Elevated Sex Hormone-binding Globulin Research Articles

Sex hormone-binding globulin and testosterone in individuals with childhood diabetes.

Insulin downregulates hepatic production of sex hormone-binding globulin (SHBG), which in turn influences sex hormone bioavailability. The effects of childhood-onset diabetes and insulin resistance in nondiabetic individuals on SHBG and testosterone in children and young adults are poorly understood. Individuals with diabetes diagnosed at <18 years of age (n = 48) and their siblings without diabetes (n = 47) were recruited for the Chicago Childhood Diabetes Registry Family Study. SHBG and total and free testosterone were measured. Participants ranged in age from 10 to 32 years; 39% were non-Hispanic white. The majority of individuals with diabetes had the classic type 1 phenotype (75%), while the remainder exhibited features of type 2 or mixed diabetes; 96% were treated with insulin. SHBG and total testosterone were higher in male subjects with diabetes compared with those in male siblings. Elevated SHBG was associated with the absence of endogenous insulin independent of sex; elevated total testosterone was similarly associated with the absence of C-peptide for male subjects only. Diabetes type and treatment were unrelated. In those without diabetes, greater insulin resistance had a small, nonsignificant association with lower SHBG and higher free testosterone. SHBG and total testosterone appear to be higher in male children and young adults with diabetes compared with nondiabetic male siblings, which is apparently related to the absence of endogenous insulin. This may have implications for sex hormone-dependent processes across the lifespan in male individuals diagnosed with diabetes as children.

Unchanged androgen-binding properties of sex hormone-binding globulin in male patients with liver cirrhosis

Men affected by liver cirrhosis frequently show clinical features of hypogonadism due to hormonal changes, in particular in the metabolism of 17beta-estradiol (E2) and testosterone (T). Sex hormone-binding globulin (SHBG), the major binding protein of these steroids in serum, is regularly elevated in such patients, with its androgen-binding properties possibly altered. In the present study, surface plasmon resonance biosensor techniques were used to determine whether the functional binding properties of this transporter are maintained in this pathology. We selected 33 male patients with cirrhosis, Child-Pugh grade A or B, and 32 healthy males served as controls. Serum concentrations of T, E2, dehydroepiandrosterone sulfate (DHEAS) and SHBG were measured. In addition, ligand-binding properties of SHBG partially purified from sera of 23 cirrhotic patients and 20 controls were analyzed by a real-time biosensor technique using a surface-coated dihydrotestosterone derivative. The sensorgrams revealed that SHBG was fully bioactive in all samples investigated without any changes in binding kinetics. Moreover, total T concentrations were not significantly different in the cirrhotic patient sera (mean+/-SD 18.0+/-8.6 nmol/L) compared to controls (15.6+/-3.7; n.s.), whereas E2 was higher (152+/-60 vs. 96+/-29 pmol/L; p<0.0001) and DHEAS was lower (1493+/-1410 vs. 5099+/-2844 nmol/L; p<0.0001). Owing to elevated SHBG levels without changes in the steroid-binding properties in sera of cirrhotic male patients, free or bioavailable T concentrations are lower. This causes a shift of the hormonal balance in favor of E2, which exhibits a lower affinity for SHBG than androgens and accounts for the endocrine symptoms.

Elevated sex-hormone binding globulin in elderly women with Alzheimer’s disease

Background: Hormone levels change significantly with increasing age. These changes may be related to, or be associated with, the emergence of age-related diseases, such as Alzheimer’s disease (AD). Methods: Five hundred and seventy-six women over the age of 65 were studied from the Washington Heights-Inwood Columbia Aging Project (WHICAP). These women were selected from a group of healthy Medicare beneficiaries that were aged 65 and older living in the geographically defined area of northern Manhattan in New York City. Serum levels of estrone (E1), estradiol (E2), total testosterone (TT), dehydroepiandosterone (DHEA), luteinizing hormone (LH), follicle stimulating hormone (FSH), and sex-hormone binding globulin (SHBG) were measured. Results: Significant differences were found between patients with AD and controls only in the level of SHBG, which was 20% higher in patients compared to controls (68.5 nmol/l versus 54.7 nmol/l, P<0.001). We also estimated levels of total E2 because after menopause, E2 is largely derived from E1. AD patients had significantly lower levels of estimated E2 (AD 0.46 versus controls 0.49, P<0.01). Differences remained significant after adjusting for age, ethnic group, education, and body mass index (BMI). Conclusions: A marked increase in SHBG levels was found in AD patients. SHBG normally responds to circulating testosterone and estrogen, therefore, elevated SHBG suggests an abnormal increase in its production and regulation. Further work is needed to clarify the cause and consequences of this observation.

