Endocrinology Topics   

Gonadal Development

Early Development

Most of the gonadal ductal structures develop from intermediate mesoderm, although some parts come from viceral mesoderm (mesenchyme), especially connective tissue and smooth muscle. Gametes develop from primordial germ cells formed from the gastrula.

The "default" sex in mammals is female. The Y chromosome allow the production of SRY protein, which then signals for the development of male gonads (testis) and inhibits female gonad development by inducing production of MIS. Testosterone from the male gonad then signals to the development of the male phenotype. In the absence of SRY, female gonads develp spontaneously.

Anti-Mullerian Hormone (Mullerian Inhibitory Substance, MIS) is a ~70 kDa glycoprotein of the TGFb growth factor superfamily. Found as a dimer, it is produced by the Sertoli cells of the embryonic testes and by the adult gonads. MIS causes atrophy of the Mullerian ducts.

If the ovaries or testes are removed from developing fetus, the Mullerian ducts develop and the Wolffian ducts atrophy, suggesting that the female is the default pathway and that gonads are not required for developmnent of the female ductal system. The Mullerian duct is sensitive to MIS only during early development (< 8 weeks in humans), therefore adult production of MIS has no deleterious effects.

Mutations in the MIS gene are associated with Persistent Mullerian Duct Syndrome (PMDS), a rare form of hermaphroditism in genetic males (XY), in which the testes do not descend.

In tandem with MIS production by Sertoli cells, production of testosterone by embryonic Leydig cells leads to differentiation of the Wolffian duct: vas deference, seminal vesicles, epidimis. Metabolism of testosterone to dihydroxytestosterone (DHT) leads to formation of the penis and scrotum. DHT is required for the normal masculinization of the external genitalia in utero. Patients that cannot make DHT before birth, due to a mutation in the gene for 5-alpha reductase Type 2, are born looking like girls but develop male external genitalia at puberty. Estradiol is another important testosterone metabolite in males and leads to sexual differentiation of the brain.

SRY (Sex Determining Region Y Gene) is the master switch. Testis development depends on inherinance of this Y chromosome-encoded transcription factor. SRY is a DNA binding protein with an HMG box binding domain, and is expressed about 48 hours before MIS. SRY may directly or indirectly activate the MIS gene promoter. Genetically female mice (XX) develop as males if made transgenic for the SRY gene locus, but they are infertile (deficient spermatogenesis). The SRY gene in humans and mice seems to be very different because female mice made transgenic for the human gene do not develop as males. Male sex-reversed patients (genetic male to phenotypic female, 46XY female) have SRY mutations, often in the HMG box. Female sex-reversed patients (genetic female to phenotypic male) may have a translocation placing part of the Y chromosome into their genome.

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Transcriptional Regulation of Early Development

Several gene products regulate sexual differentiation of the embryonic mesoderm: SOX-9, SF-1, DAX-1, M33 and Wnt-7A are the best known.

The SOX-9 gene (in chromosome 17) is a member of the family of SRY-related proteins (Sox = SRY type HMG box protein), important at early stages of sex diferentiation. Mutations in Sox-9 cause broad developmental deffects including skeletal problems like Campomelic Dysplasia (CD). Campomelic dysplasia is a disorder of the newborn characterized by congenital bowing and angulation of long bones, together with other skeletal and extraskeletal defects. Up to two-thirds of affected XY individuals have a gradation of genital defects or may develop as phenotypic females. Some CD patients are 46XY females with genital defects. These patients often die in the first month of life.

Steroidogenic factor 1 (SF-1, aka adrenal 4-binding protein, Ad4BP) is an orphan nuclear receptor encoded by the Ftz-F1 gene, homolog of the Drosophila Ftz-F1 gene. SF-1 activates steroid hydroxylase genes, for example in the adrenal cortex, and may activate the LHb gene promoter since it is expressed in developing pituitary (in gonadotropes) and there is SF-1 activity at other levels of the HPG axis. SF-1 may also activate the MIS gene promoter and Dax-1 gene promoter, although Dax-1 is still on in SF-1 knockout animals. Mice with SF-1 knockout lack adrenals and gonads and die at about postnatal day 8, probably due to corticosterone insufficiency.

The WT-1 gene (Wilm’s tumor 1) encodes a zinc finger protein transcription factor which seems to act mostly as a repressor. WT-1 may act to induce terminal differentiation and repress proliferation of certain tissue. Mice with WT-1 knockout die at midgestation with absence of kidneys and gonads. Mutations in this gene cause broad developmental disease known as WAGR for the initials of the main symptoms: Wilm's tumor of the kidney, aniridia (underdevelopment of one or both eyes), genito-urinary problems (some have features of XY sex-reversed females), and mental retardation. A severe form of this disease is known as Denys-Drash syndrome.

