Increase In Sex Hormone-binding Globulin Research Articles

Metformin 2,500 mg/day in the treatment of obese women with polycystic ovary syndrome and its effect on weight, hormones, and lipid profile

The objective of this study was to assess the efficacy and safety of metformin at the dosage of 2,500 mg/day in the treatment of obese women with PCOS and also to evaluate its effect on weight, hormones, and lipid profile. This study was a 4-month open-label clinical trial. Sixty-nine PCOS patients aged 20-35 were recruited in the study. Testosterone, free testosterone, sex hormone-binding globulin (SHBG), fasting insulin, dehydroepiandrostenedione-sulphate (DHEAS), FBS, LDH, HDL, TG, total cholesterol, body mass index (BMI), and waist-to-hip ratio were measured before treatment and after 4 months of treatment. Significant reductions in serum insulin, BMI, waist/hip ratio, and LDL were observed. In addition, a significant increase in SHBG was obtained. Over the 4 months of the trial, 12 patients faced nausea, six patients had bloating, five patients had diarrhea and two had headache; none of these symptoms were severe except for two cases that dropped out due to severe vomiting. The results of this study show that 2,500 mg daily dose of metformin in obese patients with PCOS is effective in the reduction of BMI, waist hip/ratio, LDL, serum insulin and increases SHBG. In general this dose was relatively safe and well tolerated.

Hot flushes and biochemical markers for cardiovascular disease: a randomized trial on hormone therapy

Introduction Menopausal hot flushes may affect the responses of various vascular risk factors to hormone therapy (HT). We compared the responses of biochemical markers for cardiovascular diseases to HT in recently postmenopausal women with tolerable or intolerable hot flushes.Methods Healthy, non-smoking freshly postmenopausal women (n = 150) with no previous HT use were studied. Seventy-two women reported intolerable hot flushes (≥7 moderate/severe episodes/day) and 78 women tolerable hot flushes (≤3 mild episodes/day). The participants were treated in randomized order with either transdermal estradiol gel (1 mg), oral estradiol valerate (2 mg) with or without medroxyprogesterone acetate (5 mg), or placebo for 6 months. Treatment-induced changes in lipids, lipoproteins, apolipoproteins, sex hormone binding globulin (SHBG) and high-sensitivity C-reactive protein were compared. The trial is registered in the US National Institutes of Health Clinical Research Registry (no. NCT00668603).Results Pretreatment hot flush status was not related to the responses of these markers to different forms of HT. However, when all active regimens were evaluated together as a post-hoc analysis, 7/10 markers showed a tendency toward greater beneficial changes in women with intolerable hot flushes. Furthermore, in women with intolerable hot flushes and with HT use, the increases in SHBG (Spearman's rho = − 0.570, p < 0.001) were related to the reductions in hot flushes during the use of HT.Conclusions Hot flushes appear to be no significant determinant for the responses of vascular markers to HT use.

The C282Y polymorphism of the hereditary hemochromatosis gene is associated with increased sex hormone-binding globulin and normal testosterone levels in men

Hereditary hemochromatosis resulting either from homozygosity for the C282Y polymorphism of the HFE gene, or compound heterozygosity for C282Y and H63D, manifests with liver disease and hypogonadism. However, it is unclear whether men who are heterozygotes for C282Y or H63D exhibit subtle abnormalities of sex hormone status. To evaluate whether heterozygosity for either of the HFE gene polymorphisms C282Y or H63D is associated with circulating testosterone and SHBG in men. We performed a cross-sectional analysis of 388 community-dwelling men. Men were genotyped for C282Y and H63D. Sera were analysed for testosterone and SHBG, and insulin resistance was estimated using a homeostatic model (HOMA2-IR). Mean age of men in the cohort was 56.9 yr. Men who were heterozygous for the C282Y polymorphism in the HFE gene had higher SHBG levels than men who did not carry this polymorphism (mean ± SE, 38.2 ± 1.64 vs 32.8 ± 0.71 nmol/l, p=0.006). Total and free testosterone levels did not differ in the two groups. In multivariate analysis adjusting for potential confounders including age, waist circumference, testosterone, and HOMA2-IR, C282Y heterozygosity remained associated with SHBG levels (p<0.001). The C282Y polymorphism is associated with SHBG levels in men who do not manifest iron overload. Further studies are needed to clarify potential mechanisms and determine the clinical relevance of this finding.

