Lower Sex Hormone-binding Globulin Research Articles

Association between de novo lipogenesis susceptibility genes and coronary artery disease

Background and aimsCoronary artery disease (CAD) is the principal cause of death in individuals with non-alcoholic fatty liver disease (NAFLD). The aim of this study was to use genetic epidemiology to study the association between de novo lipogenesis (DNL), one of the major pathways leading to NAFLD, and CAD risk. Methods and resultsDNL susceptibility genes were used as instruments and selected using three approaches: 1) genes that are associated with both high serum triglycerides and low sex hormone-binding globulin, both downstream consequences of DNL (unbiased approach), 2) genes that have a known role in DNL (biased approach), and 3) genes that have been associated with serum fatty acids, used as a proxy of DNL. Gene-CAD effect estimates were retrieved from the meta-analysis of CARDIoGRAM and the UK Biobank (∼76014 cases and ∼264785 controls). Effect estimates were clustered using a fixed-effects meta-analysis. Twenty-two DNL susceptibility genes were identified by the unbiased approach, nine genes by the biased approach and seven genes were associated with plasma fatty acids. Clustering of genes selected in the unbiased and biased approach showed a statistically significant association with CAD (OR:1.016, 95%CI:1.012; 1.020 and OR:1.013, 95%CI:1.007; 1.020, respectively), while clustering of fatty acid genes did not (OR:1.004, 95%CI:0.996–1.011). Subsequent exclusion of potential influential outliers did reveal a statistically significant association (OR:1.009, 95%CI:1.000; 1.018). ConclusionsDNL susceptibility genes are associated with an increased risk of CAD. These findings suggest that DNL may be involved in the pathogenesis of CAD and favor further development of strategies that target NAFLD through DNL.

Cerebrospinal fluid sex steroid hormones in bacterial meningitis.

Unfavorable outcome in bacterial meningitis is related to excessive inflammation and higher inflammatory markers have been reported in female than in male patients. Sex steroid hormones have immunomodulatory properties and can be found in the cerebrospinal fluid (CSF); however, their actions have not been studied in bacterial meningitis. We investigated the association between CSF sex steroid hormone levels and inflammatory parameters, disease severity, and outcome in pneumococcal meningitis. We identified adults with culture-proven pneumococcal meningitis in a prospective cohort study (2006-2014). We measured estradiol and testosterone in CSF using liquid chromatography-tandem mass spectrometry and sex hormone-binding globulin (SHBG) using an enzyme-linked immunoassay. Hormone levels were compared according to outcome, which was graded using the Glasgow Outcome Scale (a score of 5 indicating favorable, 1-4 unfavorable outcome). Correlation analysis was used to measure the association between hormone levels and inflammatory cytokines, chemokines, and complement factors as well as severity of illness, as measured by the Glasgow Coma Scale and the Dutch Meningitis Risk Score. We included 60 patients: 20 men, 20 premenopausal (<50 years), and 20 postmenopausal (>50 years) women. Twenty-one (35%) patients had an unfavorable outcome and 11 (18%) died. Cases with an unfavorable outcome exhibited higher estradiol (median 14.0 vs 5.0 pmol/L, P = .04) and lower SHBG (0.40 vs 1.0 nmol/L, P = .03) levels compared with those with a favorable outcome. Estradiol was positively correlated with C-reactive protein (R = 0.42, P = .001), CSF protein (R = 0.33, P = .01), and proinflammatory cytokine levels. CSF concentrations of the sex steroid hormone estradiol were associated with outcome and CSF inflammation. Understanding the dose and time-dependent interaction between sex steroid hormones and the inflammatory response in bacterial meningitis represents an important and understudied topic.

Transforming growth factor-beta 1: A new factor reducing hepatic SHBG production in liver fibrosis.

