Low Sex Hormone-binding Globulin Levels Research Articles

The Role of SHBG as a Marker in Male Patients with Metabolic-Associated Fatty Liver Disease: Insights into Metabolic and Hormonal Status

Background: Metabolic-associated fatty liver disease (MAFLD) is a spectrum of liver diseases linked to insulin resistance (IR), type 2 diabetes, and metabolic disorders. IR accelerates fat accumulation in the liver, worsening MAFLD. Regular physical activity and weight loss can improve liver function, reduce fat, and lower cardiovascular risk. This study examines the role of sex hormone-binding globulin (SHBG) in MAFLD, focusing on its potential as a biomarker and its relationship with insulin resistance. Methods: The study included 98 male patients (ages 30–55) with MAFLD, identified through systematic examinations, and 74 healthy male controls. All participants underwent abdominal ultrasound and blood tests after fasting, assessing markers such as glucose, liver enzymes (AST, ALT, γGT), lipids (cholesterol, triglycerides), insulin, SHBG, estradiol, and testosterone. SHBG levels were analyzed in relation to body mass index (BMI) and age. Results: A significant association was found between low SHBG levels and the presence of fatty liver. Individuals with MAFLD had lower SHBG levels compared to controls. BMI and age were key factors influencing SHBG, with higher BMI linked to lower SHBG in younger men, while SHBG remained stable in older individuals regardless of BMI. Conclusion: SHBG may serve as a valuable biomarker for early detection and risk assessment of MAFLD. The complex relationship between SHBG, BMI, and age highlights the importance of considering both hormonal and metabolic factors when assessing fatty liver risk. Our findings support the need for comprehensive metabolic evaluations in clinical practice.

Obesity is associated with SHBG levels rather than blood lipid profiles in PCOS patients with insulin resistance

ObjectivePolycystic ovary syndrome (PCOS) is a prevalent endocrine disorder characterized by hormonal imbalances and insulin resistance (IR). Among the metabolic abnormalities associated with PCOS, obesity is often present concurrently. Nevertheless, the correlation between obesity, sex hormone levels, and blood lipid profiles in PCOS patients with IR remains uncertain.MethodsThis is a cross-sectional study including a total of 206 Chinese women diagnosed with PCOS, enrolled between March 2016 and December 2021. The participants’ anthropometric measurements, such as weight, height, waist circumference, and hip circumference, were recorded. Additionally, fasting blood samples were collected to measure various parameters, including fasting glucose, insulin levels, lipid profiles, and sex hormone levels.ResultsOur findings highlight that obesity exhibited a significant correlation with lower levels of sex hormone binding globulin (SHBG) and elevated levels of free androgen index (FAI), fasting insulin, and HOMA-IR in PCOS patients diagnosed with IR. However, no significant association between obesity and blood lipid profiles was observed within this particular group of women.ConclusionThis study suggests that among PCOS patients with IR, lower levels of SHBG and higher levels of FAI are associated with obesity. These findings indicate that SHBG and FAI may have the potential to serve as a biomarker for the initial identification and prognosis of IR in PCOS patients.Trial registrationRetrospectively registered on 25/04/2020 at ClinicalTrials.gov Identifer: NCT04264832.

Combined effects and potential mechanisms of phthalate metabolites on serum sex hormones among reproductive-aged women: An integrated epidemiology and computational toxicology study

The reproductive age is a crucial stage for women to bear offspring. However, reproductive-aged women are simultaneously exposed to various phthalates, which may pose a threat to their reproductive health. This study employed generalized linear regression and weighted quantile sum (WQS) regression to explore the associations between monoesters of phthalates (MPAEs) and sex hormones in 913 reproductive-aged women in the National Health and Nutrition Examination Survey. Key risk factors driving hormone disruption were identified based on the weights of the WQS models. Interaction models were used to unravel the synergistic or antagonistic effects between MPAEs. The potential toxicological targets of MPAEs interfering with sex hormone-binding globulin (SHBG) levels were revealed based on prior knowledge and molecular docking of hepatocyte nuclear factor 4α (HNF4α). Compared with the first quartile, mono-benzyl phthalate (MBZP) in the second quartile exhibited a decrease in total testosterone (TT) and TT/E2 (estradiol) ratio. Mono-2-ethyl-5-carboxypentyl phthalate (MECPP) in the fourth quartile showed a decrease in SHBG and TT/E2. Additionally, mono-(carboxyoctyl) phthalate and mono-(carboxynonyl) phthalate (MCNP) were negatively associated with SHBG. Each unit increase in the WQS index of MPAE mixtures was associated with 6.73 % lower SHBG levels (95 %CI: −12.80 %, −0.24 %) with mono-(3-carboxypropyl) phthalate, MCNP, MBZP, and MECPP identified as major risk factors. Interaction analyses revealed that the effects of high-risk MPAEs on SHBG were predominantly antagonistic. Molecular docking suggested that MPAEs might compete to bind tryptophan residues of HNF4α. This study provides key information to help develop the most effective phthalate interventions and improve the reproductive health of reproductive-aged women.