Ovarian Ultrasound and Ovarian and Adrenal Hormones before and after Treatment for Hyperthyroidism

Objective: To relate thyroid, steroid and pituitary hormones to ovarian ultrasonographic findings in hyperthyroid patients before and during treatment. Study Design: Ultrasonography of the ovaries and serum hormone determination by immunoassay were performed before and during thiamazole therapy in 18 women of fertile age treated for hyperthyroidism at the Danderyd Hospital from 1996 to 1998. Results: When hyperthyreotic, the patients had elevated serum levels of sex hormone-binding globulin (SHBG) and subnormal values of cortisol, free testosterone (fT) and dehydroepiandrosterone (DHEA). In the euthyreotic state following treatment, endocrine variables were normalized. Patients with a short duration of the disease had higher pretreatment levels of free thyroxine (fT4), SHBG and testosterone and lower corticosteroid binding globulin (CBG) and cortisol levels compared to patients with a long duration of the disease. The pretreatment ultrasonographic picture was abnormal in 16 of 18 patients. Of the 8 patients who were examined by ultrasonography after 3 months of treatment, all but 1 showed a normal picture. Samples from patients showing an abnormal ultrasonographic picture had significantly higher fT4 and lower free testosterone (fT) values than samples from patients with a normal ultrasonographic picture. Conclusion: Ultrasonographic findings showing a multicystic/multifollicular picture, resembling polycystic ovaries (PCO), in hyperthyroidism may be related to direct effects of thyroid hormones on the ovaries and/or altered intraovarian androgen environment due to elevated SHBG levels. It is highly recommended to assess the thyroid status in patients with multicystic/multifollicular ovaries/PCO.

Low body size and elevated sex-hormone binding globulin distinguish men with idiopathic vertebral fracture.

Factors predisposing to vertebral fracture in men are less well defined compared with women. Most studies of osteoporosis in men have included patients with low bone mineral density (BMD), with or without vertebral fracture, or have included other fractures. To clarify these associations we investigated sex hormone levels, bone markers, and (indirectly) lean body mass (LBM) in 81 men with idiopathic vertebral fracture. Serum testosterone, estradiol, sex-hormone binding globulin (SHBG), 24-hr urinary creatinine (24-hr UCr), urinary free deoxypyridinoline (UfDPD) and serum type I procollagen carboxy-terminal propeptide, type I procollagen amino-terminal propeptide, type I collagen carboxy-terminal telopeptide, and osteocalcin were measured. SHBG was higher and 24-hr UCr lower in osteoporotic subjects. UfDPD was higher when corrected for 24-hr UCr. Serum bone turnover markers were not significantly increased, nor were serum sex hormones (and free hormone indices) significantly decreased in patients. SHBG levels were inversely related with lumbar spine and femoral neck BMD in both patients and control subjects. Free estradiol index was only correlated with BMD in men with osteoporosis. Body size is lower in men with established osteoporosis. The normal free hormone indices suggest that SHBG does not affect free hormone levels whereas the relationship between SHBG (but not sex hormones) and 24-hr UCr points to a relationship between SHBG and LBM. The association of high levels of SHBG with low levels of LBM may indicate an action via the known inverse relationship of SHBG with IGF-I, though any action through IGF-I probably occurred at an earlier age than that at which the patients presented. Estrogen has no relationship with BMD in normal men but may play a role in men with osteoporosis.

