the synthesis of x-3 fatty acids.
Finally, the importance of sexual hormones has been evidenced by a study on trans-sexuals (Childs et al., 2008). Maleto-female trans-sexuals receiving a combination of oral ethynyl estradiol and cyproterone acetate have higher DHA concentrations in their plasma within 4 months of treatment in comparison with female-to-male trans-sexuals. On the other hand,
female-to-male trans-sexuals receiving intramuscular testosterone have a lower DHA content. Altogether, these studies suggest that estradiol up-regulates, while testosterone down-regulates, the synthesis of DHA from a-linolenic acid.
Importantly, in addition to metabolic functions, lipids exert numerous functions including metabolism signaling, endocrine function, neurotransmission, and inammation. For example, low levels of serum lipids are reported in subjects chronically infected with the hepatitis C virus and are related with poorer clinical outcomes, especially in women older than
50 years of age. No age effect is described for men (Lao et al., 2010). In contrast, in men but not women, a strong negative
association was described between cholesterol and mortality from injuries, mainly caused by suicide attempts (Lindberg
et al., 1992). This is probably related to serotonin because the main metabolite of serotonin in cerebrospinal uid is directly
associated with blood cholesterol in men but not in women (Markianos et al., 2010).
It is important to stress that lipids play a pivotal role in inammation (Latin, inammare, to set on re); this process plays
a central role in many degenerative diseases, such as cardiovascular disease, diabetes, obesity, Alzheimers disease, and cancer (Libby, 2002; Nathan, 2002). The initial phase of the acute inammatory response is characterized by the production of
pro-inammatory agents derived from x-6 fatty acids, especially arachidonic acid (Simopoulos, 2002), followed by a second
phase in which lipid mediators (lipoxins, resolvins, protectins and maresins) with pro-resolution activities may be generated
(Serhan et al., 2009). In this context, EPA and DHA compete with arachidonic acid for binding and conversion by COX and
lipooxygenases (LOX). Through this activity, EPA and DHA modulate the production and bioactivity of prostanoids and leukotrienes (LT). Indeed, eicosanoids can be produced by CYP4A and CYP4F subfamilies, which catalyze the hydroxylation of
arachidonic acid to 19- and 20-hydroxyeicosatetraenoic acids (19- and 20-HETE), whereas the CYP2C and CYP2J enzymes
function as arachidonic acid epoxygenases and produce regioisomeric epoxyeicosatrienoic acids (5,6-, 8,9-, 11,12-, and
14,15-EET) (Capdevila et al., 2000; Zeldin, 2001) (Fig. 5). These eicosanoids are important mediators in the regulation of
vascular, renal, and cardiac functions (McGiff and Quilley, 1999; Roman, 2002), and their formation can be affected by
n-3 PUFA-rich diets. These dietary components may shift the CYP2C-dependent generation of physiologically active eicosanoids from arachidonic acid- to EPA-derived metabolites (Barbosa-Sicard et al., 2005).
EPA and DHA also give rise to mediators that are either anti-inammatory or less inammatory than those mediators that
are produced from arachidonic acid. In particular, when EPA acts as a substrate for COX and LOX enzymes, it gives rise to a
different family of eicosanoids, the 3-series prostaglandins and thromboxanes, the 5-series LT, and hydroxy-EPA. The
eicosanoids derived from EPA are less inammatory or even anti-inammatory compared to eicosanoids derived from
arachidonic acid; DHA can be metabolized to resolvins via LOX-initiated mechanisms (Hong et al., 2003; Radmark and
Samuelsson, 2010; Serhan et al., 2000; Serhan et al., 2002). Resolvins, lipoxins, protectins and maresins are endogenous local
acting mediators that possess potent anti-inammatory and immunoregulatory properties (Ariel and Serhan, 2007;
Bandeira-Melo et al., 2000; Chiang et al., 1999; Claria and Serhan, 1995; Levy et al., 2001; Levy et al., 2007a). 5-LOX seems

24

M. Marino et al. / Molecular Aspects of Medicine 32 (2011) 170

Fig. 5. Arachidonic cascade and possibile sex differences are shown with corsive letters, for more information see texts. COX cicloxygenases, LOX
lipoxygenases, 19- and 20-HETE, 19- and 20-hydroxyeicosatetraenoic acids, 5,6-, 8,9-, 11,12-, and 14,15-(EET), epoxyeicosatrienoic acids, 15 HPETE
hydroxyperoxyeicosatetraenoic acids. For details see the text.

to display sexgender differences because males have substantially lower biosynthetic activity compared with females, and
this seems to depend on testosterone (Pergola et al., 2008). Sexgender differences have also been described regarding phospholipase A2 (PLA2). In particular, females tend to have higher PLA2 activity levels than males (Kuslys et al., 1996). Conversely, the PLA2 associated with lipoprotein is consistently up-regulated in men compared with women (Brilakis et al.,
2008). Finally, platelets obtained from men produce more thromboxane and have more cholesterol in their membranes than
platelets collected from female blood. Interestingly, this occurs in the absence of differences in arachidonic acid conversion
through the COX and LOX pathways or in platelet phospholipid fatty acid composition (Pinto et al., 1990). In men, DHA and
DPA are equally effective in reducing platelet aggregation, whereas EPA is the most effective. In females, all three fatty acids
inhibit platelet aggregation to a similar extent and are more effective than in males (Pinto et al., 1990). In addition to DHA
and DPA, another long-chain x-6 fatty acid has been found in algal oil, which is converted to two major resolvins by soybean
15-LOX (Dangi et al., 2009). No data are currently available about sexgender disparities with respect to this x fatty acid.
Dietary polyunsaturated fatty acids appear to modulate the release of different cytokines (Meydani, 1992). The production
of interleukin-1b, interleukin-6, tumor necrosis factor (TNF)-a, and granulocyte macrophage colony-stimulating factor by
peripheral mononuclear cells is decreased by dietary polyunsaturated fatty acid supplementation in women (Endres
et al., 1989; Meydani, 1992).
In this contest it is important to recall that a growing body of evidence indicates that foods rich in x-3 polyunsaturated
fatty acids, specically EPA and DHA, confer cardioprotective effects through a reduction of triglycerides, a decrease of platelet adhesion, an improvement of endothelial function, decreased vasoconstriction, a decrease of ventricular arrhythmias and
reduced inammation (Breslow, 2006; Leaf et al., 2005). More recently, the mechanisms underlying the interactions that differentially reduce platelet aggregation via sex hormones and x-3 fatty acids have been investigated in more detail (Phang
et al., 2010). Sexgender differences have been described with EPA, DHA, and a-linoleic acid because they reduce the risk of
sudden death, arrhythmia, and fatal ischemic heart diseases, specically in women (Albert et al., 1997; Hu et al., 1999).
Importantly, dietary a-linoleic acid intake is inversely associated with sudden cardiac death in women but not in men
(Mozaffarian et al., 2005). Thus, it is not surprising that the American Heart Association Guidelines include recommendations
to consume (fatty) sh, and the 2007 update states that, as an adjunct to diet of approximately 501000 mg of EPA and DHA
may be considered in women at cardiovascular risk, and higher doses (24 g) may be used to treat women with high triglyceride levels (Mosca et al., 2007). However, several further works have investigated this eld, e.g., works have been published
on the gender differences in the x-3 polyunsaturated fatty acids acid content of tissues (Childs et al., 2008) and on the prevention cardiovascular disease in women (Wenger, 2006).
There is insufcient evidence regarding the effect on body weight because the studies to date have been small, yielding
contradictory results (Awad et al., 1990; Couet et al., 1997; Krebs et al., 2006; Kunesova et al., 2006; Williams et al., 2000).
One study reported enhanced weight loss in women on an energy-restricted diet supplemented with sh oil compared to the
non-supplemented group (Kunesova et al., 2006). Another study found that the addition of fatty sh or sh oil to an energyrestricted diet induced greater weight loss in men but not in women (Thorsdottir et al., 2007). A small but measurable
benet from x-3 polyunsaturated fatty acids has been observed in multiple randomized trials (Yokoyama et al., 2007).
Importantly, sexgender differences have been described. In particular, some ndings suggest that x-3 acids may have a
greater benecial effect in women than in men (Albert et al., 1997; Hu et al., 1999; Mozaffarian et al., 2005; Wenger,

M. Marino et al. / Molecular Aspects of Medicine 32 (2011) 170

25

2006). However, a very recent prospective study suggests an increased risk of type 3 diabetes in women that assume a large
intake of long-chain omega-3 fatty acids (Djousse et al., 2011).
It is evident that we must distinguish among fats because reducing the intake of some types of fats can reduce the risk of
several chronic diseases, whereas other types of fats are absolutely essential for our well-being. Although scarce, the research
suggests that there are relevant sexgender effects on fat homeostasis.
3.1.3. Micronutrients: vitamins and minerals
Micronutrients include iron, cobalt, chromium, copper, iodine, manganese, selenium, zinc, molybdenum, and the different
classes of vitamins. The minimal amounts of minerals and vitamins are provided by dietary guidelines that account for age
and activity level, but these guidelines usually do not consider the specic needs of women other than addressing child-bearing and lactating individuals. Because a diet rich in vitamins is strongly suggested for the prevention of many diseases, it is
important to know if these vitamins display different activities in men and women. To convert physiological requirements
into dietary requirements, adjustments are needed that take into account certain diet- and host-related factors. The dietrelated factors depend on the nature of the habitual diet and may include the chemical form of the nutrient; the nature
of the dietary matrix; and the interactions between nutrients and/or organic components, food preparation and processing
practices. Host-related factors can include gastric secretion and intestinal mobility, which change with age, ethnicity, genotype, and sex.
A discrepancy exists between the results of epidemiological studies and interventional trials. Epidemiological data have
shown a strong inverse relationship between the intake of foods rich in antioxidant vitamins and minerals, or the actual intake of these nutrients, and the risk of cancer and ischemic cardiovascular diseases (Block et al., 1992; Byers and Guerrero,
1995; Hercberg et al., 1998; Kohlmeier and Hastings, 1995; Stampfer and Rimm, 1993; Stampfer and Rimm, 1995). However,
most of published randomized placebo-controlled primary prevention trials have been unable to demonstrate these
potential benecial effects (Blot et al., 1993; Hennekens et al., 1996; Hercberg et al., 2004; Omenn et al., 1996; The
Alpha-Tocopherol-beta-Carotene-Cancer-Prevention-Study-Group, 1994), and two of the larger studies (Omenn et al.,
1996; The Alpha-Tocopherol-beta-Carotene-Cancer-Prevention-Study-Group, 1994) even suggest harmful effects. The seemingly contradictory results between the observational studies and the randomized trials could be explained by the fact that
the doses used in clinical trials are much higher than the highest levels achieved by usual dietary intake. In fact, the two trials
that observed a benecial effect on total mortality and cancer incidence used non-pharmacological doses of a combination
of several vitamins and minerals and found an effect on populations with very low baseline micronutrient statuses, such as
in a Chinese trial (Blot et al., 1993) or in the French Supplementation in Vitamins and Mineral Antioxidants Study SU.VI.MAX
study (Hercberg et al., 2004). Moreover, in the SU.VI.MAX study, the benecial effect was found only in men who had a lower
pre-randomization antioxidant status (for b-carotene and vitamin C) but not in women. However, this primary prevention
trial tested the efcacy of antioxidants in reducing cancer incidence in the general population. The authors found that oral
daily supplementation with a combination of antioxidants (120 mg vitamin C, 30 mg vitamin E, 6 mg b-carotene, 100 lg
selenium, and 20 mg zinc) for a median follow-up time of 7.5 year increased the incidence of melanoma for women but
not men (Hercberg et al., 2007). In a study that used doses comparable to that of SU.VI.MAX with a similar follow-up duration, no association was found between the use of supplemental antioxidants and melanoma risk in both sexes (Asgari et al.,
2009). Moreover, the Nurses Health Study reported no association between intake of vitamins A, C, E, and melanoma risk
among 162,000 women during more than 1.6 million person-years of follow-up (Feskanich et al., 2003). The discrepancy
could also be attributed to the inappropriate selection of patients. Patients characteristics, such as age and gender, can affect
the individual capacity to prevent oxidative stress (Malorni et al., 2007); thus, the study should require not only an enrollment of both sexes but also a sexgender analysis. Very recently, a meta-analysis that assessed the intake of vitamin A, vitamin C, vitamin E, alpha-carotene, beta-carotene, beta-cryptoxanthin, lycopene, lutein, and zeaxanthin in women from foods
and supplements suggested that antioxidant intake is not associated with the risk of developing either rheumatoid arthritis
or systemic lupus (Costenbader et al., 2010). The above results indicate that caution should be used in designing interventional trials and that the availability of baseline information on major potential confounding factors and extrapolating data
obtained from men to women.
3.1.3.1. Folate, B6 and B12.
An apple a day keeps the doctor away. Proverb
Men and women could have different requirements for vitamins, and/or vitamins can have sexgender-specic effects. In
particular, folic acid, which is used in the building of new cells and DNA production (Hankinson et al., 2001), can induce
epigenetic changes by altering the status of methylation-sensitive DNA and proteins (Waterland and Michels, 2007). The
optimal intake of folate and related B vitamins (B6 and B12) may protect against cardiovascular diseases because they have
a homocysteine-lowering effect. Homocysteine, a sulfur-containing amino acid, is a key intermediate in the methylation
cycle and is believed to increase the incidence of cardiovascular diseases (Ridker et al., 1999; Sutton-Tyrrell et al., 1997;
Voutilainen et al., 1998). Its concentrations are determined by many factors, including age and sex; homocysteine levels increase steadily with age and are higher in men than in women (Lussier-Cacan et al., 1996; Nygard et al., 1998). Major lifestyle
determinants of homocysteine in apparently healthy subjects are dietary and plasma folate, vitamins B6 and B12, smoking,
coffee consumption, and physical activity (Jacques et al., 2001). Specically, homocysteine levels in males are signicantly

26

M. Marino et al. / Molecular Aspects of Medicine 32 (2011) 170

associated with interactions between the MTHFR 677C>T genotype and both red blood cell folate and smoking status. In contrast, homocysteine levels in females are only associated with interactions between smoking status and red blood folate.
These results suggest that the biggest risk for developing a high homocysteine phenotype is gender (Stanislawska-Sachadyn
et al., 2008). The relationship between smoking status and homocysteine in females is in line with epidemiological studies
indicating that smoking interferes with estrogen metabolism and that women who smoke are relatively estrogen-decient
(Baron et al., 1990). As previously shown, estrogen decreases plasma homocysteine levels (Morris et al., 2000), and this probably occurs because estrogens inuence methionine catabolism (Blom et al., 1988; Boers et al., 1983). Another possible
mechanism through which estrogen may inuence homocysteine concentration has been suggested by Brown et al.
(2004), who postulated that estrogen-dependent changes in NOS3 activity inuence folate levels (Brown et al., 2003).
To exert its biological effects, folic acid must be transported across cell membranes, and this transport is partially mediated by the reduced folate carrier. Polymorphisms of the gene of reduced folate carrier are not strongly associated with serum folate and homocysteine concentrations in either men or women. However, in women but not in men, these
polymorphisms explained 5% of the variation in red blood cell folate levels. Relative to women with the SLC19A1 c.80GG
genotype, women with the GA and AA genotypes have higher folate concentrations. Consequently, compared to women with
the SLC19A1 c.80GA and AA genotypes, women who are homozygous for the 80G allele may be at increased risk of having a
child affected with a neural tube defect and developing pathologies that are associated with folate insufciency, such as cardiovascular diseases (Stanislawska-Sachadyn et al., 2009). Finally, the gene that encodes folate receptor a is repressed by
estrogen (Kelley et al., 2003) and directly activated by androgen (Sivakumaran et al., 2010).
There is a debate about homocysteines role as a casual cardiovascular risk factor and, conversely, if folate and B vitamins
can exert a cardio-protective effect. Importantly, there is a correlation between hyperhomocysteinemia and premature cardiovascular diseases in males; however, this correlation has not been detected in females (Foody et al., 2000). The 2004
American Heart Association guidelines for cardiovascular disease prevention in women advise folic acid (synthetic form)
supplementation for high-risk women with high levels of homocysteine (Mosca et al., 2004), but this recommendation is
omitted in the 2007 update (Mosca et al., 2007). In fact, much of the excitement around modulating the homocysteine axis
by vitamin B/folate complex has now dissipated following a spate of negative randomized trials (Albert et al., 2008; Bonaa
et al., 2006; Lonn et al., 2006; Mosca et al., 2004). Additionally, the latest meta-analysis of eight large, randomized, placebocontrolled trials regarding folic acid supplementation (0.840 mg/d) in preventing cardiovascular events showed that folic
acid supplementation did lower homocysteine by about of 25%, but this reduction had no signicant effect within 5 years
on cardiovascular events, overall cancer, or mortality (Clarke et al., 2010). The results of this meta-analysis conrm that caution is essential for those who are searching for therapies to prevent disease in the general population. Vitamins taken in
excess of the dose required to prevent deciency states have not improved our patients health and may cause harm; in fact,
there are some concerns regarding the potential risks of chronic exposure to high doses of folic acid (Sauer et al., 2009).
Folate intake is higher in men than in women (de Bree et al., 1997). Currently, it is clear that men need more folic acid
than post-menopausal women, largely because of the higher lean body mass of men (Winkels et al., 2008). Accordingly, folate status is the same or slightly lower in men than in women (Ganji and Kafai, 2006). Pre-menopausal women loose folates
monthly through menstruation, and this could increase their need for folate (Ganji and Kafai, 2006). In most countries, the
recommended dietary allowance (RDA) for folate is the same for men and women, but this value mainly derives from metabolic studies in women (COMA, 1991; Health Council, 2003; Institute of Medicine, 2000). Previously, the RDA for folate in
the US was higher for men (240 mg/d) than for women (190 mg/d) (Herbert, 1987). Importantly, RDA does not consider the
differences induced by specic female conditions and smoking.
Determining whether folate is involved in DNA methylation will require specic sexgender studies spanning all phases
of life.
3.1.3.2. Vitamin C. Ascorbic acid is a water-soluble and versatile physiological antioxidant that quenches reactive oxygen species (ROS) in both the extra- and intracellular compartments, and it is responsible for protein metabolism, including the biosynthesis of collagen, neurotransmitters, and L-carnitine (McGregor and Biesalski, 2006).
Like several other vitamins, namely, vitamin A, vitamin C, vitamin K, thiamine, riboavin, and niacin, and choline, the RDA
are higher for men than for women, and the RDA could partly depend on body weight (Olson, 1987). Vitamin C levels are
much higher in women (Table 4) than in men (Blanchard, 1991; Galan et al., 2005; Hercberg et al., 2004; Institute of
Medicine, 2000), and they seem to be related to body weight in men but not in women (Galan et al., 2005). The aboveobserved differences could be linked to different dietary consumption patterns between sexes and to some lifestyle factors.
For example, smoking and drinking alcoholic beverages, which are more frequent in men than in women, could represent
key factors because lower plasma vitamin C and b-carotene levels have been identied in smokers than in non-smokers
of both sexes (Byers and Guerrero, 1995; Marangon et al., 1998; Mezzetti et al., 1995; Wei et al., 2001).
To date, vitamin C is the only individual micronutrient for which intake has been positively associated with placental
weight at term, although its contribution is small (Mathews et al., 1999) indicating that it is of special interest in females.
High doses of vitamin C are widely used as a supplement throughout the world, but observational studies evaluating vitamin C for the primary prevention of coronary heart disease have found conicting results in women (Cook et al., 2007; Gale
et al., 1995; Osganian et al., 2003). Across multiple large clinical trials, vitamin C supplementation alone or in combination
with vitamin E and b-carotene appears to be ineffective at secondary prevention of cardiovascular diseases in pre- and postmenopausal women (Bjelakovic et al., 2007; Cook et al., 2007; MRC/BHF, 2002; Waters et al., 2002). Finally, vitamin C

