Plasma Concentrations Of Sex Hormone-binding Globulin Research Articles

Sex differences, endogenous sex-hormone hormones, sex-hormone binding globulin, and exogenous disruptors in diabetes and related metabolic outcomes.

In assessing clinical and pathophysiological development of type 2 diabetes (T2D), the critical role of the sex steroids axis is underappreciated, particularly concerning the sex-specific relationships with many relevant cardiometabolic outcomes. In this issue of the Journal of Diabetes, we provide a comprehensive overview of these significant associations of germline variants in the genes governing the sex steroid pathways, plasma levels of steroid hormones, and sex hormone-binding globulin (SHBG) with T2D risk that have been observed in many clinical and high-quality large prospective cohorts of men and women across ethnic populations. Together, this body of evidence indicates that sex steroids and SHBG should be routinely incorporated into clinical characterization of T2D patients, particularly in screening prediabetic patients, such as those with metabolic syndrome, using plasma levels of SHBG. Given that several germline mutations in the SHBG gene have also been directly related to both plasma concentrations of SHBG and clinical manifestation of T2D, targeting signals in the sex steroid axis, particularly SHBG, may have significant utility in the prediction and treatment of T2D. Further, many of the environmental endocrine disrupting chemicals may exert their potential adverse effects on cardiometabolic outcomes via either estrogenic or androgenic signaling pathways, highlighting the importance of using the sex steroids and SHBG as important biochemical markers in both clinical and population studies in studying sex-specific mechanisms in the pathogenesis of T2D and its complications, as well as the need to equitably allocate resources in studying both men and women.

Hepatic Effects of Estrogen on Plasma Distribution of Small Dense Low-Density Lipoprotein and Free Radical Production in Postmenopausal Women.

Hepatic effects of estrogen therapy on low-density lipoprotein (LDL) subfraction or oxidative stress have not been previously evaluated. The purpose of the present study was to investigate whether the differential hepatic effects of estrogen affect plasma distribution of small dense LDL and free radical production in postmenopausal women. In all, 45 postmenopausal women were given 0.625 mg/day of oral conjugated equine estrogen (CEE) (n=15), 1.0 mg/day of oral 17β estradiol (E2) (n=15), or 50 μg/day of transdermal 17βE2 (n=15) for 3 months. Subjects received either estrogen alone or with dydrogesterone at 5 mg/day. Plasma concentrations of sex hormone-binding globulin (SHBG), lipids, metallic ions, and derivatives of reactive oxygen metabolites (d-ROMs) were measured. CEE, but not oral 17βE2, increased the plasma concentrations of triglyceride, copper (Cu), and d-ROMs and the ratio of small dense LDL/total LDL cholesterol, a marker for plasma distribution of small dense LDL. Transdermal 17βE2 decreased d-ROMs concentrations but did not significantly change other parameters. Plasma concentrations of SHBG increased in the 3 groups. Estrogen-induced changes in triglyceride correlated positively either with changes in SHBG (R=0.52, P=0.0002) or the ratio of small dense LDL/total LDL cholesterol (R=0.65, P＜0.0001). Changes in Cu also correlated positively either with changes in SHBG (R=0.85, P＜0.0001) or d-ROMs (R=0.86, P＜0.0001). The hepatic effects of different routes or types of estrogen therapy may be associated with plasma distribution of small dense LDL and free radical production in postmenopausal women.

Sex hormone-binding globulin concentrations before conception as a predictor for gestational diabetes in women with polycystic ovary syndrome

Low plasma sex hormone-binding globulin (SHBG) concentrations during pregnancy have been associated with the risk of developing gestational diabetes mellitus (GDM). Women presenting with polycystic ovary syndrome (PCOS) often exhibit low plasma SHBG concentration and are at increased risk of developing GDM. In this study, we investigate whether SHBG levels before conception are predictive of GDM in women with PCOS. A total of 50 women with PCOS were enrolled and followed up during pregnancy. Initial endocrine, metabolic and physical features were assessed according to a standardized preconception screening program. At 24-26 weeks of gestational age a 100-g glucose tolerance test was performed to screen for GDM. Of the 50 women, 21 (42%) were diagnosed with GDM by a 100-g glucose tolerance test. Waist circumference, BMI, blood pressure, plasma glucose, insulin, homeostasis model assessment-insulin resistance (HOMA-IR) and SHBG levels before conception were significantly different between women who did and did not develop GDM. Stepwise logistic regression analysis showed that SHBG was the most significant predictive parameter for GDM (odds ratio 0.92; 95% confidence interval 0.87-0.97), without significant contribution of waist circumference and HOMA-IR. Receiver operator characteristic (ROC) analysis indicated that plasma SHBG (area under the curve 0.86) had the highest predictive value for subsequent development of GDM, however, the limited group size did not allow for calculation of a threshold value of SHBG. In women with PCOS, preconception SHBG levels are strongly associated with subsequent development of GDM. Regression and ROC analysis show that preconception SHBG levels may be a better predictor for GDM in PCOS women compared with waist circumference or HOMA-IR. NCT00821379.

