Pubertal Presentation of Congenital Δ5–-3β–Hydroxysteroid Dehydrogenase Deficiency*

Abstract

Partial deficiency of Δ⁵–3βhydroxysteroid dehydrogenase (3β-ol) was found in a 17-yr-old female with acne (onset at 8 yr), male-pattern hirsutism (beginning with feminization at 12 yr), and primary amenorrhea. Clitoromegaly, but not genital ambiguity, was found. Disproportionate elevations of Δ⁵–3βhydroxysteroids were demonstrated in all adrenal and ovarian steroidogenic paths. Plasma 17-hydroxypregnenolone (17-Preg) was 32,225 ng/dl, dehydroepiandrosterone (DHA) sulfate was 1,211 μg/dl, DHA was 7,853 ng/dl, and androstenediol was 406 ng/dl. These levels were all over 5 times greater than those of their immediate Δ⁴–3 keto-me abolites; the latter were nevertheless elevated (e. g.17-hydroxyprogesterone was 3,016 and androstenedione was 493ng/dl). Pregnenetriol and pregnanetriol excretion were 322 and 54 mg/day, respectively, patterns characteristic of 3β-ol deficiency. ACTH stimulated 17-Preg and DHA, though the plasma cortisol level (8.3 μxg/dl) did not rise. Dexamethasone administration reversed all of the abnormalities except that of 17-Preg, which remained modestly elevated (1,020 ng/dl). Menopausal gonadotropin stimulation elicited an estrogen surge at the expense of elevations in plasma DHA, androstenediol, and androstenedione. The addition of estrogen-progestin to dexamethasone brought plasma steroids to normal or below normal levels, although estrogen-progestin alone had no suppressive effect. Inefficient aldosterone secretion was indicated by high plasma renin. Corticoid therapy resulted in apparently ovulatory menstrual cycles. We postulate that the elevated levels of Δ⁴3-ketosteroids resulted from the action of an intact hepatic 3β-ol isozyme on secreted Δ⁵-3β-hydroxysteroids. The elevated 11-deoxycortisol blood level (721 ng/dl) is hypothesized to result from comparable hepatic conversion of secreted 3/8, 17α21-trihydroxypregn-5-en-20-one. 16α-Hydroxylat on of Δ⁵-3β-hydroxysteroids was observed to be a prominent metabolic pathway, suggesting the persistence of fetal pathways of steroid metabolism. The hereditary nature of the disorder was supported by the mother’s abnormal response to ACTH; her 17-Preg level increased excessively relative to that of 17-hydroxyprogesterone.