The effect of D- and L-thyroxine on sex hormone-binding globulin in rabbits

Serum sex hormone-binding globulin (SHBG) concentration is increased in patients with thyrotoxicosis. SHBG is also present in rabbit serum, although it does not bind estradiol-17 beta (E2). Studies were carried out in female rabbits to determine the effects of thyroid hormone on SHBG. Serum concentrations of L-T4 cholesterol, E2, progesterone, free and total testosterone (T), and SHBG were measured in immature female rabbits (8-10 weeks of age). Rabbits were ovariectomized or subjected to sham surgery at puberty (age, 14-16 weeks) and restudied 6 weeks later. Values for serum T4, T, percent free T, free T, E2, progesterone and cholesterol were similar in ovariectomized and sham treated rabbits. Serum SHBG concentration progressively decreased in all rabbits from immaturity to age 20-22 weeks and values remained constant thereafter. Ovariectomy did not affect this age-related decrease in serum SHBG concentration. The 20- to 22-week-old ovariectomized and sham-operated rabbits were treated daily with either 30 micrograms/kg L-T4 or 150 micrograms/kg D-T4 for 2 weeks. This dose of L-T4 induced a 10-25% loss of BW, whereas D-T4 treatment did not, strongly suggesting that the L-T4 but not the D-T4-treated rabbits were hypermetabolic. D-T4 and L-T4 induced similar increases in serum SHBG (D-T4, delta 132 nM; L-T4, delta 146 nM). The increase in serum SHBG activity in response to D-T4 or L-T4 was reversible, since serum SHBG concentration returned to pretreatment values 5 weeks after thyroid hormone therapy was discontinued. The 27- to 29-week-old rabbits were then treated for 2 weeks with D-T4 (150 micrograms kg-1 day-1). Serum SHBG concentration significantly increased, and there were negative correlations between the thyroid hormone-induced increase in SHBG activity and both the percent free T and free T (P less than 0.01). D-T4 administration significantly lowered the serum cholesterol concentration without altering BW.     

Empirical estimation of free testosterone from testosterone and sex hormone-binding globulin immunoassays

BACKGROUND: The growing interest in measuring blood free testosterone (FT) is constrained by the unsuitability of the laborious reference methods for wider adoption in routine diagnostic laboratories. Various alternative derived testosterone measures have been proposed to estimate FT from either additional assay steps or calculations using total testosterone (TT) and sex hormone-binding globulin (SHBG) measured in the same sample. However, none have been critically validated in large numbers of blood samples. METHODS: We analyzed a large dataset comprising over 4000 consecutive blood samples in which FT as well as TT and SHBG were measured. Dividing the dataset into samples with blood TT above and below 5 nM, using a bootstrap regression modeling approach guided by Akaike Information Criterion for model selection to balance parsimony against reduction of residual error, empirical equations were developed for FT in terms of TT and SHBG. RESULTS: Comparison between the empirical FT equations with the laboratory FT measurements as well as three widely used calculated FT methods showed the empirical FT formulae had superior fidelity with laboratory measurements while previous FT formulae overestimated and deviated systematically from the laboratory FT values. CONCLUSION: We conclude that these simple, assumption-free empirical FT equations can estimate accurately blood FT from TT and SHBG measured in the same samples with the present assay methods and have suitable properties for wider application to evaluate the clinical utility of blood FT measurements.     

Diet and sex hormone-binding globulin

The serum concentration of sex hormone-binding globulin (SHBG) is inversely related to weight and in animal studies is inversely related to protein intake. As SHBG can affect the biological activity of testosterone and estradiol, we wished to determine the role of protein intake on SHBG levels in men. Using data from the Massachusetts Male Aging Study we examined cross-sectional relationships between dietary components and SHBG levels in 1552 men (aged 40-70 yr) for whom these factors were known. Analyzed by multiple regression, controlling for testosterone and estradiol levels, age (P<0.001) and fiber intake (P = 0.02) were positively correlated to SHBG concentration, whereas body mass index (P<0.001) and protein intake (P<0.03) were negatively correlated to SHBG concentration. The intakes of calories, fat (animal or vegetable), and carbohydrate were not related to SHBG concentration. We conclude that age and body mass index are major determinants of SHBG concentrations in older men, and fiber and protein intake are also significant contributors to SHBG levels, but total caloric intake and the intake of carbohydrate or fat are not significant. Thus, diets low in protein in elderly men may lead to elevated SHBG levels and decreased testosterone bioactivity. The decrease in bioavailable testosterone can then result in declines in sexual function and muscle and red cell mass, and contribute to the loss of bone density.     

