Decreased Sex Hormone-binding Globulin Levels Research Articles

Association between secondhand smoke exposure and serum sex hormone concentrations among US female adults: a cross-sectional analysis using data from the National Health and Nutrition Examination Survey, 2013–2016

ObjectiveTo estimate the association between secondhand smoke (SHS) exposure and serum sex hormone concentrations in female adults (never smokers and former smokers).DesignCross-sectional analysis.SettingUS National Health and Nutrition Examination Survey, 2013–2016.Outcome...

Association between aldehyde exposure and sex steroid hormones among adults.

Exogenous and endogenous exposure to aldehydes is seen worldwide. Aldehydes are closely associated with human diseases, especially reproductive toxicity. However, the effect of aldehyde exposure on sex steroid hormones among adults remains uninvestigated. A total of 851 participants aged over 18years were included in this cross-sectional analysis based on data from National Health and Nutrition Examination Survey (NHANES) 2013-2014. Serum aldehyde concentrations were quantified following an automated analytical method. Sex steroid hormones including total testosterone, estradiol, and sex hormone binding globulin (SHBG) were detected. Multivariate linear regression models, forest plots, generalized additive model (GAM), and smooth curve fitting analysis were used to assess the associations between quartiles of aldehydes and sex steroid hormones levels after adjusting for potential confounders. Butyraldehyde and propanaldehyde were found to be negatively associated with estradiol and SHBG in females and males, respectively. β values with 95% confidence intervals (95% CIs) were - 20.59 (- 38.30 to - 2.88) for Q2 vs. Q1 of butyraldehyde and - 8.13 (- 14.92 to - 1.33) and - 7.79 (- 14.91 to - 0.67) for Q2 vs. Q1 and Q4 vs. Q1 of propanaldehyde. No significant associations were observed between other aldehydes and sex hormones. In premenopausal women, isopentanaldehyde was inversely associated with serum total testosterone levels (Q4 vs. Q1: OR = - 7.95, 95% CI: - 15.62 to - 0.27), whereas propanaldehyde was positively associated with serum estradiol concentration (Q3 vs. Q1: β = 28.88, 95% CI: 0.83 to 56.94). Compared with Q1, Q3 of isopentanaldehyde was associated with 3.53pg/mL higher concentration of estradiol in postmenopausal women (β = 3.53, 95% CI: 0.08 to 6.97). Moreover, in males under 40years, butyraldehyde and heptanaldehyde were inversely proportional to total testosterone levels and heptanaldehyde and butyraldehyde were negatively associated with estradiol and SHBG. Decreased total testosterone, elevated estradiol, and decreased SHBG levels were found in higher quartiles of benzaldehyde, hexanaldehyde and isopentanaldehyde, and propanaldehyde, respectively, in males aged over 60years. In male participants aged 40-60years, only hexanaldehyde was observed to be correlated with higher serum estradiol levels. In conclusion, our current research presented the association between six serum aldehydes and sex hormones. Of note, stratification analyses were conducted in participants with different menopausal statuses and age among males and females. Sex- and age-specific effect of aldehyde exposure on alterations in sex hormone levels were observed. Further studies are warranted to confirm the causal relationship and explore the underlying mechanisms.

PCOS Features and Steroid Profiles Among Young Adult Women with a History of Premature Adrenarche.

ContextPremature adrenarche (PA) may increase the risk for polycystic ovary syndrome (PCOS).ObjectiveTo study features of PCOS in young adult women with a history of PA.MethodsThirty PA and 42 control females were followed from prepuberty to young adulthood (median age 18.1 years). The main outcome measures were ovarian function, the use of contraceptives, and clinical and biochemical indicators of hyperandrogenism.ResultsWe found no differences in the use of hormonal contraceptives (50 vs 50%, PA vs controls, respectively; P > .999), indication for using contraceptives (P = .193), or in the history of oligo- (17 vs 26%, P = .392) and amenorrhea (0 vs 0%, P > .999). Among women not using hormonal contraceptives, those with a history of PA had a higher prevalence of hirsutism (27 vs 0%, P = .023) but not acne (87 vs 67%, P = .252). Steroid profiles were broadly comparable between the groups, but PA women had lower sex hormone–binding globulin (SHBG) concentrations (30.1 vs 62.4 nmol/L, P < .001) resulting in higher free androgen index (3.94 vs 2.14, P < .001). The difference in SHBG levels persisted through body mass index adjustment. SHBG correlated negatively with the homeostasis model assessment for insulin resistance (r –0.498, P = .003). Anti-Müllerian hormone concentrations were comparable between the groups (39.3 vs 32.1 pmol/L, P = .619).ConclusionPA was not associated with evident ovarian dysfunction in young adult women. However, women with a history of PA had decreased SHBG levels and thus, increased bioavailability of circulating androgens.

