Differences In Sex Hormone-binding Globulin Levels Research Articles

OR31-05 Long-Term Effects Of Gender Affirming Hormone Therapy On Insulin Sensitivity, Insulin Secretion, And Glucose Tolerance

Abstract Disclosure: S. Pinkson: None. J. Trejo: None. A. Mendoza: None. L. Gondin Hernandez: None. S. Chen: None. S. ahuja: None. D. Tripathy: None. Over the past 15 years, transgender veterans seeking Gender Affirming Hormone Therapy (GAHT) have increased significantly. The metabolic effects of long-term GAHT have been controversial possibly because of multiple confounding factors and different methodologies. We examined long-term effects of estradiol and testosterone on insulin sensitivity and insulin secretion in nondiabetic transwomen and transmen. A total of 4 groups (i) 7 transwomen (age 50 ± 4 yr, BMI 31 ± 2 kg/m2) (ii) 6 transmen (age 38 ± 4yr, BMI 33 ± 2 mg/m2) followed for 52 ± 9 months and as a control group (iii) six cisgender men (age 36 ± 4 yrs, BMI 32 ± 2 kg/m2) and (iv) 8 cisgender women (age 39 ± 4 yr, BMI 28 ± 2 kg/m2) participated in an OGTT and Botnia clamp (IV glucose tolerance test: IVGTT followed by hyperinsulinemic (80 mU.m2/min euglycemic clamp). Total testosterone (by equilibration dialysis method), estradiol, sex hormone binding globulin (SHBG) and lipid profile was measured in all subjects. Insulin, and C-peptide were measured every 30 min during the OGTT. Insulin sensitivity was measured as the M-value form last 30 minutes of insulin clamp and as Matsuda index of insulin sensitivity from the OGTT. Indices of insulin secretion (data pending) was calculated as the first phase insulin response from IVGTT (FPIR: 2-10min) and as indices of beta cell function from OGTT: Insulin secretion/insulin resistance index (Insulin 0-120/Glucose 0-120 X Matsuda index). Plasma estradiol in transwomen was 209 ± 92 pg/ml vs. 32 ± 6 pg/ml in cisgender men. Similarly, the total testosterone level in transmen was 319 ± 57 vs. 19 ± 4 ng/dl in cisgender women. There was no difference in SHBG levels between the groups. The body fat content was not different between trans or cis men (36 ± 3 vs 35 ± 1.4 % ) while it was higher in trans vs cis women (40 ± 0.8 vs 30 ± 3%). There was no difference in HbA1c (5.4 ± 0.2 vs 5.2 ± 0.2%, p=ns) between transwomen and cismen and (5.6 ± 0.1 vs 5.5 ± 0.1, p=ns) transmen and ciswomen. The glucose AUC was higher in transmen vs cisgender women (5,487 ± 994 vs. 3,420 ± 533; P < 0.05). There was no difference in glucose AUC between the transwomen and cismen. There was no difference in insulin sensitivity (M-value) between transwomen and cisgender men (6.9 ± 1.2 vs 7.0 ± 1.4 mg.kg/min, p=ns), while it tended to be worse in transmen compared to cisgender women ( 6.03 ± 1.0 vs 7.7± 0.6 mg.kg/min, p=0.1). In both groups M-Value was inversely related to BMI (r=-0.59; p<0.05). There was no relationship between insulin sensitivity and plasma total testosterone level. HDL cholesterol was lower in transmen (41 ± 2.5 vs 55 ± 4 mg/dL, p<0.05) versus cisgender women though there was no difference in triglyceride, total or LDL cholesterol between the groups. In conclusion long-term GAHT therapy does not adversely affect insulin sensitivity in trans men or women and the mildly altered glucose tolerance is likely a result of higher BMI in transmen. Presentation: Sunday, June 18, 2023

PCOS Features and Steroid Profiles Among Young Adult Women with a History of Premature Adrenarche.

