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The effect of physical activity on breast cancer risk may be partly mediated by sex steroid hormones. This review synthesized and appraised the evidence for an effect of physical activity on sex steroid hormones. Systematic searches were performed using MEDLINE (Ovid), EMBASE (Ovid), and SPORTDiscus to identify experimental studies and prospective cohort studies that examined physical activity and estrogens, progestins, and/or androgens, as well as sex hormone binding globulin (SHBG) and glucocorti-coids in pre- and postmenopausal women. Meta-analyses were performed to generate effect estimates. Risk of bias was assessed, and the GRADE system was used to appraise quality of the evidence. Twenty-eight randomized controlled trials (RCT), 81 nonrandomized interventions, and six observational studies were included. Estrogens, progesterone, and androgens mostly decreased, and SHBG increased, in response to physical activity. Effect sizes were small, and evidence quality was graded moderate or high for each outcome. Reductions in select sex steroid hormones following exercise supports the biological plausibility of the first part of the physical activity-sex hormone-breast cancer pathway. The con-firmed effect of physical activity on decreasing circulating sex steroid hormones supports its causal role in preventing breast cancer.

We undertook a systematic review and appraised the evidence for an effect of circulating sex steroid hormones and sex hormone-binding globulin (SHBG) on breast cancer risk in pre- and postmenopausal women. Systematic searches identified prospective studies relevant to this review. Meta-analyses estimated breast cancer risk for women with the highest compared with the lowest level of sex hormones, and the DRMETA Stata package was used to graphically represent the shape of these associations. The ROBINS- E tool assessed risk of bias, and the GRADE system appraised the strength of evidence. In premenopausal women, there was little evidence that estrogens, progesterone, or SHBG were associated with breast cancer risk, whereas androgens showed a positive association. In postmenopausal women, higher estrogens and androgens were associated with an increase in breast cancer risk, whereas higher SHBG was inversely associated with risk. The strength of the evidence quality ranged from low to high for each hormone. Dose-response relationships between sex steroid hormone concentrations and breast cancer risk were most notable for postmenopausal women. These data support the plausibility of a role for sex steroid hormones in mediating the causal relationship between physical activity and the risk of breast cancer.

Background: The risk of aneurysmal subarachnoid hemorrhage (aSAH) is increased in postmenopausal women compared with men of similar age, suggesting a role for sex hormones. We aimed to explore whether sex hormones, and age at menarche/menopause have a causal effect on aSAH risk by conducting a 2-sample MR study (Mendelian randomization). Methods: We obtained sex-specific genetic instruments for serum estradiol, bioavailable testosterone (BioT), SHBG (sex hormone-binding globulin), and age at menarche/menopause from genome-wide association studies. The associated sex-specific aSAH risk was estimated with inverse-variance weighted MR analyses with various statistical sensitivity analyses. Multivariable and cluster MR analyses were performed for BioT and SHBG to account for a genetic and phenotypic correlation between the 2 exposures. The clusters represented (1) single-nucleotide polymorphisms primarily increasing SHBG, with secondary decreasing effects on BioT, and (2) single-nucleotide polymorphisms affecting BioT without affecting SHBG. Results: Univariable MR analyses showed an 18% increased aSAH risk among women per 1-SD increase in genetically determined SHBG levels (odds ratio, 1.18 [95% CI, 1.05–1.34]; P =0.007). Suggestive evidence was identified for a 27% decreased risk of aSAH among women per 1-SD increase in BioT (odds ratio, 0.73 [95% CI, 0.55–0.95]; P =0.02). The latter association disappeared in cluster analysis when only using SHBG-independent variants. MR analyses with variants from the cluster with primary SHBG effects and secondary (opposite) BioT-effects yielded a statistically significant association (odds ratio, 1.21 [95% CI, 1.05–1.40]; P =0.008). No other causal associations were identified. Conclusions: Genetic predisposition to elevated serum levels of SHBG, with secondary lower serum BioT levels, is associated with an increased aSAH risk among women, suggesting that SHBG and BioT causally elevate aSAH risk. Further studies are required to elucidate the underlying mechanisms and their potential as an interventional target to lower aSAH incidence.