Endogenous sex hormones, prolactin and mammographic density in postmenopausal Norwegian women

The associations between endogenous sex hormone levels and breast cancer risk in postmenopausal women are well established. Mammographic density is a strong risk factor for breast cancer, and possibly an intermediate marker. However, the results from studies on the associations between endogenous sex hormones and mammographic density are conflicting. The authors examined the associations between circulating levels of sex hormones, sex hormone binding globulin (SHBG) and prolactin and mammographic densities among postmenopausal women not currently using postmenopausal hormone therapy (HT). The authors also examined if insulin-like growth factor-I (IGF-I) levels influenced the association between estrogen and mammographic density. Altogether, 722 postmenopausal participants in the Norwegian governmental mammographic screening program had endogenous hormone concentrations measured. Mammograms were classified according to percent and absolute mammographic density using a previously validated computer-assisted method. After adjustment for age, number of children, age at menopause, body mass index and HT use, both plasma concentrations of SHBG (p-trend = 0.003) and estrone (p-trend = 0.07) were positively associated with percent mammographic density. When the analyses were stratified according to median IGF-I concentration, the weak association between estrone and mammographic density was strengthened among women with IGF-I levels below median, while the association disappeared among women with over median IGF-I levels (p for interaction = 0.02). In summary, the authors found a positive association between plasma SHBG levels and mammographic densities among 722 postmenopausal Norwegian women not currently using HT. Further, the authors found a positive but weak association between plasma estrone concentration and mammographic density, which appeared to be modified by IGF-I levels.

Polymorphisms in the CYP19 Gene May Affect the Positive Correlations between Serum and Urine Phytoestrogen Metabolites and Plasma Androgen Concentrations in Men

Phytoestrogens have been hypothesized to protect against prostate cancer via modulation of circulating androgen concentrations. We conducted a cross-sectional study of 267 men in the Norfolk arm of the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort with 2 aims: first, to investigate the association between phytoestrogen exposure (measured from diet, urine, and serum) and plasma concentrations of sex hormone-binding globulin (SHBG), androstanediol glucuronide, testosterone and Free Androgen Index (FAI); and second, whether the association may be modified by polymorphisms in CYP19 and SHBG genes. Dietary daidzein and genistein intakes were obtained from food diaries and computed using an in-house food composition database. Urinary and serum concentrations of 3 isoflavones (daidzein, genistein, glycitein), 2 daidzein metabolites O-desmethylangolensin (O-DMA) and 2 lignan metabolites (enterodiol and enterolactone) were measured using mass spectrometry. There was no association between dietary, urinary, and serum phytoestrogens and plasma SHBG concentrations. Enterolactone was positively associated with plasma androstanediol glucuronide concentrations (urinary enterolactone: r = 0.127, P = 0.043; serum enterolactone: r = 0.172, P = 0.006) and FAI (urinary enterolactone: r = 0.115, P = 0.067; serum enterolactone: r = 0.158, P = 0.011). Both urinary and serum equol were associated with plasma testosterone (urinary equol: r = 0.332, P = 0.013; serum equol: r = 0.318, P = 0.018) and FAI (urinary equol: r = 0.297, P = 0.027; serum equol: r = 0.380, P = 0.004) among men with the TT genotype but not the CC or CT genotypes (r = -0.029 to -0.134, P = 0.091-0.717) for the CYP19 3'untranslated region (UTR) T-C polymorphism. Urinary and serum enterolactone showed similar genotype-dependent associations with testosterone but not with FAI. In this first study on phytoestrogen-gene associations in men, we conclude that enterolactone and equol are positively associated with plasma androgen concentrations, and interactions with CYP19 gene may be involved.

