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May 2011

Endogenous sex hormones and endometrial cancer risk in women in the European Prospective Investigation into Cancer and Nutrition (EPIC).

Epidemiological data show that reproductive and hormonal factors are involved in the etiology of endometrial cancer, but there is little data on the association with endogenous sex hormone levels. We analyzed the association between prediagnostic serum concentrations of sex steroids and endometrial cancer risk in the European Prospective Investigation into Cancer and Nutrition using a nested case-control design of 247 incident endometrial cancer cases and 481 controls, matched on center, menopausal status, age, variables relating to blood collection, and, for premenopausal women, phase of menstrual cycle. Using conditional regression analysis, endometrial cancer risk among postmenopausal women was positively associated with increasing levels of total testosterone, free testosterone, estrone, total estradiol, and free estradiol. The odds ratios (ORs) for the highest versus lowest tertile were 2.66 (95% confidence interval (CI) 1.50-4.72; P=0.002 for a continuous linear trend) for estrone, 2.07 (95% CI 1.20-3.60; P=0.001) for estradiol, and 1.66 (95% CI 0.98-2.82; P=0.001) for free estradiol. For total and free testosterone, ORs for the highest versus lowest tertile were 1.44 (95% CI 0.88-2.36; P=0.05) and 2.05 (95% CI 1.23-3.42; P=0.005) respectively. Androstenedione and dehydroepiandrosterone sulfate were not associated with risk. Sex hormone-binding globulin was significantly inversely associated with risk (OR for the highest versus lowest tertile was 0.57, 95% CI 0.34-0.95; P=0.004). In premenopausal women, serum sex hormone concentrations were not clearly associated with endometrial cancer risk, but numbers were too small to draw firm conclusions. In conclusion, relatively high blood concentrations of estrogens and free testosterone are associated with an increased endometrial cancer risk in postmenopausal women.

Endocr Relat Cancer. 2008 Jun;15(2):485-97

Sex hormone binding globulin: origin, function and clinical significance.

Sex hormone binding globulin (SHBG) is a glycoprotein possessing high affinity binding for 17 beta-hydroxysteriod hormones such as testosterone and oestradiol. It is probably synthesized in the liver, plasma concentrations being regulated by, amongst other things, androgen/oestrogen balance, thyroid hormones, insulin and dietary factors, it is involved in transport of sex steroids in plasma and its concentration is a major factor regulating their distribution between the protein-bound and free states. Its detailed role in the delivery of hormones to target tissues is not yet clear. Plasma SHBG concentrations are affected by a number of different diseases, high values being found in hyperthyroidism, hypogonadism, androgen insensitivity and hepatic cirrhosis in men. Low concentrations are found in myxoedema, hyperprolactinaemia and syndromes of excessive androgen activity. Concentrations are also affected by drugs such as androgens, oestrogens, thyroid hormones and anti-convulsants. Measurement of SHBG is useful in the evaluation of mild disorders of androgen metabolism and enables identification of those women with hirsutism who are more likely to respond to oestrogen therapy. Testosterone: SHBG ratios correlate well with both measured and calculated values of free testosterone and help to discriminate subjects with excessive androgen activity from normal individuals.

Ann Clin Biochem. 1990 Nov;27 ( Pt 6):532-41

Human sex hormone-binding globulin gene expression- multiple promoters and complex alternative splicing.

