Changes In Sex Hormone-binding Globulin Research Articles

Longitudinal Changes in Sex Hormone Binding Globulin (SHBG) and Risk of Incident Diabetes: The Study of Women's Health Across the Nation (SWAN).

To investigate the associations of longitudinal changes in sex hormone binding globulin (SHBG) and testosterone (T) over the menopause transition with the risk of diabetes. We followed 2,952 participants in the Study of Women's Health Across the Nation (SWAN) who were premenopausal or early perimenopausal and diabetes-free at baseline. SHBG,T, and estradiol (E2) levels were measured at up to 13 follow-up visits (over up to 17 years). We used complementary log-log-based discrete-time survival models anchored at baseline. Diabetes developed in 376 women. A 5-unit increase in time-varying SHBG was associated with a 10% reduced risk of diabetes (hazard ratio [HR] 0.91, 95% CI 0.87-0.95), adjusting for covariates, and baseline SHBG,T, and E2 levels. Time-varying T was not associated with diabetes risk. Compared with the lowest quartile for annual rate of change of SHBG since baseline (quartile 1 [Q1] -92.3 to -1.5 nmol/L), all other quartiles were associated with a decreased risk of diabetes adjusting for covariates and baseline SHBG; associations persisted after adjusting for rate of change of T and E2 (Q2 [> -1.5 to -0.2 nmol/L] HR 0.33, 95% CI 0.23-0.48; Q3 [> -0.2 to 1.3 nmol/L] HR 0.37, 95% CI 0.25-0.55; Q4 [>1.3 to 82.0 nmol/L] HR 0.43, 95% CI 0.30-0.63). Increasing levels of SHBG over the menopause transition were associated with a decreased risk of incident diabetes. Stable to increasing rates of change in SHBG were also independently associated with a decreased risk of diabetes compared with decreasing rates of change, suggesting SHBG may affect glucose through a mechanism beyond androgenicity.

The association between serum sex hormone-binding globulin changes during progestin-primed ovarian stimulation and embryo outcomes: a retrospective cohort study

Objective: This study is aimed to examine the associations between embryo outcomes and serum sex hormone-binding globulin (SHBG) changes during progestin-primed ovarian stimulation (PPOS) protocols in IVF/ICSI cycles. Research methods: This study included 2790 eligible consecutive cycles of patients aged 21–53 years undergoing PPOS treatment. Multivariable linear regression analysis was performed to explore the association between SHBG changes and embryo outcomes. Results of the study: Our results showed that the SHBG-increase rate on the HCG day and in the late follicular phase were positively and linearly correlated with available embryos in day3, with adjusted regression coefficients (β) for the SHBG-increase rate on the HCG day, in the late follicular phase were 0.6 (0.4, 0.9), 0.4 (0.2, 0.6), but in the middle follicular phase and in the early follicular phase, this correlation was not significant (p > 0.05). Conclusion: Our results indicate that serum SHBG increment may serve as a biomarker of the developmental potential of the oocytes from patients undergoing the PPOS protocol.

Estrogen/androgen balance in men with hyperestrogenism normalized by using letrozole of the aromatase inhibitor drug class

Introduction. Currently, virtually no data on comparative studies of efficacy and safety of drug class aromatase inhibitors vs. standard therapies used in patients with overweight and/or obesity with an initial testosterone deficiency and excessive estradiol are available.Aim: to study and evaluate the efficacy and safety of the use of the reversible aromatase inhibitor letrozole in adult men with overdeveloped adipose tissue and/or obesity with hyperestrogenism and testosterone deficiency.Materials and Methods. A randomized, open, interventional, comparative, single-centre clinical trial was conducted by enrolling 49 obese men. The patients were divided into 2 groups: Group 1 (n = 26) – patients received standard metformin therapy (1000 mg 2 times a day), along with letrozole (at a dose of 2.5 mg 2 times a week); Group 2 (n = 23) – patients received only standard metformin therapy. Patients were monitored for 8 weeks from the date of inclusion. Anthropometric parameters were monitored: body weight, body mass index, waist as well as hip circumference. Laboratory data were also evaluated: level of sex hormone binding globulin (SHBG), total testosterone, estradiol, glucose, uric acid, insulin. All subjects filled out questionnaires twice (before the start of the study and after its completion) – the aging symptoms questionnaire for men (Aging Males Symptoms, AMS) and IIEF (International Index of Erectile Function).Results. Total testosterone level significantly and reliably increased only in Group 1 from 10.6 to 22.2 nmol/L. In Group 2 testosterone level increased insignificantly from 9.28 to 11.02 nmol/L, and did not reach the physiological normal range. Estradiol changes also differed markedly and significantly: in Group 1, estradiol decreased from 51.4 to 24.3 pg/ml, i.e., by 2.1-fold reaching physiological range, whereas in Group 2 estradiol level decreased insignificantly from 45.1 to 44.4 pg/ml, and remained above the range of normal values. Significant changes in SHBG were observed only in Group 2. Insulin level in Group 1 significantly decreased from 10.6 to 6.6 μIU/ml, i.e., by 1.6-fold. In Group 2, insulin also decreased, but less pronounced, from 15.8 to 13.7, i.e., by 1.2-fold, which turned out to be statistically insignificant and according to the НОМА-IR index (Homeostasis Model Assessment of Insulin Resistance), it remained within the insulin resistance range. Glucose level did not change significantly in both groups. Uric acid, on the contrary, significantly changed in both groups: in Group 1, from 0.41 to 0.35 mmol/L, and in Group 2, from 0.40 to 0.36 mmol/L.Conclusion. The use of letrozole significantly increases total testosterone level in patients with initial testosterone deficiency and hyperestrogenism. At the same time, patients with androgen deficiency and hyperestrogenism, in most cases, have excess body weight due to adipose tissue, metabolic syndrome in a combination of its various components, which underlie a need to use standard methods of therapy primarily modified lifestyle and metformin, which provide the maximum positive effect in the treatment of such patients.

