NIH CONFEREIUCE
Interactions between the Hypothalamic-Pituitary-Adrenal Axis and
the Female Reproductive System: Clinical Implications
George P. Chrousos, MD; David J. Torpy, MB, BS; and Philip W. Gold, MD
The hypothalamic-pituitary-adrenal axis exerts profound,
multilevel inhibitory effects on the female reproductive
system, Corticotropin-releasing hormone (CRH) and CRH-
induced proopiomelanocortin peptides inhibit hypotha-
lamic gonadotropin-releasing hormone secretion,
whereas glucocorticoids suppress pituitary luteinizing hor-
mone and ovarian estrogen and progesterone secretion
and render target tissues resistant to estradiol. The hypo-
thalamic-pituitary-adrenal axis is thus responsible for the
"hypothalamic" amenorrhea of stress, which is also seen in
melancholic depression, malnutrition, eating disorders,
chronic active alcoholism, chronic excessive exercise, and
the hypogonadism of the Cushing syndrome. Conversely,
estrogen directly stimulates the CRH gene promoter and
the central noradrenergic system, which may explain adult
women's slight hypercortisolism; preponderance of affec-
tive, anxiety, and eating disorders; and mood cycles and
vulnerability to autoimmune and inflammatory disease,
both of which follow estradiol fluctuations. Several com-
ponents of the hypothalamic-pituitary-adrenal axis and
their receptors are present in reproductive tissues as auta-
coid regulators. These include ovarian and endometrial
CRH, which may participate in the inflammatory processes
of the ovary (ovulation and luteolysis) and endometrium
(blastocyst implantation and menstruation), and placental
CRH, which may participate in the physiology of pregnancy
and the timing of labor and delivery. The hypercortisolism
of the latter half of pregnancy can be explained by high
levels of placental CRH in plasma. This hypercortisolism
causes a transient postpartum adrenal suppression that,
together with estrogen withdrawal, may partly explain
the depression and autoimmune phenomena of the post-
partum period.
This paper is also available at http:/'/www.acponline.org.
Ann Intern Med. 1998:129:229-240.
For a glossary of terms used in this paper, see end of text.
An edited summary of a Clinical Staff Conference held on 20
Novcmher 1996 at the National Institutes of Health. Bethesda.
Maryland.
Authors who wish to cite a section of the conference and spe-
cifically indicate its author may use this example for the form of
the referenee:
Torpy D. Hypothalamic-pituitary-adrenal axis and the female
reproductive system, pp 230-232. In: Chrousos GP. moderator.
Interactions between the hypothalatnic-pituitary-adrenal axis and
the female reproduetivc system: clinical implications. Ann Intern
Mcd. 1998:129:229-240.
1 August 1998 • Annals of Internal Medicine
D r. George P. Chrousos (Developmental Endo-
crinology Branch, National Institute of Child
Health and Human Development [NICHD], Na-
tional Institutes of Health [NIH], Bethesda, Mary-
land): Ancient physicians knew of the adverse ef-
fects of stress on the reproductive system (1, 2). In
the 5th century BCE, Hippocrates of Cos explained
the impotence and infertility of the Scythians, no-
madic tribes living in what is now southern Ukraine,
as a result of their rough lives. About the men, he
wrote, "From the cold and tiredness they forget
their sexual drive and their desire to come into
union with the other sex"; about the women, he
stated, "... nor is their menstrual discharge such as
it should be, but scanty and at too long intervals."
About 500 years later. Soranos of Ephesus pub-
lished the following differential diagnosis of amen-
orrhea in his pioneering treatise on gynecology and
perinatology:
Of those who do not menstruate, some have no ail-
ment and it is physiological for them not to menstru-
ate, either because of their age. as in those too young
or too old, or because they are pregnant, or barren
singers and athletes. Others, however, do not menstru-
ate because of a disease of the uterus or of the rest of
the body, for example when subjected to under-nour-
ishment. great emaciation and wasting or to the accu-
mulation of fatty flesh, or cachexia. or fevers and long
ailment.
The hypothalamic-pituitary-adrenal axis, to-
gether with the arousal and autonomic nervous sys-
tems, constitutes the stress system (Figure 1). This
system is activated during stress and produces the
clinical phenomenology of what Hans Selye de-
scribed as the stress syndrom.e (3). Indeed, during
stress, several changes take place in the central ner-
vous system and periphery of mammals, changes
that help preserve the individual and the species.
These include the mobilizing of adaptive behaviors
and peripheral functions and the inhibiting of bio-
logically costly behaviors and vegetative functions,
such as reproduction, feeding, and growth.
The principal molecular regulators of the hypo-
thalamic-pituitary-adrenal axis are corticotropin-
releasing hormone (CRH), a 41-amino acid peptide,
and the nonapeptide arginine-vasopressin, both of
which are secreted by parvicellular neurons of the
paraventricular nucleus of the hypothalamus into
• Volume 129 • Number 3 229
 STRESS
*• Catecholamines
Tissues
Figure 1. Interactions of the reproductive system with the hypo-
thalamic-pituitary-adrenal axi5 and locus ceruleus-norepinephrine
system (tCWf). Stress generally inhibits the female reproductive system
{middle) primarily through the hypothalamic-pituitary-adrenal axis Heft)
through 1) suppression of hypothalamic gonadotropin-releasing hormone
secretion by corticotropin-releasing hormone (CflH) and CRH-induced p-
endorphin; 2) inhibition of hypothalamic gonadotropin-releasing hormone
{GnRH), pituitary luteinizing hormone {LH), and ovarian estradiol (fj,) secre-
tion by cortisol; and 3) cortisol-induced target tissue resistance to estradiol.
The locus ceruleus-norepinephrine system {right) provides positive input to
the reproductive system, which is frequently overcome by the stress-acti-
vated hypothalamic-pituitary-adrenal axis. However, sexual stimulation and
GnRH neuron activation may render the gonadal axis resistant to suppres-
sion by the hypothalamic-pituitary-adrenal axis. Through estradiol, the re-
productive system provides positive input to both components of the stress
system by stimulating CRH secretion and inhibiting reuptake and catabo-
lism of catecholamines. H-MSH = melanocyte-stimulating hormone; ACTH ^
adrenocorticotropic hormone; AVP = arginine-vasopressin; FSH = follicle-stim-
ulating hormone; NE (n) = norepinephrine stimulation via n-noradrenergic re-
ceptors; POMC = proopiomelanocortin. Solid line = stimulation; dotted line =
inhibition.
the hypophyseal portal system (3). There, they syn-
ergistically stimulate pituitary adrenocorticotropic
hormone (ACTH) secretion and, consequently, cor-
tisol secretion by the adrenal cortex. The noradren-
ergic brainstem neurons that regulate the central
arousal (locus ceruleus) and systemic sympathetic-
ad reno medullary systems are innervated and stimu-
lated by and reciprocally innervate and stimulate
the parvicellular hypothalamic CRH and arginine-
vasopressin neurons of the paraventricular nucleus.
The female reproductive system is regulated by
the hypothalamic-pituitary-ovarian axis (Figure 1).
Neurons that secrete gonadotropin-releasing hor-
mone in the preoptic and arcuate nucleus areas of
the hypothalamus secrete into the hypophyseal por-
tal system and stimulate the production of follicle-
stimulating and luteinizing hormones, which then
activate the ovary to secrete estradiol and proges-
terone (4). In addition to acting on their other
target tissues (other components of the central ner-
vous system, uterus, genitalia, and skin), both of the
gonadal steroids and another ovarian hormone, in-
hibin, exert negative feedback effects on the secre-
tion of follicle-stimulating and luteinizing hormones.
An excellent example of the effect of stress on
the female reproductive system is so-called stress-
230 1 August 1998 • Annals of Internal Medicine • Volume 129 • Number 3
induced or functional hypothalamic amenorrhea (5,
6). Indeed, the prevalence of sustained secondary
amenorrhea in normal young women is about 2%.
This rate increases markedly in proportion to
chronic stress, all the way up to 100% in prisoners
before execution. Thus, if severe enough, stress can
completely inhibit the female reproductive system.
During her reproductive years, a normal woman
is exposed to a monthly fluctuation of circulating
estradiol and progesterone that may affect her be-
havior, mood, and immune and other functions. In-
deed, epidemiologic data underscore the effect of
gonadal function on nonreproductive female pro-
cesses (7, 8). Thus, suicide attempts and allergic
bronchial asthma attacks correlate with the phase of
the menstrua! cycle, with fourfold increases in prev-
alence seen when the plasma estradiol level is at its
lowest (that is, in the late luteal and menstruation
phases) (9, 10). Other studies have suggested that
the period of peak estradiol secretion in the state
immediately before ovulation is associated with el-
evations in mood, a phenomenon that might con-
tribute to fecundity.
Hypothalamic-Pituitary-Adrenal Axis and
the Female Reproductive System
Dr. David Torpy (Developmental Endocrinology
Branch, NICHD, NIH): The hypothalamic-pituitary-
adrenal axis, when activated by stress, has an inhib-
itory effect on the reproductive system; teleologi-
cally, this makes sense (Figure 1; Table 1). Indeed,
the hypothalamic CRH neurons innervate and in-
hibit directly or indirectly, through proopiomelano-
cortin neurons, the hypothalamic control center of
the gonadal axis (11). In addition, glucocorticoids
secreted from the adrenal cortex act at the levels of
the hypothalamic. pituitary, gonadal, and end-target
tissues to suppress the gonadal axis. On the other
hand, estradiol exerts a negative, although indirect,
effect on the activity of the gonadotropin-releasing
Table 1. Interactions between the Stress System and the
Female Reproductive System*
Stress system
Hypothalamic-pituitary-adrenal axis
CRH inhibits gonadotropin-reieasing hormone secretion
(3-endorphin inhibits gonadotropin-releasing hormone secretion
Cortisol inhibits gonadotropin-releasing hormone secretion
Cortisol inhibits luteinizing hormone secretion
Cortisol inhibits estradiol and progesterone biosynthesis
Cortisol inhibits estradiol actions
Locus ceruleus-norepinephrine system
Norepinephrine stimulates gonadotropin-releasing hormone secretion
Reproductive system
Estradiol stimulates CRH synthesis
Estradiol stimulates cortisol-binding globulin secretion
Estradiol potentiates norepinephrine actions
' CRH = corticotroptn-releasing hortnotie.