ContextPremature adrenarche (PA) may increase the risk for polycystic ovary syndrome (PCOS).ObjectiveTo study features of PCOS in young adult women with a history of PA.MethodsThirty PA and 42 control females were followed from prepuberty to young adulthood (median age 18.1 years). The main outcome measures were ovarian function, the use of contraceptives, and clinical and biochemical indicators of hyperandrogenism.ResultsWe found no differences in the use of hormonal contraceptives (50 vs 50%, PA vs controls, respectively; P > .999), indication for using contraceptives (P = .193), or in the history of oligo- (17 vs 26%, P = .392) and amenorrhea (0 vs 0%, P > .999). Among women not using hormonal contraceptives, those with a history of PA had a higher prevalence of hirsutism (27 vs 0%, P = .023) but not acne (87 vs 67%, P = .252). Steroid profiles were broadly comparable between the groups, but PA women had lower sex hormone–binding globulin (SHBG) concentrations (30.1 vs 62.4 nmol/L, P < .001) resulting in higher free androgen index (3.94 vs 2.14, P < .001). The difference in SHBG levels persisted through body mass index adjustment. SHBG correlated negatively with the homeostasis model assessment for insulin resistance (r –0.498, P = .003). Anti-Müllerian hormone concentrations were comparable between the groups (39.3 vs 32.1 pmol/L, P = .619).ConclusionPA was not associated with evident ovarian dysfunction in young adult women. However, women with a history of PA had decreased SHBG levels and thus, increased bioavailability of circulating androgens.

Association of rs6259 polymorphism with SHBG levels and Poly Cystic Ovary Syndrome in Indian population: a case control study.

Polycystic ovary syndrome (PCOS) is the most common endocrinopathy of reproductive-aged women. PCOS reflects a number of possible etiologies but its pathophysiology is still unclear. The principal abnormality of the syndrome is hyperandrogenism (70-80%). The access of androgens to target tissues is regulated by sex hormone-binding globulin (SHBG), a transport protein secreted by liver i.e. specific for androgens. Present study was done to find the association of rs6259 polymorphism with SHBG levels and Poly Cystic Ovary Syndrome in Indian population. Present study was a case control study. 400 subjects were enrolled for the study and serum SHBG levels and D327N polymorphism were measured. The D327N polymorphism (wild-type and variant allele) was detected using PCR-RFLP method (restriction enzyme Bbs-I). PCOS group was found to have significantly lower SHBG levels than healthy controls. There was no significant difference in genotype distribution between PCOS and controls (χ2 = 1.0335, p = 0.59). Significant difference in SHBG levels of PCOS and control group highlights the potential of SHBG as a biomarker for PCOS. However, no significant difference in genotype distribution between PCOS and controls provided an insight that rs6259 polymorphism is not associated with the risk of PCOS and SHBG levels.

Sex Hormone–Binding Globulin, Cardiometabolic Biomarkers, and Gestational Diabetes—A Longitudinal Pregnancy Cohort Study and a Meta-analysis

Background: Sex hormone-binding globulin (SHBG) has been implicated in glucose metabolism and the development of type 2 diabetes. However, its role in glucose metabolism during pregnancy is unclear. Objectives: This study investigated the prospective associations of SHBG with cardiometabolic biomarkers during pregnancy and gestational diabetes (GDM) risk. Methods: We conducted a nested case-control study of 107 GDM cases and 214 matched controls without GDM in the NICHD Fetal Growth Studies-Singleton Cohort. GDM was ascertained by medical record review. Blood samples were drawn at 10-14, 15-26, 23-31 and 33-39 gestational weeks (GW). Prospective associations of SHBG with cardiometabolic biomarkers were estimated using Spearman’s correlation coefficient adjusting for potential confounders. Difference in SHBG levels between GDM and non-GDM women was estimated in the present study cohort and a meta-analysis of existing prospective evidence. Odds ratios (OR) for GDM by SHBG quartiles were estimated using conditional logistic regression. Results: SHBG at GW 10-14 was significantly and inversely related to fasting glucose, fasting insulin, insulin resistance and HbA1c levels, and positively related to high-density lipoprotein and cholesterol levels at GW 15-26. Cases had lower SHBG levels compared to controls at GW 10-14 (mean ± SD: 204.0 ± 97.6 vs. 220.9 ± 102.5 nmol/L) and 15-26 (305.6 ± 124.3 vs. 322.7 ± 105.1 nmol/L), yet the differences were not significant. Meta-analysis of 11 prospective studies, including ours, estimated SHBG levels to be 0.50 SD (95% CI: 0.36-0.65) lower among women with than without GDM. Conclusions: Higher SHBG levels in early pregnancy was associated with a favorable glucose metabolic profile among pregnant women. Synthesis of prospective studies supports an inverse association between SHBG levels and GDM risk. Disclosure M. Li: None. S. Rawal: None. S. Hinkle: None. S. Liu: None. F. Tekola-Ayele: None. C. Zhang: None.