Longitudinal changes in serum testosterone and sex hormone-binding globulin in men aged 40-69 years from the UK Biobank.

Testosterone and sex hormone-binding globulin (SHBG) concentrations are reported to decline during male ageing, but whether these changes reflect physiological ageing or age-related comorbidities remains uncertain. We examined longitudinal changes in serum testosterone and SHBG concentrations in middle-aged to older men, concordance between baseline and follow-up valuesand relationships with concomitant changes in lifestyle and medical factors. Population-based longitudinal cohort study. Community-dwelling men aged 40-69 years. Immunoassay serum total testosterone (n = 7812) and SHBG (n = 6491) at baseline (2006-2010) and follow-up (2012-2013). Free testosterone (cFT) was calculated. Bland-Altman analyses and concordance correlation of repeated measurements were conducted. Associations of changes in hormone concentrations with lifestyle and medical factors were explored using Spearman's rank correlation. Over 4.3 years follow-up, there was a negligible mean change (±SE) in serum total testosterone concentration (+0.06 ± 0.03 nmol/L), whereas mean SHBG concentration increased (+3.69 ± 0.12 nmol/L) and cFT decreased (-10.7 ± 0.7 pmol/L). Concordance estimates were 0.67 (95% confidence interval [CI]: 0.66-0.69) for total testosterone, 0.83 (CI = 0.82-0.84) for SHBG and 0.56 (CI = 0.54-0.58) for cFT. Changes in serum total testosterone correlated with changes in SHBG (Spearman's rank ρ = 0.33, CI = 0.30-0.35), and inversely with changes in body mass index (BMI) (ρ = -0.18, CI = -0.20 to -0.16)and waist circumference (ρ = -0.13, CI = -0.15 to -0.11) and in SHBG with changes in BMI (ρ = -0.34, CI = -0.36 to -0.32) and waist circumference (ρ = -0.21, CI = -0.24 to -0.19). In relatively healthy middle-aged to older men, mean serum total testosterone concentration is stable with ageing, while mean SHBG concentration increases. Both total testosterone and SHBG concentrations were highly concordant over time.

Effect of Eurycoma longifolia standardised aqueous root extract–Physta® on testosterone levels and quality of life in ageing male subjects: a randomised, double-blind, placebo-controlled multicentre study

BackgroundLow testosterone levels cause physiological changes that compromise the quality of life in ageing men. A standardised water extract from the root of Eurycoma longifolia (EL), known as Physta®, is known to increase testosterone levels.ObjectiveTo evaluate the safety and efficacy of Physta® in improving the testosterone levels and quality of life in ageing male subjects.DesignThis randomised, double-blind, placebo-controlled study enrolled 105 male subjects aged 50–70 years with a testosterone level <300 ng/dL, BMI ≥ 18 and ≤30.0 kg/m2. The subjects were given either Physta® 100 mg, 200 mg or placebo daily for 12 weeks. The primary endpoints were changes in serum total and free testosterone levels. The secondary endpoints included changes in the level of sex hormone-binding globulin (SHBG), dihydroepiandrosterone (DHEA), glycated haemoglobin (HbA1c), insulin-like growth factor-1 (IGF-1), thyroid function tests (T3, T4, TSH and Free T3) and cortisol. Changes in Ageing Male Symptoms (AMS) score, Fatigue Severity Scale (FSS) score and muscle strength are other secondary endpoints. The safety of the intervention products was measured by complete blood count, lipid profile, liver and renal function tests.ResultsThere was a significant increase in the total testosterone levels at week 12 (P < 0.05) in the Physta® 100 mg group and at weeks 4 (P < 0.05), 8 (P < 0.01) and 12 (P < 0.001) in the Physta® 200 mg group compared to placebo. No significant between-group differences in free testosterone levels were observed but a significant within-group increase occurred at weeks 4 (P < 0.01), 8 (P < 0.001) and 12 (P < 0.001) in the Physta®100 mg group and at weeks 2 (P < 0.01), 4 (P < 0.01), 8 (P < 0.001) and 12 (P < 0.001) in the Physta® 200 mg group. The AMS and FSS showed significant reduction (P < 0.001) in total scores at all time-points within- and between-group in both Physta® groups. DHEA levels significantly increased (P < 0.05) within-group in both Physta® groups from week 2 onwards. Cortisol levels significantly (P < 0.01) decreased in the Physta® 200 mg group, while muscle strength significantly (P < 0.001) increased in both Physta® groups at week 12 in the within-group comparison. There were no significant changes in SHBG. No safety related clinically relevant changes were observed.ConclusionSupplementation of Physta® at 200 mg was able to increase the serum total testosterone, reduce fatigue and improve the quality of life in ageing men within 2 weeks’ time.Trial registrationThis clinical study has been registered in ctri.nic.in (CTRI/2019/03/017959).