We undertook a systematic review and appraised the evidence for an effect of circulating sex steroid hormones and sex hormone–binding globulin (SHBG) on breast cancer risk in pre- and postmenopausal women. Systematic searches identified prospective studies relevant to this review. Meta-analyses estimated breast cancer risk for women with the highest compared with the lowest level of sex hormones, and the DRMETA Stata package was used to graphically represent the shape of these associations. The ROBINS-E tool assessed risk of bias, and the GRADE system appraised the strength of evidence. In premenopausal women, there was little evidence that estrogens, progesterone, or SHBG were associated with breast cancer risk, whereas androgens showed a positive association. In postmenopausal women, higher estrogens and androgens were associated with an increase in breast cancer risk, whereas higher SHBG was inversely associated with risk. The strength of the evidence quality ranged from low to high for each hormone. Dose–response relationships between sex steroid hormone concentrations and breast cancer risk were most notable for postmenopausal women. These data support the plausibility of a role for sex steroid hormones in mediating the causal relationship between physical activity and the risk of breast cancer. See related reviews by Lynch et al., p. 11 and Swain et al., p. 16

The effect of physical activity on breast cancer risk may be partly mediated by sex steroid hormones. This review synthesized and appraised the evidence for an effect of physical activity on sex steroid hormones. Systematic searches were performed using MEDLINE (Ovid), EMBASE (Ovid), and SPORTDiscus to identify experimental studies and prospective cohort studies that examined physical activity and estrogens, progestins, and/or androgens, as well as sex hormone binding globulin (SHBG) and glucocorticoids in pre- and postmenopausal women. Meta-analyses were performed to generate effect estimates. Risk of bias was assessed, and the GRADE system was used to appraise quality of the evidence. Twenty-eight randomized controlled trials (RCT), 81 nonrandomized interventions, and six observational studies were included. Estrogens, progesterone, and androgens mostly decreased, and SHBG increased, in response to physical activity. Effect sizes were small, and evidence quality was graded moderate or high for each outcome. Reductions in select sex steroid hormones following exercise supports the biological plausibility of the first part of the physical activity–sex hormone–breast cancer pathway. The confirmed effect of physical activity on decreasing circulating sex steroid hormones supports its causal role in preventing breast cancer. See related reviews by Lynch et al., p. 11 and Drummond et al., p. 28

Purpose Testosterone (T) plays an important role in men’s health and its deficiency is linked with poorer health. However, the role of nutritional and lifestyle factors in T regulation and production remains unclear. The objectives are to comprehensively test the cross-sectional associations of nutritional and lifestyle factors with T deficiency and to validate the associations in the NHANES survey. Methods We performed weighted multivariable logistic regression analysis to examine the association of 173 nutritional and lifestyle factors with T deficiency (total testosterone ≤ 3.5 ng/mL) in NHANES III as the discovery set (mean age 41). We controlled for multiple comparisons with a false discovery rate (FDR)

Frontiers in pharmacology 10, 1397 (2019). doi:10.3389/fphar.2019.01397, Published by Frontiers Media, Lausanne

Introduction: Low levels of sex hormones are common in patients with chronic kidney disease (CKD) and may be a contributing factor to bone fragility. We investigated associations between levels of sex hormones and bone mineral density (BMD) in adult kidney transplantation candidates. Methods: Volumetric BMD of spine and hip were measured by computed tomography. Parathyroid hormone (PTH), testosterone (T), estradiol (E), and sex hormone–binding globulin were measured from fasting morning blood samples. Bioavailable (Bio) T and E were calculated based on constants for protein binding. Results: A total of 146 patients (102 men and 44 women) were included in the analyses. The median age was 54 years (range, 32−72 years); 32% were diabetic; and 36% received maintenance dialysis therapy. In men, Bio T was positively associated with BMD at the lumbar spine (β = 5.02, P = 0.002), total hip (β = 6.35, P = 0.001), and femoral neck (β = 13.9, P = 0.002), independently of age, body mass index, dialysis, diabetes type 1 and 2, parathyroid hormone, and steroid exposure. Bio E was positively associated with BMD at the lumbar spine (β = 0.23, P = 0.03) and femoral neck (β = 0.61, P = 0.04) using the same fully adjusted model. In postmenopausal women, Bio T was positively correlated with lumbar spine BMD (r = 0.46, P = 0.02). Conclusion: High endogenous levels of sex hormones are associated with greater BMD in male kidney transplantation candidates. Disturbances in the gonadal axis may contribute to skeletal fragility in men with late-stage CKD. Keywords: bone density, chronic kidney disease, gonadal sex steroids, hypogonadism, osteoporosis

