Hyperandrogenism due to cortisone reductase deficiency

Hyperandrogenism due to cortisone reductase deficiency, also known as apparent cortisone reductase deficiency (ACRD), is a rare endocrine disorder characterized by impaired conversion of cortisone to cortisol. This metabolic defect results from deficiency of the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), encoded by the HSD11B1 gene, or from deficiency of hexose-6-phosphate dehydrogenase (H6PD), which provides the NADPH cofactor required for 11β-HSD1 activity. The inability to regenerate cortisol from cortisone leads to increased clearance of cortisol, which in turn drives compensatory activation of the hypothalamic-pituitary-adrenal (HPA) axis. The resulting excess adrenocorticotropic hormone (ACTH) secretion stimulates the adrenal glands, leading to overproduction of adrenal androgens. The condition primarily affects the endocrine and reproductive systems. In women, hyperandrogenism manifests as hirsutism (excess body hair), acne, menstrual irregularities, oligomenorrhea or amenorrhea, and infertility. The clinical presentation can closely mimic polycystic ovary syndrome (PCOS). In men, the condition may present with premature pseudopuberty or may remain clinically silent. Biochemically, affected individuals typically show an elevated ratio of cortisone to cortisol metabolites in urine, with increased total cortisol metabolite excretion reflecting enhanced HPA axis drive. Adrenal androgen levels, including DHEAS and androstenedione, are elevated. Treatment is aimed at suppressing the excessive ACTH drive and thereby reducing adrenal androgen production. Low-dose glucocorticoid therapy, such as dexamethasone or hydrocortisone, can effectively suppress ACTH and normalize androgen levels. In women, anti-androgen therapies and oral contraceptives may also be used to manage symptoms of hyperandrogenism. Early recognition and appropriate treatment can significantly improve symptoms and fertility outcomes.

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