Gonadal gender is heralded by the diferentiation of the primordial gonad into a testis or an ovary. If a Y chromosome is present, the gonad begins developing into a testis. Testis development is directed by a protein called the testis-determiningactor (TDF), which modulates the transcription of several genes involved in gonadal diferentiation. TDF is encoded by the sexdetermining region (SR) gene, located on the short arm of the Y chromosome. But testis development is much more complex and requires other autosomal genes (Nistal, 2015a).
he importance of the SRYgene is demonstrated in severl paradoxical conditions. First, 46,X phenotypic males can result from translocation of the Y chromosome fragment containing SRY to the X chromosome during meiosis of male germ cells Wu, 2014). Similarly, 46,Y individuals can appear phenotypically female if they carry a mutation in the SRYgene (Helszer, 2013).
Last, phenoypic gender begins at 8 weeks' gestation. Before this, urogenital tract development in both sexes is indistinguishable. Thereafter, diferentiation of the internal and external genitalia to the male phenotype is dependent on testicular function. In the absence of a testis, female diferentiation ensues irrespective of genetic gender (Table 3-1).
In males, the fetal testis secretes a protein called mullerianinhibiting substance (MIS), also called antimullerian hormone (AMH) . It acts locally as a paracrine factor to cause mullerian duct regression. Thus, it prevents the development of uterus, fallopian tube, and upper vagina. AMH is produced by the Sertoli cells of the seminiferous tubules. Importantly, these tubules appear in fetal gonads and secrete AMH before diferentiation of Leydig cells, which are the cellular site of testosterone synthesis. AMH is secreted as early as 7 weeks, and mullerian duct regression is completed by 9 to 10 weeks. Because AMH acts locally near its site of formation, if a testis were absent on one side, the mullerian duct on that side would persist, and the uterus and fallopian tube would develop on that side.
Apparently through stimulation initially by human chorionic gonadotropin (hCG), and later by fetal pituitary luteinizing hormone (LH), the fetal testes secrete testosterone. his hormone acts directly on the wolian duct to efect the development of the vas deferens, epididymis, and seminal vesicles. Testosterone also enters fetal blood and acts on the external genitalia anlage. In these tissues, testosterone is converted to 5a-DHT to cause virilization of the external genitalia.
As evident from the prior discussion, abnormal sex development may involve the gonads, internal duct system, or external genitalia. Rates vary and approximate 1 in every 1000 to 4500 births (Murphy, 2011; Ocal, 2011). The nomenclature used to describe disorders of sex development (DSDs) has evolved. Current classiication of these disorders include: (1) sex chromosome DSDs, (2) 46,Y DSDs, and (3) 46,X DSDs (Table 3-2) (Hughes, 2006).
Other important terms describe the abnormal phenotypic findings that can be found. First, some disorders of sexual development are associated with abnormal, underdeveloped gonads, that is, gonadal dysgenesis. With this, if a testis is poorly formed, it is called a dysgenetic testis, and if an ovary is poorly formed, it is called a streak gona. In afected patients, the underdeveloped gonad ultimately fails, which is indicated by elevated gonadotropin levels. Another important clinical sequela is that patients bearing a Y chromosome are at high risk of developing a germ cell tumor in the dysgenetic gonad.