Effects Of Sex Hormone-binding Globulin Research Articles

Blood lipid levels mediating the effects of sex hormone-binding globulin on coronary heart disease: Mendelian randomization and mediation analysis

Observational studies indicate that serum sex hormone-binding globulin (SHBG) levels are inversely correlated with blood lipid levels and coronary heart disease (CHD) risk. Given that dyslipidemia is an established risk factor for CHD, we aim to employ Mendelian randomization (MR) in conjunction with mediation analysis to confirm the mediating role of blood lipid levels in the association between SHBG and CHD. First, we assessed the causality between serum SHBG levels and five cardiovascular diseases using univariable MR. The results revealed causality between SHBG levels and reduced risk of CHD, myocardial infarction, as well as hypertension. Specifically, the most significant reduction was observed in CHD risk, with an odds ratio of 0.73 (95% CI 0.63–0.86) for each one-standard-deviation increase in SHBG. The summary-level data of serum SHBG levels and CHD are derived from a sex-specific genome-wide association study (GWAS) conducted by UK Biobank (sample size = 368,929) and a large-scale GWAS meta-analysis (60,801 cases and 123,504 controls), respectively. Subsequently, we further investigated the mediating role of blood lipid level in the association between SHBG and CHD. Mediation analysis clarified the mediation proportions for four mediators: high cholesterol (48%), very low-density lipoprotein cholesterol (25.1%), low-density lipoprotein cholesterol (18.5%), and triglycerides (44.3%). Summary-level data for each mediator were sourced from the UK Biobank and publicly available GWAS. The above results confirm negative causality between serum SHBG levels and the risk of CHD, myocardial infarction, and hypertension, with the causal effect on reducing CHD risk largely mediated by the improvement of blood lipid profiles.

Obesity-Dependent Association of the rs10454142 PPP1R21 with Breast Cancer.

The purpose of this work was to find a link between the breast cancer (BC)-risk effects of sex hormone-binding globulin (SHBG)-associated polymorphisms and obesity. The study was conducted on a sample of 1498 women (358 BC; 1140 controls) who, depending on the presence/absence of obesity, were divided into two groups: obese (119 BC; 253 controls) and non-obese (239 BC; 887 controls). Genotyping of nine SHBG-associated single nucleotide polymorphisms (SNP)-rs17496332 PRMT6, rs780093 GCKR, rs10454142 PPP1R21, rs3779195 BAIAP2L1, rs440837 ZBTB10, rs7910927 JMJD1C, rs4149056 SLCO1B1, rs8023580 NR2F2, and rs12150660 SHBG-was executed, and the BC-risk impact of these loci was analyzed by logistic regression separately in each group of obese/non-obese women. We found that the BC-risk effect correlated by GWAS with the SHBG-level polymorphism rs10454142 PPP1R21 depends on the presence/absence of obesity. The SHBG-lowering allele C rs10454142 PPP1R21 has a risk value for BC in obese women (allelic model: CvsT, OR = 1.52, 95%CI = 1.10-2.11, and pperm = 0.013; additive model: CCvsTCvsTT, OR = 1.71, 95%CI = 1.15-2.62, and pperm = 0.011; dominant model: CC + TCvsTT, OR = 1.95, 95%CI = 1.13-3.37, and pperm = 0.017) and is not associated with the disease in women without obesity. SNP rs10454142 PPP1R21 and 10 proxy SNPs have adipose-specific regulatory effects (epigenetic modifications of promoters/enhancers, DNA interaction with 51 transcription factors, eQTL/sQTL effects on five genes (PPP1R21, RP11-460M2.1, GTF2A1L, STON1-GTF2A1L, and STON1), etc.), can be "likely cancer driver" SNPs, and are involved in cancer-significant pathways. In conclusion, our study detected an obesity-dependent association of the rs10454142 PPP1R21 with BC in women.

Decoding connections in the European population: serum uric acid, sex hormone-binding globulin, total testosterone, estradiol, and female infertility - advanced bidirectional and mediative Mendelian randomization.

