Sex Hormone-binding Globulin Levels Research Articles

Associations between urinary concentrations of bisphenols and serum concentrations of sex hormones among US. Males

BackgroundBisphenol A (BPA) exposure and its structural analogs (BPS and BPF) might cause endocrine alterations and adverse physiological effects. Few studies to date have directly explored the association between its structural analogs (BPS, BPF) and sex hormones in adult male participants. Therefore, we aimed to assess the associations between BPA, BPS, BPF, and sex hormones in American adult men.MethodsWe used data from the U.S. National Health and Nutrition Examination Survey 2011–2016. We excluded participants without data available on sex hormones and urinary bisphenols. Furthermore, participants consuming sex hormone medications were excluded. Multivariable regression models were performed to assess the association between bisphenols and sex hormones.ResultsIn this study, 2367 participants were included. Of 2367, in 1575 participants, the data on BPS and BPF were available. We found that a per unit increase in BPF was associated with 0.575 ng/dL higher total testosterone (TT) (Model 2: 95% CI: 0.047, 1.103, P = 0.033). However, there was no significant association between BPA or BPS and TT. Furthermore, increased BPA and BPS levels were associated with higher levels of sex hormone-binding globulin (SHBG) (Model 2: β = 0.364, 95% CI: 0.158, 0.571; β = 0.25, 95% CI: 0.071, 0.429, respectively). Additionally, participants in the highest BPA exposure quartile (quartile 4) had 4.072 nmol/L higher levels of SHBG than those in quartile 1 (Model 2: 95% CI: 0.746, 7.397, P = 0.017; P for trend =0.005). Both BPA and BPS were negatively associated with free testosterone (FT, nmol/L) after full adjustment (Model 2, β = − 0.01%, P = 0.0211, P = 0.0211; Model 2, β = − 0.01%, P = 0.0258, respectively). However, BPF was positively associated with FT (Model 2, β = 0.0029%, P = 0.0028).ConclusionOur study indicated that exposure to both BPA and its substitutions could alter sex hormone levels. This finding supports the possibility that human exposure to bisphenols at environmental levels might affect the endogenous hormone balance.

High-throughput genetic clustering of type 2 diabetes loci reveals heterogeneous mechanistic pathways of metabolic disease.

Type 2 diabetes is highly polygenic and influenced by multiple biological pathways. Rapid expansion in the number of type 2 diabetes loci can be leveraged to identify such pathways. We developed a high-throughput pipeline to enable clustering of type 2 diabetes loci based on variant-trait associations. Our pipeline extracted summary statistics from genome-wide association studies (GWAS) for type 2 diabetes and related traits to generate a matrix of 323 variants × 64 trait associations and applied Bayesian non-negative matrix factorisation (bNMF) to identify genetic components of type 2 diabetes. Epigenomic enrichment analysis was performed in 28 cell types and single pancreatic cells. We generated cluster-specific polygenic scores and performed regression analysis in an independent cohort (N=25,419) to assess for clinical relevance. We identified ten clusters of genetic loci, recapturing the five from our prior analysis as well as novel clusters related to beta cell dysfunction, pronounced insulin secretion, and levels of alkaline phosphatase, lipoprotein A and sex hormone-binding globulin. Four clusters related to mechanisms of insulin deficiency, five to insulin resistance and one had an unclear mechanism. The clusters displayed tissue-specific epigenomic enrichment, notably with the two beta cell clusters differentially enriched in functional and stressed pancreatic beta cell states. Additionally, cluster-specific polygenic scores were differentially associated with patient clinical characteristics and outcomes. The pipeline was applied to coronary artery disease and chronic kidney disease, identifying multiple overlapping clusters with type 2 diabetes. Our approach stratifies type 2 diabetes loci into physiologically interpretable genetic clusters associated with distinct tissues and clinical outcomes. The pipeline allows for efficient updating as additional GWAS become available and can be readily applied to other conditions, facilitating clinical translation of GWAS findings. Software to perform this clustering pipeline is freely available.

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.

Study of Acute Coronary Syndrome in Premenopausal Women in Correlation with Sex Hormones

Objectives: Higher testosterone and lower Estrogen levels are associated with cardiovascular disease in women. However, studies on endogenous sex hormones and acute coronary syndrome (ACS) in pre-menopausal women are sparse. Material and Methods: We studied 50 pre-menopausal women presenting with ACS and age-matched controls who consented to the study with Testosterone, Estradiol, and Sex hormone-binding globulin (SHBG) levels at baseline. They were clinically followed up for 6 months duration. Results: The mean age was 37.42 ± 5.7 years. 48% patients were obese. The mean body mass index was 27.53 ± 5.41 kg/m2. Hypertension followed by Diabetes was the most common risk factor. 14% had family history of coronary artery disease (CAD). 24% had atypical chest pain at presentation. Anterior wall ST elevation myocardial infarction was the most common presentation. Single-vessel disease was seen in 38%; 24% had Non-Obstructive CAD. Ratios of Bioavailable Testosterone: Estradiol, Estradiol: Low-density Lipoprotein (LDL), Estradiol: High-density Lipoprotein, SHBG: LDL, and SHBG: HbA1c were analyzed in cases and controls and were not found to be significantly associated. Conclusion: Endogenous sex hormones were not found to be significantly associated with ACS in premenopausal women.

