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.
Parts of work
Colldén H*, Nilsson ME*, Norlén AK, Landin A, Windahl SH, Wu J, Gustafsson KL, Poutanen M, Ryberg H, Vandenput L*, Ohlsson C*. Comprehensive sex steroid profiling in multiple tissues reveals novel insights in sex steroid distribution in male mice. Endocrinology 2022; 163(3):bqac001; https://doi.org/10.1210/endocr/bqac001 Colldén H, Nilsson ME, Norlén AK, Landin A, Windahl SH, Wu J, Horkeby K, Lagerquist MK, Ryberg H, Poutanen M, Vandenput L*, Ohlsson C*. Dehydroepiandrosterone supplementation results in varying tissue-specific levels of dihydrotestosterone in male mice. Endocrinology 2022; 163(12):bqac163; https://doi.org/10.1210/endocr/bqac163 Colldén H, Landin A, Wallenius V, Elebring E, Fändriks L, Nilsson ME, Ryberg H, Poutanen M, Sjögren K, Vandenput L, Ohlsson C. The gut microbiota is a major regulator of androgen metabolism in intestinal contents. Am J Physiol Endocrinol Metab. 2019; 317(6):E1182-E1192; https://doi.org/10.1152/ajpendo.00338.2019 Colldén H, Hagberg Thulin M, Landin A, Horkeby K, Lagerquist MK, Wu J, Nilsson KH, Grahnemo L, Poutanen M, Ryberg H, Vandenput L*, Ohlsson C*. Dietary progesterone contributes to intratissue levels of progesterone in male mice. Endocrinology 2023; 164(8):bqad103; https://doi.org/10.1210/endocr/bqad103
Degree
Doctor of Philosophy (Medicine)
University
University of Gothenburg. Sahlgrenska Academy
Institution
Inst of Medicine. Department of Internal Medicine and Clinical Nutrition
Disputation
Torsdagen den 9 november 2023, kl 13.00, Hörsal Arvid Carlsson, Academicum, Medicinaregatan 3, Göteborg
Date of defence
2023-11-09
hannah.collden@gu.se
Date
2023-10-16Author
Colldén, Hannah
Keywords
androgens
progesterone
intracrinology
gastrointestinal tract
gut microbiota
Publication type
Doctoral thesis
ISBN
978-91-8069-371-4 (TRYCK)
978-91-8069-372-1 (PDF)
Language
eng