Despite observational links between serum uric acid (SUA), sex hormone-related phenotypes, and female infertility, the causality behind these associations remains uncertain. This study utilizes Bidirectional Two-Sample and Mediation Mendelian Randomization to explore the causal relationships and mediation effects of sex hormone-binding globulin (SHBG), total testosterone (TT), and estradiol on these associations. We analyzed single-nucleotide polymorphisms (SNPs) associated with SUA and sex hormone levels using data from large-scale GWAS of European populations. Female infertility data were sourced from 6,481 cases and 75,450 controls in the FinnGen Consortium. We employed methods including Inverse Variance Weighted (IVW), Weighted Median, and MR-Egger regression to assess causality. We found that elevated SUA levels causally increase the risk of female infertility (IVW OR: 1.13, P=0.047). Elevated SUA levels significantly decrease SHBG levels (β=-0.261; P=2.177e-04), with SHBG mediating 27.93% of the effect of SUA on infertility (OR=0.854; 95%CI, 0.793-0.920; P=2.853e-05). Additionally, elevated TT levels, which were associated with decreased SUA levels (β=-0.127), showed an indirect effect on infertility mediated by SUA (β=-0.0187; 95% CI, -0.041 to -0.003; P=0.046). Our findings demonstrate causal links between high SUA and increased risk of female infertility mediated by hormonal factors such as SHBG and TT. These insights suggest new avenues for infertility treatment and highlight the need for further research into these mechanisms.

Exploring Causal Relationships between Leukocyte Telomere Length, Sex Hormone-Binding Globulin Levels, and Osteoporosis Using Univariable and Multivariable Mendelian Randomization.

Recent evidence supports that leukocyte telomere length (LTL) may be positively associated with healthy living and inversely correlated with the risk of age-related diseases, including osteoporosis. Furthermore, it is important to note that sex hormone-binding globulin (SHBG) levels play a crucial role in the regulation of osteoporosis by influencing the availability of sex hormones. Hence, this study holds significant importance as it aims to unravel the roles of LTL and SHBG levels and determine which one acts as a predominant intermediary factor in influencing osteoporosis. Using Mendelian randomization (MR), we can gain valuable insights into the intricate relationships between aging, sex hormones, and bone health. Univariable and multivariable and MR analyses were employed in this study. First, we used genetic variants associated with both LTL, as determined from a study involving 472,174 European participants by Codd et al., and SHBG levels, as identified in a study conducted by Ruth et al. with 370,125 participants, as instrumental variables (IVs). Then we aimed to establish a causal relationship between LTL and SHBG levels and their potential impact on osteoporosis using univariable MR. Finally, we conducted multivariable MR to provide insights into the independent and combined effects of LTL, SHBG levels on osteoporosis risk. We used various MR methods, with the primary analysis employing the inverse-variance weighted (IVW) model. Univariable MR analysis reveals a potential causal effect of longer LTL on reduced risk of osteoporosis [odds ratio (OR): 0.85; 95% confidence interval (CI): 0.73-0.99; p = 0.03]. Conversely, higher genetically determined SHBG levels affect the risk of osteoporosis positively. (OR: 1.38; 95% CI: 1.09-1.75; p < 0.01). We observed a negative causal effect for LTL on the occurrence of SHBG (OR: 0.96; 95% CI 0.94-0.98, p < 0.01). After adjustment of using multivariable MR, the causal effect of LTL on osteoporosis (OR: 0.92; 95% CI: 0.84-1.03; p = 0.14), and the effect of SHBG on osteoporosis (OR: 1.43; 95% CI: 1.16-1.75; p < 0.01) were observed. Longer LTL may confer a protective effect against osteoporosis. Additionally, the levels of SHBG appear to play a crucial role in mediating the relationship between LTL and osteoporosis. By understanding the interplay between these factors, we can gain valuable insights into the mechanisms underlying bone health and aging and potentially identify new avenues for prevention and intervention strategies.

Mendelian randomization analyses identified bioavailable testosterone mediates the effect of sex hormone-binding globulin on prostate cancer.