Very low-calorie ketogenic diet rapidly augments testosterone levels in non-diabetic obese subjects.

The very low-calorie ketogenic diet (VLCKD) represents an opportunity to attain clinically relevant weight loss in obese patients. Functional hypogonadism represents a frequent hormonal disorder associated with obesity and visceral fat accumulation characterised by low testosterone levels and subnormal luteinising hormone (LH) levels. To evaluate the early effects of VLCKD on serum total testosterone (TT) levels in non-diabetic obese patients. Twenty-two obese male patients (mean age 39.3±11.7 years, mean body mass index (BMI) 38.2±6.4kg/m2 ) were enrolled and treated for 28 days with VLCKD. Anthropometric and hormonal variables were assessed before, during and after diet intervention. After 7 and 28 days on a VLCKD, a significant and persistent reduction in body weight, BMI, fat mass, blood glucose, insulin and homeostasis model assessment index was observed compared with baseline. TT significantly increased after 7 days (+35±64ng/dl) and 28 days (+74±97ng/dl) on a VLCKD. In addition to TT, a significant increase in serum sex hormone-binding globulin levels was observed after 7 (+2.1±4.1) and 28 days (+7.7±10.0). However, both calculated free testosterone and LH did not change after 7 or 28 days of VLCKD. Following cessation of VLCKD, hypogonadal subjects achieved a higher percentage of total weight loss (8.5%±1.5%), a greater reduction in weight (-9.94±1.66kg), fat mass (-7±2.1kg) and waist circumference (-6.31±2.65cm) and a greater improvement in glycaemia (-8.75±10.92mg/dl) as compared with eugonadal subjects. Furthermore, hypogonadal subjects exhibited a trend of higher TT increase (+98.12±71.51ng/dl) as compared with eugonadal subjects. VLCKD results in rapid improvements in TT levels associated with weight loss in male obese non-diabetic subjects, particularly in the presence of obesity-related hypogonadism.

Associations between bone mass, hormone levels, and body composition in postmenopausal women.

The aim of this study was to explore body composition parameters and hormone levels as risk factors for low bone mass (osteopenia/osteoporosis) in postmenopausal women. We analyzed biorepository samples from 139 postmenopausal women with no clinical evidence of cardiovascular disease. Inclusion criteria were menopause occurring after 40 years of age and no use of hormone therapy in the past 3 months. Bone mineral density and body composition were assessed by dual-energy x-ray absorptiometry. Sex hormone-binding globulin (SHBG) and follicle-stimulating hormone (FSH) levels were measured in all participants. Serum estradiol was measured by gas chromatography/tandem mass spectrometry in a subset of 57 participants. Free estrogen index was calculated by dividing estradiol by SHBG × 100. Body mass index (25.0 [22.5-26.5] vs 27.7 [26.6-31.9] kg/m 2 , P < 0.001), estradiol (3.0 [2.7-4.5] vs 6.0 [2.7-15.0] pg/mL, P = 0.006), waist circumference (84 ± 9 vs 93 ± 12 cm, P < 0.001), appendicular lean mass (ALM) (15.739 ± 2.129 vs 17.184 ± 2.104 kg, P = 0.001), and fat mass index (9.36 [7.29-11.43] vs 11.38 [9.95-15.33] kg/m 2 , P < 0.001) were lower in women with low bone mass by dual-energy x-ray absorptiometry. Univariate analysis showed that free estrogen index, time since menopause, SHBG, and fat mass were significant predictors of low bone mass, and ALM was a significant predictor against low bone mass. Appendicular lean mass persisted as an independent predictor against low bone mass in multivariate models with fat mass and SHBG. In turn, fat mass was no longer significant in this multivariate model after inclusion of SHBG. No association of FSH with low bone mass was observed. Appendicular lean mass was a significant independent predictor against low bone mass in postmenopausal women. Further prospective studies are needed to investigate whether lean mass, fat mass, and FSH have a direct effect on bone mass in postmenopausal women, adding to the consequences of hypoestrogenism in this group.

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.