Cortisol
Figure 2. Interactions of leptin with the stress system and the
female reproductive axis. Generally, this adipose tissue-derived hormone
inhibits the hypothalamic-pituitary-adrenal axis and stimulates the repro-
ductive system. Leptin inhibits the hypothaiamic-pituitary-adrenai axis at
both the hypothalamic and adrenocorticai levels. By contrast, leptin provides
positive input to the femaie reproductive axis through inhibition of the
hypothalamtc-pituitary-adrenal axis and arcuate proopiomelanocortin
iPOMCj neuronal system and through activation of the locus ceruleus-nore-
pinephrine system (LC/NE)- Leptin-induced inhibition of hypothalamic neu-
ropeptide Y (NPY) secretion participates in both the inhibition of the hypo-
thalamic-pituitary-adrenal axis and the activation of the locus ceruieus-
norepinephrine system. The inhibitory effect of proapiomelanocortin
neurons on the expression of neuropeptide Y via «-rnelanocyte-stimulating
hormone (a-MSH) and melanocortin receptor type 4 should be noted.
ACTH = adrenocorticotropic hormone; CRH = corticotropin-releasing hor-
mone; E; = estradiol; FSH = follicle-stimulating hormone; GnRH = gonado-
tropin-releasing hormone; LH = luteinizing hormone. Solid line = stimula-
tion; dotted line = inhibition.
hormone neuron, which has no detectable estrogen
receptor (12).
The interaction between the hypothalamic-pitu-
itary-adrenal and gonadal axes at the level of the
hypothalamus was directly examined in rhesus mon-
keys (13). Insulin-induced hypoglycemia caused an
increase in cortisol levels and a decrease in plasma
luteinizing hormone levels associated with reduced
electrical activity measured directly at the gonado-
tropin-releasing hormone neuron. When a CRH an-
tagonist was given intracerebroventricularly, the ef-
fect of insulin hypoglycemia on electrical activity at
the gonadotropin-releasing hormone pulse genera-
tor was greatly attenuated; this finding suggests that
CRH has a direct efFect on the hypothalamic neu-
rons that secrete gonadotropin-releasing hormone.
Glucocorticoids inhibit gonadal axis function at
the hypothalamic, pituitary, and uterine levels (14-
16). Sakakura and colleagues studied women who
had received prednisolone for various indications
for 1.5 to 5 months in daily doses ranging from 10
mg to 40 mg (15). All of these women had men-
strual disturbances associated with glucocorticoid
treatment, and the investigators found that pred-
nisolone reduced the peak luteinizing hormone re-
sponse to intravenous gonadotropin-releasing hor-
mone by about 60%. This suggests an inhibitory
effect of glucocorticoids on the pituitary gonadotroph.
1 August 1998 • Annals of Internal Medicine • Volume 129 • Number 3
Glucocorticoids also inhibit estradiol-stimulated
uterine growth (16). In one placebo-controlled ex-
periment done in rats, dexamethasone and estradio!
were administered for 5 days. Estradiol alone pro-
duced the expected increase in uterine weight; this
increase was significantly attenuated by daily co-
administration of dexamethasone, the effect of
which may be partly explained by the reduced in-
tracellular estrogen receptor concentrations mea-
sured in this experiment. Most likely, however, glu-
cocorticoid receptor-mediated inhibition of the
c-fos/c-jun transcription factor by protein-protein
interaction is primarily responsible for this inhibi-
tion (17); this factor is used in the signal transduc-
tion pathways of many growth factors and is directly
or indirectly stimulated by estrogen (18).
Estrogen, which is derived principally from the
ovaries, stimulates the hypothalamic-pituitary-adre-
nal axis (Figure 1). This had been suspected on the
basis of sex differences in hypothalamic-pituitary-
adrenal axis responses to stimuli in both animals
and humans (19). Compared with controls, pregnant
women and women receiving high-dose estrogen
therapy had elevated levels of free cortisol in both
morning and evening plasma samples (20). In addi-
tion, hypothalamic-pituitary-adrenal axis respon-
siveness is greater in women than in men. When
ACTH and cortisol responses to ovine CRH were
compared in 24 men and 19 women (21), the
ACTH peak response was significantly greater in
women and the cortisol response was characteristi-
cally prolonged in response to higher peak ACTH
levels.
Estrogen can induce hyperresponsiveness of the
hypothalamic-pituitary-adrenal axis to stimuli in
normal men; thus, this effect seems to be due to
estrogen rather than to other factors specific to
female physiology (22). Recently, estradiol patches
were given to normal men who were then subjected
to a psychosocial stressor—unprepared public
speaking—for 15 minutes. Cortisol and ACTH re-
sponses were greater in the estradiol recipients than
in the placebo recipients. Similarly, the plasma nor-
epinephrine response in these men was augmented
by estrogen, possibly because of the stimulation of
CRH neurons (which innervate and stimulate cen-
tral noradrenergic neurons) or because of direct
effects on the production or metabolism of norepi-
nephrine (23, 24). Estrogen stimulation of the hy-
pothalamic-pituitary-adrenal axis may be exerted
through interaction of the ligand-activated estrogen
receptor with specific DNA sequences, the estrogen-
responsive elements, in the promoter of the human
CRH gene (25, 26).
Estrogen may exert some of its physiologic neg-
ative feedback effect on the reproductive axis
through a subpopulation of CRH and proopiomel-
231

