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.     

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.     

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.     

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.     

A prospective study of sex steroids, sex hormone-binding globulin, and non-vertebral fractures in women and men: the Tromso Study

OBJECTIVES: As bone fragility is partly the result of sex hormone deficiency, we sought to determine whether circulating sex steroids or sex hormone-binding globulin (SHBG) predicts non-vertebral fractures. METHODS: Forearm bone mineral density (BMD), total estradiol and testosterone, calculated free levels, and SHBG were measured in 1386 postmenopausal women and 1364 men aged 50-84 years at baseline in the Troms? Study (1994-1995). Non-vertebral fractures were documented between 1994 and 2005. RESULTS: During 8.4 years (range 0.01-10.4) of follow-up, 281 women and 105 men suffered non-vertebral fractures. For both sexes, fracture cases had lower BMD and higher SHBG, but sex steroids were not lower. Each standard deviation (s.d.) increase in SHBG increased non-vertebral fracture risk in women (hazards ratio (HR) 1.17; 95% confidence interval (CI) 1.03-1.33) and men (HR 1.26; 95% CI 1.03-1.54). After further adjustment for BMD, the risk was not statistically significant in women (HR 1.09; 95% CI 0.95-1.24) or men (HR 1.22; 95% CI 0.99-1.49). Each s.d. decrease in BMD increased fracture risk in women (HR 1.36; 95% CI 1.19-1.56) and men (HR 1.41; 95% CI 1.15-1.73). Fracture rates were highest in participants with SHBG in the highest tertile and BMD in the lowest tertile and were 37.9 and 17.0 per 1000 person-years in women and men respectively. However, in both sexes the combination of BMD and SHBG was no better predictor of fracture risk than BMD alone. Sex steroids were not associated with fracture risk. CONCLUSIONS: Measurements of sex steroids or SHBG are unlikely to assist in decision making regarding fracture risk susceptibility.     

Correlations between serum testosterone, estradiol, and sex hormone-binding globulin and bone mineral density in a diverse sample of men

CONTEXT: The relationship between hormones and bone mineral density (BMD) in men has received considerable attention. However, most studies have been conducted in homogenous populations, and it is not known whether differences in hormones impact racial and ethnic differences in BMD. OBJECTIVE: Our objective was to examine associations of testosterone, estradiol, and sex hormone-binding globulin (SHBG) with BMD in a racially and ethnically diverse population. DESIGN: This was a population-based, observational survey. PARTICIPANTS: A total of 976 Black, Hispanic, and white randomly selected men ages 30-79 yr from the Boston Area Community Health/Bone Survey were included. OUTCOME: BMD at the hip, wrist, and spine were calculated. RESULTS: The mean age of the sample was 46.7 +/- 12.4 yr. BMD levels were highest in black men, followed by Hispanic and then white men. Associations between hormones and BMD were consistent across racial and ethnic groups. Total and free testosterone was not correlated with BMD in age- or multivariate-adjusted models. SHBG was inversely correlated with total hip and ultradistal radius BMD after age adjustment, but not with multivariate adjustment for age, lean mass, fat mass, physical activity, self-rated health, and smoking. Total and free estradiol levels were positively and significantly correlated with femoral neck and total hip BMD, even with multivariate adjustment (partial correlations ranged between 0.11 and 0.16). However, estradiol levels failed to account for racial and ethnic differences in hip BMD. CONCLUSIONS: In our diverse population, neither serum total nor free testosterone levels were associated with BMD. Correlations between BMD and estradiol were significant but did not appear to account for any of the observed racial and ethnic differences in BMD. These findings suggest that differences in hormone levels are not a major contributor to the observed differences in BMD between Black, Hispanic, and white men.     

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.     