Asprosin levels in women with and without the polycystic ovary syndrome: a systematic review and meta-analysis

Objective: This systematic review and meta-analysis aimed at summarizing the evidence concerning circulating asprosin, and related endocrine and metabolites in women with and without the polycystic ovary syndrome (PCOS).Method: We performed a comprehensive literature search in Pubmed, Web of Science, Scielo, and Chinese National Knowledge Infrastructure for studies published until May 20, 2022, that evaluated circulating asprosin levels in women with and without PCOS, regardless of language. The quality of studies was assessed with the Newcastle-Ottawa Scale. Random-effects models were used to estimate mean differences (MD) or standardized MD (SMD) and their 95% confidence interval (CI).Results: We evaluated eight studies reporting 1,050 PCOS cases and 796 controls of reproductive age. Participants with PCOS were younger (MD = −2.40 years, 95% CI −2.46 to −2.33), with higher values of asprosin (SMD = 2.57, 95% CI 1.64–3.50), insulin (SMD = 2.73, 95% CI 1.18–4.28), homeostatic model assessment of insulin resistance (SMD = 2.70, 95% CI 0.85–4.55), luteinizing hormone (SMD = 2.33, 95% CI 0.60–4.06), total testosterone (SMD = 4.06, 95% CI 1.89–6.22), dehydroepiandrosterone sulfate (SMD = 2.38, 95% CI 0.37–4.40), and triglycerides (SMD = 1.20, 95% CI 0.13 to 2.27). Moreover, PCOS women had lower circulating levels of sex hormone-binding globulin (SMD = −3.36, 95% CI −4.92 to −1.80), and high-density lipoprotein-cholesterol (SMD = −0.85, 95% CI −1.69 to −0.01); with no significant differences observed for glucose, total cholesterol, and low-density lipoprotein-cholesterol levels.Conclusion: Circulating asprosin levels were significantly higher in women with PCOS as compared to those without the syndrome.

Relationship between serum testosterone and sex hormone- binding globulin levels and some metabolic changes in Iraqi men with type 2 diabetes mellitus

The present study aimed to assess the interrelationship between serum total testosterone (S.Tes) as well as sex hormone binding globulin (SHBG) and the main components of metabolic syndrome (MetS) in type 2 diabetic men. One hundred and sixty patients having T2DM were enrolled in this study. The following characteristics were reported: age, gender, duration of T2DM , Body mass index (BMI) and arterial blood pressure.. Serum hormonal profile analyses (S.Tes, SHBG and prolactin). Serum lipid analyses (T.ch TG, HDL-C, and LDL-C). The mean age of study subjects was 49.8 5.7 years and the mean duration of disease was 5.45.2 years. Body mass index (BMI) of study group was found to be within the range of either overweight or obese class . The means of HbA1c ratio and FSG levels were 9.4 %  2.1 and 200.9  75.2 mg/dl respectively which indicated that our patients were in a bad glycemic control. All components of S. lipid profile were within normal range . Serum Testosterone and SHBG levels were within normal range but in the low values( 4.49±2.11 ,28.88±18.12 ng/ml respectively) while serum prolactin level was within normal range but in the high values (11.22±9.42 ng/ml). When study analytes were compared according to the presence of one or more metabolic syndrome characteristic then there was a significant decrease in mean value of testosterone level between obese and non obese diabetics ( 3.89±1.87 vs. 4.79±2.17 ng/ ml, P &lt; 0.001) . If hypertension was present in addition to obesity and diabetes then SHBG level was also significantly decreased in comparison with diabetics who were hypertensive but not obese (25.16±13.42 vs. 33.58±13.73 ng/ ml respectively , P &lt;0.05 ). If hypertension and obesity were present as well as lower HDL-C then significant decreases in both S. SHBG and S. Tes were detected ( (30.63±14.93 vs. 40.7± 6.33 ng/ ml and 3.73±1.9 vs. 5.57±1.53 ng/ ml respectively , P&lt;0.01). In conclusion; our T2DM patients have a bad glycemic state and are characterized by a significantly lower S. Tes mean level if they were obese. Still, the accumulation of other main characteristics of MetS which included hypertension and lower S. HDL- C results in a significantly lower mean levels of both S. Tes and S. SHBG. Obesity, among the other core characteristics of MetS, seems to have the main suppressor effect on serum testosterone and SHBG in T2DM.

