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OBJECTIVES: Pre-eclampsia (PE) and gestational hypertension (GH) are two different categories of hypertensive disorders of pregnancy. Given earlier observational research, the relationship between sex hormone-binding globulin (SHBG) and a higher risk of GH/PE is still up for dispute. Hence, the present investigation aimed to examine the possible link between SHBG and the likelihood of GH/PE. METHODS: As a first stage, single nucleotide polymorphisms from summary-level genome-wide association studies were tightly screened using quality-control techniques. Afterward, we utilized a two-sample Mendelian randomization (MR) study to examine the causal impact of SHBG on the likelihood of GH/PE. There was no indication of a relationship between blood SHBG level (n = 214,989) and GH/PE (1864 cases and 461,069 controls) in the initial study. Consensus results were obtained from the replicated analysis, which utilized MR estimates based on serum SHBG level(n = 214,989) for GH (4255 cases and 114,735 controls). RESULTS: The findings did not indicate any proof of a cause-and-effect connection between SHBG and the likelihood of GH/PE (odds ratio [OR] = 0.99, 95% confidence interval [CI] = 0.999 - 1.00, p = .34). Replicate analysis also revealed similar patterns (OR = 0.92, 95%CI = 0.82-1.05, p = .21). The above findings were demonstrated to have a strong level of robustness. CONCLUSIONS: The findings of this research did not offer definitive proof to endorse the idea that SHBG has a direct causal impact on the likelihood of GH/PE, which goes against numerous widely accepted observational studies. To ascertain the potential processes behind the relationships seen in observational studies, more investigation is needed.
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Estudio de Asociación del Genoma Completo , Hipertensión Inducida en el Embarazo , Análisis de la Aleatorización Mendeliana , Polimorfismo de Nucleótido Simple , Preeclampsia , Globulina de Unión a Hormona Sexual , Humanos , Femenino , Globulina de Unión a Hormona Sexual/análisis , Embarazo , Preeclampsia/genética , Preeclampsia/sangre , Preeclampsia/epidemiología , Hipertensión Inducida en el Embarazo/genética , Hipertensión Inducida en el Embarazo/sangre , Hipertensión Inducida en el Embarazo/epidemiología , Estudios de Casos y ControlesRESUMEN
New approach methodologies (NAMs) offer information tailored to the intended application while reducing the use of animals. NAMs aim to develop quantitative structure-activity relationship (QSAR) and quantitive-Read-Across structure-activity relationship (q-RASAR) models to predict and categorize the acute toxicity of known and unknown endocrine-disrupting chemicals (EDCs) against zebrafish. EDCs are a diverse group of toxic substances that disrupt the endocrine system of humans and animals. The q-RASAR model was constructed and verified using validation metrics (R2 = 0.886 and Q2 = 0.814) which found to be more reliable model compare to QSAR model. The substructure fingerprint was well-fitted for the classification model and it was validated using 10-fold average accuracy (Q = 86.88%), specificity (Sp = 88.89%), Matthew's correlation curve (MCC = 0.621) and receiver operating characteristics (ROC = 0.828). The dataset of unknown substances revealed that phenolphthalein (Php) exhibited a significant level of toxicity based on q-RASAR model. The docking and simulation study indicated that the computationally derived important features successfully bound to the target zebrafish sex hormone binding globulin (zfSHBG). The experimental LC50 value of 0.790 mg L-1 was very close to the predicted value of 0.763 mg L-1, which provides high confidence to the developed model.
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Several studies show that a significantly stronger association is obvious between increased body mass index (BMI) and higher breast cancer incidence. Additionally, obese and postmenopausal women are at higher risk of all-cause and breast cancer-specific mortality compared with non-obese women with breast cancer. In this context, increased levels of estrogens, excessive aromatization activity of the adipose tissue, overexpression of pro-inflammatory cytokines, insulin resistance, adipocyte-derived adipokines, hypercholesterolemia, and excessive oxidative stress contribute to the development of breast cancer in obese women. Genetic evaluation is an integral part of diagnosis and treatment for patients with breast cancer. Despite trimodality therapy, the four-year cumulative incidence of regional recurrence is significantly higher. Axillary lymph nodes as well as primary lesions have diagnostic, prognostic, and therapeutic significance for the management of breast cancer. In clinical setting, because of the obese population primary lesions and enlarged lymph nodes could be less palpable, the diagnosis may be challenging due to misinterpretation of physical findings. Thereby, a nomogram has been created as the "Breast Imaging Reporting and Data System" (BI-RADS) to increase agreement and decision-making consistency between mammography and ultrasonography (USG) experts. Additionally, the "breast density classification system," "artificial intelligence risk scores," ligand-targeted receptor probes," "digital breast tomosynthesis," "diffusion-weighted imaging," "18F-fluoro-2-deoxy-D-glucose positron emission tomography," and "dynamic contrast-enhanced magnetic resonance imaging (MRI)" are important techniques for the earlier detection of breast cancers and to reduce false-positive results. A high concordance between estrogen receptor (ER) and progesterone receptor (PR) status evaluated in preoperative percutaneous core needle biopsy and surgical specimens is demonstrated. Breast cancer surgery has become increasingly conservative; however, mastectomy may be combined with any axillary procedures, such as sentinel lymph node biopsy (SLNB) and/or axillary lymph node dissection whenever is required. As a rule, SLNB-guided axillary dissection in breast cancer patients who have clinically axillary lymph node-positive to node-negative conversion following neoadjuvant chemotherapy is recommended, because lymphedema is the most debilitating complication after any axillary surgery. There is no clear consensus on the optimal treatment of occult breast cancer, which is much discussed today. Similarly, the current trend in metastatic breast cancer is that the main palliative treatment option is systemic therapy.
