Sex Hormone-binding Globulin Levels Research Articles

Polymorphic variants of the <i>PPP1R21</i> gene associated with the level of sex hormone-binding globulin and the risk of various stages of breast cancer

Aim. To assess the relationship of polymorphic gene variants associated with the level of sex hormone-binding globulin (SHBG) according to genome-wide association studies (GWAS) with the risk of stage I–II and stage III-IV breast cancer. Materials and methods. A comparative genetic analysis was carried out on samples of patients with breast cancer: 254 patients with stages I–II and 91 with stages III–IV, and 1140 females of the control group. The paper considers 4 single nucleotide substitutions associated with the level of circulating SHBG according to GWAS: g.107546375AG PRMT6 (rs17496332), g.27519736TC GCKR (rs780093), g.48419260TC PPP1R21 (rs10454142), g.98364050TA BAIAP2L1 (rs3779195). Results. Differences in the involvement of polymorphic variants of SHBG candidate genes in the development of stages I–II and III–IV breast cancer were revealed. The rs10454142 TC polymorphic variant in the PPP1R21 gene is associated with the risk of stage I–II breast cancer: women with an allelic variant of this locus have a higher risk of early-stage disease (T/T vs. T/C vs. C/C, odds ratio 1.35, 95% confidence interval 1.05-1.75; p=0.021; ppermutat=0.027). Also, an increase in the number of C alleles in the female genotype increased the risk of stage I–II breast cancer by 17–18% per allele. There were no associations of polymorphic variants of SHBG candidate genes with the risk of severe disease (stage III–IV). The single nucleotide substitution rs10454142 TC in the PPP1R21 gene and the single nucleotide polymorphisms strongly linked to it are functionally significant (located in the regions of enhancers and promoters) in the epithelial and myoepithelial cells of the mammary gland and liver, affect the level of genome methylation, and are associated with the level of GTF2A1L gene expression.

Oestrogens in oral contraception: considerations for tailoring prescription to women's needs.

The oestrogenic component of combined oral contraceptives (COCs) has changed over years with the aim of reducing oestrogen-related side effects and risks, whilst maintaining oestrogen beneficial effects, particularly on cycle control. To describe the pharmacological profiles of different oestrogens commonly used in COCs to provide insights on contraceptive prescription tailored to women's needs. All COCs ensure a high contraceptive efficacy. COCs containing the natural oestrogens oestradiol (E2), oestradiol valerate (E2V) and estetrol (E4) have limited impact on liver metabolism, lipid and carbohydrate metabolism, haemostasis and sex hormone binding globulin levels, compared with ethinylestradiol (EE). COCs with E2 and E2V appear also to entail a lower elevation of the risk of venous thromboembolism vs. EE-containing pills. No epidemiological data are available for E4-COC. E2- and E2V-containing COCs seem to exert a less stabilising oestrogenic effect on the endometrium compared with EE-COCs. The E4-COC results in a predictable bleeding pattern with a high rate of scheduled bleeding and minimal unscheduled bleeding per cycle. Based on in vitro and in vivo animal data, E4 seems to be associated with a lower effect on cell breast proliferation. Today various COCs contain different oestrogens. Prescribers must be familiar with the different properties of each oestrogen for a tailored contraceptive recommendation, considering their safety and contraceptive efficacy, as well as women's needs and preferences.

Bisphenol A Exposure Interferes with Reproductive Hormones and Decreases Sperm Counts: A Systematic Review and Meta-Analysis of Epidemiological Studies.

Bisphenol A (BPA), an acknowledged endocrine disrupter, is easily exposed to humans via food packaging and container. However, a consensus has not been reached on the extent to which BPA exposure affects the reproductive system. We therefore conducted this systematic review and meta-analysis to elucidate the relationship between BPA exposure and male reproduction-related indicators. Up to October 2023, a comprehensive search was carried out in the PubMed, Embase, Cochrane and Web of Science, and 18 studies were ultimately included. β coefficients from multivariate linear regression analyses were pooled using a random effects model. The results showed that the urinary BPA concentration was negatively correlated with the sperm concentration (β coefficient = -0.03; 95% CI: -0.06 to -0.01; I2 = 0.0%, p = 0.003) and total sperm count (β coefficient = -0.05; 95% CI: -0.08 to -0.02; I2 = 0.0%, p < 0.001). In addition, BPA concentrations were associated with increased sex hormone-binding globulin (SHBG) levels, increased estradiol (E2) levels, and reduced biologically active androgen levels. However, the relationship between an increased risk of below-reference sperm quality and BPA exposure was not robust. This systematic review revealed that BPA exposure disrupts reproductive hormones, reduces sperm counts and may ultimately adversely affect male reproduction.