Sleep and Anabolic/Catabolic Hormonal Profile in Sedentary Middle-Aged Adults: The FIT-AGEING Study

Sleep quality plays an important role in the modulation of several aging markers. This influence could be explained by aging-induced hormonal changes. Indeed, poor sleep quality has been associated with the development of several endocrine-related health complications. This study examined the relationship of both subjective and objective sleep quantity and quality, with basal levels of selected plasma anabolic and catabolic hormones in sedentary middle-aged adults. A total of 74 volunteers (52.7% women; aged 53.7 ± 5.1) were recruited for this study. Subjective sleep quality was assessed by the Pittsburgh Sleep Quality Index (PSQI; higher scores indicate worse sleep quality), and objective sleep quality parameters (total sleep time [TST], wake after sleep onset [WASO], and sleep efficiency [SE]) were measured using a wrist-worn accelerometer. Basal levels of plasma dehydroepiandrosterone sulphate (DHEAS), total testosterone, sex hormone binding globulin (SHBG), somatotropin, and cortisol levels, were determined. Free testosterone was calculated from the total testosterone and SHBG levels. No associations of global PSQI score, TST, WASO, and SE with DHEAS, free testosterone, and somatotropin plasma levels were found, neither in men nor in women (all p ≥ 0.05). Global PSQI score was inversely related to cortisol plasma levels in women (p = 0.043). WASO was positively associated with cortisol plasma levels, while SE was negatively associated with cortisol plasma levels in women (all p ≤ 0.027). Sleep quality is not related to levels of plasma anabolic hormones, but to levels of catabolic hormones, in sedentary middle-aged adults. Therefore, these results suggest that potential changes in aging biomarkers associated with sleep disturbances, could be mediated by age-related changes in the catabolic endocrine system.

Association between aldehyde exposure and sex steroid hormones among adults.

Exogenous and endogenous exposure to aldehydes is seen worldwide. Aldehydes are closely associated with human diseases, especially reproductive toxicity. However, the effect of aldehyde exposure on sex steroid hormones among adults remains uninvestigated. A total of 851 participants aged over 18years were included in this cross-sectional analysis based on data from National Health and Nutrition Examination Survey (NHANES) 2013-2014. Serum aldehyde concentrations were quantified following an automated analytical method. Sex steroid hormones including total testosterone, estradiol, and sex hormone binding globulin (SHBG) were detected. Multivariate linear regression models, forest plots, generalized additive model (GAM), and smooth curve fitting analysis were used to assess the associations between quartiles of aldehydes and sex steroid hormones levels after adjusting for potential confounders. Butyraldehyde and propanaldehyde were found to be negatively associated with estradiol and SHBG in females and males, respectively. β values with 95% confidence intervals (95% CIs) were - 20.59 (- 38.30 to - 2.88) for Q2 vs. Q1 of butyraldehyde and - 8.13 (- 14.92 to - 1.33) and - 7.79 (- 14.91 to - 0.67) for Q2 vs. Q1 and Q4 vs. Q1 of propanaldehyde. No significant associations were observed between other aldehydes and sex hormones. In premenopausal women, isopentanaldehyde was inversely associated with serum total testosterone levels (Q4 vs. Q1: OR = - 7.95, 95% CI: - 15.62 to - 0.27), whereas propanaldehyde was positively associated with serum estradiol concentration (Q3 vs. Q1: β = 28.88, 95% CI: 0.83 to 56.94). Compared with Q1, Q3 of isopentanaldehyde was associated with 3.53pg/mL higher concentration of estradiol in postmenopausal women (β = 3.53, 95% CI: 0.08 to 6.97). Moreover, in males under 40years, butyraldehyde and heptanaldehyde were inversely proportional to total testosterone levels and heptanaldehyde and butyraldehyde were negatively associated with estradiol and SHBG. Decreased total testosterone, elevated estradiol, and decreased SHBG levels were found in higher quartiles of benzaldehyde, hexanaldehyde and isopentanaldehyde, and propanaldehyde, respectively, in males aged over 60years. In male participants aged 40-60years, only hexanaldehyde was observed to be correlated with higher serum estradiol levels. In conclusion, our current research presented the association between six serum aldehydes and sex hormones. Of note, stratification analyses were conducted in participants with different menopausal statuses and age among males and females. Sex- and age-specific effect of aldehyde exposure on alterations in sex hormone levels were observed. Further studies are warranted to confirm the causal relationship and explore the underlying mechanisms.

Exposure to heavy metals and hormone levels in midlife women: The Study of Women's Health Across the Nation (SWAN)

