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      Using human genetics to understand the disease impacts of testosterone in men and women

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          Abstract

          Testosterone supplementation is commonly used for its effects on sexual function, bone health and body composition, yet its effects on disease outcomes are unknown. To better understand this, we identified genetic determinants of testosterone levels and related sex hormone traits in 425,097 UK Biobank study participants. Using 2,571 genome-wide significant associations, we demonstrate the genetic determinants of testosterone levels are substantially different between sexes, and that genetically higher testosterone is harmful for metabolic diseases in women but beneficial in men. For example, a genetically determined 1-standard deviation higher testosterone increases the risks of Type 2 diabetes (T2D) (OR=1.37 [1.22–1.53]) and polycystic ovary syndrome (OR=1.51 [1.33–1.72]) in women, but reduces T2D risk in men (OR=0.86 [0.76–0.98]). We also show adverse effects of higher testosterone on breast and endometrial cancers in women, and prostate cancer in men. Our findings provide insights into the disease impacts of testosterone and highlight the importance of sex-specific genetic analyses.

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          Most cited references27

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          Sex hormone-binding globulin and risk of type 2 diabetes in women and men.

          Circulating sex hormone-binding globulin levels are inversely associated with insulin resistance, but whether these levels can predict the risk of developing type 2 diabetes is uncertain. We performed a nested case-control study of postmenopausal women in the Women's Health Study who were not using hormone therapy (359 with newly diagnosed type 2 diabetes and 359 controls). Plasma levels of sex hormone-binding globulin were measured; two polymorphisms of the gene encoding sex hormone-binding globulin, SHBG, that were robustly associated with the protein levels were genotyped and applied in mendelian randomization analyses. We then conducted a replication study in an independent cohort of men from the Physicians' Health Study II (170 with newly diagnosed type 2 diabetes and 170 controls). Among women, higher plasma levels of sex hormone-binding globulin were prospectively associated with a lower risk of type 2 diabetes: multivariable odds ratios were 1.00 for the first (lowest) quartile of plasma levels, 0.16 (95% confidence interval [CI], 0.08 to 0.33) for the second quartile, 0.04 (95% CI, 0.01 to 0.12) for the third quartile, and 0.09 (95% CI, 0.03 to 0.21) for the fourth (highest) quartile (P<0.001 for trend). These prospective associations were replicated among men (odds ratio for the highest quartile of plasma levels vs. the lowest quartile, 0.10; 95% CI, 0.03 to 0.36; P<0.001 for trend). As compared with homozygotes of the respective wild-type allele, carriers of a variant allele of the SHBG single-nucleotide polymorphism (SNP) rs6259 had 10% higher sex hormone-binding globulin levels (P=0.005), and carriers of an rs6257 variant had 10% lower plasma levels (P=0.004); variants of both SNPs were also associated with a risk of type 2 diabetes in directions corresponding to their associated sex hormone-binding globulin levels. In mendelian randomization analyses, the predicted odds ratio of type 2 diabetes per standard-deviation increase in the plasma level of sex hormone-binding globulin was 0.28 (95% CI, 0.13 to 0.58) among women and 0.29 (95% CI, 0.15 to 0.58) among men, a finding that suggests that sex hormone-binding globulin may have a causal role in the risk of type 2 diabetes. Low circulating levels of sex hormone-binding globulin are a strong predictor of the risk of type 2 diabetes in women and men. The clinical usefulness of both SHBG genotypes and plasma levels in stratification and intervention for the risk of type 2 diabetes warrants further examination. 2009 Massachusetts Medical Society
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            The polycystic ovary syndrome: a position statement from the European Society of Endocrinology.