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Neoplasias de la Mama , Obesidad , Humanos , Neoplasias de la Mama/patología , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/terapia , Neoplasias de la Mama/metabolismo , Femenino , Obesidad/complicaciones , Factores de Riesgo , Índice de Masa Corporal , PronósticoRESUMEN
BACKGROUND: Despite sex differences in T2D, few studies have examined the role of sex hormones. We sought to assess the impact of weight loss, the cornerstone of T2D management, on sex hormone levels. METHODS: This was an ancillary study to the Look AHEAD (Action for Health In Diabetes) Study (n=850 postmenopausal females, n=890 males, with T2D and BMI ≥25 kg/m2). We measured total testosterone (T), estradiol (E2) and sex hormone binding globulin (SHBG) and calculated bioavailable T (bioT). We examined the effect of the intensive lifestyle intervention (ILI) on hormone changes, whether changes were mediated by waist circumference and sex differences in treatment effect. RESULTS: The baseline mean age was 60 years with a higher proportion of Black females (21%) vs. males (9%) and higher mean BMI in females vs. males (36.3 vs. 34.8 kg/m2). At year 1 in females, ILI decreased E2 by 15% and bioT by 13% and increased SHBG by 21%. At year 1 in males, ILI did not change E2 levels, but increased T by 14% and increased SHBG by 18%. The effect was attenuated over 4 years, there were statistically significant sex differences in treatment effect and change in waist circumference due to ILI at year 1 was a significant mediator of sex hormone changes. CONCLUSION: Weight loss in T2D resulted in sex hormone changes, which varied by sex and were mediated by changes in WC. Changes in sex hormone due to weight loss in T2D should be considered in the context of an individual's health risks, including cardiovascular, bone health, menopausal symptoms and cognition.
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Background: Observational studies indicated that serum uric acid (SUA) was associated with male sexual hormones and erectile dysfunction (ED). However, their relationship was still heterogeneous. Aim: This study conducted 2-sample univariate mendelian randomization (UVMR) and multivariate mendelian randomization (MVMR) to explore the causal relationship between SUA and sexual hormones as well as ED. Methods: Genetic variants associated with SUA were derived from the UK Biobank database (N = 437 354). Outcomes from the IEU Open GWAS and summary data sets were sexual hormones (sex hormone-binding globulin [SHBG], testosterone, estradiol [E2], follicle-stimulating hormone, luteinizing hormone) and ED, with 3301 to 625 650 participants. UVMR analysis primarily utilized the inverse variance weighted method, complemented by MVMR analysis. Thorough sensitivity analyses were carried out to ensure the reliability of results. Moreover, mediation analysis was conducted to estimate the mediated effect between SUA and outcomes. Outcomes: The primary outcomes included results of UVMR and MVMR analysis and mediation analysis, along with sensitivity analyses involving the Cochran Q test, the MR Egger intercept test, leave-1-out analysis, and the MR-PRESSO method (mendelian randomization pleiotropy residual sum and outlier). Results: UVMR analysis revealed that an elevated SUA level could decrease levels of SHBG (ß = -0.10, P = 1.70 × 10-7) and testosterone (ß = -0.10, P = 5.94 × 10-3) and had a positive causal effect on ED (odds ratio, 1.10; P = .018). According to reverse mendelian randomization results, increased levels of SHBG (ß = -0.06, P = 4.82 × 10-4) and E2 (ß = -0.04, P = .037) could also reduce SUA levels. As shown by MVMR analysis, SUA had a negative effect on SHBG and testosterone levels (P < .05), while the significant causal relationship between SUA and ED disappeared. Furthermore, SHBG mediated 98.1% of the effect of SUA on testosterone levels. Results of other mendelian randomization analyses were not statistically significant. No pleiotropy was found by sensitivity analysis in this study. Clinical Implications: Given the causal relationship between SUA and sexual hormones, we must focus on SUA and E2 levels in men, especially patients with hypogonadism and ED. Strengths and Limitations: This study evaluated the causal effect of SUA on male sexual hormones and ED genetically for the first time, clarifying the common biases in observational studies and confirming the negative relationship between SUA and testosterone level. Limitations include a population based on European ancestry, some crossover of the samples, and unobserved confounding factors. Conclusion: Genetic studies provide evidence for the causal relationship between SUA and male sexual hormones (SHBG, testosterone, E2), while the relationship between SUA and ED should be further evaluated.
