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The vitamin D receptor is highly expressed in the gastrointestinal tract where it transacts gene expression. With current limited understanding of the interactions between the gut microbiome and vitamin D, we conduct a cross-sectional analysis of 567 older men quantifying serum vitamin D metabolites using LC-MSMS and defining stool sub-Operational Taxonomic Units from16S ribosomal RNA gene sequencing data. Faith’s Phylogenetic Diversity and non-redundant covariate analyses reveal that the serum 1,25(OH) 2 D level explains 5% of variance in α-diversity. In β-diversity analyses using unweighted UniFrac, 1,25(OH) 2 D is the strongest factor assessed, explaining 2% of variance. Random forest analyses identify 12 taxa, 11 in the phylum Firmicutes, eight of which are positively associated with either 1,25(OH) 2 D and/or the hormone-to-prohormone [1,25(OH) 2 D/25(OH)D] “activation ratio.” Men with higher levels of 1,25(OH) 2 D and higher activation ratios, but not 25(OH)D itself, are more likely to possess butyrate producing bacteria that are associated with better gut microbial health. Here, the authors investigate associations of vitamin D metabolites with gut microbiome in a cross-sectional analysis of 567 elderly men enrolled in the Osteoporotic Fractures in Men (MrOS) Study and find larger alpha-diversity correlates with high 1,25(OH)2D and high 24,25(OH)2D and higher ratios of activation and catabolism.

The choice of a vitamin D–binding protein assay is key in calculating free 25-hydroxyvitamin D levels. The results of this analysis support the use of total 25-hydroxyvitamin D as a marker of vitamin D status, regardless of race or GC genotype. To the Editor: It is unclear whether circulating free or bioavailable 25-hydroxyvitamin D is a better marker of vitamin D status than is total 25-hydroxyvitamin D, especially in racially diverse populations. Until recently, the only method to compare the levels was to estimate the level of free or bioavailable 25-hydroxyvitamin D from total 25-hydroxyvitamin D, vitamin D–binding protein (also known as gc-globulin, encoded by the GC gene), and albumin, with or without the GC genotype. Powe et al. reported that levels of vitamin D–binding protein, as measured on a monoclonal enzyme-linked immunosorbent assay (ELISA, R&D Systems), were lower in black . . .

This multicenter trial evaluated zoledronic acid versus placebo in men with osteoporosis for a primary end point of new morphometric vertebral fracture over 24 months. Zoledronic acid was associated with a significantly reduced risk of vertebral fracture. Osteoporosis is an important cause of morbidity and mortality among men. 1 , 2 Among persons older than 50 years of age, approximately 40% of all osteoporotic fractures worldwide occur in men. 3 Mortality after osteoporotic fracture is higher among men than among women. 2 , 4 Previous studies involving men with osteoporosis have focused on the surrogate outcomes of bone mineral density and bone-turnover markers, 5 – 9 but data from double-blind, randomized studies assessing antifracture efficacy are lacking. In addition, given the low awareness of the disease, 10 the development of guidelines for the detection and treatment of osteoporosis in men has been limited. 11 Hence, there . . .

Sex hormone-binding globulin (SHBG) is the high-affinity binding protein for androgens and estrogens. According to the free hormone hypothesis, SHBG modulates the bioactivity of sex steroids by limiting their diffusion into target tissues. Still, the in vivo physiological role of circulating SHBG remains unclear, especially since mice and rats lack circulating SHBG post-natally. To test the free hormone hypothesis in vivo , we examined total and free sex steroid concentrations and bioactivity on target organs in mice expressing a human SHBG transgene. SHBG increased total androgen and estrogen concentrations via hypothalamic-pituitary feedback regulation and prolonged ligand half-life. Despite markedly raised total sex steroid concentrations, free testosterone was unaffected while sex steroid bioactivity on male and female reproductive organs was attenuated. This occurred via a ligand-dependent, genotype-independent mechanism according to in vitro seminal vesicle organ cultures. These results provide compelling support for the determination of free or bioavailable sex steroid concentrations in medicine, and clarify important comparative differences between translational mouse models and human endocrinology.

