Modified-Release Hydrocortisone for Female Fertility in Congenital Adrenal Hyperplasia

OBJECTIVE: Women with classic congenital adrenal hyperplasia (CAH) suffer from reduced fecundity and fertility. This study aimed to assess fertility outcomes following treatment with modified-release hydrocortisone (MRHC), which more closely replicates the physiological circadian cortisol rhythm. METHODS: In this prospective case series, eight women with classic CAH and either menstrual irregularities or an unfulfilled desire to have children despite conventional GC therapy for a median duration of four years, including assisted reproduction, were switched to MRHC. Hormonal parameters, including morning serum progesterone, 17-hydroxyprogesterone (17OHP), androstenedione, testosterone, as well as daily salivary 17OHP profiles, were assessed before and after the switch. Clinical outcomes included menstrual cycle regularity and pregnancy. RESULTS: Descriptive analysis of morning serum samples indicate lower median concentrations of progesterone (0.9 vs. 2.1 ng/mL [2.9 vs. 6.7 nmol/l]), 17OHP (49.0 vs. 131.5 ng/dl [1.5 vs. 4.0 nmol/l]), androstenedione (76.0 vs. 261.0 ng/dL [2.7 vs. 9.1 nmol/l]), and testosterone (27.0 vs. 63.0 ng/dL [0.9 vs. 2.2 nmol/l]) after switching to MRHC with a lower median hydrocortisone dose equivalent (HDE) (30.0 v. 32.5 mg/d). Salivary 17OHP profiles showed a trend towards lower median AUC (183.9 vs. 676.5 pg×t(n)/mL) and lower concentrations across all time points. Regular menstrual cycles were restored in all patients. All five women seeking pregnancy conceived within a median of 9.8 months. Two unintended pregnancies occurred. Outcomes included six healthy live births and one early miscarriage. CONCLUSION: MRHC improved hormonal control and was associated with restoration of menstrual cyclicity and high rates of spontaneous conception with a lower HDE. Circadian optimization of GC therapy by MRHC may represent a paradigm shift in fertility management in females with CAH.