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BACKGROUND: Polycystic ovary syndrome (PCOS) is one of the most common reproductive endocrine disorders. Accumulated evidence has suggested the indispensable role of kisspeptin-G protein-coupled receptor (GPR54) system and SHBG in development of PCOS. However, potential mechanisms and their relationship are unclear. Jiawei Buzhong Yiqi Decoction (JWBZYQ) has been reported to ameliorate obese PCOS. Whereas, potential mechanisms remain elusive. PURPOSE: To determine whether JWBZYQ attenuates PCOS by regulating the kisspeptin-GPR54 system and SHBG production. And to explore potential mechanisms. METHODS: An overweight PCOS rat model was developed with testosterone propionate (TP) and high-fat diet (HFD). The efficacy of JWBZYQ was assessed by tracking changes in weight, estrous cycle, ovarian morphology, and serum sex hormone levels. Additionally, kisspeptin-GPR54 system expression in multiple organs and PI3K-AKT pathway activity in liver of different rats were detected. Modifications in SHBG production were also measured. Kisspeptin54 was administered to establish a cellular model. The levels of AKT phosphorylation and SHBG protein within HepG2 cells were analyzed. Finally, confirmatory studies were performed using AKT phosphorylation activator and inhibitor. RESULTS: JWBZYQ effectively attenuated the overweight, disrupted estrous cycle, altered sex hormone levels, and aberrant ovarian morphology in PCOS rats. Meanwhile, PCOS rats exhibited elevated levels of kisspeptin and GPR54, along with reduced SHBG levels, which could be reversed by JWBZYQ. These alterations might be connected with the activation of AKT phosphorylation. In vitro experiment identified that JWBZYQ could rectify the hyperactivated AKT phosphorylation and deficient production of SHBG caused by kisspeptin54. CONCLUSIONS: Overexpressed kisspeptin-GPR54 system inhibited SHBG synthesis in PCOS. JWBZYQ curtailed the exorbitant expression of kisspeptin and GPR54, which moderated the rise in AKT phosphorylation and subsequently promoted the production of SHBG.
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Medicamentos Herbarios Chinos , Kisspeptinas , Síndrome del Ovario Poliquístico , Proteínas Proto-Oncogénicas c-akt , Ratas Sprague-Dawley , Receptores de Kisspeptina-1 , Globulina de Unión a Hormona Sexual , Síndrome del Ovario Poliquístico/tratamiento farmacológico , Síndrome del Ovario Poliquístico/metabolismo , Animales , Femenino , Kisspeptinas/metabolismo , Medicamentos Herbarios Chinos/farmacología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Receptores de Kisspeptina-1/metabolismo , Globulina de Unión a Hormona Sexual/metabolismo , Ratas , Modelos Animales de Enfermedad , Dieta Alta en Grasa , Ovario/efectos de los fármacos , Ovario/metabolismo , Transducción de Señal/efectos de los fármacos , Humanos , Receptores Acoplados a Proteínas G/metabolismo , Propionato de TestosteronaRESUMEN
Widespread glyphosate contamination in the environment and its endocrine-disrupting potential are concerning. However, evidence of glyphosate's effects on glycemic health is limited. To examine the association between glyphosate and glucose homeostasis in the general US population, a total of 3038 individuals were enrolled from the 2013-2016 cycles of the National Health and Nutrition Examination Survey (NHANES). Survey-weighted linear regression and restricted cubic spline curves were used to detect the associations between glyphosate and glycemic disorders. The effects of interactions between sex hormones and glyphosate on glycemic outcomes were evaluated. The results showed that glyphosate was significantly linked to increased glycated hemoglobin A1c (HbA1c) levels (ß = 0.01; 95%CI, 0.01 to 0.02; p = 0.001) and the compromised homeostatic model assessment of beta-cell function (HOMA-beta) scores (ß = -0.09; 95%CI, -0.17 to -0.01; p = 0.024). More importantly, these "glyphosate-glycemic disorder" associations were significantly modified by sex hormone-binding globulin (SHBG; P for interaction < 0.05), with more pronounced relationships being identified in individuals with low SHBG levels. Our findings indicate that glyphosate is correlated with glucose dyshomeostasis. Individuals with low SHBG levels exhibited susceptibility to glyphosate-related glycemic toxicity; therefore, it might be prudent to determine glycemic health in those subjects with glyphosate exposure.