Effects of androgenic properties of progestin combined with ethinyl estradiol on vascular endothelial reactivity, plasma lipids and free radical production in women with endometriosis.

Endothelial reactivity is inhibited and oxidative stress is enhanced in women with endometriosis. Testosterone may adversely affect lipids and endothelium. We investigated the effects of androgenic properties of progestins combined with ethinyl estradiol (EE) on endothelial function, lipids and free radical production in such women. Women with endometriosis were treated with 20 μg EE + 3 mg drospirenone (DRSP) or 35 μg EE + 1 mg norethisterone (NET) for 3 months. Plasma concentrations of sex hormone-binding globulin (SHBG), lipids, copper (Cu), derivatives of reactive oxygen metabolites (d-ROMs), biological antioxidant potential (BAP), nitrite/nitrate, endothelin-1 and asymmetrical dimethylarginine (ADMA) were measured before and after treatment. Flow-mediated vasodilation (FMD) of the brachial artery was measured by ultrasonography. DRSP group, but not NET group, significantly increased FMD and concentrations of nitrite/nitrate and small dense LDL cholesterol, while decreased endothelin-1 concentrations. In both groups, ADMA and LDL cholesterol concentrations were significantly decreased, but triglyceride, SHBG, d-ROMs, Cu and ceruloplasmin concentrations increased, and BAP concentrations did not change. DRSP group significantly increased HDL cholesterol concentrations, whereas NET group decreased its concentrations. Changes in triglyceride correlated positively either with changes in SHBG (r = 0.57, P < 0.001) or with small dense LDL cholesterol (r = 0.45, P = 0.005). Changes in Cu correlated positively with changes in d-ROMs (r = 0.87, P < 0.001). Androgenic properties of progestin may counteract EE's favorable effects on endothelial function and HDL cholesterol, while eliminating its adverse effects on increased triglyceride-induced small dense LDL cholesterol in women with endometriosis.

Longitudinal changes over three years in sex steroid hormone levels in women aged 70years and over.

Sex steroid levels in women vary with increasing age from the age of 70years (70+). Whether this reflects change within individuals with age or a survival advantage is not known. This study aimed to determine the stability of circulating sex steroids and SHBG over time in individual women aged 70+. A prospective cohort study. 400 women, aged 70+ not using any sex steroid, anti-androgen/oestrogen or glucocorticoid therapy. Sex steroid concentrations, measured by liquid chromatography-tandem mass spectrometry and sex hormone-binding globulin (SHBG) by immunoassay, in paired blood samples drawn 3years apart and analysed together. 400 women, median (IQR) age 78.0 (8.6)years, were included in the analysis. Mean testosterone concentrations were statistically significantly higher in follow-up samples compared with baseline. The change was modest (mean change 31pmol/L, 95% confidence interval (CI) 2.4-59.8; p=.034), and an increase was not observed in all women. There was a statistically significant decline in mean body mass index (mean change -0.4kg/m2 , 95% CI 0.6 to -0.3; p<.001) and a significant increase in the mean serum SHBG concentration (mean change 4.0 nmol/L, 95% CI 2.7-5.4; p<.001). The change observed in testosterone was not explained by the observed change in SHBG. There was no significant change in the mean oestrone or dehydroepiandrosterone concentration. Testosterone concentrations in women aged 70+ were more likely to increase than decrease. Whether increasing testosterone concentrations in older women confer a survival advantage needs investigation.

Glycosylation may influence sex hormone-binding globulin measurements

A discordance between sex hormone-binding globulin (SHBG) measurements by 2-site ELISAs was investigated using pairings of various “in house” SHBG antibodies together with a concordant control. The 2-site monoclonal ELISAs used the same base coat (11F11) and discordance was observed with one top coat monoclonal antibody (7H9) and also when a polyclonal SHBG antibody was paired with the basecoat antibody (11F11). Sialidase treatment of the discordant sample and purified SHBG revealed increased levels using 7H9 whereas there was no change in SHBG in the concordant sample. Conversely, following sialidase treatment, the discordant sample showed no change in SHBG measured using the other monoclonal antibody pairings whereas the SHBG levels in the concordant sample declined following sialidase using the same monoclonal antibody pairings. This implicated glycosylation as a factor in antibody recognition and synthetic peptides spanning the two N-linked and one O-linked glycosylation regions showed that SHBG recognition by monoclonal antibody 7H9 could be disrupted by a peptide spanning the O-linked glycosylation site. Hence rather than immunoassay discordance being attributed to heterophile antibodies or other circulating antibodies here it can be likely attributed to glycosylation affecting antibody recognition and hence the measurement of SHBG.

