Persistent progesterone elevation in infertility revealing non-classic P450 oxidoreductase deficiency: 2 cases

Non-classic P450 oxidoreductase deficiency (NC-PORD) is a rare form of congenital adrenal hyperplasia that may remain unrecognized until adulthood. While infertility in patients already diagnosed with P450 oxidoreductase deficiency (PORD) has been described, cases in which unexplained infertility directly leads to the diagnosis of NC-PORD are rare. We report 2 women who presented with unexplained infertility and persistent elevation of progesterone levels. Rapid adrenocorticotropic hormone stimulation testing showed marked increases in progesterone and 17α-hydroxyprogesterone with suboptimal cortisol response, suggesting impaired steroidogenesis. Genetic analysis identified P450 oxidoreductase variants previously reported in PORD, supporting the diagnosis of NC-PORD. These cases suggest that persistent progesterone elevation may serve as an important clinical clue for NC-PORD in patients with infertility. In contrast to non-classic 21-hydroxylase deficiency, the broader impairment of steroidogenesis in NC-PORD may result in a more complex reproductive phenotype. Recognition of this endocrine pattern may facilitate timely diagnosis and enable mechanism-based management strategies in reproductive medicine.