The Effect of Metformin Treatment for 2 Years without Caloric Restriction on Endocrine and Metabolic Parameters in Women with Polycystic Ovary Syndrome

The aim of this study was to evaluate long-term changes in endocrine and metabolic parameters and body mass index in women with polycystic ovary syndrome (PCOS) who were treated with metformin over 2 years without caloric restriction. Twenty-six obese women with PCOS were treated with metformin over 2 years without caloric restriction. Clinical, metabolic and endocrine parameters and the body mass index were measured and an oral glucose tolerance test was carried out to calculate insulin resistance indices at the beginning and at the follow-up after 2 years. The Homeostatic Model for Assessment of Insulin Resistance (HOMA-IR) was calculated. No significant changes in body mass index or HOMA-IR were observed. However, a significant decrease in fasting and 2-h insulin levels was observed. Women showed a significant increase in sex hormone-binding globulin (SHBG) levels, while total testosterone (TT) levels and the free androgen index decreased significantly. Furthermore a significant decrease in hirsutism was observed. There was a decrease in cholesterol and an increase in high-density lipoprotein. Long-term treatment with metformin in women with PCOS appears to reduce androgen excess due to increased SHBG and decreased TT levels resulting in improvement of hirsutism as a clinical sign of androgen excess. Furthermore a significant decrease in fasting and 2-h insulin levels and slightly improved insulin resistance indices were observed.

Adiponectin and testosterone in patients with symptoms of late‐onset hypogonadism: Is there a link?

To examine the correlation between testosterone and adiponectin in symptomatic late-onset hypogonadism (LOH) patients. The study included 174 patients (>40 years old) with at least one LOH symptom and an Aging Male Symptoms score >26. The correlation between serum adiponectin levels and various factors was investigated by simple and multiple regression analyses. Serum adiponectin levels before and after testosterone replacement therapy (TRT) in 43 patients with serum free testosterone <11.8 pg/mL were also compared. Serum adiponectin levels increased with increased age (P < 0.01), decreased with increased body mass index (P < 0.01), and increased with increased sex hormone-binding globulin (P < 0.01). Multiple regression analysis revealed that body mass index and sex hormone-binding globulin were factors with an influence on serum adiponectin levels. However, no association between testosterone and adiponectin was found. In the 43 patients receiving TRT, serum adiponectin levels before and after TRT did not differ significantly. Serum adiponectin is not related to serum testosterone in symptomatic LOH patients, suggesting that TRT in these subjects does not pose a higher risk of inducing a metabolic syndrome.

