Circulating 11-oxygenated androgens across species

Abstract

The androgen precursors, dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS) are produced in high amounts by the adrenal cortex primarily in humans and a few other primates. The human adrenal also secretes 11-oxygenated androgens (11-oxyandrogens), including 11β-hydroxyandrostenedione (11OHA4), 11-ketoandrostenedione (11KA4), 11β-hydroxytestosterone (11OHT) and 11-ketotestosterone (11KT), of which 11OHT and 11KT are bioactive androgens. The 11-oxyandrogens, particularly 11KT, have been recognized as biologically important testicular androgens in teleost fishes for decades, but their physiological contribution in humans has only recently been established. Beyond fish and humans, however, the presence of 11-oxyandrogens in other species has not been investigated. This study provides a comprehensive analysis of a set of C₁₉ steroids, including the traditional androgens and 11-oxyandrogens, across 18 animal species. As previously shown, serum DHEA and DHEAS were much higher in primates than all other species. Circulating 11-oxyandrogens, especially 11KT, were observed in notable amounts in male, but not in female trout, consistent with gonadal origin in fish. The circulating concentrations of 11-oxyandrogens ranged from 0.1 to 10 nM in pigs, guinea pigs and in all the primates studied (rhesus macaque, baboon, chimpanzee and human) but not in rats or mice, and 11OHA4 was consistently the most abundant. In contrast to fish, serum 11KT concentrations were similar in male and female primates for each species, despite significantly higher circulating testosterone in males, suggesting that 11KT production in these species is not testis-dependent and primarily originates from adrenal-derived 11-oxyandrogen precursors.

Keywords: 11-Oxyandrogens; Adrenal; Primates; Steroids.

Fig. 1.. Circulating concentrations of the classic adrenal androgens in adult animals across different species.

LC-MS/MS was utilized to quantify the serum concentrations of DHEA and DHEAS in 17 species. Males and females were pooled. Only primates were shown to produce high amounts of these androgen precursors. Data are denoted as mean ± SEM. Concentrations of DHEA and DHEAS are expressed in nmol/L (nM) and μmol/L (μM) respectively. DHEA, dehydroepiandrosterone; DHEAS, DHEA sulfate.

Fig. 2.. Circulating concentrations of the 11-oxygenated derivatives of androstenedione in adult animals across different species.

LC-MS/MS was utilized to measure the serum concentrations of 11OHA4 and 11KA4 in 17 species. Males and females were pooled. In addition to all primates, guinea pigs exhibited significant serum amounts of both 11OHA4 and 11KA4. Data are denoted as mean ± SEM. Steroid concentrations are expressed in nmol/L (nM). 11OHA4, 11β-hydroxyandrostenedione; 11KA4, 11-ketoandrostenedione.

Fig. 3.. Circulating concentrations of the bioactive 11-oxyandrogens in adult animals across different species.

LC-MS/MS was utilized to measure the serum concentrations of 11OHT and 11KT in 17 species. Males and females were pooled. Primates, pigs and guinea pigs demonstrated substantial serum concentrations of 11OHT and 11KT. Data are denoted as mean ± SEM. Steroid concentrations are expressed in nmol/L (nM). 11OHT, 11β-hydroxytestosterone; 11KT, 11-ketotestosterone.

Fig. 4.. Circulating concentrations of the bioactive 11-oxyandrogens in adult females and males of 17 species.

Data are denoted as mean ± SEM. Steroid concentrations are expressed in nmol/L (nM). 11OHT, 11β-hydroxytestosterone; 11KT, 11-ketotestosterone. Non-parametric Mann-Whitney U test was used to compare the steroid concentrations between females and males. *P<0.05; N.S, not significant.

Fig.5.. Comparison of circulating levels of (A) 11KT and (B) Testosterone in females vs. males for trout and primates.

(A) While male trout synthesized substantially higher concentrations of 11KT as compared to female, no clear sex differences were observed for 11KT. (B) Testosterone, on the other hand, was synthesized in significantly elevated concentrations in male primates vs. females. Additionally, we observed that female primates produced similar quantities of 11KT and Testosterone. Data are denoted as mean ± SEM. Steroid concentrations are expressed in nmol/L (nM). 11KT, 11- ketotestosterone. Non-parametric Wilcoxon matched-pairs signed rank test was used to compare 11KT vs. Testosterone in the same sex. **P<0.01; ***P<0.001; N.S, not significant.