SAT-LB134 Aging Related Changes in Sex Hormone-Binding Globulin in Men With HIV

Background: Sex hormone-binding globulin (SHBG) is a glycoprotein that regulates the bioavailability of sex hormones, may directly affect glucose metabolism, and increases with age in the general population. SHBG concentrations are higher in people with HIV, a population in whom accelerated aging has been hypothesized. It is unclear whether age-related trajectories of SHBG differ by HIV serostatus. Methods: SHBG was measured in 182 men with HIV (MWH) and 267 men without HIV (MW/oH) from the Multicenter AIDS Cohort Study (MACS) in four U.S. cities, who had ≥2 samples over a 10 year period. Outcome measure: SHBG, log2SHBG. Multivariable linear mixed-effects regression models were used to evaluate whether SHBG (log2-transformed) and its rate of change differed by HIV serostatus after adjustment for covariates: age, race, BMI, smoking, education, hepatitis C virus infection, total testosterone concentrations, time of day of blood drawn and comorbidities (history of diabetes, kidney disease, liver disease, cancer, depression, hypertension) Results: At baseline, mean age among MWH was similar to MW/oH (51±5 vs 49±6 years). However, SHBG values were higher in MWH compared to MWo/H (65.6±48.8 nmol/L vs. 45.4±22 nmol/L, p<0.001). The rate of SHBG change with age was (1.021 (95% CI:1.010-1.028) or 2.1% per year in MWH and (1.014 nmol/L/year (95% CI:1.010-1.019) or 1.4% per year in MW/oH, p=0.05 for difference in slopes. Among MWH, higher SHBG levels were significantly associated with lower CD4+ T cell count (0.99 (5%CI:0.98-1.00), p<0.05), fewer cumulative years on zidovudine (0.98 nmol/L (95%CI:0.96,1.00), p<0.001) and greater cumulative years on non-nucleoside reverse transcriptase inhibitors drugs (1.02 (95%CI:1.00,1.04), p<0.05). Conclusion: Aging-related increases in SHBG were greater in magnitude among men with HIV and were related to poorer immunologic status and antiretroviral factors. The mechanisms and consequences of these findings require further investigation.

Effect of 7‐Day Whey Protein Supplementation on Steroid Hormones and SHBG in Women with Polycystic Ovary Syndrome (PCOS)

Polycystic ovary syndrome (PCOS) is the most prevalent endocrinopathy in women of child‐bearing age and is associated with obesity, infertility, insulin resistance, and hyperandrogenemia. Sex‐hormone binding globulin (SHBG) is suppressed as a result of hyperinsulinemia leading to an increase in free testosterone levels commonly observed in PCOS women. High levels of free testosterone contributes to hirsutism, acne, and irregular menstrual cycles in this population resulting in the need for interventions aimed at increasing SHBG concentration in PCOS women. Subsequently, estradiol and progesterone levels suffer in this population resulting in irregular menstrual cycles and infertility. Current treatments for PCOS target symptoms of the disease but not the underlying mechanisms, and typically are associated with adverse side effects. Nutritional interventions, therefore, that can ameliorate PCOS‐related issues are warranted. Whey protein has recently been shown to have improved glycemic homeostasis, reduced chronic inflammation and enhanced protein anabolism effects in people with or without insulin resistance. The purpose of this study was to examine changes in SHBG and free testosterone concentrations following 7 days of whey protein supplementation and to examine differences in baseline measurements of progesterone and estradiol between PCOS women and healthy controls (CON). Women with PCOS and CON consumed 35g of whey protein for 7 days. Baseline and Day 7 concentrations were measured via plasma and serum collection. Progesterone and estradiol concentrations were measured at baseline only whereas free testosterone and SHBG concentrations were measured at baseline and Day 7. Protocols used in this study were approved by the TWU Institutional Review Broad (IRB). Initial analyses indicate progesterone levels were lower in the PCOS group compared to CON. Currently, no other statistical differences are reported at baseline nor over time in any other variable. Additional analyses are currently being conducted. Seven days whey protein supplementation is not a viable intervention to increase fertility in PCOS women by enabling changes in steroid hormone and globulin binding concentrations. Future studies will include a prolonged intervention period to establish potential changes in the aforementioned hormones following chronic whey protein supplementation.Support or Funding InformationGlanbia Nutritionals, Inc., TWU Research Enhancement Program, TWU Human Nutrition Research funds

The effect of metformin on sex hormones in non-diabetic breast cancer patients in CCTG MA.32: A Phase III randomized adjuvant trial of metformin versus placebo in addition to standard therapy.