M. Marino et al. / Molecular Aspects of Medicine 32 (2011) 170

27

Table 4
Plasma and serum level of different of some micronutrients in women and in men.
Micronutrients

Young M

Young F

Folate
Vitamin B12
Vitamin B6
Vitamin C

/=
=
+/=


+/=a
=
+/=/
+++

+


e
+++

Retinol

a and b

+++


+++

+++


carotene
Vitamin D
a-tocoferol

=, b

/+c
+Infants,
children

Phosphate
Copper
Iron

Old
M

Old
F


+


+
=/+


References
Ganji and Kafai (2006), Lussier-Cacan et al. (1996), Sassi et al. (2002)
Sassi et al. (2002)
Dierkes et al. (2001)
Bates et al. (1999), Bates et al. (1979), Galan et al. (2005), Hercberg et al. (1994), Wallstrom
et al. (2001)
Hallfrisch et al. (1994)
Bates et al. (1999), Curran-Celentano et al. (2001), De Waart et al. (2001), Galan et al. (2005),
Hallfrisch et al. (1994), Wallstrom et al. (2001)
Bates et al. (1999)
Bates et al. (1999), Cavalca et al. (2009), Galan et al. (2005), Hallfrisch et al. (1994),
Wallstrom et al. (2001)
Bates et al. (1999)
Bates et al. (1999), Johnson et al. (1992)
Bates et al. (1999)

Women
Selenium
Zinc

cd


Arnaud et al. (2006), Niskar et al. (2003)


Galan et al. (2005)

M, male, F, female; +, sufcient elevation; ++, modest eleventation; +++, large elevation; , sufcient reduction; ++, modest eleventation; +++, large
reduction; =, no signicant differences.
a
Depends on fertile status.
b
Patients with CAD.
c
is higher in OC users.
d
Lower in OC users.
e
About 50 years.

supplementation alone or in combination with other vitamins in a cohort of women may be associated with a higher risk of
age-related cataracts among women (Rautiainen et al., 2010).
The previous studies indicate that caution should be used when consuming high doses of vitamin C, especially in women.
3.1.3.3. Vitamin A. Vitamin A, also called retinol, is needed for the normal functioning of the visual system, growth and development, maintenance of epidermal cell integrity, immune function and reproduction (Sporn et al., 1994). Free vitamin A and
carotenoids are produced during digestive process. Once ingested, they are converted into retinol, which binds retinolbinding protein, and carotenoids, which bind to lipoproteins, respectively. b-carotene concentrations are much higher in women than in men (Curran-Celentano et al., 2001; De Waart et al., 2001; Galan et al., 2005; Hercberg et al., 1994; Olmedilla
et al., 2002; Wallstrom et al., 2001). These differences could be associated with a different b-carotene consumption in women and men and to some lifestyle factors that are observed more in men than in women, such as drinking alcoholic beverages or smoking, which decrease b-carotene levels (Byers and Guerrero, 1995; Dietrich et al., 2003; Marangon et al., 1998;
Mezzetti et al., 1995; Ross et al., 1995; Wei et al., 2001). Serum b-carotene levels are inuenced by body weight in men but
not in women because they are lower in obese men in comparison with overweight, normal or underweight men, whereas
body weight does not seem to inuence serum values in women (Galan et al., 2005). Importantly, some studies have found
that neonatal vitamin A supplementation may have a benecial effect on mortality in boys but no effect in girls (Benn et al.,
2008; Humphrey et al., 1996; Rahmathullah et al., 2003). However, when a lower dosage of vitamin A is consumed, it may be
benecial among girls (Benn et al., 2005), suggesting that dosage is related to sex. However, a randomized placebo-controlled
trial conducted in HIV-infected mother-infant pairs showed that the benecial effect of multivitamins on decreasing the risk
of low birth weight is stronger among girls than among boys (Kawai et al., 2010). Maternal multivitamin supplements result
in a 32% reduction in mortality among girls, whereas no effect is seen in boys. The above results indicate that an investigation
on the use of vitamin A supplementation in the early life of boys and girls is urgently needed, keeping in mind that it increases the levels of liver glycine N-methyltransferase, a key enzyme in the regulation of S-adenosylmethionine, and that
the S-adenosylmethionine/S-adenosylhomocysteine ratio can interfere with the methylation process. The increase in glycine
N-methyltransferase is sexgender-dependent and is much more effective in males (McMullen et al., 2002).
In addition to the methylation phenomenon, vitamin A, through retinoic acid, can activate pregnane X receptors (Wang
et al., 2008), a nuclear receptor that controls the activity of many metabolic enzymes, including CYP enzymes such as
CYP3A4, which works differently in females and males. In turn, CYP3A4, together with CYP26A1, CYP26B1, and CYP26C1,
is the major retinoic acid-degrading enzyme (Thatcher et al., 2010). These last observations indicate that studying these enzymes in the context of sexgender could be of primary importance in the action of vitamin A, and new research is urgently
required to understand the importance of these processes.
3.1.3.4. Vitamin E. Vitamin E is the major chain-breaking lipid-soluble antioxidant. The term vitamin E refers to a family
of eight naturally occurring homologs that differ in the number and position of methyl groups on the ring structure of

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6-chromanol. The four tocopherol homologs (a, b, c, and d) have a saturated 16-carbon side chain, whereas the four tocotrienol homologs (a, b, c, and d) have three double bonds on the side chain. Good sources of vitamin E are vegetable oils,
nuts and nut oil seeds, egg yolk, margarine, cheese, soya beans, wheat germ, oatmeal, avocado, olives, and green leafy vegetables. Tocopherols are predominant in olive, sunower, corn, and soya beans oils, and tocotrienols are the major vitamin E
components of palm oil, of barley and rice bran (Sookwong et al., 2007; Wang et al., 1993). Women have a faster a-tocopherol disappearance rate than men, and c-tocopherol metabolism proceeds at a faster rate in women than in men (Frank et al.,
2008; Leonard et al., 2005). The x-oxidation of the vitamin E side chain is catalyzed by CYP3A and 4F (Landes et al., 2003;
Sontag and Parker, 2002), and both enzymes are more robustly expressed in females (Kalsotra et al., 2002; Sakuma et al.,
2000; Scandlyn et al., 2008). Vitamin E and A metabolism (Andreola et al., 2004) is controlled by the aryl hydrocarbon receptor, and aryl hydrocarbon receptor-null female mice have higher levels of hepatic c-tocopherol and a-tocopherol than null
males (Traber et al., 2010). These data claim that these sexgender differences should be thoroughly investigated in the near
future because vitamin E metabolism and activity could be regulated through ERb (Comitato et al., 2009).
Going back to the biological properties of vitamin E, there is evidence suggesting a role of vitamin E in cell homeostasis via
its modulation of specic signaling pathways and genes involved in proliferative, metabolic, inammatory, and antioxidant
pathways (Galli and Azzi, 2010). There is epidemiologic evidence for a benecial effect of vitamin E on cardiovascular disease
risk. However, conicting results have been reported in intervention studies that assessed the potential benet of vitamin E
intake on the risk of cardiovascular diseases (Cordero et al., 2010). The discrepancy between the ndings in the observational
and intervention studies could be attributed to inherent difculties in the study of the benecial effects of a-tocopherol but
also to deciencies in the design of the studies performed until now (Cordero et al., 2010; Kirmizis and Chatzidimitriou,
2009). However, it is important to recall precautions regarding the safety of vitamin E, especially at higher doses. There
are concerns about potential harmful effects, such as hemorrhagic stroke (The Alpha-Tocopherol-beta-Carotene-CancerPrevention-Study-Group, 1994) and cancer (Cooney, 2006; Stone et al., 2004).
Therefore, in order to nd appropriate doses for clinical trials, further studies comparing vitamin E metabolism in men
and women are warranted.
3.1.3.5. Vitamin D. Vitamin D is actually a steroid prohormone rather than a vitamin because it can be produced in the human
body through the interaction of sunlight with the skin (the use of a sunscreen with a sun protection factor of 8 or higher will
block the production of vitamin D by about 97.5%) (Misteli, 2010). Nevertheless, this nutrient is commonly characterized as a
vitamin. It is essential for physiological regulation and the stimulation of intestinal absorption of calcium (Misteli, 2010). The
1997, the RDA for vitamin D was 400 IU/d for women ages 5170 and 600 IU/d for women older than age 70. However, these
levels may not be adequate to maintain optimum bone health. In Canada, the recommended intake for women under age 50
is 400 IU/d and 800 IU/d for women over 59 (Misteli, 2010). Classically, vitamin D is pivotal for bone development, growth,
mineralization, and the maintenance of skeletal integrity. The sexgender-specic effect of vitamin D related to bone metabolism is well known and has recently been reviewed (Clarke and Khosla, 2010). Vitamin D deciency (<25 nmol/L) is found in
young women, and 70.6% of pregnant women have low vitamin D levels; the prevalence is even higher in women with gestational diabetes (<12.5 nmol/L) (Maghbooli et al., 2008).
In recent years, an array of evidence suggests that vitamin D status, particularly the level of 25, hydroxyvitamin D, or
25(OH)D, is a critical factor for the pathogenesis of cardiovascular diseases (Kim et al., 2008; Lee et al., 2008). With respect
to cancer, calcitriol (1,25-dihydroxyvitamin D3) inhibits the growth and induces the differentiation of many malignant cells,
including breast cancer, where it induces cell cycle arrest and stimulates apoptosis. Calcitriol suppresses COX-2 expression
and increases that of 15-PGDH, thereby reducing the levels and biological activity of prostaglandins and decreasing the
expression of aromatase, at least in breast cancer cells (Krishnan et al., 2010). Vitamin D has also an immunomodulating
activity and at in least in in multiple sclerosis patients it has bigger in female and it seems to be mediated by estrogens
(Correale et al., 2010)
In conclusion, studies that examine the differential effects of other vitamins from a sexgender perspective are still
scarce. More research is warranted to examine the effect of vitamins from a sexgender perspective and to better understand
the biological mechanisms that mediate such effects. This is urgent in light of the fact that vitamins can stimulate and interact with numerous signaling transduction pathways.
3.1.3.6. Minerals: iron, zinc, selenium, copper, calcium. Iron, by far the most abundant transition metal in the body, is an essential element for the utilization of oxygen. Mammalian cells employ iron and oxygen in processes that are essential for life,
including oxidative phosphorylation, the synthesis of metabolites and cofactors, and posttranslational modications
(Salahudeen and Bruick, 2009). In contrast, excess amounts of iron and oxygen result in cytotoxic oxidative stress
(Salahudeen and Bruick, 2009).
Iron is the single most important element for all mammals, and its deciency causes worldwide health issues even in
apparently healthy humans. Many sexgender differences have been described and recently reviewed (Rushton and Barth,
2010). Some studies point out that sexgender differences in iron status start in infants and pre-pubertal children.
Hemoglobin concentrations are signicantly lower in male infants compared with female infants who have not received iron,
and the prevalence of anemia and iron deciency are signicantly higher in male infants than in female infants. After iron
supplementation, boys and girls achieve similar hemoglobin concentrations (Domellof et al., 2002; Wieringa et al., 2007).
Finally, absorption of some iron salts is higher in prepubertal girls than boys (Woodhead et al., 1991).

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In adults, the situation is different; 2.7% of menstruating women and 5.3% of post-menopausal women present a total
depletion of iron stores. The frequency of iron depletion is 28.1% in women using intrauterine devices but only 13.6% in those
using OC. In menstruating women, three-quarters of anemia cases are related to iron deciency; in contrast, iron depletion
and iron-deciency induced anemia are very rare in men (Rushton and Barth, 2010). This is not surprising because 93% of
menstruating women have dietary iron intakes lower than the recommended dietary allowance; 52.6% consumed less than
two-thirds of the RDA. In post-menopausal women and men, 27.7% and 3.6%, respectively, have dietary intakes lower than
the RDA. The above data provide strong evidence that a negative iron balance prevails in many apparently healthy females,
indicating that womens diets should include foods that are rich in iron with high bioavailability. Judging by the recommended daily intakes found in government and regulatory literature, little has been done to address this situation (Rushton
and Barth, 2010).
Genetic hemochromatosis refers to a group of inherited disorders characterized by excessive dietary iron absorption and
affects more men than women (Janssen and Swinkels, 2009). Additionally, the clinical symptoms usually start later in women than in men, and men accumulate more iron and have a higher incidence of liver injury (Harrison-Findik, 2010). The
liver peptide hepcidin plays a pivotal role in iron homeostasis, and hepcidin expression in the liver is differently expressed
in males and females. Female mice express signicantly higher hepcidin levels in the liver than males (Harrison-Findik,
2010). Repeated blood transfusions, as occurs in b-thalassemia, leads to secondary iron overload. In b-thalassemia, better life
expectancy is found in females; this has been also observed in other hemoglobinopathies (Marsella et al., 2010). The above
observations indicate that sexgender is central to iron homeostasis.
Zinc is an essential trace element for human nutrition and is an integral part of many enzyme systems, including DNA
polymerase complex, whereas selenium is also an essential for humans and is required for the synthesis of selenocysteine,
now known as amino acid 21. To our knowledge, no signicant sexgender difference has been found until now.
The presence of at least 25 selenoproteins in human tissues highlights the importance of selenium in nutrition. The
importance of sexgender in the homeostasis of zinc and selenium is largely unknown; however, serum zinc and serum selenium concentrations are lower in women than in men (Galan et al., 2005; Kafai and Ganji, 2003; Viegas-Crespo et al., 2000)
and have been related to hormonal status (Viegas-Crespo et al., 2000). Additional associations between lower human serum
selenium levels and tobacco smoke, alcohol and OC have been reported (Niskar et al., 2003); thus, it is not known whether
the lower plasma levels in women is a real phenomenon or if it depends on other variables. Changes in selenium levels represent a greater risk factor for cancer in men than in women (Waters et al., 2004). This can be due to sex-based differences in
the metabolism and/or tissue distribution of selenium as well as to sex- or gender-related factors that inuence tumor biology (Waters et al., 2004). A more complete understanding of the mechanisms through which selenium modulates cancer
initiation and progression is essential to optimize dietary selenium supplementation as a cancer preventive strategy in
the clinical practice. A recent report from Australia and New Zealand recommends a dietary intake of 70 lg/d in men and
60 lg/d in women (Department of Health and Ageing, 2006).
Copper is essential for the production of red blood cells and the maintenance of the structure and functioning of the nervous system, where it is a component of numerous enzymes that affect a wide variety of metabolic processes. Copper deciency can result in anemia, neutropenia, skeletal abnormalities, and other clinical manifestations. The biological half-life of
copper ranges from 13 to 33 d, and its absorption is greater in women than in men aged 2059 years; however, its absorption
does not differ in old men and women (Johnson et al., 1992). Plasma copper and ceruloplasmin levels, the major copper-carrying protein in the blood, are signicantly higher in women than in men (Table 4). OC elevates plasma copper and enzymatic ceruloplasmin levels but does not affect copper absorption or its biological half-life in young adult women aged
2039 years (Johnson et al., 1992; Milne and Johnson, 1993).
Calcium is the most abundant mineral in the body, with 99% of calcium located within the bones and teeth. It is also located in body uids and soft tissues. Calcium has two key roles: (1) supporting structural integrity and (2) regulating metabolic function, which is essential for cellular structure; intercellular and intracellular metabolic function; signal
transmission; muscle contractions, including heart muscle; nerve function; enzymatic activity; and normal clotting of blood.
A healthy diet with adequate protein, fruits, and vegetables requires calcium and vitamin D, which stimulates calcium transport across the intestinal cells by inducing the production of a calcium-binding protein (Misteli, 2010). However, credible
evidence that calcium supplements reduce the risk of vertebral, nonvertebral, or hip fractures is lacking (Seeman, 2010).
Alternately, calcium could be decient in the diet, as calcium is generally decient in North American diets because of
the relatively limited, concentrated sources of dietary calcium, and the requirement of a large amount of available calcium
for absorption is the primary factor for calcium availability (Misteli, 2010). Daily calcium intake tends to decline with
advancing age; the intestinal absorption of calcium is reduced in older women relative to young women, and vitamin D deciency contributes to declining calcium absorption. Calcium absorption occurs predominantly in the jejunum and also in the
ileum and colon via active transport and simple passive diffusion. At low calcium intakes, active transport predominates, but
as intake increases, more is absorbed by non-specic pathways. Calcium enters the gut via the bile, via pancreatic secretions
and through desquamated cells in the mucosal lining, and it is also reabsorbed from the ileum and colon; it is lost mainly
through renal excretion. Plasma calcium is tightly maintained at a level of 90105 mg/l, of which approximately 50% is ionized. A series of calciotrophic hormones (parathyroid hormone, 1,25-dihydroxycholecalciferol, calcitonin, sex hormones,
growth hormones, corticosteroids and a variety of locally acting hormones) tightly control plasma calcium levels. Estrogen
deciency also appears to result in an increase in urinary calcium excretion and decrease in intestinal absorption (Misteli,
2010), suggesting a sex gender-effect on calcium homeostasis.