Free estradiol, free testosterone, and sex hormone-binding globulin in perimenopausal women

To determine whether menstrual status had an effect on plasma sex hormone-binding globulin (SHBG) capacity and nonprotein-bound estradiol (% free E2) and testosterone (% free T), we measured these as well as plasma FSH, total E2, and T and the MCRs of E2 and T in a group of 78 perimenopausal women. The women were allocated to 4 groups: women with cycles whose plasma FSH level was less than 40 mIU/mL (A; n = 16), women with cycles whose plasma FSH level was greater than 40 mIU/mL (B; n = 19), women who were amenorrheic for less than 1 yr (C; n = 13), and women who were amenorrheic for more than 1 yr (D; n = 30). The mean plasma SHBG values were 51.4 +/- 5.7 (+/- SE), 48.3 +/- 4.3, 45.9 +/- 5.4, and 51.1 +/- 3.7 nM in groups 1-4 respectively, and were not significantly different from one another. The mean % free E2 and % free T values also were not different between the groups. However, the mean total E2 and free E2 (% free E2 X E2/100) concentrations were significantly (P less than 0.05) higher in both groups A and B than in groups C and D. The E2 concentration was also higher in group A than in group B. There were strong correlations between the E2 and free E2 concentrations between the T and free T (% free T X T/100); (P less than 0.0001) concentrations, between SHBG capacity and weight, and between the MCRs of both E2 and T and % free E2 and % free T. In normal women, the menopause is not associated with changes in SHBG or % free steroids. Hence, the measurement of E2 could be used to predict the mass of free E2 in these women.     

Serum sex hormone-binding globulin and serum nonsex hormone-binding globulin-bound testosterone fractions in prepubertal boys with chronic renal failure

We had previously reported that serum sex hormone binding-globulin (SHBG) decreases and serum non-SHBG-bound testosterone (T) and free T increase significantly from infancy to late prepuberty in normal prepubertal children of both sexes. We had also shown an age-related delay in these changes in hypopituitary boys, which was reversed by GH treatment. Stunted growth and delayed puberty are conspicuous features of chronic renal failure (CRF). As another model of delay of growth and development, serum SHBG and serum T fractions were determined in 13 boys with CRF on chronic dialysis. In CRF, mean serum SHBG was significantly higher (99.1 +/- 68.9 nmol/L; P less than 0.05) than in 31 control (C) children of similar ages (66.2 +/- 34.9 nmol/L), while serum non-SHBG-bound T and free T were significantly lower (0.16 +/- 0.12 in CRF vs. 0.24 +/- 0.12 in C and 0.010 +/- 0.005 in CRF vs. 0.016 +/- 0.01 in C, respectively). On the other hand, serum total T (1.31 +/- 0.88 in CRF vs. 1.08 +/- 0.56 in C) and serum insulin-like growth factor-I (IGF-I; 1.06 +/- 0.74 in CRF vs. 1.35 +/- 1.70 in C) were not significantly different. A significant negative correlation between serum SHBG and chronological age as well as a significant positive correlation between serum non-SHBG-bound T and chronological age were found. For a given age, serum SHBG was higher, while serum non-SHBG-bound T was lower in patients with CRF (by analysis of covariance, P less than 0.01). It is postulated that, as has been proposed for hypopituitary boys, this delayed increment in serum T fractions could be responsible for the delay in the onset of puberty reported in CRF. It is known that GH decreases serum SHBG, acting on hepatic cells either directly or through the action of IGF-I. Since it has been suggested that patients with CRF have peripheral resistance to GH or IGF-I, the high levels of SHBG that we have detected in prepubertal boys with CRF could be taken as an additional evidence of this biological resistance.     

新诊断糖尿病成年男性患者性激素结合球蛋白的变化及其意义

目的 观察新诊断糖尿病成年男性患者性激素结合球蛋白（SHBG）的变化,探讨其与IR及胰岛早相分泌功能的关系. 方法 纳入新诊断糖尿病男性患者56例为糖尿病组,另选健康成年男性38名为正常对照组,测定SHBG,进行精氨酸刺激试验. 结果 两组SHBG、胰岛素抵抗指数（HOMA-IR）差异有统计学意义（P＜0.01）.相关分析显示,SHBG与HOMA-IR呈负相关（r=-0.219,P＜0.05）.Logistic回归分析显示,SHBG是IR的唯一有效自变量（β=-0.75,P＜0.05,OR=0.47）.二元Logistic回归分析得出HOMA-IR是糖尿病的危险因素,SHBG是糖尿病的保护因素.胰岛2 min分泌高峰值与HOMA-IR呈正相关（β=0.567,P＜0.05）. 结论 新诊断糖尿病成年男性患者存在血清SHBG降低,SHBG与HOMA-IR呈负相关.SHBG是新诊断糖尿病成年男性患者的独立保护因素.胰岛β细胞第一时相分泌功能减退与IR相关,与SHBG无相关性.     

