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CONTEXT: SHBG is known as the major sex steroid binding protein in plasma, and it regulates the bioavailability of both T and estradiol levels required for effects on target tissues. We identified a man with an undetectable SHBG concentration in combination with low total T. He presented with a 7-year history of muscle weakness, fatigue, and a low libido. OBJECTIVES: To determine the cause of the SHBG deficiency, we employed both genetic analysis of the SHBG gene and transgene SHBG expression. RESULTS: Genetic analysis identified a novel homozygous missense mutation that was predicted to be deleterious for protein function. Transgene expression showed that the mutation resulted in a block in SHBG secretion accompanied by increased expression of the endoplasmic reticulum molecular chaperone HSPA5. The mutation results in accumulation of the mutant SHBG within the cell and failure to secrete the mutant protein. Screening of family members identified one sister who was also deficient for SHBG. CONCLUSIONS: We have identified a family with a missense mutation within the SHBG gene, which results in a complete deficiency of plasma SHBG in the homozygous state. Although total T level was low in the male patient, it did not interfere with normal gonadal development and spermatogenesis, suggesting a limited role of SHBG in sexual maturation and male physiology.

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OBJECTIVE: Deficiency of anabolic sex steroids is common in heart failure (HF). The pathophysiological implications of this phenomenon, however, have not been fully elucidated. This clinical study investigated the significance of low serum androgen levels in HF. DESIGN: Prospective cohort study. Patients and Methods In 191 consecutively recruited men with HF (mean age 64 years; New York Heart Association (NYHA) class I-IV 24%/35%/35%/6%) and reduced (ejection fraction (EF) 40%, n=95) left ventricular function total and free serum testosterone, dehydroepiandrosterone sulfate (DHEAS) and sex hormone binding globulin (SHBG) were measured. The median observation period was 859 days. RESULTS: During follow-up 53 patients (28%) died. Whereas total serum testosterone was normal in most patients (91%), free testosterone and DHEAS were reduced in 79% and 23%, respectively. DHEAS and free testosterone, but not total testosterone, were inversely associated with NYHA class (both p<0.01). Lower free testosterone and DHEAS and higher SHBG predicted all-cause mortality risk (hazard ratio (HR) 0.89, 95% CI 0.82 to 0.96 per 1 ng/dl free testosterone, p=0.004; HR 0.95, 95% CI 0.89 to 1.00 per 10 microg/dl DHEAS, p=0.058; and HR 1.18, 95% CI 1.05 to 1.33 per 10 nmol/l SHBG, p=0.006, respectively; adjusted for age and NYHA class). However, further adjustment for carefully selected confounding factors abolished these associations. CONCLUSION: In male HF patients, low serum levels of androgens are associated with adverse prognosis, but this relation is confounded by indicators of a poor health state. The results suggest that low serum androgens develop as a sequel of this progressive multifaceted systemic disorder.

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BACKGROUND: Most children born small for gestational age (SGA) normalize their body size by late infancy. Between 2 and 6 yr, such SGA children develop higher circulating levels of insulin, lower levels of adiponectin, and more visceral fat than appropriate-for-gestational-age (AGA) controls, even in the absence of overweight. Here we report on their further course between 6 and 8 yr. STUDY DESIGN AND POPULATION: Longitudinal study over 2 yr comparing data from 32 AGA vs. 32 SGA children, matched for gender, height, weight, and body mass index at the age of 6 yr. MAIN OUTCOMES: Fasting insulin, dehydroepiandrosterone sulfate (DHEAS), SHBG, high-molecular-weight (HMW) adiponectin, leptin, IGF-I; body composition by absorptiometry; and abdominal fat partitioning by magnetic resonance imaging. RESULTS: Between 6 and 8 yr, novel AGA-vs.-SGA divergences emerged (higher DHEAS and lower SHBG in SGA; P < 0.001), and some earlier divergences widened further (HMW adiponectin, visceral fat; P < 0.001), whereas others stabilized (fasting insulin, IGF-I). At age 8 yr, the most discerning features of SGA children were a high ratio of visceral over sc fat in the abdominal region (69% of SGA children), HMW hypoadiponectinemia (41%), fasting hyperinsulinemia (34%), and elevated circulating IGF-I levels (31%). CONCLUSION: SGA children with spontaneous catch-up growth develop relatively high DHEAS and low SHBG levels and become more often HMW hypoadiponectinemic and viscerally adipose between 6 and 8 yr of age.

