Broad-spectrum XX and XY gonadal dysgenesis in patients with a homozygous L193S variant in PPP2R3C

Context: Homozygous and heterozygous variants in PPP2R3C are associated with syndromic 46,XY complete gonadal dysgenesis (MEGD syndrome), and impaired spermatogenesis, respectively. This study expands the role of PPP2R3C in the aetiology of gonadal dysgenesis (GD). Method: We sequenced the PPP2R3C gene in four new patients from three unrelated families. The clinical, laboratory and molecular characteristics were investigated. We have also determined the requirement for Ppp2r3c in mice (C57BL6/N) using CRISPR/Cas9 genome editing. Results: A homozygous c.578T>C (p.L193S) PPP2R3C variant was identified in one 46,XX girl with primary gonadal insufficiency, 2 girls with 46,XY complete GD, and one undervirilized boy with 46,XY partial GD. The patients with complete GD had low gonadal and adrenal androgens, low AMH, and high FSH and LH concentrations. All patients manifested characteristic features of MEGD syndrome. Heterozygous Ppp2r3c knockout mice appeared overtly normal and fertile. Inspection of homozygous embryos at 14.5, 9.5 and 8.5 days post coitum revealed evidence of dead embryos. We conclude that loss of function of Ppp2r3c is not compatible with viability in mice and results in embryonic death from 7.5 dpc or earlier. Conclusion: Our data indicate essential roles for PPP2R3C in mouse and human development. Germline homozygous variants in human PPP2R3C are associated with distinctive syndromic GD of varying severity in both 46,XY and 46,XX individuals.

Influence of a Maximal Incremental Test Until Exhaustion on the Urinary Excretion of Steroid Hormones in Trained Cyclists

This study aimed to assess the effect of a maximum incremental stress test through urinary concentrations of steroid hormones in trained cyclists. Twenty male cyclists participated in the study (23.83 ± 2.3 years; 1.76 ± 0.03 m; 66.94 ± 3.59 kg; training volume: 20.50 ± 2.35 h/week). Athletes performed a maximum incremental test until exhaustion on a cycle ergometer and urine samples were collected at three different time points: before, immediately after, and 48 h after the test. Lactate, creatinine and urinary concentrations of testicular and adrenal androgens were obtained as well as urinary concentrations of glucocorticoid hormones. An increase in lactate was observed after the test (p < 0.01). There were decreases in the urinary excretion of androgenic hormones after the test, which were significant in testosterone, androsterone, androstenedione, total adrenal androgen and total testicular androgen (p < 0.05). The values were restored after 48 h (p < 0.05). Urinary cortisol concentrations decreased after the test (p < 0.05). A decrease was also observed in the ratio of anabolic/catabolic hormones (p < 0.05) increasing 48 h after the test (p < 0.05). Increased acute physical exercise until exhaustion causes variations in the urinary excretions of steroid hormones which were restored 48 h after exercise. Urinary excretion of steroid hormones could be a valid method of monitoring training loads.

A common androgen synthesis variant is associated with COVID susceptibility

A sex discordance in COVID exists, with males disproportionately affected. More broadly, sex differences in infectious and inflammatory processes are well known, with women tending to mount stronger immune responses than men. Although there is evidence that sex hormone signaling is immunomodulatory, including downregulation of immune/inflammatory responses by androgens, the existence of numerous other physiologic differences between the sexes leads to great uncertainty in attributing worse infectious disease outcomes in men to androgen signaling. No definitive genetic data exist to support androgen-mediated immune suppression for viral susceptibility, nor for adrenal androgens. Here we show an association between inheritance of the common adrenal-permissive missense-encoding variant HSD3B1(1245C), that enables androgen synthesis from adrenal precursors10, and susceptibility to COVID. The adrenal-permissive HSD3B1(1245C) has previously been linked to suppression of inflammation in severe asthma. In analysis of COVID test results from the UK Biobank, we show that in older (≥ 70 years of age) subjects, the adrenal-permissive variant is associated with a greater chance of being COVID-positive. The effect increases with the number of HSD3B1(1245C) alleles inherited and is greater in females such that increasing androgen synthesis confers risk approaching males. Our study suggests that a common androgen synthesis variant regulates immune susceptibility to COVID infection as well as potentially other immune and inflammatory processes.