Evaluación de la globulina transportadora de hormonas esteroidales (SHBG) durante el embarazo como factor predictor de pre-eclampsia y restricción del crecimiento intrauterino

Sex-Hormone Binding Globulin (SHBG) may be associated to Pre-eclampsia (PE) and Fetal Growth Restriction (RCIU).To determine if maternal serum SHBG concentrations during the first and second trimesters are predictive biomarkers of Pre-eclampsia and RCIU.Prospective cohort study carried out in the Fetal Medicine Unit, Universidad de Chile Clinical Hospital between January, 2005 and December, 2006. Blood samples were obtained from unselected pregnant women during routine 11-14 week and 22-25 week ultrasound examinations, conforming two different study groups. Posteriorly, serum SHBG concentrations were determined in women who developed Pre-eclampsia, RCIU and their respective controls.Fifty five patients were included in the 11-14 weeks group. Nine women that developed PE, 10 that developed RCIU and 36 controls were selected from this group. There were no significant differences in SHBG levels between patients with PE, RCIU or controls (324.7 (26.6), 336.8 (33.9) and 377.5 (24.3) nmol/L, respectively). Fifty four women were included in the 22-25 weeks group. Eight women who developed Pre-eclampsia, 15 who developed RCIU and 31 controls were selected. Again, there were no significant differences in SHBG levels between patients with PE, RCIU or controls (345.5 (151.1), 383.8 (143.4) and 345.5 nmol/l (151.1), respectively).Maternal SHBG serum levels did not predict subsequent development of Pre-eclampsia and RCIU.

Sex hormone–binding globulin and risk of hyperglycemia in patients with androgenetic alopecia

Low circulating levels of sex hormone-binding globulin (SHBG) are a strong predictor of the risk of type 2 diabetes. Androgenetic alopecia (AGA) has been related to an increase in cardiovascular risk, but the mechanism of this association has not been elucidated. AGA can be associated with low levels of SHBG and insulin resistance, which could be related to hyperglycemia and type 2 diabetes. The objective of this study was to evaluate SHBG and blood glucose levels in men and women with early-onset AGA and control subjects to determine whether low levels of SHBG are associated with hyperglycemia. This case-control study included 240 patients consecutively admitted to the outpatient clinic (Dermatology Department of San Cecilio University Hospital, Granada, Spain), 120 with early-onset AGA (60 men and 60 women) and 120 control subjects (60 men and 60 women) with skin diseases other than alopecia. Of patients with AGA, 39.1% presented with hyperglycemia (>110 mg/dL) versus 12.5% of controls (P < 0.0001). AGA patients with hyperglycemia or diabetes presented lower significant levels of SHBG than alopecic patients without hyperglycemia or type 2 diabetes, respectively. Patients with AGA and hyperglycemia presented significantly lower levels of SHBG than controls with hyperglycemia (22.3 vs 39.4 nmol/L for AGA patients and controls, respectively, P = .004). No significant differences in SHBG levels were noticed between patients and controls without hyperglycemia. Binary logistic regression showed a strong association between lower SHBG levels and glucose levels greater than 110 mg/dL in patients with AGA even after additional adjustment for sex, abdominal obesity, and free testosterone (odds ratio = 3.35; 95% confidence interval = 1.9-5.7; P < .001). The study of a wider sample of AGA patients would confirm these findings and would permit analysis of the pathogenic mechanisms underlying the increase in cardiovascular risk in patients with AGA. An association between early-onset AGA, hyperglycemia/diabetes, and low levels of SHBG was observed in the current study. Low levels of SHBG could be a marker of insulin resistance and hyperglycemia/diabetes in patients with AGA.

Genetic evidence that raised sex hormone binding globulin (SHBG) levels reduce the risk of type 2 diabetes.

Epidemiological studies consistently show that circulating sex hormone binding globulin (SHBG) levels are lower in type 2 diabetes patients than non-diabetic individuals, but the causal nature of this association is controversial. Genetic studies can help dissect causal directions of epidemiological associations because genotypes are much less likely to be confounded, biased or influenced by disease processes. Using this Mendelian randomization principle, we selected a common single nucleotide polymorphism (SNP) near the SHBG gene, rs1799941, that is strongly associated with SHBG levels. We used data from this SNP, or closely correlated SNPs, in 27 657 type 2 diabetes patients and 58 481 controls from 15 studies. We then used data from additional studies to estimate the difference in SHBG levels between type 2 diabetes patients and controls. The SHBG SNP rs1799941 was associated with type 2 diabetes [odds ratio (OR) 0.94, 95% CI: 0.91, 0.97; P = 2 × 10−5], with the SHBG raising allele associated with reduced risk of type 2 diabetes. This effect was very similar to that expected (OR 0.92, 95% CI: 0.88, 0.96), given the SHBG-SNP versus SHBG levels association (SHBG levels are 0.2 standard deviations higher per copy of the A allele) and the SHBG levels versus type 2 diabetes association (SHBG levels are 0.23 standard deviations lower in type 2 diabetic patients compared to controls). Results were very similar in men and women. There was no evidence that this variant is associated with diabetes-related intermediate traits, including several measures of insulin secretion and resistance. Our results, together with those from another recent genetic study, strengthen evidence that SHBG and sex hormones are involved in the aetiology of type 2 diabetes.