Relationship between Sex Hormone-Binding Globulin and Pregnancy Outcome in Women Undergoing Controlled Ovarian Hyperstimulation for Assisted Reproduction

The purpose of this study was to determine whether the changes of sex hormone-binding globulin (SHBG) affect the pregnancy outcome in women undergoing controlled ovarian hyperstimulation (COH) for assisted reproduction. Forty-five infertile women who were undergoing pituitary desensitization and COH for in vitro fertilization (IVF) with or without intracytoplasmic sperm injection (ICSI) and 19 women with normal menstrual cycles participated in the study. Fasting blood samples of the follicular and luteal phases, including follicular fluid during oocyte retrieval, were obtained for determination of estradiol (E(2)), progesterone (P(4)), testosterone (T), and SHBG concentrations. The SHBG levels increased progressively during the course of COH, but remained constant throughout normal menstrual cycles. A positive correlation existed between E(2) and SHBG levels in both the follicular and luteal phases. The mean plasma SHBG concentration and E(2)/T ratio were significantly higher, while the level of T and the free androgen index were significantly lower, in the luteal phase of women who conceived than in those who did not conceive following COH. The changes of follicular fluid SHBG level and E(2)/T ratio were similar to those in plasma. We concluded, therefore, that increases in SHBG in the follicular and luteal phases may be a reflection of the functional state of ovarian stimulation, and further that such elevations may influence the pregnancy outcome through the modulation of circulating estrogen and androgen balance during down-regulated COH cycles for IVF/ICSI.

Second-trimester sex hormone-binding globulin and subsequent development of pre-eclampsia

Objective: To investigate whether maternal plasma sex hormone-binding globulin (SHBG) concentrations are reduced in women who subsequently develop pre-eclampsia. Methods: This was a cross-sectional study, carried out at antenatal clinics in seven hospitals in and around London. Healthy women underwent uterine artery Doppler velocimetry as a screening method for pre-eclampsia at 22-24 weeks of gestation. The first group (408 women) had normal uterine artery Doppler waveforms (mean uterine artery pulsatility index (PI) below 1.6). The second group (274 women) had increased impedance to flow in the uterine arteries (mean PI above the 95th centile, 1.6). Maternal plasma SHBG concentrations were measured retrospectively using a competitive chemiluminescent immunoassay. Pre-eclampsia was as defined by the International Society for the Study of Hypertension in Pregnancy. Results: Plasma SHBG concentrations in the 80 (11.7%) women who subsequently developed pre-eclampsia were significantly lower than in the 585 (85.8%) women with normal pregnancy outcomes (median 336, range 142-674 nmol/l vs. median 336, range 142-674 nmol/l, p = 0.001). There was a strong correlation between SHBG concentrations and body mass index (r =-0.232246, p < 0.0001). There were no significant differences in maternal plasma SHBG concentrations in women with abnormal uterine artery Doppler (n = 274) compared with controls (n = 408) (median 324, range 101-635 nmol/l vs. median 336, range 142-674 nmol/l, p = 0.09). Conclusion: Maternal plasma SHBG concentrations are reduced in women who subsequently develop pre-eclampsia.

Second-trimester sex hormone-binding globulin and subsequent development of pre-eclampsia

To investigate whether maternal plasma sex hormone-binding globulin (SHBG) concentrations are reduced in women who subsequently develop pre-eclampsia. This was a cross-sectional study, carried out at antenatal clinics in seven hospitals in and around London. Healthy women underwent uterine artery Doppler velocimetry as a screening method for pre-eclampsia at 22-24 weeks of gestation. The first group (408 women) had normal uterine artery Doppler waveforms (mean uterine artery pulsatility index (PI) below 1.6). The second group (274 women) had increased impedance to flow in the uterine arteries (mean PI above the 95th centile, 1.6). Maternal plasma SHBG concentrations were measured retrospectively using a competitive chemiluminescent immunoassay. Pre-eclampsia was as defined by the International Society for the Study of Hypertension in Pregnancy. Plasma SHBG concentrations in the 80 (11.7%) women who subsequently developed pre-eclampsia were significantly lower than in the 585 (85.8%) women with normal pregnancy outcomes (median 336, range 142-674 nmol/l vs. median 336, range 142-674 nmol/l, p = 0.001). There was a strong correlation between SHBG concentrations and body mass index (r =-0.232246, p < 0.0001). There were no significant differences in maternal plasma SHBG concentrations in women with abnormal uterine artery Doppler (n = 274) compared with controls (n = 408) (median 324, range 101-635 nmol/l vs. median 336, range 142-674 nmol/l, p = 0.09). Maternal plasma SHBG concentrations are reduced in women who subsequently develop pre-eclampsia.