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BACKGROUND: The association between frailty and sex hormone-binding globulin (SHBG) or insulin-like growth factor-1(IGF-1) levels demonstrates sex differences with inconsistent conclusions. This study aims to explore the causal relationship between frailty and SHBG or IGF-1 levels through bidirectional Mendelian randomization (MR). METHODS: We conducted two-sample bidirectional sex-stratified MR analyses using summary-level data from genome-wide association studies (GWASs) to examine the causal relationship between frailty and IGF-1 or SHBG levels, as measured by frailty index (FI) and frailty phenotype (FP). We use the random-effects inverse-variance weighted (IVW), weighted median, MR-Egger, MR-Egger intercept, and leave-one-out approaches. RESULT: The relationship between frailty and SHBG or IGF-1 levels is inversely related, with a significant decrease in SHBG levels in females. Specifically, SHBG levels significantly decrease with FI (ß = -5.49; 95 % CI: -9.67 to -1.32; FDR = 0.02) and more pronounced with FP (ß = -10.14; 95 % CI: -16.16 to -4.13; FDR = 0.01), as determined by the IVW approach. However, reverse analysis shows no significant effect of IGF-1 or SHBG levels on either FI or FP (p > 0.05). CONCLUSION: Our study indicates a negative correlation between frailty and the levels of SHBG and IGF-1. It is suggested that further research is required to establish cut-off values for SHBG and IGF-1 levels in the frailty population. This is particularly important for females at higher risk, such as those undergoing menopause, to enable comprehensive assessment and early prevention efforts. While the findings imply that reduced IGF-1 and SHBG levels may not directly contribute to frailty, it is important not to overlook the underlying mechanisms through which they may indirectly influence frailty.
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Fragilidad , Estudio de Asociación del Genoma Completo , Factor I del Crecimiento Similar a la Insulina , Análisis de la Aleatorización Mendeliana , Globulina de Unión a Hormona Sexual , Humanos , Globulina de Unión a Hormona Sexual/análisis , Globulina de Unión a Hormona Sexual/metabolismo , Factor I del Crecimiento Similar a la Insulina/metabolismo , Fragilidad/sangre , Fragilidad/genética , Femenino , Masculino , Anciano , Anciano Frágil , Factores Sexuales , Fenotipo , Péptidos Similares a la InsulinaRESUMEN
Pyrethroids are widely used insecticides with huge applications for household as well as agricultural purposes and contribute to improved product quality and higher yields. In recent decades, the demand for pyrethroids has increased significantly due to advantages such as broad-spectrum efficacy, high insecticidal potential, and lower pest resistance. However, several studies have suggested that human exposure to pyrethroids leads to reproductive problems. Sex hormone-binding globulin (SHBG) is an important hormone transport protein regulating the availability of steroids at their target site. The aim of our study was to investigate the structural interactions of commonly used pyrethroids, cypermethrin and deltamethrin, with ligand binding pocket of SHBG. Cypermethrin and deltamethrin were docked into the steroid binding pocket of SHBG using Schrodinger's induced fit docking (IFD) followed by molecular dynamics (MD) simulation studies. The resultant SHBG-pyrethroid complexes from IFD experiments were subjected to structural analysis including the molecular interactions followed by binding energy estimation. The analysis revealed that both the ligands were tightly bound in the SHBG pocket with high percentage of commonality among the SHBG residues between the indicated pyrethroid ligands and the SHBG native ligand, dihydrotestosterone (DHT). The estimated binding energy values for cypermethrin were less but close to the values calculated for the SHBG native ligand, DHT. However, the estimated binding energy values for deltamethrin were higher compared to the values calculated for SHBG native ligand, DHT. Furthermore, the MD simulation results also revealed the higher stability of SHBG-deltamethrin than SHBG-cypermethrin complex. To sum up, the results suggested that deltamethrin has a greater capability than cypermethrin to prevent sex steroid hormone from binding to SHBG, even though both pyrethroids have this ability. Consequently, this might hamper the circulatory transport of sex steroid hormones and their availability at the target site, subsequently interfering with reproductive function.