Association of Androgen Hormones, Sex Hormone-Binding Globulin, and the Menopausal Transition With Incident Diabetes Mellitus in Women With and Without HIV.

HIV is associated with alterations in androgen hormone levels and sex hormone-binding globulin (SHBG) in women. Higher SHBG has been associated with a lower risk of diabetes in the general population, but the contribution of HIV, androgen hormones, SHBG, and menopausal phase to diabetes is unclear. From April 2003 through February 2020, 896 women with HIV (WWH) and 343 women without HIV (WWOH) from the Women's Interagency HIV Study with morning total testosterone, dehydroepiandrosterone sulfate (DHEAS), and SHBG levels were followed to assess for incident diabetes. Parametric regression models were used with age as the time scale and relative times (RT) as the measure of association of hormone level and menopausal phase with incident diabetes. Analyses incorporated time-dependent androgen hormone, SHBG levels, and menopausal phase and were adjusted for race/ethnicity, enrollment year, smoking status, BMI, hepatitis C virus status, and HIV-related factors. In total, 128 (14%) WWH and 47 (14%) WWOH developed diabetes. In WWH, a doubling of SHBG and DHEAS were associated with a 7% (RT = 1.07 [95% CI: 0.82 to 1.40] and 15% (RT = 1.15 [95% CI: 0.95 to 1.39]) longer time to diabetes, respectively; in WWOH, a doubling of SHBG and DHEAS were associated with 84% (RT = 1.84 [95% CI: 0.89 to 3.82]) and 41% (RT= 1.41 [95% CI: 0.82 to 2.44]) longer times to diabetes. Total testosterone was not associated. In WWH, later menopausal phase was associated with shorter times to diabetes. Despite alterations in androgen hormone and SHBG levels in HIV, regardless of HIV status, higher SHBG and DHEAS were associated with nonstatistically significant slower progression to diabetes. The menopausal transition may be a better hormonal indicator of diabetes risk in WWH.

Ganoderma lucidum and Hypericum perforatum exhibit anti-inflammatory, antioxidant and anti-androgen effect in rat model of experimental polycystic ovarian syndrome.

Forty-two Sprague-Dawley female rats were divided into 6 groups with 7 animals in each group as listed below; Group 1: Control, Group 2: PCOS, Group 3: PCOS + HP, Group 4: HP only, Group 5: PCOS+ GLP, Group 6: GLP only. At the end of the experimental procedures, all animals underwent bilateral oophorectomy and blood samples were collected. Ovarian tissue and blood samples were used for biochemical and histopathological analysis. Follicle degeneration in the PCOS group showed a statistically significant increase compared to the other groups (p<0.05). When the PCOS+GLP and PCOS+HP groups were examined, it was determined that the cystic follicles were significantly reduced compared to the PCOS group. Whereas tumor necrosis factor-alpha (TNF-a) and interleukin-6 (IL-6) levels were elevated in PCOS rats (p<0.01). Sex hormone binding globulin (SHBG) levels were diminished (p<0.01). MDA and IGF-1 levels were increased in PCOS rats as against the remaining groups (p<0.02, p<0.02, respectively). GLP supplementation to the treatment diminished IGF-1 and malondialdehyde (MDA). GLP or HP supplementation increased reduced glutathione (GSH). GLP and HP treatment normalizes SHBG levels while correcting PCOS-induced hyperandrogenemia. Both herbs regulate the redox balance by decreasing the MDA level and increasing the GSH.

Associations between sex hormones, receptors, binding proteins and inflammatory bowel disease: a Mendelian randomization study.

