Origins of progesterone in male mice

Hannah Collden; Thulin Malin Hagberg; Andreas Landin; Anna-Karin Norlen; Henrik Ryberg; Jianyao Wu; Karin L Gustafsson; Louise Grahnemo; Karin Nilsson; Klara Sjogren; Matti Poutanen; Liesbeth Vandenput; Claes Ohlsson

doi:10.1530/endoabs.81.P130

The role of progesterone in male physiology is mainly unknown. We recently observed that progesterone was the most abundant sex hormone in orchiectomized (ORX) mice with most of it stored in white adipose tissue (WAT) (1). The aim of the present study was to use a sensitive and validated gas chromatography/tandem mass spectroscopy method to determine the origins of progesterone in male mice. Tissue levels of progesterone were high in adrenals of male mice, indicating that male progesterone may be predominantly adrenal-derived. To determine if progesterone only originates from the adrenals in males, we compared WAT levels of progesterone in ORX+ adrenalectomized (ADX) and intact mice. Surprisingly, combined orchiectomy and adrenalectomy did not reduce progesterone levels in WAT (mean ± SEM, 1.638 ± 239 pg/g vs. 1.871 ± 124 pg/g, non-significant). In both groups, we also observed high levels of progesterone along the gastrointestinal tract including the gastric contents. To evaluate food as a potential progesterone source, we analyzed progesterone levels in 20 types of mouse chow and found varying but substantial levels in all tested types (2.319-17.702 pg/g). To identify main sources of food-derived progesterone, we analyzed progesterone levels in several food items, reveling no/low levels in non-animal-derived food items, medium levels in meat and very high levels in dairy products such as cream (123.162 ± 1.282 pg/g). To functionally test if orally ingested progesterone could contribute to tissue levels, we administered isotope-labeled progesterone or vehicle by oral gavage for 10 days to adult ORX+ADX male mice, and data indicated some uptake of labeled progesterone into the WAT. Interestingly, a recent metagenomic study showed an association between gut microbiota (GM) functional traits and circulating progesterone levels in humans (2). Accordingly, we determined the impact of the GM for progesterone levels in WAT and found that germ-free male mice, completely lacking GM, had substantially increased progesterone levels in WAT compared with conventionally raised mice (+132% ± 25%; P<0.001). In conclusion, in the absence of adrenal-derived progesterone in male mice progesterone levels are maintained by an alternative progesterone source. We propose that food-derived progesterone may be taken up and maintain close to normal progesterone levels in ORX+ADX male mice. Furthermore, GM composition may regulate this uptake of progesterone.

References: 1. Colldén et al. Endocrinology. 2022; doi: 10.1210/endocr/bqac001.

2. Liu et al. Nat Genet. 2022;54(1):52-61.

Endocrine Abstracts

P130