Effect of metformin on insulin-like growth factor (IGF) I and IGF-binding protein I in polycystic ovary syndrome.

The objective of the present study was to investigate whether metformin affected plasma concentrations of insulin-like growth factor (IGF) I and IGF-binding protein I (IGFBP-I) in polycystic ovary syndrome (PCOS) patients. This was an open study conducted by the Department of Obstetrics and Gynecology at the University of Siena, Italy. Seventeen women with PCOS participated in the study and were administered metformin at a dose of 500 mg three times a day. Treatment was continued for 30-32 days, after which the pretreatment evaluation was repeated. Plasma concentrations of LH, FSH, estradiol, free testosterone, IGF-I, IGFBP-I, sex hormone-binding globulin, and insulin were evaluated. Metformin led to a significant reduction in areas under the insulin curves (9310 +/- 1509 vs. 6520 +/-1108 mU/mL x min; P < 0.05) and was associated with a decrease in plasma free testosterone levels (12.7 +/- 1.7 vs. 10.3 +/- 2 pg/mL; P < 0.05) and an increase in plasma sex hormone-binding globulin concentrations (62 +/- 8 vs. 94 +/- 13 nmol/L; P < 0.05). A nonsignificant increase in plasma IGF-I levels was observed after metformin (276 +/-48 vs. 291 +/- 71 mcg/L), with a significant increase in plasma IGFBP-I levels (0.56 +/- 0.2 vs. 0.98 +/- 0.38 mcg/L; P < 0.05). The IGF-I/IGFBP-I ratio was significantly lower (492.8 +/- 117 vs. 296.9 +/- 82; P < 0.05) at the end of therapy than before treatment. In conclusion, it seems to be appropriate to intervene with an insulin-sensitizing agent such as metformin in an attempt to break the pathogenetic link between hyperinsulinemia and hormonal perturbations in PCOS.

Association of dietary factors and selected plasma variables with sex hormone-binding globulin in rural Chinese women

Sex hormone-binding globulin (SHBG) is an important regulator of plasma sex steroids as well as a sensitive indicator of insulin resistance. SHBG may be an important diagnostic measure of risk for pathologies associated with insulin resistance syndrome (IRS) such as non-insulin-dependent diabetes mellitus (NIDDM), obesity, hypertension, dyslipidemia, and atherosclerotic cardiovascular disease. In women, SHBG is also implicated in diverse pathologies such as cancers of steroid-sensitive tissues and hirsutism. Data from an ongoing ecological study linking diet and health in rural China were analyzed to determine the relation of selected plasma variables and diet to plasma concentrations of SHBG. All data represent county mean values, pooled by age and sex, to assess the relation between biochemical and lifestyle characteristics and disease-specific mortality rates at the county level. The study sample consisted of 3250 Chinese women between the ages of 35 and 64 y living in 65 widely dispersed rural counties. Consumption patterns for 21 different food groups were derived from a food-frequency questionnaire and a 3-d dietary survey and subsequently compared. Correlation analyses of county mean values demonstrated a significant association between SHBG and insulin, testosterone, triacylglycerols, body mass index, age at menarche, and several foods. In regression analyses, after adjustments, the strongest predictors of SHBG concentrations were the dietary intake of rice (beta = 0.42, P < 0.01), fish (beta = 0.34, P < 0.05), millet (beta = -0.27, P < 0.01), and wheat (beta = -0.34, P < 0.01). When insulin, testosterone, and triacylglycerols were added to the model only triacylglycerols (beta = -0.26, P < 0.05) remained a significant independent predictor of SHBG. Additional analyses suggested that the consumption of green vegetables was modestly positively correlated with SHBG and negatively with insulin values. Consumption of rice and fish in particular appeared to favorably influence the principle plasma variables associated with a reduction in the risk for IRS pathologies.