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Measurement of total testosterone concentrations is the initial test for the diagnosis of androgen deficiency or excess in men. However, total testosterone concentrations may be affected by alterations in sex hormone binding globulin (SHBG) concentrations. Most circulating testosterone is bound to SHBG and to albumin and only 0.5-3% of circulating testosterone is unbound or free. The free fraction can be measured by equilibrium dialysis or calculated using published algorithms. The term bioavailable testosterone refers to unbound testosterone plus albumin-bound testosterone; this term reflects the view that, in addition to unbound testosterone, albumin-bound testosterone is readily dissociable and thus bioavailable. Bioavailable testosterone can be measured by precipitation methods or calculated from total testosterone, SHBG, albumin concentrations and their affinity constants. Free testosterone measurements by analog methods are frequently available, but these measurements are affected by alterations in SHBG and are inaccurate. We report the cases of a 42-year-old man with testosterone excess and a 29-year-old man with testosterone deficiency, in whom total testosterone concentrations were affected by SHBG alterations.

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We investigated 252 non-obese female subjects aged 13-39 years to evaluate if an exaggerated descent of sex hormone binding globulin (SHBG) levels during adolescence can play a role in the development of hirsutism. Body hair was assessed according to Ferriman and Gallwey (FG), with a stringent criterion of normality of < or = 4. In 13-14 years girls, SHBG and free testosterone (FT) levels were similar in "hirsute" girls (FG > 4) and controls (FG < or = 4, regular menstrual cycles, no acne). In 15-18 years girls, SHBG values were lower in "hirsute" girls, FT levels were similar in both groups, FG correlated inversely with SHBG. In 19-39 yr women, FT levels were higher in "hirsute" subjects, SHBG values were similar in both groups, FG correlated positively with FT. Lowest SHBG values were observed at 15-18 years, but the slope of the decrease from 13-14 years values was greater in the "hirsute" group. FT values increased progressively with age, but the increase was greater in the "hirsute" group. Those results suggest an important role of SHBG decrease in adolescence vs. a more accentuated testosterone increase in adults, as factors conditioning the development of hirsutism in these two different periods of life.

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We investigated 252 non-obese female subjects aged 13-39 years to evaluate if an exaggerated descent of sex hormone binding globulin (SHBG) levels during adolescence can play a role in the development of hirsutism. Body hair was assessed according to Ferriman and Gallwey (FG), with a stringent criterion of normality of < 4. In 13-14 years girls, SHBG and free testosterone (FT) levels were similar in "hirsute" girls (FG > 4) and controls (FG < 4, regular menstrual cycles, no acne). In 15-18 years girls, SHBG values were lower in "hirsute" girls, FT levels were similar in both groups, FG correlated inversely with SHBG. In 19-39 yr women, FT levels were higher in "hirsute" subjects, SHBG values were similar in both groups, FG correlated positively with FT. Lowest SHBG values were observed at 15-18 years, but the slope of the decrease from 1314 years values was greater in the "hirsute" group. FT values increased progressively with age, but the increase was greater in the "hirsute" group. Those results suggest an important role of SHBG decrease in adolescence vs. a more accentuated testosterone increase in adults, as factors conditioning the development of hirsutism in these two different periods of life.

Se investigaron 252 mujeres con peso normal, de 13 a 39 años de edad, para evaluar si un descenso exagerado en los niveles de la globulina transportadora de hormonas sexuales ("sex hormone binding globulin"; SHBG) puede tener un rol en el desarrollo de hirsutismo. Este signo fue evaluado con la escala de Ferriman y Gallwey (FG), empleando un criterio riguroso de normalidad < 4. En niñas de 13-14 años, tanto SHBG como la testosterona libre ("free testosterone"; FT) fueron similares en niñas "hirsutas" (FG > 4) y controles (FG < 4, ciclos menstruales regulares, sin acné). En adolescentes de 15-18 años, los valores de SHBG fueron menores en las "hirsutas", los niveles de FT fueron similares en ambos grupos y el índice de FG correlacionó inversamente con SHBG. En las mujeres de 19-39 años, los niveles de FT fueron mayores en las "hirsutas", los valores de SHBG fueron similares en ambos grupos y FG correlacionó positivamente con FT. Los valores más bajos de SHBG se observaron entre 15 y 18 años, pero la pendiente de disminución a partir de los valores de 13-14 años fue mayor en el grupo de "hirsutas". Los valores de FT se incrementaron progresivamente con la edad, pero el aumento fue mayor en el grupo de "hirsutas". Estos resultados sugieren un rol importante del descenso de SHBG en la adolescencia vs. un incremento más acentuado de los niveles de testosterona en las adultas, como factores que condicionan el desarrollo del hirsutismo en esos dos diferentes periodos de la vida.