Cholesterol, endocrine and metabolic disturbances in sporadic anovulatory women with regular menstruation

Sporadic anovulation among regularly menstruating women is not well understood. It is hypothesized that cholesterol abnormalities may lead to hormone imbalances and incident anovulation. The objective was to evaluate the association between lipoprotein cholesterol levels and endocrine and metabolic disturbances and incident anovulation among ovulatory and anovulatory women reporting regular menstruation. The BioCycle Study was a prospective cohort study conducted at the University at Buffalo from September 2005 to 2007, which followed 259 self-reported regularly menstruating women aged 18-44 years, for one or two complete menstrual cycles. Sporadic anovulation was assessed across two menstrual cycles. Mean total and low-density lipoprotein cholesterol and triglycerides levels across the menstrual cycles were higher during anovulatory cycles (mean difference: 4.6 (P = 0.01), 3.0 (P = 0.06) and 6.4 (P = 0.0002) mg/dl, respectively, adjusted for age and BMI). When multiple total cholesterol (TC) measures prior to expected ovulation were considered, we observed a slight increased risk of anovulation associated with increased levels of TC (odds ratio per 5 mg/dl increase, 1.07; 95% confidence interval, 0.99, 1.16). Sporadic anovulation was associated with an increased LH:FSH ratio (P = 0.002), current acne (P = 0.02) and decreased sex hormone-binding globulin levels (P = 0.005). These results do not support a strong association between lipoprotein cholesterol levels and sporadic anovulation. However, sporadic anovulation among regularly menstruating women is associated with endocrine disturbances which are typically observed in women with polycystic ovary syndrome.

C-peptide, IGF-I, sex-steroid hormones and adiposity: a cross-sectional study in healthy women within the European Prospective Investigation into Cancer and Nutrition (EPIC)

The risk of some cancers is positively associated with body weight, which may influence circulating levels of sex-steroid hormones, insulin and IGF-I. Interrelationships between these hormones and the associations with adiposity were evaluated in healthy women participating in the European Prospective Investigation into Cancer and Nutrition (EPIC). A cross-sectional analysis was performed on anthropometric and hormonal data from 743 pre- and 1217 postmenopausal women. Body mass index (BMI) and waist circumference were used as indicators of adiposity. C-peptide, Insulin Growth Factor (IGF)-I, Insulin Growth Factor binding protein (IGFBP)-3, androgens, estrogens and sex hormone binding globulin (SHBG) were measured by immunoassays; free sex steroid concentrations were calculated. BMI and waist circumference were positively correlated with estrogens in postmenopausal women and with C-peptide, free testosterone and inversely with SHBG in all women. C-peptide and IGF-I were inversely correlated with SHBG, and positively with free sex steroids in postmenopausal women. IGF-I was positively associated with postmenopausal estrogens and androgen concentrations in all women. Sex-steroid concentrations appear to be regulated along several axes. Adiposity correlated directly with estrogens in postmenopausal women and with insulin, resulting in lower SHBG and increased levels of free sex steroids. Independent of adiposity and insulin, IGF-I was associated with decreased SHBG levels, and increased concentrations of androgens and postmenopausal estrogens.

Association of the (TAAAA)n repeat polymorphism in the sex hormone-binding globulin (SHBG) gene with polycystic ovary syndrome and relation to SHBG serum levels.

