Decrease of serum sex hormone-binding globulin as a marker of androgen sensitivity. Correlation with clinical response

An evaluation of the usefulness of determining the decrease in serum sex hormone-binding globulin after exogenous testosterone was studied in 55 prepubertal patients with ambiguous external genitalia or micropenis. The biochemical response (androgen sensitivity test) was compared with the clinical response as judged by signs of androgen stimulation of external genitalia. Patients were divided in two groups according to age. Group I, 11 patients younger than 3 months and Group II, 44 patients older than 3 months. Only in 54% of Group I was there a correlation between the androgen sensitivity test and the clinical response to androgens in either a positive (4 patients) or negative sense (2 patients). On the other hand, the androgen sensitivity test and the clinical response to androgens correlated in 91% of the patients of Group II in either a positive (35 patients) or negative sense (5 patients). Two of the 4 patients with lacking correlation had a negative androgen sensitivity test and micropenis secondary to pituitary deficiency. It is concluded that in prepubertal patients older than 3 months with abnormalities of sex differentiation, the androgen sensitivity test and the clinical response to androgens are useful for evaluating androgen sensitivity. The clinical response to androgens is useful in early life when a positive response is found.     

High serum sex hormone-binding globulin (SHBG) in premature thelarche

OBJECTIVE: We determined serum sex hormone-binding globulin (SHBG), serum dehydroepiandrosterone sulphate, serum oestradiol and serum testosterone and its fractions in girls with premature thelarche. DESIGN: Blood was drawn from girls with recently diagnosed (3-12 weeks) premature thelarche. Serum was kept frozen for at least one year before hormonal determination to exclude precocious puberty by clinical evaluation. PATIENTS: Seventeen girls with premature thelarche aged 0.83-7.16 years were studied, and compared with a group of 22 normal prepubertal girls. MEASUREMENTS: SHBG was measured by saturation analysis and serum dehydroepiandrosterone sulphate, serum total oestradiol and serum total testosterone were determined by radioimmunoassay. Non-SHBG-bound testosterone and free testosterone were calculated from an equation derived from the law of mass action. RESULTS: Median serum SHBG in premature thelarche was 137 nmol/l (range 64-221), significantly higher than in normal controls, 93.7 (32-172) (P < 0.05) non-parametric test of medians. Serum SHBG decreased significantly with age in controls but not in premature thelarche. No difference was found in serum dehydroepiandrosterone sulphate. Median serum total testosterone (0.34 nmol/l, 0.17-0.97), median serum non-SHBG-bound testosterone (0.04 nmol/l, 0.02-0.10) and median free testosterone (2.2 pmol/l, 1.0-4.5) were significantly lower in premature thelarche than in control (P < 0.001). CONCLUSIONS: Serum SHBG is high and bioavailable T is low in girls with premature thelarche. This might alter the oestrogen/androgen ratio in the breast.     

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.     

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.     

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.     

血清性激素结合球蛋白与2型糖尿病患者大血管病变的关系

目的研究血清性激素结合球蛋白与2型糖尿病患者大血管病变的关系及其可能机制。方法入选2010年1月至2011年12月在我院老年内分泌科门诊及住院部就诊的80例2型糖尿病患者[男48例,女32例,平均年龄（61±8）岁],根据是否合并大血管病变分为未合并大血管病变组[B组,n=40,男23例,女17例,平均年龄（60±11）岁]和合并大血管病变组[C组,n=40,男25例,女15例,平均年龄（63±11）岁]。另以同期在我院进行健康体检者40名为健康对照组[A组,男25名,女15名,平均年龄（58±10）岁]。测定和计算3组受试者血清性激素结合球蛋白水平、体质指数、腰臀比、血压、血脂、糖化血红蛋白、空腹及餐后血糖、血清胰岛素、尿蛋白／肌酐比值、胰岛素抵抗指数。2组问均数比较采用t检验,3组问均数比较采用方差分析,性激素结合球蛋白相关因素分析采用Spearman相关分析和逐步线性回归分析。结果C组血清性激素结合球蛋白水平[（31±6）u/L]明显低于B组[（46±17）u/L]及A组[（56±14）阻∥L]（F=9．763,P〈0．01）。Spearman相关分析显示,血清性激素结合球蛋白水平与腰臀比、甘油三酯、空腹及餐后胰岛素水平、胰岛素抵抗指数、尿蛋白／肌酐比值呈负相关（r值分别为-0．216、-0．156、-0．144、-0．108、-0．263、-0．126,均P〈0．05）。多元逐步回归分析表明,血清性激素结合球蛋白水平与甘油三酯、腰臀比、胰岛素抵抗指数具有直线回归关系（r2值分别为-1．132、-0．862、-2．650,均P〈0．05）。非条件logistic回归分析显示,血清性激素结合球蛋白水平对大血管病变具有-定影响。结论血清性激素结合球蛋白可能作为危险因素参与2型糖尿病及其大血管病变的发生和发展。     