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The data, although fragmentary, suggest that sexgender may regulate mineral homeostasis and functions.
3.2. Plant-derived avonoids
I have given you every plant with seeds on the face of the earth and every tree that has fruit with seeds. This will be your food.
Genesis 1, 29
Natural polyphenols, particularly avonoids, represent a wide class of food components with well-documented biological
activity. These compounds have drawn the attention of many researchers for their ability to prevent several degenerative
diseases in humans. Often referred as to weak estrogens, avonoids were chemically synthesized before the ring structure
of the mammalian steroids was determined in the 1920s and 1930s (Barnes, 2004). They re-emerged from obscurity in
the 1940s in the form of the anti-estrogenic component of red clover, which caused infertility in sheep in Western Australia
(Bennetts et al., 1946). At present, more than 4,000 avonoids have been identied in edible plants (Manach et al., 2004;
Timberlake and Henry, 1986) and are consumed regularly in the human diet (Timberlake and Henry, 1986).
These low molecular weight substances are phenyl-benzopyrones (phenyl-chromones) that possess an assortment of
structures based on a common three-ring nucleus (Middleton et al., 2000) in which primary substituents (e.g., hydroxyl,
methoxyl, and glycosyl groups) can be further substituted (e.g., additionally glycosylated or acylated) to yield highly complex structures (Cheynier, 2005). Flavonoids have been categorized into six subclasses based on the type of heterocycle involved: avonols, avones, avanols, avanonols, avanones, and isoavones (Birt et al., 2001; Manach et al., 2004).
Epidemiological evidence has indicated that adult human diets rich in avonoids lead to signicantly decreased serum concentrations of total cholesterol, LDL, and triglycerides (Kirk et al., 1998; Ricketts et al., 2005) as well as to a reduced incidence
of cardiovascular diseases (Cassidy et al., 2000; Hertog et al., 1997) and osteoporosis (Dang and Lowik, 2005). These effects,
recognized as estrogen-mimetic effects, are currently being explored to prevent osteoporosis (Dang and Lowik, 2005;
Mikkola and Clarkson, 2002), reduce the risk of coronary artery disease (Kris-Etherton et al., 2002; Middleton et al.,
2000), and prevent the estrogen deciency-related vasomotor ushing in women during menopause (Fitzpatrick, 2003;
Mikkola and Clarkson, 2002). In addition, avonoids induce responses consistent with the protective effects of fruit- and vegetable-rich diets against cancer in both in vitro test systems and small animal models (Birt et al., 2001; Brownson et al., 2002;
Gamet-Payrastre et al., 1999; Hollman et al., 1996; Keinan-Boker et al., 2004). As a result of all these potentially benecial
effects, a huge number of preparations are now commercially available on the market as health food products. As dietary
supplements, they are obtainable as plant extracts or mixtures and contain varying amounts of isolated or concentrated
avonoids in bakery products, dairy, and infant formulas (Tomar and Shiao, 2008). The commercial success of these supplements is evident, and the consumption of these compounds in Western countries is increasing even though the clinical studies with polyphenols include a small number of subjects and their mechanisms of action are not well understood, raising
some concern about avonoid efcacy and safety.
Plant avonoid metabolism and composition are highly variable both qualitatively and quantitatively. Some of the compounds are ubiquitous, whereas others are restricted to specic families or species (e.g., isoavones in legumes). In most
cases, foods contain complex mixtures of polyphenols, which are often poorly characterized. Several factors affect the avonoid content of plants, including ripeness at the time of harvest, environmental factors, processing, and storage (Cheynier,
2005; Manach et al., 2004). Once eaten, avonoids enter a complex pathway of bio-transformation, so the molecular forms
that reach the peripheral circulation and tissues are usually different from those present in foods (Manach et al., 2004). Ring
scission occurs under the inuence of intestinal microorganisms, which also account for the subsequent demethylation and
dehydroxylation of the resulting phenolic acids (cinnamic acid derivatives and simple phenols). Intestinal bacteria also possess glycosidases capable of cleaving sugar residues from avonoid glycosides. Such glycosidases do not appear to exist in
mammalian tissues. Flavonoids can undergo oxidation and reduction reactions as well as methylation, glucuronidation,
and sulfation in animal species (Middleton et al., 2000). During the course of absorption, polyphenols are conjugated in
the small intestine and, later, in the liver (Birt et al., 2001; Hollman and Katan, 1999; Manach et al., 2004). These glucuronide
and sulfate conjugates are more readily transported in the blood and excreted in bile or urine than are the parent aglycones.
The spectrum of conjugation products may be species- and gender-dependent, and these metabolites are not necessarily biologically inert. Their solubility, the metabolic fate of compounds due to endogenous and exogenous biotransformation, and
their interactions with other dietary components determine avonoid bioavailability (Hendrich et al., 1999) and effects. Bioavailability differs greatly from one polyphenol to another, so the most abundant polyphenols in our diet are not necessarily
those leading to the highest concentrations of active metabolites in target tissues. The metabolites present in blood, resulting
from digestive and hepatic activity usually differ from the native compounds. The plasma concentrations of total avonoid
metabolites range from 0 M to 4  106 M with an intake of 50 mg aglycone equivalents, and the relative urinary excretion
ranged from 0.3% to 43% of the ingested dose, depending on the polyphenol. Gallic acid and isoavones are the most wellabsorbed polyphenols, followed by catechins, avanones, and quercetin glucosides. The most poorly absorbed polyphenols
are the proanthocyanidins, the galloylated tea catechins, and the anthocyanins (Manach et al., 2004). As a consequence, the
maximum concentration of avonoids reached in the circulation ranges from 107 M to 105 M (Manach et al., 2004).
Among the huge number of avonoids, the most studied and well characterized are the avonol quercetin and soy isoavones, such as genistein or daidzein. Traditional soy foods are generally recognized as safe, and the cardiovascular benets
of soy consumption have been sufciently substantiated to warrant approval as a health claim by the Food and Drug

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31

Administration (FDA, 1999). However, the safety and efcacy of many soy and soy isoavone supplements have not been
fully evaluated, and both the potential risks and potential benets remain unclear. Flavonols, especially quercetin, have
extensively been studied, mainly because of their wide distribution in dietary plants and their excellent antioxidant activity
(Haenen and Bast, 1999; Hanasaki et al., 1994; Terao, 2009) (see also Section 7.3.2.2). However, quercetin content in the diet
is generally quite low (Hertog et al., 1993; Justesen et al., 1997; Manach et al., 2004; Pietta et al., 1996; Sampson et al., 2002),
and it is not present in plants as an aglycone. Thus, it is normally present in its conjugated forms (e.g., glycosides). As a consequence, baseline quercetin aglycon concentrations are generally low (from 5  108 M to 8  108 M) (Erlund et al., 2002;
Noroozi et al., 2000). Quercetin aglycon maximum plasma concentrations reach 0.6 1061.5  106 M after 28 d of
supplementation with high doses of quercetin (from 0.8 g/d to 1 g/d) (Conquer et al., 1998; Moon et al., 2000). Hence, the
quercetin plasma concentration appears to be too low in vivo to exert the same effects described in vitro.
Isoavones are the most well-absorbed polyphenols (Manach et al., 2004), but these compounds are provided only by
soybean-derived products and thus are only typical of an Asiatic diet. Furthermore, in some cases, isoavone metabolites
(e.g., equol) have been shown to be more active than its precursor (e.g., daidzein) in many in vitro studies and animal models
(Manach et al., 2004). Because a great inter-individual variability in the capacity to produce equol exists and only 3040% of
the Western population can produce equol (Manach et al., 2004), only equol producers are susceptible to the action of this
compound. The biological activity of avonoid metabolites has received little attention, and only a few papers have reported
the effects of such compounds (Totta et al., 2005). Furthermore, no clear correlations between dietary habits or microora
composition and the capacity to produce avonoid metabolites have been reported (Manach et al., 2004). Intriguingly, avanones, which represent a small group of compounds mainly present in plants in their glycosidic form, are more rapidly absorbed as aglycones. In an elegant paper, Bugianesi et al. (2002) showed that peak plasma concentrations of naringenin
aglycone (a 400 ,5,7-trihydroxyavanone widely present in citrus fruits and skin tomato) were reached as early as 2 h after
the ingestion of tomato paste.
3.3. A debate: alcoholic beverages in women and men
Alcohol abuse is twice as common in men as in women and is associated with several of the other leading causes of death
in men: suicide, homicide, and unintentional accidents/injuries (Collins et al., 2009). Notably, sexgender differences in alcohol consumption are found everywhere in the world to such an extent that they can be considered universal. For instance,
men are less often abstainers, consume more alcohol and cause more problems by so doing (Jrvinen and Olafsdottir, 1989;
Wilsnack et al., 2000); women have a higher risk of developing problems from alcohol consumption because they are more
susceptible to alcohol-related organ damage, including breast cancer and osteoporosis (National Cancer Institute, 2002; NHI,
1999). Men and women have different ethanol metabolism and distribution (Baraona et al., 2001). In fact, the gastric form of
alcohol dehydrogenase is less concentrated in women than in men (Frezza et al., 1990). Furthermore, men and women have
different ethanol distribution (higher plasma level of ethanol) because women proportionally have more body fat and less
water than men of the same body weights (Frezza et al., 1990; Taylor et al., 1996). That is, women develop damage at lower
levels of consumption over a shorter period of time. Alcohol abuse is a separate concern that will not be discussed in detail in
this article, but there is also accumulating scientic evidence indicating that light to moderate drinking done on a daily basis
may signicantly reduce the risks of coronary heart disease and all-cause mortality.
The benecial effects of alcoholic beverages are dependent on the amount of alcohol consumed and the pattern of drinking. The relationship between alcohol consumption and the risk of cardiovascular diseases is described by a J-shaped curve,
where light to moderate drinkers have less risk than abstainers, and heavy drinkers are at the highest risk because increased
alcohol consumption is associated with increased risk of hemorrhagic stroke (Mukamal, 2007). A meta-analysis of over 1
million individuals show that consumption of 1 drink daily by women and 1 or 2 drinks daily by men is associated with
a reduction in total mortality of 18% (Di Castelnuovo et al., 2006) versus abstainers. Among women, the risk of cardiovascular
diseases is decreased upon the consumption of up to 31 g alcohol per d, whereas a decreased risk was observed upon consumption of up to 87 g alcohol per d for men (Corrao et al., 2000). Accordingly, a large Danish cohort study suggests that
drinking frequency is a more important determinant among men than in women (Tolstrup et al., 2006). However, intakes
of >2 drinks daily in women and >3 drinks daily in men are associated with increased mortality in a dose-dependent fashion
(Di Castelnuovo et al., 2006). In fact, moderate alcohol consumption is particularly associated with a decreased risk of cardiovascular diseases, whereas only light alcohol consumption may be associated with a slightly reduced risk of ischemic
stroke (Mukamal, 2007). Altogether, these data suggest that the use of alcoholic beverages can affect the health of women
and men in a sexgender specic manner (US Department of Health and Human Services Alcohol Alert, 2004).
The basis of benecial effect of ethanol beverages are still unclear, but existing results suggest that light to moderate
alcohol consumption protects against cardiovascular diseases mainly through the elevation of HDL (Gaziano et al., 1993;
Mukamal et al., 2005). As reported above, some studies indicate that HDL will rise about 5% with 1 drink per day and
10% with 23 drinks per day (Davies et al., 2002; Greeneld et al., 2005; Mukamal, 2007; Mukamal et al., 2005). Looking
at the results of a meta-analysis that summarized the results of 42 small-scale intervention studies with alcohol (Rimm
et al., 1999), the increment of HDL-cholesterol per gram of alcohol is larger among men than among women, although only
3 out of 61 data records for women were included. In addition, for other lipoprotein fractions, different effects have been also
observed. Among men, triglycerides increase signicantly with each gram increment of alcohol consumption, but such an
effect has not been described for women. Indeed, other studies among post-menopausal women reported that moderate

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alcohol consumption decreases concentrations of LDL and triglycerides while among men such effects have not been observed (Baer et al., 2002; van der Gaag et al., 2000). Another plausible mechanism for the benecial effect of alcohol is
the enhancement of insulin sensitivity. Consuming a moderate amount of alcohol increases insulin sensitivity and glucose
metabolism for the ensuing 1224 h (Greeneld et al., 2005; Turner et al., 2001). Thus, the 2007 American Diabetic Association guidelines state, In individuals with diabetes, light to moderate alcohol intake (1 or 2 drinks per day; 1530 g alcohol)
is associated with a decreased risk of cardiovascular disease, which does not appear to be due to an increase in HDL cholesterol (American Diabetes Association, 2006).
The effect of ethanol on insulin sensitivity seems to be sexgender specic because two trials observed a signicant increase in insulin sensitivity after moderate alcohol consumption in post-menopausal women (Davies et al., 2002; Joosten
et al., 2008), whereas the effect on insulin sensitivity was undetectable in men (Beulens et al., 2008; Beulens et al., 2006;
Beulens et al., 2007; Cordain et al., 1997; Cordain et al., 2000; Zilkens et al., 2003). The biological mechanism through which
alcohol improves insulin sensitivity appears to involve the suppression of fatty acid release from adipose tissue (Greeneld
et al., 2005), a tissue that presents notable gender differences (see Chapter 2). Finally, alcohol consumption patterns and the
type of alcoholic beverage consumed could also affect the benecial effect of cardiovascular disease prevention, and this can
occur in a sexgender specic way.
An increased risk of breast cancer (about 9%) is induced by alcohol consumption in women, and each alcoholic drink per
day could be relevant (Smith-Warner et al., 1998); this must also to be taken into account before stating a recommended
intake for women.
Maternal alcohol use during pregnancy contributes to develop fetal alcohol syndrome and a wide range of effects on exposed offspring, including hyperactivity and attention problems, learning and memory decits, and problems with social and
emotional development (Department of Health and Human Services, 1981).
Specic randomized trials with alcohol have not been performed, and residual unmeasured confounding factors could
play a role in the benets associated with light to moderate drinking in observational studies (Jackson et al., 2005; Thun
et al., 1997). Awaiting for more solid studies and taking into account some important guidelines (American Diabetes
Association, 2006; Ellison, 2005), it seems necessary to adopt a more prudent approach in suggesting a moderate use of alcoholic beverages, especially for women.

4. Special cases
4.1. Cancer
The close relationship between diet and cancer is suggested by the large variation in rates of specic cancers in different
countries and by the striking changes observed in the incidence of cancer in migrating populations (Beliveau and Gingras,
2007; Willett, 2000). These observations are strengthened by experimental data obtained from studies using cellular and
animal models (Beliveau and Gingras, 2007; Espin et al., 2007; Fenton and Hord, 2004).
The chemopreventive activity of plant-based food may be associated with the ability of certain food constituents to block
the progression of latent microtumors (Beliveau and Gingras, 2007). This effect could be elicited via the modulation of the
enzymatic systems responsible for neutralizing free radicals (Conney, 2003; Ioannides and Lewis, 2004) and/or by directly
inducing cancer cell death by apoptosis (see Chapter 7). For example, phenethyl isothiocyanate from cruciferous vegetables,
curcumin from turmeric, resveratrol from grapes, and naringenin from grapefruit all possess strong pro-apoptotic activity
against cells isolated from a variety of tumors (Karunagaran et al., 2005; Totta et al., 2004; Totta et al., 2005).
However, avonoids have variable effects on different types of cancer (Adlercreutz et al., 2004; Boccardo et al., 2006).
Epidemiological, animal and cell culture studies have demonstrated that soy-derived isoavones, rye bran, or isolated lignans may play a protective role (Adlercreutz, 2002; Kurahashi et al., 2007; Verheus et al., 2007). Moreover, soy-derived
isoavones could be more benecial against cancer if consumed before puberty or during adolescence or at very high doses
(Adlercreutz, 2002; Moutsatsou, 2007; Peeters et al., 2003). Similarly, high vitamin E intake has been proposed to reduce the
risk of some forms of cancer, including prostate and colon cancer (Cooney, 2006; Stone et al., 2004). Studies based on animal
and cell cultures have demonstrated that specic avonoids, such as genistein and resveratrol, may have diverse effects on
cancer growth, inhibiting cell proliferation but also stimulating tissue growth (e.g., uterine and breast cancers), depending on
the dose and the exposure duration (Day et al., 2000; Messina et al., 2006).
The importance of diet in cancer prevention has been conrmed, and the WCRF/AICR Second Expert Report made these
ten recommendations for cancer prevention:








Be as lean as possible without becoming underweight.


Be physically active for at least thirty minutes every day.
Avoid sugary drinks. Limit consumption of energy-dense foods.
Eat a variety of vegetables, fruits, whole grains and legumes such as beans.
Limit consumption of red meats (such as beef, pork and lamb) and avoid processed meats.
If consumed at all, limit daily alcoholic drinks to 2 for men and 1 for women.
Limit consumption of salty foods and foods processed with salt (sodium).

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33

 Do not use supplements to protect against cancer.


