Non-classical congenital adrenal hyperplasia: current insights into clinical implications, diagnosis and treatment

Non-classical congenital adrenal hyperplasia (NCCAH) is a milder variant of 21-hydroxylase deficiency, an autosomal recessive disorder leading to impaired cortisol biosynthesis and compensatory adrenal androgen excess. Unlike the classical form, NCCAH typically presents later in life, often mimicking polycystic ovary syndrome (PCOS) in women and remaining largely asymptomatic in men.

A literature search was conducted in MEDLINE (PubMed) in October 2024 using the term "Non-Classical Congenital Adrenal Hyperplasia" in combination with keywords related to sex differences, diagnosis, genetics, clinical presentation, metabolic risk, fertility, and treatment.

NCCAH prevalence varies significantly by ethnicity, ranging from 3.7% in Ashkenazi Jews to 0.1% in other Caucasian populations. In females, NCCAH often presents with symptoms of androgen excess, including hirsutism (60-80%), acne (30%), androgenic alopecia (2-8%), menstrual irregularities (56%), and, in rare cases, clitoromegaly (6-20%). Many affected women are misdiagnosed with PCOS, delaying appropriate management. In males, NCCAH remains largely asymptomatic and it is often diagnosed only through familial genetic screening or incidentally in fertility evaluations. A small percentage exhibit premature pubarche, tall stature, gynecomastia, or testicular adrenal rest tumors (TARTs). Regarding metabolic risks, conflicting evidence suggests that NCCAH may be associated with mild insulin resistance, obesity, and an increased cardiovascular risk, particularly in women. Bone mineral density (BMD) appears normal or even increased in NCCAH, possibly due to prolonged androgen exposure, though fracture risk remains uncertain. Treatment is generally reserved for symptomatic patients, with glucocorticoids, antiandrogens, and oral contraceptives being the main therapeutic approaches. While glucocorticoids reduce adrenal androgen excess, they pose risks of adrenal suppression and metabolic complications, making alternative therapies such as cyproterone acetate, spironolactone, and estrogen-progestin combinations preferable in many cases. Fertility outcomes in NCCAH are variable. Women may experience infertility due to androgen excess, dysovulation, and progesterone-mediated implantation issues. In males, fertility does not appear significantly impaired.

NCCAH remains an underdiagnosed and poorly characterized condition, particularly in males. Further research is needed to establish standardized diagnostic thresholds, assess long-term metabolic risks, and optimize treatment strategies.