The investigators sought evidence-based criteria for identifying late-onset hypogonadism in men between the ages of 40 and 79 years on the basis of the association between symptoms and a low testosterone level. The data suggest that late-onset hypogonadism can be defined by the presence of at least three sexual symptoms with a total testosterone level of less than 11 nmol per liter and a free testosterone level of less than 220 pmol per liter. The data suggest that late-onset hypogonadism can be defined by the presence of at least three sexual symptoms with a total testosterone level of less than 11 nmol per liter and a free testosterone level of less than 220 pmol per liter. The clinical importance of an age-related reduction in the testosterone level 1 – 3 remains controversial. 4 , 5 Because of the uncertainty regarding the nature of testosterone deficiency in aging men, 6 – 9 recent guidelines have suggested that so-called late-onset hypogonadism be regarded as a clinical and biochemical state with advancing age, characterized by particular symptoms and a low level of serum testosterone. 10 , 11 However, few data on hypogonadism in aging men are available 4 , 8 , 12 because of the lack of evidence regarding the exact criteria for identifying testosterone deficiency in older men who do not have pathological hypogonadism. 6 , 13 Although a familiar array . . .

Bone and muscle development are important processes in pubertal maturation. The aim of this study was to investigate associations between pubertal timing and bone density and body composition in young adult men. In this observational study, bone and body composition was cross-sectionally assessed by dual-energy X-ray absorptiometry in 2056 healthy young men with median age 19, who retrospectively self-reported if they experienced pubertal changes at an earlier, similar or later age than their peers. Associations between voice break timing and bone and body composition were analyzed by linear regression. Men reporting earlier voice break than their peers (n = 417, 20%) had higher lumbar bone mineral density (BMD) and higher total body BMD. Apart from higher BMI, there were no differences in body composition. Men who reported later voice break (n = 353, 17%) had lower lumbar bone mineral content, bone area and volume, but similar BMD. They had lower BMI, lean mass and fat mass, resulting in a lower fat-to-muscle ratio. In conclusion, even after adult height has been reached, physiological variations in pubertal timing were associated with differences in bone and body composition in young adult men.

Background Endurance exercise has the potential to affect reproductive function, with amenorrhea in female athletes. However, most studies focus on women. Evidence on the association between endurance exercise and male fertility is limited. Objective To synthesise existing literature on exercise-induced alterations in semen parameters and to assess the clinical impact on male fertility. Methods Studies reporting on the association between semen parameters and endurance exercise in healthy men were eligible. Men attending fertility clinics were excluded. We searched MEDLINE (PubMed), Embase, SPORTDiscus, Cochrane Central Register of Controlled Trials (CENTRAL), ClinicalTrials.gov and International Clinical Trials Registry Platform (ICTRP) from their inception to May 28th 2022. JBI Critical Appraisal Tool was used to assess the potential risk of bias. Results Thirteen studies met inclusion criteria, reporting on 280 subjects. Eight articles reported on endurance runners, three on cyclists and four on triathletes. Four studies did not find any statistically significant sperm alterations. Five reported significant changes in semen parameters, but these were not clinically relevant, as semen parameters remained well above World Health Organisation (WHO) thresholds. Four articles reported a decrease in semen quality with potential clinical consequences as they found a reduced number of sperm cells exhibiting normal morphology in cyclists and triathletes and a greater amount of DNA fragmentation in triathletes. Conclusion Endurance exercise can have a negative effect on semen quality, although rarely with a clinically relevant impact on male fertility. Evidence is however limited, with poor quality of the included studies. Registration : PROSPERO International prospective register of systematic reviews (CRD42022336753). Key Points Results suggest that endurance exercise can decrease semen quality, although without a clinically relevant impact on male fertility potential. The available evidence is limited and lacks comparability due to poor methodology. High quality studies are necessary to further assess the relationship between endurance exercise and semen quality.