SHBG levels are frequently low in women with polycystic ovary syndrome (PCOS) and may contribute to increased tissue exposure to free androgens. A (TAAAA)n repeat polymorphism in the promoter of the SHBG gene has been described recently, and its transcriptional activity has been shown to be related to the number of tandem repeats. Recent evidence also suggests that prenatal exposure to androgen excess may program for the development of the PCOS phenotype during adulthood. Our aim was to investigate the possible association of the functional (TAAAA)n polymorphism in the promoter of the SHBG gene with PCOS and its relation to SHBG levels. We studied 185 women with PCOS and 324 normal controls. Genotype analysis revealed six (TAAAA)n alleles containing 6-11 repeats. The distribution of these alleles was different in the two groups. Women with PCOS had a significantly greater frequency of longer (TAAAA)n alleles (more than eight repeats) than normal women who had shorter alleles (less than eight repeats) in higher frequency (P = 0.001). Furthermore, in the PCOS group, carriers of the longer allele genotypes had lower SHBG levels [1.17 +/- 0.68 micro g/dl (35.1 +/- 20.5 nmol/liter)] than those with shorter alleles [1.51 +/- 0.93 microg/dl (45.3 +/- 28 nmol/liter P = 0.02). A novel (TAAAA)n allele, which has not been previously reported, was found in low frequency, mainly in the control population. From these results, there is evidence that there may be a genetic contribution to decreased SHBG levels frequently seen in women with PCOS. The SHBG gene may act as a susceptibility gene for PCOS and may provide the genetic link for the developmental origin hypothesis for PCOS that was recently proposed on the basis of experimental observation in prenatally androgenized sheep and primates.

Receiver operating characteristic analysis of the performance of basal serum hormone profiles for the diagnosis of polycystic ovary syndrome in epidemiological studies.

We have used receiver operating characteristic (ROC) analysis to determine the diagnostic performance of several serum parameters, in order to evaluate their potential usefulness in establishing the diagnosis of polycystic ovary syndrome (PCOS) in epidemiological studies. Prospective study. One hundred and fourteen women reporting spontaneously for blood donation were included in the study. Menopausal and oral contraceptive-treated women were excluded. Serum samples were obtained at the moment of donation, independently of fasting, time of day or day of menstrual cycle. Measurements included total testosterone, sex hormone-binding globulin (SHBG), dehydroepiandrosterone sulfate (DHEAS), LH, FSH and estradiol. The free testosterone (FT) concentration and the free androgen index (FAI) were calculated from testosterone and SHBG levels. ROC curves were calculated for all these serum determinations. Eight patients were diagnosed with PCOS, according to the presence of oligomenorrhea, hirsutism, acne and/or hyperandrogenemia, and exclusion of non-classic congenital adrenal hyperplasia, hypothyroidism and hyperprolactinemia. Of the parameters studied SHBG, FAI, FT and DHEAS were considered adequate measures for the diagnosis of PCOS. For example, serum SHBG levels showed an area under the ROC curve of 0.875+/-(S.E.(w))0.045 (95% confidence interval 0.800-0.929). A SHBG decision threshold <37 nmol/l had a sensitivity of 87.5%, a specificity of 86.8%, a positive likelihood ratio of 6.63, and a negative likelihood ratio of 0.14, for the diagnosis of PCOS. Our present results strongly suggest that decreased SHBG levels, and increased FAI, free testosterone concentration and DHEAS concentrations, are highly effective as single analytical procedures in epidemiological studies for the detection of PCOS in women of reproductive age.

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.

A pharmacokinetic study of injectable testosterone undecanoate in hypogonadal men.

Testosterone undecanoate (TU) provides testosterone (T) replacement for hypogonadal men when administered orally but requires multiple doses per day and produces widely variable serum T levels. We investigated the pharmacokinetics of a newly available TU preparation administered by intramuscular injection to hypogonadal men. Eight patients with Klinefelter's syndrome received either 500 mg or 1,000 mg of TU by intramuscular injection; 3 months later, the other dose was given to each man (except to one, who did not receive the 1,000-mg dose). Serum levels of reproductive hormones were measured at regular intervals before and after the injections. Mean serum T levels increased significantly at the end of the first week, from less than 10 nmol/L to 47.8+/-10.1 and 54.2+/-4.8 nmol/ L for the lower and higher doses, respectively. Thereafter, serum T levels decreased progressively and reached the lower-normal limit for adult men by day 50 to 60. Pharmacokinetic analysis showed a terminal elimination half-life of 18.3+/-2.3 and 23.7+/-2.7 days and showed a mean residence time of 21.7+/-1.1 and 23.0+/-0.8 days for the lower and higher doses, respectively. The area under the serum T concentration-time curve and the T-distribution value related to serum T concentration were significantly higher following the 1,000-mg dose than following the 500-mg dose. The 500-mg dose, when given as the second injection, yielded optimal pharmacokinetics (defined as mean peak T values not exceeding the normal range and persistence of normal levels for at least 7 weeks), suggesting that repeated injections of 500 mg at 6-8-week intervals may provide optimal T replacement. The mean serum levels of estradiol were normalized following the injections, and prolactin levels were normal throughout the study. Significant decrease of serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels was observed, with the decrease in LH levels being more pronounced. There were no significant differences in serum LH and FSH levels between the two doses. Sex hormone-binding globulin (SHBG) levels before any T therapy were near the upper limit of normal for adult men and were reduced by approximately 50% just prior to the second dose of TU. The decreased SHBG levels produced by the first TU injection could have led to lower peak total T levels and to a more rapid clearance of T following the second TU injection. We conclude that single-dose injections of TU to hypogonadal men can maintain serum T concentration within the normal range for at least 7 weeks without immediately apparent side effects. It is likely that this form of T would require injections only at 6-8-week or longer intervals, not at the 2-week intervals necessary with currently used T esters (enanthate and cypionate). This injectable TU preparation may provide improved substitution therapy for male hypogonadism and, in addition, may be developed as an androgen component of male contraceptives.

