2026-08-08 | Female infertility in nonclassic congenital adrenal hyperplasia: beyond hyperandrogenism
Nonclassic congenital adrenal hyperplasia (NCCAH) is a common autosomal recessive endocrinopathy, primarily caused by partial 21-hydroxylase ( CYP21A2 ) deficiency, and represents a significant but often underrecognized cause of female infertility. Clinically, affected women frequently present with hyperandrogenism, menstrual irregularities, and ovulatory dysfunction, which can lead to misdiagnosis as polycystic ovary syndrome (PCOS). Traditionally, reproductive failure in NCCAH has been attributed solely to androgen excess disrupting folliculogenesis. However, recent evidence reveals a multifactorial pathophysiology. Beyond hyperandrogenism, premature follicular-phase progesterone elevation, disruption of the hypothalamic–pituitary–ovarian (HPO) axis, impaired endometrial receptivity, and increased risk of early pregnancy loss collectively contribute to infertility. Accurate diagnosis requires a structured approach, including basal and adrenocorticotropic hormone (ACTH)-stimulated 17-hydroxyprogesterone (17-OHP) measurement, comprehensive endocrine profiling, and genetic testing. Therefore, fertility optimization should extend beyond isolated androgen suppression. This review critically summarizes current knowledge of NCCAH-related infertility mechanisms and proposes an integrated, multidisciplinary management strategy—encompassing targeted targeted glucocorticoid (GC) therapy, ovulation induction, assisted reproductive technology (ART), careful obstetric monitoring, and genetic counseling—to improve fertility and pregnancy outcomes in this patient population.
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2026-07-30 | Insulin Resistance Emerges Early After Glucocorticoid Treatment in Adult Patients With 21-Hydroxylase Deficiency.
Metabolic disorders, particularly insulin resistance (IR), represent important complications in adults with 21-hydroxylase deficiency (21OHD). Glucocorticoid (GC) therapy is a known risk factor, yet evidence from longitudinal analyses remains scarce. In this study, based on a large, genetically characterized, single-center cohort of Chinese adults with 21OHD, we performed both cross-sectional and longitudinal analyses to investigate the risk factors for IR. We found that nearly one-third of young adult 21OHD patients had IR. Current GC use remained independently associated with IR (OR 13.30, 95% CI 2.54-69.55; p = 0.002), whereas neither genotype nor androgen levels showed an association. We followed 52 patients without IR at baseline; incident IR occurred in 57.1% (4/7) of GC-naive patients and 68.9% (31/45) of previously GC-exposed patients, with median times to IR onset of 14.7 and 13.1 months, respectively. Importantly, dexamethasone use was independently associated with incident IR (HR 7.04, 95% CI 1.81-27.34; p = 0.005). Daily 1000 mg metformin therapy for 6 months did not significantly improve IR (median HOMA-IR, 2.50-2.82; p = 0.460) and only provided a modest benefit in body weight (median BMI, 23.6-22.5 kg/m2; p = 0.046). These findings suggest that ongoing GC therapy, particularly dexamethasone, is a risk factor for IR in adults with 21OHD, and new onset IR generally emerged within approximately 1 year after regular treatment.
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2026-07-14 | Reproduction and fertility issues in women with congenital adrenal hyperplasia: pathophysiology, management, and recent clinical advances.
Congenital adrenal hyperplasia (CAH), commonly caused by 21-hydroxylase deficiency (21-OHD), is an autosomal recessive disorder of adrenal steroidogenesis with significant implications for reproductive health. This review examines the pathophysiological mechanisms, fertility outcomes, and management strategies pertaining to reproductive function in women with classical and non-classical (NC) CAH. Fertility is generally reduced in women with classical CAH compared to the general population, owing to a combination of anatomical alterations from prenatal androgen exposure and reconstructive surgery, hypothalamic-pituitary-ovarian (HPO) axis dysregulation driven by excess adrenal androgens and progesterone, anovulation, and psychosexual factors, including altered gender-related behaviour and reduced reproductive intent. In NC CAH, fertility is only mildly impaired and most women can conceive; however, miscarriage rates are substantially higher in the absence of treatment. Optimised glucocorticoid replacement therapy is the cornerstone of management, restoring ovulatory cycles and improving conception rates in both phenotypes by suppressing adrenal androgen and progesterone excess. When ovulation fails to occur, induction with clomiphene citrate or gonadotropins may be employed; in vitro fertilisation with preimplantation genetic testing represents an option for refractory cases at high genetic risk. Pregnancy in CAH requires careful obstetric monitoring, glucocorticoid dose adjustment, and stress-dose coverage during labour. Prenatal treatment with dexamethasone to prevent virilisation of possibly affected female foetuses remains a subject of ongoing ethical and clinical debate. A multidisciplinary approach-encompassing endocrinology, reproductive medicine, surgery, and psychological support-is essential for optimising reproductive outcomes and quality of life in women with CAH.