Exposure to heavy metals may alter the circulating levels of sex hormones. However, epidemiologic studies on heavy metals and sex hormones have been limited, and results have been inconsistent. We assessed the associations of heavy metals assayed in urine, including arsenic, cadmium, lead, and mercury, with repeated measures of serum estradiol (E2), follicle-stimulating hormone (FSH), testosterone, and sex hormone-binding globulin (SHBG) levels in the Study of Women's Health Across the Nation Multi-Pollutant Study. The sample included 1355 White, Black, Chinese, and Japanese women, aged 45–56 years at baseline (1999–2000), whose serum hormone levels were repeatedly measured through 2017. Urinary metal concentrations were measured at baseline. Linear mixed effect models were used to calculate percent changes in serum hormone levels per doubling of urinary metal concentrations, adjusting for demographics, socioeconomic status, lifestyle, health-related factors, and urinary creatinine. After multivariable adjustment, a doubling of urinary metal concentration was associated with lower E2 levels by 2.2% (95% CI: 4.0%, −0.3%) for mercury and 3.6% (95% CI: 5.7%, −1.6%) for lead; higher FSH levels by 3.4% (95% CI: 0.9%, 5.9%) for lead; and higher SHBG levels by 3.6% (95% CI: 1.3%, 5.9%) for cadmium. The overall joint effect using the Bayesian kernel machine regression showed that metal mixtures were inversely associated with E2 and positively associated with FSH levels. No association was found between metals and testosterone levels. Results from this prospective cohort study demonstrate that environmental heavy metal exposures, including cadmium, mercury, and lead, may disturb circulating levels of E2, FSH, and SHBG in midlife women.

Association of sex steroid hormones and new bone formation rate after iliac onlay grafting: a prospective clinical pilot study

PurposeThe present prospective study evaluates the association between new bone formation rate in the iliac onlay graft and sex steroid hormone serum levels.MethodsA total of 15 partially or completely edentulous postmenopausal females and 9 males with less than 5 mm height of the remaining alveolar bone underwent iliac onlay grafting followed by dental implant placement using a two-stage approach. Sex hormone binding globulin and 17β-estradiol serum levels were investigated by electrochemiluminescence immunoassay, while total testosterone level was analyzed using radioimmunoassay. At the time of implant placement, 12 weeks after grafting, bone biopsies were obtained and analyzed histomorphometrically. Statistical analysis was performed using linear mixed models.ResultsGrafting procedure was successfully performed in all patients. The mean new bone formation rate was 32.5% (116 samples). In men the mean new bone formation rate (38.1%) was significantly higher (p < 0.01) than in women (27.6%). Independent of gender 17β-estradiol and testosterone were positively associated to overall new bone formation rate, albeit a significant influence was only seen for 17β-estradiol in men (p = 0.020). Sex hormone binding globulin had no influence on new bone formation rate (p = 0.897). There was no significant association between new bone formation rate and age (p = 0.353) or new bone formation rate and body mass index (p = 0.248).ConclusionPositive association of 17ß-estradiol as well as testosterone with new bone formation rate after iliac onlay grafting indicates a role of sex steroid hormones in alveolar bone regeneration, although the observed influence was only significant for 17ß-estradiol in men.Graphical

RF10 | PMON242 Free Testosterone is an Independent Predictor of Metabolic Syndrome Severity in U.S. Adolescent Girls Ages 12-19, National Health and Nutrition Examination Survey (NHANES) 2013-2016

Abstract Background Metabolic syndrome (MetS) affects ∼10% of U.S. adolescents, especially those with obesity. Adolescent obesity is associated with adolescent hyperandrogenemia (HA), while adult HA is associated with increased risk of MetS in both asymptomatic women and women with polycystic ovary syndrome (Torchen et al, Obesity [Silver Spring] 2020). Yet, the relationship between HA and severity of MetS during adolescence remains unclear. We investigated whether free testosterone (T) concentrations independently predict MetS severity in adolescent girls. Methods We performed a weighted analysis using data from the National Health and Nutrition Examination Survey (NHANES) for 2013–2016, utilizing a cross-sectional study design. In particular, we analyzed data from a nationally-representative sample of 230 girls aged 12-19 years. We performed regression analysis to evaluate whether free T (independent variable) predicted MetS Severity Z-score (outcome). In a multiple regression model, we adjusted for total percent body fat, age (months), and menarche status (premenarcheal vs. postmenarcheal). Free T was calculated (Vermuelen equation) from total T and sex hormone binding globulin (SHBG). MetS severity was determined by a calculator validated for children (Gurka et al, Metabolic Syndrome Severity Calculator, doi: 10.5281/zeondo.2542213; Gurka et al, Cardiovascular Diabetology 2012) using reported fasting labs and anthropometric parameters. As secondary analyses, we (1) repeated the above analysis substituting SHBG for free T in the primary cohort, and (2) repeated the above analysis substituting total T for tree T in an expanded cohort (n=251). Results In the primary cohort, MetS z-score was -0.27 (-0.41 to -0.13) [mean (95% CI)]; free T 4.0 pg/ml (3.7–4.3); total T 28.7 ng/dL (27.1–30.3); SHBG 60.8 nmol/L (54.0–67.6); total percent body fat 34.5% (33.3–35.6). In simple regression analyses, free T (R=0.11) and percent body fat (R=0.57) each predicted MetS z-score (p&amp;lt;0.001 for each), but age (p=0.68) and menarche status (p=0.18) did not. Our adjusted regression model accounted for 60% of the variance in MetS z-score (R2=0.60). Higher free T and percent body fat were independently associated with higher MetS z-score, while younger age was independently associated with higher MetS z-score (p&amp;lt;0.001 for each). When substituting SHBG and total T for free T, model R2 values were 0.61 and 0.59, respectively, with only percent body fat and age being significant independent predictors of MetS z-score in each model (SHBG, p=0.06; total T, p=0.90). Conclusion We conclude that free T is an independent predictor of MetS severity in a nationally-representative sample of adolescent girls aged 12 to 19 years. Total T was not an independent predictor of MetS severity, suggesting that the relationship between free T and MetS z-score may partly reflect obesity-associated reductions in SHBG levels. These data suggest that HA may contribute to MetS severity in adolescent girls. Presentation: Saturday, June 11, 2022 1:06 p.m. - 1:11 p.m., Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

