Dietary progesterone contributes to intra-tissue levels of progesterone in male mice.

Progesterone serum levels have been identified as a potential predictor for treatment effect in men with advanced prostate cancer, which is an androgen-driven disease. Although progesterone is the most abundant sex steroid in orchiectomized (ORX) male mice, the origins of progesterone in males are unclear. To determine the origins of progesterone and androgens, we first determined the effect of ORX, adrenalectomy (ADX), or both (ORX+ADX) on progesterone levels in multiple male mouse tissues. As expected, intra-tissue androgen levels were mainly testicular-derived. Interestingly, progesterone levels remained high after ORX and ORX+ADX with the highest levels in white adipose tissue (WAT) and in the gastrointestinal tract. High progesterone levels were observed in mouse chow and exceptionally high progesterone levels were observed in food items such as dairy, eggs, and beef, all derived from female animals of reproductive age. To determine if orally ingested progesterone contributes to tissue levels of progesterone in males, we treated ORX+ADX and sham mice with isotope labeled progesterone or vehicle by oral gavage. We observed a significant uptake of labeled progesterone in WAT and prostate, suggesting that dietary progesterone may contribute to tissue levels of progesterone. In conclusion, although adrenal-derived progesterone contributes to intra-tissue progesterone levels in males, non-adrenal progesterone sources also contribute. We propose that dietary progesterone is absorbed and contributes to intra-tissue progesterone levels in male mice. We speculate that food with high progesterone content could be a significant source of progesterone in males, possibly with consequences for men undergoing androgen deprivation therapy for prostate cancer.