A better knowledge of the hormonal etiology of prostate cancer is essential for its prevention and treatment. The goal of this study was to provide causal estimates of the connection between sex hormone-binding globulin and prostate cancer and investigate the possible mediating function of other modifiable risk indicators. We used two-step, two-sample multivariable Mendelian randomization using single-nucleotide polymorphisms as instrumental variables for exposure and mediators. Single-nucleotide polymorphisms associated with sex hormone-binding globulin and bioavailable testosterone were screened via a genome-wide association study enrolling European-descent adult male individuals. Summary-level data for prostate cancer (79,148 cases and 61,106 controls) were extracted from the PRACTICAL consortium. The total effect of sex hormone-binding globulin on prostate cancer risk was decomposed into direct and indirect effects through the mediator, bioavailable testosterone. An inverse-variance-weighted method was the primary Mendelian randomization analysis method. Sensitivity analyses were performed via Mendelian randomization-Egger regression, heterogeneity test, pleiotropy test, and leave-one-out test. The directionality that exposure causes the outcome was verified using Mendelian randomization-Steiger test. In the univariable Mendelian randomization analysis, genetically predicted higher sex hormone-binding globulin levels had a causal association with lower prostate cancer risk (odds ratio = 0.944, 95% confidence interval = 0.897-0.993, p = 0.027) and an inverse association with bioavailable testosterone level (odds ratio = 0.945, 95% confidence interval = 0.926-0.965, p = 1.62E-07) without controlling for other factors. Moreover, an increase of one standard deviation (59.5 pmol/L) in genetically predicted bioavailable testosterone level was significantly associated with a 22.0% increase in the overall prostate cancer risk (odds ratio = 1.220, 95% confidence interval = 1.064-1.398, p = 0.004) after adjusting for sex hormone-binding globulin level. The effect size ratio of bioavailable testosterone-mediated sex hormone-binding globulin to prostate cancer was further analyzed to clarify the importance of the mediating effect. Notably, the mediator bioavailable testosterone explained 19.28% (95% confidence interval = 10.76%, 73.78%) of the total effect of sex hormone-binding globulin level on prostate cancer risk. The results support the potentially protective causal effect of genetically predicted higher sex hormone-binding globulin levels against prostate cancer with mediation by the modifiable risk factor, bioavailable testosterone. More research is needed to determine how this possible sex hormone-binding globulin-bioavailable testosterone-prostate cancer link works. Targeting sex hormone-binding globulin and bioavailable testosterone traits may be a valuable strategy for preventing prostate cancer.

Effect of Sex Hormone-Binding Globulin on Polycystic Ovary Syndrome: Mechanisms, Manifestations, Genetics, and Treatment.

Polycystic ovary syndrome (PCOS) is one of the most common endocrine diseases causing infertility in women of childbearing age. It is characterized by hyperandrogenemia (HA), chronic anovulation, and polycystic ovary morphology (PCOM). Most women with PCOS have metabolic abnormalities. Sex hormone-binding globulin (SHBG), a transport carrier that binds estrogen and androgens and regulates their biological activity, is usually used as an indicator of hyperandrogenism in women with PCOS. Low serum SHBG levels are considered a biomarker of metabolic abnormalities and are associated with insulin resistance (IR), HA, and abnormal glucose and lipid metabolism in PCOS patients. SHBG is also related to the long-term prognosis of PCOS, whereas SHBG gene polymorphism is associated with PCOS risk. In addition, the administration of metformin (MET), glucagon-like peptide-1 receptor agonists (GLP-1 RAs), thiazolidinediones (TZDs), compound oral contraceptives (COCs), as well as nutrient supplements such as inositol (MI), vitamin D, and synbiotics can regulate SHBG levels to ameliorate PCOS complications and improve prognosis. This review focuses on the interaction between SHBG and various PCOS complications as well as the regulation of SHBG by various drugs and nutrients and its therapeutic effects on PCOS.

Causal effect of sex hormone-binding globulin and testosterone on coronary heart disease: A multivariable and network Mendelian randomization analysis