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Prostate cancer (PC) is a common and widespread cancer that affects men globally. A complicated interaction of hormonal variables influences its development. Sex hormone-binding globulin (SHBG) is a crucial element in controlling the availability of sex hormones, especially androgens, which have a notable impact on the development and progression of PC. SHBG controls the levels of free, active androgens in the body, which helps regulate androgen-dependent processes associated with PC. The equilibrium between SHBG and androgens plays a critical role in maintaining the stability of the prostate. When this balance is disrupted, it is associated with the development and advancement of PC. The processes responsible for SHBG's role in PC are complex and have multiple aspects. SHBG primarily binds to androgens, preventing them from interacting with androgen receptors (ARs) in prostate cells. It reduces the activation of androgen signaling pathways essential for tumor development and survival. In addition, SHBG can directly affect prostate cells by interacting with specific receptors on the cell surface. This review thoroughly examines the role of SHBG in PC, including its physiological activities, methods of action, and clinical consequences.
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Research has indicated that sex hormone-binding globulin (SHBG) is associated with glucose homeostasis and may play a role in the etiology of type 2 diabetes (T2D). While it is unclear whether SHBG may mediate sex differences in glucose control and subsequently, incidence of T2D. We used observational data from the German population-based KORA F4 study (n = 1937, mean age: 54 years, 41% women) and its follow-up examination KORA FF4 (median follow-up 6.5 years, n = 1387). T2D was initially assessed by self-report and validated by contacting the physicians and/ or reviewing the medical charts. Mediation analyses were performed to assess the role of SHBG in mediating the association between sex (women vs. men) and glucose- and insulin-related traits (cross-sectional analysis) and incidence of T2D (longitudinal analysis). After adjustment for confounders, (model 1: adjusted for age; model 2: model 1 + smoking + alcohol consumption + physical activity), women had lower fasting glucose levels compared to men (ß = -4.94 (mg/dl), 95% CI: -5.77, -4.11). SHBG levels were significantly higher in women than in men (ß = 0.47 (nmol/l), 95% CI:0.42, 0.51). Serum SHBG may mediate the association between sex and fasting glucose levels with a proportion mediated (PM) of 30% (CI: 22-41%). Also, a potential mediatory role of SHBG was observed for sex differences in incidence of T2D (PM = 95% and 63% in models 1 and 2, respectively). Our novel findings suggest that SHBG may partially explain sex-differences in glucose control and T2D incidence.
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Glucemia , Diabetes Mellitus Tipo 2 , Homeostasis , Globulina de Unión a Hormona Sexual , Humanos , Globulina de Unión a Hormona Sexual/metabolismo , Globulina de Unión a Hormona Sexual/análisis , Diabetes Mellitus Tipo 2/epidemiología , Diabetes Mellitus Tipo 2/sangre , Masculino , Femenino , Persona de Mediana Edad , Incidencia , Glucemia/metabolismo , Alemania/epidemiología , Estudios Transversales , Anciano , Factores Sexuales , Adulto , Factores de Riesgo , Estudios LongitudinalesRESUMEN
BACKGROUND: This study sought to investigate the correlation between serum sex hormone-binding globulin (SHBG) levels and nutrition indicators and the malnutrition exposure risk in men and postmenopausal women with type 2 diabetes mellitus (T2DM). METHODS: A cross-sectional analysis was conducted, involving patients diagnosed with T2DM at the Guangdong Provincial People's Hospital between May 2018 and December 2019. RESULTS: The study comprised 551 participants (363 men, mean age of 55.55 ± 11.57 years), among whom 167 (30.31%) were classified as with malnutrition exposure risk (GNRI ≤ 98). Multivariable logistic regression analysis revealed that SHBG (OR = 1.04, 95% CI: 1.02-1.05, P < 0.001), glycated hemoglobin (OR = 1.36, 95% CI: 1.22-1.51, P < 0.001), hemoglobin (OR = 0.96, 95% CI: 0.94-0.97, P < 0.001), and non-alcoholic fatty liver disease (OR = 0.41, 95% CI: 0.23-0.73, P < 0.003) were independently associated with the malnutrition exposure risk. SHBG was inversely correlated with body mass index (males: r = -0.34; postmenopausal females: r = -0.22), albumin (males: r = -0.30; postmenopausal females: r = -0.20), transferrin (males: r = -0.28; postmenopausal females: r = -0.19), and prealbumin (males: r = -0.35; postmenopausal females: r = -0.30) (all P < 0.05). CONCLUSIONS: Serum SHBG levels are correlated with nutritional indicators and the risk of malnutrition in men and postmenopausal women with T2DM. A multicenter prospective study is imperative to verify this result in the future.