SHBG and Insulin resistance - Nexus revisited.

Sex hormone binding globulin (SHBG) is a liver-synthesized glycoprotein. Low SHBG levels are associated with insulin resistance (IR). Specific single nucleotide polymorphisms (SNPs) in the SHBG gene are linked to IR. Therefore, it is of interest to provide a review on the comprehensive overview for SHBG related to IR.

Association of Adiposity Phenotypes with 27-Hydroxycholesterol and Sex Hormones: The Multiethnic Cohort Study.

The distribution of body fat has been linked to circulating levels of lipids and sex-steroid hormones. The cholesterol metabolite and endogenous selective estrogen receptor modulator, 27-hydroxychlolesterol (27HC), may be influenced by adiposity phenotypes, particularly among females. No study has examined the relationships of 27HC and steroid hormones with adiposity phenotypes. To investigate the associations of 27HC and steroid hormones with detailed adiposity phenotypes among a multiethnic population of postmenopausal females. A cross-sectional study was conducted among 912 postmenopausal females from the Multiethnic Cohort- Adiposity Phenotype study. Multivariable linear regression examined the associations of circulating levels of 27HC, steroid hormones, and sex hormone-binding globulin (SHBG) with detailed adiposity phenotypes, adjusting for demographics, lifestyle factors, diabetes status, and use of lipid lowering drugs. Subgroup analyses were conducted across race and ethnicity. Total fat mass (P-trend=0.003), subcutaneous adipose tissue (SAT) (P-trend=0.006), and superficial subcutaneous adipose tissue (sSAT) (P-trend=4.41x10-4) were inversely associated with circulating 27HC levels. In contrast, visceral adipose tissue (VAT) (P-trend=0.003) and liver fat (P-trend=0.005) were positively associated with 27HC levels. All adiposity phenotypes were associated with higher levels of free estradiol, testosterone and lower levels of SHBG. Generally, similar patterns of associations were observed across race and ethnicity. Adiposity phenotypes, such as SAT, VAT, and liver fat, were differentially associated with circulating 27HC, while consistent directions of associations were seen for circulating hormones among postmenopausal females. Future studies are warranted to further understand the biology and relationships of 27HC and adiposity-related diseases.

Sex Hormone-Binding Globulin as more than a Biomarker of Metabolic Diseases and Reproductive Disorders: What Physicians Should Know?

Until recent years, Sex Hormone-Binding Globulin (SHBG) has been considered of less a priority in the management of metabolic and chronic inflammatory states. However, emerging research highlights the remarkable role of SHBG in the screening and follow-up of patients not only with metabolic disorders but also in influencing reproductive outcomes. The present review aims to consolidate current knowledge on the involvement of SHBG in various clinical conditions. The search was performed using multiple databases to identify original studies measuring SHBG levels in conditions such as type-2 diabetes, metabolic syndrome (MetS), male obesity secondary hypogonadism, Polycystic Ovarian Syndrome (PCOS), male equivalent of PCOS, Nonalcoholic Fatty Liver Disease (NAFLD), infantile obesity, and early puberty. Among a total of 93,735 studies, 62 met the inclusion criteria, encompassing data from 127,771 subjects comprising both patients and controls. Studies were predominantly cross-sectional and observational cohorts, with MetS and NAFLD being the most extensively investigated conditions. Across all clinical conditions, significantly lower SHBG levels were consistently observed among patients compared to matched controls. The decrease in SHBG was found to be significantly associated with adverse reproductive, metabolic, and cardiovascular outcomes. These findings underscore the importance of considering SHBG as a valuable marker in routine clinical practice. Clinicians are encouraged to recognize the potential of SHBG as a useful marker in the assessment and management of various health conditions within their routine practice.

Gonadal hormones and metabolic syndrome in middle-aged and elderly males: results from a prospective cohort study in China.