BackgroundAlthough observational studies have shown an association between sex hormone-binding globulin (SHBG), testosterone (T) and cardiovascular diseases (CVD), controversy remains. In this study, we aim to explore the causal effects of SHBG and T on Coronary heart disease (CHD). MethodsWe used univariable, network and multivariable mendelian randomization (MR) analysis to investigate the causal effect of SHBG and T on CHD. We performed inverse variance weighted (IVW) MR as the primary analysis, with the robustness of this approach further tested by other methods in sensitivity analysis. The SHBG and T were collected from the UK Biobank data, about 180,000 men aged 40 to 69 years. CHD was collected from CARDIoGRAMplusC4D 1000 Genomes-based GWAS, which was a meta-analysis including 48 studies and involving 60,801 CHD cases and 123,504 controls. ResultsUsing univariable MR-IVW, the results suggested that a one standard deviation (SD) increase in SHBG, the risk of CHD decreased by approximately 14% (OR (95% CI): 0.86(0.76,0.97)), and that a SD increase in total testosterone (TT), the risk also decreased, approximately 8% (OR (95% CI): 0.92(0.85,0.99)). Multivariable MR showed that both SHBG and TT had no direct causal effect with CHD (a SD increase in SHBG: OR (95% CI):0.75(0.57,1.00), P = 0.053; a SD increase in TT: OR (95% CI): 1.05(0.90,1.22), P = 0.53). In the network MR analysis, the results suggested that TT might act as mediator in the causal pathway from SHBG to CHD and account for 93% of the total effect of SHBG on CHD, and that SHBG might be a mediator in the causal pathway from TT to CHD and account for 67% of the total effect of TT on CHD. ConclusionsGenetically predicted SHBG and TT were negatively correlated with CHD in both univariable and network MR, which may provide a causal explanation behind the observed conclusion. In addition, TT and SHBG had a bidirectional causal effect. Further work is required to disentangle the downstream effects of SHBG/TT on CHD and the molecular pathways involved, as the simultaneous regulation of SHBG and TT may make it a viable strategy for the prevention or treatment of CHD.

Protective Effect of Sex Hormone-Binding Globulin against Metabolic Syndrome: In Vitro Evidence Showing Anti-Inflammatory and Lipolytic Effects on Adipocytes and Macrophages.

Sex hormone-binding globulin (SHBG) is a serum protein released mainly by the liver, and a low serum level correlates with a risk for metabolic syndrome including diabetes, obesity, and cardiovascular events. However, the underlying molecular mechanism(s) linking SHBG and metabolic syndrome remains unknown. In this study, using adipocytes and macrophages, we focused on the in vitro effects of SHBG on inflammation as well as lipid metabolism. Incubation with 20 nM SHBG markedly suppressed lipopolysaccharide- (LPS-) induced inflammatory cytokines, such as MCP-1, TNFα, and IL-6 in adipocytes and macrophages, along with phosphorylations of JNK and ERK. Anti-inflammatory effects were also observed in 3T3-L1 adipocytes cocultured with LPS-stimulated macrophages. In addition, SHBG treatment for 18 hrs or longer significantly induced the lipid degradation of differentiated 3T3-L1 cells, with alterations in its corresponding gene and protein levels. Notably, these effects of SHBG were not altered by coaddition of large amounts of testosterone or estradiol. In conclusion, SHBG suppresses inflammation and lipid accumulation in macrophages and adipocytes, which might be among the mechanisms underlying the protective effect of SHBG, that is, its actions which reduce the incidence of metabolic syndrome.

Sex Hormone Binding Globulin Modifies Testosterone Action and Metabolism in Prostate Cancer Cells.

Sex Hormone Binding Globulin (SHBG) is the major serum carrier of sex hormones. However, growing evidence suggests that SHBG is internalised and plays a role in regulating intracellular hormone action. This study was to determine whether SHBG plays a role in testosterone uptake, metabolism, and action in the androgen sensitive LNCaP prostate cancer cell line. Internalisation of SHBG and testosterone, the effects of SHBG on testosterone uptake, metabolism, regulation of androgen responsive genes, and cell growth were assessed. LNCaP cells internalised SHBG by a testosterone independent process. Testosterone was rapidly taken up and effluxed as testosterone-glucuronide; however this effect was reduced by the presence of SHBG. Addition of SHBG, rather than reducing testosterone bioavailability, further increased testosterone-induced expression of prostate specific antigen and enhanced testosterone-induced reduction of androgen receptor mRNA expression. Following 38 hours of testosterone treatment cell morphology changed and growth declined; however, cotreatment with SHBG abrogated these inhibitory effects. These findings clearly demonstrate that internalised SHBG plays an important regulatory and intracellular role in modifying testosterone action and this has important implications for the role of SHBG in health and disease.

