Molecular aspects and treatment concepts of intersexuality

Abstract

The increasing knowledge of the molecular pathogenesis of sexual differentiation have provided the basis for a more comprehensive diagnostic work-up and the therapeutic management of newborns with ambiguous external genitalia or external genitalia which contrasts the karyotype. The determination of the sex in mammals is governed by the development of the bipotential primordium into a testis or an ovary, which results in a female or male phenotype of the secondary sex characteristics through the production of hormones. The primary requirement for sexual differentiation are early growth and survival factors, e.g. WT1, that control the proliferation of the bipotential gonad The sry gene was identified as the primary genetic switch, which turns on the development of the gonadal primordium into a testis. Subsequently other downstream genetic factors (Dax1, Sox9) have been identified, which are essential for a normal testis development. Human mutations of these genetic factors, controlling the development of the bipotential gonad or the testis result in male pseudohermaphroditism. The most frequent causes of an impaired virilization of an embryo with a 46XY karyotype are molecular defects of androgen biosynthesis (e.g. 17β hydroxysteroiddehydrogenase deficiency) and action (androgen receptor defects). However in or than half of the newborns with an XY karyotype and ambiguous or female external genitalia the cause is still unknown. In patients with female pseudohermaphroditism the major differential diagnosis is congenital adrenal hyperplasia leading to a prenatal stimulation of fetal adrenal androgen production. Developmental defects of the female gonad into an ovary (e.g. in patients with Turner Syndrome) do not result in ambiguous external genitalia and therefore these diagnoses are not considered as intersexuality. The basic cellular and molecular research will help to understand the pathways that control testis and ovary development, but for the development of treatment concepts for affected newborns it is crucial to perform clinical studies which aim to define the impact of these genetic factors as well as of fetal and neonatal hormones on the development of a male or female gender identification. Regarding the increasing knowledge of genetic and molecular basis of intersexuality, it is no longer justified to assign a sex of rearing only according to the karyotype, the physical appearance and surgical possibilities.