Low plasma sex hormone-binding globulin (SHBG) levels are present in fatty liver disease, which represents a spectrum of diseases ranging from hepatocellular steatosis through steatohepatitis to fibrosis and irreversible cirrhosis. We have previously determined that fat accumulation reduces SHBG production in different nonalcoholic fatty liver disease mouse models. In the present work, we are interested in elucidating the molecular mechanisms reducing SHBG plasma levels in liver fibrosis. For this purpose, in vivo studies were performed using the human SHBG transgenic mice developing liver fibrosis induced by carbon tetrachloride (CCl4 ). Our results clearly showed that CCl4 induced liver fibrosis and reduced SHBG production by reducing hepatocyte nuclear factor 4 alpha (HNF-4α). The SHBG reduction could be influenced by the increase in transforming growth factor-beta 1 (TGF-β1), which was increased in mice developing liver fibrosis. Therefore, we decided to evaluate the role of TGF-β1 in regulating hepatic SHBG production. Results obtained in both HepG2 cells and human SHBG transgenic mice showed that TGF-β1 reduced significantly SHBGmessenger RNA and protein levels. Mechanistically TGF-β1 downregulated P1-HNF-4α isoforms and increased P2-HNF-4α isoforms via Smad3 and Stat3 pathways through TGF-β1 receptor I, resulting in transcriptional repression of the SHBG gene. Takentogether, we found for the first time that TGF-β1 is a new factor regulating hepatic SHBG production in liver fibrosis. Further research is needed to determine the role of this reduction in hepatic SHBG production in the progression of nonalcoholic steatohepatitis.

Associations of Sex Steroids and Sex Hormone-Binding Globulin with Non-Alcoholic Fatty Liver Disease: A Population-Based Study and Meta-Analysis.

Background: Prior studies have reported inconsistent results or less well-explored associations between sex hormones and non-alcoholic fatty liver disease (NAFLD). Here, we aimed to investigate the associations of NAFLD with sex steroids and sex hormone-binding globulin (SHBG) in the population-based study and conduct a comprehensive systematic review and meta-analysis of all published observational studies. Methods: Analyses included 755 men and 1109 women with available data on sex steroids, SHBG, and ultrasound-based NAFLD from the Rotterdam Study. Multivariable regression models were used to examine the associations. Additionally, we searched five databases from inception to 1 April 2022 and performed a systematic review and meta-analysis. Random-effects (DerSimonian-Laird) method was used for meta-analysis, odds ratios (ORs) were calculated for the effect estimate, subgroup and leave-one-out sensitivity analyses were conducted, and meta-regression was performed to explore the pooled statistics with high heterogeneity. Results: In the Rotterdam Study, lower levels of SHBG were associated with NAFLD in both sexes, while lower testosterone was associated with NAFLD only among women. Similarly, the meta-analysis of 16 studies indicated no sex-specific association between SHBG and NAFLD (men: OR = 0.37, 95%CI 0.21–0.53; women: OR = 0.40, 95%CI 0.21–0.60), yet there was a sex-specific association between testosterone and NAFLD (men: OR = 0.59, 95%CI 0.42–0.76; women: OR = 1.06, 95%CI 0.68–1.44). Moreover, men with NAFLD had lower estradiol levels than those without NAFLD. Conclusions: Lower SHBG levels were associated with NAFLD in both sexes, but testosterone levels were associated in a sex-specific manner. In addition, our results showed estradiol with the potential as a protective factor for NAFLD in healthy men.

Longitudinal analysis of the impact of oral contraceptive use on the gut microbiome.

Introduction. Evidence has linked exogenous and endogenous sex hormones with the human microbiome.Hypothesis/Gap statement. The longitudinal effects of oral contraceptives (OC) on the human gut microbiome have not previously been studied.Aim. We sought to examine the longitudinal impact of OC use on the taxonomic composition and metabolic functions of the gut microbiota and endogenous sex steroid hormones after initiation of OC use.Methodology. We recruited ten healthy women who provided blood and stool samples prior to OC use, 1 month and 6 months after starting OC. We measured serum levels of sex hormones, including estradiol, progesterone, sex hormone-binding globulin (SHBG), and total testosterone. Shotgun metagenomic sequencing was performed on DNA extracted from faecal samples. Species and metabolic pathway abundances were determined using MetaPhlAn2 and HUMAnN2. Multivariate association with linear models was used to identify microbial species and metabolic pathways associated with OC use and endogenous levels of sex hormones.Results. The percentage variance of the microbial community explained by individual factors ranged from 9.9 % for age to 2.7 % for time since initiation of OC use. We observed no changes in the diversity or composition of the gut microbiome following OC initiation. However, the relative abundance of the biosynthesis pathways of peptidoglycan, amino acids (lysine, threonine, methionine, and tryptophan), and the NAD salvage pathway increased after OC initiation. In addition, serum levels of estradiol and SHBG were positively associated with Eubacterium ramulus, a flavonoid-degrading bacterium. Similarly, microbes involving biosynthesis of l-lysine, l-threonine, and l-methionine were significantly associated with lower estradiol, SHBG, and higher levels of total testosterone.Conclusion. Our study provides the first piece of evidence supporting the association between exogenous and endogenous sex hormones and gut microbiome composition and function.

