Complexities of gender assignment in 17β-hydroxysteroid dehydrogenase type 3 deficiency: is there a role for early orchiectomy?

Abstract

Background17β-Hydroxysteroid dehydrogenase type-3 (17βHSD-3) deficiency is a rare cause of 46,XY disorders of sex development. The enzyme converts androstenedione to testosterone, necessary for masculinization of male genitalia in utero. 17βHSD-3 deficiency is frequently diagnosed late, at puberty, following virilization, with consequent female-to-male gender reassignment in 39-64%. The decision for sex of rearing is difficult, especially if diagnosed in early childhood. Consensus guidelines are equivocal or support male gender assignment. Long-term outcomes data to guide decisions are also lacking; however, in the few cases of early diagnosis and orchiectomy, female gender retention appears more likely.We report two patients with 17βHSD-3 deficiency, who presented at unusual ages, in whom female gender was chosen. We performed a focused literature review and summary of gender outcomes in 17βHSD-3 deficiency following early orchiectomy.CasesPatient A was a phenotypic female who presented at one year of age with bilateral inguinal hernias and external female genitalia. Testes were identified at surgery. The karyotype was 46,XY. She was initially diagnosed with complete androgen insensitivity syndrome; however, androgen receptor mutation analysis was negative. Human chorionic gonadotropin stimulation yielded a low testosterone: androstenedione ratio (0.6, normal >0.8). Genetic testing demonstrated compound heterozygosity for two known mutations of the HSD17B3 gene. She underwent bilateral orchiectomy at two years of age.Patient B was born with female genitalia and virilized at 13 years of age. She did not seek evaluation until 22 years of age. Her karyotype was 46,XY. She had bilateral inguinal testes and low testosterone: androstenedione ratio (0.3). HSD17B3 gene sequencing showed her to be a compound heterozygote for two known mutations. She identified herself as female and underwent bilateral orchiectomy and estrogen replacement therapy.ConclusionsThese two patients highlight the complexities of diagnosis and management in 17βHSD-3 deficiency. Although existing data are limited, early orchiectomy is likely to result in retention of female gender identity, avoiding the complications related to virilization in adolescence. As such, it is important to pursue a definitive diagnosis to guide clinical decisions, and to have the support and long term follow up with an inter-disciplinary disorders of sex development team.

Gender Assignment, Reassignment and Outcome in Disorders of Sex Development: Update of the 2005 Consensus Conference

“…Recent studies confirmed previous reports of a high rate of later patient-initiated gender change [55,56], although the risk may be smaller if gonadectomy has been performed prior to puberty. Interestingly, in one study no actual gender change was reported in the diagnostic groups [64], but gender identities of participants were not all typically female.…”

“…Moreover, postnatal androgens may contribute to long-term gender outcome, both in early infancy [54] and at later stages, then perhaps mediated not only through organizational effects of sex hormones on the developing brain, but also through virilization of the body and associated effects on self-image and on the reactions of the social environment, as seen in cases of 46,XX CAH with poor hormonal control [47] and in untreated 5α-reductase-2 deficiency [55] and 17β-hydroxysteroid dehydrogenase-3 deficiency [56]. Such issues need to be considered in gender assignment decisions.…”

DEPTOR Deficiency-Mediated mTORc1 Hyperactivation in Vascular Endothelial Cells Promotes Angiogenesis

“…Because DEPTOR was an mTOR inhibitor [23], the activity of mTORC1 was examined at first. When the mTOR signaling pathway was activated, the phosphorylation of PS6 (S235/236) was upregulated [23].…”

Gender identity, gender assignment and reassignment in individuals with disorders of sex development: a major of dilemma

“…Moreover, it has been suggested that unidentified pre-and postnatal factors, a better knowledge of the natural history of the disorder in some areas, and sociocultural issues may participate, all together, in influencing gender identity and role [77,161,163]. In fact, biological factors aside, socialization and learning, have been shown to contribute significantly to gender identity and role [168]. Up to now, data supporting a male gender assignment in these subjects are not as strong as for 5-alpha-reductase deficiency.…”

“…Moreover, it should be taken into account that an intermediate risk for germ-cell tumors exists for 17-beta-HSD-3 deficiency, and there are no reports of fertility thus far [140]. In particular, regarding the latter, it is unknown whether early testosterone therapy and orchidopexy would result in a more favorable outcome [168]. Consequently, female gender assignment may be appropriate in some situations; regular testicular evaluation is required for those reared male who have not had their testes removed [147].…”