Luteinizing
hormone
Follicle-Stimulating
Hormone
Bslradiol
Progesterone
CRH
Leptin
Childhood
Figure 3. Hormonal changes and periods of increased vulnerability to mood disturbances and autoimmune disorders during a woman's life
span. The increasing activity of the reproductive axis during puberty and the decreasing activity of the same axis during the first stages of menopause are
associated with changes in Ihe activity of the stress system, represented here by changes in hypothalamic corticotropin-releasing hormone {CRH) secretion. The
monthly concurrent fluctuation of ovarian estradioi and hypothalamic CRH secretion is also shown (see Figure 4 for details).
anocortin neurons that inhibit gonadotropin-releas-
ing hormone and, hence, follicle-stimulating hor-
mone and luteinizing hormone secretion. Evidence
from studies in nonhuman primates suggests that in
the period immediately before ovulation, a decrease
in estradiol levels leads to reduced hypothalamic
CRH secretion. This effectively disinhibits the gona-
dotropin-releasing hormone (GnRH) neuron and
possibly participates in the generation of the ovula-
tory luteinizing hormone surge (27). This takes
place simultaneously with a delayed estrogen-in-
duced central noradrenergic surge that has an ad-
ditional positive effect on the gonadotropin-releas-
ing hormone neuron (24).
Estradiol also downregulates glucocorticoid re-
eeptor binding in the anterior pituitary, hypothala-
mus, and hippocampus: this tends to increase hypo-
thalamie-pituitary-adrenal axis activity by interfering
with glucocorticoid negative feedback, whereas pro-
gesterone opposes these effects (28). It is not known
whether the changes induced by estrogen in neuro-
nal CRH and glucocorticoid receptor activities are
mechanistically related, but they do alter the system
in the same direction. One should also keep in mind
the regulatory feedback loops and adaptations that
take place over time as new equilibria are estab-
lished in the relation shown in Figure 1 (29, 30).
The newly discovered adipocyte-derived peptide
hormone leptin interacts directly and indirectly with
both the adrenal and gonadai axes, and its levels are
higher in women than in men (31, 32) (Figure 2).
By promoting satiety and sympathetic system out-
232 1 August 1998 • Annals of Internal Medicme • Volume 129 • Number 3
Monthly Ructuation
I/' 1 1
r
. _
^ _
Inicmiitteni Vulnerability ^ H Pcriod.'i or
Vulnerabiliiy
1 ---
Puberty Reproductive Maturity Menooause
flow, leptin is thought to provide the peripheral
signal to a central mechanism regulating the size of
body fat stores (33). Leptin suppresses the hypo-
thalamic-pituitary-adrenal axis by inhibiting hypo-
thalamic CRH and adrenocortical cortisol secretion
(34, 35) while it stimulates gonadai function by po-
tentiating the activity of the gonadotropin-releasing
hormone neuron (36). Thus, increasing leptin may
be involved in the control of the onset of puberty, a
phenomenon long known to be temporally related
to the acquisition of a certain fat mass (36-38).
Low leptin levels may be involved in the adaptive
activation of the hypothalamic-pituitary-adrenal
axis and the inhibition of gonadai function that
takes place in starvation and anorexia nervosa (39-
41). Some of the effects of leptin on the central
nervous system are mediated by inhibition of the
potent orexogen neuropeptide Y, which normally
stimulates the CRH neuron and inhibits the locus
ceruleus-norepinephrine system (42-44).
Central and Peripheral Roles of
Corticotropin-Releasing Hormone
Dr. George P. Chrousos: The marked changes
that take place in a woman's reproductive system
during her life are bound to affect the functioning
of the stress system. The first of these changes takes
place at puberty, when gonadarche is slowly estab-
lished with increasing ovarian follicle growth and
circulating estradiol levels first and then the estab-
lishment of ovulatory menstrual cycles within the characteristic "hot flashes" and so-called climacteric
next 2 to 3 years (Figure 3). During this time, the depression (Table 2).
stress system receives increasing intermittent posi- "Reproductive" CRH has been identifled in var-
tive input from estradiol. Puberty is a period of ious reproductive tissues and can, accordingly, be
increasing vulnerability to disorders or states char- ovarian, testicular, endometrial, or placental. It is a
acterized by disturbances or changes in hypotha- form of "tissue" corticotropin-releasing factor
lamic CRH secretion (3, 45), such as melancholic (CRH found in peripheral tissues) and is analogous
and atypical depression, eating disorders, chronic to the "immune" CRH found in immune organs
active alcoholism or other addictions, and chronic and inflammatory sites (48). The functions of im-
active athleticism, as well as seasonal affective dis- mune CRH may shed light on those of reproductive
order, the chronic fatigue and fibromyalgia syndromes, CRH and are briefly discussed below.
and several autoimmune disorders (Table 2). Inflammatory sites examined by immunohisto-
Once established, the monthly fluctuations of es- chemistry and extraction-chromatography contain
tradiol that accompany menstrual cycles are ex- large amounts of immune CRH, which is identical
pected to influence the secretion of central nervous to hypothalamic CRH (48). Endothelial cells, mac-
system CRH and catecholamines until menopause rophages, and tissue fibroblasts all have CRH in
(Figure 4). Decreased secretion of CRH in the late their cytoplasm. Immune neutralization and CRH
luteal and menstruation phases would be expected antagonist experiments have demonstrated marked
and might help explain the presence of luteal dys- inhibition of inflammation indices, such as the vol-
phoric mood disorder (the premenstrual tension ume of the inflammatory exudate and its leukocyte
syndrome) and the increased incidence of suicides concentration (48-51). Immune CRH is present at
and enhanced vulnerability to autoimmune and al- high levels in many sites of experimental inflamma-
lergic inflammatory phenomena seen during these tion in the rat and mouse and in all natural inflam-
periods (7, 8, 46, 47) (Table 2). Finally, during the matory sites examined thus far in humans. The lat-
perimcnopausal period and early menopause, there ter include the inflamed joints of patients with
is a progressive, intermittent decrease in estradiol rheumatoid arthritis and osteoarthritis and the thy-
levels that would be expected to be associated with roid glands of patients with Hashimoto thyroiditis
decreased activity of the CRH and locus ceruleus- (52, 53). The exact mechanisms by which immune
norepinephrine systems and naight help explain the CRH exerts its proinflammatory actions are not
known, but one mechanism is the degranulation of
mast cells (54). Indeed, CRH causes vasodilation,
Table 2. Potential Pathogenic Effects of Central and increases vascular permeability, and allows extravasa-
Peripheral Corticotropin-Releasing Hormone
in Women* tion of plasma through the capillary vessel walls (48).
In inflammatory sites, CRH is not only generated
Changes States
by immune system cells but is also secreted from
Central CRH the terminals of sympathetic postganglionic nerves
Increased secretion Psychiatric hypercortisolism and primary afferent nerves, whose cell bodies in
Melancholic depression
Eating disorders the sympathetic and dorsal root ganglia contain
Chronic active alcoholism large amounts of CRH (48). Secretion of immune
Chronic active exercise
Somatic sequelae CRH is suppressed by glucocorticoids and soma-
Osteoporosis tostatin. Female rats have greater inflammatory re-
Viscera! obesity
infertility
sponses and produce more immune CRH in inflam-
Decreased secretion Atypical depression matory sites than male rats do, and the presence of
Seasonal affective disorder
Chronic fatigue and fibromyalgia
estrogen seems to cause the difference. Despite high
syndromes local produetion of immune CRH in inflammatory
Rheumatoid arthritis
Postpartum biues, depression, and
sites, concurrent plasma concentrations are ex-
autoimmunlty tremely low, probably as a result of rapid clearance
Premenstrual tension syndrome
Climacteric depression
mechanisms.
Peripheral CRH Corticotropin-releasing hormone and its recep-
Increased secretion of immune CRH Inflammatory disorders
Increased secretion of placental CRH Premature labor tors are also present in rat and human ovaries (Ta-
Decreased secretion of placental CRH Delayed labor ble 3). Ovarian CRH is primarily found in the theca
Decreased secretion of ovarian CRH Ovarian dysfunction
Anovulation and stroma and also in the cytoplasm of the ovum
Defective corpus luteum function itself (55, 56). Corticotropin-releasing hormone re-
Increased secretion of ovarian CRH Early menopause
Decreased secretion of endometrial ceptors, which are type 1 (similar to those of the
CRH Infertility anterior pituitary), are also found primarily in the
Early spontaneous abortion
stroma and theca and in the cumulus oophorus,
CRH = conicottopin-teleasing hormone. whereas the foflicular fluid contains CRH as well.
1 August 1998 • Annals of Internal Medicine • Volume 129 • Number 3 233