 It is best for mothers to breastfeed exclusively for up to 6 months and then add other liquids and foods.
 After treatment, cancer survivors should follow the recommendations for cancer prevention.
These recommendations were published in 2007 and remain valid. However, whether diet has sexgender specic effects
in cancer prevention remains a matter of debate. Only some episodic sexgender specic effects have been described. For
example, casecontrol and prospective studies have shown that colon cancer is consistently associated with an excess of
body weight (or BMI), and this association is stronger for men than for women (Chan and Giovannucci, 2010). For rectal cancer, an association with body weight is also observed for men but not for women, although to a lesser extent than for colon
cancer. In a separate meta-analysis of prospective studies, the colon cancer risk was higher when waist circumference was
increased (about 33% increased risk in men and 16% increased risk in women per 10-cm increment in waist circumference)
(Chan and Giovannucci, 2010). A cohort study based on serum fatty acid measurements (Kojima et al., 2005) showed that
linoleic acid signicantly decreased the risk of colon cancer in men but not in women
In the EPIC study, an increase of glycated hemoglobin was associated with a modestly increased risk of colorectal cancer
in women but not in men (Young and Le Leu, 2004). Recent data from a large prospective US cohort suggest either a weak or
non-existent association, with a possible differential effect according to sex with x-3 fatty acids: intake of marine n-3 fatty
acids is not associated with colorectal cancer risk among men, but it is partially associated with lower risk among women
(Daniel et al., 2009). This benet is attenuated after adjustment for other risk factors (Daniel et al., 2009), so additional potential sex differences have also been suggested (Geelen et al., 2007).
Regarding folic acid, two of the earliest epidemiological papers put forth a hypothesis that men may benet from folate
more than women in preventing colorectal neoplasia (Du et al., 2010). Colorectal cancer is more common in men than women, and the difference is more striking among pre-menopausal women and age-matched men (DeCosse et al., 1993; Guo
et al., 2004; Wong et al., 2005). The possible estrogen-induced molecular mechanisms underlying these effects are beginning
to be claried (Caiazza et al., 2007; Galluzzo et al., 2007; Marino and Ascenzi, 2008).
A further point concerns ber. A higher ber intake has been hypothesized to reduce the risk of colorectal cancer in men
and women. However, when lifestyle and dietary factors were taken into account, the association remained signicant in
men but not in women (Du et al., 2010). These results on ber are in line with the results of Jacobs et al. (2006), which indicate that men may experience more benet from dietary ber than women.
Further sexgender differences have been described relative to red meat. Women who rapidly acetylate meat-associated
carcinogens have a particularly high risk of colorectal cancer. In contrast, women who are slow acetylators do not have a
signicantly higher risk of cancer with increased red meat intake (Chan and Giovannucci, 2010). More research is indispensable in this eld.
Cancer-associated malnutrition must also be considered. Malnutrition can be the result of the local effects of a tumor, the
host response to the tumor and anticancer therapies (Arends, 2010). Cancer patients often undergo a reduced food intake
(due to systemic effects of the disease, local tumor effects, psychological effects or adverse effects of treatment), and alterations in nutrient metabolism and energy expenditure may also contribute to changes in the nutritional status of cancer patients (Arends, 2010). The consequences of malnutrition are multiple and include a reduction of chemotherapy efcacy and
an increase in chemotherapy-induced toxicity, with drug adverse reactions being more frequent and severe. Malnutrition
can also modify the pharmacokinetics of drugs (Oshikoya et al., 2010). In addition, cancer-related malnutrition is associated
with signicant health care-related costs. Nutritional support that addresses the specic needs of this patient group is required to help to improve prognosis and reduce the consequences of cancer-associated nutritional decline. Additionally, this
aspect should be viewed through gender glasses because of the important metabolic differences that exist between men
and women. Conversely, the hypothesis that certain dietary regimens could exert a cancer prevention activity has also been
considered. For instance, very recently, caloric restriction has been suggested to have a potential preventive activity on cancer onset via a complex framework of metabolic pathways (Fontana et al., 2010; Longo and Fontana, 2010). However,
although intriguing, this hypothesis is still theoretical, inapplicable and under debate in the literature because of concerns
about iatrogenic diseases, such as mood disturbances or immune system alterations. In any case, possible gender differences regarding this issue need to be analyzed.
4.2. Obesity, diabetes mellitus and cardiovascular disease prevention in women and men
Persons who are naturally very fat are apt to die earlier than those who are slender. Aphorisms II: 44 Hippocrates
A complete discussion about this matter is largely beyond the scope of this paper, which is focused on sexgender differences. The prevalence of obesity is rising rapidly (WHO, 2007). The worldwide increase of obesity represents a key factor
for the rise of glucose intolerance and also represents a major determinant in the development of diabetes mellitus. Approximately 250 million people are affected by diabetes mellitus worldwide, and the prevalence rate will undergo a further
marked increase during the next decades (International Diabetes Federation, 2006). Obesity and diabetes mellitus are considered important risk factors for cardiovascular diseases and are known as sexgender-associated diseases (Mosca et al.,
2007). In this context, numerous female conditions may induce extra cardiovascular risks, such as pregnancy-related diseases (gestational diabetes, pre-eclampsia), polycystic ovarian syndrome and the post-menopausal state.

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A WHO report (WHO, 2007) shows comparable rates of overweight persons between both sexes in Europe, but obesity, as
dened by BMI, ranges from 7% to 36% in women and 5% to 23% in men. What is clear is that in both genders, particularly in
women, the increased risk of dibates mellitus becomes clearly relevant when BMI rises above 30. One study has pointed to a
difference between older and younger women. Younger women displayed a 10% increased risk for each BMI point elevation,
whereas in women aged over 50, the increased risk was very low (2%). Men, on the other hand, have a more linear and constant relationship between mortality and BMI. This may also be due to different storage patterns between men and women,
with men usually developing central obesity with large amounts of intra-abdominal fat (Pischon et al., 2008). Men also show
a clear association between increasing BMI and coronary disease mortality. In women, this correlation has been more difcult to establish (Jousilahti et al., 1999). Independent of the BMI, a waist circumference >102 cm in men and >89 cm in women (highest quintile) is associated with a signicantly increased mortality risk (+33% in men and +28% in women).
Abdominal obesity has been reported as a predictive marker of mortality in normal as well as overweight men and women
(Pischon et al., 2008).
Obesity seems to be a more relevant risk factor for diabetes in women than in men, although men predominantly feature
visceral adiposity, which is associated with a higher risk of developing atherosclerosis (Blouin et al., 2008). Weight gain in men
is related to liver enzymes, whereas inammatory parameters only rise in women, supporting the concept that weight gain
triggers clusters of changes in cardiovascular risk factors in a sex-dependent manner (Berrahmoune et al., 2008). Even changes
in glucose concentrations are associated with an increased risk of early atherosclerosis in women (Ford et al., 2008; Huxley
et al., 2006). There is no evident sex-related difference in the prevalence of diabetes, but the number of women with diabetes
(+10%) and its precursor impaired glucose tolerance (+20%) is higher than in men, especially in elderly women, who more often feature isolated impaired fasting glucose (DECODE Study Group, 2003; Legato et al., 2006; Williams et al., 2003). Men, on
the other hand, have a higher prevalence of impaired fasting glucose (Legato et al., 2006). Sex differences are also shown in
diagnostic tests, for example, the greater convenience of measuring fasting blood glucose has to be weighed against its lower
sensitivity to detect pre-diabetes or diabetes in women, particularly those women with a history of gestational diabetes
(Legato et al., 2006). The prevalence of isolated impaired glucose tolerance is higher in women than in men, whereas the prevalence of isolated impaired fasting glycemia is higher in men than in women (Sicree et al., 2008; Tripathy et al., 2000). This
could be linked to differences in body size (Janghorbani and Amini, 2008; Rathmann et al., 2008; Sicree et al., 2008). The same
amount of glucose (75 g) is usually given to men and women during a standard oral glucose tolerance test. Indeed, women are
generally shorter and have a smaller body size and a smaller absolute amount of fat-free mass than men. They may thus be less
able to metabolize the xed amount of glucose. This notion is supported by the observation of a higher risk of developing type
2 diabetes in men than in women with isolated impaired glucose tolerance (Magliano et al., 2008). This suggests that women
with isolated impaired glucose tolerance may be healthier than their male counterparts. Moreover, women are more commonly diagnosed with diabetes on the basis of a 2 h post-OGTT, and plasma glucose levels are compared with fasting plasma
glucose levels (Williams et al., 2003), and the risk of gestational diabetes is greater in shorter compared with taller women
(Anastasiou et al., 1998). A recent Danish study (Faerch et al., 2010) showed that the higher plasma fasting glucose and glycosylated hemoglobin levels observed in men compared with women are not related to differences in anthropometry but
rather reect differences in insulin sensitivity and b-cell function. In contrast, the higher 2 h post-OGTT plasma glucose levels
observed in women compared with men may be sustained by different body sizes and body compositions, and the differences
disappear when the glucose amount is adjusted on the basis of anthropometric characteristic of the individuals.
These observations conrm that until now, diabetes mellitus has been seen with a male-oriented bias. To overlap humans with men appears must be re-considered: at least from a biomedical point of view, the human race comprises both
women and men, and further efforts should be made for a reappraisal of this issue. Women with diabetes show a greater
increase of risk of cardiovascular diseases and a higher mortality than men (Legato et al., 2006).
As previously mentioned, little information is available regarding sexgender differences in nutrient requirements. Energy requirements are usually based on both gender and body size. Recently, some food groups and supplements have been
recommended for preventing coronary heart disease in women (Eilat-Adar and Goldbourt, 2010). However, only a few points
have been investigated as concerns the sexgender-specic nutrient issue. Clear gender differences exist with regard to iron
metabolism and calcium homeostasis. Specically, because of menstrual blood loss, women have a higher dietary iron
requirement than men, and bone loss and osteoporosis are obvious nutrition-related concerns for womens health.
Maintaining a healthy body weight for height is widely recognized a critical part of any overall risk-reduction strategy.
However, the effect of diet quality on weight change relative to other body weight determinants is insufciently understood,
and it has been rarely considered from a sexgender point of view. Although it is not uncommon to observe greater weight
loss in men than in women, this could be due to the greater initial body weight or to a greater degree of caloric restriction,
rather than an inherent specic sexgender disparity (Lovejoy and Sainsbury, 2009). Furthermore, age and physical activity
among women as well as weight uctuation and smoking status in men are stronger predictors of weight change than diet
quality, at least among American adults (Kimokoti et al., 2010). As discussed above, physical exercise may be less effective as
an approach to weight loss in women than in men (Lovejoy and Sainsbury, 2009). However, exercise is clearly associated
with a linear reduction of risk in women. The magnitude of this reduction comparing the lowest and the highest quintile
for exercise is approximately 50% (Manson et al., 2002). Interestingly, the relationship and the magnitude of the relationship
are nearly as great for those undertaking regular brisk walking as for those undertaking regular vigorous exercise (Manson
et al., 2002). However, several recent studies show that exposure to exercise training programs with ad libitum diet does
cause loss of body fat in men but is far less effective in women (Donnelly et al., 2003; Potteiger et al., 2003), and the

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association between a sedentary lifestyle and cardiac risk is stronger in women than in men (Manson et al., 2002). Nonetheless, some studies do suggest that females lose less weight with a comparable degree of energy restriction than males, even
after matching for initial body weight (Sartorio et al., 2005). Women also lose less weight than men after bariatric surgery
(Tymitz et al., 2007). Furthermore, studies consistently nd that men lose more abdominal, visceral fat during weight loss
than women (Janssen and Ross, 1999; Wirth and Steinmetz, 1998), an effect also seen in mice subjected to caloric restriction
or lipectomy (Shi et al., 2007). Post-menopausal women lose less visceral fat during weight reduction than pre-menopausal
women (Park and Lee, 2003), a nding that is likely related to the important role of estrogen in regulating abdominal fat
stores in women. Surprisingly, the rst randomized clinical trial to look specically at use of the Mediterranean diet for
the prevention of diabetes among nondiabetic subjects at high cardiovascular risk halved the incidence of new-onset diabetes over 4 years compared with a low-fat diet, and this occurs in the absence of signicant changes in body weight or physical activity (Salas-Salvado et al., 2011 ). Of special interest is the fact that the risk reduction was obtained in the absence of
weight loss, which was identied as a cause of risk reduction in the Diabetes Prevention Program (Knowler et al., 2002), indicating that one can reduce his/her risk without weight loss by changing the foods one eats. A non-energy-restricted traditional Mediterranean diet, which includes low glycemic-load carbohydrates; high levels of unsaturated fat; a high amount of
antioxidants in the form of a widely varied mix of fruits and vegetables; and whole, minimally processed foods and legumes,
nuts, and lean proteins, especially sh, could be a useful tool for preventing diabetes and also reducing postprandial elevation of blood sugar and serum lipids (Mente, 2009; OKeefe et al., 2008).
With regard to the long-term regulation of body weight and energy balance, some studies have suggested that meal
frequency may play an important role. For example, population studies have suggested that consuming more frequent
but smaller meals may be associated with lower body weight (Ma et al., 2003). It appears, however, that the effect of meal
frequency on the regulation of energy balance differs between men and women. Carefully controlled studies have found that,
although the relationship between increased meal frequency and reduced appetite/body weight is strong in men, it is absent
in women (Drummond et al., 1998; Westerterp-Plantenga et al., 2003). These data imply that adopting the strategy of
consuming more frequent small meals throughout the day may be effective for weight regulation in men but could be less
effective in women (Lovejoy and Sainsbury, 2009). Further research is needed, however, to determine whether this epidemiological observation can be translated into clinical interventions.
The relationship between dietary factors and coronary heart disease has been a major focus of health research for almost
half a century. More recently, prospective cohort studies and randomized controlled trials have examined these associations
in large populations with long follow-up periods. However, the results of cohort studies and randomized controlled trials can
have discrepancies (e.g., vitamin E and b-carotene intake) (Mente, 2009). The results of some randomized controlled trials of
dietary supplements paradoxically revealed adverse effects on cardiovascular diseases for certain nutrients that exert protective effects in cohort studies (Ness, 2001; Rapola et al., 1997; The Alpha-Tocopherol-beta-Carotene-Cancer-Prevention-StudyGroup, 1994; Yusuf et al., 2000). This generates confusion among health care providers, policy makers, and the population.
Before declaring that specic dietary factors should be used in large or minimal amounts, it is necessary to have the best available scientic evidence either for men or women. Last year, Mente and co-workers (Mente, 2009) made a systematic revision
of the literature examining the association between nutrient consumption, dietary components, and dietary patterns and cardiovascular and related clinical outcomes applying Bradford Hill criteria. In applying the previous algorithm, strong evidence
supports a valid association between the intake of protective factors (vegetables, nuts, and monounsaturated fatty acids) and
Mediterranean diet. Less important evidence support a valid association with high-quality dietary patterns, and harmful factors, including the intake of trans-fatty acids and foods with a high glycemic index or load and cardiovascular diseases and
related clinical outcomes (Mente, 2009). Finally, moderate evidence exists for consumption of sh, marine x-3 fatty acids,
folate, whole grains, dietary vitamins E and C and b-carotene, alcohol, fruits, and ber cardiovascular diseases and related clinical outcomes. Insufcient evidence has been presented for intake of supplementary vitamin E and C, saturated and polyunsaturated fatty acids, total fat, a-linolenic acid, meat, eggs, and milk and cardiovascular diseases and related clinical outcomes
(Mente, 2009). When only high-quality studies are considered, strong evidence is present for monounsaturated fatty acids.
However, only a Mediterranean dietary pattern has been studied in randomized controlled trials and signicantly associated
with cardiovascular diseases. A 10- year follow-up study indicated that the Mediterranean diet decreases mortality resulting
from cardiovascular diseases and cancer in both older men and women (Knoops et al., 2004). However, a valid association has
found been only for a limited number of dietary factors and dietary patterns with cardiovascular diseases.

5. Conditions specic to women


5.1. Inuence of oral contraceptives and hormonal replacement therapy on nutrition
OC is widely used worldwide. Since 1945, 80% of women born in the United States have used OC (Blackburn et al., 2000),
and its use is still increasing, especially in more developed countries (Population Reference Bureau, 2008). Estrogen and progestin associations are also widely used as hormonal replacement therapy in post-menopausal women, although their use
has greatly decreased in recent years (Usher et al., 2006).
The estrogenprogestin association may modify either CYP or P-glycoprotein activities (Frohlich et al., 2004). P-glycoprotein activity can be also inhibited by progestin alone and testosterone (Bebawy and Chetty, 2009), whereas it can be induced

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by natural and synthetic estrogens (Bebawy and Chetty, 2009). P-glycoprotein, like CYP, is vulnerable to inhibition, activation, or induction by food constituents. For examples, curcumin, ginsenosides, piperine, and some catechins in green tea such
as () epicatechin, can promote the overall effective function of P-glycoprotein mediated efux, whereas silymarin from milk
thistle inhibits P-glycoprotein (Zhou et al., 2004).
Moreover, some food and beverage components regulate the expression and function of CYP genes, which impact xenobiotic elimination and may also signicantly affect disease pathogenesis (Murray, 2006). Dietary components may regulate
the CYP enzyme by the direct activation of transcription factors or by the indirect modulation of signal transduction pathways (Murray, 2007). For example, dietary lipid directly activates PPAR-a or other nuclear hormone receptors to elicit CYP
induction, whereas vitamin A deciency downregulates the growth hormone-responsive CYP2C11 by perturbing janus kinase-signal transducers and activators of transcription signaling (Murray, 2007). PPAR-a, PPAR-c and liver X receptor-a
can be activated by naringenin aglicone, which reduces circulating levels of LDL and VLDL (Goldwasser et al., 2010). Importantly, 17b-estradiol inhibits the actions of PPAR-a, and the importance of estrogen in controlling PPAR-a is conrmed by the
fact brates synthetic agonists of PPAR-a act as an efcient weight controller under estrogen-free conditions by regulating
nutritionally induced body weight and adiposity in male mice but not in females with normal ovary function (Yoon, 2010).
PPAR-c can be also activated by geinstein (Xiang et al., 2010). Components of grapefruit such as naringenin can inhibit
CYP3A, which is more highly expressed in women than in men, and CYP1A2, thus interfering with drugs, foods and beverages
that are substrates of this enzyme such as caffeine, which is present in coffee and many other beverages (Fuhr et al., 1993; Li
et al., 2007). Additionally, grapefruit juice can inactivate intestinal CYP3A4 (Murray, 2006), decreasing the presystemic oxidation and increasing the systemic bioavailability of food components. Dietary interactions may complicate drug therapy,
but the inhibition of certain CYP reactions may also protect the individual against toxic metabolites and free radicals generated by CYP, and this seems to occur with the use of teas and cruciferous vegetables. These components, which inhibit human CYP enzymes, may also reduce the bioactivation of chemical carcinogens (Murray, 2006). Thus, food constituents
modulate CYP expression and function by a range of mechanisms, with the potential for both deleterious and benecial outcomes (Murray, 2006); because OC can modulate the activity of some enzymes, it is possible that OC could interact with
foods at this level.
Other food components, such as methylenedioxyphenyl compounds and isothiocyanates, certain dietary indoles, avonoids and inquinates, can activate CYP1A expression either by direct ligand interaction with the aryl hydrocarbon receptor
or by augmenting the interaction of the aryl hydrocarbon receptor with xenobiotic response elements (Murray, 2006).
The above observations lead to the suggestion that the bio-availability of foods can be modied by OC and hormonal
replacement therapy and vice versa, and examples of OC and food interactions have been described in many sections of this
review.
5.2. Pregnancy
Numerous reviews and guidelines are dedicated to maternal nutrition in pregnancy (Lain and Catalano, 2007; Murphy
et al., 2006). Here, we underline only some aspects that are associated with the sex of fetuses. Briey, pregnancy in humans
has one very characteristic feature compared to other mammals: human fetuses grow very slowly to give plenty of time to
develop our large brain. The slow pregnancy allows sufcient time to accrue the additional nutrients that must be supplied
to the fetus and the other products of conception (uterus, placenta, extra maternal fat, expanded blood volume and developed breasts). Therefore, human pregnancy has modest nutritional requirements, and most of these can be obtained from a
slight increase in a healthy, balanced diet (only about 1015% extra) (Lain and Catalano, 2007). However, increased caloric
intake is necessary during the second and third trimesters to cope with the bulk of fetal and placental growth (Murphy et al.,
2006).
Fetal sex, as already mentioned, affects fetal growth, with male fetuses typically being larger than female fetuses (Thomas
et al., 2000). Tamimi and colleagues (Tamimi et al., 2003) studied maternal dietary intake during the second trimester of
pregnancy and observed that women pregnant with a male fetus have a higher energy intake compared with women pregnant with a female fetus. After adjustment for confounding factors, this related to an extra 796 kJ/d, which came from 8%
more protein, 9.2% more carbohydrates, and more than 10% greater lipid intakes in women pregnant with a male fetus compared with women pregnant with a female fetus. Fetal sex-specic signals may have an important inuence on fetal growth
regulation; however, the nature of these signals is not understood.
Glucose is an important nutrient that controls fetal growth. Physiologic changes in carbohydrate and lipid metabolism
occur during pregnancy, often with precise timing, to ensure a continuous supply of nutrients to the growing fetus despite
intermittent maternal food intake, and they are required to satisfy the demands of the mother and the developing fetus.
Early gestation can be viewed as an anabolic state in the mother with an increase in maternal fat stores and small
increases in insulin sensitivity (Lain and Catalano, 2007). Hence, nutrients are stored in early pregnancy to meet the fetoplacental and maternal demands of late gestation and lactation. In contrast, in late pregnancy, glucose becomes the major
fuel (Harding, 2001), and it is better characterized as a catabolic state with decreased insulin sensitivity. An increase in insulin resistance results in elevated maternal glucose and FFA concentrations, allowing for greater substrate availability for fetal
growth (Lain and Catalano, 2007), producing exaggerated changes in postprandial concentrations of metabolic fuels (e.g.,
glucose and VLDL) and amino acids, and serving to shunt ingested nutrients to the fetus after feeding (Butte, 2000). The insulin resistance may be dependent on alterations in the hormonal milieu induced by pregnancy (Butte, 2000). Changes in

