Metabolism in vitro of testosterone (T) to 17β-hydroxy-5α-androstane-3-one (DHT) and 5α-androstane-3α,17β-diol (3α) by the 800 g supernatant fraction of ileum from rats

Androgens exert important effects both in androgen-responsive tissues and in the intestinal tract. To determine the impact of the gut microbiota (GM) on intestinal androgen metabolism, we measured unconjugated (free) and glucuronidated androgen levels in intestinal contents from the small intestine, with a low bacterial density, and from cecum and colon, with a high bacterial density. Using a specific, sensitive gas chromatography-tandem mass spectrometry method, we detected high levels of glucuronidated testosterone (T) and dihydrotestosterone (DHT) in small intestinal content of mice of both sexes, whereas in the distal intestine we observed remarkably high levels of free DHT, exceeding serum levels by >20-fold. Similarly, in young adult men high levels of unconjugated DHT, >70-fold higher than in serum, were detected in feces. In contrast to mice with a normal GM composition, germ-free mice had high levels of glucuronidated T and DHT, but very low free DHT levels, in the distal intestine. These findings demonstrate that the GM is involved in intestinal metabolism and deglucuronidation of DHT and T, resulting in extremely high free levels of the most potent androgen, DHT, in the colonic content of young and healthy mice and men.

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The gut microbiota is a major regulator of androgen metabolism in intestinal contents

Colldén

Landin

Wallenius

et al. 2019

American Journal of Physiology-Endocrinology and Metabolism

150

116

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5α-Reduced glucocorticoids: a story of natural selection

Nixon¹,

Upreti²,

Andrew³

2011

Journal of Endocrinology

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5a-Reduced glucocorticoids (GCs) are formed when one of the two isozymes of 5a-reductase reduces the D 4-5 double bond in the A-ring of GCs. These steroids are largely viewed inert, despite the acceptance that other 5a-dihydro steroids, e.g. 5a-dihydrotestosterone, retain or have increased activity at their cognate receptors. However, recent findings suggest that 5a-reduced metabolites of corticosterone have dissociated actions on GC receptors (GRs) in vivo and in vitro and are thus potential candidates for safer anti-inflammatory steroids. 5a-Dihydro-and 5a-tetrahydro-corticosterone can bind with GRs, but interest in these compounds had been limited, since they only weakly activated metabolic gene transcription. However, a greater understanding of the signalling mechanisms has revealed that transactivation represents only one mode of signalling via the GR and recently the abilities of 5a-reduced GCs to suppress inflammation have been demonstrated in vitro and in vivo. Thus, the balance of parent GC and its 5a-reduced metabolite may critically affect the profile of GR signalling. 5a-Reduction of GCs is up-regulated in liver in metabolic disease and may represent a pathway that protects from both GC-induced fuel dyshomeostasis and concomitant inflammatory insult. Therefore, 5a-reduced steroids provide hope for drug development, but may also act as biomarkers of the inflammatory status of the liver in metabolic disease. With these proposals in mind, careful attention must be paid to the possible adverse metabolic effects of 5a-reductase inhibitors, drugs that are commonly administered long term for the treatment of benign prostatic hyperplasia.

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Metabolism in vitro of testosterone (T) to 17β-hydroxy-5α-androstane-3-one (DHT) and 5α-androstane-3α,17β-diol (3α) by the 800 g supernatant fraction of ileum from rats

Cited by 2 publications

References 21 publications

The gut microbiota is a major regulator of androgen metabolism in intestinal contents

The gut microbiota is a major regulator of androgen metabolism in intestinal contents

5α-Reduced glucocorticoids: a story of natural selection

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