Male Gynecomastia

A 62-year-old man with known coronary artery disease and ischemic left ventricular dysfunction presented with chest discomfort. His history was remarkable for New York Heart Association (NYHA) class IV congestive heart failure with depressed left ventricular ejection fraction. Physical examination revealed severe gynecomastia. The patient had been taking spironolactone (25 mg) daily for 8 years as part of his medication regimen for congestive heart failure. Spironolactone had been prescribed on the basis of RALES (Randomized Aldactone Evaluation Study), which reported spironolactone's benefits in reducing morbidity and mortality in patients with NYHA class III or IV heart failure.1Mosenkis A Townsend RR Gynecomastia and antihypertensive therapy.J Clin Hypertens (Greenwich). 2004; 6: 469-470PubMed Google Scholar Gynecomastia is a well-described adverse effect of spironolactone and is related to dose and duration of treatment; overall prevalence is 10%.1Mosenkis A Townsend RR Gynecomastia and antihypertensive therapy.J Clin Hypertens (Greenwich). 2004; 6: 469-470PubMed Google Scholar Spironolactone induces gynecomastia by decreasing testosterone production, increasing peripheral conversion of testosterone to estradiol, and displacing estradiol from sex hormone-binding globulin.1Mosenkis A Townsend RR Gynecomastia and antihypertensive therapy.J Clin Hypertens (Greenwich). 2004; 6: 469-470PubMed Google Scholar, 2Prisant LM Chin E Gynecomastia and hypertension.J Clin Hypertens (Greenwich). 2005; 7: 245-248Crossref PubMed Scopus (14) Google Scholar Generally, discontinuation of treatment results in resolution of gynecomastia. In 1999, RALES reported that spironolactone, in addition to standard therapy, decreases morbidity and death rates in patients with NYHA class III or IV heart failure. Gynecomastia or breast discomfort was reported as an adverse event in 10% of the men who participated in RALES.3Pitt B Zannad F Remme WJ Randomized Aldactone Evaluation Study Investigators et al.The effect of spironolactone on morbidity and mortality in patients with severe heart failure.N Engl J Med. 1999; 341: 709-717Crossref PubMed Scopus (7555) Google Scholar Other trials in which spironolactone was used have reported similar rates.4Chapman N Dobson J Wilson S Anglo-Scandinavian Cardiac Outcomes Trial Investigators et al.Effect of spironolactone on blood pressure in subjects with resistant hypertension.Hypertension. 2007; 49 (Epub 2007 Feb 19.): 839-845Crossref PubMed Scopus (513) Google Scholar Gynecomastia is defined as at least 2 cm of dense, subareolar tissue.2Prisant LM Chin E Gynecomastia and hypertension.J Clin Hypertens (Greenwich). 2005; 7: 245-248Crossref PubMed Scopus (14) Google Scholar It is seen in obese and elderly patients. Gynecomastia develops because of alterations in the ratio of free androgen to estrogen. Usual causes include enhanced peripheral aromatization of androgen to estrogen (obesity), displacement of estrogen from sex hormone-binding globulin, or decreased metabolism. Decreases in free androgen may occur as a result of increased sex hormone-binding globulin, increased metabolism, or impaired synthesis of androgen. Declining androgen synthesis is associated with the development of gynecomastia in elderly men. Gynecomastia can be an adverse effect of medications. Many antihypertensive medications have been associated with the development of gynecomastia, but it is highest with spironolactone.1Mosenkis A Townsend RR Gynecomastia and antihypertensive therapy.J Clin Hypertens (Greenwich). 2004; 6: 469-470PubMed Google Scholar Dosages higher than 150 mg/d have been associated with up to a 52% prevalence of the adverse effect. Generally, the effects are reversible after discontinuation of the drug. TABLEAntihypertensive Medications Associated With Gynecomastia Potassium-sparing diuretics SpironolactoneCalcium channel blockers NifedipineAmlodipineDiltiazemVerapamilAngiotensin-converting enzyme inhibitors CaptoprilEnalaprilα-Receptor blockers DoxazosinPrazosinCentrally acting agents ClonidineMethyldopaReserpine Open table in a new tab Spironolactone induces gynecomastia by blocking androgen production, by blocking androgens from binding to their receptors, and by increasing both total and free estrogen levels.1Mosenkis A Townsend RR Gynecomastia and antihypertensive therapy.J Clin Hypertens (Greenwich). 2004; 6: 469-470PubMed Google Scholar, 5Rose LI Underwood RH Newmark SR Kisch ES Williams GH Pathophysiology of spironolactone-induced gynecomastia.Ann Intern Med. 1977; 87: 398-403Crossref PubMed Scopus (156) Google Scholar Production of testosterone is decreased by inhibiting 17α-hydroxylase and 17,20-desmolase, which are enzymes in the testosterone synthesis pathway. Estrogen levels are increased by enhancing the peripheral conversion of testosterone to estradiol and by displacing estradiol from sex hormone-binding globulin. A selective aldosterone antagonist (eplerenone) has a lower incidence of gynecomastia, but the cost is higher.6Pitt B Remme W Zannad F Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study Investigators et al.Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction [published correction appears in N Engl J Med. 2003;348(22):2271].N Engl J Med. 2003; 348 (Epub 2003 Mar 31.): 1309-1321Crossref PubMed Scopus (4086) Google Scholar

Age modulates effects of thyroid dysfunction on sex hormone binding globulin (SHBG) levels.

Symptoms of thyroid dysfunction are difficult to detect in elderly people and TSH is sometimes unreliable. We therefore tested the value of SHBG as a marker of thyroid hormone action on the liver to determine the thyroid status of elderly people. Aging euthyroid men and women have a significant increase in SHBG (p > 0.0001). In aging women the decrease in SHBG with hypothyroidism and increase with hyperthyroidism are highly significant (p < 0.0001 and p < 0.0005 respectively). No significant variation in SHBG was observed in men with thyroid dysfunction. SHBG can help to determine the thyroid status of aging women.