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37

pancreatic b cell responsiveness occur in parallel with the growth of the feto-placental unit and its hormones synthesis such
as human chorionic somatomammotropin, progesterone, cortisol, and prolactin (Butte, 2000). These metabolic changes are
progressive and may be accentuated in women who develop gestational diabetes mellitus (Butte, 2000). There are fetal sex
differences in insulin-like growth factor (IGF)-II concentrations in umbilical cord serum, which are higher in male neonate
umbilical cords (Gluckman et al., 1983). Cord plasma IGF-I and insulin-like growth factor-binding protein-3 levels are higher
in female neonates than in males (Vatten et al., 2002). Vatten et al. also found that IGF-I in the umbilical cord plasma is lower
among females compared with males (Vatten et al., 2002). A recent study found that both IGF-I and insulin growth factorbinding protein-3 concentrations in cord blood are higher in females than males (Geary et al., 2003), whereas IGF-I-II levels
are similar between male and female babies, and growth hormone levels are higher in males than in females (Geary et al.,
2003). We recall that United Nations International Multiple Micronutrient Preparation affects birth weight, which seems to
occur through elevation of cord IGF-I and leptin in males but not in females (Roberfroid et al., 2010). Sexgender differences
have been found in vitamin A levels in umbilical cord, and levels are lower in boy than in girls (Yassai and Malek, 1989).
Protein intake may be particularly important, and some studies have found a relationship between low protein intake in
late pregnancy and reduced birth weight (Murphy et al., 2006). A Cochrane systematic review, which uses trials conducted in
developing countries and/or in poor communities, demonstrated that balanced protein-energy supplementation can reduce
the risk of small for gestational age neonates by approximately 30% (Kramer and Kakuma, 2003). It is important to stress that
maternal protein deprivation modies hepatic lipogenic transcription factors and lipid enzymes such as lipolytic lipoprotein
lipase (Berney et al., 1997; Desai et al., 1996). Lipid dysfunction is sexgender dependent. In particular, males exhibit
changes of lipid abnormalities in the absence of obesity, whereas females have decreased hepatic cholesterol content and
show no adverse changes in hepatic triglyceride content, transcription factor sterol regulatory element-binding protein1c, fatty acid synthase, or lipoprotein lipase. In animals, After moderate maternal food restriction (25%) during pregnancy
followed by ad libitum diet during lactation (to mimic the human situation in which the infants are nursed by their own
mothers), liver and lipid alterations were already present at 3 weeks of age and were more prominent in males than in females (Choi et al., 2007). The use of particular foods and beverages could affect fetal growth. For example, a high caffeine
intake in the third trimester may be a risk factor for fetal growth retardation, in particular if the fetus is a boy (Vik et al.,
2003). Caffeine is present in high concentration in many beverages (coca cola, energy drinks, coffee). Tobacco smoking,
the most important established determinant of restricted fetal growth (Kramer, 1998), has a sex-specic effect because it
increases susceptibility to low birth weight, especially in the female fetus (Voigt et al., 2006).

6. Sexgender specic nutritional requirements in early life: timing and the critical window
6.1. Is the placenta sexually dimorphic?
The placenta maintains fetal homoeostasis by performing a wide range of physiological functions, which after birth are
carried out by the kidney, gastrointestinal tract, lungs and endocrine glands of the neonate. The main functions of the placenta are to produce and secrete a vast array of hormones, cytokines and signaling molecules; provide an immunological
barrier between fetus and mother; and mediate the transfer of oxygen, water, ions and nutrients. Thus, the placenta is
the link between maternal nutrition and fetal growth. However, the relationship between maternal nutrition and placental
size in humans is complicated. For example, low dietary intake of carbohydrates in early pregnancy has been reported to
increase placental weight, particularly when combined with high protein intake in late pregnancy (Godfrey et al., 1996).
In experimental models of severe maternal undernutrition, both protein malnutrition and the restriction of total caloric intake impair placental and fetal growth (Dwyer et al., 1992; Jansson et al., 2006; Roberts et al., 2001). This observation is reminiscent of reports from the Dutch famine winter during World War II, which showed that exposure to severe caloric
restriction early in pregnancy and a high caloric intake in the second half of pregnancy results in increased placental growth
(Lumey, 1998). Little is known about how the placenta senses maternal nutritional status. Jansson et al. proposed the concept of a nutrient sensor within the placenta (Jansson et al., 2006), which is linked to nutrient transport and cell growth
pathways and may be dialed up or down in response to placental nutrient supply (Roos et al., 2009). Maternal nutrition is
also likely to have an important effect on epigenetic mechanisms within the placenta (Gheorghe et al., 2009); epigenetic control of placental gene expression and function is an additional potential nutrient sensor mechanism. In human female placenta, X inactivation is either random or skewed (Looijenga et al., 1999; Zeng and Yankowitz, 2003). Importantly, the
placenta is the only tissue that can globally reactivate the inactive X chromosome in vitro at a specic gestational time point
(Migeon et al., 2005). These studies highlight the possibility that the human placenta of a female fetus may be capable of
inducing non-random X inactivation in an adverse intrauterine environment in the early stages of implantation. Accordingly,
murine female fetus placentas demonstrate more striking alterations in gene expression in response to maternal diet than in
male placentas, suggesting that female placentas are more sensitive to nutritional perturbations than male placentas (Mao
et al., 2010).
The placenta can adapt or modify its capacity to supply nutrients to meet the nutrient requirements of the fetus, and this
also occurs through an abundance of transporters that are highly sex-specic in rodents (Jansson and Powell, 2007; Klaassen
and Aleksunes, 2010; Myatt, 2006). However, in human placenta, the Na+/H+ exchanger is sex-regulated (Speake et al., 2010).
Nutrient transporters are responsive to inammatory cytokines (Jones et al., 2009; Thongsong et al., 2005); thus, a

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pro-inammatory state, as associated with maternal obesity, is a potential contributing factor to modied nutrient transport
in the placenta, and this could occur in a sex-specic manner.
At birth, boys tend to be longer than girls at any placental weight (Eriksson et al., 2010). In the womb, boys grow faster
than girls and are therefore at greater risk of becoming undernourished. Boys placentas may therefore be more efcient than
girls but may have less reserve capacity (Eriksson et al., 2010). In men, hypertension is associated with a long minor diameter
of the placental surface, whereas in women, hypertension is associated with a small placental area, which may reduce nutrient delivery to the fetus. In addition, in men, hypertension is linked to the mothers socioeconomic status, whereas in women, it is linked to the mothers height as an indicator of mother protein metabolism (Eriksson et al., 2010). These results
suggest that boys are more dependent on their mothers diets, which may enable them to capitalize food supply, but it
makes them vulnerable to food shortages.
The above observations indicate that it is time to stop considering the placenta as an asexual organ and that it is time to
consider the gender of the placenta when designing experimental protocols.
6.2. Timing and critical windows
As already mentioned, timing is very important because the nutritional needs of fetuses vary with the stage of pregnancy,
including the embryonic stage, during which growth is initially dependent upon simple molecules such as pyruvate and is
then increasingly inuenced by amino acid concentrations (Martin et al., 2003). Nutritional conditions may be especially
important in early pregnancy (Harding, 2001). Both the inadequate (e.g., folate deciency) and excessive intake (e.g., excess
of vitamin A) of certain nutrients have been related to undesired birth outcomes and pregnancy complications (Rothman
et al., 1995; Tamura and Picciano, 2006), especially if they occur in the so-called sensitive periods or specic window
(Haste et al., 1991).
Current public health guidelines recommend that women consume a supplemental dose of 400 lg of folic acid per day in
the month preceding and during the rst trimester of pregnancy to reduce the risk of neural tube defects in children (Centers
for Disease Control, 1992). However, recent studies suggest that supplemental folic acid intake during pregnancy could negatively affect respiratory health in early life (Haberg et al., 2009; Whitrow et al., 2009). Furthermore, higher maternal erythrocyte folate concentrations at 28 weeks predict higher offspring adiposity and higher homocysteine concentrations (Yajnik
et al., 2008). Folic acid plays an important role in methylation, and animal studies suggest that it can have some sex-specic
effect. Supplementing the maternal diet with methyl donors such as folate, betaine, and choline induces hypermethylation of
the 267 Agouti viable yellow (Avy) locus and a consequent darker coat color phenotype in offspring (Cooney et al., 2002;
Waterland and Jirtle, 2003; Wolff et al., 1998). However, this darker coat color persists into the second generation only when
it is transmitted through the female lineage (Cropley et al., 2006).
Feto-placental metabolism is also variable during the pregnancy (Anderson, 2005), and this could inuence food availability; as is observed with drugs, this variability could be sexgender-specic (Hodge and Tracy, 2007; Myllynen et al., 2007). In
pregnancy, the activity of some enzymes such as uridine diphosphate glucoronosyl-transferase is increased, whereas the
activity of CYP2C19 and N-demethylation activity are decreased when compared with non pregnant state (Anderson and
Carr, 2009). Although CYP3A is induced both in the liver and intestines at all stages of pregnancy, near the end of pregnancy,
its expression is 2- to 3-fold higher in comparison with the post-partum period (Hebert et al., 2008). Additionally, liver
P-glycoprotein is controlled by sexual hormones, and its function is modied by pregnancy (Pavek et al., 2009). These maternal variations could inuence the bioavailability of foods, and the metabolic process could be sexgender specic.
Notably, the timing of the sensitive windows of development could also be sexgender- and tissue-specic (Dunn et al.,
2010) and these factors indicate that experimental designs should include both sexes at different ages.
6.3. Early events and developmental plasticity
Sexually dimorphic differences have been found with respect to fetal growth morbidity and mortality, with the male fetus
being at higher risk of a poor outcome than the female fetus in association with complications such as placental insufciency,
pre-eclampsia, infections, intra-uterine growth restriction and pre-term delivery (Christensen et al., 2001; Di Renzo et al.,
2007; Stevenson et al., 2000; Vatten and Skjaerven, 2004).
The quantity and quality of the maternal diet during pregnancy is of extreme importance, not just for the health of the
mother but also for the pregnancy outcome and the health and development of the fetus. Maternal diet during pregnancy has
permanent effects on the health and well-being of the offspring in later life (Barker, 1992; Waterland and Garza, 1999). The
concept of the plasticity of the developmental program comes from epidemiological studies such as those conducted on the
children conceived during the Dutch famine of 19441945, which have highlighted the association between poor maternal
nutrition, lowered birth weight and subsequent adult diseases (Ravelli et al., 1999). These modications may be partially
mediated through altered organ growth that results in permanent changes in structure, metabolism, and/or homeostatic regulatory systems (Desai et al., 1995; Desai et al., 2005; Lucas et al., 1996). In fact, a suboptimal environment during fetal and
neonatal development in both humans and experimental animals impacts offspring susceptibility to later alterations in carbohydrate metabolism (Ravelli et al., 1999; Zambrano et al., 2005a; Zambrano et al., 2005b) and atherogenic lipid prole
(Desai and Hales, 1997; Gluckman and Hanson, 2004; Roseboom et al., 2001). In recent years, a growing body of evidence
has proven the relevance of plasticity in the developmental program and the fact that it is sexgender specic (Freedman

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39

et al., 2002; Lucas et al., 1996). Studies of maternal asthma (Murphy et al., 2005; Murphy et al., 2003), pre-eclampsia (Stark
et al., 2009; Stark et al., 2006), and preterm delivery (Stark et al., 2008a,b) indicate that male and female fetuses, as well as
neonates, use different mechanisms to cope with an adverse environment or events. In particular, the presence of maternal
untreated asthma reduces female fetal growth, but in the presence of pharmacological (corticosteroids)-treated asthma, female fetal growth is comparable to the non-asthmatic population. Conversely, the male fetus continues to grow normally in
the presence of chronic, untreated maternal asthma (Murphy et al., 2003). However, when asthma worsens with an acute
exacerbation, the male fetus shows signs of compromise, which include intra-uterine growth restriction, preterm delivery
and stillbirth (Murphy et al., 2005). The authors suggest that males seem to employ strategies that allow them to continue
normal growth in an adverse intrauterine environment, which then places them at risk of compromise in the presence of a
second stressful event, such as an acute asthma attack. Females adapt to the poor intrauterine environment of chronic
maternal asthma by reducing their growth so that they are smaller. This allows them to survive any further compromises
in the intrauterine environment to nutrition or oxygen supply as the pregnancy progresses (Clifton, 2010). The previous
changes in females are accomplished in variations in placental activities of11b-hydroxysteroid dehydrogenases (11bHSD)-2 (Murphy et al., 2003), indicating that placental 11b-HSD-2 activity is regulated in a sexgender-specic manner.
Similar sexgender specic changes have been found in the rat, in which maternal exposure to alcohol in late gestation is
associated with decreased placental 11b-HSD-2 mRNA expression in only female fetuses (Wilcoxon et al., 2003). These
changes in placental 11b-HSD-2 are associated with signicant sexgender-specic changes in female birth weight
(Wilcoxon et al., 2003). Another important sexgender difference with respect to the development of hypertension is that
intra-uterine growth restriction and postnatal nutritional restraint cause nephron deciency and modest renal insufciency
in female rats, whereas it produces severe hypertension in male rats (Moritz et al., 2009). Furthermore, pre-eclampsia is
associated with normal growth trajectories of the male fetus and growth reduction in the female fetus; sex-specic alterations have been also found in maternal peripheral microvascular function (Stark et al., 2009; Stark et al., 2006).
Children of obese and diabetic pregnant are often macrosomic (Catalano and Ehrenberg, 2006; Henriksen, 2006; Langer
et al., 1989; Leguizamon and von Stecher, 2003); however, studies of diabetic women have shown that maintaining low
blood glucose levels during pregnancy through excessively tight glycemic control lead to a greater incidence of small for gestational age neonates (Langer et al., 1989; Leguizamon and von Stecher, 2003). Epigenetic misprogramming, which is associated with overweight or diabetic mothers, overnutrition or undernutrition during development, is widely thought to have a
persistent effect on the health of the offspring (Attig et al., 2010). Although the mechanisms are still poorly understood, epigenetic marks that have failed to be erased before implantation or in the germ line may be transmitted to the next generation
in a sex-specic manner and lead to transgenerational effects (Attig et al., 2010; Seghieri et al., 2002). In particular, macrosomia is also associated with maternal glucose intolerance and macrosomia is greater in male fetuses than female fetuses
(Ricart et al., 2009). Evidently, optimizing the nutritional environment to which male or female fetuses and neonates are exposed during development is a promising approach to improve the health of the population worldwide. Interventions to offset the programming of disease may include improvements in the quality of diets for pregnant women and neonates to
target gatekeeper genes or related processes.
Finally, a few studies show that a malprogramming phenotype can be reversed or alleviated by nutritional interventions
(Attig et al., 2010). Epigenetic modication of hepatic gene expression in the offspring induced by dietary protein restriction
of pregnant rats can be prevented by folic acid supplementation (Attig et al., 2010). Additionally, folic acid prevents changes
to the methylation status of the glucocorticoid receptor and PPAR-a promoters and leads to the normalization of glucocorticoid receptor and PPAR-a expression. Notably, the diet intervention can have sexgender specic effects (Attig et al., 2010);
more importantly, the sexgender effect of diet can be transferred to other generations. There are some data that nutritional
intervention can prevent metabolic alteration induced by environmental changes during the lactation period. In fact, metabolic alterations induced by psychological distress (maternal separation) and painful stimulus during lactation produces
permanent metabolic alteration (overweight, increase in plasma lipids and fasting glucose) in male mice (Loizzo et al.,
2006; Loizzo et al., 2010). The metabolic alterations are related to alterations in the hypothalamus-pituitary adrenal axis
(Loizzo et al., 2010) and can be prevented by taurine (Loizzo et al., 2007). Taurine is a sulfur semi-essential amino acid
and is added to many milk formulas; taurine plays a role in glucose metabolism (Franconi et al., 2004; Franconi et al.,
2006b), especially during early life (Aerts and Van Assche, 2002; Cherif et al., 1998; Dahri et al., 1991).
In conclusion, the fetus and neonate can no longer be considered asexual because his/her sex determines physiological
dymormhic responses and these responses signal their needs to the mother also signaling their different needs to the
mother. Indeed, the need for research in this area has emerged because, in the era of evidence-based medicine, it is time
to acknowledge the importance of gender and to consider that environmental factors (such as diet) can have specic impacts
depending on their direct and/or indirect access to the epigenetic machinery at a given age (critical periods) and in relation
to sex.
6.4. Infant feeding and weaning
Breast milk is promoted by the World Health Organization and the Ministry of Health as the best food for infants
(Ministry of Health, 2008; WHO/UNICEF/UNFPA/UNAIDS, 2003). However, some sexgender-dependent effects are still present with breastfeeding; it protects girls, but not boys, against viral pneumonia and, probably, against hospitalization (Libster
et al., 2009). The same authors reafrm the particular susceptibility of non-breastfed females to respiratory viruses. These