Associations of serum sex hormone-binding globulin and sex hormone concentrations with hip fracture risk in postmenopausal women

CONTEXT: Endogenous estradiol, testosterone, and SHBG may influence the risk of hip fracture. DESIGN AND METHODS: From the Women's Health Initiative Observational Study, 39,793 eligible postmenopausal women did not have a previous hip fracture and were not using estrogen or other bone-active therapies. Of these, 400 who had a first-time nonpathological hip fracture (median follow-up, 7 yr) were matched to 400 controls by age, ethnicity, and baseline blood draw date. Estradiol, testosterone, and SHBG were measured in banked baseline serum. RESULTS: Compared with women in the lowest tertiles, those with bioavailable testosterone in the highest tertile had a lower risk [odds ratio (OR) = 0.62; 95% confidence interval (CI) = 0.44-0.88]; those with bioavailable estradiol in the highest tertile had a lower risk (OR = 0.44; 95% CI = 0.29-0.66), and those with SHBG in the highest tertile had a higher risk (OR = 1.90; 95% CI = 1.31-2.74) of hip fracture. In models with all three hormones and potential confounders, high SHBG remained a strong independent risk factor (OR = 1.76; 95% CI = 1.12-2.78), high bioavailable testosterone remained protective (OR = 0.64; 95% CI = 0.40-1.00), but estradiol no longer was associated (OR = 0.72; 95% CI = 0.42-1.23). CONCLUSIONS: High serum SHBG is associated with an increased risk of subsequent hip fracture and high endogenous testosterone with a decreased risk, independent of each other, serum estradiol concentration, and other putative risk factors. But endogenous estradiol has no independent association with hip fracture.     

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.     

Interpretation of sex hormone-binding globulin levels in thyroid disorders.

Sex hormone-binding globulin (SHBG) levels were followed in three groups of female subjects to evaluate interrelationships between its levels and parameters characterizing thyroid function. In the first part of the study the data from 201 patients with thyroid and other endocrine dysfunctions were grouped according to SHBG or basic laboratory parameters of thyroid function (thyrotropin, free thyroxine). Particular attention was paid to the presence of antithyroid antibodies (against thyroglobulin or thyroid peroxidase). Analysis of covariance revealed that SHBG changes were significant only in hyperthyroidism, and were not influenced by the presence of antibodies. Age was a minor factor influencing SHBG levels, in contrast to thyroid status. In a well-defined group of 16 females with severe hypothyroidism after total thyroidectomy because of thyroid cancer the low SHBG levels increased significantly to physiologic values after reaching normal thyroid function, irrespective of contraceptive use. In the final part of the study SHBG levels were correlated with the basic laboratory data, reflecting thyroid function in a sample of normal female population (129 subjects) screened for iodine deficiency in one region of the Czech Republic. After adjustment for age, the only significant positive correlation was between SHBG and free triiodothyronine.     

Characterization of sex hormone-binding globulin isoforms in hypothyroid women.

Liver sex hormone-binding globulin (SHBG) biosynthesis is regulated by triiodothyronine (T3). This regulation is responsible for increased serum SHBG concentrations in hyperthyroid states. However, in hypothyroidism, normal SHBG levels are frequently found. To understand this we have characterized circulating SHBG isoforms according to their sialic acid content, which determines its half-life, in euthyroid and hypothyroid women. Six euthyroid (aged 56 +/- 8 years) and five hypothyroid women (51 +/- 13 years) were studied. Their body mass index (BMI) range was 20-25. Hypothyroidism diagnosis was based on clinical findings, elevated basal thyrotropin (TSH) and decreased T3 and thyroxine (T4) values. Total SHBG was measured by radioimmunoassay (RIA) and SHBG isoforms were isolated using preparative isoelectrofocusing. For comparisons, two-tailed t test was applied. No statistical difference was found between the total SHBG levels of hypothyroid and euthyroid postmenopausal women. Three groups of SHBG isoforms were isolated in the euthyroid group: S(I): pl: 5.0-5.2: 20% +/- 4%, S(II) : pl 5.2-5.4: 50% +/- 3% and S(III): pl 5.4-5.6: 29% +/- 4%. In hypothyroid patients, although the three groups of isoforms were isolated in the same pH range, S(I) and S(II) proportions were different (p < 0.001) when compared to normal women: S(I): 34% +/- 4%, S(II): 33% +/- 9.9% and S(III): 29% +/- 5.7%. These results show that hypothyroid patients have a higher proportion of more acidic SHBG isoforms. This variation may explain the normal levels of serum SHBG observed in hypothyroidism.     

