Human Gonads Do Not Contribute to the Circulating Pool of 11-Oxygenated Androgens

Abstract

Abstract Context Androstenedione (A4) and testosterone (T) are produced by both the adrenal glands and the gonads. The adrenal enzyme 11β-hydroxylase (CYP11B1) executes the final step in cortisol synthesis; CYP11B1 also uses A4 and T as substrates, generating 11-hydroxyandrostenedione and 11-hydroxytestosterone, respectively. It has been suggested that CYP11B1 is expressed in the gonads, yet the circulating levels of all 11-oxygenated androgens (11-oxyandrogens) are similar in males and females of reproductive ages, despite enormous differences in T. Objective To assess the gonadal contribution to the circulating pool of 11-oxyandrogens. Methods We used liquid chromatography–tandem mass spectrometry to measure 13 steroids, including traditional and 11-oxyandrogens in: (i) paired gonadal and peripheral vein blood samples obtained during gonadal venograms from 11 patients (7 women), median age 37 (range, 31-51 years); and (ii) 17 women, median age 57 (range, 41-81 years) before and after bilateral salpingo-oophorectomy (BSO). We also compared CYP11B1, 17α-hydroxylase/17,20-lyase (CYP17A1), and 3β-hydroxysteroid dehydrogenase type 2 (HSD3B2) mRNA expression in adrenal, ovarian, and testicular tissue. Results A4, T, estradiol, estrone, progesterone, 17α- and 16α-hydroxyprogesterone were all higher in gonadal veins vs periphery (P < .05 for all), while four 11-oxyandrogens were similar between matched gonadal and peripheral vein samples. Equally, in women who underwent BSO, A4 (median [interquartile range]: 59.7 [47.7-67.6] ng/dL vs 32.7 [27.4-47.8] ng/dL, P < .001) and T (24.1 [16.4-32.3] vs 15.5 [13.7-19.0] ng/dL, P < .001) declined, while 11-oxyandrogens remained stable. Gonadal tissue displayed negligible CYP11B1 mRNA. Conclusion Despite producing substantial amounts of A4 and T, human gonads are not relevant sources of 11-oxyandrogens.