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above observations on viral pneumonia and hospitalization are in agreement with those reported for premature infants in
different regions of the world (Klein et al., 2008; Sinha et al., 2003; Wright et al., 1989).
Prospective studies show that the duration of breastfeeding could have sexgender-specic effects. Variations in breast
milk quality may logically have important effects on infant health, growth, and development. Recently, milk composition
was shown to correlate with the sex of the infant; mothers of male infants produced milk that had 25% more energy than
the milk of mothers of female infants (Powe et al., 2010). This nding is not restricted to humans; rhesus macaques and red
deer exhibit the same behavior (Hinde, 2007; Landete-Castillejo et al., 2004). However, greater nutritional investment in
sons may account for the greater observed growth rates in male compared to female infants, and male infants may consume
8-10% more milk than females (Michaelsen et al., 1994).
The newborn, especially if preterm, is highly prone to oxidative stress. At birth, the newborn is exposed to a relatively
hyperoxic environment caused by an increased oxygen bioavailability with greatly enhanced generation of ROS; in the preterm baby, the perinatal transition is accompanied by the immaturity of the antioxidant systems (Perrone et al., 2010), which
could increase the effect of ROS. If the sexgender differences in the redox state (Malorni et al., 2007) observed in adults
extend to infanthood, the susceptibility to oxidative stress could be sex-specic.
The increased duration of exclusive breastfeeding in infancy is associated with signicantly higher levels of total and LDL
in women (Pearce et al., 2009), whereas a long duration of breastfeeding is negatively associated with glucose homeostasis
model assessment and with insulin resistance in men but not in women (Pearce et al., 2006) and is also associated with reduced sero-prevalence of Helicobacter pylori in men but not in women (Pearce et al., 2005).
There are discordant data on the inuence of sex and gender on the timing of weaning (Erkkola et al., 2005; Hornell et al.,
1999; Pande et al., 1997; Savage et al., 1998; Scott and Binns, 1999; van den Boom et al., 1993). Sexgender differences in
weaning may reect a hidden social stereotype. It is now time to investigate the duration of breasting feeding in a sexgender perspective to optimize weaning to determine the best conditions for both boys and girls.
Soy-based infant formula, initially developed for infants who are lactose intolerant or allergic to cows milk-based formula, now account for >25% of the infant formula sold in the United States. This is the highest percentage in countries in
the Western world (for a review, see Chen and Rogan, 2004). Serum concentrations of isoavones in infants fed soy formula
can be extremely high, reaching 200 times the concentrations in infants fed cow or breast milk and 10 times higher than
adults who eat a diet high in soy.
Soy formulae routinely add methionine, iodine, carnitine, taurine, choline, inositol, DHA and arachidonic acids, and data
suggest that modern soy-based formulae support normal growth and nutritional status in healthy term infants in the rst
year of life (Mendez et al., 2002). However, the available data do not provide evidence of meaningful differences in timing
of maturation, sexual development, or fertility in adolescents or adults (Bhatia and Greer, 2008). However, some data on
reproductive health in young adults (2034 years of age) who previously participated in a controlled feeding study of soy
formula as infants suggest a longer duration of menstrual bleeding and greater menstrual discomfort in women exposed
to soy as infants (Strom et al., 2001).
It is clear that the biological impact of isoavones of soy could be very broad and complex. Genistein, a soy isoavone
with a structure similar to 17b-estradiol, acts as a natural selective estrogen receptor modulator and, at physiologically relevant concentrations, has a sexgender-specic effect, as demonstrated in the pig, where it induces more proliferation in the
coronary artery vascular smooth muscle cells of males than females (Vincent et al., 2001).
Therefore, we need to examine more closely the molecular characteristics of phytoestrogen action because they are structurally similar to estradiol (Dixon, 2004) and bind to both estrogen receptors with a major afnity of ER-b, suggesting that
they can have a multiplicity of actions. In adults, the administration of soy products seems to have different pharmacokinetic
proles in men and women, with the peak concentration of daidzein being higher in women than in men (Cassidy et al.,
2006). Given the scarcity and inconsistency of existing human data and the substantial laboratory evidence of hormonal
and other activity at doses relevant to the soy-fed infant, we conclude that more clinical and epidemiological study is warranted, and, while waiting for new data, it would be prudent to limit the use of soy milk.
The above observations indicate that sexgender specic effects are present in very early stages of life.

7. Inuence of foods on cell fate from a sexgender perspective


Chemical environmental factors, particularly food components, can have specic impacts on male and female functions,
enlarging/reducing gender differences or preventing/increasing the incidence of certain pathologies. However, systemic
homeostasis can be considered the result of individual cell homeostasis, which is a main determinant of cell fate and, ultimately, disease development. Thus, the study of molecular mechanisms of food components in cell systems, from a sex
gender perspective, may help clarify the potential impact of diet on human health.
At the cellular level, nutrients and their byproducts can impact proteins, lipids and nucleic acids; change cell metabolism
and cell genomics; modify organelle function; and inuence cell fate. Cell proliferation, differentiation and cell death pathways may be the targets of several nutrients that are thus capable of inuencing or determining cell and tissue homeostasis.
For example, the direct/indirect access of food components to the epigenetic machinery and chromatin on specic sets of
target genes and/or at the whole genome level could alter the DNA methylation pattern. This can markedly modify cell
integrity and function. As an example, epigallocatechin-3-gallate, a polyphenol present in green tea, inhibits histone

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41

acetyltransferase and DNA methyltransferase activities (Gilbert and Liu, 2010). Despite epigenetic changes, certain nutrients,
e.g., plant-derived avonoids and vitamins, can modulate a wide spectrum of responses because their chemical structure is
compatible with putative antioxidant properties. However, avonoids and some vitamins also possess pro-oxidant properties, which can contribute to the activation of a pro-apoptotic cascade important for their activities, for example, anti-cancer
activities (Galati et al., 2000). Furthermore, some food components can modulate the activity of several kinases and protein
functions (e.g., surface and endocellular receptors) via competitive or allosteric interactions (Marino and Bulzomi, 2009),
modifying cell metabolism and proliferation rate.
7.1. Sexgender, antioxidants and cell fate
Cellular redox imbalance is pivotal to the pathogenesis of a number of human diseases, and differences in the occurrence
of oxidative stress between males and females have been demonstrated (Malorni et al., 2007). Controlling the intracellular
redox state by mean of an efcient antioxidant machinery is thus necessary to maintain cell homeostasis. To this aim, the
endogenous antioxidant defense system exists, and its effectiveness is closely related to the consumption of dietary antioxidant compounds. Experimental data indicate a close relationship between endogenous antioxidant defenses, specically
glutathione (GSH) and its related enzymes, and dietary antioxidants, such as vitamins and polyphenols. The strengthening
of the cellular antioxidant defense system by specic nutrients represents a central event in determining the fate of the cells.
This question (i.e., the redox-associated mechanisms leading to the process of cell demise) has acquired great importance
over recent years in view of the key role exerted by programmed cell death (apoptosis) and its disturbances in a plethora
of human pathologies. For instance, a defect or an increase in apoptosis has been associated with a number of human infectious or degenerative pathologies as well as cancer and dysmetabolisms. Disturbances of tissue homeostasis are due to an
imbalance between cell proliferation and apoptosis. Since the metabolic needs of the cells are normally provided by nutrients, the amount, the features and the interaction of nutrients with the cells are of great relevance. For instance, nutrient
metabolism clearly represents, at the cellular level, a key factor in determining cell fate, e.g., proliferation or death. In turn,
aside from the fact that an excess or a lack of apoptosis is pathogenetic, the alteration of cell fate pathways in certain cell
types can also be pivotal. Nutrients can thus be considered direct effectors or, alternatively, co-factors and boosters of cell
pathology. A further example is represented by a form of cytoprotection that takes place in a cell once nutrients are lacking.
This process is called autophagy, and defects in this process lead to important tissue alterations (Deretic and Klionsky, 2008).
Hence, considering cell fate alterations as being pivotal in the cascade of events leading to human pathologies and taking into
account the key role of the metabolism and dysmetabolism of nutrients by the cell in determining these pathologies, we will
summarize the features of various forms of cell injury and their mechanisms, including redox alterations, the implication of
nutrients and, last, the fact that cell sex appears to represent a key and innovative variable in this complex scenario.
7.2. Cytology and cytopathology in male and female cells
7.2.1. Oxidative stress
Oxidative reactions are an essential part of the metabolic process because oxygen is the ultimate electron acceptor in the
electron ow system that produces adenosine triphosphate (ATP), a key molecule in the metabolic process. Problems may
arise when electron ow and energy production become uncoupled, so oxygen free radicals (ROS) are excessively produced.
ROS is a collective term that embraces a wide range of O2-derived free radicals (O.), hydroxyl (HO), peroxyl RO2 , alkoxyl
(RO) radicals and non-radical species, such as superoxide anion and hydrogen peroxides (H2O2). Furthermore, because NO
production appears to be estrogen dependent, NO-derivatives, including reactive nitrogen species (RNS), such as peroxynitrite, should be taken into account. For example, recently, when in examining the key role of NO in cell signaling, some works
evaluated the sexgender disparities in nitrosative stress. The better preservation of renal function during ischemiareperfusion of the kidney is associated with high NO concentration and low peroxynitrite levels in females, whereas
increased oxidative and nitrosative stress worsens renal damage in male (Rodriguez et al., 2010).
ROS and RNS are continuously produced within the cell, particularly in the mitochondria and peroxisomes, as a result of
mitochondrial electron transfer processes and the activity of several enzymes, such as Krebs cycle enzyme complexes,
p66Shc, xantine oxidase, NADPH oxidase, myeloperoxidase, LOX, and COX (Cadenas and Sies, 1985). Furthermore, ROS
can be generated as a consequence of the intracellular metabolism (e.g., by CYP); foreign compounds, toxins, drugs and
foods; or exposure to environmental factors such as pollutants, heavy metals or ultraviolet (UV) radiation (Hanukoglu,
2006). Notably, after interaction with their receptors, growth factors and cytokines stimulate an intracellular transient increase of ROS that is mostly represented by hydrogen peroxide, which activates specic signaling pathways. Important
examples are TNF-a, platelet-derived growth factor, epidermal growth factor and insulin (Han et al., 2009). ROS generation
seems to be sexgender-specic (Malorni et al., 2007).
Recent studies have revealed the importance of translating ROS-generation to the activation/suppression of specic signaling pathways (Malorni et al., 2007). In particular, two different paradigmatic examples can be considered from a sexgender perspective. The rst example comes from the cardiovascular studies. Elevated levels of redox indexes (i.e., myocardial
protein carbonyl and other protein oxidation parameters such as advanced oxidation protein products, nitrotyrosine, protein
hydroperoxide, total thiols, non-protein thiols, 4-hydroxyalkenal, malondialdehyde, GSH and glutathione disulde (GSSG))
have been hypothesized to contribute to the extent of protein, but not lipid, oxidation in aged male rats much more than

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in female (Kayali et al., 2007). The second paradigmatic example concerns metals. Published data from 11 countries clearly
indicate that mortality from cardiovascular diseases is positively correlated with liver iron levels, suggesting that redoxactive iron in tissues could be the atherogenic portion of total iron stores (Yuan and Li, 2003). This iron hypothesis, and
related nutritional supply rules should be better analyzed from a sexgender perspective in a near future. For instance, anemia is highly prevalent in patients with chronic heart failure and is associated with age and gender, and it appears to be mediated by an impaired iron metabolism (Le Jemtel and Arain, 2010). Hence, it is clear that the redox imbalance inside the cell
can alter either molecules, including DNA, proteins, and lipids, or constituents, including metals, that are critical for cell
survival, and that sexgender disparity on this point (Malorni et al., 2007) will be a target of future research in several research elds, cellular nutrition being rst and foremost.
Notably, as mentioned above, depending on their concentrations, ROS can be benecial or harmful to cells and tissues. At
low physiological levels, ROS function as redox messengers in intracellular signaling and regulation, whereas excess ROS
induces oxidative modication of cellular macromolecules, inhibits protein function, and can promote cell death. Notably, an
important cellular target or sensor of ROS is the thiol functional group (R-SH) of some amino acids, e.g., cysteine. Cellular
thiols are critical in sensing and coupling redox changes to biochemical pathways because they can easily react with oxidants (Winterbourn and Hampton, 2008). In their oxidized state, such as disulde, thiols can determine marked structural
and functional alterations of molecules that also result in cytopathology and death. These oxidative thiol modications can
constitute a facile switch for modulating protein function, akin to phosphorylation (Forman et al., 2010). The reversibility of
this reaction also contributes to the key activity switch of thiol groups. The controlled production of ROS in healthy cells is
thus critical to maintain cell homeostasis. As mentioned above, ROS may also be highly damaging because they can attack
biological macromolecules, namely lipids, proteins, and nucleic acids; denaturate them or generate oxidized products that
can alter cell functions, including metabolic or catabolic pathways; and cause membrane and DNA damage, enzyme inactivation and, ultimately, cell death (Circu and Aw, 2010).
Oxidative stress ensues when the level of ROS exceeds the antioxidant capacity of the cell and the intracellular redox
homeostasis is altered. The term oxidative stress has been used for many years to describe an irreversible imbalance between pro-oxidants and antioxidants species in favor of the former, and it has a pivotal role in the pathogenesis of aging
and several degenerative diseases, such as atherosclerosis, cardiovascular disease, type 2 diabetes and cancer (de Moura
et al., 2010; Kaneto et al., 2010; Patten et al., 2010; Queen and Tollefsbol, 2010; Victor et al., 2009). However, slight variations
in the intracellular redox environment and in the detoxication machinery can have profound effects on a number of intracellular signaling molecules, thereby modifying cell functions and cell fate. In this context, it was recently suggested that ROS
production and detoxication machinery are sexgender dependent and that XX and XY cells have a determining role in the
response to oxidative insults (Malorni et al., 2008; Straface et al., 2009). In particular, the basal differences in the redox state
of freshly isolated cells from males and females indicate that XX cells have higher GSH content and that this can provide
these cells with greater protection from oxidants (see below) (Malorni et al., 2008).
7.2.2. Oxidative stress and cell injury
The intracellular redox state is a key determinant of cell fate. Whether the cells are committed to aging, dying or living
depends on small shifts in the particular circumstances or disease condition. A small amount of ROS regulates cell proliferation and differentiation, while a large amount of ROS induces deleterious damage and apoptosis in cells by a specic signal
pathway (Yoon et al., 2002). Mild oxidative stress can accelerate telomere shortening, cause DNA double-strand breaks and
trigger irreversible arrest of cell growth, contributing to premature senescence (Chen et al., 2004). Conversely, as mentioned
previously, excessive ROS production can cause damage to the cellular machinery and, ultimately, cell death. Lipid oxidation
can alter membrane permeability, modify lipidprotein interactions, and form bioactive degradation products (Leonarduzzi
et al., 2000). Oxidation of proteins can lead to the fragmentation of the polypeptide chain, oxidation of amino acid side
chains, and generation of proteinprotein cross linkages (Baynes, 2001; Squier, 2001). Moreover, ROS, by modifying the
activity of several key enzymes, determine the reorganization of actin cytoskeleton (Fig. 6) via thiol groups oxidation and
side-by-side protein cross links and initiate the collapse of the mitochondrial membrane potential (Dwm), the mitochondrial
translocation of Bax and Bad, and the release of several different molecules that form the macromolecular apoptosome,
which activates the caspase cascade to induce apoptosis, into the cytosol (Skulachev, 2006).
Furthermore, the generation of ROS or the uctuation of the cellular redox state leads to the stimulation of various signaling systems, such as p53 and mitogen-activated protein kinases (MAPKs). p53 is considered the guardian of genome
integrity because it can inuence the cell cycle, DNA repair and the apoptotic response after stress insults (Vousden,
2000). Normally, the p53 levels are very low in the cells because it is constantly degraded by the proteasome (Boyd et al.,
2000). In situations of cellular stress, p53 degradation is stopped, and its levels rapidly increase. In response to low levels
of cellular stress, p53 has an antioxidant role and protects the cells from oxidative DNA damage, whereas in response to severe cellular stress, high concentrations of p53 promote the expression of genes that contribute to ROS formation and p53mediated apoptosis (Tomko et al., 2006). A good paradigmatic example of this issue is represented by lung cancer, one of the
most common cancers in the world. Although, historically, more men than women have died from lung cancer as a result of
higher numbers of male smokers, the sex mortality ratio is now showing signs of narrowing. However, sexgender differences have recently been found: tumors in women with lung cancer may be different from those in men with lung cancer
and, importantly, some biomarkers are differentially expressed in female and male patients. Among these is the p53 molecule, a molecule deeply involved in cell fate and apoptosis (Paggi et al., 2010). A type of mutation that is infrequent in lung

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Fig. 6. Morphological features of actin network in human broblasts from male (A) and female (C). Note the well-evident actin stress bers aligned to form
a structural network. After oxidative stress induced by ultraviolet radiation (see (Malorni et al., 2008)) the collapse of actin laments was detectable in cells
from males (B), whereas actin network in cells from females appeared as substantially maintained (D). Note however the spots due to the actin side-by-side
cross-links probably induced by to oxidative alterations of thiol groups (D). This disparity of cytoskeleton was associated with a different cell fate: cells from
females tended to remain rmly attached to the substrate whereas cells from males detached and underwent massive apoptosis (see text for detail).
Notably, dietary polyphenols were capable of protecting cell cytoskeleton from oxidative imbalance-associated remodeling and then from apoptosis.

cancers, i.e. the GT transversion, was more frequently found in the p53 gene in lung tumors of women than in men (Planchard et al., 2009). Future research into lung cancer needs to address these sexgender differences more specically.
Protein kinases contribute to the regulation of life and death decisions made in response to various stress signals. Therefore, the cells fate is determined by cross-talk between the cellular signaling pathways and the cellular redox state through a
strict regulatory mechanism. Phosphorylation of c-Jun N-terminal kinase (JNK) and p38 kinase, which increases the p53
response, may inuence the expression of pro- and antiapoptotic proteins such as Fas ligand and Bcl-2 family proteins, leading to apoptosis. Conversely, phosphorylation of apoptosis signal-regulating kinase (ASK)1, mediated by treonin kinase AKT,
inhibits the activation of JNK/p38, thus protecting cells from apoptosis (Matsuzawa and Ichijo, 2005). A good example of this
issue that takes sexgender into account concerns cardiomyocytes. Female adult mouse cardiomyocytes have a greater survival advantage when challenged with oxidative stress-induced cell death due to the activation of AKT and inhibition of glycogen synthase kinase-3, a proline-directed serine-threonine kinase, and caspase 3 through an ER-a-mediated mechanism
(Wang et al., 2010). A further paradigmatic example is red wine polyphenols. Red wine polyphenols determine a redoxsensitive PI3K/AKT-dependent NO-mediated relaxation of isolated rat aortic rings and a structural remodeling of cultured
endothelial cells. These effects are more pronounced in the aortas of female rats than in the aortas of male rats (Kane
et al., 2009). However, discrepancies exist between in vitro studies (i.e., in cultured cells) and in vivo analyses both in murine
models and in humans. Unfortunately, the majority of results provided by in vitro studies could not be reproduced in vivo,
probably due to the known targeting difculties encountered in treatments with polyphenols and, in general, antioxidants.
Sexgender can also represent a key variable for cells fate. A different susceptibility to oxidative stress occurs in cells
from males and females. In particular, vascular smooth muscle cells (VSMCs) from male rats undergo oxidative stressmediated apoptosis, whereas cells from females undergo premature senescence (Malorni et al., 2008). Cells from females
are hypothesized to be more plastic to adapt themselves to changes induced by oxidative stress. Moreover, the antioxidant
defenses are apparently different in XX and XY cells, and this can lead to or contribute to the observed sexgender disparity
(Malorni et al., 2008). For example, the exposure of vascular cells from male and female rats to sub-cytotoxic doses of UVB
(200 mJ/cm2) clearly displayed a sexgender difference in terms of ROS production. In fact, in comparison to cells from female rats, cells from males (i) produce more ROS and higher levels of 4-hydroxynonenal, an end-product of membrane lipid
peroxidation, and (ii) undergo alterations of their morphological features with shrinking, loss of cellcell contacts possibly
due to oxidative changes and consequent remodeling of the cytoskeleton. This can also result in the loss of cellbasement
membrane interaction, leading to anoikis. In contrast, cells from female rats respond to oxidative stress by an adhesionassociated resistance to apoptosis, so-called anoikis resistance. This is apparently due to a more adhesive phenotype that
is characterized by a well-organized actin microlament cytoskeleton, increased phosphorylated focal adhesion kinase,
and, more importantly, a higher propensity to undergo survival by autophagy (Straface et al., 2009) (see below).