The Relation between the Plasma Level of Testosterone Hormone and the Severity of COVID-19 in Iraqi Patients

Coronavirus disease 2019 discovered in December 2019, Wuhan, China. It was transmitted globally producing the present COVID-19 pandemic. Concerns have been raised about the potential impact of COVID-19 on male reproductive organs and male fertility as the number of infections in the male community has increased. The objectives of current study are studying the relationship between the plasma levels of testosterone and the markers of immune reaction with the severity and mortality in a sample of COVID-19 patients. A cross section study included NO= 103 male patients affected by SARS- CoV-2 pneumonia, diagnosed by PCR and chest CT scan, (≥ 18 years old), and recovered in the respiratory intensive care unit (RICU). Several biochemical risk factors were determined Free Testosterone, sex hormone binding globulin (SHBG) were measured by Enzyme-Linked Immunosorbent Assay(ELISA), D-dimer, Ferritin, CRP, Urea, Creatinine were measured by automated method by using Abbott Architect c4000 and Complete Blood Count(CBC). The results show that the serum free testosterone and SHBG levels a significant lower in non-survivor patients than survivor patients with COVID-19. While the other biomarkers (D-dimer, Ferritin, Urea, Creatinine) were significant higher in non-survivor patients than survivor patients. The CRP, WBC and lymphocyte showed that no significant between the both group of patients. In conclusion the study showed that lower free testosterone and SHBG levels enable significant role in increasing risk of COVID-19 mortality amongst adult male patients

Can we rely on total testosterone measurement to exclude hypogonadism in erectile dysfunction?

Although male hypogonadism (MH) is a prevalent comorbidity in patients presenting for erectile dysfunction (ED), its screening relies solely on total testosterone (TT). Ageing and other conditions can increase sex hormone-binding globulin (SHBG) and lower free testosterone (FT) causing symptomatic MH despite normal TT. The primary objective was to measure the prevalence of normal TT/low FT among patients presenting for ED. From January 2019 to December 2020, 408 patients referred for sexual dysfunction were screened; 180 men with a confirmed diagnosis of ED were included. MH was screened using TT, SHBG, albumin and LH. FT was calculated (cFT). Low TT, high SHBG and low cFT were defined as <345 ng/dL, >50 nmol/L and <6.5 ng/dL, respectively. Patients were divided into groups according to TT/cFT status and to age group. The frequency of normal TT/low cFT was 17.2%. From all 31 patients with normal TT/low cFT, only four (12.9%) had either hyperthyroidism, hepatic disease or HIV infection, while 23 (74.2%) were older than 60 years. Patients with normal TT/low cFT were older (65.57 ± 10.43 vs. 56.79 ± 10.63 yo, p = 0.001) and had higher SHBG (78.48 ± 40.14 vs. 52.35 ± 20.39 nmol/L, p = 0.014) than patients with normal TT/cFT. Patients over 60 years represented 48.9% of the sample, 52.5% had elevated SHBG and their frequency of normal TT/low cFT was 26.3%. Normal TT/low cFT is frequent and can be missed by current screening recommendations for MH in patients presenting for ED. Ageing seems to be the main culprit as elevated SHBG prevalence increases steeply after the sixth decade. TT cannot solely be relied on to exclude biochemical MH in patients presenting for ED, especially in patients over 60 years old. Current guidelines for MH screening in ED should be amended.