529 Background: The effect of metformin on sex hormones (SHs) levels that may impact breast cancer (BC) outcome, is unclear. We evaluated the effect of metformin on SHs in a subgroup of women enrolled in the placebo-controlled MA.32 trial, a phase III randomized study of nondiabetic subjects with T1-3, N0-3 BC randomized to receive metformin 850 mg po bid or placebo for 5 years. Methods: Our substudy was conducted on the group of post-menopausal women with estrogen receptor (ER) and progesterone receptor (PR) negative BC and not receiving endocrine treatment enrolled in the trial. Post-menopausal was defined as prior bilateral oophorectomy or &gt; 12 months since last menses without prior hysterectomy. Fasting blood and adherence to study drug at baseline and 6 months was required. Sex hormone binding globulin (SHBG), free testosterone and estradiol serum levels were evaluated using Roche Modular competitive ECLIA (electrochemiluminescense immunoassay). We compared change from baseline to 6 months in estradiol, SHBG and free testosterone between study arms using Wilcoxon sum rank tests and regression models to adjust for baseline BMI and weight change. Results: 304 women were eligible, 135 metformin vs 169 placebo; tumor stage and prior (neo)adjuvant chemotherapy (98% in both arms) and HER2 targeted treatment were well balanced between arms. At baseline mean age was 58.2±6.9 vs 57.6±7.9 years, mean BMI 26.9±4.9 vs 28.6±6.2 Kg/m2, median estradiol 29.82 vs 31.01 pmol/L, SHBG 80.6 vs 73.7 nmol/L and free testosterone 0.02 vs 0.03 nmol/L in metformin vs placebo patients, respectively. In univariable analysis, median estradiol decreased significantly between baseline and 6 months on the metformin vs placebo arm (-4.81 vs 0 pmol/L, p = &lt; 0.0001); this difference remained significant after controlling for baseline BMI (p = 0.0001) and weight change (mean weight change -1.8±3.5 vs 0.4±3.5 Kg, p = &lt; 0.0001 for metformin vs placebo respectively) between baseline and 6 months (p = 0.0007). In contrast, there was no significant change in SHBG or free testosterone (median change SHBG -5.5 vs -5.9 nmol/L, p = 0.33; median change free testosterone 0 vs 0 nmol/L, p = 0.33 for metformin vs placebo respectively). Conclusions: Metformin lowered estradiol levels, independent of weight change in non-diabetic post-menopausal women with ER and PR negative BC enrolled onto MA.32 trial. This observation suggests a new metformin action that has potential relevance to BC management.

Long-term weight loss maintenance, sex steroid hormones, and sex hormone-binding globulin.

We tested the effects of weight loss on serum estradiol, estrone, testosterone, and sex hormone-binding globulin (SHBG) in overweight/obese women 18 months after completing a year-long, 4-arm, randomized-controlled dietary weight loss and/or exercise trial. From 2005 to 2008, 439 overweight/obese, postmenopausal women (BMI >25 kg/m), 50 to 75 years, were randomized to a year-long intervention: diet (reduced calorie, 10% weight loss, N = 118), exercise (225 min/wk moderate-to-vigorous activity, N = 117), combined diet + exercise (N = 117), or control (N = 87). At 12 months, 399 women provided blood; of these, 156 returned at 30 months and gave a blood sample. Hormones and SHBG were measured by immunoassay. Changes were compared using generalized estimating equations, adjusting for confounders. At 30 months, participants randomized to the diet + exercise intervention had statistically significant increases in SHBG levels versus controls (P = 0.001). There was no statistically significant change in SHBG in the exercise or diet intervention arms. Hormone levels did not vary by intervention arm from baseline to 30 months. Participants who maintained weight loss at 30 months had statistically significantly greater decreases in free estradiol and free testosterone (Ptrend = 0.02 and Ptrend = 0.04, respectively) and increases in SHBG (Ptrend < 0.0001) versus those who did not have sustained weight loss. Levels of other analytes did not vary by weight loss at 30 months. Sustained weight loss results in reductions in free estradiol and testosterone and increases in SHBG 18-month post-intervention.

Relationship between sex hormone binding globulin and blood coagulation in women on postmenopausal hormone treatment.

: Postmenopausal hormone therapy increases the risk of venous thrombosis. Sex hormone binding globulin (SHBG) is a suggested marker of 'total estrogenicity'. The study objective was to evaluate the impact of hormone therapy on SHBG and the association with coagulation variables. The study populations comprised 202 healthy postmenopausal women randomized to treatment with low-dose or conventional-dose hormone therapy, tibolone or raloxifene (RET-study) and 140 women with a history of venous thrombosis randomized to conventional-dose hormone therapy or placebo (EVTET-study). SHBG was determined in serum collected at baseline and after 12 weeks. In healthy women, conventional-dose hormone therapy increased SHBG with mean 9.7 (95% confidence interval 4.8-14.5) nmol/l, low-dose hormone therapy by mean 5.9 (0.4-11.5) nmol/l, raloxifene by mean 7.2 (3.9-10.4) nmol/l, while tibolone reduced SHBG with mean -25.1 (-29.9 to -20.4) nmol/l. SHBG correlated with protein S, tissue factor pathway inhibitor (TFPI) and protein C at baseline, and with protein S and TFPI after 12 weeks, but the change in SHBG from baseline to 12 weeks was only associated with the change in activated protein C (APC) resistance. In women with a history of venous thrombosis, the mean increase in SHBG was 13.6 (8.4-18.9) nmol/l in the conventional-dose hormone therapy group, with no change in the placebo group. Baseline SHBG was higher among women who developed recurrent venous thrombosis on conventional-dose hormone therapy. SHBG correlated with several coagulation inhibitors, but the change in SHBG induced by postmenopausal hormone therapy was only associated with the change in APC resistance.