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7.3. The antioxidant defense systems in XX and XY cells


It is absolutely clear that maintaining redox homeostasis represents a crucial event in the prevention of cell damage, and
it is easily understandable why humans have developed sophisticated mechanisms to cope with an excess of free radicals
produced by oxidative stress. These protective mechanisms scavenge or detoxify ROS, block their production, or sequester
transition metals that are the source of free radicals. These mechanisms include endogenous enzymatic and non-enzymatic
antioxidant defenses and other exogenous mechanisms supplied by the diet.
7.3.1. Endogenous defense systems
GSH plays a central role in the regulation of intracellular redox balance. This cysteine-containing tripeptide is the major
non-enzymatic regulator of intracellular redox homeostasis. Ubiquitous in millimolar concentrations in all cell types, it participates in redox reactions by the reversible oxidation of its active thiol (Fig. 7). Intracellular GSH can be found either in
reduced (GSH) or oxidized (GSSG, glutathione disulde) forms. The GSH buffer system modulates the cells response to redox
changes, and it is important in the regulation of many cellular metabolic processes and in the maintenance of cellular viability (Malorni et al., 2007). Finally, GSH can exert a regulatory role by covalently binding to proteins through a process called
glutathionylation (Filomeni et al., 2005). Under normal cellular redox conditions, the major portion of glutathione is in its
reduced form and is distributed throughout the nucleus, endoplasmic reticulum and mitochondria. In the presence of oxidative stress, the GSH concentration rapidly decreases while the level of GSSG which is potentially highly cytotoxic increases because of the reduction of peroxides or as a result of free radical scavenging. This mechanism has two important
consequences: (1) the thiol redox status of the cell will shift and activate transcriptional elements, and (2) GSSG may be preferentially secreted by the cell and degraded extracellularly, increasing the cellular depletion of GSH. Being both a nucleophile
and a reductant, GSH can react with electrophilic toxicants (to produce non-toxic, water-soluble compounds readily excreted
in urine) and oxidizing species (to avoid damage to the biological macromolecules), respectively. GSH can directly scavenge
free radicals or act as an enzymatic substrate, including GPx and glutathione-S-transferases (GST), which are involved in the
detoxication/reduction of hydrogen peroxide, lipid hydroperoxides and electrophilic compounds. During the reaction catalyzed by GPx, the exaggerated production of GSSG can lead to the formation of mixed disuldes in cellular proteins or to the
release of excess GSSG by the cell. During the GST-mediated reactions, GSH is conjugated with electrophiles, and the GSH
adducts are actively secreted by the cell. Mixed disulde formation, together with GSSG or GS-conjugated efux, can result
in the depletion of cellular GSH. To meet the increased requirement for GSH, cells can react by de novo synthesis or by reducing the formed GSSG.
GSH is de novo synthesized in two sequential ATP-dependent reactions catalyzed by c-glutamylcysteine synthetase
(c-GCS), the rate-limiting enzyme, and glutathione synthase (Huang et al., 2000). Furthermore, the nutritional aspects of sulfur amino acids should be considered because sulfur amino acid deciency remains a signicant nutritional problem (Bos
et al., 2009). In particular, cysteine is considered semidispensable because it can be synthesized by all tissues in the body
via the trans-methylation of methionine and requires an adequate source of methionine and serine precursors. Thus, the bioavailability of cysteine, derived from methionine, proteolysis, or diet, has a critical inuence on cellular redox function and
susceptibility to oxidative stress. GSSG can be reduced to GSH by the action of GR, a avoenzyme that utilizes NADPH as a
reductant (Argyrou and Blanchard, 2004). In conclusion, the presence of GSH is essential but not in itself sufcient to prevent

Fig. 7. Glutathione and related enzymes. Reduced glutathione (GSH) can directly scavenge free radicals or act as a substrate for glutathione peroxidases
(GPx) and glutathione transferases (GST) during the detoxication of hydrogen peroxide, lipid hydroperoxides and electrophilic compounds. During
GST-mediated reactions, GSH is conjugated with various electrophiles, and the GSH-adducts thus formed are actively secreted by the cell. The production of
oxidized glutathione (GSSG) by GPx can lead to: (i) the release of GSSG by the cell to maintain the intracellular GSH/GSSG ratio, or (ii) the back-reduction to
GSH by glutathione reductase (GR) utilizing NADPH as reductant. The resulting depletion of cellular GSH can be replaced by de novo synthesis through two
sequential ATP-dependent reactions catalyzed by c-glutamylcysteine synthetase (c-GCS) the rate-limiting enzyme and glutathione synthetase.
Reprinted with permission from (Masella et al., 2005).

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the cytotoxicity of ROS. In fact, the efciency of the entire GSH cycle, which is determined by the functionality of glutathionerelated enzymes and the availability of amino acids, is of fundamental importance.
With respect to sexgender differences, some papers dealing with the implication of GSH in sexgender differences at
cellular level have pointed out that GSH and GSSG clearly represent key factors in XX and XY cell physiology and pathology
(Malorni et al., 2007). Although large variations in sulfur amino acid content occur in the human diet, these variations are not
correlated simply with GSH levels in vivo as reected in the blood plasma pool. Plasma levels of GSH vary with sexgender,
age, and dietary habits, and these factors could affect the risk of toxicity (Jones et al., 1995; Malorni et al., 2007). However, as
concerns nutrition, few specic data are available so far.
7.3.2. Exogenous antioxidants
The defense against the detrimental effects of ROS achieved by nutritional antioxidant molecules has been considered
pivotal in determining the risk of disease. There is ample epidemiological evidence to support the health benets of diets
rich in fruits, vegetables, legumes, whole grains and nuts; however, evidence that these effects are due to specic nutrients
or phytochemicals is limited, and even less is known about the gender specicity of their effect. The ingested amount depends on the diet type, antioxidant type (vitamin A, vitamin E, vitamin C, single polypenol) and bioavailability of the single
component. Other diet components, such as minerals (e.g., zinc, copper, iron, and selenium), play relevant roles in cell defenses against oxidative stress, and are present in many antioxidant enzymes, such as superoxide dismutase and glutathione
peroxidases. However, some minerals can also be involved in free radical generation and oxidative stress by Fenton reactions
that are initiated with transition metals and hydrogen peroxide, leading to the formation of highly unstable radicals that affect biological macromolecules (Youdim et al., 2005).
7.3.2.1. Vitamins and the redox state of the cell. Vitamin E molecules readily donate hydrogen to free radicals, making them
inactive and becoming relatively unreactive free radicals themselves. The primary oxidation product of a-tocopherol is
a-tocopheryl quinone, which can be conjugated to yield glucuronate after reduction to hydroxyquinone. The major biological
role of vitamin E is to protect polyunsaturated lipids in plasma membranes and lipoproteins from free radical attack. More
recent research demonstrated that tocotrienols play a specic role that goes beyond their known vitamin E antioxidant activity (Parker et al., 1993; Sen et al., 2007). A growing body of evidence supports the concept that a-tocopherol has properties
independent of its antioxidant/radical scavenging ability and that these properties are linked to its capability of modulating
specic signaling pathways (e.g., ROS-generated pathways) and transcription factors, thus modifying cell fate and functions
(Galli and Azzi, 2010).
Vitamin A has many important physiological functions during development and adult life through its regulation of cell
processes such as proliferation and differentiation, and it acts on the central nervous system, reproductive system, visual
system, cardiovascular system and other systems in the body. Retinoic acid, the active derivative of vitamin A, acts through
retinoid receptors, which are ligand-induced transcription factors that belong to the nuclear receptor family (Pemrick et al.,
1994). Retinoic acid is involved in signal transduction pathways that regulate embryonic development, tissue homeostasis,
and cellular differentiation, proliferation, and metabolism. Besides the cellular control capacity, vitamin A has antioxidant
properties, principally in lipophilic environments, due its liposolubility. However, evidence exists that it also has pro-oxidant
properties (Dal-Pizzol et al., 2001; Zanotto-Filho et al., 2008). The antioxidant properties of carotenoids closely relate to a
number of conjugated double bonds within the central part of the molecules and to various functional groups on ring structures (Burton and Ingold, 1984). The main carotenoid, b-carotene, has two 6-carbon rings separated by an 18-carbon conjugated chain of double bonds. Carotenoids are very efcient at scavenging singlet oxygen and peroxyl radicals but, also at
quenching singlet oxygen, as for lycopene, (Di Mascio et al., 1989).
A further important actor is vitamin C, ascorbic acid. It is an electron donor, and it is likely that all of its biochemical and
molecular roles are based on this function. Vitamin C is indeed a powerful antioxidant because it can donate a hydrogen
atom to form a stable ascorbyl free radical, which can be converted back to reduced ascorbate or can undergo further oxidation to dehydroascorbate. This latter, although unstable, is more fat-soluble than ascorbate, and it is very rapidly taken up
by erythrocytes, where it can be reduced back by GSH or NADPH.
On the other hand, pro-oxidant activity has also been detected for other vitamins. Paradigmatic is the case of vitamin K,
or, more appropriately, a group of 16 known vitamin K-dependent proteins. For example, naturally occurring vitamin K compounds comprise a plant form, phylloquinone (vitamin K(1)) and a series of bacterial menaquinones (vitamin K(2)) as well as
menadione (vitamin K3). Genetic loss of less-critical K proteins, dietary vitamin K inadequacy, human polymorphisms or
mutations, and vitamin K deciency induced by chronic anticoagulant (warfarin/coumadin) therapy are all linked to ageassociated conditions, such as bone fragility after estrogen loss (osteocalcin) and arterial calcication linked to cardiovascular disease, which are of great importance from a sexgender perspective (McCann and Ames, 2009). Putative non-cofactor
functions of vitamin K include the suppression of inammation, the prevention of brain oxidative damage and a role in
sphingolipid synthesis. Anticoagulant drugs block vitamin K recycling and, thereby, the availability of reduced vitamin K.
Phylloquinone is transported mainly by triglyceride-rich lipoproteins, whereas menaquinones are transported mainly by
LDL, which in turn can undergo oxidation. In this complex scenario, these vitamins can activate the steroid receptors that
initiate their catabolism. This may also be of relevance from a gender perspective. An important issue in this eld is represented by the increased risk of fracture in humans, mainly in women. Disturbances of vitamins (e.g., of vitamins A, D, and K)

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in the diet have widely been considered as a pathogenetic and therapeutic challenge for the management of postmenopausal osteoporosis (Lewiecki, 2009; Mitchner and Harris, 2009).
7.3.2.2. Dietary polyphenols as antioxidants. Polyphenols were discussed in Section 3.2 here, we will specically discuss their
capacity to counteract conditions of oxidative stress that accompany many pathologies, such as diabetes mellitus, ischemiareperfusion, cancer, and inammatory diseases. Several polyphenols have been demonstrated to have clear antioxidant
properties in vitro because they can act as chain breakers or radical scavengers depending on their chemical structures,
which also inuence their antioxidant power (Hu et al., 1995; Nijveldt et al., 2001; Rabbia et al., 2002; Rice-Evans, 1995,
2001; Rice-Evans et al., 1996). As a consequence, many of their biological actions have been attributed to those antioxidant
properties (Luximon-Ramma et al., 2002). Polyphenols can also exert multiple biological effects mainly through direct interactions with receptors or enzymes involved in signal transduction (Masella et al., 2005).
In particular, experimental data indicate that they may offer an indirect protection by activating the endogenous defense
system and show the existence of a tight interrelation between endogenous antioxidants (specically, GSH and its related
enzymes) and dietary polyphenols (Steele et al., 2000). Extra virgin olive oil polyphenols, such as oleoeuropein and protocatechuic acid (PCA) upregulate the expression and the activity of both GPx and GR in macrophages (Masella et al., 2004).
Recently, new evidence has been provided that PCA increases the expression of glutathione-related enzymes, mainly by
inducing the JNK-mediated phosphorylation of the transcription factor nuclear related factor (Nrf)2, a major regulator of
antioxidant/detoxifying enzymes (Vari et al., 2010) (Fig. 8). This nding further supports the concept that PCA, as well as
several other polyphenols, improves antioxidant cellular defenses in critical target cells such as macrophages, whose dysfunction has been implicated in many pathophysiological processes that entail inammation and atherogenesis (Sica
et al., 2007; Yan and Hansson, 2007). In light of the recently published work on the sexgender disparities in macrophages
(Amoruso et al., 2009; Corcoran et al., 2010), this point could provide important new insights in the eld of inammation.
Moreover, several other protective effects have been recently described for PCA, such as antiviral, antimicrobial, antiinammatory and anticarcinogenic effects, and the ability to interact with cell receptors or modulate certain signaling pathways, including cell injury and death processes (Halliwell et al., 2005). Thus, PCA is a good candidate for the development of
cytopathological studies on cell sex. However, these data were obtained by in vitro studies and not in vivo. Hence, it is not
yet known whether they can be translated into humans. A further interesting point has been raised by the elegant works of a
Spanish research group. These authors observed that mitochondria from females produce fewer ROS than those from males.
Interestingly, phytoestrogens, which are present in soy and wine, may have some of the effects of estrogens. They may
increase the expression of longevity-associated genes, including those encoding the antioxidant enzymes (e.g., superoxide
dismutase and glutathione peroxidase), without their undesirable effects (Vina et al., 2005).
7.4. Nutrients as modulators of XX and XY cell fate
All three forms of cell injury, necrosis, apoptosis and autophagy, have been associated with human pathological conditions. In some instances, a defect of injury is pathogenetic; in others, an excess of injury causes a disease. In any case, the

Fig. 8. Polyphenols induce phase II gene expressions through ARE activation. Polyphenols induce phase II genes by inuencing the pathways that regulate
ARE/EpRE activation. Polyphenols may (i) modify the capability of Keap1 in sequestering Nrf2 and/or (ii) activate MAPK proteins (ERK, JNK and p38),
probably involved in Nrf2 stabilization. Nrf2 would thus translocate in the nucleus where it would transactivate the ARE/EpRE containing promoter of phase
II genes. Reprinted with permission from (Masella et al., 2005).

