Dietary Progesterone Contributes to Intratissue 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, intratissue androgen levels were mainly testicular derived. Interestingly, progesterone levels remained high after ORX and ORX + ADX with the highest levels in white adipose tissue 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 white adipose tissue and prostate, suggesting that dietary progesterone may contribute to tissue levels of progesterone. In conclusion, although adrenal-derived progesterone contributes to intratissue progesterone levels in males, nonadrenal progesterone sources also contribute. We propose that dietary progesterone is absorbed and contributes to intratissue 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.

Dehydroepiandrosterone Supplementation Results in Varying Tissue-specific Levels of Dihydrotestosterone in Male Mice.

Dehydroepiandrosterone (DHEA), an adrenal androgen precursor, can be metabolized in target tissues into active sex steroids. It has been proposed that DHEA supplementation might result in restoration of physiological local sex steroid levels, but knowledge on the effect of DHEA treatment on local sex steroid levels in multiple tissues is lacking. To determine the effects of DHEA on tissue-specific levels of sex steroids, we treated orchiectomized (ORX) male mice with DHEA for 3 weeks and compared them with vehicle-treated ORX mice and gonadal intact mice. Intra-tissue levels of sex steroids were analyzed in reproductive organs (seminal vesicles, prostate, m. levator ani), major body compartments (white adipose tissue, skeletal muscle, and brain), adrenals, liver, and serum using a sensitive and validated gas chromatography-mass spectrometry method. DHEA treatment restored levels of both testosterone (T) and dihydrotestosterone (DHT) to approximately physiological levels in male reproductive organs. In contrast, this treatment did not increase DHT levels in skeletal muscle or brain. In the liver, DHEA treatment substantially increased levels of T (at least 4-fold) and DHT (+536%, P < 0.01) compared with vehicle-treated ORX mice. In conclusion, we provide a comprehensive map of the effect of DHEA treatment on intra-tissue sex steroid levels in ORX mice with a restoration of physiological levels of androgens in male reproductive organs while DHT levels were not restored in the skeletal muscle or brain. This, and the unexpected supraphysiological androgen levels in the liver, may be a cause for concern considering the uncontrolled use of DHEA.

A probiotic mix partially protects against castration-induced bone loss in male mice.

Studies in postmenopausal women and ovariectomized mice show that the probiotic mix Lacticaseibacillus paracasei DSM13434, Lactiplantibacillus plantarum DSM 15312 and DSM 15313 (L. Mix) can protect from bone loss caused by sex steroid deficiency. Whether probiotic bacteria can protect bone also in sex steroid-deficient males is less studied. We used the orchiectomized mouse as a model for age-dependent bone loss caused by decreasing sex hormone levels in males. We treated 10-week-old male mice with either vehicle (veh) or L. Mix for 6 weeks, starting 2 weeks before orchiectomy (orx) or sham surgery. Importantly, mice treated with L. Mix had a general increase in total body bone mineral density (BMD) and lean mass (P ≤ 0.05) compared with veh-treated mice. Detailed computer tomography analysis of dissected bones showed increased trabecular BMD of the distal metaphyseal region of the femur in L. Mix compared to veh-treated orx mice (+8.0%, P ≤ 0.05). In the vertebra, L. Mix treatment increased trabecular bone volume fraction BV/TV (+11.5%, P ≤ 0.05) compared to veh in orx mice. Also, L. Mix increased the levels of short-chain fatty acids (SCFAs) such as propionate and acetate and important intermediates in SCFA synthesis such as succinate and lactate in the cecal content of male mice. In conclusion, L. Mix treatment resulted in a general increase in BMD in adult male mice and prevented trabecular bone loss in femur and vertebra of orx mice. These bone protective effects of L. Mix were associated with increased levels of SCFAs in the cecal content of male mice.

Comprehensive Sex Steroid Profiling in Multiple Tissues Reveals Novel Insights in Sex Steroid Distribution in Male Mice.

