Female infertility in nonclassic congenital adrenal hyperplasia: beyond hyperandrogenism

Abstract

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.