Synthesis and regulation of sex hormone-binding globulin in obesity

Sex hormone-binding globulin (SHBG) is a plasma glycoprotein with high binding affinity for testosterone and dihydrotestosterone and lower affinity for estradiol. SHBG is synthesized in the liver, and its plasma level is important in the regulation of plasma free and albumin-bound androgens and estrogens. Obesity and particularly excess visceral fat, known risk factors for cardiovascular and metabolic diseases, are associated with decreased testosterone levels in males and SHBG levels in both sexes. SHBG is usually positively correlated with high-density lipoprotein cholesterol and negatively correlated with triglyceride and insulin concentrations. A positive association between SHBG and various measures of insulin sensitivity has been demonstrated in both sexes, suggesting that decreased SHBG levels may be one of the components of the metabolic syndrome. We have examined pituitary-adrenocortical function, glucose tolerance, and lipoprotein and hormone levels in a large cohort of Finnish males. Abdominal obesity appears to be associated with slight hypocortisolemia and increased sensitivity to exogenous adrenocorticotropin stimulation, which may contribute to the hyperinsulinemia and related metabolic changes including decreased SHBG levels in males.     

The association of age-related differences in serum total testosterone and sex hormone-binding globulin levels with the prevalence of diabetes

BackgroundAge-related differences of sex hormones are traditionally considered detrimental to certain diseases particularly in middle-aged and elderly males, however, it is imprudent to conclude without elucidating the influences of other age-related pathophysiology apart from reproductive aging. We sought to examine serum testosterone and sex hormone-binding globulin (SHBG) levels from different decades of life and their associations with the prevalence of diabetes in each respective decade.Materials and methodsA total of 6296 males participated in this multicenter cross-sectional study, aged between 40–79 years. Information on diabetes and associated risk factors were obtained by questionnaires. Serum total testosterone (TT), SHBG and calculated free testosterone (fT) were determined.ResultsAge-related stable level of TT even with significantly lower level of fT did not result in a higher age-related odds of diabetes. Whereas, age-related higher SHBG level was associated with a lower age-related odds of diabetes [−5.88 % (p = 0.038), −14.28 % (p = 0.003) and −23.53 % (p = 0.001) for males aged 50–59, 60–69, 70–79 years, respectively]. Also, the combined age-related differences of TT and SHBG levels were found associated with a lower age-related odds of diabetes [−2.21 % (p = 0.040), −8.16 % (p = 0.025) and −14.37 % (p = 0.002) for males aged 50–59, 60–69, 70–79 years, respectively].ConclusionsThe differences in hormonal levels of each age group category showed a negative association with the prevalence of diabetes in middle-aged and elderly males, however, this association could be deterred in the presence of obesity.     

Quantitative determination of sex hormone-binding globulin capacity in the plasma of normal and diabetic pregnancies.

Sex hormone-binding globulin (SHBG) capacity was measured in a longitudinal study in plasma samples from normal subjects, diabetics, and gestational diabetics and throughout pregnancy, together with unconjugated plasma estradiol. In normal women SHBG capacity (expressed in ng DHT bound per ml of plasma) increased from 23.7 +/- 13.7 (SD) in the 5-8th week period, to 74.5 +/- 20.7 in the 17-20th week period, and to 102 +/- 24 in the 37-40th week period. In diabetics the SHBG capacity for the same periods of time were respectively: 25.3 +/- 17.2, 83.1 +/- 29.1, and 111.6 +/- 22.6. Plasma levels of unconjugated estradiol were 55% higher in the diabetics than in the normal subjects in the second half of gestation, as reported in detail in another publication. From the imbalance between the close to normal SHBG capacity and the higher plasma levels of unconjugated estradiol in the diabetics, it is suggested that the unbound, i.e., metabolically active, fraction of plasma estradiol reaches higher levels in diabetics than in normal subjects in the second half of gestation.     

Prostatic distribution of sex hormone-binding globulin and cortisol-binding globulin in benign hyperplasia.

Sex hormone-binding globulin-(SHBG) and cortisol-binding globulin-(CBG) like proteins have been demonstrated in prostatic tissue surgically removed from patients with benign prostatic hyperplasia. These proteins are not easily removed by superfusion of tissue slices. Epithelial tissue was separated from stroma and found not to contain the SHBG- or CBG-like proteins. Substantial amounts of these proteins, however, remained associated with the stroma. It is suggested that they may be constituents of interstitial fluid in this tissue compartment. The possible significance of this in benign prostatic hyperplasia is discussed.     

Variations of sex hormone-binding globulin in thyroid dysfunction.

