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Life expectancy in the developed West is currently stagnated and remains shorter in men than women. Well-established evolutionary biology theory suggests lifespan trades-off against reproductive success, possibly sex-specifically. We examined whether a key driver of reproductive success, testosterone, affected survival using a Mendelian randomization longevity study in the UK Biobank to obtain unbiased estimates, along with control exposures. We applied published genetic instruments for testosterone to obtain inverse variance weighted estimates of associations with survival to (i.e., age at) recruitment, in 167,020 men and 194,174 women. We similarly obtained estimates for a positive control (smoking initiation), and a negative control (absorbate), a marker of vitamin C metabolism. Testosterone was associated with poorer survival (0.10 years younger at recruitment per effect size of testosterone, 95% confidence interval (CI) 0.004 to 0.20). As expected, smoking initiation was also associated with poorer survival (0.37 years younger, 95% CI 0.25 to 0.50), but not absorbate (0.01 years younger, 95% CI - 0.09 to 0.11). Several aspects of a healthy lifestyle (low animal fat diet) and several widely used medications (statins, metformin, dexamethasone and possibly aspirin) may modulate testosterone. Explicitly designing interventions sex-specifically based on these insights might help address stagnating life expectancy and sexual disparities.

Sex differences have been shown in laboratory biomarkers; however, the extent to which this is due to genetics is unknown. In this study, we infer sex-specific genetic parameters (heritability and genetic correlation) across 33 quantitative biomarker traits in 181,064 females and 156,135 males from the UK Biobank study. We apply a Bayesian Mixture Model, Sex Effects Mixture Model (SEMM), to Genome-wide Association Study summary statistics in order to (1) estimate the contributions of sex to the genetic variance of these biomarkers and (2) identify variants whose statistical association with these traits is sex-specific. We find that the genetics of most biomarker traits are shared between males and females, with the notable exception of testosterone, where we identify 119 female and 445 male-specific variants. These include protein-altering variants in steroid hormone production genes (POR, UGT2B7). Using the sex-specific variants as genetic instruments for Mendelian randomization, we find evidence for causal links between testosterone levels and height, body mass index, waist and hip circumference, and type 2 diabetes. We also show that sex-specific polygenic risk score models for testosterone outperform a combined model. Overall, these results demonstrate that while sex has a limited role in the genetics of most biomarker traits, sex plays an important role in testosterone genetics.

Polycystic ovary syndrome (PCOS) is a highly complex disorder influenced by genetic and environmental factors. Previous genome-wide association studies (GWAS) on Han Chinese, Korean, and European populations identified multiple PCOS-susceptible loci; however, only a few studies reported the association of susceptibility genes with disease phenotypic traits. This cross-sectional study aimed to investigate the association between PCOS susceptibility genes from GWAS and disease-related clinical features. A total of 1,810 reproductive-aged women were recruited, including 927 control women and 883 women with PCOS, diagnosed based on the European Society for Human Reproduction and Embryology criteria. Genomic DNA was extracted and genotyped, and a Bonferroni test was performed to determine the association between 12 independent SNPs and the clinical features of PCOS. In women with PCOS, rs11031006, nearest to FSHB, was significantly associated with free testosterone (P = 1.94 × 10 -3 ) and luteinizing hormone (P = 1.96 × 10 -3 ) levels. The menstruation number per year, ovarian follicular number, ovarian volume, and insulin sensitivity index were not associated with any SNP. In the control group, no SNPs were associated with any PCOS traits. Collectively, our results suggest that FSHB may play an important role in the development and progression of PCOS.

Proximate control of the development of sexual dimorphism is still hotly debated in reptiles. In some squamates, many male-typical exaggerated traits including body size were assumed to be controlled by masculinization by male gonadal androgens. We performed a manipulative experiment to test the importance of this mechanism in the development of pronounced sexual differences in body size and size of head casque in the chameleon Chamaeleo calyptratus. Castrated males attained male-typical body size highly deviating from the body size of control females. Ontogenetic allometries of casque size on head length revealed that sexes depart considerably in casque growth later in the ontogeny; however, castrated males still follow male-typical casque growth. Paradoxically, exogenous testosterone led in females to slight increase of casque size, which might reflect interference with the feminizing effects of female gonadal hormones. The results in males strongly suggest that masculinization by male gonadal androgens during growth is not required for the development of sexual dimorphism in body size and casque size in the chameleon. The ontogeny of sexually dimorphic body size and exaggerated traits in at least some squamates is likely controlled by other proximate mechanism, possibly by feminization by ovarian hormones.