Quantitative Analysis of Sex-Hormone-Binding Globulin Glycosylation in Liver Diseases by Liquid Chromatography–Mass Spectrometry Parallel Reaction Monitoring

Sex-hormone-binding globulin (SHBG) is a liver-secreted glycoprotein and a major regulator of steroid distribution. It has been reported that the serum concentration of SHBG changes in liver disease. To explore the involvement of SHBG in liver disease of different etiologies in greater detail, we developed a sensitive and selective liquid chromatography-mass spectrometry parallel reaction monitoring workflow to achieve quantitative analysis of SHBG glycosylation microheterogeneity. The method uses energy-optimized "soft" fragmentation to extract informative Y ions for maximal coverage of glycoforms and their quantitative comparisons. A total of 15 N-glycoforms of two N-glycosites and 3 O-glycoforms of 1 O-glycosite of this low-abundance serum protein were simultaneously analyzed in the complex samples. At the same time, we were able to partially resolve linkage isoforms of the fucosylated glycoforms and to identify and quantify SHBG N-glycoforms that were not previously reported. The results show that both core and outer-arm fucosylation of the N-glycoforms increases with liver cirrhosis but that a further increase of fucosylation is not observed with hepatocellular carcinoma (HCC). In contrast, the α-2-6 sialylated glycoform of the O-glycopeptide of SHBG increases in liver cirrhosis, and a significant 2-fold further increase is observed in HCC. In general, we do not find a significant contribution of different liver disease etiologies to the observed changes in glycosylation; however, elevation of the newly reported HexNAc(4)Hex(6) N-glycoform is associated with alcoholic liver disease.

Circulating adiponectin increases in obese women after sleeve gastrectomy or gastric bypass driving beneficial metabolic changes but with no relationship with carotid intima-media thickness

Obesity surgery induces beneficial effects in metabolic and cardiovascular parameters. Adiponectin increase might be associated with some of these changes. However, direct comparison between different surgical techniques has not been extensively performed. We studied 20 obese women submitted to laparoscopic Roux en Y gastric bypass (RYGB) and 20 to sleeve gastrectomy (SG). Twenty control women matched for age and baseline metabolic profiles were also included. Both patients and controls were followed up for one year after surgery or conventional treatment with diet and exercise, respectively. Serum adiponectin was measured at baseline, 6 months and 1 year after, as well as lipid profiles, sex hormone binding globulin (SHBG), fasting glucose and insulin. Carotid intima-media thickness was measured by ultrasonography at baseline and after 1 year. Circulating adiponectin increased after obesity surgery (more markedly following RYGB than after SG), whereas no changes were observed in the controls (Wilks' λ=0.659, P<0.001 for the interaction, P<0.001 for RYGB vs. controls, P=0.016 for SG vs. controls, P=0.040 for RYGB vs. SG). The percentage increment in adiponectin correlated positively with changes in SHBG (r=0.404, P=0.002) and negatively with changes in weight (r=-0.531, P<0.001), waist circumference (r=-0.426, P=0.001), fasting glucose (r=-0.356, P=0.006), and insulin (r=-0.496, P<0.001). No correlation was found with carotid intima-media thickness (r=-0.055, P=0.679). RYGB induces a higher increase in adiponectin than SG, which parallels SHBG, the reduction of fasting insulin and insulin resistance. On the other hand, no association was found with carotid intima-media, lipid profiles or blood pressure.

Sex difference determined the role of sex hormone-binding globulin in obese children during short-term weight reduction program.

The relationship between hyperinsulinemia and decreased sex hormone-binding globulin (SHBG) levels has been observed in obese adults and children. Weight reduction not only increased insulin sensitivity but also elevated serum SHBG levels in obese adults and children. However, the correlation between the changes in insulin resistance indices and serum SHBG concentration during weight reduction program (WRP) is not fully understood, particularly in obese children. This study is to evaluate whether SHBG level is a potential biomarker that can be used to assess insulin resistance in obese children during a short-term WRP. Forty-eight obese Taiwanese children (11.7 ± 2.2 years; 25 boys and 23 girls) participating in 8-week WRP were studied. Anthropometric measurements, lipid profiles, insulin resistance indices, and serum SHBG concentration were recorded at baseline and at the end of the WRP. The results showed body weight (BW), body mass index (BMI), body fat percentage (BF%), body fat weight (BFW), and insulin resistance indices such as fasting insulin, fasting insulin to glucose ratio, homeostasis model assessment (HOMA) of insulin resistance, log (HOMA) all significantly decreased after the 8-week WRP. With respect to lipid profiles, only high-density lipoprotein cholesterol (HDL-C) levels increased in both sexes. At baseline, insulin resistance indices were inversely correlated with SHBG concentrations in girls, but not in boys. The difference in SHBG after WRP was 2.58 nmol/L (95% confidence interval [CI]: −3.51, 8.66) in boys and 0.58 nmol/L (95% CI: −5.23, 6.39) in girls. There was a trend toward increased serum SHBG levels in boys (P = .39) and girls (P = .84) after weight loss, but a significantly negative correlation between the change in SHBG and in each of the insulin resistance indices only in the girls after adjusting age and ΔBFW during WRP.In conclusion, short-term WRP has the potential effects of decreased BW, BMI, BF%, and BFW, as well as increased serum HDL-C levels and insulin sensitivity in obese Taiwanese children. Although serum SHBG levels moderately increased in both sexes during short-term WRP, measuring the change in SHBG concentrations might be a potential biomarker to evaluate improvement in insulin resistance in girls only, and not in boys.