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Aging is a complex process. In males after the 40th year of life the total serum testosterone (T) levels are decreased, especially the serum levels of so-called bioavailable testosterone (BT), whereas the serum levels of sex hormone binding globulin (SHBG) are increased. This androgen deficiency in males does not always cause symptoms. In symptomatic males a detailed history is required supported by screening questionnaires for androgen deficiency, followed by a clinical examination; the serum levels of T and SHBG should also be determined. In patients with normal serum levels of T and increased SHBG serum levels, free testosterone, obtained by calculation from the T and SHBG levels, is a reliable and simple index of BT to show the presence of androgen deficiency. Further endocrinological examinations are only recommended for differential diagnosis in the aging male. Before testosterone replacement therapy is started in symptomatic males with hypogonadism, risk factors, especially cancer of the prostate, have to be excluded.

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BACKGROUND: Polycystic ovary syndrome (PCOS), the most frequent endocrinopathy in women with estimated prevalence of 5-10 %, is characterised by a hormonal and metabolic imbalance of polygene autosomal trait. The complexity of symptoms and genetic base started up the hypothesis on the existence of male equivalent of PCOS. Precocious loss of hair before 30 years of age was suggested as one of the male symptoms of this syndrome. OBJECTIVES: The aim was to confirm the association of lower levels of follicle stimulating hormone (FSH) and sexual hormone binding globulin (SHBG) or higher free androgen index (FAI) in premature balding men with a reduced insulin sensitivity. PATIENTS/METHODS: The study included 30 men with premature hair loss (defined as grade 3 vertex or more on the alopecia classification scale by Hamilton with Norwood modification) starting before 30 years of age. The hormonal values of the investigated group were compared with those regarded as normal reference values obtained in a group of 256 males in the age of 20-40 years during the Czech population study of iodine deficiency. In all men with premature baldness besides hormonal level determinations insulin tolerance test was carried out. RESULTS: The observed group was divided into two subgroups. The first one showed similar hormonal changes as women with PCOS, namely subnormal SHBG, FSH or increased FAI. The other had either no anomalies in steroid spectrum or only lower SHBG. The groups did not differ either in BMI or in age. The group with hormonal profile resembling that of women with PCOS, showed significantly higher insulin resistance than the group without these changes. CONCLUSIONS: The findings are consistent with the hypothesis that at least a part of the men with premature androgenic alopecia could be considered as a male equivalent of the polycystic ovary syndrome of the women. These premature balding men represent a risk group for the development of impaired glucose tolerance or diabetes mellitus type 2.

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Low levels of sex hormone-binding globulin (SHBG) are considered to be an indirect index of hyperinsulinemia, predicting the later onset of diabetes mellitus type 2. In the insulin resistance state and in the presence of an increased pancreatic ß-cell demand (e.g. obesity) both absolute and relative increases in proinsulin secretion occur. In the present study we investigated the correlation between SHBG and pancreatic ß-cell secretion in men with different body compositions. Eighteen young men (30.0 ± 2.4 years) with normal glucose tolerance and body mass indexes (BMI) ranging from 22.6 to 43.2 kg/m2 were submitted to an oral glucose tolerance test (75 g) and baseline and 120-min blood samples were used to determine insulin, proinsulin and C-peptide by specific immunoassays. Baseline SHBG values were significantly correlated with baseline insulin (r = -0.58, P<0.05), proinsulin (r = -0.47, P<0.05), C-peptide (r = -0.55, P<0.05) and also with proinsulin at 120 min after glucose load (r = -0.58, P<0.05). Stepwise regression analysis revealed that proinsulin values at 120 min were the strongest predictor of SHBG (r = -0.58, P<0.05). When subjects were divided into obese (BMI >28 kg/m2, N = 8) and nonobese (BMI £25 kg/m2, N = 10) groups, significantly lower levels of SHBG were found in the obese subjects. The obese group had significantly higher baseline proinsulin, C-peptide and 120-min proinsulin and insulin levels. For the first time using a specific assay for insulin determination, a strong inverse correlation between insulinemia and SHBG levels was confirmed. The finding of a strong negative correlation between SHBG levels and pancreatic ß-cell secretion, mainly for the 120-min post-glucose load proinsulin levels, reinforces the concept that low SHBG levels are a suitable marker of increased pancreatic ß-cell demand