BACKGROUND: Human sex hormone-binding globulin (SHBG) regulates free sex steroid concentrations in plasma and modulates rapid, membrane based steroid signaling. SHBG is encoded by an eight exon-long transcript whose expression is regulated by a downstream promoter (P(L)). The SHBG gene was previously shown to express a second major transcript of unknown function, derived from an upstream promoter (P(T)), and two minor transcripts. RESULTS: We report that transcriptional expression of the human SHBG gene is far more complex than previously described. P(L) and P(T) direct the expression of at least six independent transcripts each, resulting from alternative splicing of exons 4, 5, 6, and/or 7. We mapped two transcriptional start sites downstream of P(L) and P(T), and present evidence for a third SHBG gene promoter (P(N)) within the neighboring FXR2 gene; PN regulates the expression of at least seven independent SHBG gene transcripts, each possessing a novel, 164-nt first exon (1N). Transcriptional expression patterns were generated for human prostate, breast, testis, liver, and brain, and the LNCaP, MCF-7, and HepG2 cell lines. Each expresses the SHBG transcript, albeit in varying abundance. Alternative splicing was more pronounced in the cancer cell lines. P(L)- P(T)- and P(N)-derived transcripts were most abundant in liver, testis, and prostate, respectively. Initial findings reveal the existence of a smaller immunoreactive SHBG species in LNCaP, MCF-7, and HepG2 cells. CONCLUSION: These results extend our understanding of human SHBG gene transcription, and raise new and important questions regarding the role of novel alternatively spliced transcripts, their function in hormonally responsive tissues including the breast and prostate, and the role that aberrant SHBG gene expression may play in cancer.

BMC Mol Biol. 2009 May 5;10:37

Sex hormone binding globulin and aging.

New and more active concepts of steroid binding globulin action are emerging from recent research. As a result, examination of steroid levels in aging humans and the role of steroid binding globulins need to be re-visited. This review will discuss the possibility that sex hormone binding globulin (SHBG) plays an active role in the aging process. It will discuss the changes in blood levels of SHBG in aging humans in association with sexual activity, prostate hypertrophy and cancer, uterine leiomyoma, breast cancer, obesity and particularly the relationship between SHBG and HDL-cholesterol, Alzheimer’s disease, osteoporosis, and cardiovascular disease. Starting with the idea that SHBG is an active participant in steroid action demands a re-evaluation of data demonstrating a primary change in blood SHBG levels in association with various pathologies. Here we discuss the postulate that SHBG may act at its own receptor at the plasma membrane level to influence other receptors such as scavenger receptors and HDL-cholesterol receptors. We will also suggest that SHBG is a critical marker for mating and thus may be an important physiological molecule in control of aging.

Horm Metab Res. 2009 Mar;41(3):173-82

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.

Int J Obes Relat Metab Disord. 2000 Jun;24 Suppl 2:S64-70

Non-sex hormone-binding globulin-bound testosterone as a marker for hyperandrogenism.

Recent evidence suggests that the biologically active testosterone includes both the free and albumin-bound fractions, while the sex hormone-binding globulin (SHBG)-bound steroid dissociates less readily. To examine the significance of the non-SHBG-bound testosterone (i.e. free plus albumin bound) in hyperandrogenism, we obtained single blood samples from 17 normal women, 20 regularly menstruating but hirsute women, and 20 oligoamenorrheic hirsute women. Each serum sample was analyzed for total testosterone by RIA, SHBG-binding capacity was determined by protein precipitation with 50% saturated (NH4)2SO4, and albumin was measured by colorimetry. Non-SHBG-bound and free testosterone and the testosterone to SHBG molar ratio were then calculated. Non-SHBG-bound testosterone was also assayed using differential protein precipitation. There were significant differences among the groups in the mean values of all variables (all P less than 0.05) except albumin. Measurement and calculation of serum non-SHBG-bound testosterone produced similar results, suggesting that the binding equation is valid. There was considerable overlap between normal (control mean +/- 2 SD) and abnormal subjects in all variables except non-SHBG-bound testosterone, for which only 3 regularly menstruating and 2 oligoamenorrheic hirsute subjects were in the normal range. As total testosterone levels increased, there was a significant increase in the ratio of non-SHBG-bound testosterone to free testosterone. These data suggest that albumin becomes increasingly more important in testosterone binding as the total serum testosterone level increases and that non-SHBG-bound testosterone may be the optimal marker to identify hyperandrogenism in hirsute women

J Clin Endocrinol Metab. 1985 Nov;61(5):873-6

Decreased bioavailable testosterone in aging normal and impotent men.

