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

BACKGROUND: 17β-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. CASES: Patient 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. CONCLUSIONS: These 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

Effects of sotatercept on haemodynamics and right heart function : analysis of the STELLAR trial

BACKGROUND: In the phase 3 STELLAR trial, sotatercept, an investigational first-in-class activin signalling inhibitor, demonstrated beneficial effects on 6-min walk distance and additional efficacy endpoints in pre-treated participants with pulmonary arterial hypertension (PAH). METHODS: This analysis evaluated data from right heart catheterisation (RHC) and echocardiography (ECHO) obtained from the STELLAR trial. Changes from baseline in RHC and ECHO parameters were assessed at 24 weeks. An analysis of covariance (ANCOVA) model was used to estimate differences in least squares means with treatment and randomisation stratification (mono/double triple therapy; World Health Organization functional class II III) as fixed factors, and baseline value as covariate. RESULTS: Relative to placebo, treatment with sotatercept led to significant (all p\u3c0.0001 except where noted) improvements from baseline in mean pulmonary artery (PA) pressure (-13.9 mmHg), pulmonary vascular resistance (-254.8 dyn·s·cm), mean right atrial pressure (-2.7 mmHg), mixed venous oxygen saturation (3.84%), PA elastance (-0.42 mmHg·mL·beat), PA compliance (0.58 mL·mmHg), cardiac efficiency (0.48 mL·beat·mmHg), right ventricular (RV) work (-0.85 g·m) and RV power (-32.70 mmHg·L·min). ECHO showed improvements in tricuspid annular plane systolic excursion (TAPSE) to systolic pulmonary artery pressure ratio (0.12 mm·mmHg), end-systolic and end-diastolic RV areas (-4.39 cm and -5.31 cm, respectively), tricuspid regurgitation and RV fractional area change (2.04% p\u3c0.050). No significant between-group changes from baseline were seen for TAPSE, heart rate, cardiac output, stroke volume or their indices. CONCLUSION: In pre-treated patients with PAH, sotatercept demonstrated substantial improvements in PA pressures, PA compliance, PA-RV coupling and right heart function