Abstract
Background: The term “adrenal androgen” is often used to describe the adrenal-produced androgen precursors, dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS). The human adrenal, however, also secretes 11-oxygenated androgens that include 11-hydroxyandrostenedione (11OHA4), 11-ketoandrostenedione (11KA4), 11-hydroxytestosterone (11OHT) and 11-ketotestosterone (11KT), of which 11OHT and 11KT are bioactive. These clinically important steroids have been implicated in diseases of androgen excess, including premature adrenarche, congenital adrenal hyperplasia and polycystic ovary syndrome. While the production of these steroids is established in humans, their presence in other mammalian species has not been examined. Objectives: The goal of this study was to characterize circulating 11-oxyandrogens across species and identify possible animal models to study the regulation and functions of these steroids. Methods: To eliminate possible confounding contributions of testicular androgens, serum was obtained from a range of adult female animals, including birds, rodents, domestic animals and primates (15 species, n=5 each). Sera concentrations of DHEA, DHEAS, 11OHA4, 11KA4, 11OHT and 11KT were analyzed by liquid chromatography-tandem mass spectrometry. Results: As previously demonstrated, significant amounts of circulating DHEA and DHEAS were found only in primates. 11-oxyandrogens also circulated at similar concentrations in all the primates studied (rhesus monkeys, baboons, chimpanzees and humans) of which 11OHA4 was observed to be the most abundant circulating steroid. As expected, neither rats or mice had circulating 11-oxyandrogens, likely because they lack adrenal 17α-hydroxylase/17,20-lyase expression. Low levels of 11-oxyandrogens were detected in dogs, cows, sheep and horses. Interestingly, pigs and guinea pigs had significant circulating levels of 11-oxyandrogens. Circulating levels of 11OHA4 and 11KA4 in pigs (3.2 ± 0.8 nM; 0.4 ± 0.1 nM respectively) and guinea pigs (7.0 ± 0.2 nM; 1.2 ± 0.1 nM) were similar or higher than humans (3.4 ± 0.6 nM; 0.4 ± 0.1 nM). Serum concentrations of 11OHT in guinea pigs were lower (0.1 ± 0.02 nM) as compared to humans (0.3 ± 0.04 nM) and pigs (0.5 ± 0.2 nM). Conversely, circulating 11KT levels were most abundant in humans (0.7 ± 0.2 nM), followed by guinea pigs (0.4 ± 0.1 nM) and pigs (0.2 ± 0.03 nM). Conclusions: 11-oxygenated androgens are produced in multiple primate species. In addition, guinea pigs and pigs have circulating concentrations of 11-oxyandrogens similar to those seen in primates, and could be considered as appropriate animal models to define the physiology of the 11-oxyandrogens.