Validity of radioimmunological methods for determining free testosterone in serum

Objective: To assess serum free testosterone (free T) concentrations in various groups of women by means of an ultrafiltration technique (UFT) or two RIAs and to investigate the influence of levonorgestrel (LNG) and norethisterone (NET) on free T. Design: Experimental study with serum samples from various groups of patients. Setting: Obstetrics and gynecology department of a university. Patient(s): Samples from 20 normal healthy women, 20 menopausal women, 21 pregnant women, 23 women using oral contraceptives (OC), 20 hyperandrogenemic women, 20 hirsute patients with normal total testosterone (total T), 18 patients with acne (normal total T), and 9 women with adrenogenital syndrome (AGS). Intervention(s): Blood samples were taken by venipuncture. Main Outcome Measure(s): Serum concentrations of free T. Result(s): Mean free-T levels determined by UFT amounted to 5–6 pg/mL in most groups, except in patients with hyperandrogenemia (8.3 pg/mL) or AGS (10.7 pg/mL) and in women using OC (1.9 pg/mL). The values were twofold to fourfold and threefold to sevenfold higher than those determined with the RIAs. The proportion of free T as determined by UFT was 0.9–1.2% of total T and was 0.55% during OC treatment. The presence of 10 ng/mL of LNG or NET increased free-T levels by only 13%. Conclusion(s): Serum free-T levels determined with RIA are much lower than those measured with the UFT. The ratio between the UFT and RIA values may vary depending on the endocrine status. In women with normal or elevated sex hormone–binding globulin levels, nortestosterone derivatives increase free T levels only slightly.

Endocrine effects of the podophyllotoxine derivative drug CPH 82 (Reumacon®) in patients with rheumatoid arthritis

CPH 82 is a non-steroid antirheumatic drug containing two benzylidenated podophyllotoxin glucosides with no affinity for the glucocorticoid receptor. Treatment with CPH 82 as single drug therapy significantly decreased serum and urinary cortisol and cortisol metabolites, serum adrenal androgens and urinary androgen metabolites, plasma ACTH and serum interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-alpha), and increased serum levels of sex hormone-binding globulin (SHBG). Significant positive correlations were found between serum TNF-alpha and plasma ACTH and between serum IL-6 and TNF-alpha on the one hand and serum and urinary cortisol and cortisol metabolites on the other. The initial action of CPH 82 on adrenal steroidogenesis may be a reduction in cytokine levels due to the drugs' antiinflammatory effect. This causes decreased ACTH stimulation, resulting in a reduced adrenocortical steroid secretion. Accumulation of the drug in the adrenal cortex may also affect adrenal steroidogenesis. The elevated SHBG levels may be caused by a weak estrogenic activity of the drug.

Decreased estradiol levels and free androgen index and elevated sex hormone-binding globulin levels in male idiopathic osteoporosis.

Estrogen deficiency is an important pathogenetic factor in female osteoporosis, and androgens are known to have anabolic effects on bone. In this study we have compared 12 men with idiopathic osteoporosis, age 27-55 years, with 12 age-matched men, with respect to serum levels of sex steroids, biochemical markers of bone turnover, bone density, and body composition. All subjects showed values within the normal range for all hormonal parameters. The patient group compared with the controls had significantly lower serum levels of estradiol (71 +/- 13 versus 85 +/- 14 pmol/liter, P < 0.03); estradiol/sex hormone-binding globulin (SHBG) ratio (22.4 +/- 12.1 versus 39.5 +/- 18.6 pmol/mg, P < 0.02); free androgen index (51.0 +/- 19.4 versus 74.1 +/- 33.1%, P < 0.05); and higher SHBG (3.7 +/- 1.6 versus 2.5 +/- 1.0 mg/liter; P < 0.04). The men with idiopathic osteoporosis had significantly lower body mass index (23.2 +/- 2.8 versus 25.9 +/- 3.3 kg/m2, P < 0.05); and a tendency to lower percentage of total body fat (14.2 +/- 5.5 versus 18.6 +/- 6.0%; P < 0.10) than the controls. Regression analyses revealed that bone mineral density in femoral neck correlated significantly and positively with the ratio estradiol/SHBG (r = 0.67; P < 0.04) and negatively with SHBG concentrations (r = -0.63; P < 0.04) in the group of patients. These findings could represent a pathogenetic mechanism in male idiopathic osteoporosis.

Normal serum concentrations of sex hormone binding-globulin in patients with hyperthyroidism due to subacute thyroiditis.