Luteinizing
Hormone
FoJJicle-.Stimulating
Honnonc
Estradiol
Progesterone
Prolifcraiivc Phase
Figure 4. Hormonal changes and period of increased vulnerability to mood disorders and autoimmune phenomena during the menstrual
cycle. The decreased activity of the reprodurtive axis in the late luteal and early follicular phases is associated with concurrent changes in the activity of the
5tress system, represented here by changes in hypothalamic corticotropin-reieasing hormone (CRH) secretion.
The findings suggest that CRH may participate in
the communication between the ovum and the cumu-
lus oophorus and may influence ovarian steroid bio-
synthesis. Incubation of granulosa-lutein cells with
CRH suppresses estradiol and progesterone secretion
in a dose-dependent, interleukin-1-mediated manner
(57, 58). In this sense, ovarian CRH has antirepro-
ductive actions that might be related to the earlier
menopausal failure of ovaries in women exposed to
high psychosociai stress (59). We believe that a
major physiologic function of ovarian CRH is its
participation in the "aseptic" inflammatory phenom-
ena of the ovary, including ovulation and luteolysis.
The human endometrium also contains CRH
(Table 3). In fact, the endometrial glands are full of
CRH during both the proliferative and the secretory
phases of the cycle (60). In the luteal phase, CRH is
probably secreted into the lumen of the uterus,
where it may participate in the inflammatory phe-
nomena of blastocyst implantation and (later in the
cycle) of menstruation. Compared with interimplan-
tation sites, implantation sites in rat endometrium
show local extravasation of plasma and contain in-
creased amounts of CRH messenger RNA and
CRH (61). We found CRH expression in human
decidualized endometrial stroma, and other re-
searchers demonstrated that CRH itself decidual-
ized endometrial stroma cells synergistically with
progesterone (60, 62). It is interesting that the effect
of estradiol on CRH transcription in immortalized
human uterine epithehal cells seems to be inhibitory
rather than stimulatory; this may explain, to some
extent, the contraceptive properties of the "day af-
ter" pill, which contains high doses of estrogen (63).
234 1 August 1998 • Annals of Internal Medicine * Volume 129 • Number 3
Ovulaiion
Secretory Phase
The latter half of human pregnancy is associated
with hypercortisolism (Figure 5). Indeed, the levels
of free plasma cortisol and 24-hour urinary free
cortisol excretion in pregnancy overlap with levels in
patients with mild Cushing syndrome (64). In the
same vein, dexamethasone cannot properly suppress
cortisol in late pregnancy, just as it cannot in the
Cushing syndrome. Placental CRH causes this hy-
percortisolism of human pregnancy (Table 3). By 28
to 30 weeks" gestation, CRH levels in plasma are
similar to those in the portal system, whereas the
levels of CRH-binding protein are similar to those
in nonpregnant women and normal men (65, 66). At
34 to 35 weeks' gestation, CRH-binding protein
concentrations decrease by two thirds, whereas total
and free CRH levels are markedly increased in
plasma during labor and return to undetectable
amounts within hours after delivery.
In the early 1980s, several groups demonstrated
that placental CRH was produced by the syncy-
tiotrophoblast, chorion, amnion, and decidua and
that it was the product of the same gene that pro-
duces hypothalamic CRH (65, 67). Incubation of
human placental tissue with CRH caused secretion
of j8-endorphin and a-melanocyte-stimulating hor-
mone in a dose-dependent manner (68). In addi-
tion, CRH caused stimulation of prostaglandin-Es
and prostaglandin-Foo:, both of which have a role in
labor and delivery; in contrast, CRH receptors were
shown in the myometrium, where CRH had a con-
strictive effect in synergy with oxytocin (69-71). In
addition, CRH was found to stimulate nitric oxide
production by the endothelium of placental vessels
and to cause the dilation of these vessels, thus fa- Table 3. Reproductive Corticotropin-Releasing Hormone
cilitating fetoplacental circulation (72). and Its Potential Physiologic Functions*
To determine whether placental CRH was se- Site of Production Function
creted in a pulsatile or circadian fashion in the third
trimester of pregnancy and whether there were any Ovarian CRH (theca, stroma, ovum) Suppression of ovarian
correlations over time between placental CRH and steroidogenesis
Inflammatory phenomena
the hypothalamic-pituitary-adrenal axis hormones, Ovulation
we studied normal pregnant women in the 34th Luteolysis
Endometrial CRH {endometrial glands,
week of pregnancy (Figure 6). We found CRH, decidua) Inflammatory phenomena
ACTH, and cortisol pulsations but, in contrast to Decidualisation
Implantation
ACTH and cortisol (which were secreted in a cir- Menstruation
cadian fashion), plasma CRH did not have a circa- Placental CRH (cytotrophoblast,
syncytiotriophobla5t, amnion,
dian rhythm (73). In the time cross-correlation anal- chorion) Maternal hypercortisolism
yses, CRH levels correlated positively with those of Fetoplacental circulation
Fetal adrenal function
ACTH and cortisol, which means that either CRH Timing of labor
causes secretion of ACTH and cortisol or cortisol Labor and delivery