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Diabetes Mellitus Tipo 2 , Desnutrición , Posmenopausia , Globulina de Unión a Hormona Sexual , Humanos , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/epidemiología , Diabetes Mellitus Tipo 2/complicaciones , Globulina de Unión a Hormona Sexual/análisis , Globulina de Unión a Hormona Sexual/metabolismo , Femenino , Masculino , Persona de Mediana Edad , Estudios Transversales , Posmenopausia/sangre , Desnutrición/sangre , Desnutrición/epidemiología , Anciano , Biomarcadores/sangre , Estado Nutricional , Factores de Riesgo , Índice de Masa Corporal , Adulto , PronósticoRESUMEN
BACKGROUND: Metabolic syndrome (MetS) presents a notable public health challenge on a global scale, exerting a considerable impact on individuals' health and quality of life. There is mounting evidence indicating a robust association between MetS and levels of sex hormones. Therefore, the study aims to explore the relationship between sex hormone binding-globulin (SHBG) and MetS, and to provide evidence that could inform the development of effective prevention strategies for MetS. METHODS: Data for this cross-sectional investigation were collected during the 2013-2016 cycle of the National Health and Nutrition Examination Survey (NHANES), from which 5,499 adults were sampled. The criteria established by the Adult Treatment Program III of the National Cholesterol Education Program were utilized to define MetS. SHBG levels were measured using a standardized technique. Multivariate-adjusted logistic regression, multivariate restricted cubic spline, and threshold effect analyses were utilized to investigate the association between SHBG levels and MetS. Moreover, the stratified analyses and interaction tests of covariables were presented in a forest plot. Finally, sensitivity analysis was utilized to ensure the robustness of the results. RESULTS: Overall, 1822 participants had MetS. After adjusting for possible confounders, SHBG levels were associated with MetS (Odds ratio [OR], 0.984; 95% confidence interval [CI], 0.981-0.986; P < 0.01). The multivariate restricted cubic spline analysis demonstrated a non-linear association between SHBG and MetS (P < 0.001). With two piecewise regression models, the adjusted OR of developing MetS was 0.964 (95% CI, 0.959-0.969; P < 0.001) among people with SHBG < 76.653 nmol/L, but there was no correlation between SHBG and MetS in participants with SHBG ≥ 76.653 nmol/L. The stability of the association between SHBG levels and MetS was confirmed using subgroup analysis and sensitivity analyses. CONCLUSIONS: Our results suggest that reduced SHBG levels are associated with an increased prevalence of MetS in adults, particularly when SHBG levels are below 76.653 nmol/L. More investigation is required to understand comprehend the mechanisms underlying these results and to delve into their clinical implications.
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Background: 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. Methods: 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. Results: 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. Conclusion: 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.
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Hormona Luteinizante , Síndrome Metabólico , Globulina de Unión a Hormona Sexual , Humanos , Masculino , Síndrome Metabólico/epidemiología , Síndrome Metabólico/sangre , Persona de Mediana Edad , China/epidemiología , Estudios Prospectivos , Anciano , Globulina de Unión a Hormona Sexual/metabolismo , Globulina de Unión a Hormona Sexual/análisis , Hormona Luteinizante/sangre , Testosterona/sangre , Hormona Folículo Estimulante/sangre , Hormonas Gonadales/sangre , Adulto , Estudios de Seguimiento , Estudios Longitudinales , Estudios de CohortesRESUMEN
Objective: To assess the performance of the Sex Hormone-Binding Globulin (SHBG) assay as a diagnostic indicator of Gestational Diabetes Mellitus (GDM) in the study population. Design: Analytical cross-sectional study. Setting: Hospital-based, Benue State University Teaching Hospital (BSUTH), Makurdi, Nigeria. Participants: Women with singleton pregnancies at 24 to 28 weeks gestational age attending Antenatal care at BSUTH, Makurdi. Intervention: Serum SHBG levels were assayed by ELISA during a diagnostic 75-gram Oral Glucose Tolerance Test (OGTT) for assessment of GDM in the cohort of consecutively selected participants who met the inclusion criteria. Main Outcome Measures: Serum levels of SHBG and presence of GDM in the participants. Result: Serum SHBG was significantly negatively correlated (rpb = - 0.534, p-value < 0.001) with the presence of GDM. It had an area under the ROC curve of 0.897 (95% Confidence Interval = 0.858-0.935; p-value < 0.001). A cut-off value of 452.0 nmol/L indicative of GDM had a diagnostic odds ratio of 21.4 in the study population. Conclusion: SHBG is a valuable diagnostic indicator for GDM in the study population. Funding: None declared.