Gender differences existed in inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC). Observational studies have revealed associations between sex hormones and IBD, such as estrogen and testosterone. However, the exact relationship between these sex hormones and IBD is unclear. Based on the genome-wide association studies data of eight sex hormones, two sex hormone receptors, sex hormone-binding globulin (SHBG), total IBD and its two subtypes, we performed a two-sample Mendelian randomization (MR) study to analyze their mutual relationship. For estradiol (E2), progesterone (PROG), bioavailable testosterone (BAT), total testosterone (TT) and SHBG, sex-stratified MR analyses were also performed. Inverse variance weighted method, MR-Egger regression and Weighted median method were used for causal analyses. Sensitivity analyses were conducted to test the stability of causal relationships. Besides, a reverse MR analysis was performed to estimate the reverse causation. E2 (P=0.028) and TT (P=0.034) had protective effects on CD. Sex-stratified analyses revealed protective roles of E2 in males on total IBD (P=0.038) and CD (P=0.020). TT in females had protective effects on total IBD (P=0.025) and CD (P=0.029), and BAT in females decreased the risk of developing CD (P=0.047) and UC (P=0.036). Moreover, SHBG in males was also associated with a decreased risk of CD (P=0.021). The reversed MR analysis showed that CD was negatively correlated with estrogen receptor (P=0.046). UC was negatively correlated with PROG in females (P=0.015) and positively correlated with SHBG levels in males (P=0.046). Findings of this study revealed the mutual causal associations between sex hormones and the risk of developing IBD.

Sex hormones and neuromyelitis optica spectrum disorder: a bidirectional Mendelian randomization study.

Females are considered to have an increased susceptibility to neuromyelitis optica spectrum disorder (NMOSD) than males, especially aquaporin-4 (AQP4) antibody positive NMOSD, indicating that sex hormones may be involved in the NMOSD pathogenesis. However, the causality between sex hormones and NMOSD still remains unclear. Based on the genome-wide association study (GWAS) data of three sex hormones (estradiol (E2), progesterone (PROG) and bioavailable testosterone (BAT)), sex hormone-binding globulin (SHBG), age of menarche, age of menopause, and NMOSD (total, AQP4 + and AQP4 -), we performed a two-sample bidirectional Mendelian randomization (MR) study. Sex-stratified GWAS data of E2, PROG, BAT, and SHBG was obtained for gender-specific MR analysis. Causal inferences were based on the inverse variance weighted method, MR-Egger regression, and weighted median method. The reverse MR analysis was also performed to assess the impact of NMOSD on hormone levels. PROG in females had aggravative effects on NMOSD (P < 0.001), especially AQP4 - NMOSD (P < 0.001). In the reverse MR analysis, total NMOSD was found to decrease the level of BAT (P < 0.001) and increase the level of SHBG (P = 0.001) in females. Findings of this MR analysis revealed mutual causal associations between sex hormones and NMOSD, which provided novel perspectives about the gender-related pathogenesis of NMOSD.

Urinary phthalate/DINCH metabolites associations with kisspeptin and reproductive hormones in teenagers: A cross-sectional study from the HBM4EU aligned studies

BackgroundExposure to phthalate/DINCH metabolites can induce human reproductive toxicity, however, their endocrine-disrupting mechanisms are not fully elucidated. ObjectiveTo investigate the association between concentrations of phthalate/DINCH metabolites, serum kisspeptin, and reproductive hormones among European teenagers from three of the HBM4EU Aligned Studies. MethodsIn 733 Belgian (FLEHS IV study), Slovak (PCB cohort follow-up), and Spanish (BEA study) teenagers, ten phthalate and two DINCH metabolites were measured in urine by high-performance liquid chromatography-tandem mass spectrometry. Serum kisspeptin (kiss54) protein, follicle-stimulating hormone (FSH), total testosterone (TT), estradiol (E2), and sex hormone-binding globulin (SHBG) levels were measured by immunosorbent assays. Free Androgen Index (FAI) was calculated as a proxy of free testosterone. Adjusted sex-stratified linear regression models for individual studies, mixed effect models (LME) accounting for random effects for pooled studies, and g-computation and Bayesian kernel machine regression (BKMR) models for the phthalate/DINCH mixture were performed. ResultsThe LME suggested that each IQR increase in ln-transformed levels of several phthalates was associated with lower kisspeptin [MnBP: %change (95%CI): −2.8 (−4.2;-0.4); MEHP: −1.4 (−3.4,0.2)] and higher FSH [∑DINP: 11.8 (−0.6;25.1)] levels in females from pooled studies. G-computation showed that the phthalates/DINCH mixture was associated with lower kisspeptin [−4.28 (−8.07;-0.34)] and higher FSH [22.13 (0.5;48.4)] also in females; BKMR showed similar although non-significant pattern. In males, higher phthalates metabolites [MEHP: −12.22 (−21.09;-1.18); oxo-MEHP: −12.73 (−22.34;-1.93)] were associated with lower TT and FAI, although higher DINCH [OH-MINCH: 16.31 (6.23;27.35), cx-MINCH: 16.80 (7.03;27.46), ∑DINCH: 17.37 (7.26;29.74)] were associated with higher TT levels. No mixture associations were found in males. ConclusionWe observed sex-specific associations between urinary concentrations of phthalate/DINCH metabolites and the panel of selected effect biomarkers (kisspeptin and reproductive hormones). This suggests that exposure to phthalates would be associated with changes in kisspeptin levels, which would affect the HPG axis and thus influence reproductive health. However, further research is needed, particularly for phthalate replacements such as DINCH.