stimulates placental CRH secretion, or both. In-
deed, glucocorticoids stimulate placental CRH se-
cretion in cultured human placental cells (74). Thus,
in the last trimester of pregnancy, the placenta se-
cretes CRH, which seems to be under the positive
influence of cortisol. Circulating placental CRH
then causes ACTH secretion, in synergy with portal
parvicellular arginine-vasopressin, which thus seems
to be responsible for generating the pulsations and
* CRH = corticotropin-releasing hormone. ..... . . . .
circadian rhythm of ACTH and cortisol (75). The
persistent elevation of plasma ACTH and a-mela-
nocyte-stimulating hormone levels then may cause
some hypertrophy of the adrenal cortices in normal
pregnant women.
Thus, placental CRH seems to be responsible for
the maternal hypercortisolism of pregnancy; for

Pregnancy Labor and Posipartum

Delivery

Progesterone

Estradiol

CRH-
Binding Protein

'I Period of Vulnerability

CRH

ACTH

J_J_

Conisol

12 24 38 Day 1 3 6 12
Weeks Weeks
Figure 5. Hormonal changes and period of increased vulnerability to mood disorders and autoimmune phenomena during pregnancy and
the postpartum period. The increasing levels of corticotropin-releasing hormone [CRH) in the last trimester, aiong with the decreasing levels of CRH-binding
protein, may participate in the initiation and progression of labor. The decreased secretion of estradiol and hypothalamic CRH in the postpartum penod is
associated with changes in the activity of the stress system, represented here by decreased CRH secretion. ACTH = adrenocorticotropic hormone.

1 August 1998 • Annals of Internal Medicine • Volume 129 • Number 3 235

maintaining proper blood supply to the fetus (prob-
ably by activating the nitric oxide synthase of these
vessels); and, later, before labor begins, for causing
increased myometrial contractility. Plasma levels of
CRH are markedly elevated in preeclamptic or
eclamptic mothers, in mothers with intrauterine in-
fections, and in healthy pregnant women during
normal labor. Longitudinal studies of many hun-
dreds of pregnant women demonstrated that in the
latter half of pregnancy, one could predict the onset
of labor by plasma levels of CRH (76). Thus,
women who delivered prematurely had higher levels
of CRH, equivalent to those of women close to
term; the opposite biochemical profile was seen in
women with postmature labor. On the basis of these
data, CRH was proposed to be the biological clock
that times labor and delivery.
Anoxia, the inflammatory cytokines, several pros-
taglandins, and glucocorticoids themselves cause
placental CRH secretion in vitro and in vivo. This
means that sustained anoxia caused by preeclampsia
or eclampsia, increases of circulating cytokine levels
caused by infection or inflammation, and increases
of glucocorticoid concentration caused by physical
or emotional stress may all initiate premature labor
through increases in CRH secretion (Figure 7). Po-
tent CRH receptor antagonists that might be helpful
in delaying premature labor and delivery are being
developed, and preliminary results are promising (51).
The clinical implications of placental CRH ex-
tend beyond pregnancy, labor, and delivery (76, 77)
(Figures 5 and 6). The postpartum period is char-
acterized by an increased incidence of psychiatric
and autoimmune manifestations. Indeed, the "post-

NONPREGNANT PREGNANT POSTPARTUM

STATE STATE STATE

CRH AVP CRH AVP

ACTH
C
/ if
\1 II ^
' ' ACTH
\ I

\J,Cortisol Corlisol Cortisol

a.in. •p.m. p.m.

a.m.
PlHsma
MUM
Portal
CRH
M M Placenta]
CRH
Portal
CRH
A A AA

Ponal
AVP
M M Portal
AVP
Portal
AVP

Plasma
M M
Plasma Plasma
ACTH
^ ACTH ACTH
t\
'lasma Plasma ^lasma
Cortisol Corlisol !]ottisol

