Cortisol and Aldosterone Responses to Hypoglycemia and Na Depletion in Women With Non-Classic 21-Hydroxylase Deficiency

Abstract

Background Non-classic 21-hydroxylase deficiency is usually diagnosed in post-pubertal women because of androgen excess. Indication of systematic steroid replacement therapy is controversial because the risk of acute adrenal insufficiency is unknown. In order to specify this risk we evaluated the cortisol and aldosterone secretions in response to appropriate pharmacologic challenges. Methods In this prospective case–control non-inferiority study we investigated 20 women with non-classic 21-hydroxylase deficiency carrying biallelic CYP21A2 mutations and with serum 17-hydroxyprogesterone (17OHP) >10 ng/mL after stimulation with Synacthen® (tetracosactrin) and 20 age- and body mass index-matched healthy women with 17OHP after Synacthen® <2 ng/mL. Each participant underwent sequentially an insulin tolerance test to evaluate cortisol secretion and a sodium depletion test, obtained by oral administration of 40 mg of furosemide under low sodium diet (<20 mmol during 24 hours), to evaluate renin and aldosterone secretion. Findings The peak serum cortisol concentration after insulin hypoglycemia was lower in patients than in controls (mean difference –47 ng/mL, 90% CI, –66, P = 0.0026). A peak serum cortisol above a cutoff value of 170 ng/mL was obtained in all controls but only in 55% of patients (P = 0.0039). Twenty-four hours after sodium depletion, blood pressure, plasma sodium, potassium, and serum aldosterone concentrations were comparable between the two groups, but patients had higher stimulated renin concentrations than controls (P = 0.0044). Interpretation Patients with non-classic 21-hydroxylase deficiency frequently display partial cortisol insufficiency and compensated defect in aldosterone secretion. Their clinical management should systematically include assessment of adrenal functions.

Non-classic cytochrome P450 oxidoreductase deficiency strongly linked with menstrual cycle disorders and female infertility as primary manifestations

“…In particular, all affected women exhibited a concomitant increase of serum P and 17-OHP that misleadingly suggested NC-CAH/21-OHD. Interestingly, P levels were higher than 17-OHP in 3 cases whereas the opposite is usually seen in NC-CAH/21-OHD (Kamenicky et al 2019).…”

“…Biochemical assessment included measurement of serum reproductive hormones (E2, LH, FSH, P, AMH), androgen levels (TT, androstenedione, dehydroepiandrosterone sulfate [DHEA-S]), as well as adrenal precursors (17-OHP, 21-deoxycortisol, corticosterone) before and after ACTH stimulation according to standard procedures (intravenous administration of cosyntropin 0.25 mg) (Dorin, Qualls, and Crapo 2003). Androgens and adrenal precursors were measured by liquid chromatography-mass spectrometry [LC-MS] as previously described (Kamenicky et al 2019), while commercial immunoassays were used for the remaining hormonal measurements. Pelvic ultrasound and/or MRI was used to assess endometrial thickness and to measure antral follicle count [AFC] when possible.…”

Combining metabolomics and machine learning models as a tool to distinguish non-classic 21-hydroxylase deficiency from polycystic ovary syndrome without adrenocorticotropic hormone testing

“…Training set (KB): Nineteen women with NC21OHD with biallelic CYP21A2 mutations were included as the training set in this study. These patients were previously evaluated in a clinical study (Kamenický et al, 2020) performed at inclusion visit. Main clinical and genetics characteristics of these patients have been described elsewhere (Kamenický et al, 2020).…”

“…These patients were previously evaluated in a clinical study (Kamenický et al, 2020) performed at inclusion visit. Main clinical and genetics characteristics of these patients have been described elsewhere (Kamenický et al, 2020). In brief, seven of these patients carried the mild p.V281L CYP21A2 mutation in the homozygous state and 12 were compound heterozygotes with at least one minor mutation (for details see Supplementary Table SI).…”

“…Besides the classical form (C21OHD), which is due to complete or severe 21OH deficiency revealed at birth, there exists the nonclassical form (NC21OHD), which is due to partial enzymatic defect, with late-onset symptoms; diagnosis is usually made in late childhood or after puberty (3). The partial preservation of cortisol and aldosterone secretion in patients with NC21OHD (Kamenický et al, 2020) is explained by the existence of at least one of the alleles of a CYP21A2 mutation encoding a 21-hydroxylase that retains a minimum residual enzyme activity of 50% (New et al, 2013). NC21OHD is most often revealed in adolescent girls and young women by a clinical pattern of hyperandrogenism accompanied by oligomenorrhea associated with increased circulating testosterone (Admoni et al, 2006).…”