Effects of polymorphisms of the sex hormone-binding globulin (SHBG) gene on free estradiol and bone mineral density

Background Polymorphisms of the sex hormone-binding globulin (SHBG) gene are associated with differences in SHBG levels, influencing the risk for breast cancer and polycystic ovarian syndrome, but no association has been reported for osteoporosis in postmenopausal women. Objective To determine the effect of G to A substitution in the 5′UTR (rs1799941) and the Asp356Asn (rs6259) polymorphisms of the SHBG gene on bone mineral density (BMD). Methods This is a cross-sectional study in a university-based research center from May, 2002 to December, 2007. A total of two hundred and thirteen healthy postmenopausal Caucasian women ≥ 1 year from last menstrual period participated to this study. Serum estradiol by ultrasensitive radioimmnunoassay, serum sex hormone-binding globulin by immunoradiometric assay, and urinary NTx by enzyme-linked immunoassay were measured. BMD measurements were performed by dual energy X-ray absorptiometry and genotyping by Pyrosequencing. Results There were no significant differences in SHBG levels associated with either rs1799941 or rs6259. Using a p value of < 0.00625 for significance, we found that subjects with the A allele (GA+AA) for the rs1799941, had a trend for lower free estradiol index (FEI) compared to the GG genotype ( p = 0.04). They also had significantly lower BMD at the intertrochanter ( p = 0.003) and trend for lower BMD at the total hip ( p = 0.02). There was no significant difference in FEI levels between the genotypes for the rs6259 polymorphism, but women with the Asn allele (Asp/Asn+Asn/Asn), had significantly lower BMD in the total femur ( p = 0.004) and intertrochanter (0.002) compared to those with the Asp/Asp genotype. Conclusions Our data suggest that polymorphisms of the SHBG gene are associated with significant differences in BMD at the proximal femur sites. Thus, genetic variations in the SHBG gene may influence BMD at the hip in postmenopausal women.

Genetic polymorphisms are associated with serum levels of sex hormone binding globulin in postmenopausal women

BackgroundEstrogen activity plays a critical role in bone homeostasis. The serum levels of sex hormone binding globulin (SHBG) influence free estrogen levels and activity on target tissues. The objective of this study was to analyze the influence of common polymorphisms of the SHBG gene on serum SHBG, bone mineral density (BMD), and osteoporotic fractures.MethodsFour biallelic polymorphisms of the SHBG gene were studied by means of Taqman assays in 753 postmenopausal women. BMD was measured by DXA and serum SHBG was measured by ELISA.ResultsAge, body weight, and two polymorphisms of the SHBG gene (rs6257 and rs1799941 [A/G]) were significantly associated with serum SHBG in unadjusted and age- and weight-adjusted models. Alleles at the rs1799941 locus showed the strongest association with serum SHBG (p = 0.0004). The difference in SHBG levels between women with AA and GG genotypes at the rs1799941 locus was 39%. There were no significant differences in BMD across SHBG genotypes. The genotypes showed similar frequency distributions in control women and women with vertebral or hip fractures.ConclusionSome common genetic variants of the SHBG gene, and particularly an A/G polymorphism situated in the 5' region, influence serum SHBG levels. However, a significant association with BMD or osteoporotic fractures has not been demonstrated.

Changes of Sex Hormone-binding Globulin/SHBG Expression in the Hypothalamo-hypophyseal System of Rats During Pregnancy, Parturition and Lactation