The association between triglycerides/high-density lipoprotein cholesterol ratio, insulin resistance, and serum androgen levels in patients with polycystic ovary syndrome

Objectives: Insulin resistance and dyslipidemia are common comorbidities of polycystic ovary syndrome. We aim to evaluate the association between triglycerides/high-density lipoprotein cholesterol ratio, insulin resistance, and serum androgen levels in patients with polycystic ovary syndrome. Methods: We enrolled a total of 40 polycystic ovary syndrome patients and 20 healthy control subjects in this cross-sectional study. The polycystic ovary syndrome patients were divided into two subgroups obese and non-obese. The triglycerides/high-density lipoprotein cholesterol ratio and homeostatic model assessment of insulin resistance were calculated for all individuals. Demographic characteristics, serum levels of metabolic parameters, and androgens were compared between the study subgroups. P-value &amp;lt; 0.05 was accepted as statistically significant. Results: The triglycerides/high-density lipoprotein cholesterol ratio was higher in obese polycystic ovary syndrome patients than in other groups (3.64 ± 3.06 vs. 1.07 ± 0.36 in control and 1.18 ± 0.53 in non-obese group, p &amp;lt; 0.005). The triglycerides/high-density lipoprotein cholesterol ratio was positively correlated with homeostatic model assessment of insulin resistance (r=0.546, p &amp;lt; 0.001), total testosterone (r=0.402, p = 0.010), and free androgen index (r=0.609, p &amp;lt; 0.001) while was negatively correlated with sex hormone-binding globulin (r=-0.497, p = 0.001). Obese polycystic ovary syndrome patients had higher serum total testosterone levels, higher free androgen index, and lower sex hormone-binding globulin than non-obese polycystic ovary syndrome patients (0.71 ± 0.49 ng/mL vs. 0.45 ± 0.16 ng/mL, p = 0.006; 3.1 ± 1.91 vs. 1.01 ± 0.49, p &amp;lt; 0.005; and 26 ± 10.3 nmol/L vs. 59.6 ± 43.7 nmol/L, p &amp;lt; 0.005, respectively). Obese polycystic ovary syndrome patients had also worse lipid parameters, including high triglycerides and low high-density cholesterol when compared with other groups. Conclusions: The triglycerides/high-density lipoprotein cholesterol ratio was correlated with the homeostatic model assessment of insulin resistance, and androgenic hormonal profiles including total testosterone and free androgen index in patients with polycystic ovary syndrome.

Abstract P219: Associations Between Endogenous Sex Hormone Levels And Adipokine Levels In The Multi-ethnic Study Of Atherosclerosis (MESA)

Background: Differences in sex hormone levels contribute to sex differences in cardiovascular disease (CVD). Adipokines, which are central to cardiometabolic disease, differ by sex and have divergent associations with CVD. However the link between sex hormones and adipokines is not well established. We hypothesized that an androgenic sex hormone profile is associated with higher leptin &amp; resistin and lower adiponectin levels among postmenopausal women and men. Methods: We performed an analysis of 1822 adults in MESA who had sex hormones and adipokines measured. Sex hormones [Testosterone (T), estradiol (E2), sex hormone binding globulin (SHBG)] were measured at exam 1; free T was estimated. Serum adipokines [leptin, resistin, adiponectin] were measured at visits 2 or 3, an average of 2.6 yrs later. We used multivariable linear regression to examine the cross-sectional associations between sex hormones and adipokines. Results: The mean age was 63 (10), 48% were women; 41% White, 13% Chinese American, 20% Black, 26% Hispanic. Leptin: After adjusting for demographics (model 1), higher free T &amp; E2 and lower SHBG were associated with greater leptin levels in women and men; higher DHEA was associated with lower leptin in men ( Table ). With full covariate adjustment (model 3), this remained statistically significant for E2 &amp; SHBG in women and for DHEA in men. Adiponectin: With demographic adjustment, higher free T, E2, DHEA &amp; lower SHBG were associated with lower adiponectin in women, and higher free T &amp; lower SHBG with lower adiponectin in men. After full covariate adjustment, these same relationships were slightly attenuated but remained significant for women and men. Resistin: no association in either sex. Conclusion: A more androgenic profile (higher free T &amp; lower SHBG) was independently associated with lower adiponectin in men and women. Higher E2 &amp; lower SHBG in women, and lower DHEA in men, were associated with leptin. These findings may provide mechanistic insight into the interplay between sex hormones, adipokines and CVD risk.

Abstract P139: Changes In Sex Hormones In Premenopausal Black And White Women Associated With Childbearing: The Cardia Women’s Study.

