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Second, we used Steiger filtering of our genetic instruments, to exclude variants with stronger effects on metabolic traits compared to their effects on sex hormones. First, in light of the substantial overlap between genetic determinants of testosterone and SHBG within each sex, our cluster-based analyses allowed us to identify subsets of variants that alter testosterone independent of SHBG. Similarly, while our SHBG-related clusters in men and women were not independent of testosterone, and therefore cannot inform the debate about SHBG-specific metabolic effects, they reflect the actual downstream biological effects of SHBG on (higher) total testosterone and (lower) bioavailable testosterone. Hence, in both men and women, cluster analyses resulted in genetic instruments that allowed us to test specific testosterone-increasing effects, independent of SHBG.
Plots show effect on ln(odds) of Type 2 diabetes (y axes) in men of the following sex hormone genetic instruments (x axes; effect size in units). One of these variants (rs ) is common and has been used in several previous MR studies of SHBG16,19, whilst the other (rs6258) is rare (~1% MAF) and alters SHBG’s binding affinity for testosterone. Here we used two variants in low linkage disequilibrium as more specific but less powerful genetic instruments. Outcome data for number of sexual partners was based on previously analysed data from UK Biobank39 have been undertaken on the relationship between more general aggressive behavior, and feelings, and testosterone.|Labcorp is trusted by over 400,000 physicians and contracted with 700+ health plans nationwide. A graduate of Quinnipiac University, he spent time in college as a beat reporter covering the men’s ice hockey team. "This idea that you do one test for testosterone and that sorts everything out? Not the case I'm afraid." The IOC defended Khelif's eligibility amid the controversy, releasing a statement before the Olympics that said "every person has the right to practice sport without discrimination."|We observed three major themes regarding genetically determined T’s contribution to disease. Although highly valuable, clinical trials to investigate the relationship of T levels to many complex phenotypes would be often infeasible or unethical to conduct. Reflecting the results from FinnGen, for most traits there was no evidence for substantial causality, but the few suggested causal relationships involved traits with clear biological links to T function. In the LCV and MR-Egger analyses, we found statistically significant evidence (p 5 and Supplementary Data 12). Notably, the behavioral traits showing significant correlations were clearly linked to metabolism (smoking, sleep duration and exercise).|More than 3% of US men aged 30 years or older received a prescription for testosterone in 2013, just prior to a US Food and Drug Administration safety communication on its possible cardiovascular risks4, and rates of prescribing are even higher in Canada5. Testosterone supplementation is commonly used for its effects on sexual function, bone health and body composition, yet its effects on disease outcomes are unknown. We greatly thank all UK Biobank, the Young Finns study, and FinnGen participants, as well as the principal investigators, laboratory personnel and data management teams behind these efforts. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. Besides the gained medical insight, underscoring some critical factors that should be considered when assessing these connections, our study therefore provides a novel reference point for future genetic and epidemiological studies on T. Given the combination of analysis strategies—for the MR estimates, 1 SD change in circulating T levels as the basic unit—we were well positioned to detect any substantial effects normal variation in adult T levels, excluding clinical conditions, would have on disease and health.|In addition to separating testosterone from SHBG effects, defining such clusters is an important step for downstream analyses to minimise the pleiotropic effects of SNPs that may have much stronger effects on other sex hormones. Hence, this cluster (termed "male SHBG cluster", Methods) represents a genetic instrument with primary SHBG-increasing effects, and secondary divergent effects on total (higher) and bioavailable testosterone (lower) that are consistent with the known hormone-regulatory role of SHBG. To validate these findings, we performed replication using three available datasets (Methods) - a previously published GWAS meta-analysis of SHBG levels in 21,791 individuals19, 9,138 individuals with testosterone measurements from the EPIC-Norfolk study and published data on 2,913 individuals from the Twins UK study with nine sex hormones measured20. After extensive quality control (Methods), serum levels of SHBG, total testosterone and estradiol were available in up to 425,097 individuals with genetic data in UK Biobank (UKBB) (Table S1). This study substantially advances our understanding of the genetic regulation of sex hormone levels, increasing the number of known genetic determinants by two orders of magnitude.