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Diabetes Gestacional , Prueba de Tolerancia a la Glucosa , Globulina de Unión a Hormona Sexual , Humanos , Femenino , Diabetes Gestacional/diagnóstico , Diabetes Gestacional/sangre , Embarazo , Globulina de Unión a Hormona Sexual/análisis , Estudios Transversales , Adulto , Nigeria , Curva ROC , Adulto Joven , Biomarcadores/sangre , Ensayo de Inmunoadsorción EnzimáticaRESUMEN
Objectives: To investigate longitudinal changes in SHBG and free testosterone (free T) levels among Black middle-aged African men, with and without coexistent HIV, and explore associations with incident dysglycaemia and measures of glucose metabolism. Design: This longitudinal study enrolled 407 Black South African middle-aged men, comprising primarily 322 men living without HIV (MLWOH) and 85 men living with HIV (MLWH), with normal fasting glucose at enrollment. Follow-up assessments were conducted after 3.1 ± 1.5 years. Methods: At baseline and follow-up, SHBG, albumin, and total testosterone were measured and free T was calculated. An oral glucose tolerance test at follow-up determined dysglycaemia (impaired fasting glucose, impaired glucose tolerance, type 2 diabetes) and glucose metabolism parameters including insulin sensitivity (Matsuda index), insulin resistance (homeostasis model assessment of insulin resistance), and beta(ß)-cell function (disposition index). The primary analysis focussed on MLWOH, with a subanalysis on MLWH to explore whether associations in MLWOH differed from MLWH. Results: The prevalence of dysglycaemia at follow-up was 17% (n = 55) in MLWOH. Higher baseline SHBG was associated with a lower risk of incident dysglycaemia (odds ratio 0.966; 95% confidence interval 0.945-0.987) and positively associated with insulin sensitivity (ß = 0.124, P < .001) and ß-cell function (ß = 0.194, P = .001) at follow-up. Free T did not predict dysglycaemia. In MLWH, dysglycaemia prevalence at follow-up was 12% (n = 10). Neither baseline SHBG nor free T were associated with incident dysglycaemia and glucose metabolism parameters in MLWH. Conclusion: SHBG levels predict the development of dysglycaemia in middle-aged African men but do not exhibit the same predictive value in MLWH.
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SCOPE: Polycystic ovary syndrome (PCOS) is closely related to non-alcoholic fatty liver disease (NAFLD), and sex hormone-binding globulin (SHBG) is a glycoprotein produced by the liver. Hepatic lipogenesis inhibits hepatic SHBG synthesis, which leads to hyperandrogenemia and ovarian dysfunction in PCOS. Therefore, this study aims to characterize the mechanism whereby liver lipogenesis inhibits SHBG synthesis. METHODS AND RESULTS: This study establishes a rat model of PCOS complicated by NAFLD using a high-fat diet in combination with letrozole and performs transcriptomic analysis of the liver. Transcriptomic analysis of the liver shows that the expression of neurite growth inhibitor-B receptor (NgBR), hepatocyte nuclear factor 4α (HNF4α), and SHBG is low. Meantime, HepG2 cells are treated with palmitic acid (PA) to model NAFLD in vitro, which causes decreases in the expression of NgBR, HNF4α, and SHBG. However, the expression of HNF4α and SHBG is restored by treatment with the AMP-activated protein kinase (AMPK) agonist AICAR. CONCLUSIONS: NgBR regulates the expression of HNF4α by activating the AMPK signaling pathway, thereby affecting the synthesis of SHBG in the liver. Further mechanistic studies regarding the effect of liver fat on NGBR expression are warranted.
Asunto(s)
Proteínas Quinasas Activadas por AMP , Dieta Alta en Grasa , Factor Nuclear 4 del Hepatocito , Hiperglucemia , Letrozol , Hígado , Síndrome del Ovario Poliquístico , Globulina de Unión a Hormona Sexual , Animales , Letrozol/farmacología , Factor Nuclear 4 del Hepatocito/metabolismo , Factor Nuclear 4 del Hepatocito/genética , Femenino , Síndrome del Ovario Poliquístico/metabolismo , Dieta Alta en Grasa/efectos adversos , Hígado/metabolismo , Hígado/efectos de los fármacos , Globulina de Unión a Hormona Sexual/metabolismo , Globulina de Unión a Hormona Sexual/genética , Células Hep G2 , Humanos , Proteínas Quinasas Activadas por AMP/metabolismo , Ratas Sprague-Dawley , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/etiología , Ratas , Transducción de Señal/efectos de los fármacos , Lipogénesis/efectos de los fármacosRESUMEN
Sex hormone-binding globulin (SHBG) is a homodimeric glycoprotein produced by the human liver and secreted into the systemic circulation where it binds with high affinity sex steroids regulating their availability in blood and accessibility to target tissues. Plasma SHBG levels are altered in metabolic disorders such as obesity, anorexia, and insulin resistance. Several reports have shown that diets in terms of total calories or fat, fiber, or protein content can alter plasma SHBG levels. However, there are many components in a diet that can affect SHBG gene expression in the liver. In order to unravel the molecular mechanisms by which diets regulate SHBG production, it would be necessary to analyze single diet components and/or nutritional factors. This review summarizes the recent advances in identifying different nutritional factors regulating SHBG production and the related molecular mechanism, as well as the clinical implications.