Serum estradiol (E2) and estrone (E1) levels exhibit substantial heritability. To investigate the genetic regulation of serum E2 and E1 in men. Genome-wide association study in 11,097 men of European origin from nine epidemiological cohorts. Genetic determinants of serum E2 and E1 levels. Variants in/near CYP19A1 demonstrated the strongest evidence for association with E2, resolving to three independent signals. Two additional independent signals were found on the X chromosome; FAMily with sequence similarity 9, member B (FAM9B), rs5934505 (P = 3.4 × 10-8) and Xq27.3, rs5951794 (P = 3.1 × 10-10). E1 signals were found in CYP19A1 (rs2899472, P = 5.5 × 10-23), in Tripartite motif containing 4 (TRIM4; rs17277546, P = 5.8 × 10-14), and CYP11B1/B2 (rs10093796, P = 1.2 × 10-8). E2 signals in CYP19A1 and FAM9B were associated with bone mineral density (BMD). Mendelian randomization analysis suggested a causal effect of serum E2 on BMD in men. A 1 pg/mL genetically increased E2 was associated with a 0.048 standard deviation increase in lumbar spine BMD (P = 2.8 × 10-12). In men and women combined, CYP19A1 alleles associated with higher E2 levels were associated with lower degrees of insulin resistance. Our findings confirm that CYP19A1 is an important genetic regulator of E2 and E1 levels and strengthen the causal importance of E2 for bone health in men. We also report two independent loci on the X-chromosome for E2, and one locus each in TRIM4 and CYP11B1/B2, for E1.

Low testosterone (T) in men, especially its free fraction, has been associated with loss of energy. In accordance, orchidectomy (ORX) in rodents results in decreased physical activity. Still, the mechanisms through which T stimulates activity remain mostly obscure. Here, we studied voluntary wheel running behavior in three different mouse models of androgen deficiency: ORX, androgen receptor (AR) knock-out (ARKO) and sex hormone binding globulin (SHBG)-transgenic mice, a novel mouse model of “low free T”. Our results clearly show a fast and dramatic action of T stimulating wheel running, which is not explained by its action on muscle, as evidenced by neuromuscular studies and in a muscle-specific conditional ARKO mouse model. The action of T occurs via its free fraction, as shown by the results in SHBG-transgenic mice, and it implies both androgenic and estrogenic pathways. Both gene expression and functional studies indicate that T modulates the in vivo sensitivity to dopamine (DA) agonists. Furthermore, the restoration of wheel running by T is inhibited by treatment with DA antagonists. These findings reveal that the free fraction of T, both via AR and indirectly through aromatization into estrogens, stimulates physical activity behavior in male mice by acting on central DA pathways.

Bone's microporosity plays important roles in bone biology and bone mechanical quality. In this study, we explored the accuracy and reproducibility of nondestructive desktop μCT for 3D visualization and subsequent morphometric analysis of mouse cortical bone microporosity including the vascular canal network and osteocyte lacunae. The accuracy of measurements was evaluated in five murine fibula using confocal laser scanning microscopy (CLSM) in conjunction with Fluorescein isothiocyanate (FITC) staining as the reference method. The reproducibility of μCT-derived cortical bone microstructural indices was examined in 10 fibulae of C57Bl/6J male mice at a nominal resolution of 700 nanometer. Three repeated measurements were made on different days. An excellent correlation between μCT and CLSM was observed for both mean lacuna volume (r = 0.98, p = 0.002) and for mean lacuna orientation (r = 0.93, p = 0.02). Whereas the two techniques showed no significant differences for these parameters, the mean lacuna sphericity acquired from μCT was significantly higher than CLSM (p = 0.01). Reproducibility was high, with precision errors (PE) of 1.57-4.69% for lacuna parameters, and of 1.01-9.45% for vascular canal parameters. Intraclass correlation coefficient (ICC) showed a high reliability of the measurements, ranging from 0.998-1.000 for cortical parameters, 0.973-0.999 for vascular canal parameters and 0.755-0.991 for lacuna parameters. In conclusion, desktop μCT is a valuable tool to quantify the 3D characteristics of bone vascular canals as well as lacunae which can be applied to intact murine bones with high accuracy and reproducibility. Thus, μCT might be an important tool to improve our understanding of the physiological and biomechanical significance of these cannular and lacunar structure in cortical bone.