Gonadal Abnormalities

Male and Female Gonadal Abnormalities 

 Gonadal Abnormalities Internal genitalia abnormalities, Leyding Cell hypoplasia, XY gonadal dysgenesis, Mullerian inhibitor, gonadal dysgenesis, Wolffian structures.

    In males, a number of gonadal abnormalities may exist. One of these is known as the vanishing testis syndrome: an XY fetus develops tests that then undergo atrophy. The reason for this remains speculative, although torsion, thrombosis and viral infections have been suggested. However, the failure of the development of the tests leads to a female default state, as above (similar).

    In Leyding Cell hypoplasia the Leyding cells responsibility for the production of testosterone either completely fail to produce this or produce it in only small quantities. A range of abnormalities may result, dependent on the level of androgen produced, and therefore the phenotype may range from female through to the hypospadiac male.

    In XY gonadal dysgenesis, a genetic abnormality leads to an abnormal testicular development. The testis fails to secrete androgen or Mullerian inhibitor, resulting in an XY female. If the genetic abnormality leads to an enzyme deficiency in the biosynthetic pathway to androgen, testosterone will fail to be secreted by the testis. 

    However, some androgen may be produced, depending on which enzyme is absent in the pathway. Therefore some effect on the external genitalia may be possible and a varying degree of virilism will occur. If the biosynthetic production of Müllerian inhibitor is deficient, its absence will, of course, mean the persistence of the Müllerian duct. This is an extremely rare syndrome.

    In the female, gonadal dysgenesis may occur, and in this situation (similar to Turner's syndrome) the gonad is present only as a streak. These individuals have been found to have small fragments of a Y chromosome and. as a result of this, the gonad may undergo mitotic change, which leads to ne development of a gonadal tumor, eg a gonadoblastoma. 

    The Mullerian structures remain and the Wolffian structures regress, because of the absence of tests. At puberty, the failure of development of the ovary will mean that there is no possibility for the production of oestradiol, and a failure of secondary sexual characteristic growth will occur,

    In the rare condition known as mixed gonadal dysgenesis, there is a testis and a streak gonad in the same individual. The chromosome complement is typically 46 XX or a mosaic with a Y component. Here, strangely, the Wolffian structures develop only on the side of the testis, but all Müllerian structures regress. The external genitalia in this rare condition may be ambiguous, depending on the functional capacity of the testis.

    In true hermaphrodites, the gonad may develop into either a testis or an ovary, or a combination of the two known as an ovotestis. Here, a number of permutations may occur, with either a testis and an ovary, or an ovotestis with a testis, an ovary or another ovotestis . 

    This usually results from a mosaic XX:XY karyotype, and the predominance of either ovarian or testicular tissue in the gonad depends on the percent- age of cell lines in the mosaic. As can be seen from, the combination of gonads will determine the degree of virilization: the greater the testicular component, the more virilized the resulting development and the more likely the presence of Müllerian inhibitor. 

    Thus, in the true hermaphrodite, it is possible to get co-existent Müllerian and Wolffian structures in terms of internal development, and varying degrees of masculinization of the external genitalia, depending on the combination of gonads.

Internal genitalia abnormalities

    In males there are three fundamental changes that may lead to abnormalities of the internal genitalia. The first of these is androgen insensitivity. In this condition the fetus fails to develop androgen receptors due to mutations in the androgen receptor gene. Failure to possess the receptor means that although the testis will be producing testosterone, the androgenic effect cannot be translated into the end organ as it is not recognized by the cell wall. 

    The result here is that the fetus develops in the default female state, as it is unable to recognize the androgenic impact. This is the commonest type of XY female and the Wolffian ducts regress, as they also have no androgen receptor. However, the Müllerian ducts also regress because the testis is normal and produces Müllerian inhibitor. Girls with this abnormality present with primary amenorrhoea at puberty.

    A further aberration in XY females also exists with a condition known as 5a-reductase deficiency. As outlined above, this enzyme is responsible for the conversion of testosterone to dihydrotestosterone resulting in virilization of the cloaca. If this enzyme is absent, the external genitalia will be female but the internal genitalia will be male. The Müllerian ducts will regress. Here again, this female will present with primary amenorrhoea.

    Finally, a rare condition known as Müllerian inhibitory deficiency may mean that an XY male may have persistent Müllerian structures, due to the absence of Müllerian inhibitory factor, and co-existent male and female internal structures.

    In 46 XX females, a genetic defect that results in failure of development of the uterus, cervix and vagina is known as the Rokitansky syndrome. This is the second most common cause of primary amenorrhoea in women, the first being Turner's syndrome. Here the ovaries are normal, and the external genitalia are normally female. 

    The internal genitalia are either absent or rudimentary. Variations on this may lead to development of the vagina without development of the uterus, or development of the uterus without subsequent development of the cervix or vagina, and a functional uterus may result. The aetiology of this developmental abnormality remains to be clarified. 

    It is probably, however, a defect in the genes responsible for the development of the internal fee genetalia These genes, known as the homeobox genes, are likely to possess either deletions, which may be partial or complete, or point mutations and, as a consequence of these variations, the resulting structures of the internal genitalia will vary in their development. 

    However, the overall effect of this developmental abnormality is a failure of uterine and vaginal development, leading to infertility. These patients will present at puberty with either primary amenorrhoea or, in circumstances when a small portion of uterus may be functional, with cyclical abdominal pain due to retained menstrual blood.

    Two other developmental abnormalities may occur. The first of these is maldevelopment of the uterus, in which fusion defects occur from the extreme of a double uterus with a double cervix through to the normally fused uniform uterus. 

    These abnormalities have been classified and result from the failure of fusion of the paramesonephric ducts at their lower border. A mal- developed uterus may be associated with some degree of reproductive failure.

    The development of the vagina involves a down-growth of the vaginal plate and subsequent union of this with the cloaca and thereafter canalization. This process can also fail, leading to the second developmental abnormality, transverse vaginal septae, in which the passage of the vagina is interrupted and therefore at menstrual blood is trapped in an upper vagina that does not connect to the lower vagina. 

    In the unusual condition of a double uterus, a double vagina- can also exist, and failure to develop the full double vaginal system may result in a blind hemivagina, again leading to a collection of menstrual blood at puberty.