A comprehensive atlas of sex steroid distribution in multiple tissues is currently lacking, and how circulating and tissue sex steroid levels correlate remains unknown. Here, we adapted and validated a gas chromatography tandem mass spectrometry method for simultaneous measurement of testosterone (T), dihydrotestosterone (DHT), androstenedione, progesterone (Prog), estradiol, and estrone in mouse tissues. We then mapped the sex steroid pattern in 10 different endocrine, reproductive, and major body compartment tissues and serum of gonadal intact and orchiectomized (ORX) male mice. In gonadal intact males, high levels of DHT were observed in reproductive tissues, but also in white adipose tissue (WAT). A major part of the total body reservoir of androgens (T and DHT) and Prog was found in WAT. Serum levels of androgens and Prog were strongly correlated with corresponding levels in the brain while only modestly correlated with corresponding levels in WAT. After orchiectomy, the levels of the active androgens T and DHT decreased markedly while Prog levels in male reproductive tissues increased slightly. In ORX mice, Prog was by far the most abundant sex steroid, and, again, WAT constituted the major reservoir of Prog in the body. In conclusion, we present a comprehensive atlas of tissue and serum concentrations of sex hormones in male mice, revealing novel insights in sex steroid distribution. Brain sex steroid levels are well reflected by serum levels and WAT constitutes a large reservoir of sex steroids in male mice. In addition, Prog is the most abundant sex hormone in ORX mice.

Pasteurized Akkermansia muciniphila protects from fat mass gain but not from bone loss.

Probiotic bacteria can protect from ovariectomy (ovx)-induced bone loss in mice. Akkermansia muciniphila is considered to have probiotic potential due to its beneficial effect on obesity and insulin resistance. The purpose of the present study was to determine if treatment with pasteurized Akkermansia muciniphila (pAkk) could prevent ovx-induced bone loss. Mice were treated with vehicle or pAkk for 4 wk, starting 3 days before ovx or sham surgery. Treatment with pAkk reduced fat mass accumulation confirming earlier findings. However, treatment with pAkk decreased trabecular and cortical bone mass in femur and vertebra of gonadal intact mice and did not protect from ovx-induced bone loss. Treatment with pAkk increased serum parathyroid hormone (PTH) levels and increased expression of the calcium transporter Trpv5 in kidney suggesting increased reabsorption of calcium in the kidneys. Serum amyloid A 3 (SAA3) can suppress bone formation and mediate the effects of PTH on bone resorption and bone loss in mice and treatment with pAkk increased serum levels of SAA3 and gene expression of Saa3 in colon. Moreover, regulatory T cells can be protective of bone and pAkk-treated mice had decreased number of regulatory T cells in mesenteric lymph nodes and bone marrow. In conclusion, treatment with pAkk protected from ovx-induced fat mass gain but not from bone loss and reduced bone mass in gonadal intact mice. Our findings with pAkk differ from some probiotics that have been shown to protect bone mass, demonstrating that not all prebiotic and probiotic factors have the same effect on bone.

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

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.

[Compatibility of intravenous medications needs attention. Catheter occlusion, treatment failure and embolisms can be prevented]. / Blandbarhet av intravenösa läkemedel behöver uppmärksammas - Kateterocklusion, terapisvikt och embolier kan förebyggas.

When dealing with more drugs than available lumens, intravenous medications need to be co-administered in the same catheter. This type of scenario may induce therapeutic risks, such as catheter occlusion, changes in drug effect or embolization of precipitated particles. Various sources are available to provide information on compatibilities of intravenous medications. When using these sources, the applicability of the information must be assessed, comparing concentrations, diluents used and other pharmaceutical aspects. For the last three years, a group of pharmacists at Sahlgrenska University Hospital has worked on a project collecting and validating compatibility data for intravenous medications. In the future, this data will be available to more hospitals in Sweden.