Sex hormone-binding protein, hyperinsulinemia, insulin resistance and noninsulin-dependent diabetes.

Possible data complicating sex hormones, especially testosterone, in the etiology of cardiovascular disease and noninsulin-dependent diabetes mellitus (NIDDM) comes from the much higher rates of cardiovascular disease in men than in women. Pharmacological administration of anabolic steroids to both men and women increases glucose and insulin concentrations and also insulin resistance. In vivo assessment of sex hormones and binding proteins in both premenopausal and postmenopausal women has suggested that increased free testosterone and decreased sex hormone-binding globulin (SHBG) is associated with higher glucose and insulin concentrations. In a few studies, increased insulin resistance has been associated with decreased SHBG levels. Some data suggests that visceral fat mediated the associates of sex hormones with insulin in women. Little prospective data is available on the association of sex hormones to the development of NIDDM in women but in two studies, low SHBG concentrations predicted NIDDM in Gothenburg and San Antonio. Recently, attention has focused on the role of sex hormones in relation to insulin in men. Surprisingly, higher levels of testosterone have been associated with improved cardiovascular risk factors (such as high-density lipoprotein cholesterol) and lower glucose and insulin levels. Total testosterone and SHBG have been associated with defects in nonoxidative glucose disposal and upper body adiposity in normoglycemic Finnish men. The latter observation is of interest since specific defects in nonoxidative glucose disposal are observed in normoglycemic relatives of subjects with NIDDM. The temporal relationship between sex hormones and insulin has been controversial. The traditional view of sex hormones increasing insulin resistance has been challenged in women by studies showing that insulin stimulates androgen production in the ovary. Recent data [JCEM 1995;80:654-658] suggests that insulin stimulates testosterone production and suppresses SHBG production in normal and obese men. On the other hand, administration of testosterone to centrally obese hypogonadal middle-aged men has improved insulin sensitivity.

Clinical utility of sex hormone-binding globulin measurement.

The high-affinity binding of the sex hormone-binding globulin (SHBG) for testosterone and to a lesser extent for estradiol influences the circulating levels of these sex steroid hormones, their biodisposal to target cells as well as their mutual balance. Although the regulation of SHBG is still not completely understood, in vitro studies performed with human hepatocarcinoma (Hep G2) cells have shown that estrogens and thyroxine stimulate SHBG secretion, by increasing the steady state of its mRNA concentrations. These observations are in good agreement with studies showing that SHBG levels increase during oral administration of estrogens as well as in patients with thyrotoxicosis. Interestingly, SHBG levels are normal in syndromes such as the abnormal transport of thyroid hormones and/or the syndrome of thyroid hormone resistance, which can be confused with thyrotoxicosis. By contrast, the effects of androgens are controversial. In many patients with hirsutism, SHBG concentrations are low and correlate negatively with both body mass index and fasting insulin levels. Because of the inhibitory effect of both insulin and insulin-like growth factor-1 on SHBG secretion by Hep G2 cells in vitro, it has been proposed that SHBG levels could be a marker of insulin resistance and/or hyperinsulinism in humans. Furthermore, an increased risk for either noninsulin-dependent diabetes and/or the overall mortality are associated with decreased SHBG levels in postmenopausal women. Finally, in men, SHBG levels are positively correlated with the concentration of high-density lipoprotein cholesterol. Therefore, the measurement of SHBG in clinical practice can be a useful diagnostic tool for: (1) correctly interpretating testosterone and estradiol serum concentrations; (2) investigating androgen-estrogen balance in gonadal and sexual dysfunctions; (3) assessing the peripheral effect of the hormones which regulate SHBG productions, and (4) evaluating insulin resistance and cardiovascular risk.

