Lower Sex Hormone-binding Globulin Research Articles

Association of Testosterone and Sex Hormone-Binding Globulin With All-Cause and Cardiovascular Disease Mortality in Older Chinese Men.

The associations of high and low testosterone with all-cause and cardiovascular disease (CVD) mortality risk in men are conflicting. Our objective was to examine associations of total testosterone, free testosterone, bioavailable testosterone, and sex hormone-binding globulin (SHBG) with all-cause and CVD mortality in older Chinese men. Total testosterone and SHBG were assayed, and free testosterone and bioavailable testosterone were calculated using Vermeulen formula. Cox proportional hazards regression was used to assess the associations with risks of all-cause and CVD mortality, giving hazard ratios (HRs) and 95% confidence intervals (CIs). Of 3948 men aged 50+ years, 949 deaths (312 CVD) occurred during an average 10.5-year follow-up. After multivariable adjustments, the highest, versus the third, quartile of total testosterone and free testosterone were associated with higher all-cause mortality risk (1.17 [0.97-1.41] and 1.45 [1.20-1.74], respectively), whereas free testosterone was associated with higher CVD mortality risk (1.88 [1.33-2.66]). Similar positive associations were found for bioavailable testosterone and all-cause mortality risk (1.27 [1.05-1.54]). Lower SHBG (quartile 1 vs quartile 3) was associated with higher all-cause and CVD mortality risk (1.25 [1.04-1.52] and 1.28 [1.08-1.52], respectively). Consistent associations were observed in relatively healthy men and men excluded death during the first year. Higher total testosterone, free testosterone, and bioavailable testosterone were associated with higher all-cause mortality in older men, higher free testosterone was associated with higher CVD mortality whilst lower SHBG was associated with higher all-cause and CVD mortality. Clarification and confirmation of causality require further mechanistic studies.

Obesity contributes to telomere shortening in polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is a multifactorial disorder and obesity occurs in 38% to 88% of these women. Although hyperandrogenism may contribute to telomere lengthening, increased body mass index (BMI) is associated with telomere erosion. We sought to compare leukocyte telomere length (LTL) in PCOS women with normal, overweight, and obese BMI. We evaluated the relationship between LTL and clinical variables of PCOS and inflammatory biomarkers independent of BMI. A total of 348 women (243 PCOS and 105 non-PCOS) were evaluated for anthropometric measures, total testosterone, androstenedione, estradiol (E2), follicle-stimulating hormone (FSH), luteinizing hormone (LH), sex hormone-binding globulin (SHBG), free androgen index (FAI), fasting insulin and glycemia, lipid profile, homocysteine, C-reactive protein (CRP) and homeostatic model of insulin resistance (HOMA-IR). LTL was measured by qPCR. The PCOS group presented higher weight, waist circumference, BMI, testosterone, LH, fasting insulin, FAI, and HOMA-IR, and lower E2, SHBG, and fasting glycemia measures compared with the non-PCOS. When stratified by BMI, LTL was increased in all subgroups in PCOS compared to non-PCOS. However, in the PCOS group, LTL was lower in overweight (P = 0.0187) and obese (P = 0.0018)compared to normal-weight women. The generalized linear model showed that BMI, androstenedione, homocysteine, and CRP were associated with telomere biology. Women with PCOS had longer LTL, however, overweight or obesity progressively contributes to telomere shortening and may affect reproductive outcomes of PCOS, while androstenedione may increase LTL.

Association of sex hormones with non-alcoholic fatty liver disease: An observational and Mendelian randomization study.

Sex-specific associations of sex hormone-binding globulin (SHBG) and bioavailable testosterone (BAT) with NAFLD remain indeterminate. We aimed to explore observational and genetically determined relationships between each hormone and NAFLD. We included 187 395 men and 170 193 women from the UK Biobank. Linear and nonlinear Cox regression models and Mendelian randomization (MR) analysis were used to test the associations. During 12.49 years of follow-up, 2209 male and 1886 female NAFLD cases were documented. Elevated SHBG levels were linearly associated with a lower risk of NAFLD in women (HR (95% CI), .71 (.63, .79)), but not in men (a "U" shape, pnon-linear  < .001). Higher BAT levels were associated with a lower NAFLD risk in men (HR (95% CI), .81 (.71, .93)) but a higher risk in women (HR (95% CI): 1.25 (1.15, 1.36)). Genetically determined SHBG and BAT levels were linearly associated with NAFLD risk in women (OR (95% CI): .57 (.38, .87) and 2.21 (1.41, 3.26) respectively); in men, an "L-shaped" MR association between SHBG levels and NAFLD risk was found (pnon-linear  = .016). The bidirectional MR analysis further revealed the effect of NAFLD on SHBG and BAT levels in both sexes. Consistently, linear associations of lower SHBG and higher BAT levels with increased NAFLD risk were both conventionally and genetically found in women, while in men, SHBG acts in a nonlinear manner. In addition, NAFLD may affect SHBG and BAT levels.