Introduction: Sex hormone binding globulin (SHBG) levels in blood are associated with bioavailability of sex hormones, glucose metabolism, and cardiometabolic health of premenopausal women. Low SHBG levels are associated with insulin resistance in women. Pregnancy is characterized by 6-10-fold increase in SHBG levels. This study is designed to evaluate the long-term associations among pregnancy, and SHBG, free and total testosterone levels in premenopausal women. Methods: Premenopausal women, aged 20-32 years, from the CARDIA Women’s Study cohort were tested for levels of serum SHBG, free testosterone, and total testosterone. Hormonal, anthropometric, socio-demographic, and behavioral data, along with self-reported pregnancy and birth data, were collected at baseline (1987-88 [Y0]; n=1,191) and after eight years (Y8; n=809) and 14 years (Y14; n=474) for follow-up. Participants who were pregnant, breastfeeding, had diabetes, hysterectomy, or were using oral contraceptive at any time point were excluded. Participants were divided in parity groups of 0, 1, and 2+births for analyses. Eight-year decrements of SHBG, free and total testosterone were used for primary analyses and 14-year decrements were used for secondary analyses Results: SHBG levels decreased more in parous than nulliparous women in a fully adjusted model including race, CARDIA field center, age, education, alcohol, smoking status, baseline BMI, weight gain and change in waist girth. Total testosterone decreased more in parous women between Y0-Y10 but not thereafter. No significant differences in free testosterone levels were observed among parity change groups in fully adjusted models. Hormone decrement analyses from fully adjusted model Conclusion: Childbearing is associated with a more pronounced long term decrease in SHBG but not with free testosterone levels in premenopausal women. A strong association was observed among parity and total testosterone decrements at 8-year but not 14-year follow-up.

Association between sex hormone-binding globulin and kidney function in men: results from the SPECT-China study.

The association between sex hormone-binding globulin (SHBG) and renal function has rarely been reported in men. We aimed to investigate the above association in a community-based Chinese population. A total of 5027 men were included from the survey on prevalence for metabolic diseases and risk factors, which is a population-based study conducted from 2014 to 2016 in Eastern China. The estimated glomerular filtration rate (eGFR) was calculated according to the chronic kidney disease Epidemiology Collaboration equation. Low eGFR was defined as eGFR <60 mL·min -1 ·1.73 m -2 . After adjusting for age, smoking, metabolic factors, and testosterone, through increasing quartiles of SHBG, a significantly positive association between SHBG quartiles and eGFR was detected in men (Q1 vs. Q4, β -2.53, 95% confidence interval -3.89, -1.17, Ptrend < 0.001). Compared with the highest quartile of SHBG, SHBG in the lowest quartile was associated with 96% higher odds of low eGFR (odds ratio 1.96, 95% confidence interval 1.10, 3.48) in the model after full adjustment. According to the stratified analyses, the associations between a 1-standard deviation increase in serum SHBG and the prevalence of low eGFR were significant in men aged ≥60 years old, waist circumference <90 cm, diabetes (no), hypertension (yes), dyslipidemia (no), and nonalcoholic fatty liver disease (no). Lower serum SHBG levels were significantly associated with lower eGFR and a higher prevalence of low eGFR in Chinese men independent of demographics, lifestyle, metabolic-related risk factors, and testosterone. Large prospective cohort and basic mechanistic studies are warranted in the future.

Sex Hormone-Binding Globulin and Its Association to Cardiovascular Risk Factors in an Italian Adult Population Cohort

Abnormal sex hormone-binding globulin (SHBG) and sex hormone concentrations are the cause or the consequence of cardiometabolic diseases, however, the clinical correlates of SHBG is clearly less understood. In our study we investigate sex- and age-specific serum SHBG levels and their association with cardiovascular risk (CVR) factors and high-risk conditions in an adult cohort of Italian population. Data from 1176 men and 2236 women, aged 20–81 were analyzed and serum SHBG determined in stored samples using an immunoassay. SHBG concentrations, higher in women than in men in the younger age groups, exhibited a curvilinear increase with age in men and a U-shaped curve across the lifespan in women, with a decrease from the 2nd to the 6th decade of age and an increase after the 6th decade when SHBG concentrations were similar in both sexes. Low SHBG serum levels correlated with the traditional CVR factors diabetes, obesity, and hypertension, whereas high level of SHBG correlated with cholesterol HDL. These associations were more numerous in women than in men, in whom decreased with age. The sex- and age specific differences observed in our population-based cohort should be considered in establishing reference ranges and clinical cut-off points to improve CVR score charts and therapeutic approaches.

