Disorders of Sex Development-Novel Regulators, Impacts on Fertility, and Options for Fertility Preservation

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.

Keywords: disorder of sex development; fertility; fertility preservation; gonads; ovary; sex determination; testis.

Figure 1

Timeline of genes involved in gonadal development. Genes shown are known to play a role in sex-specific gonadal development in human and mice. Testis-related genes (blue) and ovary-related genes (pink) represent a regulatory pathway which leads to Sertoli and granulosa cell development, respectively. The orange arrows represent an antagonistic action. Interactions that are postulated but unproven are indicated with (?). The ectopic gonadal expression of Sox3 (represented by red dotted line) induces testis differentiation by upregulating Sox9 in a similar way to Sry.

Figure 2

Options for fertility preservation in sex chromosome DSD (aneuploid). * Mostly mosaics. ** Postpubertal. # Potential for gonadal tissue cryopreservation based on published literature indicating presence of germ cells +/− tissue cryopreservation; however, there are no reports of successful restoration of fertility and this should be considered within the context of an ethically approved research study.

Figure 3

Options for fertility preservation in sex chromosome DSD (mixed gonadal dysgenesis). * Usually dysgenetic. ** May be possible for IVF. *** Rare case reports. # Potential for gonadal tissue cryopreservation based on published literature indicating presence of germ cells +/− tissue cryopreservation; however, there are no reports of successful restoration of fertility and this should be considered within the context of an ethically approved research study.

Figure 4

Options for fertility preservation in 46,XX DSD. * Optimise therapy for CAH. ** Postpubertal. # Potential for gonadal tissue cryopreservation based on published literature indicating presence of germ cells +/− tissue cryopreservation; however, there are no reports of successful restoration of fertility and this should be considered within the context of an ethically approved research study.

Figure 5

Options for fertility preservation in 46,XY DSD with gonadal dysgenesis. GD—gonadal dysgenesis. * Often dysgenetic. ** May be possible for milder phenotypes. # Potential for gonadal tissue cryopreservation based on published literature indicating presence of germ cells +/− tissue cryopreservation; however, there are no reports of successful restoration of fertility and this should be considered within the context of an ethically approved research study.

Figure 6

Options for fertility preservation in 46,XY DSD associated with impaired androgen production. * Optimise therapy for CAH. # Potential for gonadal tissue cryopreservation based on published literature indicating presence of germ cells +/− tissue cryopreservation; however, there are no reports of successful restoration of fertility and this should be considered within the context of an ethically approved research study.

Figure 7

Options for fertility preservation in 46,XY DSD associated with impaired androgen action. * Single case report. ** Single case report (high-dose testosterone). # Potential for gonadal tissue cryopreservation based on published literature indicating presence of germ cells +/− tissue cryopreservation; however, there are no reports of successful restoration of fertility and this should be considered within the context of an ethically approved research study.