Placental mRNA Expression of Neurokinin B Is Increased in PCOS Pregnancies with Female Offspring.

Current research suggests that polycystic ovary syndrome (PCOS) might originate in utero and implicates the placenta in its pathogenesis. Kisspeptin (KISS1) and neurokinin B (NKB) are produced by the placenta in high amounts, and they have been implicated in several pregnancy complications associated with placental dysfunction. However, their placental expression has not been studied in PCOS. We isolated mRNA after delivery from the placentae of 31 PCOS and 37 control women with term, uncomplicated, singleton pregnancies. The expression of KISS1, NKB, and neurokinin receptors 1, 2, and 3 was analyzed with real-time polymerase chain reaction, using β-actin as the reference gene. Maternal serum and umbilical cord levels of total testosterone, sex hormone-binding globulin (SHBG), free androgen index (FAI), androstenedione, dehydroepiandrosterone sulfate (DHEAS), Anti-Mullerian hormone (AMH), and estradiol were also assessed. NKB placental mRNA expression was higher in PCOS women versus controls in pregnancies with female offspring. NKB expression depended on fetal gender, being higher in pregnancies with male fetuses, regardless of PCOS. NKB was positively correlated with umbilical cord FAI and AMH, and KISS1 was positively correlated with cord testosterone and FAI; there was also a strong positive correlation between NKB and KISS1 expression. Women with PCOS had higher serum AMH and FAI and lower SHBG than controls. Our findings indicate that NKB might be involved in the PCOS-related placental dysfunction and warrant further investigation. Studies assessing the placental expression of NKB should take fetal gender into consideration.

Distinct Reproductive Phenotypes Segregate With Differences in Body Weight in Adolescent Polycystic Ovary Syndrome.

Polycystic ovary syndrome (PCOS) is a heterogenous clinical syndrome defined by hyperandrogenism and irregular menses. In adult women with PCOS, discrete metabolic and reproductive subgroups have been identified. We hypothesize that distinct phenotypes can be distinguished between adolescent girls who are lean (LN-G) and girls with obesity (OB-G) at the time of PCOS diagnosis. Data were extracted from the CALICO multisite PCOS database. Clinical data collected at the time of diagnosis were available in 354 patients (81% with obesity) from 7 academic centers. Patients with body mass index (BMI) < 85th percentile for age and sex were characterized as lean (LN-G) and those with BMI percentile ≥ 95th percentile as obese (OB-G). We compared metabolic and reproductive phenotypes in LN-G and OB-G. Reproductive phenotypes differed between the groups, with LN-G having higher total testosterone, androstenedione, and LH levels, while OB-G had lower sex hormone binding globulin (SHBG) and higher free testosterone. Metabolic profiles differed as expected, with OB-G having higher hemoglobin A1c, alanine aminotransferase, and serum triglycerides and more severe acanthosis nigricans. LN-G with PCOS had a distinct reproductive phenotype characterized by increased LH, total testosterone, and androstenedione levels, suggesting neuroendocrine-mediated ovarian androgen production. In contrast, phenotypes in OB-G suggest hyperandrogenemia is primarily driven by insulin resistance with low SHBG levels. These observations support the existence of distinct metabolic and reproductive subtypes in adolescent PCOS characterized by unique mechanisms for hyperandrogenemia.

Gestational Diabetes Mellitus in the Setting of Polycystic Ovarian Syndrome: A Systematic Review.

Gestational diabetes mellitus (GDM) is the most common complication ofpregnancy that arises in the 2nd and 3rd trimesters, leading to significant complications for the mother and her neonates, such as an increased rate of pregnancy-induced hypertension and miscarriages, while neonates may have a large birth weight, hypoglycemia, or macrosomnia. Numerous risk factors can lead to GDM; however, a significant one is polycystic ovarian syndrome (PCOS). PCOS is the most common endocrine pathology beginning before puberty, and due to significant hormonal changes, it is not diagnosed until after puberty. PCOS requires at least three of the following symptoms: hyperandrogenism, menstrual irregularities, or polycystic ovary morphology.While it is agreed that women with PCOS are at a significantly increased risk of GDM, no publication to our knowledge has evaluated the full relationship of GDM in the setting of PCOS. This paper aimed to assess this relationship and determine how it may differ for pregnant women with only GDM by determining the prevalence of GDM, the variations within phenotypes, the influence of fertilization methods, specific risk factors, maternal outcomes, and neonatal outcomes. The prevalence of GDM was significantly increased in women with PCOS compared to healthy controls, and some studies have found that phenotype A may be more likely to lead to GDM.Risk factors were similar to pregnant women with only GDM, but with GDM and PCOS specifically, preconception low sex hormone-binding globulin, increased BMI > 25 kg/m2, and preconception impaired glucose tolerance were specific. While maternal outcomes were similar to pregnant women with only GDM, women with GDM and PCOS were even more likely to develop pregnancy-induced hypertension and early miscarriage. Neonates from mothers with GDM and PCOS were more likely to have low birth weights compared to mothers with just GDM who had high birth weights. The evaluation of the relationship between GDM and PCOS allows for illumination of the need to evaluate influences that currently lack research, such as phenotype variation and influences of fertilization method. This also promotes the need to develop predictive algorithms based on risk factors to prevent these adverse outcomes for mothers and neonates.