With the aim of understanding the variations of the levels of sex hormone-binding globulin (SHBG) in thyroid dysfunction, we studied the influence of factors that also modify SHBG, such as menopausal status, age, and body mass index (BMI) in women with hypothyroidism and hyperthyroidism, both overt and subclinical. Statistical analysis was performed by means of analysis of variance (ANOVA), stepwise multiple regression, and partial correlation. The ANOVA showed a significant statistical difference among the means of SHBG of all groups (p<0.01). The difference was due to the group that included hyperthyroid women. Multiple regression analysis showed that the main factors influencing SHBG were BMI and age, except for the hyperthyroid group, where the most important independent variables were triiodothyronine (T3) and thyroxine (T4). Partial correlation controlling the effect of BMI and age showed no association between SHBG and the other variables in all groups except for the subclinical hyperthyroid and hyperthyroid, where we found a significant association between SHBG and T4 and T3. The premenopausal or postmenopausal status did not modify SHBG levels. When the patients are taken as a whole, BMI, age, T4, and T3 all have an association with SHBG levels according to the multiple regression analysis.     

Identification of sex hormone-binding globulin in the human hypothalamus

Gonadal steroids are known to influence hypothalamic functions through both genomic and non-genomic pathways. Sex hormone-binding globulin (SHBG) may act by a non-genomic mechanism independent of classical steroid receptors. Here we describe the immunocytochemical mapping of SHBG-containing neurons and nerve fibers in the human hypothalamus and infundibulum. Mass spectrometry and Western blot analysis were also used to characterize the biochemical characteristics of SHBG in the hypothalamus and cerebrospinal fluid (CSF) of humans. SHBG-immunoreactive neurons were observed in the supraoptic nucleus, the suprachiasmatic nucleus, the bed nucleus of the stria terminalis, paraventricular nucleus, arcuate nucleus, the perifornical region and the medial preoptic area in human brains. There were SHBG-immunoreactive axons in the median eminence and the infundibulum. A partial colocalization with oxytocin could be observed in the posterior pituitary lobe in consecutive semithin sections. We also found strong immunoreactivity for SHBG in epithelial cells of the choroid plexus and in a portion of the ependymal cells lining the third ventricle. Mass spectrometry showed that affinity-purified SHBG from the hypothalamus and choroid plexus is structurally similar to the SHBG identified in the CSF. The multiple localizations of SHBG suggest neurohypophyseal and neuroendocrine functions. The biochemical data suggest that CSF SHBG is of brain rather than blood origin.     

Interactions of sex hormone-binding globulin with target cells

Sex hormone-binding globulin (SHBG) was initially described as a plasma protein synthesized in, and secreted by, the liver. It was discovered by its ability to bind certain androgens and estrogens and, for many years, was believed to serve as a transporter/reservoir for the steroids which it bound. Subsequently, it became clear that the cell membranes of selected tissues contained a receptor for SHBG (R_SHBG). This review deals with what is known of that receptor – its anatomy, physiology and biochemistry.     

Determinants of sex hormone-binding globulin in normal postmenopausal women

OBJECTIVE: To examine the factors influencing the levels of sex hormone-binding globulin (SHBG) in normal postmenopausal women by assessing the relationship between SHBG and measured anthropometric, metabolic and hormonal variables. DESIGN: Cross-sectional, observational study. SUBJECTS and METHODS: Seventy normal postmenopausal women aged 47-71 years (mean 58 years), participated in the study. Information was collected on medical, reproductive and smoking history, alcohol use, dietary intake and physical activity. Body composition measurements using dual-energy absorptiometry, and analyses of biochemical and hormonal indices were performed. RESULTS: Bivariate correlation coefficients indicated that SHBG was inversely related to body weight (r = - 0.44), fat mass (r = - 0.35), and abdominal obesity (r = - 0.42). It was also inversely related to the glucose and insulin levels during an oral glucose tolerance test (- 0.24 < r < - 0.40), serum oestradiol (r = - 0.26), and physical activity (r = - 0.24). Multiple regression analysis indicated that significant independent correlates of SHBG concentration were fat mass, physical activity, alcohol intake, serum oestradiol, and insulin-like growth factor-1, all having a negative impact on SHBG. CONCLUSIONS: From these observed associations, it is concluded that maintenance of body weight, moderate alcohol consumption, and physical activity will tend to reduce SHBG concentrations in postmenopausal women, thereby increasing the levels of free oestradiol. This mechanism could mediate the beneficial effects of these factors in preventing the development of osteoporosis and cardiovascular disease.     

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.     

Changes of sex hormones and sex hormone-binding globulin levels in male adults with hyperthyroidism before and after antithyroid drug treatment

<正>Objective To observe the changes of sex hormone and sex hormone-binding globulin (SHBG) levels in young male patients with hyperthyroidism before and after antithyroid drug (ATD) treatment. Methods Between January 2015 and July 2016,forty male patients with hyperthyroidism aged 19-52 years (with an median age of