Serum concentrations of sex hormone binding-globulin (SHBG) were determined in patients with hyperthyroidism (n = 94; 12 men, 82 women) due to either Graves' disease (n = 59; 11 men, 48 women), autonomous thyroid adenomas (n = 23; 1 man, 22 women), or subacute thyroiditis (n = 12; all women). Elevated serum concentrations of SHBG were initially seen in 57 of 82 patients (69%) with hyperthyroidism due to either Graves's disease or due to autonomous adenoma. Elevated serum SHBG concentration was more frequent in patients with serum total thyroxine (TT4) concentrations greater than 15.0 microg/dL (32/39 [82%]; including 3 patients with autonomous adenoma) compared to those with serum TT4 concentration between 11.0 and 15.0 microg/dL (21/27 [77%]; including 7 patients with autonomous adenoma), or patients with an isolated elevation of serum total triiodothyronine (TT3) concentration (4/16 [25%]; including 2 patients with autonomous adenoma). Serum SHBG concentration normalized when patients became euthyroid. Only 1 of 12 patients in the hyperthyroid phase of subacute thyroiditis had an elevated serum concentration of SHBG. Serum concentrations of thyroid binding globulin (TBG) and transcortin (CBG) were normal in all but 1 patient. In patients with hyperthyroidism as a result of Graves' disease or autonomous adenoma serum SHBG concentrations were elevated with the greatest elevation found in patients with the highest serum T4 concentrations. The normal concentrations of SHBG in the hyperthyroid phase of subacute thyroiditis most likely reflects the shorter duration of exposure to increased thyroid hormone in this condition.

Influence of some biological indexes on sex hormone-binding globulin and androgen levels in aging or obese males.

Several aspects of the regulation of androgen secretion and plasma levels in males remain controversial. Among these, we cite the problem of whether the age-related decrease in testosterone (T) levels is an intrinsic aging phenomenon or is a sequel of previous illness, the mechanisms underlying the increase in sex hormone-binding globulin (SHBG)-binding capacity in aging men and the supranormal capacity observed immediately after a weight-reducing diet, and the role of insulin in the age-associated decrease in dehydroepiandrosterone (sulfate) [DHEA (DHEAS)] levels. To gain further insight into these issues, we investigated the influence of age, smoking, body mass index (BMI), serum albumin, insulin, GH, and insulin-like growth factor I (IGF-I) levels, respectively, on androgen levels and SHBG-binding capacity in a nonobese healthy population (n = 250) as well as in an obese population (n = 50) before and after weight loss. The influence of GH supplementation on SHBG, DHEAS, DHEA, and insulin levels was studied in a small group of men (n = 8) with isolated GH deficiency. In nonobese healthy men, age was inversely correlated with serum levels of all androgens studied (although total T levels stayed relatively stable until age 55 yr) as well as with albumin, GH, and IGF-I levels and positively correlated with BMI, insulin levels, and SHBG-binding capacity. Nevertheless, SHBG levels were significantly negatively correlated with insulin levels (P < 0.001) as well as with mean 24-h GH and IGF-I levels. Among possible confounding factors affecting (free) T [(FT)] levels in healthy men, smoking appeared to be accompanied by higher (F)T levels than those in nonsmokers. BMI increased with age, but although BMI was negatively correlated with T, FT, and SHBG, respectively, the age-dependent decrease in T levels persisted after correction for BMI. Data not corrected for BMI may, nevertheless, overestimate the age-associated decrease in T levels. The albumin concentration decreased with age, and if FT is the feedback regulator of plasma T levels, albumin concentration might be a codeterminant (although, evidently, less important than SHBG) of T levels and contribute to the age-associated decrease in T levels. In any case, albumin concentration is a codeterminant of DHEAS concentration. T, DHEA, and DHEAS levels were significantly correlated, but this correlation disappeared after controlling for age; hence, there is no evidence for an adrenal-gonadal interaction in men. In obese men, T, FT, and SHBG levels were significantly lower than those in the nonobese men and inversely correlated with BMI; DHEAS levels were slightly lower than those in the nonobese controls, but no significant correlation between DHEA or DHEAS, and insulin levels was observed. After a weight-reducing, protein-rich diet, resulting in a mean weight loss of +/- 15 kg, SHBG-binding capacity increased to normal values notwithstanding the fact that the subjects were still obese and that the insulin levels remained higher than those in the nonobese controls. Considering that after weight loss, GH and IGF-I levels remained lower than those in the nonobese controls, that adult men with isolated GH deficiency presented with higher SHBG levels than normal controls, which decreased to normal levels during GH substitution, and that elderly men have elevated SHBG levels notwithstanding high insulin levels, we suggest that the low GH and/or IGF-I levels might play a role in the elevated SHBG levels observed in both elderly males and obese men after a weight-reducing diet. As weight loss did not influence DHEAS levels notwithstanding an important decrease in insulin levels, our data do not support a role of insulin in the regulation of plasma DHEAS levels.