Endogenous sex hormones and nonalcoholic fatty liver disease in US adults.

Sex steroid hormones and sex hormone-binding globulin (SHBG) have a role in predisposing individuals to nonalcoholic fatty liver disease (NAFLD), but their effects are known to differ between men and women. The testosterone-to-estradiol ratio (T/E2 ratio) and free androgen index (FAI) were known biomarkers for the hormonal milieu. We investigated whether sex steroid hormones, T/E2 ratio, FAI, and SHBG were associated with NAFLD in US adults. A cross-sectional analysis using the 2013-2016 National Health and Nutrition Examination Survey (NHANES) was performed. NAFLD was defined by utilizing the Hepatic Steatosis Index (HSI) and the US fatty liver index (USFLI) without other causes of chronic liver disease. Out of 8687 subjects (49.5% male), low total testosterone levels were associated with progressively higher odds of NAFLD in men. Increasing T/E2 ratio was inversely associated with higher odds of NAFLD in men. Low serum SHBG levels were independently associated with an increased risk of NAFLD regardless of sex and menopausal status. Increasing FAI was independently associated with NAFLD. When we additionally adjusted for SHBG, T/E2 ratio, not total testosterone, was inversely associated with NAFLD in a dose-dependent manner. Increasing FAI was associated with higher odds of NAFLD in premenopausal women and marginally associated with NAFLD in postmenopausal women. The T/E2 ratio and SHBG were inversely associated with an increased risk of NAFLD in men. In women, increasing FAI was associated with NAFLD, whereas SHBG was inversely associated with NAFLD.

Maternal pre-pregnancy BMI and reproductive health in adult sons: a study in the Danish National Birth Cohort.

Is maternal pre-pregnancy BMI associated with semen quality, testes volume, and reproductive hormone levels in sons? Maternal pre-pregnancy BMI was associated with an altered reproductive hormone profile in young adult sons, characterized by higher levels of oestradiol, LH, and free androgen index (FAI) and lower levels of sex hormone-binding globulin (SHBG) in sons born of mothers with pre-pregnancy overweight and obesity. Evidence suggests that maternal pre-pregnancy BMI may influence reproductive health later in life. Only one pilot study has investigated the association between maternal pre-pregnancy BMI and reproductive health outcomes in sons, suggesting that a high BMI was associated with impaired reproductive function in the adult sons. A population-based follow-up study of 1058 young men from the Fetal Programming of Semen Quality (FEPOS) cohort nested within the Danish National Birth Cohort (DNBC), 1998-2019, was carried out. In total, 1058 adult sons (median age 19 years, 2 months), born 1998-2000 by mothers included in the DNBC, participated in FEPOS. At a clinical examination, they provided a semen and blood sample, measured their testes volume, and had height and weight measured. Maternal pre-pregnancy BMI was obtained by self-report in early pregnancy. Semen characteristics, testes volume, and reproductive hormone levels were analysed according to maternal pre-pregnancy BMI categories and as restricted cubic splines using negative binomial and ordinary least square regression models. Mediation analyses examined potential mediation by the sons' birthweight, pubertal timing, fat mass, and BMI. Additional analyses investigated the role of paternal BMI in the potential associations between maternal BMI and reproductive health outcomes. We found no consistent associations between maternal pre-pregnancy BMI and semen characteristics or testes volume. Sons of mothers with higher pre-pregnancy BMI had higher oestradiol and lower SHBG levels, both in a dose-dependent manner. Sons of mothers with pre-pregnancy obesity (≥30 kg/m2) had higher LH levels and a higher FAI than sons born by mothers with normal pre-pregnancy BMI (18.5-24.9 kg/m2). The mediation analyses suggested that the effect of maternal pre-pregnancy BMI on higher levels of oestrogen, LH, and FAI was partly mediated by the sons' birthweight, in addition to adult fat mass and BMI measured at the clinical examination, whereas most of the effect on lower levels of SHBG was primarily mediated by the sons' own fat mass and BMI. Paternal BMI was not a strong confounder of the associations in this study. This study was based in a population-based cohort with a low prevalence of overweight and obesity in both mothers and adult sons. Some men (10%) had blood for reproductive hormone assessment drawn in the evening. While several potential confounding factors were accounted for, this study's inherent risk of residual and unmeasured confounding precludes provision of causal estimates. Therefore, caution should be given when interpreting the causal effect of maternal BMI on sons' reproductive health. Given the widespread occurrence of overweight and obesity among pregnant women, it is imperative to thoroughly examine the potential consequences for reproductive hormone levels in adult sons. The potential effects of maternal pre-pregnancy obesity on sons' reproductive hormone profile may potentially be partly avoided by the prevention of overweight and obesity in the sons. The project was funded by the Lundbeck Foundation (R170-2014-855), the Capital Region of Denmark, Medical doctor Sofus Carl Emil Friis and spouse Olga Doris Friis's Grant, Axel Muusfeldt's Foundation (2016-491), AP Møller Foundation (16-37), the Health Foundation, Dagmar Marshall's Fond, Aarhus University, Independent Research Fund Denmark (9039-00128B), and the European Union (ERC, BIOSFER, 101071773). Views and opinions expressed are, however, those of the authors only and do not necessarily reflect those of the European Union or the European Research Council. Neither the European Union nor the granting authority can be held responsible. The authors declare that they have no conflict of interest. N/A.