Tissue available (bioavailable) testosterone (T) includes circulating free T (FT) and albumin-bound T. A reasonable assessment of bioavailable T can be made by using 50% ammonium sulfate to precipitate sex hormone-binding globulin (SHBG)-bound T. The supernatant non-SHBG-bound T (non-SHBG-T) correlates well with physiological androgen activity. To assess bioavailable T in normal aging men, we analyzed serum samples from seven healthy aged men (65-83 yr old) and compared the results to samples from 13 young men (22-39 yr old). Mean serum T, FT, and LH concentrations were not significantly different in the 2 groups. However, the mean absolute non-SHBG-T level was significantly lower (P less than 0.005) in the older group. In a separate population of 20 impotent but otherwise healthy men (5 27-37 yr old, 10 48-64 yr old, and 5 66-69 yr old), the mean absolute non-SHBG-T concentration was lower in middle-aged (P less than .01) and elderly men (P less than 0.001) than in young men. The absolute FT was lower only in the elderly group (P less than 0.05), while mean LH and T levels were similar in all 3 age groups. These data suggest that serum concentrations of tissue available T are decreased in aged men and that non-SHBG-T measurement is a more sensitive indicator of this decrease than are serum T or serum FT measurements. These changes appear to begin by middle age.

J Clin Endocrinol Metab. 1986 Dec;63(6):1418-20

Glucose tolerance and plasma testosterone concentrations in men. Results of the Asturias Study.

BACKGROUND AND OBJECTIVE: Studies in men have demonstrated a correlation between serum concentrations of androgens and sex hormone binding globulin (SHBG) with the presence of impaired glucose tolerance, diabetes and metabolic syndrome. The aim of this study was to evaluate circulating levels of total testosterone, SHBG, and bioavailable testosterone in the cohort of the Asturias Study and their association with the degree of glucose tolerance and metabolic syndrome. PATIENTS AND METHODS: The study population consisted of 282 men aged 36 to 85 years old with normal concentrations of total testosterone. The degree of glucose tolerance and the presence of metabolic syndrome were evaluated. RESULTS: Serum concentrations of testosterone and bioavailable testosterone were negatively correlated with age, body mass index, waist circumference, blood glucose, glycated hemoglobin levels and insulin. Serum concentrations of total testosterone, bioavailable testosterone and SHBG were lower in men with glucose intolerance or diabetes than in those with normal glucose tolerance. After multivariate analysis, age and total testosterone levels were independent predictors of the presence of diabetes or glucose intolerance. The risk of glucose intolerance or diabetes mellitus was over 2.5 times higher in men with total testosterone levels in the lowest quartile than in those with total testosterone in the top quartile.CONCLUSIONS: In this general population sample from Asturias, men with lower plasma concentrations of total testosterone—even when within the normal range—have an increased risk of glucose intolerance or diabetes, regardless of age and body mass index.

Endocrinol Nutr. 2011 Jan;58(1):3-8

Associations of endogenous testosterone and SHBG with glycated haemoglobin in middle-aged and older men.

Low circulating levels of testosterone and sex hormone-binding Objective: globulin (SHBG) are associated with increased cardiovascular risk in men. This association may be partially mediated through changes in glucose metabolism, but relatively few data are available on the relationship between sex hormones and markers of long-term glycaemia. We assessed the associations of endogenous testosterone and SHBG with glycated haemoglobin (HbA(1c)) in men. Design and Crosssectional study of 1,292 men from the Norfolk population of subjects: European Prospective Investigation into Cancer (EPIC-Norfolk). Measurements: HbA(1c) , total testosterone (TT) and SHBG levels were measured and free testosterone (FT) levels were calculated. Multiple linear regression models were Men used to assess the associations of TT, SHBG and FT with HbA(1c). Results: with self-reported diabetes or undiagnosed diabetes had lower testosterone and SHBG levels. In non-diabetic men, HbA(1c) levels were inversely associated with TT and calculated FT independently of age, body mass index, smoking, alcohol consumption and physical activity. The adjusted change in HbA(1c) was 0.055 (95% CI 0.025; 0.085) per standard deviation (sd) decrease in TT and 0.041 (95% CI 0.010; 0.073) per sd decrease in calculated FT respectively. SHBG levels were inversely associated with HbA(1c) after multivariable adjustment (beta = 0.038 In middle-aged and older per sd decrease (95% CI 0.004; 0.071)). Conclusions: men, low endogenous testosterone and SHBG levels are associated with glycaemia, even below the threshold for diabetes. Further studies are needed to determine the effects of interventions that raise testosterone levels in men having increased HbA(1c) and subnormal testosterone levels.