Purpose : The nutritional intervention program “DiOGenes” focuses on how obesity can be prevented and treated from a dietary perspective. We generated differential plasma proteome profiles in the DiOGenes cohort to identify proteins associated with weight loss and maintenance and explore their relation to body mass index, fat mass, insulin resistance and sensitivity. Experimental Design : Relative protein quantification was obtained at baseline and after combined weight loss/maintenance phases using isobaric tagging and MS/MS. A Welch t-test determined proteins differentially present after intervention. Protein relationships with clinical variables were explored using univariate linear models, considering collection center, gender and age as confounding factors. Results : 473 subjects were measured at baseline and end of the intervention; 39 proteins were longitudinally differential. Proteins with largest changes were sex hormone-binding globulin, adiponectin, C-reactive protein, calprotectin, serum amyloid A, and proteoglycan 4 (PRG4), whose association with obesity and weight loss is known. We identified new putative biomarkers for weight loss/maintenance. Correlation between PRG4 and proline-rich acidic protein 1 (PRAP1) variation and Matsuda insulin sensitivity increment was showed. Conclusions and Clinical Relevance : MS-based proteomic analysis of a large cohort of non-diabetic overweight and obese individuals concomitantly identified known and novel proteins associated with weight loss and maintenance. This article is protected by copyright. All rights reserved

Summary Trade-offs between immune function and other physiological and behavioral processes are central in ecoimmunology, but one important problem is how to distinguish a reallocation of resources away from the immune system from a reallocation or redistribution within the immune system. While variation in baseline values of individual immune parameters is well established, studies in wild animals on multiple parameters during an immune response are lacking. It also remains to be tested if and how immune responses correlate with baseline values that vary e.g. over the course of an annual cycle. We studied immunological responses to an endotoxin challenge in skylarks (Alauda arvensis), a partial migrant bird breeding in temperate zones. We compared birds injected with the endotoxin LPS with un-injected controls, characterizing immunological responses with leukocyte profiles, titres of lytic enzymes and natural antibodies, and concentrations of haptoglobin and heat shock proteins. We did this in five annual-cycle stages to test if the response varied throughout the year. The endotoxin challenge affected 6 of 10 measured parameters. Lysis titers and proportions of heterophils increased; haptoglobin concentrations and proportions of lymphocytes, basophils and eosinophils decreased. The variable effects on different immune components demonstrate the complexity of an immune response. We found no evidence that the response differed between annual-cycle stages. The response was independent of baseline measures taken directly upon capture in the field, indicating that birds were facing no immunological ceiling when mounting an immune response. Values of five parameters collected under field conditions were significantly related to values taken under standardised lab conditions. We conclude that multiple parts of the immune system are modulated during an immunological response and that responses are not re-organised throughout the annual cycle.

Ubiquitous chemicals may interfere with the thyroid system that is essential in the development and physiology of vertebrates. We applied a surface plasmon resonance (SPR) biosensor-based screening method for the fast screening of chemicals with thyroxine (T4) transport disrupting activity. Two inhibition assays using the main thyroid hormone transport proteins, T4 binding globulin (TBG) and transthyretin (TTR), in combination with a T4-coated biosensor chip were optimized and automated for screening chemical libraries. The transport protein-based biosensor assays were rapid, high throughput and bioeffect-related. A library of 62 chemicals including the natural hormones, polychlorinated biphenyls (PCBs), polybrominated diphenylethers (PBDEs) and metabolites, halogenated bisphenol A (BPA), halogenated phenols, pharmaceuticals, pesticides and other potential environmentally relevant chemicals was tested with the two assays. We discovered ten new active compounds with moderate to high affinity for TBG with the TBG assay. Strikingly, the most potent binding was observed with hydroxylated metabolites of the brominated diphenyl ethers (BDEs) BDE 47, BDE 49 and BDE 99, that are commonly found in human plasma. The TTR assay confirmed the activity of previously identified hydroxylated metabolites of PCBs and PBDEs, halogenated BPA and genistein. These results show that the hydroxylated metabolites of the ubiquitous PBDEs not only target the T4 transport at the TTR level, but also, and to a great extent, at the TBG level where most of the T4 in humans is circulating. The optimized SPR biosensor-based transport protein assay is a suitable method for high throughput screening of large libraries for potential thyroid hormone disrupting compounds. © 2008 Elsevier Inc. All rights reserved.