Association between childhood obesity and infertility in later life: a systematic review of cohort studies

BackgroundThe global prevalence of childhood obesity has exhibited a troubling surge in recent years. Due to the raised questions regarding its potential correlation with infertility in adulthood, this systematic review has been undertaken to explore the relationships between childhood obesity, and infertility later in life.MethodsA comprehensive search was performed in three international databases (PubMed, Web of Science, and Scopus). All cohort (retrospective or prospective), case-cohort, and nested case-control studies until April 2022 which assessed the association of obesity in children and adolescents with male and female infertility indicators in later life were included. The quality of the included studies was assessed by Newcastle-Ottawa quality assessment checklists.ResultOut of the initial 32,501 documents, eleven eligible studies with a total sample size of 498,980 participants were included. Five studies focused on the number of offspring and indicated that obesity, especially in adolescence had an association with later life lower number of children, nulliparity, and childlessness in both men and women. Concerning conceiving problems, two studies showed that obesity before age 12 increased the risk of female fertility problems in the future. Two studies reported that obesity in early life raised the risk of impaired female reproductive system such as menstrual or ovulatory problems. As well as females, a study discovered that obesity in men during their 20s was linked to an elevated risk of low sperm motility and poor sperm morphology. Another study has reported men with higher pre-pubertal BMI had lower sex hormone-binding globulin; however, the same association was not seen between childhood BMI and semen quality.ConclusionThe evidence suggests a positive association between childhood obesity with infertility indicators in later life. Childhood weight reduction strategies are suggested to be implemented in societies in order to reduce infertility rates in later life.

THU652 Associations Of Testosterone, Dihydrotestosterone, Estradiol And Sex Hormone-binding Globulin With All-cause And Cardiovascular Mortality, And Incident Cardiovascular Events In Men: Individual Participant Data Meta-analyses

Abstract Disclosure: B.B. Yeap: None. R.J. Marriott: None. L. Antonio: None. S. Bhasin: None. A.S. Dobs: None. D.J. Handelsman: None. G.J. Hankey: None. R. Haring: None. A.M. Matsumoto: None. C. Ohlsson: None. E.S. Orwoll: None. D.M. Vanderschueren: None. G.A. Wittert: None. F.C. Wu: None. K. Murray: None. Studies examining associations of circulating sex steroids with mortality risk in men show inconsistent results for testosterone (T), with limited data for dihydrotestosterone (DHT) and estradiol (E2). We aimed to clarify associations of sex steroids, sex hormone-binding globulin (SHBG) and luteinising hormone (LH) with risks of all-cause and cardiovascular disease (CVD) mortality and incident CVD events in men, by conducting individual participant data (IPD) meta-analyses of prospective cohort studies with sex steroids measured using mass spectrometry. The Androgens In Men Study protocol was registered (PROSPERO: CRD42019139668) and published (BMJ Open 2020;10:e034777). A systematic review (completed Dec 2019) identified relevant studies (BMJ Open 2021;11:e048013). IPD were requested. Cox proportional hazards analyses related total T, SHBG, LH, DHT and E2 concentrations to risk of all-cause mortality and CVD deaths, and risk of incident CVD events. Models were adjusted for age and other sociodemographic factors, lifestyle factors, medical conditions and medications. Summary curves and hazard ratios (HRs) with 95% confidence intervals (CIs) were determined using two-stage random-effects IPD meta-analyses. Summary estimates were obtained from 11 studies (24,596 men), with median baseline age 49-76 years and 4-20 years follow-up among studies. Associations of T with all-cause and CVD mortality risk were non-linear. Risk of all-cause mortality increased for men with baseline T concentrations &amp;lt;8.7 nmol/L, and risk of CVD death increased for men with baseline T &amp;lt;5.3 nmol/L. Lower SHBG concentrations were associated with lower risk of all-cause mortality (median Quintile [Q]1 vs Q5 [Q1:Q5], 20.6 vs 68.3 nmol/L; HR=0.85, CI=0.77-0.95), and CVD death (HR=0.81, CI 0.65-1.00). Men with LH &amp;gt;10 IU/L or E2 &amp;lt;5.1 pmol/L had higher all-cause mortality, with no association of LH or E2 with CVD deaths. Associations of DHT with all-cause and CVD mortality risk were non-linear. Men with lower baseline DHT concentrations had higher risk of all-cause mortality (median Q1:Q5, 0.69 vs 2.45 nmol/L; HR=1.19, CI=1.08-1.30) and CVD deaths (HR=1.29, CI=1.03-1.61), with risk increasing for DHT &amp;gt;2.45 nmol/L. Men with baseline DHT concentrations &amp;lt;0.59 nmol/L had increased risk of incident CVD events, no other hormones were associated with this outcome. Our results suggest greater all-cause and CVD mortality risk among men with very low baseline T, higher baseline SHBG, or either lower or very high baseline DHT concentrations. There was greater risk of CVD events among men with very low baseline DHT concentrations. Potential mechanisms by which SHBG and DHT might influence mortality risk in ageing men merit further investigation. Presentation: Thursday, June 15, 2023