Effect of Sex Hormone-Binding Globulin on Polycystic Ovary Syndrome: Mechanisms, Manifestations, Genetics, and Treatment.

Polycystic ovary syndrome (PCOS) is one of the most common endocrine diseases causing infertility in women of childbearing age. It is characterized by hyperandrogenemia (HA), chronic anovulation, and polycystic ovary morphology (PCOM). Most women with PCOS have metabolic abnormalities. Sex hormone-binding globulin (SHBG), a transport carrier that binds estrogen and androgens and regulates their biological activity, is usually used as an indicator of hyperandrogenism in women with PCOS. Low serum SHBG levels are considered a biomarker of metabolic abnormalities and are associated with insulin resistance (IR), HA, and abnormal glucose and lipid metabolism in PCOS patients. SHBG is also related to the long-term prognosis of PCOS, whereas SHBG gene polymorphism is associated with PCOS risk. In addition, the administration of metformin (MET), glucagon-like peptide-1 receptor agonists (GLP-1 RAs), thiazolidinediones (TZDs), compound oral contraceptives (COCs), as well as nutrient supplements such as inositol (MI), vitamin D, and synbiotics can regulate SHBG levels to ameliorate PCOS complications and improve prognosis. This review focuses on the interaction between SHBG and various PCOS complications as well as the regulation of SHBG by various drugs and nutrients and its therapeutic effects on PCOS.

Correlation Between Serum Uric Acid and Body Fat Distribution in Patients With Polycystic Ovary Syndrome.

ObjectiveThis study aims to investigate the correlation between serum uric acid levels and body fat distribution in patients with polycystic ovary syndrome (PCOS).MethodsBetween May 2017 and March 2021, a total of 199 patients with PCOS were recruited from the Department of Endocrinology and Metabolism at the Shanghai Tenth People’s Hospital. Anthropometric characteristics, metabolic parameters, and reproductive hormones were measured. Hyperuricemia was defined as serum uric acid (SUA) greater than 420 μmol/l. Dual-energy X-ray absorptiometry (DEXA) was used to measure body fat distribution.ResultsThe prevalence of hyperuricemia in patients with PCOS was 28.64%. PCOS patients with hyperuricemia are more obese and have a higher waist-to-hip ratio (WHR) and worse lipid metabolism than those without hyperuricemia. According to SUA quartiles, patients in the highest quartile had higher total testosterone (TT), body fat accumulation, and lower sex hormone-binding globulin (SHBG) than patients in the lowest quartile. SUA was correlated with percentage of total body fat, arm fat mass, leg fat mass, trunk fat mass, android/gynoid (A/G) ratio, and visceral adipose tissue (VAT) mass. After controlling possible confounders, logistic regression analysis found that only excessive VAT mass could significantly increase the risk of hyperuricemia in patients with PCOS.ConclusionIn patients with PCOS, a high level of VAT mass, but not other fat compartments, will exacerbate the risk of hyperuricemia. Attention should be paid to the role of excessive VAT in the occurrence and development of PCOS with hyperuricemia.

Lower serum testosterone concentrations are associated with a higher incidence of dementia in men: The UK Biobank prospective cohort study.

The association of testosterone concentrations with dementia risk remains uncertain. We examined associations of serum testosterone and sex hormone-binding globulin (SHBG) with incidence of dementia and Alzheimer's disease. Serum total testosterone and SHBG were measured by immunoassay. The incidence of dementia and Alzheimer's disease (AD) was recorded. Cox proportional hazards regression was adjusted for age and other variables. In 159,411 community-dwelling men (median age 61, followed for 7 years), 826 developed dementia, including 288 from AD. Lower total testosterone was associated with a higher incidence of dementia (overall trend: P=.001, lowest vs highest quintile: hazard ratio [HR]=1.43, 95% confidence interval [CI]=1.13-1.81), and AD (P=.017, HR=1.80, CI=1.21-2.66). Lower SHBG was associated with a lower incidence of dementia (P<.001, HR=0.66, CI=0.51-0.85) and AD (P=.012, HR=0.53, CI=0.34-0.84). Lower total testosterone and higher SHBG are independently associated with incident dementia and AD in older men. Additional research is needed to determine causality.