The effect of sex hormone-binding globulin (SHBG) protein polymorphism on the levels of SHBG, testosterone, and insulin in healthy Indonesian men

Background: Sex hormone-binding globulin (SHBG) is a protein. The synthesis of SHBG protein is encoded by SHBG gene. Protein polymorphism of SHBG can occur because of a mutation of D327N exon 8 in SHBG gene. D327N mutation causes the addition of glycosylation so that molecular weight of SHBG protein increases. Protein polymorphism of SHBG is suspected to affect the levels of SHBG, testosterone, and insulin in the blood circulation. Objective: To determine the effect of protein polymorphism of SHBG on the levels of SHBG, testosterone, and insulin in healthy adult men. Materials and Methods: Serum samples were collected from 179 healthy adult men. Electrophoresis and western blotting were performed to determine the phenotype of SHBG. All subjects were divided into two groups based on SHBG phenotype; group I (normal SHBG phenotype) n = 159 subjects and group II (variant SHBG phenotype) n = 38 subjects. Result: The levels of serum SHBG, testosterone, and insulin were measured using radioimmunoassay method. The levels of SHBG, total testosterone, and free testosterone between normal SHBG phenotype do not differ with variant SHBG phenotype (p > 0.05), but insulin levels between normal SHBG phenotype compared with variant SHBG phenotype was different (p < 0.05). Conclusion: Protein polymorphisms of SHBG was not found to affect the levels of SHBG, total testosterone, and free testosterone. Protein polymorphism of SHBG was found to affect the insulin levels in the blood serum.

Combined effects of sex hormone-binding globulin and sex hormones on risk of incident type 2 diabetes.

The aim of the present study was to investigate the combined effects of sex hormone-binding globulin (SHBG) and sex hormones on the risk of type 2 diabetes (T2D). A nested case-control study of Chinese participants in the Environment, Inflammation and Metabolic Diseases Study (2008-13) was performed. Of the 3510 subjects free of diabetes, 145 men and 87 women developed diabetes over the 5-year follow-up. One age- and sex-matched control subject was selected for each case. Baseline concentrations of SHBG, estradiol, testosterone, and dehydroepiandrosterone sulfate (DHEA-S) were divided into tertiles and subjects were classified as having low, intermediate and high levels accordingly. After multivariate adjustment, men with low SHBG levels had a fourfold greater risk of T2D than men with high SHBG levels. Conversely, men with high estradiol levels had a fourfold greater risk of T2D than men with low estradiol levels. Men with low SHBG + high estradiol had a 20-fold greater risk of T2D than men with high SHBG + low estradiol (odds ratio [OR] 20.23; 95% confidence interval [CI] 4.62-51.33). These risk associations in men were not observed for testosterone or DHEA-S, alone or in combination with SHBG. Compared with low SHBG, the risk of T2D decreased with increasing SHBG tertile (OR 0.92 [95% CI 0.21-4.53], 0.14 [95% CI 0.10-0.74]; Ptrend = 0.043) after multivariate adjustment in women. Estradiol, testosterone, and DHEA-S levels showed no association with T2D in women. Low SHBG in conjunction with high estradiol has an additive detrimental effect on the risk of T2D in men.

Androgenic sex steroids contribute to metabolic risk beyond intra‐abdominal fat in overweight/obese black and white women

To determine the independent contribution of androgenic sex hormones beyond visceral adipose tissue (VAT) on metabolic risk. A cross-sectional evaluation of 66 (36 white and 30 black) premenopausal overweight/obese women using multiple regression analyses to determine the independent effects of sex hormone-binding globulin (SHBG), total testosterone (TT), and free testosterone using the free androgen index (FAI) on metabolic variables above VAT. SHBG contributed to the variance in insulin (P = 0.003), insulin resistance using HOMA-IR (P = 0.006), and high-density lipoprotein cholesterol2 (P = 0.029). TT contributed to the variance in systolic and diastolic blood pressure (P < 0.001), total cholesterol (P = 0.003), low-density lipoprotein cholesterol (P = 0.003), and apolipoprotein B (P = 0.004). FAI contributed to the variance in the greatest number of metabolic variables beyond VAT. There was also a significant race-FAI interaction for fasting glucose (P = 0.013). A Pearson's correlation coefficient showed a significant relationship between FAI and glucose in white women (r = 0.48, P = 0.003) while showing no relationship in black women (r = -0.01, P = 0.941). Our study showed that androgenic sex steroids contributed significantly to the variance in metabolic variables associated with health risk. However, they do not provide sufficient information relevant to glucose status in black women.