Influence of toremifene on the endocrine regulation in breast cancer patients

In a combined phase I–II study, the hormonal effects of toremifene (TOR) were investigated in 30 patients. Half of the patients received continuous therapy of TOR 60 mg and half 300 mg of TOR orally daily. Serum concentrations of oestradiol (E 2), progesterone (PROG), testosterone (TE), follicle stimulating hormone (FSH), luteinising hormone (LH), prolactin (PRL), human growth hormone (hGH) and sex hormone binding globulin (SHBG) were monitored prior to the treatment and at the second, sixth, eighth and twelfth weeks. The influence of TOR upon the hypothalamo-hypophyseal axis was investigated by the TRH (thyroid-stimulating hormone releasing hormone) functional test using 400 μg intravenous injection of TRH for stimulation of PRL secretion. The concentration of E 2 decreased during the TOR therapy with 60 mg and 300 mg causing 82 and 71% decreases, respectively (non-significant). PRL was significantly ( P < 0.001) suppressed. Both these effects reflect the anti-oestrogenic action of TOR. SHBG increased significantly at both doses of TOR, probably due to a direct oestrogen-like effect of TOR in the liver. TE decreased as a consequence of the elevated SHBG. The TRH-induced PRL release was suppressed by both doses of TOR. There were 17 and 27% reductions at 12 weeks in the 60 and 300 mg groups, respectively. Other hormones measured were not significantly affected by TOR. The hormonal effects of 60 and 300 mg doses of TOR did not differ significantly. Anti-oestrogenic (i.e. decrease of E 2), and partially oestrogenic (i.e. increase of SHBG) properties as well as the antiprolactinic effects of TOR may have an overall beneficial effect in the clinical management of breast cancer patients.

Elevation of hormone-binding globulins in acute intermittent porphyria

Sex hormone-binding globulin (SHBG), thyroxine-binding globulin (TBG) and cortisol-binding globulin (CBG) were measured in plasma of 26 patients with acute intermittent porphyria (AIP). Twelve patients had clinically manifest disease and all had elevated SHBG levels. All but one of 14 patients with latent porphyria had normal SHBG levels. TBG was elevated in 9 of the patients with clinically manifest porphyria and CBG elevated in three. Levels of TBG and CBG were either normal or only slightly elevated in those with latent porphyria. In a prospective study of 30 attacks of AIP in 7 patients, SHBG levels fell between admission and discharge, the fall being significant in the group of 21 attacks treated with haem arginate ( p < 0.001). Our findings suggest that a close correlation exists between elevated SHBG and clinical expression of AIP.

Thyroxine uptake by human hepatoma cells from serum of patients submitted to long-term thyroxine suppressive therapy.

The significance of thyroxine (T4) uptake from serum in the assessment of thyroid status was evaluated, using human hepatoma (Hep G2) cells, in 30 euthyroid subjects, 6 hypothyroid and 19 hyperthyroid patients, and in 23 athyreotic cancer patients under T4 suppressive therapy. Cellular thyroxine (CT4) was determined according to Sarne and Refetoff, J. Clin. Endocrinol. Metab. 61: 1046, 1985. CT4 averaged 9.9 +/- 2.8 pg/well (mean +/- SD, range 5.7-15.3) in euthyroid subjects, 1.5 +/- 1.0 pg/well (range 0.05-4.2) in hypothyroid patients, 40.5 +/- 18.8 pg/well (range 18.3 +/- 104.7) in hyperthyroid patients, and 23.7 +/- 7.2 pg/well (range 14.2-40.2) in T4-treated patients. In eu-, hypo- and hyperthyroid patients, a significant correlation was observed between CT4 and free T4 index (FT4I), free T4 (FT4) or Sex Hormone Binding Globulin (SHBG) values. In T4-treated patients, CT4 values were correlated with FT4I values, but not with FT4 or SHBG levels. All T4-treated patients with elevated SHBG levels had elevated FT4, FT4I and CT4 values. In contrast, of the 16 T4-treated subjects with normal serum SHBG concentrations, all but one had normal FT3, 3 (19%) had elevated FT4, 10 (62%) elevated FT4I and 13 (81%) elevated CT4, but all (100%) had undetectable TSH levels. Thus, considering serum SHBG concentrations as a parameter of hepatic tissue response to thyroid hormone, CT4 values, at least in T4-treated patients, do not accurately reflect the liver responsiveness to thyroid hormone action.