Sex hormone-binding globulin and antithrombin III activity in women with oral ultra-low-dose estradiol

Oral oestrogen increases the risk of venous thromboembolism (VTE) and increases production of sex hormone-binding globulin (SHBG) in a dose-dependent manner. SHBG has been suggested to be involved in venous thromboembolism. We examined the effects of oral ultra-low-dose oestradiol on circulating levels of SHBG and coagulation parameters, and we compared the effects to those of transdermal oestradiol. Twenty women received oral oestradiol (500 μg) every day (oral ultra-low-dose group) and 20 women received a transdermal patch (50 μg) as a transdermal group. In addition, the women received dydrogesterone continuously (5 mg) except for women who underwent hysterectomy. Circulating SHBG, antithrombin III (ATIII) activity, d-dimer, thrombin–antithrombin complex and plasmin–α2 plasmin inhibitor complex were measured before and 3 months after the start of treatment. SHBG was significantly increased at 3 months in the oral ultra-low-dose group, but not in the transdermal group. However, percent changes in SHBG were not significantly different between the two groups. In both groups, ATIII was significantly decreased at 3 months. In conclusion, even ultra-low-dose oestradiol orally increases circulating SHBG level. However, the magnitude of change in SHBG caused by oral ultra-low-dose oestradiol is small and is comparable to that caused by transdermal oestradiol.Impact statementOral oestrogen replacement therapy increases production of SHBG which may be related to increase in VTE risk. However, the effect of oral ultra-low-dose oestradiol on SHBG has not been clarified.Even ultra-low-dose oestradiol orally increases circulating SHBG levels, but the magnitude of change in SHBG caused by oral ultra-low-dose oestradiol is small and is comparable to that caused by transdermal oestradiol.VTE risk in women receiving oral ultra-low-dose oestradiol may be comparable to that in women receiving transdermal oestradiol.

Effects of Combat Deployment on Anthropometrics and Physiological Status of U.S. Army Special Operations Forces Soldiers.

U.S. Army Special Operations Forces (SOF) soldiers deploy frequently and conduct military operations through special warfare and surgical strike capabilities. Tasks required to execute these capabilities may induce physical and mental stress and have the potential to degrade soldier physiological status. No investigations have longitudinally characterized whether combat deployment alters anthropometrics or biochemical markers of physiological status in a SOF population of frequent deployers. Effects of modern combat deployment on longitudinal changes in anthropometrics and physiological status of elite U.S. Army SOF soldiers (n = 50) were assessed. Changes in measures of body composition, grip strength, physiological status, and health behaviors from baseline to postdeployment were determined with paired t test and McNemar's statistic. Baseline measures were obtained between 4 and 8 weeks before deployment. Deployment length was a uniform duration of time between 3 and 6 months (all soldiers completed the same length of deployment). Post hoc analyses determined change in body mass within quartiles of baseline body mass with paired t test and associations between change in sex hormone-binding globulin (SHBG) and change in body mass with correlation coefficient. The study was approved by the Human Use Review Committee at the U.S. Army Research Institute of Environmental Medicine, Natick, Massachusetts. In response to deployment, increases in lean mass (77.1 ± 7.6 to 77.8 ± 7.5 kg), maximum grip strength (57.9 ± 7.2 to 61.6 ± 8.8 kg), and conduct of aerobic (156 ± 106 to 250 ± 182 minutes/week) and strength training (190 ± 101 to 336 ± 251 minutes/week) exercise were observed (p < 0.05). Increases in serum SHBG (35.42 ± 10.68 to 38.77 ± 12.26 nmol/L) and decreases in serum cortisol (443.2 ± 79.3 to 381.9 ± 111.6 nmol/L) were also observed (p < 0.05). Body mass changes were dependent on baseline body mass. Soldiers in the lowest quartile of baseline body mass increased body mass (75.6 ± 2.6 vs. 76.6 ± 2.8 kg, p = 0.03), as did those in the second quartile (81.6 ± 2.0 vs. 83.7 ± 3.5 kg, p = 0.02). Those in the third quartile also tended to increase body mass (89.2 ± 2.6 vs. 90.9 ± 3.3 kg, p = 0.05), while those in the upper quartile tended to decrease body mass (98.5 ± 3.6 vs. 96.7 kg, p = 0.06). Change in SHBG was inversely correlated with change in body mass (r = -0.33, p = 0.02). There were no changes in fat mass, body fat percentage, waist circumference, neck circumference, total testosterone, calculated bioavailable or free testosterone, high-sensitivity C-reactive protein, tumor necrosis factor-α, interleukin-1β, or interleukin-6. Inflammatory markers were skewed toward lower values. Overall, physiological status of elite SOF soldiers characterized by multiple prior deployments was minimally impacted by combat deployment, in the absence of major unit casualties. The majority experienced some adaptive changes, including increased lean mass, grip strength, time spent engaged in exercise, and decreased levels of the stress hormone cortisol. Mechanisms contributing to inverse correlations between change in SHBG and change in body mass may be further clarified. Future investigations may also more fully characterize the degradation and optimization of health and physiological status of SOF training and deployment cycles with in-theater data collection and repeated measures.