Abstract 011: Sex Hormone-Binding Globulin (SHBG) and Risk of Clinical Diabetes in American Black, Hispanic, and Asian/Pacific Islander Postmenopausal Women.

BACKGROUND: Recent prospective studies have shown a strong inverse association between sex hormone-binding globulin (SHBG) levels and risk of clinical diabetes in Whites. However, it remains unknown whether this relation extends to other racial/ethnic populations. METHODS: We evaluated the association between baseline levels of SHBG and risk of clinical diabetes in the Women’s Health Initiative Observational Study. Over a median follow-up of 5.9 years, 542 postmenopausal women developed clinical diabetes (338 Blacks, 128 Hispanics, 76 Asians) and were matched to 1,110 controls (707 Blacks, 249 Hispanics, 154 Asians). To complement our protein-level findings, we also genotyped 5 SHBG polymorphisms. We performed Mendelian randomization analysis to assess the potential causal relation between SHBG levels and risk of clinical diabetes. RESULTS: Overall, higher levels of SHBG at baseline were associated with a significantly lower risk of clinical diabetes (Relative risk [RR]=0.24, 95% confidence interval [CI]=0.15-0.39 for highest versus lowest quartile of SHBG, adjusted for BMI and other known diabetes risk factors). The associations remained consistent across ethnic groups (p-for-heterogeneity=0.72): RR=0.29 (95%CI=0.16-0.54) for Blacks, RR=0.26 (95%CI=0.09-0.74) for Hispanics, and RR=0.32 (95%CI=0.06-1.73) for Asians, comparing highest to lowest quartiles of SHBG. In addition, SHBG polymorphisms affected diabetes risk proportional to serum SHBG levels. Mendelian randomization analysis confirmed the significant direct effect of SHBG on diabetes development (p=0.03). CONCLUSIONS: In this prospective cohort of postmenopausal women, we observed a robust, inverse relation between serum levels of SHBG and clinical diabetes risk in American Blacks, Hispanics, and Asian/Pacific Islanders. Genetic variants associated with SHBG levels demonstrated a similar relationship, providing support for a causal role of SHBG in the pathogenesis of type 2 diabetes.

The synergistic effect of sex hormone-binding globulin and aromatase genes on polycystic ovary syndrome phenotype.

Experimental evidence suggests that fetal exposure to androgen excess may program the development of polycystic ovary syndrome (PCOS) in utero. The aim of this study was to examine whether the sex hormone binding globulin (SHBG)(TAAAA)n and the cytochrome P450, family 19 (CYP19)(TTTA)n polymorphisms, known to influence sex hormone-binding globulin (SHBG) levels and aromatase activity respectively, play a synergistic role in the development of PCOS. We studied 180 women with PCOS and 160 healthy women of reproductive age. The body mass index (BMI) was recorded and the hormonal profile determined from the third to fifth day of menstrual cycle. DNA was extracted from blood leucocytes and the SHBG(TAAAA)n and CYP19(TTTA)n polymorphisms were genotyped. Genotype analysis revealed 6 SHBG(TAAAA)n alleles with 6-11 repeats and 6 CYP19(TTTA)n alleles with 7-12 repeats. Women were subdivided into four groups: those with short SHBG (< or = 8 TAAAA repeats) and CYP19 alleles (< or = 9 TTTA repeats), those with short SHBG-long CYP19 alleles, those with long SHBG-short CYP19 alleles, and those with long SHBG and CYP19 alleles. Women with PCOS tended to have at greater frequency, long SHBG-short CYP19 alleles compared with controls (57.3 vs 42.4%, P=0.07). Importantly, PCOS women with long SHBG-short CYP19 alleles had the lowest SHBG levels (P=0.02) and the highest total testosterone (P=0.008), free androgen index (P=0.002), DHEAS (P=0.02), and testosterone/estradiol ratio (P=0.03), compared with those with other genotypes. This association was independent of age, BMI, and insulin resistance indexes. We speculate that the SHBG and CYP19 genes may have a synergistic role in the developmental programming of PCOS, by affecting androgen bioavailability and aromatization respectively.