Sex hormone-binding globulin (SHBG) is expressed in hypothalamic magnocellular neurons. High co-localization rates of SHBG with oxytocin have been observed in the hypothalamus, indicating that SHBG plays a role in pregnancy, parturition and lactation. Further studies have shown that hypothalamic SHBG expression is malleable to changing steroid conditions. In this study, we have examined SHBG levels in the supraoptic and paraventricular hypothalamic nuclei and in the posterior pituitary lobe of late pregnant, parturient and early lactating rats by IN SITU hybridization, immunocytochemistry, and ELISA. Immunocytochemical and biochemical analysis showed that the SHBG levels increased during late pregnancy in hypothalamic nuclei. During parturition, SHBG levels fell in the magnocellular nuclei but increased in the posterior pituitary lobe. SHBG levels increase again during lactation. At day six of lactation, there was no significant difference in SHBG levels compared to normal cycling female rats, which served as control in this study. IN SITU hybridization showed increased SHBG mRNA signal during late pregnancy. The highest SHBG expression was observed during parturition. Our data indicate that hypothalamic SHBG expression changes during pregnancy, parturition and lactation, parallel to ovarian steroid and co-localized OT levels. This may in part be linked to known steroid actions on synthesis and secretion of magnocellular hypothalamic peptide hormones, important for the control of parturition and lactation.

Interrelationship of serum levonorgestrel and sex hormone-binding globulin levels following vaginal and oral administration of combined steroid contraceptive tablets

Ten women were treated daily with a standard dose contraceptive tablet containing 0.25 mg levonorgestrel (LNG) in combination with 0.05 mg ethinylestradiol. Five women used the tablet vaginally, while the other five used it orally. Blood samples were taken at frequent intervals on the first day of treatment and after 1 and 2 hours on treatment days 7 and 14. Serum LNG levels were measured by radioimmunoassay, and sex hormone-binding globulin (SHBG) was quantitated by charcoal assay. On day 1, peak concentrations of LNG (5.1 ng/ml) occurred within 2 hours in the oral group, whereas in the vaginal group a peak of 2.2 ng/ml was reached after 4 hours. After 24 hours, mean serum concentrations of LNG were 1.1 and 0.69 ng/ml in the oral and vaginal groups, respectively. In both groups, mean LNG concentrations increased dramatically on days 7 and 14 compared to day 1. There was no significant difference between the two groups in LNG concentrations, except after 2 hours on day 1. SHBG levels were increased after one day of treatment. By day 14 of treatment, there was a 3.5- to 4.5-fold rise in SHBG levels from pretreatment values in both groups. However, there was no significant difference in SHBG levels between the two groups throughout the study. A high correlation was found between serum levels of SHBG and LNG in both the vaginal and oral groups. The results suggest that the increase in serum LNG levels in women receiving combined contraceptive tablets either vaginally or orally is due to increased levels of SHBG. Also, the measured concentrations of LNG in the vaginal group are consistent with the previously reported clinical contraceptive efficacy of combined contraceptive tablets administered vaginally.

Serum oestrogen levels in postmenopausal women: comparison of American whites and Japanese in Japan

Serum oestrone (E1), oestradiol (E2) and sex hormone binding globulin (SHBG) levels were studied in postmenopausal Japanese women in Japan (n = 91) and postmenopausal American white women (n = 38). The Japanese women were deliberately chosen to be from a rural agricultural area in order to get samples which represent as closely as possible the traditional Japanese 'lifestyle' that gave rise to the low rates of breast cancer in Japan. E1 levels were 47%, and E2 levels 36%, greater in the American women; these differences were only reduced to 43% and 27% after adjustment for the lower weight of the Japanese. These results were all statistically highly significant. There was little difference in SHBG levels between the Japanese and the American women. These results for E1 and E2 could be an important part of the explanation why Japanese and American breast cancer rates continue to diverge further after the menopause.

Sex steroid hormone binding globulin levels and free 17β-estradiol and testosterone in cynomolgus monkeys during different reproductive states

The effect of differences in sex hormone binding globulin (SHBG) levels associated with reproductive status on free 17β-estradiol (E 2) and testosterone (T) was characterized in cynomolgus monkeys. Cycling female cynomolgus monkeys had higher SHBG levels than males, pregnant and lactating females ( P < 0.05). Ovariectomized females were not different than control females, suggesting no hypoestrogenic effect. The percentage of free T was elevated in pregnant animals ( P < 0.05) compared to normal males and females, but the percentage of free E 2 was similar between these groups. Although a gender difference in the percentages of free E 2 and T was not detected, there was a gender difference in the free T and E 2 concentrations due to endogenous secretion. Increased free E 2 concentrations during pregnancy were the result of endogenous secretion rather than the decreased binding capacity of SHBG; the increased percentage of free T during pregnancy significantly increased free T concentrations. These data suggest that the gender difference in SHBG levels in cynomolgus monkeys is due to androgenic influences and that estrogens have minimal influence. Furthermore, the decrease in SHBG levels during pregnancy and lactation may not be entirely dependent on these androgenic influences.