Time Time Time

Figure 6. Top. The inypothalamic-pituitary-adrenai axis in the nonpregnant {left), pregnant {middle), and postpartum (right) states. Bottom. HEuristic,
simplified representation of the secretion of the hypothalamic-pituitary-adrenai axis hormones in the morning and afternoon, corresponding to the states
shown in the upper panels. During pregnancy, placental corticotropin-releasing hormone (CRHHnduced hypercortisoiism suppresses the hypothaiamic CRH
neuron. In the immediate postpartum period, the loss of piacental CRH and of estradioi input to the hypothalamic CRH neuron results in a period of low
hypothalamic CRH secretion and, hence, increased vulnerability to mood disturbances, such as postpartum blues, depression, or psychosis, or to autoimmune
disorders, such as postpartum thyroiditis. In the nonpregnant state, the pulsatility and circadian rhythm of the hypothalamic-pituitary-adrenal axis are
maintained by pulsations of hypothalamic CRH and arginine-vasopressin {AVP). In the pregnant state, peripheral placental CRH usurps the role of hypothalamic
CRH and causes hypercortisolism while pulsatility and circadian rhythm are maintained by arginine-vasopressin. In the postpartum state, hypothalamic (portal)
CRH is initially suppressed and gradually returns to normal. During this period, pulsatility and circadian rhythm are possibly maintained by portal arginine-
vasopressin as input from portal CRH gradually increases over time; the predominance of arginine-vasopressin might explain the decreased cortisol suppress-
ibiiity by dexamethasone previously seen in the early postpartum period. ACTH = adrenocorticotropic hormone; Ej = estradiol; P4 = progesterone. Solid line
= stimulation; dotted line = inhibition. Adapted from reference 73.