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association between nutrient-induced dysmetabolism and cell stress, mainly due to ROS formation or intracellular antioxidant function failure, may lead to increased cell death. Conversely, certain nutrients or diet components can function as cell
protectants and help cells survive in adverse conditions (e.g., in adverse microenvironmental conditions). In this regard, it is
worth noting that polyphenols have contrasting effects on the physiological processes of cells, such as proliferation and
apoptosis. Specically, they can either improve survival and protect cells against cytotoxicity by inhibiting apoptosis or, conversely, induce apoptosis and prevent tumor growth, depending on the concentration and the cell system studied (Chung
et al., 2003). Because dysregulated apoptosis characterizes chronic-degenerative diseases, polyphenols have been proposed
as therapeutic agents for several pathologies, including cancer and cardiovascular diseases (Giovannini et al., 2007).
Sexgender disparity in human pathology has only partially been investigated so far. For example, some disturbances of
the immune system homeostasis, including autoimmune or infectious diseases (e.g., systemic lupus erythematosus, AIDS)
have been associated with both sexgender disparity and cell death disturbances. In the same vein, pharmacological treatments aimed at controlling cell damage can exert differential effects in men and women. The interaction of these issues with
food nutrients and their metabolism still remains a matter of debate and an innovative end-point in preventive medicine as
well as in the management of human diseases. In this chapter, some of these important points will specically be described.
However, the general idea is that diet components could represent a sort of risk factor or additional risk factor for human
diseases, whereas they can also represent a formidable option for the challenge of nutritional and nutriomic research in the
near future: the possibility to develop a specic eld of investigation that takes into account the possible implication of
nutrients as key factors in determining cell fate and, consequently, the occurrence of gender disparities in human cell injury-associated human diseases. In few words, if disturbances of cell death programs represent pathogenetic determinants
and if the programming for death depend on, among other factors, the cell sex, it is conceivable that future nutritional studies should address this point: how does food intake inuence (induce or prevent) the onset or progression of human diseases
from a sexgender perspective?
7.4.1. Necrosis
Cellular necrosis can be induced by a number of external sources, including injury, infection, cancer, infarction, poisons,
inammation and a lack of nutrients. Necrosis is a form of cell death caused by ATP depletion and the rapid disruption of cell
membrane integrity, resulting in spillage of intracellular contents into interstitial and extracellular space, which initiates
inammation and damages neighboring cells (Searle et al., 1982). Necrosis was traditionally considered as a passive and
chaotic process. Emerging evidence indicates that specic molecular pathways underlie cellular destruction during necrosis.
Genetic and biochemical evidence shows that necrosis is orchestrated and executed by appropriate mechanisms, depending
on the death-initiating stimulus (Tavernarakis, 2007; Vanlangenakker et al., 2008). Cells suffer necrosis when exposed to
excessive stress and adverse environmental conditions such as a lack of oxygen or essential nutrients (i.e., in the case of
ischemia during a heart attack or following stroke), elevated temperature, toxic or corrosive compounds and excessive
mechanical strain or trauma (Tavernarakis, 2007). An important and highly relevant corollary in the investigations on the
mechanisms of necrosis is the emerging potential for prevention or therapeutic intervention. Although necrotic cell death
was once considered inevitable after being induced, the recent identication of signaling pathways and genes required
for cell demise offers opportunities for the development of innovative intervention strategies that counteract or ameliorate
pathological conditions with a signicant necrosis component. The study by Casey et al. (2007) holds such a promise for
heart damage following acute myocardial infarction and ischemia. In this and other cardiovascular pathologies, the ensuing
cardiomyocyte cell death is a major contributor to heart dysfunction and failure. Very little information, however, is available on the possible sexgender differences in the susceptibility to necrotic insults. In fact, literature data are referred to
toxic and pro-oxidant insults only, and lead us to hypothesize that further studies in this eld are required (Hirata-Koizumi
et al., 2008; Kataranovski et al., 2009; Oliver et al., 2009).
7.4.2. Apoptosis
Apoptosis plays a key role in the pathogenesis of a variety of human diseases, including degenerative or dysmetabolic
diseases. Briey, apoptosis, also called type 1 programmed cell death, is an energy-dependent, genetically determined process by which cells self-destruct. The early phases of this process are characterized by cytoplasmic shrinkage, compaction
and aggregation of chromatin to the nuclear membrane; these initial events produce the condensed, contracted nuclear
and cytoplasmic particles that are evident at later stages. Apoptosis occurs after the engagement of TNF family receptors
(CD95/Fas, TNF-a, TRAIL, etc.) or as a result of the direct targeting of certain drugs (e.g., staurosporine) on the mitochondria,
and proceeds through the activation of a complex cascade of specic proteases, caspases, or other lysosomal proteases such
as cathepsins, to cell death (Degterev and Yuan, 2008).
In addition to apoptotic programmed cell death, several additional issues could be modulated by food intake into a cell,
including reversible cell alterations such as changes of cell contractility or changes in cellcell interaction pathways. Transient starvation (i.e., the transient lack of certain essential nutrients such as growth factors) of any cell activates a complex
framework of intracellular events with the aim of counteracting this injury. One of these events, autophagy, a housekeeping
mechanism of cytoprotection, will be described below. However, the cell response to stressors (e.g., to the ROS increase) normally takes place very rapidly, and the cytopathological changes mentioned above are usually overwhelmed. For example,
the pro-oxidant status caused by certain nutrient excess or defect can lead to signicant alterations of cell cytoskeleton

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integrity (e.g., a side-by-side crosslinking of laments due to oxidation of thiol groups) that can be counteracted by providing
the cell with a cysteine-rich diet.
A good example of cell damage due to the lack of cell food can be represented by the apoptotic cell death observed in a
variety of cardiovascular diseases. Cardiomyocyte apoptosis occurs in end-stage heart failure and may contribute to heart
failure in a variety of situations (Clarke et al., 2007). In myocardial infarction (MI), myocytes initiate apoptosis in response
to ischemia, but, owing to the energy demands of the program and the dwindling respiratory capacity of the cells, apoptosis
stalls. Therefore, during prolonged ischemia, myocytes shift from an initial apoptotic to a necrotic fate, whereas oxygen is
restored following reperfusion, allowing apoptosis to complete. The key to deciding the myocyte fate is the level of ATP, a
factor required for the completion of apoptosis in most cells. Thus, acute MI manifests both forms of cell death, with apoptosis occurring predominantly at the hypoperfused border zones between a central area of necrosis and viable myocardium.
Hence, as a general rule, the nutrient deprivation associated with ischemic insults can trigger cell suicide (Nakai et al., 2007).
Furthermore, the pathophysiology of atherosclerosis, an inammatory condition triggered by the presence of lipids in the
vascular wall and one of the main risk factors for coronary heart disease and other cardiovascular diseases, involves both
apoptosis and proliferation at different phases of its progression. Specically, apoptosis is frequently observed in endothelial
cells, macrophages, and VSMCs in atherosclerotic plaques (Seimon and Tabas, 2009). In early lesions, the apoptosis of endothelial cells promotes platelet and neutrophil aggregation and induces up-regulation of inammatory genes and cytokine
release, thereby amplifying the inammatory response. In advanced atherosclerotic plaques, up to 50% of the apoptotic cells
are macrophages, and this may promote core expansion and plaque instability (Littlewood and Bennett, 2003). Finally, VSMC
apoptosis may cause the rupture of the brous cap, leading to collagen exposure, platelet activation, thrombosis and potential occlusion (Littlewood and Bennett, 2003; Siow et al., 1999). Epidemiological studies have reported that polyphenol intake is associated with a reduced risk for cardiovascular diseases (Arts and Hollman, 2005; Hertog et al., 1995). Several
mechanisms have been proposed by which polyphenols may exert these protective effects (Curin and Andriantsitohaina,
2005), including plasma cholesterol and triglyceride reduction, blood pressure control, the inhibition of platelet aggregation,
the promotion of NO-induced endothelial relaxation, and the inhibition of LDL oxidation (Covas et al., 2006; Estruch et al.,
2006; Fito et al., 2005; Franconi et al., 2006a; Masella et al., 2004; Medina-Remon et al., 2010). A more detailed discussion on
clinical studies and polyphenols are reported in Sections 7.3.2.2 and 3.2.
Because plaque rupture is mainly related to apoptosis, an important role in preventing the onset and progression of atherosclerosis may be played by the anti-apoptotic activity of polyphenols on cell homeostasis. There is in vitro evidence that
polyphenols exert protective effects against oxidized LDL- and H2O2-induced apoptosis in human endothelial cells, VSMCs
and broblasts by affecting several proteins and signaling factors (Ruiz et al., 2006) such as caspases and MAPKs (Martin
et al., 2003; Ou et al., 2006). We have recently found (Giovannini et al., in preparation) that the treatment of J774-A1 murine
macrophages with PCA counteracted the oxidized LDL-induced activation of the mitochondrial pathway not only by inhibiting ROS production and GSH depletion but also by modulating the balance between pro-and anti-apoptotic proteins
belonging to the Bcl family. Specically, Bcl-Xl levels were signicantly decreased, whereas the anti-apoptotic Bcl-2 protein
was over-expressed. Furthermore, PCA was able to counteract the oxidized LDL-induced increase in p53 and p66Shc expression, key signals in determining cell fate, suggesting that these molecules could be the primary targets in its anti-apoptotic
activity.
A growing body of evidence indicates that polyphenols can exert pro-apoptotic effects in cancer cells by directly interacting with the specic proteins and signaling pathways responsible for the regulation of the apoptotic process. In particular,
these pro-apoptotic activities are frequently associated with the activation of p53 (Fini et al., 2008; Halder et al., 2008). However, the apoptosis induced by different polyphenols appears to be mediated by the activation of different signaling pathways, and these differences probably depend on the cell type and/or the polyphenol used. Epigallocathechine gallate,
which is found in green tea and shows strong anticancer activity, activates JNK pathway in human colorectal carcinoma cells,
whereas in human prostate carcinoma cells, it stabilizes p53 and down-regulates NF-jB (Ramos, 2007), as do the polyphenols of extra virgin olive oil in human monocytes and in macrophages derived from monocytes (Brunelleschi et al., 2007).
Sexgender can represent a key variable in this issue. A different apoptotic susceptibility may be found in cells from males
and females. In particular, smooth muscle cells from male rats more readily undergo oxidative stress-mediated apoptosis in
comparison with cells from females (Malorni et al., 2008). Cells from females may be more plastic, adapting themselves to
microenvironmental changes. Fittingly, the antioxidant defenses are apparently different from XX and XY cells, and this can
lead to or contribute to the observed sexgender disparity (Malorni et al., 2008). In particular, cells from females appear to be
more resistant to stressors. As a consequence, exogenous supplementation with antioxidants may be mainly fruitful to XY
cell survival. On the other hand, XX and XY cells may respond differently to nutrients, likely because of different interactions
between the nutrients and genes.
7.4.3. Autophagy
Authophagy, also called type 2 programmed cell death, was initially considered a cell death mechanism characterized by
the presence of an abnormal (auto)phagic behavior of non-professional phagocytes that engulf and digest organelles and
other materials. However, the role of autophagy should be considered a sort of housekeeping behavior that allows the cells
to recycle debris and represents a survival option more than a cell death mechanism (Reggiori and Klionsky, 2005). Autophagy
is thus considered a key cytoprotection mechanism characterized by the sequestration of cytoplasm in double-membraned
vesicles called autophagosomes. Autophagosomes subsequently fuse with lysosomes, leading to the degradation of their

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content. This process is important for cellular homeostasis and is a survival response upregulated in response to stress or starvation. However, excess autophagy can lead to cell death due to the excessive digestion of organelles and essential proteins
(Kitsis et al., 2007; Tinari et al., 2008).
Dysmetabolic conditions, starvation or the withdrawal of growth factors or nutrients are typical inducers of autophagy. In
particular, the alterations of this important cytoprotective process can be triggered by adverse microenvironmental conditions in which the cells fail to receive enough nutrients and try to counteract this energy deciency by using (i.e., recycling)
all wasted materials inside their cytoplasm. Thus, autophagy represents a mechanism of housekeeping that can parallel proteosomal function and be triggered in absence of certain nutrients. For example, regarding the heart, autophagy can function
as a pro-survival pathway during nutrient deprivation, ischemic damage and other forms of cellular stress (Decker and
Wildenthal, 1980; Hamacher-Brady et al., 2006; Martinet et al., 2007; Mizushima et al., 2004; Nakai et al., 2007; Sybers
et al., 1976; Yan et al., 2005). Autophagosomes increase in response to sub-lethal ischemia in the perfused heart suggesting
that active autophagy may serve as a protective response to myocardial ischemia-reperfusion injury (Decker and Wildenthal,
1980). Chronic ischemia may induce autophagy and increase lysosomal activity in the myocardium (Yan et al., 2005). However, further studies are required to better elucidate the conditions under which autophagy provides protection versus cell
death.
Sexgender dependent differences in adaptation to nutrient starvation have been poorly investigated and are thought to
hinge on female versus male preferences for fat versus protein sources, respectively. However, whether these differences can
be reduced to neurons, independent of typical nutrient deposit such as adipose tissue, skeletal muscle, and liver, was previously unknown. An elegant work (Du et al., 2009) showed that segregated male neurons in culture are more vulnerable
to starvation than neurons from females. Nutrient deprivation decreased mitochondrial respiration, increased autophagosome formation, and produced cell death more profoundly in neurons from males versus females. Starvation-induced neuronal death was attenuated by 3-methyladenine, an inhibitor of autophagy; Atg7 knockdown using small interfering RNA; or
L-carnitine, which is essential for the transport of fatty acids into mitochondria. All these experimental procedures were
more effective in neurons from males instead of females.
Relative tolerance to nutrient deprivation in neurons from females was associated with a marked increase in triglyceride
and free fatty acid content and a cytosolic phospholipase A2-dependent increase in the formation of lipid droplets. Importantly, similar sex differences in sensitivity to nutrient deprivation were seen in broblasts. However, although the inhibition
of autophagy using Atg7 small interfering RNA inhibited cell death during starvation in neurons, it increased cell death in
broblasts, implying that the role of autophagy during starvation is both sex- and tissue-dependent and, probably, cell cycle-dependent. Thus, during starvation, neurons from males more readily undergo autophagy and die, whereas neurons from
females mobilize fatty acids, accumulate triglycerides, form lipid droplets, and survive longer.
7.4.4. Cross-talk between apoptosis and autophagy
Autophagic and apoptotic pathways are regulated by certain common factors and share common components, each of
which may regulate and modify the activity of the other (Hsieh et al., 2009; Levine and Yuan, 2005). For instance, ROS trigger
apoptosis and are also essential for autophagy and specically regulate Atg4 activity (Nishida et al., 2008). Mitochondria may
function as a switch between apoptosis and autophagy (Nishida et al., 2008). Depolarization of mitochondria during the
mitochondrial permeability transition in response to low-intensity stress leads to the induction of autophagy, which
selectively removes damaged mitochondria as a cytoprotective mechanism (Kim et al., 2007). With increasing stress, proapoptotic factors are released from mitochondria undergoing the mitochondrial permeability transition. Under extreme
stress (e.g., by a prolonged lack of nutrients or interaction with certain ligands), the mitochondrial permeability transition
occurs in all mitochondria and the intracellular supply of ATP is exhausted. An important challenge in this eld is represented by autoimmune diseases, which are often more frequent in women. A specic connection between dietary factors
and the onset of autoimmunity or modulation is a very recent nding in medicine and in studies dealing with the role of
apoptosis in the maintenance of the immune system homeostasis (Selmi and Tsuneyama, 2010).
A functional and efcient intracellular metabolism of nutrients represents a pre-requisite for all cell processes (i.e., either
for cell proliferation or cell damage and, eventually, death). The study of the cell microenvironment and the analysis of the
metabolic features of the cell, considered the main minimal unit composing the different tissues, have been vastly improved
in recent years. This is because disturbances of micronutrient availability, as well as alterations of the extra and intra-cellular
milieu, are key factors in the maintenance of cell homeostasis, which regulates tissue homeostasis. Disturbances in micronutrients or their uptake by the cell, a lack of specic nutrients or an excess of others, or the imbalance of the redox state of
the cell lead to alterations of cell fate, (i.e., in terms of proliferation or death rates). Each of these changes to the cells own
program is detrimental to the organism, so almost all human pathologies are associated with increased or decreased values
of these two key parameters. On the other hand, we have known for many years that human diseases often display significant gender disparities. This is the case for immune, cardiovascular, neurodegenerative and infectious diseases as well as
several forms of cancer (Paggi et al., 2010; Ruggieri et al., 2010). Several, if not all these diseases, reect or are due to cell
dysmetabolisms and/or alterations of nutritional needs. They are the result of a complex framework of events that needs
the continuous balance of intracellular signals to decide between cell survival and death. The idea that the sexgender or
cell sex issue could inuence cell fate is quite new and intriguing. As a general rule, the literature clearly suggest that hormones can strongly inuence cell fate (e.g., that the hormone receptors can be modulated to impact all cell processes and
that besides or despite hormones, cells from males and females have different metabolic needs and nutritional agent

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processing or detoxication features). Furthermore, under stress, cells from males and females undergo different responses,
with cells from females being capable of a more efcient adaptive response. Altogether, these insights demand a reappraisal
of the pathogenetic mechanisms of several human diseases from a gender perspective, and the nutritional issue clearly represents the most complex but also the most fascinating challenge of cell biology and cell pathology studies in the near future.
8. Conclusions
Food and beverages are the only physical matter that mammals, including humans, take into their body, with the only
exception being air and drugs. It is therefore reasonable that nutrition exerts the strongest life-long environmental impact
on human health. The interplay between nutrition and health has been known for centuries. As an example, James Lind, a
Scottish surgeon in the British Royal Navy, described the value of lemon citrus in the treatment of scorbutus in his 1753 book
A Treatise of the Scurvy (Bartholomew, 2002). This could be considered as a paradigmatic example of the reappraisal of
using nutrients in medical care that thus took place about 300 years ago.
Nutrition research has entered a new era that is attempting to translate empirical knowledge to evidence-based molecular nutrition as occurs in other medicinal elds. This translation is a real need because food components interact with our
organism at the organ, cellular and molecular levels. The nutritional improvement of one health aspect must not be compromised by deterioration of another (Kussmann et al., 2007). Hence, nutritional studies can provide clues useful to the understanding of the pathogenetic determinants of human diseases and/or give rise to important prevention strategies (for
instance, see the series of works claiming for caloric restriction in the prevention of human diseases, including cancer)
(Longo and Fontana, 2010).
Hence, the control of cell fate represents an important and innovative target for biomedical research and a challenge for
nutritional studies such as studies in early life events.
Beyond evidence-based nutrition and evidence-based medicine, personalized nutrition and personalized medicine are
now invoked to adapt food and medicine to individual needs. A rst step to obtain personalized nutrition is the consideration
of physiological sexgender differences because they can affect many processes, including food and liquid bioavailability and
metabolism.
Vast differences exist in bioavailability both within and among nutrient groups (Ammerman et al., 1995; Groff et al.,
1995); what is less known is how sex and gender affect the bioavailability even though the above reported observations
strongly suggest that sexgender play a fundamental role in bioavailability of foods and liquids. This is of particular relevance today because through engineering food crops, it is possible to increase the concentration of specic nutrients (Grusak
and DellaPenna, 1999). It is also relevant because of the presence of a multitude of so-called nutritional supplements that
are available without prescription, forgetting that essential nutrients at higher dose levels (e.g., selenium, cysteine, and vitamins) could modify the safety prole, producing toxic effects, and these could occur in a sexgender-specic manner.
Considering the physiological differences between men and women, food and beverages could also have different healthy
benets in men and women. As an example, consider the availability of many compounds with estrogenic activities; they can
affect many parameters in a sexgender way, but different effects are not limited to food and beverages that contain estrogenic compounds. However, understanding the effect of diet on disease in the context of dietary intake, such as intake of
nutrients that can mimic endogenous hormones like estrogen, may provide a unique perspective to the problem of sex differences in cardiovascular risk, prognosis, and outcome avoiding toxic effects.
Although modern nutrition research focuses on health promotion, disease prevention, performance improvement, and
risk assessment, it is still a relatively young compared to clinical and medical applications. The future development and success of nutrition and health will depend on several factors, including study design, which should be based on standardized
diets and ingredients and stratied cohorts and ideally follow a double-blinded, placebo-controlled crossover design that includes data generation, analysis and processing and addresses genetic and epigenetic phenomena. All of these steps must
consider sexgender-specic aspects.
Acknowledgments
Some experimental concepts described in this paper are based on work conducted in the laboratories of the authors.
These experimental studies are supported by grants from the Ministry of Health Ricerca Finalizzata-2008. The authors thank
past and present members of their laboratories who contributed with data and discussions to the ideas presented here.
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