Causal relationship between sex hormone-binding globulin and risk of neuroblastoma: A bidirectional two-sample Mendelian randomization study.

The causal relationship between sex hormone-binding globulin (SHBG) and neuroblastoma (NB) remains unknown. This study aimed to explore the causality between SHBG and the risk of NB using bidirectional two-sample Mendelian randomization (MR) study. Instrumental variables associated with SHBG were obtained from the genome-wide association study (GWAS) of European containing 214,989 females and 185,221 males from the UK Biobank. Summary-level data for NB were derived from the IEU OpenGWAS project with 1,627 patients and 3,254 controls. The inverse-variance weighted (IVW) method served as the primary analytical tool. The IVW method revealed a significant positive causal relationship between male SHBG and the risk of NB [odds ratio (OR) = 2.169, 95% confidence interval (CI): 1.207-3.897, P = 0.010]. Conversely, female SHBG showed no significant causal link with NB [IVW OR = 1.004, 95% CI: 0.542-1.860, P = 0.990]. No significant reverse causality was detected. Sensitivity analyses validated these findings. Elevated SHBG levels in males, but not in females, can causally increase the risk of NB. This gender-specific effect indicates a potential differential role of SHBG in the etiology of NB. Further research is needed to elucidate the underlying mechanisms of this gender disparity. Monitoring SHBG levels, especially in males, could be pivotal in NB risk assessment and management. This study highlights a novel gender-specific aspect in the risk of NB, emphasizing the potential role of male SHBG levels in NB incidence, and sets the stage for targeted preventative strategies and further investigation into gender-based biological mechanisms.

Liraglutide improved the reproductive function of obese mice by upregulating the testicular AC3/cAMP/PKA pathway.

The incidence of male reproductive dysfunction is increasing annually, and many studies have shown that obesity can cause severe harm to male reproductive function. The mechanism of male reproductive dysfunction caused by obesity is unclear, and there is no ideal treatment. Identification of effective therapeutic drugs and elucidation of the molecular mechanism involved in male reproductive health are meaningful. In this study, we investigated the effects of the GLP-1 receptor agonist liraglutide on sex hormones, semen quality, and testicular AC3/cAMP/PKA levels in high-fat-diet-induced obese mice. Obese mice and their lean littermates were treated with liraglutide or saline for 12weeks. Body weight was measured weekly. Fasting blood glucose (FBG) was measured using a blood glucose test strip. The serum levels of insulin (INS), luteinizing hormone (LH), follicle stimulating hormone (FSH), testosterone (T), free testosterone (F-TESTO), estradiol (E2), and sex hormone binding globulin (SHBG) were detected using ELISA. The sperm morphology and sperm count were observed after Pap staining. The mRNA and protein expression levels of testicular GLP-1R and AC3 were measured by RT-qPCR and Western blot, respectively. Testicular cAMP levels and PKA activity were detected using ELISA. Liraglutide treatment can decrease body weight, FBG, INS, HOMA-IR, E2 and SHBG levels; increase LH, FSH, T, and F-TESTO levels; increase sperm count; decrease the sperm abnormality rate; and increase GLP-1R and AC3 expression levels and cAMP levels and PKA activity in testicular tissue. Liraglutide can improve the sex hormone levels and semen quality of obese male mice. In addition to its weight loss effect, liraglutide can improve the reproductive function of obese male mice, which may also be related to the upregulation of AC3/cAMP/PKA pathway in the testis. This work lays the groundwork for future clinical studies.

