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Sex differences, endogenous sex-hormone hormones, sex-hormone binding globulin, and exogenous disruptors in diabetes and related metabolic outcomes.
Liu, S, Sun, Q
Journal of diabetes. 2018;(6):428-441
Abstract
In assessing clinical and pathophysiological development of type 2 diabetes (T2D), the critical role of the sex steroids axis is underappreciated, particularly concerning the sex-specific relationships with many relevant cardiometabolic outcomes. In this issue of the Journal of Diabetes, we provide a comprehensive overview of these significant associations of germline variants in the genes governing the sex steroid pathways, plasma levels of steroid hormones, and sex hormone-binding globulin (SHBG) with T2D risk that have been observed in many clinical and high-quality large prospective cohorts of men and women across ethnic populations. Together, this body of evidence indicates that sex steroids and SHBG should be routinely incorporated into clinical characterization of T2D patients, particularly in screening prediabetic patients, such as those with metabolic syndrome, using plasma levels of SHBG. Given that several germline mutations in the SHBG gene have also been directly related to both plasma concentrations of SHBG and clinical manifestation of T2D, targeting signals in the sex steroid axis, particularly SHBG, may have significant utility in the prediction and treatment of T2D. Further, many of the environmental endocrine disrupting chemicals may exert their potential adverse effects on cardiometabolic outcomes via either estrogenic or androgenic signaling pathways, highlighting the importance of using the sex steroids and SHBG as important biochemical markers in both clinical and population studies in studying sex-specific mechanisms in the pathogenesis of T2D and its complications, as well as the need to equitably allocate resources in studying both men and women.
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The Effect of Vitamin D Supplementation on the Androgenic Profile in Patients with Polycystic Ovary Syndrome: A Systematic Review and Meta-Analysis of Clinical Trials.
Azadi-Yazdi, M, Nadjarzadeh, A, Khosravi-Boroujeni, H, Salehi-Abargouei, A
Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme. 2017;(3):174-179
Abstract
It is suggested that vitamin D status is associated with androgenic profile in women with polycystic ovarian syndrome (PCOS). Although several clinical trials are known in this regard, the results were inconsistent. Therefore, this study was aimed to conduct a systematic review and meta-analysis of published clinical trials to elucidate the possible effect of vitamin D supplementation on the androgen levels in adult females with PCOS. PubMed, SCOPUS, and Google Scholar were searched to identify related articles published up to January 2017. Mean ± standard deviation (SD) of changes in serum total testosterone, sex hormone binding globulin (SHBG), and free testosterone were extracted to calculate Hedges' g to be used as effect size for meta-analysis. DerSimonian and Liard random effects model was incorporated to summarize the effects. Six clinical trials with 183 participants aged 18-41 years with follow-up period between 3-24 weeks were included. Our analysis revealed that vitamin D supplementation significantly reduces total testosterone (Hedges' g=-0.32, 95% CI: -0.55 to -0.10; p=0.005); this effect remained significant in single group trials after subgroup analysis. Vitamin D supplementation did not affect serum free testosterone (Hedges' g=-0.21, 95% CI: -0.44 to 0.079; p=0.08) or SHBG levels (Hedges' g=0, 95% CI, 0.22-0.22; p=0.98). The present systematic review and meta-analysis revealed that vitamin D supplementation might significantly affect serum total testosterone while it is not effective in improving other markers of androgenic profile. Future double-blind, placebo-controlled clinical trials are highly recommended.
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Novel insights in SHBG regulation and clinical implications.