RF03 | PMON300 Sex Hormones, Sex Hormone Binding Globulin, and Gonadotropins in Men with Inguinal Hernias

Abstract Background More than 1 in 4 men will undergo inguinal hernia repair during their lifetime. Age is a significant risk factor for inguinal hernias in men with increased incidence in older age. Sex steroid hormone changes are observed with a higher ratio of serum estradiol (E2) to testosterone (T) as men age. We previously demonstrated that a shift from androgen to estrogen action caused inguinal hernia formation in a transgenic male mouse model with increased estrogen action in lower abdominal muscle tissues. However, age-related changes in serum E2 levels in men are conflicting, as some studies have reported increases but others have noted unchanged or even decreased E2 levels with advancing age. Method: This study was performed on 212 men with inguinal hernias, aged 20 to 90 years, stratified at 10-year intervals of age (20-30, 31-40, 41-50, 51-60, 61-70, 71-80, 81-90 years). We assessed total T (TT), total E2 (TE2), dehydroepiandrosterone (DHEA), sex hormone-binding globulin (SHBG), and gonadotropins (FSH and LH). Body mass index (BMI) was calculated using height and weight. Results The BMI distribution was balanced for men with inguinal hernias among all age groups. TE2 was low in 23.7%, normal in 65.8%, and high in 10.5% of men 50 years or younger. In contrast, the percentage of patients with high TE2 was increased 2.6-fold in men over the age of 50 (20.1% in low, 52.3% in normal, and 27.6% in high). TT was normal in all men 50 years and younger but was low in 3.5% and normal in 96.5% of men over the age of 50. We found that serum TE2 levels and the ratio of TE2/TT positively correlated with age (p=0.001). In addition, serum TE2 levels were significantly higher in the advanced age groups (71-80 and 81-90 years) than in the young age group (20-40 years). Serum TT levels decreased but did not reach significance in the advanced age groups compared to the young age group. Remarkably the ratio of E2/T was higher in the advanced age groups than in the young age group (20-30 years). Serum DHEA levels in men over the age of 50 were significantly higher than in men 50 years or younger. SHBG levels were higher in men over 70 years than men 50 years or younger (p&amp;lt; 0.01). Serum levels of FSH and LH in men over 60 years were 3-fold greater than in men 50 or younger (p&amp;lt;0.01). Conclusions Our findings suggest a correlation of increased estrogen action in the formation of inguinal hernias at an advanced age. This points to a potential utilization of inhibitors of estrogen synthetase or estrogen antagonists in a subset of elderly inguinal hernia patients with increased circulating estrogen as a non-surgical intervention. Presentation: Saturday, June 11, 2022 1:42 p.m. - 1:47 p.m., Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

Maternal age at menarche and reproductive health in young adult men: a cohort study.

