Congenital adrenal hyperplasia (CAH) is a genetic disorder of adrenal steroidogenesis that can lead to subfertility. P450 oxidoreductase (POR) mutations cause combined deficiencies in 21-hydroxylase, 17α-hydroxylase, and 17,20 lyase enzymes.
This case reports a 39-year-old woman referred to endocrinology with primary infertility and elevated, acyclical progesterone secretion. Menarche occurred at age 15, with regular menstrual cycles until she developed oligo-amenorrhoea in her mid 30’s. Assisted reproductive technologies were pursued from age 35, after failure of natural conception. Multiple cycles of ovarian stimulation had yielded good follicular response with paradoxically low oestradiol and persistently elevated progesterone. On clinical examination the patient was normotensive, with female phenotype without evidence of hyperandrogenism or hypocortisolism. Initial endocrine investigations demonstrated LH 8 IU/L, FSH 8 IU/L, oestradiol <70 pmol/L, progesterone 31 nmol/L, 17-hydroxyprogesterone (17OHP) 16.1 nmol/L (<8.9), 9 a.m. cortisol 185 nmol/L, ACTH 14 pmol/L (<11), with normal thyroid hormones and prolactin. Subsequent short Synacthen test showed baseline 17OHP 19.8 nmol/L with peak at 42.8 nmol/L and suboptimal peak cortisol of 356 nmol/L. Repeated cortisol levels were borderline (100-250 nmol/L) with ACTH in the upper part of the reference limit (7-11 pmol/L). Adrenal and ovarian imaging found no abnormality.
Serum steroid profile by liquid chromatography-tandem mass spectrometry found abnormally low androstenedione, testosterone, oestradiol, DHEA, DHEAS and elevations in several steroid precursors (11-deoxycorticosterone, 21-deoxycortisol, corticosterone, pregnenolone, 17-hydroxypregnenolone), suggestive of partial POR deficiency. Sequence analysis of a CAH gene panel identified compound heterozygosity in POR; one variant of likely pathogenicity (frameshift with premature stop codon) and another variant of uncertain significance predicted to be deleterious in silico, confirming a diagnosis of partial POR deficiency. Progesterone was suppressed with prednisolone with subsequent successful ovarian stimulation and oocyte retrieval. This genetic variant and phenotype have not previously been reported.