Simó, R, Sáez-López, C, Barbosa-Desongles, A, Hernández, C, Selva, DM
Trends in endocrinology and metabolism: TEM. 2015;(7):376-83
Abstract
Sex hormone-binding globulin (SHBG) is produced and secreted by the liver into the bloodstream where it binds sex steroids and regulates their bioavailability. Traditionally, body mass index (BMI) was thought to be the major determinant of SHBG concentrations and hyperinsulinemia the main cause for low SHBG levels found in obesity. However, no mechanisms have ever been described. Emerging evidence now shows that liver fat content rather than BMI is a strong determinant of circulating SHBG. In this review we discuss evidence demonstrating that insulin might not regulate SHBG production, describe putative molecular mechanisms by which proinflammatory cytokines downregulate SHBG, and comment on recent findings suggesting dietary SHBG regulation. Finally, clinical implications of all of these findings and future perspectives are discussed.
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Endogenous sex hormones, metabolic syndrome, and diabetes in men and women.
Kim, C, Halter, JB
Current cardiology reports. 2014;(4):467
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Abstract
Endogenous sex hormones predict impairments of glucose regulation. Cross-sectional studies suggest that lower levels of testosterone in men and higher levels in women increase risk of metabolic syndrome and diabetes, whereas lower levels of sex hormone binding globulin in both men and women increase risk of metabolic syndrome and diabetes. In a systematic review, we summarize existing longitudinal studies, which suggest similar patterns. However, these studies are often limited to a single sex steroid measure. Whether these associations are primarily a marker of adiposity, and whether these associations differ between younger eugonadal vs older hypogonadal adults is also uncertain. The impact of exogenous sex steroid therapy may not reflect relationships between sex hormones and impaired glucose regulation that occur without supplementation. Therefore, examination of endogenous sex steroid trajectories and obesity trajectories within individuals might aid our understanding of how sex steroids contribute to glucose regulation.
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Impact of diet and adiposity on circulating levels of sex hormone-binding globulin and androgens.
Morisset, AS, Blouin, K, Tchernof, A
Nutrition reviews. 2008;(9):506-16
Abstract
This review summarizes studies on the effect of various diets on circulating androgen levels and sex hormone-binding globulin (SHBG). Reduced caloric intake leading to significant weight loss increases SHBG levels regardless of diet composition, particularly in women. Cross-sectional studies show that dietary composition is generally not associated with SHBG levels independent of obesity level. No clear conclusion can be reached regarding the effect of various eating habits or dietary composition on circulating androgens. The evidence indicates that dietary effects on circulating SHBG, and possibly androgens, can be expected if body weight or fatness and/or insulin homeostasis are modulated.
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Obesity, endogenous hormones, and endometrial cancer risk: a synthetic review.
Kaaks, R, Lukanova, A, Kurzer, MS
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2002;(12):1531-43
Abstract
Endometrial cancer is a disease of the affluent, developed world, where epidemiological studies have shown that > or =40% of its incidence can be attributed to excess body weight. An additional proportion may be because of lack of physical activity. Alterations in endogenous hormone metabolism may provide the main links between endometrial cancer risk, and excess body weight and physical inactivity. Epidemiological studies have shown increased endometrial cancer risks among pre- and postmenopausal women who have elevated plasma androstenedione and testosterone, and among postmenopausal women who have increased levels of estrone and estradiol. Furthermore, there is evidence that chronic hyperinsulinemia is a risk factor. These relationships can all be interpreted in the light of the "unopposed estrogen" hypothesis, which proposes that endometrial cancer may develop as a result of the mitogenic effects of estrogens, when these are insufficiently counterbalanced by progesterone. In our overall synthesis, we conclude that development of ovarian hyperandrogenism may be a central mechanism relating nutritional lifestyle factors to endometrial cancer risk. In premenopausal women, ovarian hyperandrogenism likely increases risk by inducing chronic anovulation and progesterone deficiency. After the menopause, when progesterone synthesis has ceased altogether, excess weight may continue increasing risk through elevated plasma levels of androgen precursors, increasing estrogen levels through the aromatization of the androgens in adipose tissue. The ovarian androgen excess may be because of an interaction between obesity-related, chronic hyperinsulinemia with genetic factors predisposing to the development of ovarian hyperandrogenism.