|The authors would like to thank Evgeny A. Lysenko, Tatiana F. Vepkhvadze, Egor M. Lednev and Daniil V. Popov for their help with determination of muscle fiber composition. While many more genetic factors undoubtedly remain undiscovered (Ahmetov et al. 2021), these five provide a basis on which future, more comprehensive, genetic assessments might augment systems of identifying and nurturing talent in elite power sports. Second, there may be other SNPs acting on the traits of interest that the present study was unable to detect. First, none of the associations between SNPs and CSA of muscle fibers passed correction for multiple testing, but we felt justified to use five SNPs in the polygenic analysis given that we used SNPs which were initially found in GWAS, meaning that in the discovery phase (Ruth et al. 2020) these SNPs have passed correction for multiple testing at genome-wide significance (P –8). Molecular inhibition of DOCK3 in skeletal muscle increases phosphorylated AKT levels, which influences the muscle morphology and function (Alexander et al. 2014). Furthermore, the DOCK family of proteins has been shown to bind to regulators of PTEN/AKT signaling (Jungmichel et al. 2014), an important signaling for muscle hypertrophy.|A study in animals showed that consuming oxidized frying oil (compared to fresh soybean oil) decreased testosterone concentrations significantly. It’s fairly inexpensive (~$28 for men, total testosterone), so you may want to consider testing before you start any Lifehacks and then test again after a few months to see if it’s working for you. Studies show that they can accumulate in the different cell types there, including damaging the Leydig cells that produce the majority of male testosterone.refrefrefref|Recent efforts have used genetics to address the potential causal contribution of adult T to selected complex traits in both sexes, including T2D, body composition and hormonal cancers, or have examined the effects of free T more broadly in males based on the UK Biobank data23,24,26,27,28. Yet, through the emergence of genetic and biomarker data from large biobanks, currently more than a hundred, mostly autosomal, loci for serum total T, SHBG and free T have been identified, with evidence for sex-specific genetic effects23,24,25. Although testosterone levels in men tend to be much higher than in women, both sexes generate this vital hormone, albeit in different amounts and with slightly different physiological effects.}
Another study showed that under inflammatory conditions, the polystyrene microplastics had an even stronger negative effect on testosterone production.refrefref A recent study showed that microplastics can reduce the expression of the enzymes needed for testosterone production, such as 17β-hydroxysteroid dehydrogenase (HS17B1 gene in the synthesis diagram above). Recently, researchers looked at whether the tiny bits of plastic that ingest each day also adsorb hormones circulating in the body. Testosterone levels have been declining for men over the past 50+ years. In women, the AR repeats may play a role in PCOS (polycystic ovary syndrome), which is caused by higher androgen levels.ref Genetic variants in the SHBG gene- see the Genotype Report section below- can affect the amount of testosterone available in the body.
Regular exercise can increase testosterone production, particularly strength training and high-intensity interval training. Contrarily, a diet high in processed foods, sweets, and binge drinking can have a deleterious impact on hormone balance. These variables cover a wide spectrum of lifestyle, nutritional, behavioral, and environmental aspects that can influence hormonal balance and increase or reduce testosterone production.
Sexual arousal and masturbation in women produce small increases in testosterone concentrations. Testosterone levels follow a circadian rhythm that peaks early each day, regardless of sexual activity. It is unclear if the use of testosterone for low levels due to aging is beneficial or harmful. As demonstrated by a meta-analysis, substitution therapy with testosterone results in a significant reduction of inflammatory markers. Conflicting results have been obtained concerning the importance of testosterone in maintaining cardiovascular health.
Total testosterone was quantified first and aliquots were re-frozen before SHBG quantification. After the QC steps, our study included altogether 177,499 men and 205,141 women. Inverse normalized values of the remaining residuals were used as phenotype values for the GWAS analyses. We removed outliers for genotype heterozygosity and missingness, as well as samples with sex chromosome aneuploidies, mismatches between reported and inferred sex, and samples that UK Biobank did not use in relatedness calculations29. Notably, the reported testosterone and free T levels in the UK biobank are on average lower than for many other cohorts, for example YFS (Supplementary Data 2 and 6)23,26, which may be partly accountable for UK Biobank measures being based on immunoassays instead of mass spectrometry. Analytical range for the immunoassays of total testosterone and SHBG were 0.35 to 55.52 and 0.33 to (226–242) nmol/L, respectively.
Furthermore, testosterone increased the risk of endometrial cancer but reduced the risk of ovarian cancer, again with consistent findings across sensitivity models (Figure ED6, Table S27). We found evidence that testosterone increased the risk of estrogen receptor (ER)+ but not ER-breast cancer, with consistent findings across all MR models and instruments (Figure ED6, Table S27). These effects were most evident with bioavailable testosterone, with positive findings across all MR models and all instruments (unfiltered, Steiger-filtered and cluster-filtered) (Figure ED7-8, Table S21). Bars indicate 95% confidence interval around the point estimates from inverse-variance weighted analyses. We then performed a series of MR analyses using two-sample inverse variance-weighted (IVW), Egger and weighted median models (Methods). - https://gitea.alexandermohan.com/daryledmondsto