Associations of Serum Testosterone and Sex Hormone-Binding Globulin With Incident Cardiovascular Events in Middle-Aged to Older Men.

The influence of testosterone on risk for cardiovascular events in men is uncertain. Previous observational studies of sex hormones and incident cardiovascular disease in men have reported inconsistent findings, limited by cohort sizes and different selection criteria. To analyze associations of serum total testosterone and sex hormone-binding globulin (SHBG) with incident cardiovascular events in men. Cohort study. UK Biobank prospective cohort. Community-dwelling men aged 40 to 69 years. Testosterone and SHBG were assayed, and free testosterone was calculated. Cox proportional hazards regression was done, with outcomes of incident myocardial infarction (MI), hemorrhagic stroke (HS), ischemic stroke (IS), heart failure (HF), and major adverse cardiovascular events (MACE), adjusted for sociodemographic, lifestyle, and medical factors. Of 210700 men followed for 9 years, 8790 (4.2%) had an incident cardiovascular event. After adjustment for key variables, lower total testosterone concentrations (quintile 1 vs. quintile 5) were not associated with incident MI (fully adjusted hazard ratio [HR], 0.89 [95% CI, 0.80 to 1.00]), HS (HR, 0.94 [CI, 0.70 to 1.26]), IS (HR, 0.95 [CI, 0.82 to 1.10]), HF (HR, 1.15 [CI, 0.91 to 1.45]), or MACE (HR, 0.92 [CI, 0.84 to 1.00]). Men with lower calculated free testosterone values had a lower incidence of MACE (HR, 0.90 [CI, 0.84 to 0.97]). Lower SHBG concentrations were associated with higher incidence of MI (HR, 1.23 [CI, 1.09 to 1.38]) and lower incidence of IS (HR, 0.79 [CI, 0.67 to 0.94]) and HF (HR, 0.69 [CI, 0.54 to 0.89]), but not with HS (HR, 0.81 [CI, 0.57 to 1.14]) or MACE (HR, 1.01 [CI, 0.92 to 1.11]). Observational study; single baseline measurement of testosterone and SHBG. Men with lower total testosterone concentrations were not at increased risk for MI, stroke, HF, or MACE. Calculated free testosterone may be associated with risk for MACE. Men with lower SHBG concentrations have higher risk for MI but lower risk for IS and HF, with causality to be determined. Western Australian Health Translation Network, Medical Research Future Fund, and Lawley Pharmaceuticals.

The Impact of Macronutrient Intake on Sex Steroids During Onset of Puberty

IntroductionIncreased fiber intake has been associated with decreased breast cancer risk, while increased animal protein intake with increased risk. The objective of this study is to examine the relationship of dietary fiber and protein intake to estrogen and sex hormone–binding globulin (SHBG) concentrations at puberty onset. MethodsThese analyses were conducted using the Cincinnati puberty cohort of the Breast Cancer and the Environment Research Program, with girls followed every 6 months from ages 6 and 7. The analyses included serum measurements at 6-month intervals for estrogen and SHBG concentrations, from 18 months prior to breast stage 2 (onset of puberty). Dietary intake was documented via 24-hour dietary recalls every 3 months. Dietary factors of interest included total energy intake; total and animal protein; total, soluble, and insoluble fiber; and lignan and flavanol intake. ResultsThis study included 260 participants who generated 871 serum specimens and 3,000 days of diet intake. In longitudinal models, estradiol was associated inversely with insoluble fiber intake; estrone positively with animal protein intake; SHBG with greater insoluble fiber and lower total protein intake; and ratio of estrone to SHBG, a measure of bioavailable estrogen, positively with animal protein. ConclusionsGreater protein intake, especially animal protein, led to greater estrogen concentrations and lower SHBG; greater animal protein and greater caloric intake led to increased bioavailable estrogen. This relationship may have served an evolutionary advantage in the past for greater fertility with adequate high-quality protein; in contemporary women, a modest decrease in animal protein may be beneficial in reducing breast cancer risk.

Collegiate male athletes exhibit conditions of the Male Athlete Triad.