Sex hormone-binding globulin (SHBG) mitigates ER stress and improves viability and insulin sensitivity in adipose-derived mesenchymal stem cells (ASC) of equine metabolic syndrome (EMS)-affected horses

BackgroundEquine metabolic syndrome (EMS), which encompasses insulin resistance, low-grade inflammation and predisposition to laminitis is a critical endocrine disorder among the most prevalent conditions affecting horses from different breeds. According to the most recent research, low human sex hormone-binding globulin (SHBG) serum levels correlate with an increased risk of obesity, insulin resistance and diabetes, and may contribute to overall metabolic dysregulations. This study aimed to test whether exogenous SHBG could protect EMS affected adipose-derived stromal stem cells (EqASCEMS) from apoptosis, oxidative stress, ER stress and thus improve insulin sensitivity.MethodsEqASCEMS wells were treated with two different concentrations (50 and 100 nM) of exogenous SHBG, whose biocompatibility was tested after 24, 48 and 72 h of incubation. Several parameters including cell viability, apoptosis, cell cycle, reactive oxygen species levels, ER stress, Pi3K/MAPK activation and insulin transducers expression were analysed.ResultsObtained data demonstrated that exogenous SHBG treatment significantly promoted ASCs cells proliferation, cell cycle and survival with reduced expression of p53 and p21 pro-apoptotic mediators. Furthermore, SHBG alleviated the oxidative stress caused by EMS and reduced the overaccumulation of intracellular ROS, by reducing ROS + cell percentage and regulating gene expression of endogenous antioxidant enzymes (Sod 1, Cat, GPx), SHBG treatment exhibited antioxidant activity by modulating total nitric oxide (NO) levels in EMS cells as well. SHBG treatment dampened the activation of ER stress sensors and effectors in EqASCEMS cells via the upregulation of MiR-7a-5p, the decrease in the expression levels of ATF-6, CHOP and eiF2A and the restoration of PDIA3 chaperone protein levels. As a consequence, SHBG application substantially improved insulin sensitivity through the modulation of Pi3K/Akt/Glut4 insulin signalling cascades.ConclusionOur results suggest that the SHBG is endowed with crucial beneficial effects on ASCs metabolic activities and could serve as a valuable therapeutic target for the development of efficient EMS treatment protocols.1CMnBWH6nCsmkUsG-EU1vwVideo

Sex-specific and sex-independent steroid-related biomarkers in early second trimester maternal serum associated with autism

BackgroundPrenatal exposure to maternal metabolic conditions associated with inflammation and steroid dysregulation has previously been linked to increased autism risk. Steroid-related maternal serum biomarkers have also provided insight into the in utero steroid environment for offspring who develop autism.ObjectiveThis study examines the link between autism among offspring and early second trimester maternal steroid-related serum biomarkers from pregnancies enriched for prenatal metabolic syndrome (PNMS) exposure.Study designEarly second trimester maternal steroid-related serum biomarkers (i.e., estradiol, free testosterone, total testosterone, and sex hormone binding globulin) were compared between pregnancies corresponding to offspring with (N = 68) and without (N = 68) autism. Multiple logistic regression analyses were stratified by sex and gestational duration. One-way ANCOVA with post hoc tests was performed for groups defined by autism status and PNMS exposure.ResultsIncreased estradiol was significantly associated with autism only in males (AOR = 1.13 per 100 pg/ml, 95% CI 1.01–1.27, p = 0.036) and only term pregnancies (AOR = 1.17 per 100 pg/ml, 95% CI 1.04–1.32, p = 0.010). Autism status was significantly associated with decreased sex hormone binding globulin (AOR = 0.65 per 50 nmol/L, 95% CI 0.55–0.78, p < 0.001) overall and when stratified by sex and term pregnancy status. The inverse association between sex hormone binding globulin and autism was independent of PNMS exposure.LimitationsThe relative racial and ethnic homogeneity of Utah’s population limits the generalizability of study results. Although significant differences by autism status were identified in concentrations of sex hormone binding globulin overall and of estradiol in participant subgroups, differences by PNMS exposure failed to reach statistical significance, which may reflect insufficient statistical power.ConclusionBoth elevated maternal serum estradiol in males only and low maternal serum sex hormone binding globulin in both sexes are associated with increased autism risk. Further investigation is merited to identify how steroid, metabolic, and inflammatory processes can interact to influence neurodevelopment in early second trimester.

