October 16, 2001.

sex determination

Reproductive structure-functions:  innate bidirectional potency

The main checkpoints of sex determination:

1.	Chromosomal sex
2.	Gonadal sex
3.	Genital sex
4.	Gender identity
5.	Sexual orientation

The development of chromosomal sex and gonadal sex:  no classic hormones are involved

The development of genital sex:  determined by classic hormones

The development of gender identity:  psychological self-identification; 18 – 30 month old

reproductive organs

Reproductive organs:

1.  Gonads:  	ovaries or testes, genetically determined
function:  gametogenesis and steroidogenesis

develop in response to the presence or absence of androgens and other hormones from the testes
develop in response to the presence or absence of androgens and other hormones from the testes

develop in response to the presence or absence of androgens and other hormones from the testes

2.  Internal genitalia:   uterine tubes, uterus, vagina in females 
epididymis, ductus deferens, seminal vesicle, 
prostate, bulbourethral gland in males 

3.  External genitalia:  labia majora and minora and clitoris in females
penis in males

sexual differentiation:  
I.  development of primitive  bipotential  gonads and genitalia
 
During week 5 of intrauterine life:  Urogenital ridge develops

During week 6 of intrauterine life:  indifferent (primitive) gonad develops

Regulated by WT-1 (Willms tumor 1) gene and SF-1 (steroidogenic factor-1) gene

1.  Primitive gonad:  identical in both sexes
- cortex
- medulla

2.  Primitive genital tracts:  identical in both sexes
	-  Müllerian tract
-  Wolffian tract

sexual differentiation:  
II.  development of female  gonads and genitalia

After week 6 of intrauterine life in   females:

DAX-1 gene is active in females;  Active DAX-1 gene permits the development of ovaries and suppresses the development of testes by suppressing the expression of SF-1 gene.

Female:  medulla  regression
cortex  ovary, no hormones

Up to week 7 the embryo has both male and female primordial genital ducts (internal genitalia)

After week 7, in females: müllerian duct system differentiates  uterine tubes, uterus, upper third of vagina
wolffian duct system degenerates

External genitalia bipotential up to week 8.

Then, in females:  urogenital slit remains open, female type external genitalia develop

By week 12:  ovaries are present, müllerian ducts develop, external genitalia remain feminine and wolffian duct regresses

sexual differentiation:  
III.  development of male gonads and genitalia

After week 6 of intrauterine life in MALES:

“Sex determining region Y gene” is expressed  its product is a transcription factor (“sry protein”).

sry protein suppresses DAX-1 gene 

SF-1 expression is disinhibited (i.e., in the absence of DAX-1, SF-1 is not suppressed)

The effects of SF-1:	-     stimulates SOX9 expression  testicular differentiation  (Sertoli cells)
-	stimulates anti-müllerian hormone secretion by Sertoli cells
(AMH:  536 aa., growth factor family, related to inhibin and activin, acts on type II TGF receptors)
-	stimulates testosterone secretion by Leydig cells

Internal genitalia:  Up to week 7 the embryo has both male and female primordial genital ducts 

After week 7, in males: 

1.	Wolffian duct system proliferates in response to testosterone  epididymis, vas deferens, seminal vesicle
2.	Prostate develops in response to dihydrotestosterone (DHT)
3.	Müllerian duct system degenerates (in response to AMH)

External genitalia:  Bipotential up to week 8.

Then, in males:  urogenital slit disappears, male type external genitalia develop in response to dihydrotestosterone

___________

The effects of AMH and testosterone are unilateral (paracrine)

Testosterone secretion is stimulated -  by hCG through wk 8 – 12 ( hCG crucial for masculinization!)
-	  by LH from the pituitary through wk 13-30

the ontogeny of the hypothalamic-pituitary-gonadal axis

GnRH is synthesized by week 8

LH and FSH producing cells are present in the pituitary by week 10-13. 

LH and FSH secretion is at peak at mid-gestation.

Males:
-  Testosterone peaks ~14-15 weeks (due to the stimulatory effects of hCG)

-  After week 20, FSH, LH and testosterrone decline (due to the acquisition of steroid receptors in GnRH secreting cells in the hypothalamus  developing feedback mechanisms)

-  After birth, testosterone sharply rises, reaches low-adult level ~ 3 month of age;  during the second half of the first year, FSH, LH and testosterone levels decrease to the childhood level.

Females:

-  at birth, relatively high estrogen levels and low FSH/LH
-  periodic changes between low high/high FSH and high FSH/low estrogen periods in first 6 month of age;  during the second half of the first year, FSH, LH and estrogen levels decrease to the childhood level.

the abnormalities of the sexual differentiation 

I.  abnormalities of the sex chromosomes

1.  XO (Turner’s sy.):  rudimentary gonads
female-type external genitalia
no further maturation at puberty

2.  47 XXY (Klinefelter’s sy.):  most common sex chromosome disorder (2 out of 1000 males)
normal male genitalia except hypogonadism: 
-	seminiferous tubules are abnormal  azoospermia  infertility
-	Leydig cell dysfunction  androgen levels  LH and FSH  
eunuchoid features
delayed epiphyseal closure
androgen/estrogen ratio   slight feminization
often mental retardation

3.  XXX (“superfemale”):  no symptoms

4.  YO:  lethal

5.  XX/XY mosaic pattern:  true hermaphroditism

II.  hormonal abnormalities

1.  Female pseudohermaphroditism:  due to excessive androgen exposure

2.  Male pseudohermaphroditism: due to lack of androgen effects
-  defective testes  MIS  female-type internal genitalia
-  17-hydroxylase deficiency
-  5-reductase deficiency

3.  Testicular feminization:  a form of male pseudohermaphroditism
caused by complete androgen resistance
MIS is present  no female internal genitalia
lack of testosterone effect  female-type external genitalia

After puberty:  increased LH secretion (because of the loss of androgenic feed back)   LH stimulates Leydig cells  testosterone  converted to estrogens  female secondary sexual characteristics

socially function as normal women

puberty

During childhood:  juvenile pause of gonadotropin and sex steroid secretion

Adolescence:  
-	the final maturation of the reproductive system
-	development of secondary sexual characteristics
-	growth spurt

Puberty:  	the time when the endocrine and gametogenic functions first develop to the point where reproduction is possible

The events of adolescence:

Adrenarche (6 - 10 yr):  adrenal androgens  (pituitary adrenal androgen-stimulating hormone?)
Telarche
Pubarche
Menarche - spermarche

Girls:  8-13 yr
Boys:  9-14 yr

Control of the onset of puberty:  leptin from adipocytes  pulsatile GnRH secretion starts

Precocious puberty

pseudoprecocious puberty:  	early exposure to androgens and estrogens
true precocious puberty:  	gonadotropin secretion from the pituitary