Androgen status in women with late onset or persistent acne vulgaris.

Summary The androgen status of fifty women with persistent or late onset acne vulgaris has been investigated. Abnormalities of serum androgens and sex hormone binding globulin (SHBG) alone or in combination were present in 52% of the patients. Elevated serum testosterone and low SHBG were the commonest abnormalities found (46%). Raised levels of serum dehydroepiandrosterone (DHA) and DHA sulphate were present in 16% and 12% of patients respectively, but elevation of one or other of these androgens was the sole abnormality in only 6% of patients. Serum prolactin was raised in 18% of patients but there was no correlation between prolactin and androgen levels. There was also no correlation between the androgen levels and the severity, distribution or pattern of acne or the presence of hirsuties or irregular periods. The hormonal abnormalities found in this group of patients with acne are similar to those seen in females with the polycystic ovary syndrome and idiopathic hirsuties.

Factors underlying infertility in the alcoholic.

In an effort to identify the factor(s) contributing to loss in sexual competence in alcoholics, a pilot study was made of the interrelationships of hepatic disease, plasma hormone levels and importnce in 35 male patients in an alcohol unit. Contrary to previous reports, impotence was not a direct concomitant of hepatic disease, elevated sex hormone-binding globulin capacity or hyperestrinism. The most significant aberration found was a nearly 30% lower mean free testosterone concentration which appeared to be secondary to a mean total testosterone concentration 20% below that of the subjects with normal sexual function. We conclude from this that impotence results from testicular secretion impaired by the action of alcohol or its metabolite, acetaldehyde.

A rapid method for the measurement of sex hormone binding globulin capacity of sera

A simple rapid method for the measurement of sex hormone binding globulin (SHBG) capacity, using 0.2ml of serum, is described. [4- 14C] Testosterone is used as the saturating ligand at one dose level for all samples except pregnancy sera. Albumin bound [4- 14C] testosterone is separated from the globulins with ammonium sulphate and the labelled globulin fraction counted. Pre-treatment of sera with a charcoal suspension under defined optimum conditions removes endogenous steroids associated with the binding proteins without affecting the binding [4- 14C] testosterone to SHBG. The method shows good reproducibility with a coefficient of variation of 4% for male and 4.7% for female serum. Association constants measured for normal male, female and pregnancy sera were 3.6 × 10 8 M −1 , 3.2 × 10 8 M −1, and 1.7 × 10 8 M −1 at 20°, respectively. Normal males gave SHBG capacities of 5.0 ± 0.36 × 10 −8 M/1; females, 7.80 ± 1.24; prepubertal children, 7.01 ± 1.8. Women with amenorrhoea and hirsute women with polycystic ovaries had the lowest SHBG capacities of all, at 4.19 ± 0.75 and 4.06 ± 0.97 respectively. Post-menopausal women also had low levels, 5.25 ± 1.25. Five males with selective hypogonadotrophic hypogonadism had a mean value of 5.69 ± 0.84 which was significantly higher than the normal males. Two patients with Kallman's syndrome had elevated SHBG capacities. Two patients with panhypopituitarism and one patient with Klinefelter's syndrome had low SHBG capacities when compared with normal males. One patient with growth hormone deficiency had a normal SHBG capacity. Pregnancy sera had the highest capacities at 29.03 ± 3.76. No day to day variation in SHBG capacity could be demonstrated over a three day period in the sera from ten normal males.