Sex Hormone-binding Globulin Selectively Modulates Estradiol-regulated Genes in MCF-7 Cells

Human sex hormone-binding globulin inhibits the effects of estradiol on proliferation and apoptosis of breast cancer cells. We report here the effect of sex hormone-binding globulin on estradiol regulation of gene expression in MCF-7 breast cancer cells using a selected set of genes. Estradiol upregulates genes that are positive regulators of proliferation (e.g., bcl-2, c-fos, c-myc, cyclin D) or/and related to more aggressive form of breast cancer (e.g. BRCA-1, EGF-R) and downregulates two genes (c-jun and ERalpha). Sex hormone-binding globulin modulates only a selected group of estradiol-controlled genes (inhibiting upregulation of bcl-2, c-myc, EGF-R, PR, and downregulation of ERalpha), starting 48 hours after treatment. Our study demonstrates that in breast cancer cells, sex hormone-binding globulin is effective on few selected genes which are involved in cell growth and apoptosis or related to cell estrogen-dependence and that the protein regulation of estradiol effect is selected and specific. Sex hormone-binding globulin action in estrogen breast cancer cells is strongly associated to cell growth and estrogen-sensitivity.

Age‐related changes in testosterone and SHBG among Turkana males

To determine age-related changes in biologically available testosterone (T) among men in a subsistence society and their relationship to energetic status, T, sex hormone binding globulin (SHBG) and anthropometric measures were compared among nomadic and settled Turkana pastoralists of northern Kenya. Hormonal measures were available for 104 nomadic men and 72 settled men, estimated ages 20-90 years. Comparison of the two subpopulations revealed significantly higher blood T (32.7+/- 15.1 vs. 23.4+/-15.2 nM) and SHBG (53.8+/- 19.5 vs. 39.7+/- 20.nM) but not free testosterone index (FTI) (65.6+/- 39.3 vs.66.3+/- 45.9) among the nomads. Total blood T did not exhibit a significant linear decline with age in either subgroup, while SHBG values showed a significant linear increase among the nomads. When controlled for energetic status, FTI showed a significant decrease with age among the nomads, but not the settled males. Total blood T was negatively associated with waist circumference among the nomads, but not the settled males. FTI showed a marginally significant negative association with waist circumference, suprailiac skinfold, and % body fat among the nomads but no associations with body composition among the settled group. These results add additional evidence that T is related to energetic status under conditions of negative energy balance and suggest that cross-population variation in the slope of age-related declines in free serum T and salivary T may be related to energetic status through the effects of SHBG.

Sex hormone-binding globulin stimulates chorionic gonadotrophin secretion from human cytotrophoblasts in culture.

The effects of sex hormone-binding globulin (SHBG) on the secretion of human chorionic gonadotrophin (HCG) and cAMP by cultured human cytotrophoblasts were investigated. Cytotrophoblasts obtained from normal term placentae were cultured in serum-free medium with or without the addition of human SHBG. The presence of SHBG in the medium increased the release of HCG and the accumulation of cAMP. Ligand-free SHBG was able to raise both HCG and cAMP concentrations and the maximal response was observed with 1 nM of the steroid-binding globulin. Addition of either oestradiol or 5alpha-dihydro-testosterone (DHT) to cultures previously incubated with SHBG in a final molar ratio of 1:10 resulted in a further increase of HCG and cAMP concentrations. This effect was blocked when cultured placental cells were exposed to SHBG that was previously saturated with DHT or when incubated in the presence of steroids only. The results of the present study provide evidence for the in-vitro regulation of HCG secretion by SHBG and further support the concept that this steroid-binding protein may act as a mediator of steroid action at the cellular level. Finally, the increase in cAMP suggests that SHBG receptor located in the surface of syncytiotrophoblast membranes is coupled to adenylate cyclase as part of the G-protein receptor family. Our results may provide new insights into the biological implications of extracellular steroid-binding proteins as well as new perspectives on the endocrinology of pregnancy.