Expression of nuptial color is usually energetically costly, and is therefore regarded as an 'honest signal' to reflect mate quality. In order to choose a mate with high quality, both sexes may benefit from the ability to precisely evaluate their mates through optimizing visual systems which is in turn partially regulated by opsin gene modification. However, how terrestrial vertebrates regulate their color vision sensitivity is poorly studied. The green-spotted grass lizard Takydromus viridipunctatus is a sexually dimorphic lizard in which males exhibit prominent green lateral colors in the breeding season. In order to clarify relationships among male coloration, female preference, and chromatic visual sensitivity, we conducted testosterone manipulation with mate choice experiments, and evaluated the change of opsin gene expression from different testosterone treatments and different seasons. The results indicated that males with testosterone supplementation showed a significant increase in nuptial color coverage, and were preferred by females in mate choice experiments. By using quantitative PCR (qPCR), we also found that higher levels of testosterone may lead to an increase in rhodopsin-like 2 (rh2) and a decrease in long-wavelength sensitive (lws) gene expression in males, a pattern which was also observed in wild males undergoing maturation as they approached the breeding season. In contrast, females showed the opposite pattern, with increased lws and decreased rh2 expression in the breeding season. We suggest this alteration may facilitate the ability of male lizards to more effectively evaluate color cues, and also may provide females with the ability to more effectively evaluate the brightness of potential mates. Our findings suggest that both sexes of this chromatically dimorphic lizard regulate their opsin expression seasonally, which might play an important role in the evolution of nuptial coloration.

In a similar manner to erectile dysfunction (ED), osteocalcin (OC) is also said to be associated with cardiovascular disease (CVD); however, the effect of OC in ED is unclear. This study was conducted based on the Fangchenggang Area Male Health and Examination Survey (FAMHES) project that ran between September and December 2009. ED was evaluated using the International Index of Erectile Function (IIEF-5). OC was shown to be associated with mild (unadjusted: OR = 0.647; P = 0.016) or moderate (unadjusted: OR = 0.453; P = 0.007) ED. Meanwhile, higher OC levels were more prominently associated with ED (unadjusted: OR = 0.702; P = 0.014). When subdividing the groups by age, the correlation between OC and ED presented in those aged 40-49 years, even in the multi-adjusted model, for those with moderate (OR = 0.255, P = 0.044) and severe (OR = 0.065, P = 0.005) ED. The relationship between OC and ED was also associated with a high level of testosterone, non-obesity, drinking, and non-metabolic syndrome. In summary, OC may play a protective role in middle-aged (40-49 years) men with moderate-severe ED, especially those with a high level of testosterone, non-obesity, drinking, and non-metabolic syndrome.

Previous studies have reported that insulin resistant and low testosterone are related. The triglyceride and glucose index (TyG) well mirrors insulin sensitivity. No study investigated the application of TyG in male hypogonadism. We aimed to explore whether TyG was associated with hypogonadism, and also evaluate the ability of TyG compared to HOMA-IR as a possible hypogonadism predictor. A total of 4299 male subjects were enrolled from 22 sites in East China. Hypogonadism was defined as total testosterone <11.3 nmol/L. 695 (16.2%) hypogonadal men had significantly higher TyG index. The prevalence of hypogonadism stepwise increased across increasing TyG quartiles (P < 0.01). TyG was negatively associated with sex hormones and hypogonadism after adjustment for age, current smoking status, hypertension and overweight/obesity (all P for trend <0.01). The full-adjusted odds ratio was 6.1 for the highest quartile compared with the lowest quartile of TyG (95% CI 4.51, 8.25, P < 0.001). On ROC curve analysis, a larger area under the curve was found for TyG (0.71, 95% CI 0.69,0.73) than for HOMA-IR (0.68, 95% CI 0.66,0.70). Thus, the TyG was significantly associated with a higher prevalence of hypogonadism in Chinese men. TyG had a better predictive power for hypogonadism than HOMA-IR.