Phthalate metabolites and sex steroid hormones in relation to obesity in US adults: NHANES 2013-2016.

Obesity and metabolic syndrome pose significant health challenges in the United States (US), with connections to disruptions in sex hormone regulation. The increasing prevalence of obesity and metabolic syndrome might be associated with exposure to phthalates (PAEs). Further exploration of the impact of PAEs on obesity is crucial, particularly from a sex hormone perspective. A total of 7780 adult participants in the National Health and Nutrition Examination Survey (NHANES) from 2013 to 2016 were included in the study. Principal component analysis (PCA) coupled with multinomial logistic regression was employed to elucidate the association between urinary PAEs metabolite concentrations and the likelihood of obesity. Weighted quartiles sum (WQS) regression was utilized to consolidate the impact of mixed PAEs exposure on sex hormone levels (total testosterone (TT), estradiol and sex hormone-binding globulin (SHBG)). We also delved into machine learning models to accurately discern obesity status and identify the key variables contributing most to these models. Principal Component 1 (PC1), characterized by mono(2-ethyl-5-carboxypentyl) phthalate (MECPP), mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), and mono(2-ethyl-5-oxohexyl) phthalate (MEOHP) as major contributors, exhibited a negative association with obesity. Conversely, PC2, with monocarboxyononyl phthalate (MCNP), monocarboxyoctyl phthalate (MCOP), and mono(3-carboxypropyl) phthalate (MCPP) as major contributors, showed a positive association with obesity. Mixed exposure to PAEs was associated with decreased TT levels and increased estradiol and SHBG. During the exploration of the interrelations among obesity, sex hormones, and PAEs, models based on Random Forest (RF) and eXtreme Gradient Boosting (XGBoost) algorithms demonstrated the best classification efficacy. In both models, sex hormones exhibited the highest variable importance, and certain phthalate metabolites made significant contributions to the model's performance. Individuals with obesity exhibit lower levels of TT and SHBG, accompanied by elevated estradiol levels. Exposure to PAEs disrupts sex hormone levels, contributing to an increased risk of obesity in US adults. In the exploration of the interrelationships among these three factors, the RF and XGBoost algorithm models demonstrated superior performance, with sex hormones displaying higher variable importance.

Effects of depot medroxyprogesterone acetate, the copper IUD and the levonorgestrel implant on testosterone, sex hormone binding globulin and free testosterone levels: ancillary study of the ECHO randomized clinical trial