Hemostatic, metabolic, and androgenic risk factors for coronary heart disease in physically active and less active postmenopausal women.

Physically active postmenopausal women have a lower incidence of coronary heart disease (CHD) than their more sedentary peers, but little information is available concerning the responsible mechanisms. The primary aim of this study was to test the hypothesis that physically active post-menopausal women demonstrate more favorable levels of hemostatic, metabolic, and androgenic CHD risk factors than less active control subjects. If so, a secondary aim was to determine which of the characteristics associated with a physically active lifestyle, ie, low body fat, a high-carbohydrate/low-fat diet, high maximal aerobic capacity (aerobic fitness), and high levels of physical activity, are most closely related to this lower risk profile. To address these aims, we compared CHD risk factors in physically very active women (n = 14; age, 55 +/- 2 years) with those in healthy, nonobese sedentary control subjects (n = 17; age, 56 +/- 1 years). Maximal aerobic capacity (fitness) was 83% higher (P < .001) in the physically active women. Concentrations of plasminogen activator inhibitor type 1 activity and tissue plasminogen activator antigen were lower (more favorable) (P < .005) in the physically active women versus control subjects, whereas plasma fibrinogen levels did not differ. The physically active women had lower (P < .01) fasting plasma insulin and glucose concentrations as well as smaller responses to an oral glucose challenge. Both total-body and abdominal fat levels were lower (P < .001) and lipid and lipoprotein profiles were generally more favorable (P < .05) in the physically active women.(ABSTRACT TRUNCATED AT 250 WORDS)

Sex Hormone Binding Globulin: Origin, Function and Clinical Significance

Sex hormone binding globulin (SHBG) is a glycoprotein possessing high affinity binding for 17 beta-hydroxysteriod hormones such as testosterone and oestradiol. It is probably synthesized in the liver, plasma concentrations being regulated by, amongst other things, androgen/oestrogen balance, thyroid hormones, insulin and dietary factors, it is involved in transport of sex steroids in plasma and its concentration is a major factor regulating their distribution between the protein-bound and free states. Its detailed role in the delivery of hormones to target tissues is not yet clear. Plasma SHBG concentrations are affected by a number of different diseases, high values being found in hyperthyroidism, hypogonadism, androgen insensitivity and hepatic cirrhosis in men. Low concentrations are found in myxoedema, hyperprolactinaemia and syndromes of excessive androgen activity. Concentrations are also affected by drugs such as androgens, oestrogens, thyroid hormones and anti-convulsants. Measurement of SHBG is useful in the evaluation of mild disorders of androgen metabolism and enables identification of those women with hirsutism who are more likely to respond to oestrogen therapy. Testosterone:SHBG ratios correlate well with both measured and calculated values of free testosterone and help to discriminate subjects with excessive androgen activity from normal individuals.

No change in plasma free testosterone ratio and plasma sex hormone-binding globulin concentration during hCG stimulation.

Plasma sex hormone-binding globulin (SHBG) levels and free testosterone ratios were determined independently after administration of hCG for 4 consecutive days to eight normal men. Correcting for nonspecific dihydrotestosterone binding, no changes in plasma SHBG were found. The free testosterone ratio, measured by equilibrium dialysis, did not change despite doubling of total plasma testosterone. The increase in plasma testosterone after hCG stimulation was due to increased production only, with equivalent changes in free testosterone concentration, and was not a result of changes in SHBG concentration.

Sex hormone binding globulin as a reliable indicator of hormone dependence in human breast cancer.

One hundred nine pre- and postmenopausal mammary carcinoma cases were studied to elucidate the role of sex hormone binding globulin (SHBG) in the hormone dependence of human breast cancer. Our findings indicate that there is a significant negative correlation between SHBG binding capacity and plasma testosterone concentration. All patients with high SHBG titers were found to be cytosol estrogen receptor (CER) positive and the plasma SHBG binding capacity of CER positive was significantly higher than that of CER negative patients. We also found that the level of pretherapy plasma SHBG concentration is a reliable indicator in predicting the efficacy of hormone therapy. Our findings also confirm that, for a tumor to be hormone dependent, high plasma SHBG concentration and estrogen receptors must be present simultaneously. The present pretherapy determination of SHBG titers is easier and more reliable than previous methods for determining the hormone dependence of human breast tumors.