Relationship between sex hormone-binding globulin levels and features of the metabolic syndrome

Previous studies have demonstrated that reduced plasma levels of sex hormone-binding globulin (SHBG) are related to alterations in several features of the metabolic syndrome in both men and women. We investigated whether SHBG level was a global predictor of the metabolic syndrome in a sample of 203 men, 173 premenopausal, and 46 postmenopausal women for whom we also obtained a detailed assessment of the metabolic profile, including body composition (hydrostatic weighing), abdominal adipose tissue areas (computed tomography), plasma lipid-lipoprotein levels, and glucose homeostasis (oral glucose challenge). Low SHBG levels were associated with increased total and abdominal adiposity in men as well as in pre- and postmenopausal women. Low SHBG levels were also associated with an altered metabolic profile, especially in premenopausal women. Subjects were subdivided according to the presence of 0, 1 to 2, or 3 or more features of the metabolic syndrome. Twenty-five percent of men were characterized by 3 features or more, whereas most premenopausal women (61.3%) had a healthy metabolic profile (0 features) and 6.9% were characterized by 3 or more features. Most postmenopausal women (54.3%) were characterized by 1 to 2 components of the metabolic syndrome, and 13.0% were characterized by 3 or more components. The proportion of subjects characterized by the metabolic syndrome (3 components or more) was lower in subjects with SHBG values in the upper tertile compared with the lower tertile in both men and premenopausal women (17.7% v 28.4% and 1.7% v 14.0%, respectively). Logistic regression analyses indicated that an SHBG level in the upper tertile was associated with a significant reduction in the probability of being characterized by the metabolic syndrome (odds ratios of 0.35, P =.02 for men and.11, P =.05 for premenopausal women, with the lower tertile as a reference). The logistic regression was not significant in postmenopausal women. These results suggest that plasma SHBG level may represent a significant predictor of the metabolic syndrome in men and premenopausal women.     

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.     

Total estradiol, free estradiol, sex hormone-binding globulin, and the fraction of estradiol bound to sex hormone-binding globulin in human follicular fluid

Sex hormone-binding globulin (SHBG), percent free estradiol (E2), the fraction of E2 bound to SHBG, and total E2 were measured in the serum and follicular fluid of 12 women (25 follicles) who had received gonadotropin stimulation in an in vitro fertilization program. The women were classified as high or low responders based on peak serum E2 levels (high responders: peak E2, greater than 1500 pg/ml; low responders: peak E2, less than 1000 pg/ml). During treatment, serum levels of SHBG increased in high responders from 55 +/- 8.8 (+/- SEM) to 96 +/- 16 nM (P less than 0.01), but did not change in low responders. SHBG was more concentrated in follicular fluids from high responders (142 +/- 12.5 nM) than in those from low responders (44.4 +/- 5.8 nM). A positive correlation was found between serum and follicular fluid levels of SHBG (r = 0.873; P less than 0.01). In follicular fluid, total E2 levels, which varied from 100-2650 ng/ml, correlated (r = 0.790; P less than 0.01) closely with SHBG levels. The percent free E2 averaged 5.9% (range, 4-10.6%) in follicular fluid compared to 1.8% (range, 1.5-2.1%) in serum. An inverse correlation (r = -0.661; P less than 0.01) was found between total E2 concentrations and percent free E2 in follicular fluid. The relationship between serum and follicular fluid levels of SHBG suggests that SHBG in follicles arises from the circulation. Although SHBG is present in follicular fluid in amounts similar to those in serum, the large quantities of E2 in preovulatory follicules exceed the binding capacity for SHBG, and the majority of E2 appears to be bound to albumin. Hence, it seems unlikely that SHBG in follicular fluid regulates estrogen action in ovarian target cells.     

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.     

Relation of age and smoking to serum levels of total testosterone and dehydroepiandrosterone sulfate in aged men

Background:   Hormonal factors have been extensively investigated in the area of geriatric medicine in the search for potential anti-aging agents or useful biomarkers for senescence in men. However, inconsistent results have been published so far concerning the relation of anthropometric and life-style factors to endocrine factors. To confirm the relationships between epidemiological parameters and sex hormone levels, we examined the relation of age and smoking to serum levels of total testosterone (T) and dehydroepiandrosterone sulfate (DHEA) in aged men.
Methods:   The subjects included men aged 50–74 years, 40 current smokers and 27 never smokers. Serum levels of T and DHEA were assayed with a radioimmunoassay kit.
Results:   Serum T did not decrease with age, and was significantly higher in smokers than for non-smokers. Serum DHEA decreased with age more sharply in non-smokers than for smokers.
Conclusion:   These data suggest that serum DHEA decreases with aging, but serum T does not, and that serum levels of these hormones are influenced by cigarette smoking.     