Clin Endocrinol (Oxf). 2010 Dec 15

Lower sex hormone-binding globulin is more strongly associated with metabolic syndrome than lower total testosterone in older men: the Health in Men Study.

BACKGROUND: Reduced circulating testosterone and sex hormone-binding globulin (SHBG) are implicated as risk factors for metabolic syndrome. As SHBG increases with age while testosterone declines, we examined the relative contributions of SHBG and testosterone to the risk of metabolic syndrome in older men. METHODS: We conducted a cross-sectional study of 2,502 community-dwelling men aged > or = 70 years without known diabetes. Metabolic syndrome was defined using the National Cholesterol Education Program-Third Adult Treatment Panel (NCEP-ATPIII) criteria. Early morning fasting sera were assayed for total testosterone, SHBG and LH. Free testosterone was calculated using mass action equations. RESULTS: There were 602 men with metabolic syndrome (24.1%). The risk of metabolic syndrome increased for total testosterone < 20 nmol/l, SHBG < 50 nmol/l and free testosterone < 300 pmol/l. In univariate analyses SHBG was associated with all five components of metabolic syndrome, total testosterone was associated with all except hypertension, and free testosterone was associated only with waist circumference and triglycerides. In multivariate analysis, both total testosterone and especially SHBG remained associated with metabolic syndrome, with odds ratios of 1.34 (95% confidence interval (CI): 1.18-1.52) and 1.77 (95% CI: 1.53-2.06) respectively. Men with hypogonadotrophic hypogonadism (total testosterone < 8 nmol/l, LH < or = 12 IU/l) had the highest prevalence of metabolic syndrome (53%, P<0.001). CONCLUSIONS: Lower SHBG is more strongly associated with metabolic syndrome than lower total testosterone in community-dwelling older men. SHBG may be the primary driver of these relationships, possibly reflecting its relationship with insulin sensitivity. Further studies should examine whether measures that raise SHBG protect against the development of metabolic syndrome in older men.

Eur J Endocrinol. 2008 Jun;158(6):785-92

SHBG, Sex Hormones, and Inflammatory Markers in Older Women.

Context: In premenopausal and older women, high testosterone and estradiol (E2) and low SHBG levels are associated with insulin resistance and diabetes, conditions characterized by low-grade inflammation. Objective: The aim of the study was to examine the relationship between SHBG, total testosterone, total E2, and inflammatory markers in older women. Design and Patients: We conducted a retrospective cross-sectional study of 433 women at least 65 yr old from the InCHIANTI Study, Italy, who were not on hormone replacement therapy or recently hospitalized and who had complete data on SHBG, testosterone, E2, C-reactive protein (CRP), IL-6, soluble IL-6 receptor (sIL-6r), and TNF-. Relationships between sex hormones and inflammatory markers were examined by multivariate linear regression analyses adjusted for age, body mass index, smoking, insulin, physical activity, and chronic disease. Results: In fully adjusted analyses, SHBG was negatively associated with CRP (P = 0.007), IL-6 (P = 0.008), and sIL-6r (P = 0.02). In addition, testosterone was positively associated with CRP (P = 0.006), IL-6 (P = 0.001), and TNF- (P = 0.0002). The negative relationship between testosterone and sIL-6r in an age-adjusted model (P = 0.02) was no longer significant in a fully adjusted model (P = 0.12). E2 was positively associated with CRP (P = 0.002) but not with IL-6 in fully adjusted models. In a final model including E2, testosterone, and SHBG, and all the confounders previously considered, SHBG (0.23 ± 0.08; P = 0.006) and E2 (0.21 ± 0.08; P = 0.007), but not testosterone (P = 0.21), were still significantly associated with CRP. Conclusion: In late postmenopausal women not on hormone replacement therapy, SHBG and E2 are, respectively, negative and positive, independent and significant correlates of a proinflammatory state.

J Clin Endocrinol Metab. 2011 Jan 14