The DAX-1 gene on human chromosome Xp21 (?) encodes a nuclear receptor-related protein that acts as a transcription factor. DAX-1 seems to work downstream from SF-1. XY mice lacking DAX-1 appear normal until sexual maturation, they have hypogonadism (poor testicular development) although the pituitay seems to function normally. XX mice lacking DAX-1 appear normal, may have minor ovulation peculiarities but are fertile.

DAX-1 is mutated in an X-linked disorder in humans, characterized by adrenal hypoplasia congenita (AHC, adrenal gland not fully developed) and hypogonadotropic hypogonadism (HHG, failure of sexual maturation at puberty). Therefore Dax-1 seems to be important in the HPG axis (?). Dax-1 overexpression in XY mice makes them sex reversed. But mice and humans are different in this respect: different doses are required, and there are differences in timing and methods of action (this also seems to be the case for SRY). In humans, too much DAX-1, due to gene duplication, causes Dosage-Sensitive Sex Reversal (DSS): a male-to-female sex reversal with gonadal dysgenesis (despite normal SRY). XXY patients do not get DSS because of inactivation of one X chromosome. Thus in humans Dax-1 may be the "antitestis" gene and antagonistic to SRY. <revisit Dax-1 later, notes are confusing>

The M33 gene is the human homologue of Drosophila polycomb. It encodes a protein presumed to be a transcription factor that may disrupt steps upstream of SRY. M33 knockout mice often die, and the survivors are genetic males (XY) but phenotypic female. Both sexes have reproductive developmental problems and are infertile.

The Wnt-7A gene is a human homologue of Drosophila wingless that encodes an intracellular signaling molecule. Wnt7A knockouts are either XY pseudohermaphrodites or XX infertile.

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Genetic Sex

Genetic sex is determined by the chromosomal complement of the fertilized egg, in mammals: XX for female, XY for male. In most birds and reptiles, the chromosomosomal compliment is ZW for females and ZZ for males, the W chromosome inducing ovarian differentiation. Males or females may be heterogametic in fishes and amphibians. Some fish are hermaphrodites and can shed sperm and eggs, either at same time or in different developmental stages. Some reptiles are all-female parthenogenic, meaning that eggs develop without need for sperm activation, while others are are gynogenic, meaning that there is activation of the egg by sperm, but no genetic material contribution.

Gonadal sex is determined by hormones which drive gonadal development. Phenotypic sex is regulated by gonadal sex (?) and in mammals is expressed in three main areas: external features, internal urogenital system and the CNS. External features include external genitalia and secondary sex characteristics. The sexual pattern of the CNS then determines pituitary gonadotropin secretion and sexual behaviour. But in lower organism like fishes, an individual may change gonadal sex due to social or environmental stimuli. The sea bass is a teleost fish that can change from male to female in a matter of days, both physically and in behaviour. Other fishes like the midshipman fish cannot change sex but have two kinds of males: Type I builds the nest fo the female's eggs, while Type II (smaller, develops earlier) sneaks in and deposits its sperm.

The normal human genotypes are 46XX (female) and 46XY (male). Human embryos with sexual genotype other than XX or XY may suffer gonadal dysgenesis (45XO; Turner's Syndrome), seminiferous tubule dysgenesis (47XXY; Klinefelter's Syndrome), or Trisomy X (XXX). The YO phenotype is embrionic letal.

In Turner's Syndrome (45X0 female), the external genitalia is female but the gonads do not develop internally (gonadal dysgenesis). These patients have short stature, webbed neck and primary amenorrhea, and may suffer heart defects. Trisomy X symptoms vary widely, the one consistent feature is tall stature. Some XXX females exhibit no or very few symptoms, while others have more severe features of developmental delay and/or behavioral abnormalities.

Klinefelter's syndrome occurs 1:1000 male births. These patients are 47XXY, 48XXXY or 48XXYY. They suffer hypergonadotropic hypogonadism: pituitary hormones FSH and LH levels may be high due to lack of feedback. They have deficient gonadal function, small testes and lwe testosterone levels. Testes develop but germ cells degenerate after birth and there is a failure of puberty (no sperm). Gynecomastia (breast enlargement) may occur due to imbalance in the estrogen/androgen ratio. May have eunochoidal proportions or antisocial behaviour. [Enunuchoidal body proportions: span > height by 2 in ; pubic to floor length > crown to pubic length by 2 in ; due to delayed fusion of the epiphyses and continued long bone growth]

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Kallman's syndrome is due to a defect in development of hypothalamic GnRH cells, thus patients have low FSH and LH levels (hypogonadotropic hypogonadism). It occurs in 1:10,000 births and is more common in males than females. Other defects may include eunuchoidal proportions, cleft palate, and anosmia (no sense of smell; GnRH cells are near olfactory bulb). Is due to a defect in the X-linked anosmin gene, which codes a protein that helps cells migrate.

