Lecture #17: Sex Differentiation and Development
I. GONADAL STEROID HORMONE SYNTHESIS AND CHEMISTRY (Fig. 15.3)
1. The same cytochrome P450scc enzyme is present in the gonads.
2. However, gonads have an abundance of 17a-hydroxylase and 17-20 lyase activity to lead to androstenedione and testosterone and estradiol.
3. In the ovaries there are additional enzymes (P450arom) to convert testosterone to E2.
a. first, there is hydroxylation of the C-19 carbon,
b. second, there is a removal of the newly formed hydroxymethyl group,
c. third, there is aromatization to form a phenolic hydroxyl group at the C-3.
II. REMARKS ABOUT SEX DIFFERENTIATION AND
DEVELOPMENT
A. DIFFERENTIATION OF THE GONADAL (GENITAL) RIDGE (Fig. 16.3)
1. There is a gonadal ridge of indistinguishable sex, up to about 4-5 weeks of age.
2. This embryonic ridge has an outer (female) cortex and an inner (male) medulla.
3. The natural tendency appears to be cortical development and medullary regression.
4. The Y chromosome apparently has a Sry gene (sex-regulating Y-gene). (Fig. 16.2)
5. The Sry gene produces a testis determining factor (a protein) that leads to medullary development.
6. The regulatory protein must act on the X chromosome, because occasionally XX females can become masculinized without Sry gene transcripts.
7. The medullary tissue begins to differentiate into testes during the 7th week of age.
8. The cortical tissue begins to differentiate into ovaries around 13-16 weeks after fertilization.
9. The gonocytes (primordial germ cells) migrate from the endoderm to mesodermal gut tissue from which they invade the differentiating genital ridge.
10. In XX embryos, the gonocytes stay at the periphery, but in XY they invade the medulla.
B. DEVELOPMENT OF SEX DIFFERENCES (Fig. 16.3)
1. Female development of gonads and genitalia is autonomous, but fertility needs the XX genotype.
a. the primary sex cords degenerate and disappear.
b. strands of the epithelial sex cords extend inward toward medullary tissue.
c. the gonocytes are carried along with this inward proliferation.
2. Male development requires the inductive action of testosterone & androgens.
a. the primary sex cords develop into the seminiferous tubules [seminiferous].
b. the strands of epithelial tissue differentiate into Sertoli cells [Sertoli cell].
c. the gonocytes become imbedded within these sustentacular cells.
C. DIFFERENTIATION OF THE GENITAL DUCTS (Fig. 16.4a)
1. In female, the Mullerian duct [Mullerian] gives rise to oviduct, uterus, and inner vagina.
(Wolffian ducts [Wolffian] atrophy by programmed cell death).
2. In male, the testes produce a Mullerian inhibiting factor (MIF), or Mullerian regression factor.
3. In male, the development of Wolffian ducts depends on androgens to form vas deferens, seminal vesicles, and epididymis.
D. DIFFERENTIATION OF THE EXTERNAL GENITALIA (Fig. 16.4b)
1. At the indifferent stage there are the genital tubercles [genital], genital folds, & genital swelling.
2. There is a natural tendency for the phenotype of the female genitalia to develop.
a. tubercle becomes clitoris.
b. fold becomes labia minora and outer vagina.
c. swelling becomes labia majora.
3. Differentiation of male genitalia is induced by testicular androgen production.
a. tubercle becomes glans penis.
b. fold becomes penil shaft and urethra [urethra].
c. swelling becomes scrotum.
4. Dependency of normal male externa genitalia on 5a-reductase in cells of the genitalia.
a. in some tissues of males, there is 5a-reductase to form dihydrotestosterone (DHT) (Fig. 16.7)
b. the external genitalia [genitalia] and prostrate have this enzyme for DHT (Fig. 16.8)
E.
GONADAL STEROIDS AND BRAIN DIFFERENTIATION
(NOTE: Adult male has a tonic/pulsating output of GnRH, while female has a cyclic output.)
1. Preliminary findings: (cycling originates in the hypothalamus!!!)
a. in the castrated neonate male rat, transplanted ovaries will cycle normally.
b. in the castrated adult male rat, transplanted ovaries fail to cycle.
c. thus, the hypothalamohypophyseal control of pituitary patterns is programmed early.
2. Secondary findings:
a. a single injection of testosterone into female a few days postnatally results in acyclic adult females.
b. thus, testosterone conditions the hypothalamus to be tonic, rather than cyclic.
3. Tertiary findngs:
a. deprivation of testosterone in the male leads to female sex behavior.
b. such male animals will take the female mating posture.
c. thus, testosterone seemed of critical importance to male brain development.
4. However, estradiol treatment masculinizes the brain of both the male and female rat.
a. brain possesses the aromatase enzymes for converting testosterone to estradiol.
b. aromatase inhibitors impair brain differentiation of males.
c. 3H-labeled testosterone is recovered from brain as labeled estradiol.
d. the effects of testosterone are blocked by estrogen receptor antagonists, but not by testosterone receptor antagonists.
e. dihydrotestosterone does not mimic this testosterone action, even though it is a potent androgen.
5. Then, why doesn't estradiol masculinize the female brain?
a. estradiol production by fetal ovaries may be minimal.
b. a-fetoprotein [a-fetoprotein] is present in blood of female fetuses to bind up estradiol.
c. proof comes from giving antibodies to a-fetoprotein and observing masculinity.
d. synthetic estrogens such as diethylstilbestrol [DES] aren't bound by a-fetoprotein, and masculinize the fetal brain of females.
6. Sexually dimorphic nucleus of preoptic area (POA) is 5X larger in male rodents.
III. CAUSE OF THE ONSET OF PUBERTY???
1. The gonads are capable of responding to pituitary hormones.
2. The gonotropes in the pituitary are capable of responding to GnRH.
3. Onset of puberty appears to be related to maturation (aging) of CNS.
IV. CHARACTERISTICS OF PUBERTY