BackgroundRobust information on relative effects of hormonal contraceptives on endogenous androgens is important for understanding beneficial and adverse effects, method choice and development of new methods.MethodsIn this ancillary study at the East London, South Africa site of the ECHO multicentre randomized trial, we compared effects of three contraceptive methods on serum androgen levels among contraceptive users aged 18 to 35 years. Participants were allocated by centrally-managed randomization to open label depot medroxyprogesterone acetate (DMPA-IM), copper intrauterine device (IUD) or levonorgestrel implant.The primary outcome was free testosterone at 6 months.ResultsWe analysed stored baseline and 6-month serum samples in 398/615 participants (DMPA-IM 131/205, IUD 135/205 and implant 132/205). Median testosterone levels at baseline were DMPA-IM 0.82, IUD 0.9 and implant 0.87 nmol/L; at 6 months, DMPA 0.68 (lower than IUD, mean percentage difference 28.35, (p <  0.001), IUD 0.86 (unchanged) and implant 0.66, lower than IUD, mean percentage difference − 22.98, p <  0.001).Median SHBG levels at baseline were DMPA 52.4, IUD 50.5 and implant 55.75 nmol/L; at 6 months, DMPA 40.65, lower than IUD (mean percentage difference 21.19, p = 0.005), IUD 49.1 (unchanged), and implant 23.35 nmol/L, lower than IUD (mean percentage difference − 50.04, p <  0.001 and than DMPA (mean percentage difference − 39.45, p <  0.001).Free testosterone levels at baseline were DMPA 10, IUD 12 and implant 11 pmol/L; at 6 months, DMPA 11, less than IUD (mean percentage difference 13.53, p = 0.047), IUD 12 and implant 14, higher than IUD (mean percentage difference 14.15, p = 0.038) and than DMPA, (mean percentage difference 29.60, p <  0.001).ConclusionsThis is the first randomized trial to show lower SHBG and higher free testosterone with the levonorgestrel implant than with DMPA, and contrasts with reports of increased SHBG with combined oral ethinyl estradiol/levonorgestrel use, and reduced androgens (and impaired sexual function) reported with the etonorgestrel implant. The higher free testosterone with the LNG implant might improve sexual function, mood and bone health as well as increasing side-effects such as acne and hirsutism, and is consistent with the greater sexual activity (with respect to multiple sex partners, new sex partner and unprotected sex) with the implant compared with DMPA documented in the ECHO study.ECHO trial registrationClinicalTrials.gov, number NCT02550067 15/09/2015.Plain English summaryContraception, or family planning, is central to the role of women in societies. It is most important to have accurate information on the relative side-effects of various contraceptive options in order to empower women to make informed choices regarding their preferred method.Hormonal contraceptives contain various forms of the female sex hormones, estrogens and/or progestogens. These hormones have direct effects on the users, as well as modifying the levels of the users’ own circulating sex hormones, both the ‘female’ and the ‘male’ sex hormones (androgens).In this study, consenting participants requesting contraception, were allocated randomly to receive either depot medroxyprogesterone acetate (DMPA-IM) a 3-monthly progestogen injection, the copper intrauterine device (IUD), a non-hormonal contraceptive inserted within the womb, or the levonorgestrel implant, a device placed under the skin which releases a progestogen for 5 years.We measured the participants’ androgen levels after 6 months, and found for the first time that the active form of testosterone (free testosterone) was 29% higher with the implant than with DMPA-IM. The level with the IUD was intermediate, and significantly different from the other two methods.This finding is relevant to the effects experienced by users of these methods, because free testosterone has effects on sexual function, bone health and mood, as well as on conditions such as acne and hair distribution patterns.

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.

Coffee intake reduced gout risk by decreasing urate and urea while increasing SHBG levels in plasma: a mediation Mendelian randomization study.

This study aims to investigate the causal relationships between specific dietary habits and the risk of gout, while identifying the mediators involved in these associations. We initially assessed the causal effects of five dietary habits on gout by two-sample Mendelian randomization (MR). Subsequently, we identified mediators from five plasma metabolites by two-step MR, including urate, urea, sex hormone-binding globulin (SHBG), interleukin-18 (IL-18), and C-reactive protein (CRP). Next, we quantified the proportion of mediation effects by multivariable Mendelian randomization (MVMR). Last, we performed reverse MR analyses. Sensitivity analyses were conducted to enhance the robustness of our findings. Only coffee intake demonstrated a significant negative casual effect on gout (inverse variance weighted: OR = 0.444, p = 0.049). In two-step MR, coffee intake decreased urate and urea while increased SHBG levels, but did not affect IL-18 and CRP levels. Besides, urate and urea showed positive causal effects while SHBG exhibited a negative impact on gout. In mediation analysis, urate, urea, and SHBG respectively mediated 53.60%, 16.43%, and 4.81% of the total causal effect of coffee intake on gout. The three mediators collectively mediated 27.45% of the total effect. Reverse MR analyses suggested no significant reverse causal effects. Sensitivity analyses supported the reliability of our causal inferences. Coffee intake reduced gout risk by decreasing urate and urea while increasing SHBG levels in plasma. These findings accentuate the benefits of coffee intake for gout management. The mediators may provide a novel insight into potential therapeutic targets for gout prevention. Key Points • This study determines the causally protective effect of coffee intake on gout. • We reveal that coffee intake reduced the risk of gout by decreasing urate and urea while increasing SHBG levels in plasma. • Identifying specific mediators in the causal pathway from coffee intake to gout provides valuable information for clinical interventions of gout.