Background: There is some evidence regarding the effect of poly unsaturated fatty acid intake on androgen levels and gonadal function in polycystic ovary syndrome (PCOS). Objective: This study was conducted to determine the effect of omega-3 supplementation on sex hormone-binding protein (SHBG), testosterone, free androgen index (FAI) and menstrual status in women with PCOS. Materials and Methods: This double-blind randomized clinical trial was conducted on 78 overweight/obese women with PCOS. Participants were randomized to receive omega-3 (3gr/day) or placebo for 8 weeks. Data about weight, height and nutrient intake as well as blood samples were collected before and after intervention. Serum concentrations of testosterone (nmol/L) and SHBG (nmol/L) were measured. FAI was also calculated as the ratio of testosterone to SHBG. Results: Seventy eight patients (age: 26.92±5.46 yrs, Body Mass Index: 31.69±4.84 Kg/m2) completed the study. There was no significant difference in mean age, weight, height, Body Mass Index and intake of energy, and macronutrients between 2 study groups before and after treatment. All the participants had irregular periods. After the trial the percentage of regular menstruation in the omega-3 group was more than the placebo group (47.2% vs. 22.9%, p=0.049). Furthermore, testosterone concentration was significantly lower in the omega-3 group compared with placebo, after supplementation (p=0.04). SHBG and FAI did not change in either group. Conclusion: Omega-3 supplementation could reduce serum concentrations of testosterone and regulate menstrual cycle without significant effect on SHBG and FAI. Future studies with longer period of supplementation are warranted. This article extracted from M.Sc. thesis. (Niloufar Vaziri) Registretion ID in IRCT: IRCT201112318564N1

BACKGROUND: Sex may influence the relationship between HPA axis functioning and obesity. This has been suggested to be due to sex-specific differences in body composition, body fat distribution and psychological variables. Age and the use of oral contraceptives may also influence the relationship between HPA axis functioning and obesity. OBJECTIVE: To systematically investigate whether body composition, body fat distribution, psychological variables, age, or possibly oral contraceptive use contribute to sex differences in HPA axis activity in response to a meal. METHODS: Subjects were men (n=19) and women (n=19) between 18 and 51years old with BMI between 20.3 and 33.2kg/m(2). HPA axis activity was measured by salivary free cortisol levels before consuming a meal, and at 45, 75 and 125min postprandial on four repeated test days. Anthropometric and body composition measurements were performed. Questionnaires were used to assess cognitive eating behavior and trait anxiety level. RESULTS: No differences between the test days in postprandial cortisol responses appeared. Responses were significantly higher in men compared with women (p

Some compounds, including brominated diphenyl ethers (BDEs), can interfere with thyroid hormone (TH) receptor (TR)-mediated TH-signalling. In this study, the TR isoform selectivity of some TH disrupting compounds was investigated with TR alpha/beta specific reporter gene assays. For this purpose, the effects of compounds on 3,3',5-triiodothyronine (T-3)-induced TR alpha- or TR beta-activation were tested in green monkey kidney fibroblast (CV-1) cells transiently transfected with Xenopus TRs and a luciferase reporter gene. The T-3-like BDE-OH and diiodobiphenyl (DIB) increased T-3-induced TR alpha-activation, but not T-3-induced TRP-activation. BDE28 (100 nM) did not act via TR alpha, but almost tripled T-3-induced TRP-activation relative to T-3 at its EC50. BDE206 (100 nM) was antagonistic on both TRs with a maximum repression -54% relative to T-3 at its EC50. Contrary to previous results obtained with the T-screen, HBCD was inactive. The present study illustrates the importance of testing potential TH disrupting compounds in model systems that enable independent characterization of effects on both T3-induced TRs. (c) 2006 Elsevier B.V. All rights reserved.

We have produced a monoclonal hybridoma cell line (S1B5) that secretes an IgG2α immunoglobulin with a high affinity (Kd 0.38 × 10−11 M) for 125I-labelled sex hormone binding globulin (SHBG), and which will specifically immunoprecipitate SHBG from serum. The antibody is produced in high titre in culture medium and ascites fluid, and can be purified to apparent homogeneity by protein A affinity chromatography. When examined by isoelectrofocussing, a characteristic series of bands, which bind 125I-SHBG, are observed at pH 8.5–9. Competitive, superimposable displacement of 125I-SHBG from the antibody is achieved with dilutions of human, chimpanzee and gorilla sera at comparable SHBG concentrations. Partial cross-reaction is observed with sera from other Old World primates, but not with sera from New World monkeys or any other vertebrate species studied.