The primary purpose of this study was to determine prevalence of the Male Athlete Triad (MAT) conditions: low energy availability (EA), low bone mineral density (BMD), and low testosterone in male collegiate athletes from different sports. Participants included 44 collegiate male athletes (age, 20.4 ± 0.2 years; body mass index, 25.3 ± 1.3kg/m2) from 7 sports (cross country, soccer, basketball, wrestling, track, golf, and baseball). Resting metabolic rate, 3-day food intake, 7-day exercise energy expenditure, body composition, and reproductive and metabolic hormones were assessed. Of the total participants, 15% had low EA, 0% had low BMD, 28% had low total testosterone (TT), and 80% had low calculated free testosterone (cFT). There were no significant correlations between EA, BMD, TT, and cFT. Insulin and sex hormone binding globulin (SHBG) were below and on the upper end of the reference range for healthy male adults, respectively. Insulin was negatively correlated with total (r = -0.330, p= 0.043) and lumbar spine BMD z-scores (r = -0.413, p= 0.010). Low TT and low cFT were the most prevalent MAT conditions among all athletes. Further research should investigate the relationship between insulin and SHBG and the role of these hormones in the MAT. Novelty: Assessment of energy availability alone is not sufficient to identify physiological disturbances in collegiate male athletes. Low total and/or free testosterone may be present in some collegiate male athletes, regardless of BMD status. Low insulin and high SHBG concentration may portray the presence of conditions of the MAT in male collegiate athletes.

Associations of endogenous sex hormone levels with the prevalence and progression of valvular and thoracic aortic calcification in the Multi-Ethnic Study of Atherosclerosis (MESA)

Background and aimsSex hormones (SH) may contribute to sex differences in cardiovascular disease (CVD). High free testosterone (T) and low sex hormone binding globulin (SHBG) have been associated with progression of coronary artery calcification in women. We now examined the association of SH with extra-coronary calcification (ECC) prevalence and progression among MESA participants. MethodsWe studied 2,737 postmenopausal women and 3,130 men free of clinical CVD with baseline SH levels. ECC measurements [ascending and descending thoracic aortic calcification (ATAC, DTAC), mitral annular calcification (MAC), aortic valve calcification (AVC)] were obtained by computed tomography at baseline and after 2.4 ± 0.9 years. We used multivariable Poisson regression to evaluate associations with ECC prevalence and incidence (Agatston scores >0) and linear mixed effects models for ECC progression, per 1-SD increment in log(SH) in women and men separately. ResultsThe mean age was 65 ± 9 and 62 ± 10 years for women and men, respectively. In women, greater free T and lower SHBG were associated with MAC incidence in a demographic-adjusted model only. In men, lower free T was associated with MAC prevalence, DTAC incidence and progression, while greater SHBG was associated with MAC prevalence and DTAC progression after further adjusting for CVD risk factors. ConclusionsIn this diverse cohort free of CVD, we found some associations of SH with ECC measures. In particular, free T was inversely associated with prevalent MAC and DTAC progression in men independent of CVD risk factors. SH may influence vascular calcification, but further work is needed to understand clinical implications of these findings.

Establishment of sex difference in circulating uric acid is associated with higher testosterone and lower sex hormone-binding globulin in adolescent boys

Men have higher circulating levels of uric acid than women. This sex difference is suspected to be a result of suppressive effects of estradiol on uric acid. If so, estradiol would be inversely associated with circulating uric acid. This study aimed to test this hypothesis. This cross-sectional study included 9472 participants (weighted sample size of 184,342,210) aged 12–80 years from the 2013 to 2016 US National Health and Nutrition Examination Survey. Associations of sex hormones with uric acid were analyzed using weighted least squares regression, adjusting for demographic characteristics, lifestyle risk factors, and comorbidities. Neither free nor bioavailable estradiol was inversely associated with circulating uric acid in adolescent boys or girls, or adult men or women, or perimenopausal women after full adjustment. The sex difference in uric acid was established during adolescence as a result of a dramatic increase in uric acid in adolescent boys. During adolescence, the increase in estradiol in girls over time was accompanied by a relatively unchanged level of uric acid. All three fractions of estradiol (free, bioavailable, and total) were positively associated with uric acid in adolescent boys and girls after full adjustment. In adolescent boys, all three fractions of testosterone were positively associated with serum uric acid, and sex hormone-binding globulin was inversely associated with uric acid after full adjustment. These results suggest that estradiol is not inversely associated with circulating uric acid in adolescents and the establishment of sex difference in circulating uric acid during adolescence is associated with higher testosterone and lower sex hormone-binding globulin in adolescent boys.