Reproduction and fertility issues in women with congenital adrenal hyperplasia: pathophysiology, management, and recent clinical advances

Abstract

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.