Research has shown that gonadal hormones are involved in metabolic pathways relevant to metabolic syndrome (MetS). Nevertheless, no longitudinal study has been conducted on the association between SHBG and MetS in Chinese. The objective of our study was to determine whether there is any association between middle-aged and elderly males in China. A total of 531 eligible male subjects, aged above 40 years or older, without MetS at baseline, were recruited. Sex hormone binding globulin (SHBG), total testosterone (TT), follicle-stimulating hormone (FSH), and luteinizing hormone (LH) were measured. A harmonized definition and recommended thresholds for the Chinese population were used to determine metabolic syndrome. During 3.2 years of follow-up, 20.7% of subjects had developed MetS. Compared with the non-MetS group, subjects in the new-onset MetS group had significantly lower SHBG (43.5 nmol/L [28.8, 74.9] vs 53.7nmol/L [33.8, 115.0], P=0.0018), TT (18.1nmol/L [13.6-21.7] vs 19.5nmol/L[15.0-23.6], P=0.0204), and LH (5.13mIU/L [3.63-7.29] vs 5.87mIU/L [4.05-8.36]) at baseline. The incidence of MetS was decreased according to elevated SHBG quartiles (Q1:26.9%, Q2:22.7%, Q3:21.1%, Q4:12.1%, P for trend =0.0035), TT (Q1: 25.2%, Q2:23.7%, Q3: 17.3%, Q4: 16.7%, P for trend=0.0425), and LH (Q1:25.0%, Q2:21.8%, Q3: 21.8%, Q4: 14.3%, P for trend=0.0411). Compared with those in quartile 4, the OR[CI] of incident MetS for participants in Quartile 1 was 2.33[1.13-4.79] after multiple adjustments. But associations between incident MetS and different quartiles of LH, TT, and FSH were not observed after multiple adjustments. In the subgroup analyses, the significant association between SHBG level and Mets was detected in subjects over 60 years or older, with normal BMI, without insulin resistance, and with eGFR ≥90 mL/min per 1.73m2. Compared with TT, LH, and FSH, a lower level of SHBG is significantly related to the incidence of MetS among middle-aged and elderly males in China.

Metabolic disparities between obese and non-obese patients with polycystic ovary syndrome: implications for endometrial receptivity indicators

Objective To investigate the differences in the metabolic indicators and sex hormones between obese and non-obese patients with polycystic ovary syndrome (PCOS), and their impacts on endometrial receptivity (ER). Methods We selected 255 individuals with PCOS, and categorized them into the obese groups, including the OP group (obese patients with PCOS) and the ON group (obese patients without PCOS), and selected 64 individuals who were categorized in the non-obese groups, namely, the control groups, which comprise the NP group (non-obese patients with PCOS) and the NN group(non-obese patients without PCOS). The one-way analysis of variance (ANOVA) and Mann-Whitney U tests were used to compare the metabolic indicators, and sex hormone-associated and ER-associated indicators between the groups. The correlation between the aforementioned clinical markers and ER was analyzed using the Pearson’s correlation coefficient. Results (1) In comparison with the NP group, the OP group exhibited higher levels (p < .01) of free androgen index (FAI), anti-müllerian hormone (AMH), fasting insulin (FINS), insulin level within 60 min, 120 min, and 180 min—60minINS, 120minINS, and 180minINS, respectively, fasting blood glucose (FBG), blood glucose level within two hours (2hGlu), homeostatic model assessment for insulin resistance (HOMA-IR), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), waist-to-hip ratio (WHR), waist circumference, hip circumference, the ratio of the maximum blood flow velocity of the uterine artery during systole to the blood flow velocity of the uterine artery at the end of diastole (uterine artery S/D), and blood flow resistance index (RI) of the uterine artery. In comparison with the NP group, the OP group exhibited lower levels (p < .01) of sex hormone binding globulin (SHBG), dehydroepiandrosterone (DHEA), high molecular weight adiponectin (HMWA), and high-density lipoprotein cholesterol (HDL-C). (2) In the PCOS group, RI was significantly positively correlated with FAI, FINS, 120minINS, HOMA-IR, and WHR (p < .01), and significantly negatively correlated with SHBG, HDL-C, and HMWA (p < .01); uterine artery S/D was significantly positively correlated with FAI, FINS, 2hGlu, HOMA-IR, LDL-C, and WHR (p < .01), significantly positively correlated with 120minINS and FBG (p < .05), and significantly negatively correlated with SHBG and HMWA (p < .01). Conclusion (1) The OP group exhibited obvious metabolic disorders and poor ER, which was manifested as low levels of SHBG and HMWA, and high levels of FAI, HOMA-IR, WHR, uterine artery S/D, and RI. (2) In patients with PCOS, there was a substantial correlation between ER-associated indicators RI and uterine artery S/D and FAI, FINS, 120minINS, HOMA-IR, WHR, SHBG, and HMWA.