A cross-sectional study of the association between circulating sex hormone-binding globulin levels and selected adipokines in women with polycystic ovary syndrome.

Changes in the proportion of pro-inflammatory and anti-inflammatory adipokines may reflect the accumulation of lipids in the liver and the development of insulin resistance. Both liver steatosis and insulin resistance result in decreased sex hormone-binding globulin (SHBG) synthesis. This study aimed to analyze associations between circulating SHBG and adipokines levels in women with polycystic ovary syndrome (PCOS). A cross-sectional cohort study involved 87 women with phenotype A of PCOS (39 normal weight and 48 obese). Body mass, height, and waist circumference were measured, and BMI was calculated. In addition, body composition was assessed using the bioimpedance method. Serum SHBG levels and plasma apelin-36 and apelin-12, adiponectin, leptin, omentin-1, and RBP-4 were determined by using the ELISA method. The participants were divided into subgroups with SHBG concentrations above and below this lower limit [N = 35 (40.2%) and N = 52 (59.8%), respectively]. The median adiponectin, apelin-12, and apelin-36 levels were significantly lower, and leptin levels were significantly higher in the subgroup with low SHBG levels than that in the subgroup above the lower limit of the reference range, while there were no differences in median omentin-1 and RBP-4 between the study subgroups. There were positive correlations between SHBG and omentin-1, adiponectin, apelin-36, and apelin-12 levels, as well as negative correlation with leptin levels. However, after adjustment by BMI, waist circumference, and body fat percentage, only the association between SHBG and omentin-1 remained significant. Our results show associations between circulating SHBG and adipokine levels in women with PCOS and support the role of hormonal dysfunction of the adipose tissue in the pathogenesis of PCOS.

Putative causal inference for the relationship between obesity and sex hormones in males: a bidirectional Mendelian randomization study.

Obesity is a chronic disease with a high prevalence rate and is an established risk factor for human health. Body mass index (BMI) is a common and primary indicator used in assessing obesity. This work aims to investigate the putative causal relationship among BMI, sex hormone-binding globulin (SHBG), bioavailable testosterone (BioT), and estradiol levels. We conducted a bidirectional Mendelian randomization study, using single-nucleotide polymorphisms (SNPs) strongly associated with BMI, SHBG, BioT, and estradiol as instrumental variables. All SNPs were identified from the genome-wide association study (GWAS) summary data of large sample studies recruiting more than 150,000 European adult male individuals. The inverse-variance-weighted (IVW) approach was used as a primary algorithm for putative causal estimation. Genetically predicted elevated BMI was associated with decreased SHBG (IVW, β = -0.103, 95% confidence interval [CI] [-0.113 to -0.092], P = 1.50 × 10-77) and BioT levels (IVW, β = -0.139, 95% CI [-0.165 to -0.113], P = 9.54 × 10-26) and high estradiol levels (IVW, β = 0.014, 95% CI [0.009-0.019], P = 2.19 × 10-7). Increased SHBG levels were causally associated with low BMI (IVW, β = -0.051, 95% CI [-0.098 to -0.005], P = 0.030) and BioT (IVW, β = -0.126, 95% CI [-0.175 to -0.077], P = 5.97 × 10-7) and high estradiol levels (IVW, β = 0.046, 95% CI [0.035-0.056], P = 6.51 × 10-17). Conversely, no evidence of an effect of estradiol imbalance on SHBG levels (IVW, β = 1.035, 95% CI [-0.854 to 2.926], P = 0.283) and BMI (IVW, β = 0.091, 95% CI [-0.094 to 0.276], P = 0.336) was obtained. However, increased BioT levels were causally associated with lower SHBG levels (IVW, β = -0.044, 95% CI [-0.061 to -0.026], P = 8.76 × 10-7), not BMI (IVW, β = -0.006, 95% CI [-0.035 to 0.023], P = 0.679). The findings support a network putative causal relationship among BMI, SHBG, BioT, and estradiol. SHBG, BioT, and estradiol may partly mediate the effect of obesity on male health. Reasonably modulating BioT and estradiol, especially SHBG, facilitated the attenuation of the harmful effects of obesity on male health.

Sex Hormone Binding Globulin is an Independent Predictor for Insulin Resistance in Male Patients with Newly Diagnosed Type2 Diabetes Mellitus.

