Abstract
Disorders (or differences) of sex development (DSD) are a heterogeneous group of congenital conditions with variations in chromosomal, gonadal, or anatomical sex. Impaired gonadal development is central to the pathogenesis of the majority of DSDs and therefore a clear understanding of gonadal development is essential to comprehend the impacts of these disorders on the individual, including impacts on future fertility. Gonadal development was traditionally considered to involve a primary ‘male’ pathway leading to testicular development as a result of expression of a small number of key testis-determining genes. However, it is increasingly recognized that there are several gene networks involved in the development of the bipotential gonad towards either a testicular or ovarian fate. This includes genes that act antagonistically to regulate gonadal development. This review will highlight some of the novel regulators of gonadal development and how the identification of these has enhanced understanding of gonadal development and the pathogenesis of DSD. We will also describe the impact of DSDs on fertility and options for fertility preservation in this context.
Highlights
Genetic sex is determined from the point of conception
Together these results suggest that ectopic expression of Dmrt1 in ovaries is sufficient to promote testicular differentiation in mice even though it is dispensable for the initial establishment of Sertoli cell fate during fetal life
Whilst it is likely that cases of 46,XY DSD in individuals with deletions of chromosome 9p24 are due to loss of DMRT1, it cannot be excluded that other genes in this region contribute, or cause, the observed gonadal phenotypes [121,122,123]
Summary
The developing gonad remains bipotential until approximately six weeks post-conception, as until this point it can develop into an ovary or a testis. In the XY gonad, at approximately seven weeks post conception, SRY is expressed in Sertoli cell precursors, and can be thought of as the dominant ‘switch’ in promotion of testicular development [7]. Primordial germ cells migrate into the developing gonad from approximately five weeks gestation at which point they are termed gonocytes [15]. Gonocytes in both sexes express pluripotency markers and undergo further development towards a spermatogonial or oogonial fate. Germ cell survival and development in both sexes is dependent on unique interactions with the somatic cell populations of the gonad; failure in the development of both somatic cells and germ cells during gonad development can impact on germ cells and future fertility
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