            Polycystic ovary syndrome (PCOS) is the most common ovarian disorder associated with androgen excess in women, which justifies the growing interest of endocrinologists. Great efforts have been made in the last 2 decades to define the syndrome. The presence of three different definitions for the diagnosis of PCOS reflects the phenotypic heterogeneity of the syndrome. Major criteria are required for the diagnosis, which in turn identifies different phenotypes according to the combination of different criteria. In addition, the relevant impact of metabolic issues, specifically insulin resistance and obesity, on the pathogenesis of PCOS, and the susceptibility to develop earlier than expected glucose intolerance states, including type 2 diabetes, has supported the notion that these aspects should be considered when defining the PCOS phenotype and planning potential therapeutic strategies in an affected subject. This paper offers a critical endocrine and European perspective on the debate on the definition of PCOS and summarises all major aspects related to aetiological factors, including early life events, potentially involved in the development of the disorder. Diagnostic tools of PCOS are also discussed, with emphasis on the laboratory evaluation of androgens and other potential biomarkers of ovarian and metabolic dysfunctions. We have also paid specific attention to the role of obesity, sleep disorders and neuropsychological aspects of PCOS and on the relevant pathogenetic aspects of cardiovascular risk factors. In addition, we have discussed how to target treatment choices based according to the phenotype and individual patient's needs. Finally, we have suggested potential areas of translational and clinical research for the future with specific emphasis on hormonal and metabolic aspects of PCOS.
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              Endogenous sex hormones and prostate cancer: a collaborative analysis of 18 prospective studies.

              Sex hormones in serum have been hypothesized to influence the risk of prostate cancer. We performed a collaborative analysis of the existing worldwide epidemiologic data to examine these associations in a uniform manner and to provide more precise estimates of risks. Data on serum concentrations of sex hormones from 18 prospective studies that included 3886 men with incident prostate cancer and 6438 control subjects were pooled by the Endogenous Hormones and Prostate Cancer Collaborative Group. Relative risks (RRs) of prostate cancer by fifths of serum hormone concentration were estimated by use of conditional logistic regression with stratification by study, age at recruitment, and year of recruitment. All statistical tests were two-sided. No associations were found between the risk of prostate cancer and serum concentrations of testosterone, calculated free testosterone, dihydrotestosterone, dehydroepiandrosterone sulfate, androstenedione, androstanediol glucuronide, estradiol, or calculated free estradiol. The serum concentration of sex hormone-binding globulin was modestly inversely associated with prostate cancer risk (RR in the highest vs lowest fifth = 0.86, 95% confidence interval = 0.75 to 0.98; P(trend) = .01). There was no statistical evidence of heterogeneity among studies, and adjustment for potential confounders made little difference to the risk estimates. In this collaborative analysis of the worldwide data on endogenous hormones and prostate cancer risk, serum concentrations of sex hormones were not associated with the risk of prostate cancer.
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                Author and article information

                Journal
                9502015
                Nat Med
                Nat. Med.
                Nature medicine
                1078-8956
                1546-170X
                04 January 2020
                10 February 2020
                February 2020
                10 August 2020
                : 26
                : 2
                : 252-258
                Affiliations
                [1 ]University of Exeter Medical School, University of Exeter, Exeter, UK
                [2 ]Medical Research Council (MRC) Epidemiology Unit, University of Cambridge, Cambridge, UK
                [3 ]Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK
                [4 ]Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK
                [5 ]International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health, University of Copenhagen, Copenhagen, Denmark
                [6 ]Department of Growth and Reproduction, University of Copenhagen, Copenhagen, Denmark
                [7 ]Department of Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Australia
                [8 ]Oxford Centre for Diabetes, University of Oxford, Oxford, UK
                [9 ]Oxford NIHR Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Oxford, UK
                [10 ]MRC Biostatistics Unit, University of Cambridge, Cambridge, UK
                [11 ]BHF Cardiovascular Epidemiology Unit, University of Cambridge, Cambridge UK
                [12 ]Department of Paediatrics, University of Cambridge, Cambridge, UK
                Author notes
                [# ]Correspondence to Timothy M Frayling ( T.M.Frayling@ 123456exeter.ac.uk ) and John R.B. Perry ( john.perry@ 123456mrc-epid.cam.ac.uk )
                [$]

                current address: Genentech, 340 Point San Bruno Boulevard, South San Francisco, CA 94080

                [*]

                denotes equal contribution

                Article
                EMS85353
                10.1038/s41591-020-0751-5
                7025895
                32042192
                5a5a7084-755c-4d90-ac2e-5bb849abe48a

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