This study explored the correlation between sex hormones, sex hormone binding globulin (SHBG), and insulin resistance in male patients with newly diagnosed type2 diabetes mellitus (T2DM). A total of 48 male patients with newly diagnosed T2DM were enrolled in this study between March 2022 and December 2022. Clinical characteristics, sex hormones, and SHBG levels were collected. All enrolled subjects received intensive hypoglycemic treatment with insulin pump for 1week to achieve glycemic control, then the steady-state glucose infusion rate (GIR), an indicator of insulin sensitivity, was determined by the hyperinsulinemic-euglycemic clamp. Correlation analysis and multivariate logistic regression analysis were performed to explore the association of clinical characteristics, sex hormones, and SHBG with insulin sensitivity. The optimal cutoff value to predict insulin resistance was calculated using receiver operating characteristic (ROC) curve. According to the GIR cut-point value of 5.700mg/(kgmin), there were 40 patients with insulin resistance (IR group) and 8 patients without (non-IR group). The IR group exhibited lower testosterone and SHBG levels than the non-IR group (all p < 0.050). Correlation analysis showed that insulin sensitivity was positively associated with testosterone and SHBG, while negatively associated with body mass index, fasting blood glucose, alanine aminotransferase, aspartate aminotransferase, total cholesterol, triglyceride, and apolipoproteinB (all p < 0.050). Multivariate logistic regression analysis demonstrated that SHBG is an independent predictor for insulin resistance (p = 0.029). Further ROC curve analysis revealed that the optimal cutoff value of SHBG to predict insulin resistance is 17.200nmol/L, with the corresponding area under the curve (AUC) and its 95% confidence interval (CI) being 0.813 and 0.691-0.934. SHBG is an independent predictor for insulin resistance in male patients with newly diagnosed T2DM. KY20220314-01.

Frequency and Clinical Significance of Low or High Sex Hormone Binding Globulin Levels in Patients Suspected of Harboring Abnormal Testosterone Levels

Purpose: We aim to examine the frequency of low or high sex hormone binding globulin (SHBG) levels and to investigate whether they are associated with comorbidities and hormonal derangements in patients suspected of harboring abnormal testosterone levels. Methods: This was a retrospective study of adult patients who underwent SHBG testing as part of a panel for testosterone at UCLA Health between May and July 2019. Results: A total of 1102 male and 689 female patients underwent SHBG testing; the most common indications of the tests were suspected hypogonadism in male and hyperandrogenism in female patients. Eight male (0.7%, 9.4±1.0 nmol/L) and 66 female patients (9.6%, 21.7±5.2 nmol/L) exhibited low SHBG levels, and 113 male (10.3%, 106.6±29.6 nmol/L) and 118 female (17.1%, 187.1±59.6 nmol/L) patients exhibited high SHBG levels. Patients with low SHBG levels were younger, had higher body mass index, and less commonly receive sex hormone treatments than those with high SHBG levels but they were not different in other assessed clinical parameters. Bioavailable and free testosterone levels were not different in males with low or high SHBG levels but were significantly higher in females with low SHBG levels than in those with high SHBG levels.

Causality between COVID‐19 and female reproductive function: A Mendelian randomization study

AbstractCoronavirus disease 2019 (COVID‐19) has experienced a global pandemic, and currently, the emergence of its variants has posed challenges in terms of prevention and treatment. Nonetheless, the effect of COVID‐19 infection on female reproductive function is unclear. This study aimed to systematically evaluate for the first time the causal effect of COVID‐19 on female reproductive function. Genetic correlations were assessed using linkage disequilibrium score regression. Mendelian randomization (MR) analysis was performed using summary statistics of two variables, including COVID‐19 severity and eight female reproductive traits. The three degrees of severity had genetically significant associations with sex hormone‐binding globulin (SHBG) concentrations (rg = –0.153, p = 0.004; rg = –0.187, p &lt; 0.001; rg = –0.180, p = 0.003). Additionally, MR showed that SHBG (β = –0.020, p = 0.040) and total testosterone levels (β = –0.061, p = 0.009) followed a decreasing trend, as the COVID‐19 infection higher. No significant genetic association was found between COVID‐19 infection and total estradiol concentrations, menstruation, and female infertility. Simultaneously, MR found no causal relationships between COVID‐19 infection and total estradiol concentrations, menstruation, and female infertility (all p &gt; 0.05). In conclusion, COVID‐19 was causally associated with lower SHBG and total testosterone concentrations, offering invaluable insights that will help guide clinical decision‐making.

(098) ERβ Polymorphism (rs1256049; 1082G&amp;gt;A) Association with Male Infertility: A Meta-analysis