Regulation of production and secretion of sex hormone-binding globulin in HepG2 cell cultures by hormones and growth factors.

Regulation of the production and secretion of sex hormone-binding globulin (SHBG) was investigated in HepG2 cell cultures by measuring SHBG protein concentrations intra- and extracellularly and studying changes in SHBG messenger ribonucleic acid levels. Insulin (10 nmol/L), insulin-like growth factor-I (15 nmol/L), and epidermal growth factor (20 nmol/L) decreased SHBG levels in parallel both intra- and extracellularly. Ten nmol/L 17 beta-estradiol, 10 nmol/L testosterone, and 100 nmol/L to 1 mumol/L cortisol increased SHBG levels inside the cells, but did not increase its release into the culture medium. Two hundred and fifty to 500 nmol/L 17 beta-estradiol and 500 nmol/L to 1 mumol/L testosterone increased SHBG levels intra- and extracelularly, but relative to control values, the increase was considerably greater inside the cells. T3 (10 nmol/L) increased SHBG levels, but unlike the effect seen with steroids, the increase was equally evident within the cells and the medium. Northern hybridization showed that insulin decreased and 17 beta-estradiol and T3 increased SHBG messenger ribonucleic acid levels marginally. The variable secretion of SHBG is hypothesized to be due to the different effects of hormones and growth factors on either the glycan moiety of SHBG or the expression of the alternatively spliced transcripts of the SHBG gene.

Serum testosterone fractions in women: Normal and abnormal clinical states

The potential usefulness of determining serum testosterone (T) fractions in women, ie, sex hormone-binding globulin (SHBG)-bound T, albumin-bound T (Alb-T), and free T (FT) fractions, was explored in a variety of clinical situations. Serum T, SHBG, and albumin concentrations were measured by standardized methods and using binding constants of T to SHBG and albumin, we calculated serum T fractions, which agreed remarkably with measured values of SHBG-T and nonbound T. Serum T levels did not change in normal women examined during the follicular and luteal phases of the menstrual cycle, but SHBG levels were elevated in the luteal phase, changing the distribution of T, with increased SHBG-T and less T distributed to other fractions. Women taking oral contraceptives had decreased serum T levels, but use of androgen-like oral contraceptives decreased SHBG levels and T distribution to this binding protein, whereas use of non-androgen-like oral contraceptives increased SHBG levels, resulting in the expected shift of T fractions. Women receiving phenytoin for seizure disorders and women with Graves' disease exhibited increased SHBG levels with concomitant increased SHBG-T and decreased distribution of T to nonbound fractions. Women with hirsutism exhibited decreased SHBG levels irrespective of total serum T levels, and the T SHBG ratio was elevated in this population. However, of interest were women with morbid obesity (nonhirsute) who had similar low levels of SHBG and T SHBG ratios that were indistinguishable from those of hirsute women. Determination of T fractions may provide a more useful clinical tool in evaluating hirsute women than simple measurement of serum T levels, although at present, T fractionation studies are not useful indicators of hyperandrogenism when morbid obesity is coexistent.

Abnormal sex steroid secretion and binding in massively obese women.

We have measured the plasma concentrations of sex steroids and sex hormone-binding globulin (SHBG) in twenty-three massively obese women and ten age-matched lean female volunteers. In the obese women increased plasma testosterone (obese 3.2 +/- 0.5 nmol/l controls 1.7 +/- 0.5 nmol/l, P less than 0.3) and androstenedione concentrations (obese 9.7 +/- 1.2 nmol/l, controls 4.4 +/- 0.6 nmol/l, P = less than 0.01) an increased ratio of oestrone:oestradiol (obese 2.4 +/- 0.4, controls 1.0 +/- 0.1, P = less than 0.1) and decreased SHBG levels (obese 30 +/- 4 nmol/l, controls 60 +/- 8 nmol/l, P = less than 0.001) were found. Obesity differed from the polycystic ovary syndrome (in which a similar pattern of changes of sex steroid concentrations and binding are seen) in that it was associated with normal increases in serum luteinizing hormone (LH) follicle stimulating hormone (FSH) levels in response to the administration of LHRH. We conclude that the common occurrence of menstrual abnormalities in obesity results from abnormal secretion and binding of sex steroids. In addition, the unaltered secretion of LH and FSH in the presence of such changes is evidence for a disorder of hypothalamic function.