Asunto(s)
Globulina de Unión a Hormona Sexual , Humanos , Globulina de Unión a Hormona Sexual/metabolismo , Globulina de Unión a Hormona Sexual/fisiología , Hígado/metabolismo , Obesidad/metabolismo , Dieta , Fibras de la Dieta/metabolismo , Animales , Proteínas en la Dieta/metabolismo , Grasas de la Dieta/metabolismo , Resistencia a la InsulinaRESUMEN
CONTEXT: Cardiorespiratory fitness, commonly assessed as maximal volume of oxygen consumption (VO2max), has emerged as an important predictor of morbidity and mortality. OBJECTIVE: We investigated the causality and directionality of the associations of VO2max with body composition, physical activity, diabetes, performance enhancers, and longevity. METHODS: Using publicly available summary statistics from the largest genome-wide association studies publicly available, we conducted a bidirectional two-sample Mendelian randomization (MR) study. Bidirectional MR tested directionality, and estimated the total causal effects, whereas multivariable MR (MVMR) estimated independent causal effects. Cardiorespiratory fitness (VO2max) was estimated from a submaximal cycle ramp test (N≈90,000) and scaled to total body weight, and in additional analyses to fat-free mass (mL/min/kg). RESULTS: Genetically predicted higher (per one standard deviation increase) body fat percentage was associated with lower VO2max (ß=-0.36 [95% CI: -0.40, -0.32], p=6E-77). Meanwhile, genetically predicted higher appendicular lean mass (0.10 [0.08,0.13] p=3E-16), physical activity (0.29 [0.07,0.52]), and performance enhancers (fasting insulin, hematocrit, and free testosterone in men) were all positively associated with VO2max (p<0.01). Genetic predisposition to diabetes had no effect on VO2max. MVMR showed independent causal effects of body fat percentage, appendicular lean mass, physical activity, and hematocrit on VO2max, as well as of body fat percentage and type 2 diabetes (T2D) on longevity. Genetically predicted VO2max showed no associations. CONCLUSION: Cardiorespiratory fitness can be improved by favorable body composition, physical activity, and performance enhancers. Despite being a strong predictor of mortality, VO2max is not causally associated with T2D or longevity.
RESUMEN
BACKGROUND: Previous observational studies have indicated an inverse correlation between circulating sex hormone binding globulin (SHBG) levels and the incidence of polycystic ovary syndrome (PCOS). Nevertheless, conventional observational studies may be susceptible to bias. Consequently, we conducted a two-sample Mendelian randomization (MR) investigation to delve deeper into the connection between SHBG levels and the risk of PCOS. METHODS: We employed single-nucleotide polymorphisms (SNPs) linked to serum SHBG levels as instrumental variables (IVs). Genetic associations with PCOS were derived from a meta-analysis of GWAS data. Our primary analytical approach relied on the inverse-variance weighted (IVW) method, complemented by alternative MR techniques, including simple-median, weighted-median, MR-Egger regression, and MR Pleiotropy RESidual Sum and Outlier (MR-PRESSO) testing. Additionally, sensitivity analyses were conducted to assess the robustness of the association. RESULTS: We utilized 289 SNPs associated with serum SHBG levels, achieving genome-wide significance, as instrumental variables (IVs). Our MR analyses revealed that genetically predicted elevated circulating SHBG concentrations were linked to a reduced risk of PCOS (odds ratio (OR) = 0.56, 95% confidence interval (CI): 0.39-0.78, P = 8.30 × 10-4) using the IVW method. MR-Egger regression did not detect any directional pleiotropic effects (P intercept = 0.626). Sensitivity analyses, employing alternative MR methods and IV sets, consistently reaffirmed our results, underscoring the robustness of our findings. CONCLUSIONS: Through a genetic epidemiological approach, we have substantiated prior observational literature, indicating a potential causal inverse relationship between serum SHBG concentrations and PCOS risk. Nevertheless, further research is needed to elucidate the underlying mechanism of SHBG in the development of PCOS.