The effects of low-protein diet and testosterone on sex hormone-binding globulin capacity in male rabbits

The effects of a low-protein high-carbohydrate (LPHC) diet (8% protein 65% to 72% carbohydrate) were compared to those of regular rabbit chow (14% to 16% protein 57% to 64% carbohydrate) on sex hormone-binding globulin (SHBG) capacity in 12 male rabbits. The six rabbits who were fed the LPHC diet for 8 weeks showed a significant increase in their mean SHBG capacity (mean +/- SE: from 70 +/- 16 nmol/L to 332 +/- 45 nmol/L, P less than .01) whereas the six rabbits fed the standard diet showed a slight decrease (from 106 +/- 22 nmol/L to 76 +/- 20 nmol/L, NS). These changes in SHBG capacity were mirrored by a decrease in percent-free T (from 2.64 +/- 0.26% to 1.64 +/- 0.16%, P less than .01) in the LPHC diet group and no change in percent-free T in the regular diet group (from 2.36 +/- 0.21% to 2.19 +/- 0.10%). The changes in SHBG capacity and percent-free T were not associated with significant changes in testosterone (T), free T, estradiol (E2), thyroxine, triiodothyronine, thyroxine-binding globulin, or cortisol binding globulin levels. In a subsequent experiment, testosterone cyclopentyl propionate (TCP) was administered to six male rabbits while on regular rabbit chow and again after 6 weeks of the LPHC diet. TCP administration did not cause any significant change in the SHBG capacity, but the LPHC resulted again in a significant (P less than .05) increase in SHBG capacity from 80 +/- 18 nmol/L. to 198 +/- 22 nmol/L.(ABSTRACT TRUNCATED AT 250 WORDS)     

Testosterone, sex hormone-binding globulin, and frailty in older men

OBJECTIVES: To determine whether testosterone (T) levels are associated with frailty or its components. DESIGN: Population-based cohort study conducted in three waves (T1: 1987-1989, T2: 1995-1997, T3: 2002-2004). SETTING: Communities in the Boston, Massachusetts, area. PARTICIPANTS: Six hundred forty-six men aged 50 to 86 at T(3) with complete data on frailty components and hormone measurements. MEASUREMENTS: The frailty phenotype was defined as the presence of three or more of the following: weight loss, exhaustion, low physical activity, slowness, and weakness. Men were classified as frail (> or = 3 components), intermediate (1-2 components), and nonfrail (0 components). Whether total and free T or sex hormone-binding globulin (SHBG) levels were associated cross-sectionally with frailty and with degree of frailty was determined. Potential confounders such as age, chronic disease, lifestyle factors, diet, and physical activity were considered. RESULTS: No association was observed between total or free T and the frailty phenotype after adjusting for confounders. Conversely, a significant association was observed between SHBG and frailty phenotype with an adjusted odds ratio of 1.25 (95% confidence interval=1.06-1.46) per 10-nM increase in SHBG levels. Associations between hormones and degree of frailty were similar to those for overall frailty. Of frailty components, grip strength and physical activity, but not exhaustion, slow walking, or weight loss, were associated with total T levels, whereas SHBG was related to weight loss, exhaustion, and physical activity. CONCLUSION: Total and free T levels were not associated with frailty phenotype, but SHBG was. Furthermore, T and SHBG levels were associated with some, but not all, components of frailty. Therefore, T trials in older men should focus on men experiencing decreases in strength.     

Androgens, estrogens, and sex hormone-binding globulin in middle-aged men

Although the administration of estrogens and androgens can affect the concentrations of sex hormone-binding globulin (SHBG) in men, the relationships between endogenous estrogens and androgens and SHBG are uncertain. Therefore, in a randomly selected cohort of 1640 middle-aged men we measured androgen, estrogen, and SHBG concentrations and obtained the subjects' weight, ethanol intake, and smoking histories. The data were analyzed by stepwise multiple regression, with SHBG as the dependent variable, to compare the role of hormones with that of other factors in the control of SHBG levels. Neither estrone or estradiol nor the testosterone/estradiol ratio was predictive of SHBG levels. However, SHBG concentrations were positively correlated with total testosterone and negatively correlated with percent free and percent albumin-bound testosterone. SHBG concentrations were negatively correlated with estrone sulfate, but were positively correlated with the testosterone/estrone sulfate ratio and the concentrations of free and albumin-bound testosterone. In addition, in all models tested age and body mass index (wt/ht2), but not smoking or ethanol, were strong predictors of SHBG concentrations. Thus, when present in physiological amounts in the blood as a result of glandular secretion, there is a positive relationship between SHBG concentrations and testosterone and, to a lesser extent, free- and albumin-bound testosterone, but age and body mass index appear to be more important in predicting the SHBG concentration.     