236 1 August 1998 • Annals of Internal Medicine • Volume 129 • Number 3

 Preeclampsia/Eciampsia
Anoxic Conditions
Placental *• Labor
CRH
[nfliimmatory Cytokmes
Infeclion/lnflammation
Figure 7. Corticotropin-releasing hormone (CRH) as a mediator of
premature labor. Anoxic conditions, such as preeclampsia or eclampsia;
increased concentrations of infiammatory cytokines associated with intra-
uterine infection or inflammation; and increased levels of cortisol arising
from any kind of physical or emotional stress may promote premature labor
through the secretion of placental and fetal membrane corticotropin-releas-
ing hormone.
partum blues," a mild form of transient depression,
occurs in 60% to 70% of women; full-blown post-
partum depression affects about 10%; and very se-
vere postpartum psychosis affects about 1 in 1000.
In addition, autoimmune diseases, such as "postpar-
tum thyroiditis" and rheumatoid arthritis, frequently
develop or are acutely exacerbated during the first
few months postpartum.
Although several depressive conditions, such as
melancholic depression and anorexia nervosa, are
typically associated with high hypothalamic CRH
secretion, other states, such as atypical or seasonal
depression, the chronic fatigue and fibromyalgia
syndromes, and the Cushing syndrome before and
during the first year after cure, arc all associated
with decreased production of hypothalamic CRH (3,
77-79). We hypothesized that the postpartum pe-
riod might be associated with low hypothalamic
CRH secretion, which would predispose patients to
atypical depression and autoimmune phenomena.
We prospectively studied 17 pregnant women who
were healthy and had no personal or family history
of depression (77). Psychometric testing was done
serially beginning with the 20th week of pregnancy
and continuing up to a year postpartum. We did
ovine CRH stimulation tests at 3, 6, and 12 weeks
postpartum. Nine women had normal affect through-
out, but 7 developed postpartum blues and 1 devel-
oped full-fledged postpartum depression. Plasma
levels of ACTH before and after ovine CRH
showed little response at 3 weeks, a better but still
suppressed response at 6 weeks, and an almost nor-
mal response at 12 weeks. Cortisol levels remained
in the upper normal range throughout, mostly be-
cause plasma cortisol-binding globulin levels were
about twice the normal level at 3 weeks, and it took
about 3 months or longer for them to decrease to
within the normal range. When we separated the
women at 3, 6, and 12 weeks into those with the
blues or depression and those without a mood dis-
1 August 1998 • Annals of Internal Medicine • Volume 129 • Number 3
order, the former had marked suppression of the
ACTH response to ovine CRH compared with the
latter. Thus, whereas the overall data showed a
transient suppression of hypothalamic CRH secre-
tion in the postpartum period, women with the
blues or depression had a more severe suppression
that lasted longer.
In the postpartum state, the major source of
CRH and estrogen, the placenta, is no longer
present, whereas the hypothaiamic CRH neuron is
probably suppressed as a result of previous exposure
to high levels of cortisol for more than 3 months
and because of concurrent estrogen deficiency (Fig-
ures 5 and 6). Despite the suppressed ACTH re-
sponses, total plasma cortisol levels were not low in
our postpartum women, probably because of the
elevated cortisol-binding globulin concentrations
and because the adrenal glands were probably hy-
pertrophic and, hence, hyperresponsive to ACTH
from their increased function during the last months
of pregnancy. High-dose estrogen has a marked anti-
depressant effect during this time, possibly because
it reestablishes normal stress system secretion of
CRH and norepinephrine (80).
These data may be extended to two other forms
of estrogen-related depressive syndromes in women.
One is the premenstrual tension syndrome, a con-
dition associated with mild alterations of hypotha-
lamic-pituitary-adrenal axis function throughout the
cycle (46). The time of maximal emotional distur-
bance coincides with the decrease of plasma estra-
diol levels during the latter part of the luteal phase
of the cycle, when plasma progesterone levels are
still elevated. The other is climacteric depression, a
condition about which we have a suggestion but no
conclusive evidence of hypothalamic-pituitary-adre-
nal axis dysfunction (81). Studies measuring morn-
ing plasma cortisol levels indicated that these levels
were decreased by about 40% to 50%. These stud-
ies suggest that estrogen withdrawal took place dur-
ing the perimenopausal and early menopausal period
and was probably accompanied by transient hypoacti-
vation of the stress system. Women with both of these
estrogen and, hence, CRH withdrawal states show
mood improvements with estrogen therapy.
Conclusions
Dr. Philip W. Gold (Clinical Neuroendocrinology
Branch, National Institute of Mental Health, Be-
thesda, Maryland): Corticotropin-releasing hormone
and estrogens seem to play crucial roles in the
sexual dimorphism of the physiologic and patho-
physiologic manifestations of the human stress re-
sponse. In addition to coordinating the behavioral,
neuroendocrinc, metabolic, and immune conipo-
237
nents of the stress response, CRH seems to have
direct reproductive regulatory roles at the hypothal-
amus, influencing gonadotropin-releasing hormone
secretion, and at the periphery, promoting inflam-
matory phenomena, such as ovulation and implan-
tation. Placental CRH drives the pituitary-adrenal
axis to produce high cortisol secretion during the