Genetically predicted high serum sex hormone-binding globulin levels are associated with lower ischemic stroke risk: A sex-stratified Mendelian randomization study

ObjectiveCross-sectional and cohort studies have found insufficient evidence of a causal relationship between sex hormone-binding globulin and ischemic stroke, only associations. Here, we performed a sex-stratified, bidirectional, two-sample Mendelian randomization analysis to evaluate whether a causal relationship exists between sex hormone-binding globulin and ischemic stroke. MethodsSingle-nucleotide polymorphisms associated with sex hormone-binding globulin and ischemic stroke were screened from genome-wide association studies summary data as instrumental variables to enable a bidirectional, two-sample Mendelian randomization study design. Inverse-variance weighted analysis was used as the main method to evaluate potential causality, and additional methods, including the weighted median and MR-Egger tests, were used to validate the Mendelian randomization results. Cochran's Q statistic, MR-Egger intercept test, and Mendelian Randomization-Pleiotropy Residual Sum and Outlier global test were used as sensitivity analysis techniques to assure the reliability of the results. Multivariable analysis was used to show the robustness of the results with key theorized confounders. ResultsInverse-variance weighted analysis showed that genetically predicted higher serum sex hormone-binding globulin levels were associated with significantly decreased risk of ischemic stroke in males (odds radio = 0.934, 95 % confidence interval = 0.885-0.985, P = 0.012) and females (odds radio = 0.924, 95 % confidence interval = 0.868-0.983, P = 0.013). In an analysis of ischemic stroke subtypes, genetically predicted higher serum sex hormone-binding globulin levels were also associated with significantly decreased risk of small-vessel occlusion in both males (odds radio = 0.849, 95 % confidence interval = 0.759-0.949, P = 0.004) and females (odds radio = 0.829, 95 % confidence interval = 0.724-0.949, P = 0.006). The association remained in sensitivity analyses and multivariable analyses. The reverse analysis suggested an association between genetically predicted risk of cardioembolism and increased serum sex hormone-binding globulin in females (Beta = 0.029 nmol/L, Standard Error = 0.010, P = 0.003). ConclusionOur findings provide new insight into the etiology of ischemic stroke and suggest that modulating serum sex hormone-binding globulin may be a therapeutic strategy to protect against ischemic stroke.

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.

Oxidative stress in polycystic ovary syndrome: a case-control study.

To compare the serum levels of biochemical and oxidative stress markers i.e., malondialdehyde (MDA) and paraoxonase-1(PON1) in polycystic ovary syndrome (PCOS) patients and healthy female individuals of reproductive age group (18-40 years). This case-control study was conducted in Dow University of Health Sciences (DUHS), Karachi from June 2019 to October 2020. Seventy Subjects including 35 PCOS patients that have primary subfertility problem (cases) and 35 healthy and fertile females (controls) were recruited. Serum samples were collected for analysis of insulin, sex hormone-binding globulin, testosterone, fasting blood glucose and lipid profile. PON 1 and MDA levels were estimated by ELISA. Comparison between the two groups was done using independent t-test. The patients had significantly increased mean body mass index (28.5+4.6 kg/m2 vs 25.7+4.5 kg/m2, p=0.014), systolic (129.6±13.9 mm of Hg vs 113±7.7 mm of Hg, p<0.001) and diastolic (78.7±8.8 mm of Hg vs 74.6±6.7 mm of Hg, p=0.032) blood pressures compared to controls. The high-density lipoprotein cholesterol levels were significantly lower in PCOS (42.2±8.6mg/dl) than controls (48.8±11.8mg/dl, p=0.009, p=0.009). Serum insulin (14.3±5.8 uIU/mL) vs (10.0±5.2 uIU/mL), p=0.002 and testosterone levels (1.3±0.9 nmol/L) vs (0.82±0.3 nmol/L), p<0.001 were significantly higher whereas sex hormone binding globulin (SHBG) levels (35.2±19.7nmol/L vs 58.8±31.0 nmol/L) were significantly lower in patients than healthy controls (p<0.001). Both oxidative stress markers, paraoxonase 1 (7.7±2.4 vs 6.4±2.6 μg/mL, p=0.04) and malondialdehyde (2.5±1.0 vs 1.9+0.51μg/mL, p=0.034) levels were significantly elevated in PCOS patients than controls. No significant correlation was found between dietary habits and life style between cases and controls. The study reported significantly elevated levels of oxidative stress markers in PCOS patients.

Low levels of sex hormone-binding globulin predict an increased breast cancer risk and its underlying molecular mechanisms.