Secular decline in male testosterone and sex hormone binding globulin serum levels in Danish population surveys

CONTEXT: Adverse secular trends in male reproductive health have been reported to be reflected in increased testicular cancer risk and decreased semen quality in more recently born men. These secular trends may also be reflected by changes in Leydig cell function. OBJECTIVE: The objective of the study was to examine whether an age-independent time trend in male serum testosterone levels exists. DESIGN AND SETTING: Testosterone and SHBG were analyzed in 5350 male serum samples from four large Danish population surveys conducted in 1982-1983, 1986-1987, 1991-1992, and 1999-2001. Free testosterone levels were calculated. The effects of age, year of birth, and time period on hormone levels were estimated in a general linear statistical model. MAIN OUTCOME MEASURES: Testosterone, SHBG, and calculated free testosterone levels in Danish men in relation to age, study period, and year of birth were measured. RESULTS: Serum testosterone levels decreased and SHBG levels increased with increasing age. In addition to this expected age effect, significant secular trends in testosterone and SHBG serum levels were observed in age-matched men with lower levels in the more recently born/studied men. No significant age-independent effect was observed for free testosterone. Adjustment for a concurrent secular increase in body mass index reduced the observed cohort/period-related changes in testosterone, which no longer were significant. The observed cohort/period-related changes in SHBG levels remained significant after adjustment for body mass index. CONCLUSIONS: The observed age-independent changes in SHBG and testosterone may be explained by an initial change in SHBG levels, which subsequently lead to adjustment of testosterone at a lower level to sustain free testosterone levels.     

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.     

Serum levels of sex hormone-binding globulin (SHBG) are not associated with lower levels of non-SHBG-bound testosterone in male newborns and healthy adult men

OBJECTIVE: It is generally accepted that SHBG decreases the bioavailability and activity of testosterone (T). In in vitro experiments increased levels of SHBG will be associated with decreased levels of non-SHBG bound testosterone (non-SHBG-T). However, in vivo SHBG can alter both production and clearance rates and thus plasma levels of T. DESIGN AND PATIENTS: In order to study the effect of SHBG on the levels of non-SHBG-T in vivo in the presence of an active hypothalamo-pituitary-gonadal (HPG) axis we conducted a cross sectional study in 400 healthy adult men with an age range of 40-80 years and in 106 newborn boys. MEASUREMENTS: In both groups, regression coefficients (beta) and partial correlation coefficients (r) were calculated for the relationship between SHBG and T or non-SHBG-T. Adult men were divided into age groups per decade (40-50 years, 51-60 years, 61-70 years and 71-80 years) to study possible differences in the impact of SHBG on the level of non-SHBG-T throughout ageing. RESULTS: Higher levels of SHBG were associated with higher levels of total testosterone in neonates (beta = 0.02 +/- 0.004, r = 0.44, P < 0.001) but not with non-SHBG-T (beta = -0.001 +/- 0.001, r = 0.05, P = 0.52). In adult men there was a significant age related increase in levels of SHBG and an age-related decrease of both total and non-SHBG-T. Higher SHBG was strongly associated with higher total testosterone in all age groups (beta = 0.26, 0.26, 0.26 and 0.23 for 40-50 years, 51-60 years, 61-70 years and 71-80 years, respectively, P < 0.001 for all age groups). Higher SHBG was not or only slightly associated with higher non-SHBG-T beta = 0.02 (P = 0.32), beta = 0.04 (P = 0.03), beta = 0.04 (P = 0.02) and beta = 0.02 (P = 0.16) for 40-50 years, 51-60 years, 61-70 years and 71-80 years, respectively. CONCLUSIONS: In contrast to general belief, SHBG levels barely influence levels of non-SHBG-bound testosterone both in male newborns and healthy adult men: the influence, if any, is positive. Consequently the age related increase of SHBG does not account for the age related decline in non-SHBG-T in healthy adult men.     

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.     

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.