Interrelation of sex hormone-binding globulin and the androgen-estrogen balance in patients with hypercorticism

The concentration of testosterone and estradiol in the blood plasma and the binding capacity of testosterone-estradiol binding globulin (TEBG) were studied in 30 women and 6 men with Icenko-Cushing's disease in the active phase and in 24 women with hormonally active adrenal tumors. In hypercorticism against a background of unchanged of lowered concentration of plasma estradiol there was a decrease in the concentration of testosterone and an increase in the testosterone-estradiol binding capacity (TEBC) in men and an increase in the concentration of testosterone and a decrease in TEBC in women. The authors have assumed that the testosterone/TEBC ratio reflects more accurately change in the dynamics of androgens than isolated concentrations of testosterone and TEBG, and recommended its determination for the assessment of the body androgenic saturation in disturbed function of the adrenal or sex glands.     

Serum sex hormone-binding globulin in amiodarone-treated patients. A marker for tissue thyrotoxicosis

The lodinated antiarrhythmic drug amiodarone frequently causes an elevation of the serum thyroxine (T4) level in patients who remain clinically euthyroid. Less frequently, true iodine-induced hyperthyroidism may occur. The clinical and laboratory distinction between these two conditions is often difficult. Since the serum sex hormone-binding globulin (SHBG) concentration is elevated in hyperthyroidism, this study was carried out to evaluate the serum SHBG concentration as a possible marker of hyperthyroidism in patients receiving amiodarone. Patients treated with amiodarone were divided into three groups: clinically euthyroid with normal serum T4 and triiodothyronine (T3) concentrations, clinically euthyroid with elevated serum T4 and normal T3 concentrations, and clinically hyperthyroid with elevated serum T4 and T3 concentrations. The mean serum SHBG concentration was significantly elevated in amiodarone-induced hyperthyroid patients, while it was normal in euthyroid patients treated with amiodarone who had normal or elevated serum T4 concentrations. The results suggest that the hyperthyroxinemia induced by amiodarone is not associated with excess thyroid hormone action in the liver unless the serum T3 concentration is also elevated.     

Progressive decrease in serum sex hormone-binding globulin from infancy to late prepuberty in boys

Serum Sex hormone-binding globulin (SHBG) levels and affinity constant (Ka) of SHBG-dihydrotestosterone association were determined in 91 boys, aged 3 months to 15 yr, all at Tanner stage I of pubertal development. A gradual decrease in serum SHBG as a function of age was found in spite of unchanged serum testosterone levels. Ka values at different ages were not significantly different. Since steroids bound to SHBG are not transported into most tissues, particularly brain, a decrease in SHBG will have the effect of increasing tissue entrance of non-SHBG-bound sex hormones despite unchanged plasma concentrations. We speculate that the gradually increasing androgen and estrogen milieu of the brain created by this mechanism might be of physiological significance in triggering the onset of puberty.     

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.     

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.     

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.     

Plasma sex hormone-binding globulin and androgen levels in the management of hirsute patients

Hirsutism in women is a manifestation of excessive androgen action. This may be due to excessive exposure, or to increased sensitivity, of peripheral tissues to androgens. The present study was undertaken to estimate the percentage of hirsute patients with hyperandrogenaemia and to examine the effect of correction of hyperandrogenaemia on the clinical presentation. Plasma testosterone, dihydrotestosterone, sex hormone-binding globulin (SHBG) and androstenedione were determined in 58 hirsute patients before and following 3 months therapy with dexamethasone, 0.5 mg nocte. Testosterone expressed as a function of SHBG (testosterone/SHBG) provides an index of the non-protein bound testosterone fraction. Plasma levels of androstenedione were significantly elevated in 28% of hirsute patients, testosterone in 31% and testosterone/SHBG was elevated in 52%. Five per cent of patients had an elevated androstenedione value together with a normal testosterone/SHBG value. A subgroup of 13 hirsute patients with oligomenorrhoea had significantly higher values for androstenedione and testosterone/SHBG than eumenorrhoeic hirsute patients, and plasma testosterone, androstenedione and testosterone/SHBG values were more frequently elevated. In hirsute patients dexamethasone therapy resulted in suppression of plasma testosterone and androstenedione values, a significant increase in plasma SHBG and a marked fall in testosterone/SHBG. Following treatment with dexamethasone hyperandrogenaemia was corrected in 64% of hirsute patients, a decrease in the rate of hair growth or a resumption of a normal menstrual pattern occurred in 70% and concordant hormonal and clinical changes occurred in 79% of patients. These observations indicate that the testosterone/SHBG ratio is a sensitive index of hyperandrogenaemia, the correction of which is associated with clinical improvement.     