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.

Otklonjena insulinska rezistencija - hormonske korelacije u gestacijskom dijabetesu

Background: To investigate the correlation between the variations of cortisol and insulin-like growth factor 1 (IGF1) and sex hormone binding globulin (SHBG) levels with insulin resistance and glucolipid metabolism in gestational glucose diabetics. Methods: The study included 110 pregnant women diagnosed with gestational diabetes mellitus in the GDM group, and 130 healthy pregnant women in the control group. Data collection, examination of relevant indexes, and comparison of differences in indexes between groups were conducted. Pearson correlation analysis was utilized to identify risk variables associated with GDM development, while binary logistic regression was employed to determine risk factors for GDM development. Results: The GDM group showed significantly greater levels of FPG, HbA1c, FINS, TG, FFA, Lp-PLA2, HOMA-IR, Cortisol, and IGF-1 compared to the control group (P&lt;0.05), but considerably lower levels of SHBG, and HOMA-b. HOMA-IR was found to be positively correlated with FPG, HbA1c, FINS, TG, FFA, Lp-PLA2, Cortisol and IGF-1, whereas, negatively correlated with SHBG. FINS and SHBG were found to be independent protective factors for GDM (OR=0.463, 0.801, P&lt;0.05), whereas, HbA1c, TG, FFA, and gestational BMI were found to be independent risk factors for GDM (OR=1.992, 4.234, 1.990, 1.629, P&lt;0.05). Conclusions: SHBG, IGF-1, and Cortisol are all linked to glucose-lipid metabolism indices, and aberrant serum hormone expression is a major contributor to insulin resistance.

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.

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.

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.

Associations of low sex hormone-binding globulin and androgen excess in early pregnancy with fasting and post-prandial hyperglycaemia, gestational diabetes, and its severity.

We studied whether androgen excess and low sex hormone-binding globulin (SHBG) measured in early pregnancy are independently associated with fasting and post-prandial hyperglycaemia, gestational diabetes (GDM), and its severity. This nationwide case-control study included 1045 women with GDM and 963 non-diabetic pregnant controls. We measured testosterone (T) and SHBG from biobanked serum samples (mean 10.7 gestational weeks) and calculated the free androgen index (FAI). We first studied their associations with GDM and secondly with the type of hyperglycaemia (fasting, 1 and 2h glucose concentrations during the oral glucose tolerance test), early-onset GDM (<20 gestational weeks) and the need for anti-diabetic medication. After adjustments for gestational weeks at sampling, pre-pregnancy BMI, and age, women with GDM had 3.7% (95% CI 0.1%-7.3%) lower SHBG levels, 3.1% (95% CI 0.1%-6.2%) higher T levels, and 4.6% (95% CI 1.9%-7.3%) higher FAI levels than controls. SHBG was inversely associated with fasting glucose, whereas higher FAI and T were associated with higher post-prandial glucose concentrations. Women with early-onset GDM had 6.7% (95% CI 0.7%-12.7%) lower SHBG levels and women who needed insulin for fasting hyperglycaemia 8.7% (95% CI 1.8%-14.8%) lower SHBG levels than other women with GDM. Lower SHBG levels were associated especially with early-onset GDM, higher fasting glucose and insulin treatment, whereas androgen excess was associated with higher post-prandial glucose values. Thus, a low SHBG level may reflect the degree of existing insulin resistance, while androgen excess might impair post-prandial insulin secretion.