Accumulating evidence during the last decades revealed that androgen can exert membrane initiated actions that involve signaling via specific kinases and the modulation of significant cellular processes, important for prostate cancer cell growth and metastasis. Results of the present work clearly show that androgens can specifically act at the membrane level via the GPCR oxoeicosanoid receptor 1 (OXER1) in prostate cancer cells. In fact, OXER1 expression parallels that of membrane androgen binding in prostate cancer cell lines and tumor specimens, while in silico docking simulation of OXER1 showed that testosterone could bind to OXER1 within the same grove as 5-OxoETE, the natural ligand of OXER1. Interestingly, testosterone antagonizes the effects of 5-oxoETE on specific signaling pathways and rapid effects such as actin cytoskeleton reorganization that ultimately can modulate cell migration and metastasis. These findings verify that membrane-acting androgens exert specific effects through an antagonistic interaction with OXER1. Additionally, this interaction between androgen and OXER1, which is an arachidonic acid metabolite receptor expressed in prostate cancer, provides a novel link between steroid and lipid actions and renders OXER1 as new player in the disease. These findings should be taken into account in the design of novel therapeutic approaches in prostate cancer.

Opposite-sex attraction in most mammals depends on the fine-tuned integration of pheromonal stimuli with gonadal hormones in the brain circuits underlying sexual behaviour. Neural activity in these circuits is regulated by sensory processing in the accessory olfactory bulb (AOB), the first central station of the vomeronasal system. Recent evidence indicates adult neurogenesis in the AOB is involved in sex behaviour; however, the mechanisms underlying this function are unknown. By using Semaphorin 7A knockout (Sema7A ko) mice, which show a reduced number of gonadotropin-releasing-hormone neurons, small testicles and subfertility, and wild-type males castrated during adulthood, we demonstrate that the level of circulating testosterone regulates the sex-specific control of AOB neurogenesis and the vomeronasal system activation, which influences opposite-sex cue preference/attraction in mice. Overall, these data highlight adult neurogenesis as a hub for the integration of pheromonal and hormonal cues that control sex-specific responses in brain circuits.

Genetic factors contribute strongly to sex hormone levels, yet knowledge of the regulatory mechanisms remains incomplete. Genome-wide association studies (GWAS) have identified only a small number of loci associated with sex hormone levels, with several reproductive hormones yet to be assessed. The aim of the study was to identify novel genetic variants contributing to the regulation of sex hormones. We performed GWAS using genotypes imputed from the 1000 Genomes reference panel. The study used genotype and phenotype data from a UK twin register. We included 2913 individuals (up to 294 males) from the Twins UK study, excluding individuals receiving hormone treatment. Phenotypes were standardised for age, sex, BMI, stage of menstrual cycle and menopausal status. We tested 7,879,351 autosomal SNPs for association with levels of dehydroepiandrosterone sulphate (DHEAS), oestradiol, free androgen index (FAI), follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin, progesterone, sex hormone-binding globulin and testosterone. Eight independent genetic variants reached genome-wide significance (P<5 × 10(-8)), with minor allele frequencies of 1.3-23.9%. Novel signals included variants for progesterone (P=7.68 × 10(-12)), oestradiol (P=1.63 × 10(-8)) and FAI (P=1.50 × 10(-8)). A genetic variant near the FSHB gene was identified which influenced both FSH (P=1.74 × 10(-8)) and LH (P=3.94 × 10(-9)) levels. A separate locus on chromosome 7 was associated with both DHEAS (P=1.82 × 10(-14)) and progesterone (P=6.09 × 10(-14)). This study highlights loci that are relevant to reproductive function and suggests overlap in the genetic basis of hormone regulation.