Congenital anorchia is a rare, vanishing testes syndrome. Testes are present during early development and there is masculinization of external genitalia, but the testes dissapear before birth. This patients suffer failure of puberty, gynecomastia, lack of sperm and eunuchoidal proportions.

Male pseudohermaphrodites have a 46XY karyotype and have testes but no external genitalia and a female phenotype. This is due to either 5a-reductase deficiency, 17-hydroxylase deficiency, androgen resistance, or Persistent Mullerian Duct syndrme (PMDS). [5a-reductase converts testosterone to DHT; 17-hydroxylase generates the androgen precursors 17-hydroxy pregnenolone and 17-hydroxy progesterone] 7-hydroxylase deficiency can also cause hyperaldosteronism, as well as no androgen production in the adrenal and gonads.

Males pseudohermaprodites qith 5a-reductase deficiency have ambiguous genitalia ta birth including a blind vaginal pouch and internalized testes. Some virilization at puberty is due to testosterone action: penis enlargement, voice deepens, muscle mass increase, testes enlarge and descend, leading to socialization as male. This patients still have no beard, no acne and a small prostate, but erection is possible and semen is produced. Inseminiation is not possible because the urethra opens into the vaginal pouch. This codition was discovered by Juliane Imperato-McGinley at al at Salinas, Dominican Republic. Children are usually raised as girls but "become" boys at puberty. They are known as "guevedoce" or "machiembra".

Propecia (finasteride) is a specific inhibitor of 5a-reductase Type II, which is more abundant in the scalp (?). Inhibition of the TYpe II enzyme blocks periferal generation of DHT, resulting in significan reduction of serum concentrations. Finasteride is contraindicated in women when they are potentially pregnant because it may cause abnormalities of the external genitalia of a male fetus.

Androgen resistance is due to mutation of the androgen receptor and low affinity for DHT. PMDS is due to mutations in MIS or its receptor and leads to cryptochordism (no testicular desent). Androgen resistant/insensitive patients (about 1:40,000 births) have an androgen receptor defect. They may have either Complete Androgen Insensitivity Syndrome (CAIS) or Partial Androgen Insensitivity Syndrome (PAIS, aka Reifenstein Syndrome). Patients with 46XY karyotype suffer testicular feminization (?) and may be male pseudohermaphrodites with female external genitalia. The normal testes produce MIS therefore they have no Müllerian-derived structures, i.e. the vagina is a blind pouch. The androgen receptor gene is in the X chromosome.

Female pseudohermaphrodites have 46XX karyotype and ovaries but the external genitalia is male. This can be caused by enzyme deficiencies: 21-hydroxylase, 3b-hydroxysteroid dehydrogenase, 11-hydroxylase, and others, or by maternal ingestion of androgens or a maternal virilizing tumor.

True hermaphroditism often carries a 46XX karyotype, but can also be 46XY or a mosaic. Both male and female gonads are present. The mechanism is unclear but may be due to SRY gene mutation or an autosomal dominant mutation that allows testicular determination without SRY.

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Phenotypic Sex

Phenotypic sex refers to the physical and behavioural characteristics associated with either gender.

The brain is inherently female, unless androgens direct it to a male fate. Androgens alter brain development , especially the hypothalamus and other regions that mediate sexual behaviour and gonadotropin secretion. Androgens act through local conversion to estrogens by aromatase. Sex hormones may differentiate the human brain from about 6 weeks of age. Social effects are also clearly important in the perception of gender by humans.

The preoptic area is larger in male rats than in female rats due to the action of sex hormones. The male rat brain directs mounting behaviour, while in females directs cyclic release of FSH and LH. In male frogs, clasping behaviour is DHT-dependent. In birds, males have high brain androgens during courtship behavior, although in species were the female is dominant in courtship she has higher gonadal (?) androgens.

In studies of brain structure and sexual orientation, the size of the interstitial nuclei of the anterior hypothalamus (INAH 1, 2, 3, 4) were measured postmortenm in women, heterosexual men and homosexual men. INAH 1, 2 and 4 were the same size in all groups but INAH 3 was the same size in women and homosexual men but two-times larger in heterosexual men (LeVay & Hamer 1994; Scientific American 270(5):44). Still, since behaviour can change brain structures, it is not known if the size difference is the cause of sexual prefference or the brain is actually changed by the behaviour.

In vertebrates, testosterone or DHT act at puberty to reach sexual maturation. Behaviour changes to incllude courtship, agression and display. Sexual organs mature: the endoplasmic reticulum of seminal vesicles and prostate become more active (?), while the penis and scrotum enlarge and change character. Changes of the skin include acne, pubic and faical hair, recession of the male hairline, and colorization. Acne is related to increased sebaceous gland activity. Skin, hair and feathers aquire androgen-dependent pigmentation.

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