Sexual Differentiation

Anomalies
Sexual Differentiation
Genetic sexul (chromosomal)
Gonadal sex
Phenotypic sex - internal and external genital
organs (IGO, EGO)
Psychosocial sex
Chromosomal Sex
46 XX,46XY
Kariotype, Barr body
(sexual chromatine)






Anomalies: 45 X,0 Turner sd; 47XXY- Klinefelter sd

Gonadal Sex
Testicular differentiation begins in the 8th
week of gestation; SRY gene is needed
- the Sertoli cell secretes AMH (Anti-Mullerian
hormone),
- the Leydig cell secretes testosterone
If SRY gene is lacking, from the 12th week of
gestation, the ovary develops
IGO Differentiation
EGO Differentiation
Organogenesis of the Male
Gonads and Genital Organs
Klinefelter Syndrome
The most frequent cause of genetic male hypogonadism
(1/400)
Gonadal dysgenesis of seminiferous tubes XXY
Hyalinisation + fibrosationof seminiferous tubes

azoospermia
Leydig cells anomalies hypogonadism
Increased LH Increased estrogen secretion
Clinical Features
Diagnosis
Positive Barr body test
XXY kariotype or mosaicism
Spermogram azoospermia
Serum testosterone normal or decreased
FSH always increased
LH increased or normal
Testicular biopsy
(seminiferous tube hyalinisation and
pseudoadenomatous accumulations in the Leydig cell)
Treatment
Hypogonadism substitutive treatment
- testosterone enanthate/cypionate i.m.
- testosterone undecanoate orally
Infertility not possible
Gynecomastia - surgery
Turner Syndrome
Gonadal dysgenesis 45, X0
1/2000-2500 female newborns
Short stature (SHOX gene
haploinsufficiency)+ sexual infantilism +
somatic anomalies
Turner Syndrome clinical features
Newborns: lymphedema
Characteristic facies
Turner Syndrome clinical features
Habitus and bone alterations
Other features
Aortic coartaction, bicuspid aortic valve, HTN
Renal malformations (rotations, ureteral duplication)
Recurrent otitis media
Pigmentary nevi
Associated autoimmune disorders: DM, Hashimoto
thyroiditis, rheumathoid arthritis etc.
Diagnosis
Kariotype 45 X0;
Negative Barr body test
Estradiol - decreased, gonadotropes - increased
Gynecological exam: genital infantilism
Indications for kariotype
determination:
- Short statura (< 2,5 SD)
- Sugestive somatic anomalies
- Primary amenhorea with
increased FSH
Treatment
Objectives: maximization of the final height +
sexualization
Treatment with GH ideally started early before estrogen
therapy, with higher doses than in pituitary dwarfism
Hormonal substitution therapy
- estrogens: 12-13 years, ethinylestradiol or conjugated estrogens, 21
days/month
- after 1 year a progestative is being added
Intersexuality
Gonadal true hermaphroditism
Hormonal
1. Male pseudohermaphroditism
2. Female pseudohermaphroditism
Psychic
True Hermaphroditism
Presence of both gonads ovotestis
Kariotype 46 XX (66%), 46 XY (10%), mosaicism
Clinical: ambiguous EGO, cryptorchidism -
frequently, ovotestis in the labioscrotal fold
IGO differentiation correspunds to the ipsilateral
gonad
have gynecomastia, menstruation
Paraclinical: hCG positive test (testosterone) and
positive menotropine test (estradiol)

Appearance
Therapeutic Attitude
Sex assignement depending on predominent
secondary sexual characteristics before 3 years of
age (usually grown up as women)
Surgical excision of the gonadic structures that
are contrary to the phenotypical sex
Female Pseudohermaphroditism
Normal ovaries and mullerian derivatives +
ambiguous EGO
Its the result of androgens excess in the fetal
and postnatal periods
The masculinization degree depends on the
stage of gonadal differentiation at the moment
of exposure
Female Pseudohermaphroditism
Causes
Fetal source:
- Congenital adrenal hyperplasia (21 hydroxylase
deficiency, 11 hydroxylase deficiency)
- Resistance to glucocorticoids
Maternal source:
- Iatrogenic testosterone or androgens ingestion
- Ovarian or adrenal tumors that produce
virilization
Congenital Adrenal Hyperplasia
21 hydroxylase deficiency
Clinical forms: classical salt-wasting, classical simple-virilizing,
and nonclassical forms depending on the degree of enzyme
alteration
CYP21 deficit decrease of cortisol aldosterone synthesys

increase of adrenal increase of ACTH secretion
androgens synthesys
In patients not treated after birth, the virilization continues
along with the rapid growth and precocious bone maturation
Treatment in CAH
Cocorticoids in doses that would permit a normal
growth and development (10-15 mg HC/m
2
/day),
three times a day
Those that waist salt: fludrocortisone
Plastic surgery of the EGO
Male Pseudohermaphroditism
Testicles + internal/external genital organs that
are not completely masculinized; hypospadias is
the mildest form
Causes:
- Defect of testicular receptor for LH/hCG
- Enzymatic deficiencies in testosterone synthesys
- Target tissue defects: testicular feminization
syndrome
- Dysgenesys
Testicular Feminization Syndrome
Karyotype 46 XY, bilateral testes, female
phenotype
Physiopathology : androgen receptor deficit, 5
alpha reductase deficit EGO and IGO
masculinization is not being produced
Clinical: feminine EGO, short blind-pouch
vagina, absence of Mullerian derivatives
Puberty: feminine secondary sexual characteristics,
no pilosity

