Reproductive Embryology - Pathology

EMBRYOLOGICAL DEVELOPMENT OF THE GENITAL TRACT

Early embryo=

Small indifferent gonads. The primitive structures which will become gonads and genital tract are identical at this stage. Paired mesonephric ducts (Wolffian) or paramesonephric (Mullerian) ducts fuse caudally with urogenital sinus.
(Metanephros - becomes the kidney).

Gonadal differentiation

This is determined by the presence of the SRY gene of the Y chromosome (sex determining region of the Y chromosome) which encodes “testicular determining factor” protein (TDF).
Lack of SRY gene (i.e. XX females) leads to ovarian differentiation.

Development of phenotypic sex

The sex of the embryonic gonad normally determines which reproductive duct system develops.

• Testes induce development of mesonephric (Wolffian) duct system in to epididymis and vas deferens and cause regression of paramesonephric (Mullerian) duct by ”mullerian inhibitory substance”, (MIS).
• Absence of testes in presence of ovaries allows paramesonephric ducts to develop under influence of oestrogen to oviduct, uterus, cervix and cranial vagina.

Summary of determinants of sexual development

Chromosomal or genetic sex = sex chromosomes Gonadal sex = ovary or testis Phenotypic sex = usually determined by gonad

ANOMALIES OF DEVELOPMENT

INTERSEX

This relates to developmental abnormalities resulting in discordance between genetic, gonadal or phenotypic sex and includes true hermaphrodites, pseudohermaphrodites and other forms of sex reversal.

• HERMAPHRODITISM

A true hermaphrodite is an individual possessing gonads of both sexes, this is rare. Failure of embryological differentiation of gonads during foetal life leads to the presence of both ovarian and testicular tissue (ovotestis or one of each type). The tract is predominantly female, although there is often an enlarged clitoris and reduced vulval lips. Usually XX with H-Y antigen (protein normally coded for by Y chromosome).

Pseudohermaphrodite gonads are of one sex and the ducts and external genitalia are modified towards, or are of, the opposite sex.

Male pseudohermaphrodite = testis-like gonads + predominantly female genitalia. More common.

Female pseudohermaphrodite = ovary-like gonads + male-like genitalia. Rare.

Male pseudohermaphrodites are commonly found amongst pigs (and goats). Affected animals behave like males and may mount. There is a sub-anal genital opening with a prominent clitoris. Testes may be in a scrotal structure or intra abdominal and there are poorly developed uterine horns which may contain mucus-like secretion.

Aetiology: Genetic. In goats the characteristic is linked to a gene for polledness (dominant); homogygotes are hermaphrodites with a wide range of masculinisation. Chromosomal studies in pigs, goats and dogs (Cocker Spaniels) have shown that most pseudohermaphrodites are basically genetic female despite the testis-like nature of their gonads. (XX sex reversal)

Equine conditions:

1. XY Sex-reversal: an inherited trait with XY Karyotypes but variably female phenotype of external genitalia. Wide range of morphology from near-normal tract with inactive ovaries, to hypoplastic ovaries or ovotestes with aplastic genital tract. Thought to involve Y chromosome mutation.
2. Testicular feminisation: XY genotype with testosterone producing but sterile gonads internally and female external genitalia. The vagina is blind-ending with absence of internal genital tract. These male pseudohermaphrodites exhibit male behaviour and have significant testosterone levels.

• FREEMARTIN SYNDROME (i.e. Chimeras)

A freemartin is a masculinised female born co-twin with a normal male. 11/12 female calves born co-twin to a male will be freemartins. The condition is mainly recognised in cattle, but occurs in sheep, goats and pigs.
During foetal development placental anastomosis allows blood to be shared by the twins (anastamosis occurs in 90% of bovine twins, <2% in other species).Each twin acquires genetically distinct population of blood cells from the other twin - CHIMERISM. Blood tests can be used to demonstrate different chromosome complement in nucleated WBC and presence of two blood groups in each twin.

Aetiology: Testes develop earlier in embryonic life than ovaries and impair normal female development by the production of TDF, MIS and testosterone which enters the female twins circulation via the placental anastomosis.

Consequences:

1. Paramesonephric (Mullerian) ducts do not form or atrophy.
2. Mesonephric (Wolffian) ducts persist in the female twin and may form rudimentary male tubular genitalia.

Morphological features:

1. External genitalia may appear relatively normal - condition only detected at puberty or
2. Enlarged clitoris, long tufts of hair round vulva, skin fold from groin to umbilicus.
3. Vulva and vestibule patent but vestibule or vagina is blind-ended - can be checked using speculum or probe.
4. Vagina never communicates with uterus. Uterus variably under developed - fibrous cords or non-patent tubes.
5. Ovaries are usually small, cord-like thickenings in the ovarian ligament +/- seminiferous tubules.

Information by kind permission of Professor RW Else