A direct effect of hyperinsulinemia on serum sex hormone-binding globulin levels in obese women with the polycystic ovary syndrome

To determine whether hyperinsulinemia can directly reduce serum sex hormone-binding globulin (SHBG) levels in obese women with the polycystic ovary syndrome, six obese women with this disorder were studied. Before study, ovarian steroid production was suppressed in each woman by the administration of 7.5 mg of a long-acting GnRH agonist, leuprolide depot, im, on days -56, -28, and 0. This resulted in substantial reductions in serum concentrations of testosterone (from 1.72 +/- 0.29 nmol/L on day -56 to 0.32 +/- 0.09 nmol/L on day 0), non-SHBG-bound testosterone (from 104 +/- 16 pmol/L on day -56 to 19 +/- 5 pmol/L on day 0), androstenedione (from 7.25 +/- 1.65 nmol/L on day -56 to 2.78 +/- 0.94 nmol/L on day 0), estrone (from 371 +/- 71 pmol/L on day -56 to 156 +/- 29 pmol/L on day 0), estradiol (from 235 +/- 26 pmol/L on day -56 to 90 +/- 24 pmol/L on day 0), and progesterone (from 0.28 +/- 0.12 nmol/L on day -56 to 0.08 +/- 0.02 nmol/L on day 0). Serum SHBG levels, however, did not change (18.8 +/- 2.8 nmol/L on day -56 vs. 17.8 +/- 2.6 nmol/L on day 0). While continuing leuprolide treatment, the women were administered oral diazoxide (300 mg/day) for 10 days to suppress serum insulin levels. Diazoxide treatment resulted in suppressed insulin release during a 100-g oral glucose tolerance test (insulin area under the curve, 262 +/- 55 nmol/min.L on day 0 vs. 102 +/- 33 nmol/min.L on day 10; P less than 0.05) and deterioration of glucose tolerance. Serum testosterone, androstenedione, estrone, estradiol, and progesterone levels did not change during combined diazoxide and leuprolide treatment. In contrast, serum SHBG levels rose by 32% from 17.8 +/- 2.6 nmol/L on day 0 to 23.5 +/- 2.0 nmol/L on day 10 (P less than 0.003). Due primarily to the rise in serum SHBG levels, serum non-SHBG-bound testosterone levels fell by 43% from 19 +/- 5 pmol/L on day 0 to 11 +/- 4 pmol/L on day 10 (P = 0.05). These observations suggest that hyperinsulinemia directly reduces serum SHBG levels in obese women with the polycystic ovary syndrome independently of any effect on serum sex steroids.     

Effects of thyroid hormone on sex hormone-binding globulin gene expression in human cells.

We have used a human hepatoblastoma cell line to establish a model system for thyroid hormone (T3) action in human cells. HepG2 cells were grown for 3 days in Dulbecco's Modified Eagle's Medium containing fetal calf serum and were maintained in serum-free medium for experimental manipulations. [125I]T3 incubated with cells was bound by newly secreted protein and degraded. After 24-h exposure to HepG2 cells in Dulbecco's Modified Eagle's Medium, only 35-40% of the radioactivity was recovered as authentic T3. Degradation of hormone was neither time nor concentration dependent, and occurred to a greater degree in the absence of cells, suggesting an interaction between the hormone and the plastic culture dish. After 4 days, in the absence of fetal calf serum and considering hormone binding and degradation, the concentration of free T3 available to cells was approximately 15% of that added initially. Sex hormone-binding globulin (SHBG) was secreted by HepG2 cells in the absence of T3 and was specifically stimulated by the addition of T3. After 4 days, maximum stimulation occurred with added T3 concentrations of 10(-8) M or greater, and half-maximal stimulation of SHBG secretion was observed at about 3 x 10(-11) M free T3. No significant changes in total secreted protein or cellular DNA content were observed under similar conditions. Northern analysis of RNA extracted from HepG2 cells revealed a SHBG mRNA of 2 kilobases, which was stimulated in a dose-responsive manner by T3. No stimulation of corticosteroid-binding globulin mRNA was seen. Stimulation of the SHBG gene in HepG2 cells may be a useful model for investigation of T3 action in human cells.