latter part of pregnancy. Withdrawal of placental
CRH after delivery provokes a secondary hypotha-
lamic CRH deficiency with varying consequences for
mood disorders and autoimmune phenomena. Cor-
ticotropin-releasing hormone may be the placental
clock determining the onset of parturition. Thns,
disturbances in placenlal CRH production may ac-
count for premature or delayed parturition in some
cases. In addition to its profound feminizing effects,
estrogen stimulates CRH gene expression and nor-
adrenergic function. Alterations in estrogenic tone
during the menstrual cycle, the postpartum period,
and the climactery may be involved in the mood
disturbances and alterations in immune function
seen at these times.
The World Health Organization has determined
that unipolar depression confers greater overall
morbidity on women than any other cause does. It
is conservatively estimated that 9% to 12% of adult
women are affected by unipolar depression, with a
ratio of affected females to affected males of at least
2:1. The classic form of depression, melanchoha, is
a state of pathologic hyperarousal characterized by
profound anxiety about the adequacy of self, dread
for the future prospects of such a deficient self,
insomnia, anorexia, loss of libido, and other mani-
festations compatible with a hyperfunctional stress
system (3, 82). We and others have demonstrated
hypersecretion of central nervous system CRH in
melancholia, which results not only in the hypercor-
tisolism and increased sympathetic activity of this
condition but also in many of its other clinical and
biochemical manifestations, including hypogonad-
ism, inhibition of the growth hormone and thyroid
axes, and mild immunosuppression (3, 48, 83). The
constellation of these biochemical changes leads to
several serious public health consequences, includ-
ing osteoporosis and increased risk for bone frac-
ture (84) and shortened life expectancy, mostly from
cardiovascular disease (85). Patients with melancho-
lia have a twofold increased risk for dying from
ischemie heart disease and a mortality rate of ap-
proximately 50% after acute, serious physical illness
(this rate is 10% in nondepressed patients) {86, 87).
This may be due to the adverse effects of chronic
hypercortisolism on visceral fat, lipid metabolism,
insulin sensitivity, blood coagulation, and arterial
pressure (for example, changes constituting the met-
abolic syndrome X and participating In the devel-
opment of atherosclerosis) (88). Long-term adminis-
238 1 August 1998 • Annals of Internal Medicine • Volume 129 • Number 3
tration of antidepressant agents leads to suppression
of CRH secretion and, it is hoped, to alleviation of
its long-term behavioral, biochemical, and somatic
sequelae (89, 90).
Although melancholic depression is easier to rec-
ognize, another prevalent form of major depres-
sion—atypical depression—is also more common in
women than in men (3, 82). Atypical depression
seems to be the antithesis of melancholia. Patients
feel lethargic, fatigued, and unmotivated and dem-
onstrate hyperphagia and hypersomnia. Dysphoria
in patients with atypical depression more closely
reflects feeling less alive than usual rather than
intense anxiety about self. Several lines of evidence
suggest that the lethargy, fatigue, hypersomnia, and
hyperphagia of atypical depression are associated
with hyposecretion of CRH (3). This hyposecretion
may contribute to a significant increase in the inci-
dence of allergic and autoimmune phenomena in
this form of depression and in its two homolog
transient states, the postpartum blues or depression
and the postcure state of patients with the Cushing
syndrome (48, 77, 79).
Glossary
Arcuate nucleus: Hypothalamic nucleus that contains
neurons secreting peptides of importance to reproduction
and the stress response, including gonadotropin-releasing
hormone; neuropeptide Y; and proopiomelanocortin-de-
rived peptides. such as (3-endorphin and a-melanocyte-
stimuiating hormone.
c-fos/c-jun transcription factor: A heterodimeric factor
that stimulates the promoters of many genes related to
cellular growth and replication.
Locus ceruleus-norepinephrine system: Noradrenergic
nuclei of the brain stem that regulate arousal and sym-
pathetic system activity.
Orexogen: Any substance with appetite-stimulating
properties, such as neuropeptide Y.
Paraventricular nucleus: Hypothalamic nucleus contain-
ing neurons secreting CRH and arginine-vasopressin,
which regulate pituitary corticotropin secretion.
Parvicellular neurons: Small-cell body neurons of the
hypothalamus that secrete CRH or arginine-vasopressin
in the hypophyseal portal system. Contrast with magno-
cellular neurons that secrete arginine-vasopressin into the
systemic cireulation.
Proopiomelanocortin: Precursor molecule for cortico-
tropin, /3-endorphin, and a-meianocyte-stimulating hor-
mone expressed primarily in the arcuate nucleus of the
hypothalamus and the anterior pituitary gland.
Stress: State of threatened homeostasis. ,, ,,., •
Requests for Reprinls: George P. Chrousos, MD, National Insti-
tutes of Health, Building 10, Room 10N262, 10 Center Drive
MSC 1862, Belhesda, MD 20892-1862.
Current Author Addresses: Dr. Chrousos: National Institutes of
Health, Building 10, Room 10N262, 10 Center Drive MSC 1862,
Bethesda, MD 20892-1862.
Dr. Torpy: Ouccn Elizabeth Hospital, 28 Woodville Road, Ad-
elaide, South Australia 5011, Australia.
Dr. Gold: National Institutes of Health, Building 10, Room
2D46, 10 Center Drive, MSC1284, Bethesda, MD 20892-1284.
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