Is maternal age at menarche associated with reproductive health in sons measured by semen quality, testes volume and reproductive hormone levels? Later maternal age at menarche was associated with impaired semen characteristics, lower testes volume and altered levels of reproductive hormones, while earlier maternal age at menarche was not strongly associated with reproductive outcomes in sons. Both earlier and later maternal age at menarche may be associated with altered male reproductive health outcomes. This is the first study to investigate the potential association between maternal age at menarche and semen quality, testes volume and reproductive hormone levels in sons. In this population-based cohort study, we used data from the Fetal Programming of Semen Quality Cohort nested within the Danish National Birth Cohort. In total, 5697 sons born in 1998-2000 were invited to participate in the cohort in 2017-2019. In total, 1043 (18% of the invited) young men with information on maternal age at menarche provided a semen and blood sample, measured their testes volume, and filled in a questionnaire on health behavior and pubertal development. Maternal age at menarche was reported by the mothers during pregnancy and examined categorically (as earlier, at the same time or later than their peers), continuously and modeled as splines. We estimated relative percentage differences in the reproductive outcomes using negative binomial regression models. Further, we did a mediation analysis to investigate the potential mediating role of timing of the sons' pubertal development. Sons whose mothers had age at menarche later than peers had 15% lower (95% CI: -27%; 0%) sperm concentration, 14% lower (95% CI: -28%; 1%) total sperm count, 7% higher (95% CI: 0%; 14%) proportion of nonprogressive or immotile spermatozoa, 6% lower (95% CI: -11%; 0%) testes volume, 6% lower (95% CI: -12%; 1%) luteinizing hormone, 6% lower (95% CI: -12%; 1%) sex hormone-binding globulin and 5% lower (95% CI: -9%; 0%) testosterone levels compared with sons whose mothers had age at menarche at the same time as peers. Our study did not suggest that earlier maternal age at menarche was strongly associated with semen quality, testes volume or reproductive hormones in sons. However, the spline analyses indicated a potential inverted U-shaped association for sperm concentration and testes volume, and levels of sex hormone-binding globulin and testosterone. We found no strong evidence of mediation by timing of the sons' own pubertal development. There was a rather low participation rate in the Fetal Programming of Semen Quality Cohort and we tried to counter it by applying selection weights. Maternal age at menarche was recalled during pregnancy, which may introduce misclassification, most likely nondifferential. Inaccuracy of the sons' recalled pubertal development years after the event may result in underestimation of the possible mediating role of pubertal timing. Our findings may represent a degree of shared heritability of reproductive health or be a result of an underlying epigenetic profile or unknown shared environmental, cultural or dietary exposure, causing both altered age at menarche and impaired reproductive health outcomes in sons. However, the exact mechanism for the investigated association remains unknown. This article is part of the ReproUnion collaborative study, cofinanced by the European Union, Intereg V ÖKS (20200407). The FEPOS project was further 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), A.P. Møller Foundation (16-37), the Health Foundation and Dagmar Marshall's Fond. Additionally, this study received funding from Aarhus University. There are no competing interests. N/A.

Reference intervals for free testosterone in adult men measured using a standardized equilibrium dialysis procedure.

Free testosterone (FT) determination may be helpful in evaluating men suspected of testosterone deficiency especially in conditions with altered binding-protein concentrations. However, methods for measuring FT by equilibrium dialysis and reference intervals vary among laboratories. To determine reference intervals for FT in healthy, nonobese men by age groups as well as in healthy young men, 19-39 years, using a standardized equilibrium dialysis procedure METHODS: We measured FT in 145 healthy, nonobese men, 19 years or older, using a standardized equilibrium dialysis method performed for 16-h at 37°C using undiluted serum and dialysis buffer that mimicked the ionic composition of human plasma. FT in dialysate was measured using a CDC-certified liquid chromatography tandem mass spectrometry assay. In healthy nonobese men, the 2.5th, 10th, 50th, 90th, and 97.5th percentile values for FT were 66, 91, 141, 240, and 309 pg/ml, respectively; corresponding values for men, 19-39 years, were 120, 128, 190, 274, and 368 pg/ml, respectively. FT levels by age groups exhibit the expected age-related decline. FT levels were negatively associated with body mass index, age, and sex hormone-binding globulin (SHBG) levels. Percent FT was lower in middle-aged and older men than young men adjusting for SHBG level. Further studies are needed to determine how these reference intervals apply to the diagnosis of androgen deficiency in clinical populations and in men of different races and ethnicities in different geographic regions. Reference intervals for free FT levels (normative range 66-309 pg/ml [229-1072 pmol/L] in all men and 120-368 pg/ml [415-1274 pmol/L] in men, 19-39 years), measured using a standardized equilibrium dialysis method in healthy nonobese men, provide a rational basis for categorizing FT levels. These intervals require further validation in other populations, in relation to outcomes, and in randomized trials.

Sex-specific differences in bone mineral density loss after sleeve gastrectomy

Sleeve gastrectomy is an effective bariatric procedure; however, sleeve gastrectomy-related adverse skeletal outcomes have been increasingly reported. High levels of sex hormone-binding globulin (SHBG) have been documented to be a risk factor of bone mineral density (BMD) loss with different effects observed between sexes. The aim of this study was to identify sex-specific changes in BMD following sleeve gastrectomy and to evaluate the role of SHBG in this process. This retrospective study included 19 middle-aged men and 30 non-menopausal women with obesity who underwent sleeve gastrectomy in China. Anthropometrics, bone turnover markers, calciotropic hormones, BMD, SHBG, and gonadal steroids were measured preoperatively and at 6 and 12 months postoperatively. Longitudinal changes in BMD, bone turnover markers and SHBG were compared between sexes by linear mixed models. Multiple stepwise regression analysis was used to identify the predictors of BMD loss at the investigated bone sites. Over the 12-month study period, total hip and femoral neck BMD decreased, while lumbar spine BMD remained largely unchanged in both sexes. Linear mixed models revealed significant sex × time interaction effects in total hip BMD and SHBG, showing that men had a significantly greater reduction in total hip BMD and less increase in SHBG after sleeve gastrectomy than women. In the multivariate model, SHBG was significantly associated with total hip BMD loss in men (adjusted β = -0.533, P = 0.019) but not women while total estrogen was significantly associated with total hip BMD loss in women (adjusted β = 0.508, P = 0.01) but not men. Significant sex-specific BMD changes were observed after sleeve gastrectomy in the current study. Sleeve gastrectomy-related increase in SHBG may be a specific risk factor for total hip BMD loss in men. Our results indicate that sex-specific screening may be warranted to facilitate personalized postoperative bone care in this population.