Evaluation of Glucose Metabolism and Cardiovascular Risk Factors in Prepubertal Girls with Premature Pubarche

Premature pubarche (PP) is a risk factor for metabolic syndrome (MS). The aim was to evaluate if glucose-insulin metabolism, cardiovascular risk factors, familial cardiovascular risk factors (FCVRF) created a risk for insulin resistance (IR) and if PP was a risk factor alone for MS in normal weight prepubertal girls with PP. Thirty-five prepubertal, non-obese girls with PP with normal birth weight and 35 age-matched control girls were evaluated for FCVRF, anthropometric measurements, blood pressure, lipid profile, fasting blood glucose-insulin, hemoglobin A1c (HbA1c), sex hormone binding globulin (SHBG), leptin, adiponectin, tumor necrosis factor-alpha (TNF-α), androgen levels, and bone age. Oral glucose tolerance test was performed in PP participants. Homeostasis model of assessment of IR (HOMA-IR), fasting glucose/insulin ratio, atherogenic index (AI), and free androgen index (FAI) were calculated. PP participants were further stratified by FCVRF. HbA1c, lipid profile, testosterone, leptin, adiponectin, TNF-α, HOMA-IR, glucose/insulin ratio, AI, and fasting glucose-insulin levels were similar. In the PP group FAI was significantly higher (p=0.001), whereas SHBG was significantly lower (p=0.010) than the control group. Leptin levels of FCVRF+ and FCVRF- subgroups were 15.2±9.1 and 9.7±7.2 ng/mL, respectively and the difference was significant (p=0.016). As PP does not appear to be a risk factor alone for impaired glucose metabolism and IR in prepubertal non-obese girls with normal birth weight, it is our opinion that it is unnecessary to examine in detail such cases before puberty. Low SHBG levels in the PP group and high leptin levels in FCVRF+ subgroup might suggest that these may be predictive for MS in the future.

Association of Exposure to Phthalate Metabolites With Sex Hormones, Obesity, and Metabolic Syndrome in US Women

Obesity and metabolic syndrome are highly prevalent among the US population and are associated with the dysregulation of sex hormones. An increase in obesity and metabolic syndrome may also be associated with exposure to phthalates. The association of exposure to phthalate metabolites with sex hormones and metabolic health has been understudied in the female population. To evaluate the association between exposure to common phthalate metabolites with total testosterone (TT) levels, sex hormone-binding globulin (SHBG) levels, obesity, and metabolic syndrome among women. This cross-sectional study used data collected from the National Health and Nutrition Examination Survey during 2013 to 2016. Female participants aged 15 years or older with urinary profiles containing common phthalate metabolites were included in this study. Statistical analyses were performed from March 15, 2021, to April 30, 2022. Urinary concentrations of phthalate metabolites were classified into tertiles, and the lowest tertile was used as a reference category. The concentrations of phthalate metabolites and their composite scores based on clustering were also used in the analysis. Serum concentrations of TT and SHBG were dichotomized into high TT levels (>46 ng/dL [to convert to nanomoles per liter, multiply by 0.0347] for age <50 years and >32 ng/dL for age ≥50 years) and low SHBG levels (<2.85 μg/mL [to convert to nanomoles per liter, multiply by 10.53]) as established for the female population. Obesity was defined as a body mass index of 30 or more (calculated as weight in kilograms divided by height in meters squared), and metabolic syndrome was defined using the National Cholesterol Education Program criteria. The serum concentrations of TT and SHBG were also included in the validation analyses. Modified Poisson models were used to estimate the adjusted relative risk (RR) with 95% CIs for the associations. Among the 2004 women included in this study, the mean (SD) age was 46.6 (18.5) years (14.7% Hispanic participants, 62.7% non-Hispanic White participants, and 13.2% non-Hispanic Black participants; 17.4% of participants were born outside the US [weighted percentages]; 230 (11.8%) had high TT levels, 210 (10.4%) had low SHBG levels, 825 (39.8%) had obesity, and 965 (45.5%) had metabolic syndrome (weighted percentages). Of the 13 phthalate metabolites, 8 had the highest tertile level greater than 6.2 ng/mL (range, 0.5-75.2 ng/mL). High levels of exposure to mono(2-ethyl-5-carboxypentyl) phthalate (RR, 1.84 [95% CI, 1.33-2.54]), mono(2-ethyl-5-oxohexyl) phthalate (RR, 1.77 [95% CI, 1.21-2.59]), mono(2-ethyl-5-hydroxyhexyl) phthalate (RR, 1.94 [95% CI, 1.34-2.81]), and monobenzyl phthalate (RR, 1.75 [95% CI, 1.21-2.54]) were associated with low SHBG levels but not with high TT levels. High levels of exposure to some of these metabolites were also associated with obesity and metabolic syndrome. Most associations were specific to premenopausal or postmenopausal women. In this cross-sectional study, exposure to certain phthalate metabolites could be associated with low SHBG levels, obesity, and metabolic syndrome depending on menopausal status.

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.

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.