Sex hormone-binding globulin and male sexual development

The masculinization of the brain, reproductive tract and many other structures is critically dependent on the testicular hormone, testosterone (T). In many species, T circulates bound with high affinity to sex hormone-binding globulin (SHBG). This protein has a wide phylogenetic distribution and SHBG or SHBG-like proteins are produced by the liver, testes, placenta, brain and other tissues. SHBG activity is detectable during gestation and its expression is both stage- and tissue-dependent. Although SHBG binds circulating androgens, it is argued that the trapping of steroids in the circulation is not the principal function of this protein. The specific binding and uptake of SHBG by various tissues has been observed and suggests that SHBG may directly affect the delivery of androgen signals to target tissues. Effects of SHBG on androgen metabolism, tissue retention, cellular targeting, and action are reviewed. Evidence to date indicates that SHBG is able to enhance or inhibit the uptake of androgens in a cell- and tissue-specific manner. Future work will be necessary to demonstrate whether such actions of SHBG are important for normal male reproductive development.

Expression of sex hormone-binding globulin mRNA in uterine leiomyoma, myometrium and endometrium of human subjects.

This study was designed to evaluate the effect of sex hormone-binding globulin (SHBG) on the estrogen-dependent growth of human uterine leiomyoma. Levels of SHBG mRNA were analyzed using competitive reverse transcription-polymerase chain reaction-Southern blot analysis (RT-PCR-SBA). In normal uterine endometria, the levels of SHBG mRNA in the early/mid and late proliferative phases of the menstrual cycle were significantly lower than in the secretory phase (p < 0.01). In uterine myometria and leiomyomas, SHBG mRNA level showed no significant differences during the menstrual cycle, while the ratio of leiomyoma SHBG level to the corresponding myometrium SHBG level was >1 in 21 out of 23 cases (91%). Our results suggest that steroidal regulation of intracellular SHBG synthesis in the myometrium and the leiomyoma might differ from that in the endometrium, and that the mechanism of SHBG expression in leiomyoma might, in the process of tumorigenesis, be altered from that of corresponding normal myometrium, contributing to SHBG overexpression and the abundant estrogen supply.

Biological Effects of Sex Hormone-Binding Globulin on Androgen-Induced Proliferation and Androgen Metabolism in LNCaP Prostate Cells*

The effects of purified human sex hormone-binding globulin (SHBG) on androgen-sensitive cell proliferation were examined using a human prostatic cell line (LNCaP-FGC). Cells were grown for 5 days in medium supplemented with 10% charcoal-dextran-stripped human serum (10% CDHuS) and various concentrations of 5 alpha-dihydrotestosterone (DHT). In 10% CDHuS, without SHBG, the proliferative response of these cells to androgens was typically biphasic. At low androgen concentrations, cell yields were increased in a dose-dependent manner, reaching maximal levels at 0.3 nM DHT. However, at high androgen concentrations, cell proliferation was inhibited. Addition of purified human SHBG to the medium reduced the effectiveness of DHT on both phases of the proliferative response in a dose-dependent manner. These effects of SHBG appeared to be due primarily to the high affinity binding of DHT by SHBG. Proliferative responses induced by the synthetic androgen methyltrienolone (R1881), which binds poorly to SHBG, were not affected by added SHBG. Furthermore, analysis of the protein binding of DHT revealed that cell proliferation correlated best with the concentration of DHT not bound to SHBG. The presence of SHBG in the medium also altered the uptake and metabolism of DHT. LNCaP-FGC cells rapidly metabolized DHT to a polar glucuronidase-sensitive conjugate of DHT. In 10% CDHuS, LNCaP-FGC cells conjugated virtually all of the added DHT during the 5-day experiment. However, in medium containing SHBG, the SHBG-bound DHT remained unconjugated; more than 90% of the DHT initially bound to SHBG was present in the medium at the end of the experiment as unconjugated DHT. Uptake of radiolabeled DHT by cells was also inhibited by SHBG. In summary, these experiments provide evidence that 1) SHBG-bound DHT is not a signal for DHT-induced cell proliferation and 2) SHBG inhibits the uptake and metabolism of DHT by LNCaP-FGC cells.