Plasma Cortisol and Aldosterone Responses to Insulin Tolerance Test and Sodium Depletion in Women with Non Classic 21-Hydroxylase Deficiency

Presentation Number: OR03-4
Date of Presentation: April 2nd, 2017

Peter Kamenický*1, Anne Blanchard2, Antonin Lamaziere3, Bruno Donadille4, Lise Duranteau5, Sylvie Salenave1, Laurence Pietri6, Marie-Laure Raffin-Sanson7, Jean-François Gautier8, Philippe Chanson1, Sophie Christin Maitre4, Yves Le Bouc9, Sylvie Brailly Tabard10 and Jacques Young11
1Univ Paris-Sud, Université Paris-Saclay; Assistance Publique-Hôpitaux de Paris, Hôpital de Bicêtre, Service d’Endocrinologie et des Maladies de la Reproduction, France, 2Assistance Publique-Hôpitaux de Paris, Hôpital Européen George Pompidou, Centre d'Investigations Cliniques, France, 3INSERM, Laboratoire de lipidomique; Université Pierre et Marie Curie, France, 4Assistance Publique-Hôpitaux de Paris, Hôpital Saint Antoine, Service d’Endocrinologie, France, 5Assistance Publique-Hôpitaux de Paris, Hôpital de Bicêtre, Service d’Endocrinologie Pédiatrique, FRANCE, 6Hopital Saint Joseph, Service d'Endocrinologie, France, 7Assistance publique hôpitaux de Paris, Hôpital Ambroise Paré, Service d'Endocrinologie, France, 8Assistance Publique-Hôpitaux de Paris, Hôpital Lariboisière, Service d’Endocrinologie, France, 9INSERM UMRS 938, FRANCE, 10Assistance Publique-Hôpitaux de Paris, Hôpital Bicêtre, Service de Génétique Moléculaire, Pharmacogénétique, et Hormonologie, France, 11AP-HP, Hôpital de Bicêtre, Le Kremlin-Bicêtre, France


Background Non-classic form of congenital adrenal hyperplasia (NC-CAH) is due to mutations in CYP21A2 gene, encoding 21-hydroxylase, which can impair cortisol biosynthesis. Usually, the disease is diagnosed in pubertal/post-pubertal women because of androgen excess. However, the risk of acute adrenal insufficiency in adult patients with NC-CAH is not known, and indication of systematic glucocorticoid replacement therapy is still controversial. The aim of the present study was to evaluate in women with NC-CAH cortisol and aldosterone secretions in response to physiological challenges.

Experimental design: Prospective controlled clinical study ( Id: NCT01862380) at a tertiary referral medical center and clinical investigation center. We investigated 20 women with NC-CAH with biallelic CYP21A2 mutations (homozygotes or compound heterozygotes) and serum 17-hydroxyprogesterone >10ng/mL after stimulation with 250 μg-Synacthen comparatively to 20 age- and BMI-matched healthy women (17-hydroxyprogesterone after Synacthen <2ng/mL). Women were eligible if they did not receive glucocorticoid treatment > 1 year and estrogen-based oral contraception > 3 months preceding inclusion.

Interventions Each participant underwent sequentially two tests separated by a 2 to 7-day washout period: insulin tolerance test (ITT) considered the gold standard to evaluate cortisol secretion and a sodium depletion test to stimulate endogenous renin and aldosterone secretion. Sodium depletion was obtained by oral administration of 40 mg furosemide under low sodium diet (< 20 mmol during 24 hours). Steroid levels were measured by LC-MSMS.

Results Women with NC-CAH had lower pic plasma cortisol concentrations during ITT compared to healthy volunteers: 17.2 μg/dL (13.1-22.8) vs. 21.2 μg/dL (17.1-33.5), P=0.0002. A peak plasma cortisol concentration above a cutoff value of 17.0 μg/dL was obtained in all healthy women but only in 60% of women with NC-CAH. Patients with NC-CAH had higher baseline ACTH and renin concentrations. 24-hours after sodium depletion, plasma aldosterone concentrations were comparable between the two groups, but NC-CAH women had higher stimulated active renin concentrations compared to healthy women: 67 mUI/L (15-156) vs. 39 mUI/L (6-87), P=0.003.

Conclusions: 40% women with NC-CAH have subnormal glucocorticoid adrenal function. Their aldosterone production is maintained normal by increased renin-angiotensin system activity. In addition to treatment of androgen excess, the clinical management of women with NC-CAH should thus include assessment of their cortisol and aldosterone production. Although systematic chronic replacement therapy seems not required, transient glucocorticoid supplementation and rehydration during periods of stress should be considered in patients with documented partial adrenal deficiency.


Nothing to Disclose: PK, AB, AL, BD, LD, SS, LP, MLR, JFG, PC, SC, YL, SB, JY