Effects of vitamin D supplementation during weight loss on sex hormones in postmenopausal women.

The aim of the study was to compare the effects of vitamin D3 supplementation versus placebo on serum sex hormones in postmenopausal women completing a 12-month diet + exercise weight loss program. Two hundred eighteen overweight or obese women (50-75 y) with serum 25-hydroxyvitamin D at least 10 to less than 32 ng/mL ("insufficient") were randomized to either weight loss + 2,000 IU/day oral vitamin D3, or to weight loss + daily placebo. Serum sex hormone-binding globulin, estrone, total, free, and bioavailable estradiol, and testosterone were measured by radioimmunoassay before randomization and at 12 months. Mean changes were compared between groups (intent-to-treat) using generalized estimating equations. The 12-month changes in sex hormone-binding globulin, estrone, total, free, and bioavailable estradiol, and testosterone did not differ between groups (all P > 0.05). However, a greater increase in serum 25-hydroxyvitamin D was associated with a greater increase in sex hormone-binding globulin (Ptrend = 0.01), and larger decreases in free and bioavailable estradiol (Ptrend = 0.04, Ptrend = 0.03, respectively). In post-hoc analyses, we compared women randomized to vitamin D whose serum 25-hydroxyvitamin D remained insufficient (n = 38), to women who became replete (25-hydroxyvitamin D ≥32 ng/mL; n = 53). Replete women showed greater reductions in bioavailable estradiol (-1.8 vs -0.7 pg/mL), free testosterone (-0.8 vs -0.3 pg/mL), and bioavailable testosterone (-1.8 vs -0.6 ng/dL), and a greater increase in sex hormone-binding globulin (10.6 vs 4.7 nmol/L) (all P < 0.05), even after adjusting for differences in total 12-month weight loss. Overall, 12-month changes in sex hormone did not differ between groups. However, vitamin D repletion was associated with greater reductions in sex hormones during weight loss, with a possible dose-dependent effect. Future studies should test higher doses and target circulating 25-hydroxyvitamin D levels when measuring such effects.

Effects of intraperitoneal insulin versus subcutaneous insulin administration on sex hormone-binding globulin concentrations in patients with type 1 diabetes mellitus.

AimsElevated sex hormone-binding globulin (SHBG) concentrations have been described in patients with type 1 diabetes mellitus (T1DM), probably due to low portal insulin concentrations. We aimed to investigate whether the route of insulin administration, continuous intraperitoneal insulin infusion (CIPII), or subcutaneous (SC), influences SHBG concentrations among T1DM patients.MethodsPost hoc analysis of SHBG in samples derived from a randomized, open-labeled crossover trial was carried out in 20 T1DM patients: 50% males, mean age 43 (±13) years, diabetes duration 23 (±11) years, and hemoglobin A1c (HbA1c) 8.7 (±1.1) (72 (±12) mmol/mol). As secondary outcomes, testosterone, 17-β-estradiol, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) were analyzed.ResultsEstimated mean change in SHBG was −10.3nmol/L (95% CI: −17.4, −3.2) during CIPII and 3.7nmol/L (95% CI: −12.0, 4.6) during SC insulin treatment. Taking the effect of treatment order into account, the difference in SHBG between therapies was −6.6nmol/L (95% CI: −17.5, 4.3); −12.7nmol/L (95% CI: −25.1, −0.4) for males and −1.7nmol/L (95% CI: −24.6, 21.1) for females, respectively. Among males, SHBG and testosterone concentrations changed significantly during CIPII; −15.8nmol/L (95% CI: −24.2, −7.5) and −8.3nmol/L (95% CI: −14.4, −2.2), respectively. The difference between CIPII and SC insulin treatment was also significant for change in FSH 1.2U/L (95% CI: 0.1, 2.2) among males.ConclusionsSHBG concentrations decreased significantly during CIPII treatment. Moreover, the difference in change between CIPII and SC insulin therapy was significant for SHBG and FSH among males. These findings support the hypothesis that portal insulin administration influences circulating SHBG and sex steroids.