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Low levels of sex hormone-binding globulin (SHBG) are considered to be an indirect index of hyperinsulinemia, predicting the later onset of diabetes mellitus type 2. In the insulin resistance state and in the presence of an increased pancreatic beta-cell demand (e.g. obesity) both absolute and relative increases in proinsulin secretion occur. In the present study we investigated the correlation between SHBG and pancreatic beta-cell secretion in men with different body compositions. Eighteen young men (30.0 +/- 2.4 years) with normal glucose tolerance and body mass indexes (BMI) ranging from 22.6 to 43.2 kg/m2 were submitted to an oral glucose tolerance test (75 g) and baseline and 120-min blood samples were used to determine insulin, proinsulin and C-peptide by specific immunoassays. Baseline SHBG values were significantly correlated with baseline insulin (r = -0.58, P < 0.05), proinsulin (r = -0.47, P < 0.05), C-peptide (r = -0.55, P < 0.05) and also with proinsulin at 120 min after glucose load (r = -0.58, P < 0.05). Stepwise regression analysis revealed that proinsulin values at 120 min were the strongest predictor of SHBG (r = -0.58, P < 0.05). When subjects were divided into obese (BMI > 28 kg/m2, N = 8) and nonobese (BMI < or = 25 kg/m2, N = 10) groups, significantly lower levels of SHBG were found in the obese subjects. The obese group had significantly higher baseline proinsulin, C-peptide and 120-min proinsulin and insulin levels. For the first time using a specific assay for insulin determination, a strong inverse correlation between insulinemia and SHBG levels was confirmed. The finding of a strong negative correlation between SHBG levels and pancreatic beta-cell secretion, mainly for the 120-min post-glucose load proinsulin levels, reinforces the concept that low SHBG levels are a suitable marker of increased pancreatic beta-cell demand.

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Factors influencing sex-hormone binding globulin (SHBG) concentrations in obesity are poorly understood. Preliminary observations suggest that dietary lipids may be involved and there are data confirming a direct inhibiting effect of insulin. Since only some obese subjects show lowered SHBG levels, we performed this study with the aim of defining obese women with low SHBG (LSO) (2 SD above normal values) in comparison with those presenting normal globulin concentrations (NSO). These groups were selected from a larger group of obese women with a history of normal menses and aged less than 40 years. An age-matched group of normal weight healthy women served as controls. Both LSO and NSO had similar body mass index and percentage body fat, but the waist to hip girth ratio (WHR), an index of body fat distribution, was significantly higher in LSO (0.88 +/- 0.04) than in NSO (0.81 +/- 0.09; P less than 0.05). Gonadotropin and androgen concentrations were similar in both groups, whereas estrone (E1) levels were higher in LSO (32.8 +/- 15.8 pg/ml) than in NSO (19.4 +/- 6.2 pg/ml; P less than 0.05; controls: 23.5 +/- 7.8 pg/ml; P less than 0.05). Moreover, compared to NSO, LSO women had significantly higher glucose-stimulated insulin and C-peptide levels. Partial regression analysis revealed significant correlation coefficients between SHBG, stimulated insulin values (r = -0.38; P less than 0.05) and WHR (r = 0.40; P less than 0.005). Therefore, compared to NSO, LSO women have distinctive clinical and endocrine characteristics, namely more pronounced hyperinsulinemia, higher E1 concentrations and a central type body fat distribution.

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