Changes in Adrenal Androgens and Steroidogenic Enzyme Activities From Ages 2, 4, to 6 Years: A Prospective Cohort Study

Context The levels of adrenal androgens are increased through the action of steroidogenic enzymes with morphological changes in the adrenal zona reticularis. Objective We investigated longitudinal changes in androgen levels and steroidogenic enzyme activities during early childhood. Design and Participants From a prospective children’s cohort, the Environment and Development of Children cohort, 114 boys and 86 girls with available blood samples from ages 2, 4, and 6 years were included. Outcome Measurements Serum concentrations of adrenal androgens using liquid chromatography-tandem mass spectrometry and steroidogenic enzyme activity calculated by the precursor/product ratio. Results During ages 2 to 4 years, 17,20-lyase and dehydroepiandrosterone (DHEA) sulfotransferase activities increased (P &lt; 0.01 for both in boys). During ages 4 to 6 years, 17,20-lyase activity persistently increased, but 3β-hydroxysteroid dehydrogenase (HSD) and 17β-HSD activities decreased (P &lt; 0.01 for all). Serum DHEA sulfate (DHEA-S) levels persistently increased from 2, 4, to 6 years, and DHEA, 17-hydroxyprogesterone, and androstenedione levels increased during ages 4 to 6 years (P &lt; 0.01 for all). Serum DHEA-S levels during early childhood were associated with body mass index z-scores (P = 0.001 in only boys). Conclusion This study supports in vivo human evidence of increased 17,20-lyase and DHEA sulfotransferase activities and decreased 3β-HSD activity during early childhood.

OR25-03 The Effects of Crinecerfont (NBI-74788), a Novel CRF1 Receptor Antagonist, on Adrenal Androgens and Precursors in Patients with Classic Congenital Adrenal Hyperplasia: Results from A Multiple-Dose Phase 2 Study

Introduction: Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency (21OHD CAH) is a rare autosomal recessive disease that results in impaired cortisol synthesis and excess androgen production. Compounds that inhibit adrenocorticotropic hormone (ACTH) release could reduce adrenal androgen production and thus the amounts of exogenous glucocorticoids needed to decrease these androgen levels. This study evaluated the effect of crinecerfont (NBI-74788), a novel, non-steroidal, and selective corticotropin-releasing factor-1 (CRF1) receptor antagonist on adrenal androgens and precursors in adults with 21OHD CAH. Methods: This open-label, multiple-dose study enrolled men and women (18–50 years old) with 21OHD CAH. A sequential-cohort design evaluated 4 crinecerfont oral dosing regimens: 50 mg QHS (Cohort 1); 100 mg QHS (Cohort 2); 100 mg QD (Cohort 3); and 100 mg alternative dosing (Cohort 4). Each regimen was administered for 14 consecutive days. ACTH, 17-hydroxy-progesterone (17OHP), and androstenedione (A4) were measured serially over a 24-hour period, at baseline and after 14 days of dosing. Results: Analyses included 23 participants: Cohort 1 (4 women, 4 men: mean age 31.1 years); Cohort 2 (5 women, 2 men: mean age 32.9 years); and Cohort 3 (3 women, 5 men: mean age 30.9 years). Cohort 4 is ongoing. At baseline, median plasma ACTH, serum 17OHP, and serum A4 levels were as follows: Cohort 1 (ACTH, 151 pg/mL; 17OHP, 5352 ng/dL; A4, 270 ng/dL); Cohort 2 (ACTH, 232 pg/mL; 17OHP, 12821 ng/dL; A4, 597 ng/dL); and Cohort 3 (ACTH, 470 pg/mL; 17OHP, 6451 ng/dL; A4, 299 ng/dL). After 14 days of once-daily crinecerfont 50 mg, Cohort 1 patients had median percent reductions from baseline in plasma ACTH (-54%), serum 17OHP (-60%), and serum A4 (-21%). Median percent reductions were generally larger with 100 mg in Cohort 2 (ACTH, -67%; 17OHP, -75%; A4, -47%) and Cohort 3 (ACTH, -69%; 17OHP, -55%; A4, -43%), consistent with a dose-related response. Adverse events were mostly mild; no clinically significant findings from routine laboratory tests, vital signs, or electrocardiograms were noted. Conclusions: Results of this Phase 2 study of crinecerfont, a novel, orally administered, selective CRF1-receptor antagonist, indicated clinically meaningful reductions of elevated ACTH, 17OHP, and A4 in adults with 21OHD CAH after 14 days of treatment. Further studies are warranted to evaluate the effects of chronic crinecerfont therapy on maintenance of adrenal steroid production, clinical endpoints of disordered steroidogenesis, and reductions in GC exposure in both adult and pediatric patients with 21OHD CAH.

A Challenging Case of Adrenal Insufficiency Presenting with Hypertensive Crisis

Adrenal insufficiency is the deficient production or action of glucocorticoids, with or without deficiency in mineralocorticoids or adrenal androgens. It usually presents with anorexia, abdominal pain, weakness, weight loss, fatigue, and hypotension. We report a case of 67 year old male, who is known to have hypertension, presented to emergency room with severe headache and was found to have high blood pressure 241/135mmHg and hypoosmolar hyponatremia. He was started on intravenous nicardipine and his blood pressure dropped suddenly, became orthostatic, and required fluid resuscitation but his headache resolved. On next day, the cosyntropin test was suggestive of primary adrenal insufficiency. The patient was started on oral hydrocortisone with improvement in his blood pressure and hyponatremia.