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 11βhydroxyandrostenedione (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 11oxyandrogens in other species has not been investigated. This study provides a comprehensive analysis of a set of C 19 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 adrenal-derived 11-oxyandrogen precursors.

Do Dehydroepiandrosterone (DHEA) and Its Sulfate (DHEAS) Play a Role in the Stress Response in Domestic Animals?

“…In primates, DHEA circulates in the blood mainly in its sulfated form (DHEAS) at micromolar levels. DHEAS is particularly high in humans and chimpanzees (13), and represents a circulating reservoir for DHEA. The conversion of DHEA into DHEAS is primarily catalyzed by the sulfotransferase type 2A1 (SULT2A1) enzyme (Figure 1), although other sulfotransferase enzymes such as SULT1E1 or members of the SULT2B family can catalyze DHEAS synthesis (18).…”

“…DHEAS is present in the plasma of rat, dog, and pig at nanomolar levels, and it is undetectable (14) or very low (13,24) in the plasma of ruminants, guinea pig, and rabbit. Moreover, in non-primate mammals the adrenals are not elective sites of DHEA sulfonation.…”

“…Moreover, in non-primate mammals the adrenals are not elective sites of DHEA sulfonation. Among domestic mammals, the male pig shows the higher circulating DHEAS concentrations (13). However, SULT2A1 and SULT2B1 are poorly expressed in the boar adrenals in comparison with testes (36), and available data suggest that DHEA sulfonation occurs mainly in testicles and epididymis (36)(37)(38)(39)(40).…”

“…Therefore, DHEA and DHEAS could also be considered as important players in the stress response and potential biomarkers of stress in domestic animals. However, different animal species can display specific features in the synthesis, regulation and biological role of these steroids to satisfy their own physiological requirements (13).…”

“…DHEA is present in the circulation of primate mammals in large amounts (20-60 nM), while lower amounts (around 1-3 nM or less) of this steroid can be found in the blood of rodents and domestic animals, such as rabbits, dogs, pigs, cattle, sheep, and horses (13,14). DHEA is synthesized in steroidogenic tissues (adrenals, gonads, and placenta) and in the nervous system from pregnenolone through the 5 pathway, thanks to the activity of the enzyme cytochrome P450c17 (CYP17A) (Figure 1).…”