Sex hormone-binding globulin (SHBG) is a serum glycoprotein exhibiting the unique feature of binding sex steroids with high affinity and specificity. Over the past few decades, there have been significant breakthroughs in our understanding of the function and regulation of SHBG. The biological role of SHBG has expanded from being considered a simple sex hormone transporter to being associated with several complex physiological and pathological changes in a variety of target tissues. Many factors can affect the plasma SHBG levels, with fluctuations in circulating levels affecting the development of various diseases, such as increasing the risk of developing breast cancer. This article reviews the clinical significance of changes in circulating SHBG levels in the development of breast cancer and the possible influence of these levels on endocrine drug resistance in hormone receptor-positive breast cancer. Higher levels of plasma SHBG significantly reduce the risk of estrogen receptor-positive breast cancer, especially in postmenopausal women. Moreover, the molecular mechanisms by which SHBG affects breast cancer risk are also summarized in detail. Finally, transcriptomics and proteomics data revealed that SHBG expression in breast tissue can effectively distinguish breast cancer from normal tissue. Additionally, the association between SHBG expression levels and various classical tumor-related pathways was investigated.

Longitudinal Changes in Sex Hormone Binding Globulin (SHBG) and Risk of Incident Diabetes: The Study of Women's Health Across the Nation (SWAN).

To investigate the associations of longitudinal changes in sex hormone binding globulin (SHBG) and testosterone (T) over the menopause transition with the risk of diabetes. We followed 2,952 participants in the Study of Women's Health Across the Nation (SWAN) who were premenopausal or early perimenopausal and diabetes-free at baseline. SHBG,T, and estradiol (E2) levels were measured at up to 13 follow-up visits (over up to 17 years). We used complementary log-log-based discrete-time survival models anchored at baseline. Diabetes developed in 376 women. A 5-unit increase in time-varying SHBG was associated with a 10% reduced risk of diabetes (hazard ratio [HR] 0.91, 95% CI 0.87-0.95), adjusting for covariates, and baseline SHBG,T, and E2 levels. Time-varying T was not associated with diabetes risk. Compared with the lowest quartile for annual rate of change of SHBG since baseline (quartile 1 [Q1] -92.3 to -1.5 nmol/L), all other quartiles were associated with a decreased risk of diabetes adjusting for covariates and baseline SHBG; associations persisted after adjusting for rate of change of T and E2 (Q2 [> -1.5 to -0.2 nmol/L] HR 0.33, 95% CI 0.23-0.48; Q3 [> -0.2 to 1.3 nmol/L] HR 0.37, 95% CI 0.25-0.55; Q4 [>1.3 to 82.0 nmol/L] HR 0.43, 95% CI 0.30-0.63). Increasing levels of SHBG over the menopause transition were associated with a decreased risk of incident diabetes. Stable to increasing rates of change in SHBG were also independently associated with a decreased risk of diabetes compared with decreasing rates of change, suggesting SHBG may affect glucose through a mechanism beyond androgenicity.

SHBG Levels Do Not Correlate with Insulin Levels in PCOS with Appropriate Fasting Insulin Sensitivity

Introduction: There are several phenotypes of polycystic ovarian syndrome (PCOS), and the different phenotypes may differ metabolically. Methods: In the present retrospective study, women with PCOS having normal fasting insulin sensitivity (n = 88) were compared with women with PCOS showing impaired insulin sensitivity (n = 46) using the HPCOS (Hungarian Polycystic ovarian syndrome) database. Results: The impaired insulin sensitivity group has significantly higher body mass index (BMI) and HOMA index than the normal fasting insulin sensitivity group (BMI (kg/m2): 22.0 vs. 28.1, p &lt; 0.0001, HOMA index: 0.96 vs. 2.38, p &lt; 0.0001). The sex hormone binding globulin (SHBG) level was significantly lower, and the free androgen index proved itself significantly higher in the impaired insulin sensitivity group (p &lt; 0.05). Linear regression analysis showed a negative association of BMI with SHBG levels in both groups, while BMI had a positive correlation with insulin concentrations in both groups. However, the SHBG levels were negatively associated with insulin concentrations in the impaired insulin sensitivity group, but this inverse association could not be observed in the normal fasting insulin sensitivity group. Conclusions: The inverse linear correlation of SHBG with HOMA index and serum insulin level is not evident in all PCO syndrome phenotypes, thus SHBG has limited applicability for characterizing carbohydrate metabolism and serum insulin sensitivity.