Abstract Introduction In men, estrogen is produced in the testis by Sertoli cell, Leydig cell and germ cells that play an important role in the maturation and capacitation of sperms. The action of estrogen is mediated by two specific Receptors: Estrogen receptors α (ESRα) and Estrogen receptor β (ESRβ). The polymorphisms of the ERβ gene confer a lower sex hormone binding globulin (SHBG) and thus a stronger unbound estrogen effect, which may adversely affect human spermatogenesis. SHBG is involved in both delivering reproductive hormones to target tissues and controlling the concentration of androgens and estrogens in the serum and tissues. Two silent G/A polymorphisms of the ER□ genes i.e., rs1256049 and rs4986938 have been demonstrated. The polymorphism studied at rs1256049 is 1082G&amp;gt;A presented contrary results. Objective The study aims to demonstrate the prevalence of Estrogen Receptor Beta (ERβ) polymorphism (1082G&amp;gt;A; rs1256049) in two ethnicities i.e., Asian and Caucasian, and its association with the risk of male infertility. Methods The databases PUBMED and NCBI were searched to retrieve case-control studies, published from 2005 to date, regarding ERβ polymorphism and male infertility were selected for this meta-analysis. Results A total of 10 case-control studies out of 85articles (6 Asian + 4 Caucasian), including 1613 cases and 1654 controls, determiningERβ polymorphism and male infertility met the inclusion criteria. Significant association (p&amp;lt;0.05) was found between ERβ polymorphism and risk of male infertility on the basis of all four genetic models i.e. Allelic model (A vs G: OR= 1.19, 95% CI [1.00-1.43], I2 = 62%), additive model (AA vs GG: OR= 0.54, 95% CI [0.31-0.94], I2 = 0%), dominant model (AA+AG vs GG: OR= 1.37, 95% CI [1.11-1.69], I2 = 52%) and recessive model (AA vs AG+GG: OR= 0.55, 95% CI [0.32-0.96], I2 = 0%). In case of Caucasian population, this polymorphism is significantly associated with male infertility on the basis of allelic model (A vs G: OR= 2.10, 95% CI [1.31-3.36], I2 = 37%) as well as the dominant model (AA+AG vs GG: OR= 2.70, 95% CI [1.62-4.51], I2 = 72%), whereas in Asian population, it had a significant association on the basis of recessive model (AA vs AG+GG: OR= 0.55, 95% CI [0.31-0.96], I2 = 0%) only. Conclusions ERβ polymorphism (rs1256049 is 1082G&amp;gt;A) is linked with a higher risk of male infertility and has a more severe effect on the Caucasian population than on the Asian population. Disclosure No

The causal association between smoking initiation, alcohol and coffee consumption, and women's reproductive health: A two-sample Mendelian randomization analysis.

Objective: A number of epidemiological studies have demonstrated that smoking initiation and alcohol and coffee consumption were closely related to women's reproductive health. However, there was still insufficient evidence supporting their direct causality effect. Methods: We utilized two-sample Mendelian randomization (TSMR) analysis with summary datasets from genome-wide association study (GWAS) to investigate the causal relationship between smoking initiation, alcohol and coffee consumption, and women's reproductive health-related traits. Exposure genetic instruments were used as variants significantly related to traits. The inverse-variance weighted (IVW) method was used as the main analysis approach, and we also performed MR-PRESSO, MR-Egger, weighted median, and weighted mode to supplement the sensitivity test. Then, the horizontal pleiotropy was detected by using MRE intercept and MR-PRESSO methods, and the heterogeneity was assessed using Cochran's Q statistics. Results: We found evidence that smoking women showed a significant inverse causal association with the sex hormone-binding globulin (SHBG) levels (corrected β = -0.033, p = 9.05E-06) and age at menopause (corrected β = -0.477, p = 6.60E-09) and a potential positive correlation with the total testosterone (TT) levels (corrected β = 0.033, p = 1.01E-02). In addition, there was suggestive evidence for the alcohol drinking effect on the elevated TT levels (corrected β = 0.117, p = 5.93E-03) and earlier age at menopause (corrected β = -0.502, p = 4.14E-02) among women, while coffee consumption might decrease the female SHBG levels (corrected β = -0.034, p = 1.33E-03). Conclusion: Our findings suggested that smoking in women significantly decreased their SHBG concentration, promoted earlier menopause, and possibly reduced the TT levels. Alcohol drinking had a potential effect on female higher TT levels and earlier menopause, while coffee consumption might lead to lower female SHBG levels.

Sex hormones, SHBG and cognitive performance among older Australian women: an observational study

Objective This study aims to explore the associations between sex hormones and cognitive performance in older women. Methods Associations between sex hormones, sex hormone binding globulin (SHBG) and cognitive performance were examined in women aged at least 70 years, without dementia and not using medications that influence sex hormones. Linear and generalized linear regression models included age, body mass index, education, smoking, alcohol, living circumstances, diabetes, hypertension, depression and impaired renal function. Results The included 5511 women had a median (interquartile range) age of 73.9 (71.6–77.6) years. No associations were found for estrone, estradiol, testosterone or dehydroepiandrosterone and cognitive performance. SHBG concentrations above quartile 1 (Q1) were significantly inversely associated with processing speed (Q2, β = –0.94, 95% confidence interval [CI] − 1.64 to −0.24, p = 0.009; Q3, β = –0.82, 95% CI −1.53 to −0.10, p = 0.025; and Q4, β = –0.95, 95% CI −1.70 to −0.20, p = 0.013). Conclusions Sex hormones were not associated with cognitive performance. The finding that low SHBG is associated with better processing speed warrants further investigation. The null findings for the sex hormones establish a firm baseline to confidently explore the association between sex hormones and longitudinal cognitive performance in this population. Trial Registration International Standard Randomized Controlled Trial Number Register (ISRCTN83772183) and ClinicalTrials.gov (NCT01038583).