Testicular Feminization Syndrome

Therapeutic Attitude in the
Testicular Feminization Syndrome
Preserving of the juridical and psychological
feminine sex
Preserving of the gonad till puberty (endogen
estrogen secretion)
Post-pubertal castration (malignization risk) and
estrogen substitution
Sexul genetic
cromozomial
Sexul gonadic
Testicul, ovar
Ho care afecteaza
dezvoltarea sexuala a
fatului
Sexul Sist. Nervos
central
Sexul atribuit si
cultivat
Identitatea de gen
Organele genitale
externe
Productia hormonala
la pubertate
Puberty
Girls Physiologic Puberty
Acceleration of the growth velocity puberty leap of
approximately 25 cm
Thelarche (under estrogen action)
Other modifications estrogen induced (labiae, vaginal
mucosa, uterus and ovaries dimensions)
Adrenarche under androgens action (adrenal and
ovarian), gonadarche independent!
Menarche when positive feedback begins
Tanner Stadialization
Boys Physiologic Puberty
First sign increase in
the testes volume and
dimensions (>2,4 cm, 4
mL), because of the FSH
stimulation of the
seminiferous tubes
Gonadarche (G1-G5)
Adrenarchae
Acceleration of the
growth velocity 28 cm
puberty leap in G3-G4
Factors that Influence the Beginning Moment of the
Puberty :
- Genetic factors
- nutritional factors
- Physical activity
- Environmental factors
Precocious Puberty
Development of the secondary sexual
characteristics :
- before 8 years at girls
- before 9 years at boys
It associates with acceleration of growth,
somatic development and skeletal maturation
short final stature
Classification of the Precocious
Puberty
Central (true, GnRH dependent):
- Idiopathic
- CNS disorders
Incomplete(GnRH-independent)
Boys: gonadotropinomas, HAC, virilizing adrenal neoplasms,
Leydig cell adenomas, familial testotoxicosis
Girls: ovarian cysts, estrogen secreting neoplasms
Both sexes: severe hypothiroidism, Mc Cune Albright sd.
Variations of the precocious puberty: precocious thelarche,
precocious pubarche, precocious menarche
Idiopathic Precocious Puberty
Precocious Puberty Hypothalamic
Hamartoma
Precocious Puberty Evaluation
History: perinatal anomalies or lesions,
infections, sexual hormones exposure, similar
family history
Clinical exam Tanner stadialization
Growth curve (growth velocity)
Hormonal estrogens/testosterone,
gonadotrops, GnRH test
TSH, adrenal androgens, hCG
Imaging
Rx for bone age
measuring
Ultrasound (uterus,
ovaries sizes)
Head CT/RMN in
central precocious
puberty
Treatment of Precocious Puberty
Antisecretor treatment

Central precocious puberty:
GnRH agonists- daily or depot
preparations
- Medroxyprogesterone
acetate

Incomplete precocious
puberty:
- Ketoconazole
- Cyproterone acetate
Objectives:
1. Treatment of the cause -
radical
2. Suppression of the sexual
hh secretion - antisecretors
3. Stopping of the growth
and bone maturation
4. Psychological support
Delayed Puberty
Lack of puberty signs at 13 years at girls, 14
years at boys
Constitutionally delayed puberty short stature,
small weight, skeletal development < 2 SD, also
adrenarche delay
Delayed Puberty Causes
Hypogonadotrop Hypogonadism
- CNS disorders; tumors, acquired or congenital
disorders
- Isolated gonadotrops deficit, Kalmann sd
- Multiple pituitary insufficiency
- Other disorders: Prader Willi sd, anorexia nervosa,
hypothiroidism
Hypergonadotrop hypogonadism
- Klinefelter sd, other testicular insufficiency forms
- Turner sd, other ovarian insufficiency forms
Delayed Puberty Treatment
Constitutional delayed puberty:
- Girls: 3 months of estrogen therapy
- Boys: 3 months of depot testosterone
Permanent hypogonadism :
- Men: testosterone enanthate or cypionate IM monthly
- Women - ethinyl estradiol or conjugated estrogensdays 1-21
- after appearance of the first estrogenization signs
medroxyprogesterone acetate is being added, later oral
contraceptive pills
- in hypogonadotrop hypogonadism intermitent
GnRH, fertility may be obtained
Development of the
secondary sexual
characteristics, stimulates
initiation of the puberty