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2026-07-14 | Clinical pregnancy outcomes with assisted reproduction in patients with 17α-Hydroxylase/17, 20-lyase deficiency: a single center cohort study and integrated analysis with reported cases.
17α-hydroxylase/17, 20-lyase deficiency (17OHD) represents a rare form of congenital adrenal hyperplasia. Affected 46, XX females typically present with sexual development abnormalities, endocrine disturbances and infertility. While assisted reproductive technology (ART) enables pregnancies in these patients, our knowledge about optimal management strategies and pregnancy outcomes remains limited. We conducted a retrospective cohort study of women with 17OHD who achieved clinical pregnancy at our center between January 2009 and August 2025, followed until December 2025. Moreover, we performed a systematic review of published cases, extracting and analyzing demographic, clinical, laboratory, treatment, and outcome data. Among 20 female patients with 17OHD at our center, six desired fertility and three achieved clinical pregnancy with ART. Combined with 17 reported cases from 12 studies, a total of 20 pregnancies resulted in 23 live births. Median age at pregnancy preparation was 29 (range 21-42) years. The prevalence rates of hypertension and adrenal insufficiency were 25.0% (5/20) and 50.0% (10/20), respectively. Median follicular-phase progesterone was 20.8 nmol/L. Seventeen women conceived via frozen embryo transfer (FET) following ovarian stimulation, including nine with GnRH agonists (GnRHa), six with progestin-primed ovarian stimulation, one with GnRH antagonists, and one with GnRHa short protocol, respectively. Nearly 95% (18/19) participants received glucocorticoids before embryo transfer. Pregnancy complications (including gestational hypertension, diabetes, preeclampsia, and HELLP syndrome) occurred in 46.2% (6/13) cases. Only 25% (5/20) of the participants had term vaginal deliveries. All five offspring that were followed up developed normally. For women with 17OHD, a treatment protocol combining glucocorticoid-assisted progesterone suppression with FET represents a viable strategy to achieve pregnancy. However, such patients face high risks of adverse maternal and perinatal outcomes, requiring multidisciplinary management throughout gestation.
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2026-07-07 | Modified-release hydrocortisone (Efmody®) in children with congenital adrenal hyperplasia: a retrospective registry study
Background Replacement therapy for congenital adrenal hyperplasia (CAH) in childhood includes hydrocortisone and, in salt-wasting forms, addition of fludrocortisone. Immediate-release hydrocortisone often fails to adequately suppress early morning 17-hydroxyprogesterone (17OHP) levels. Hydrocortisone modified-release capsules (HMRC, Efmody ® ) were approved by the EMA in 2021 for the treatment of patients aged ≥12 years with CAH. This study evaluates the efficacy and safety of HMRC in children and adolescents based on real-world data collected from the I-CAH registry. Methods A single-center retrospective analysis of children with CAH was conducted. Linear mixed models (LMMs) were used to calculate pre–post comparisons of 17OHP saliva profiles, growth rate, bone age, body mass index, hydrocortisone and fludrocortisone dosage, blood pressure, and safety parameters before and during HMRC therapy (study registration, https://drks.de/search/de , DRKS00038319). Findings The median age of the 36 children with CAH at the time of treatment switching to HMRC was 10 years (interquartile range [IQR]: 8–14 years). Of these, 15 were prepubertal and 21 were (post)pubertal. HMRC therapy was associated with a deceleration of previously increased growth velocity (pre-switch: 0.1 SDS/year, 95% CI: 0.0 to 0.2; post-switch: -0.1 SDS/year, 95% CI: –0.2 to 0.1) and with a reduction of median difference of bone age and chronological age by 0.50 years (IQR -1.17–0.27, range -2.2–2.00). Mean hydrocortisone dose increased by 2.4 mg/m²/day during HMRC treatment. Mean morning 17OHP concentrations significantly decreased from 337 ng/L (95% CI: 240–437) to 214 ng/L (95% CI: 155–294) after switching to HMRC treatment. No adrenal crisis was observed. Interpretation Twice-daily HMRC therapy can also improve CAH therapy in children and adolescents in terms of hormonal control and growth.
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