MAP for sham males was consistently higher than that for sham females, whereas androgen depletion by orchidectomy dropped blood pressure in the males, in contrast, oophorectomy followed by testosterone supplementation in females elevated blood pressure to sham male levels. We therefore used qPCR to validate the expression of 12 genes prioritized from our RNAseq data based on their regulation in response to testosterone (Table 1); Whilst global data shows no difference in incidence according to sex (26.6% of men, 26.1% of women), age-specific rates of hypertension show that the prevalence of hypertension is higher in men than in women under 50 years old whereas the converse is true after that age . These results show testosterone levels can strongly influence blood pressure regulation and alter gene activity in the brain, highlighting the connection between sex hormones and hypertension.
These clusters helped inform genetic causal inference analyses by showing primary metabolic effects of testosterone that were beneficial in men (lower fasting glucose and lower T2D risk) but harmful in women (higher PCOS risk). For T2D and related traits, the evidence of a protective effect of testosterone was most consistent when using the cluster-specific genetic instrument representing a primary (total and bioavailable) testosterone-increasing effect independent of SHBG. Testosterone levels are dependent on SHBG levels but genetic variants may allow us to separate distinct components of variation in sex hormone levels. Among men, we found partially overlapping genetic determinants between the different sex hormone traits. Despite similar heritability estimates (Table 1), the genetic component to variation in circulating testosterone levels was very different between sexes, as indicated by null genome-wide correlations between sexes (Table 1) and limited overlap of genome-wide significant signals between sexes (Tables S13-14). Finally, in the EPIC-Norfolk study we estimated the magnitude of effect a genetic risk score for SHBG and testosterone had on the respective trait levels (Figure ED2). We use these genetic variants to demonstrate likely causal associations with metabolic disease and cancer outcomes, with many divergent effects of testosterone between men and women.
In the left column, sex-biased DEGs from (A) are mapped onto plots describing age-biased expression in (D) females, and (G) males. First, to characterize effects of sex and age independently of testosterone manipulation, we conducted PCA with filtered read counts from only those individuals with intact gonads and empty implants (i.e., juvenile females, juvenile males, subadult females, and subadult males). Likewise, we tested whether DEGs inferred to be downregulated by testosterone had significantly negative mean and median log2 (FC) values for sex bias in subadults (i.e., female-biased expression) and for age bias in males (i.e., juvenile-biased expression). These various comparisons are non-independent in the sense that the subadult males and females used to characterize sex-biased expression are the same transcriptomes used to characterize age-biased expression within each sex.
At approximately 12 months of age, anoles that we refer to as "subadults" were assigned to one of four treatment groups, then euthanized at approximately 14 months of age (2 months-post treatment) to obtain RNA from liver tissue. Nevertheless, excessive or prolonged exposure to high testosterone levels can negatively impact mitochondrial function and skeletal muscle metabolism. These ARs have the capability to recognize and bind specific sequences within the mitochondrial genome, effectively acting as transcription factor, consequently modulating mitochondrial gene transcription. Thus, the AR may directly regulate mitochondrial transcription or indirectly lead to the same effect by activating the NRFs/TFAM-TFB2M/mitochondrial genes axis (Figure 2).
Mendelian randomisation is a genetic approach to understand the causal effects of putative risk factors on disease. Testosterone therapy has established positive effects in randomised controlled trials on sexual function, lean mass, muscle strength and bone mineral density, and reductions in whole body and intra-abdominal fat6. However, such phenotypic observations are prone to confounding due to the substantial effects of ageing and adiposity on circulating testosterone concentrations3. We also show adverse effects of higher testosterone on breast and endometrial cancers in women, and prostate cancer in men. Correlation between genetically predicted testosterone… MH, CR, and RC developed the ideas and analyses in this study; CC and RC conducted the experiments; CC generated the transcriptome data; MH led the statistical analyses and created the figures with assistance from CR and RC; MH and RC wrote the manuscript. Testosterone stimulates growth in length and mass as well as the expression of genes of these growth-regulatory pathways (Cox et al., 2015, 2017).
Given their known sexually dimorphic expression patters21 further supports the validity of our data set (Supplemental Table 1). As an internal control, we indeed found that Kdm5d and Xist were the two most differentially expressed genes between XX and XY eNSCs at baseline. (A) Experimental design to explore both the activational and organizational effects of testosterone exposure on undifferentiated embryonic neural stem cells harvested from E13.5–14 male and female C57/BL6/J mice. These activational and persisting changes that occur as a result of hormonal exposures demonstrate the long-term effects of hormonal influence and shed light on the biological basis of sex-biased neuro-psychiatric disorders18.
Testosterone is a contributory trait in the complex nature of athletic phenotypes, and can influence athletic performance (e.g., increased neuronal activity, bone growth and hemoglobin levels) (Wood and Stanton 2012). Not surprisingly, testosterone is the most common form of doping in sport; however, it should be mentioned that due to the dynamic regulation of its endogenous production, testosterone concentrations may vary considerably within and among individuals. Testosterone administration has been shown to increase muscle mass and strength in a dose-dependent manner in young and older men (Bhasin et al. 2001; Bhasin et al. 2005) and in young women (Horwath et al. 2020). Other anabolic or anti-catabolic mechanisms have also been proposed (Dubois et al. 2012), all suggestive that testosterone plays an important role in muscle mass regulation. In skeletal muscle, testosterone and its metabolite, dihydrotestosterone, have a well-defined anabolic property, mainly through an increase in protein synthesis via the activation of the mammalian target of rapamycin (mTOR) pathway together with the androgen receptor (AR) signaling (Basualto-Alarcon et al. 2013; Zeng et al. 2017). In addition, testosterone plays a clear role on several non-reproductive tissues, regardless of gender.