Androgens and progesterone in tissues and the gastrointestinal tract - Mapping of tissue-specific sex steroid levels in mice

Abstract

Sex steroids such as androgens can exert both positive and negative effects in tissues and are important in physiology and pathophysiological states of men and women. Androgens originate mainly from the gonads. Local androgen levels in tissues are also regulated by intracrine processes, resulting in local levels not always being reflected by circulating levels. Mouse models are commonly used to study sex steroid-related disorders, but a lack of sufficiently sensitive and specific methods has prohibited accurate measurement of the low sex steroid levels in mouse tissues. Here, we developed and validated a gas chromatography – tandem mass spectrometry method capable of determining a broad panel of sex steroids in tissues and used it to map local sex steroid levels in tissues of mice in different conditions/treatments. We found that supplementing castrated male mice with dehydroepiandrosterone (DHEA) caused high androgen levels in the prostate and liver, raising concerns about the unsolicited use of DHEA by the public. Also, the gut microbiota was involved in the deconjugation of intestinal androgens, suggesting a possible mechanism for the relationship between androgen-related conditions and the gut microbiota proposed by experimental and epidemiological studies. Finally, progesterone was the most abundant sex steroid in castrated male mice, and the progesterone levels were surprisingly unaffected by both adrenalectomy and castration. We found that dietary progesterone was absorbed into tissues of male mice; therefore, we suggest food as a possible source of progesterone in men, perhaps of relevance for men with prostate cancer. In conclusion, measurement of local sex steroid levels in tissues is a novel method that could bring new understanding of pathways and mechanisms in androgen-related disorders and contribute to future development of more selective treatments for sex steroid-related diseases.