Associations between COVID-19 infection and sex steroid hormones.

AimsCoronavirus disease 2019 (COVID-19) is caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and within a few months of the first outbreak, it was declared a global pandemic by the WHO. The lethal virus SARS-CoV-2 is transmitted through respiratory droplets and enters host cells through angiotensin-converting enzyme 2 (ACE-2) receptors. ACE-2 receptors are highly expressed in many tissues, including testes. Therefore, the objective of this study was to summarize the available literature regarding the correlation between sex hormone levels and COVID-19.MethodsThe PubMed, Web of Science, Embase, and Cochrane Library databases were reviewed systematically through August 2022 for studies comparing sex hormone levels between different patient groups: COVID-19 versus no COVID-19, more severe versus less severe COVID-19, and non-survivors versus survivors. Various types of clinical research reporting sex hormone levels, including free testosterone (FT), luteinizing hormone (LH), follicle-stimulating hormone (FSH), 17β-oestradiol (E2), the oestradiol-to-testosterone ratio (E2/T), prolactin (PRL), and sex hormone-binding globulin (SHBG), were included. Random- or fixed-effects models were used to calculate weighted mean differences (WMDs) and 95% confidence intervals (CIs). Heterogeneity among the studies was assessed by the I2 index, and data analyses were performed using meta-analysis with Stata version 12.0.ResultsTwenty-two articles that included 3369 patients were ultimately included in the meta-analysis. According to analysis of the included studies, patients with COVID-19 had significantly low T/LH, FSH/LH, and SHBG levels and high levels of LH, and E2/T, but their levels of FT, FSH, PRL, E2, and progesterone were not affected. Publication bias was not found according to funnel plots and Egger’s regression and Begg’s rank correlation tests.ConclusionLow T/LH, FSH/LH, and SHBG serum levels and high LH, and E2/T levels may increase the risk of COVID-19. Additionally, the greater is the clinical severity of COVID-19, the higher is the probability of increases in LH, and E2/T serum levels and decreases in T/LH, FSH/LH, and SHBG levels. COVID-19 may have unfavourable effects on gonadal functions, which should be taken seriously by clinicians. Routine monitoring of sex hormone levels might help clinicians to evaluate disease severity in patients with COVID-19.

Role of sex hormone-binding globulin in the free hormone hypothesis and the relevance of free testosterone in androgen physiology.

According to the free hormone hypothesis, biological activity of a certain hormone is best reflected by free rather than total hormone concentrations. A crucial element in this theory is the presence of binding proteins, which function as gatekeepers for steroid action. For testosterone, tissue exposure is governed by a delicate equilibrium between free and total testosterone which is determined through interaction with the binding proteins sex hormone-binding globulin and albumin. Ageing, genetics and various pathological conditions influence this equilibrium, hereby possibly modulating hormonal exposure to the target tissues. Despite ongoing controversy on the subject, strong evidence from recent in vitro, in vivo and human experiments emphasizes the relevance of free testosterone. Currently, however, clinical possibilities for free hormone diagnostics are limited. Direct immunoassays are inaccurate, while gold standard liquid chromatography with tandem mass spectrometry (LC-MS/MS) coupled equilibrium dialysis is not available for clinical routine. Calculation models for free testosterone, despite intrinsic limitations, provide a suitable alternative, of which the Vermeulen calculator is currently the preferred method. Calculated free testosterone is indeed associated with bone health, frailty and other clinical endpoints. Moreover, the added value of free testosterone in the clinical diagnosis of male hypogonadism is clearly evident. In suspected hypogonadal men in whom borderline low total testosterone and/or altered sex hormone-binding globulin levels are detected, the determination of free testosterone avoids under- and overdiagnosis, facilitating adequate prescription of hormonal replacement therapy. As such, free testosterone should be integrated as a standard biochemical parameter, on top of total testosterone, in the diagnostic workflow of male hypogonadism.