Assessment of uterus, bone, serum lipids, and hormones in postmenopausal breast cancer patients treated with TAS-108, a novel steroidal antiestrogen: Results of a randomized phase II study

1120 Background: TAS-108, a novel steroidal antiestrogen, has demonstrated a favorable safety profile, including lower agonistic activity on uterus than tamoxifen and supportive effect on bone in preclinical studies. The potential tissue-specific effect of TAS-108 was investigated in postmenopausal breast cancer patients included in a randomized phase II study. (The clinical efficacy and safety results were presented at the 31st San Antonio Breast Cancer Symposium). Methods: Postmenopausal women aged 20–80 years with hormone receptor-positive metastatic breast cancer were eligible for this study and treated with oral TAS-108 (40, 80, or 120 mg/day) once a day. Endometrial thickness (ET) was measured by ultrasonography. The change in Bone Mineral Density (BMD) at lumber spine was assessed by dual energy X-ray absorptiometry. Hormone levels, bone metabolism markers, and serum lipid parameters were also measured at regular intervals. Wilcoxon signed-rank test was used to assess the significance of changes or percentage changes from baseline. Results: Ninety one patients with a median age of 62 years (range 44–80) were included in the analysis population. TAS-108 did not cause significant endometrial thickening (median baseline ET 3.3 mm, last point ET 3.6 mm; n = 36). In particular, after at least 1 year of treatment in 13 cases, no clinically significant increase in ET was found. No change was observed in median BMD (+0.74%; n = 20). Serum carboxy-terminal telopeptide of type I collagen (I CTP) levels remained unchanged although the decrease in osteocalcin levels was significant (p = 0.019; n = 49) in patients without bone metastasis. Median triglyceride levels significantly decreased from 104.0 to 85.0 mg/dl (p = 0.000) after 4 weeks of treatment, while there were no changes in other lipid parameters. An increase in sex hormone-binding globulin and testosterone levels were observed. Conclusions: TAS-108 may have no harmful effects within these parameters and could be used safely. However, further study in a greater number of cases is needed to identify the effect of the long-term use of TAS-108 on the uterus and bone. [Table: see text]

Testicular function and fertility in men with homozygous alpha-1 antitrypsin deficiency.

Fertility and testicular function were studied in eight men with severe homozygous (Pi ZZ variant genotype) alpha-1 antitrypsin (AAT) deficiency. Age- and marital duration standardized fertility, clinical androgenic features, mean testicular volume, plasma luteinizing hormone (LH) and follicle-stimulating hormone (FSH) and semen analysis were all normal apart from a reduction in semen volume. Mean plasma total and free testosterone were elevated and the percentage free testosterone reduced compared with age-matched, healthy fertile controls indicative of increased sex-hormone binding globulin (SHBG) levels representing an early marker for subclinical hepatic dysfunction associated with AAT-deficiency. In view of the preservation of normal fertility and testicular function despite chronic respiratory disease and premature death with deleterious AAT gene variants, it is proposed that the high prevalence of genetic polymorphism in the AAT protein may be maintained by the chronological asynchrony of the periods of maximal male reproductive activity (40 years) and the late onset (greater than 40 years) of symptoms in severe AAT deficiency rather than by any balance between reduced reproductive fitness of homozygotes and heterozygote advantage.

Thyroid hormones act indirectly to increase sex hormone-binding globulin production by liver via hepatocyte nuclear factor-4α

Thyroid hormones increase hepatic sex hormone-binding globulin (SHBG) production, which is also regulated by hepatocyte nuclear factor-4alpha (HNF-4alpha) in response to changes in the metabolic state of the liver. Since the human SHBG promoter lacks a typical thyroid hormone response element, and because thyroid hormones influence metabolic state, we set out to determine whether thyroid hormones mediate SHBG expression indirectly via changes in HNF-4alpha levels in HepG2 human hepatoblastoma cells, and in the livers of transgenic mice that express a 4.3 kb human SHBG transgene under the control of its own 0.8 kb promoter sequence. Thyroid hormones (triiodothyronine (T(3)) and thyroxine (T(4))) increase SHBG accumulation in HepG2 cell culture medium over 5 days, and increase cellular SHBG mRNA levels. In addition, T(4) treatment of HepG2 cells for 5 days increased HNF-4alpha mRNA and HNF-4alpha levels in concert with decreased cellular palmitate levels. Plasma SHBG levels were also increased in mice expressing a human SHBG transgene after 5 days treatment with T(3) along with increased hepatic HNF-4alpha levels. In HepG2 cells, the human SHBG promoter failed to respond acutely (within 24 h) to T(4) treatment, but a 4-day pre-treatment with T(4) resulted in a robust response that was prevented by co-treatment with HNF-4alpha siRNA, or by blocking the beta-oxidation of palmitate through co-treatment with the carnitine palmitoyltransferase I inhibitor, etomoxir. These data lead us to conclude that thyroid hormones increase SHBG production indirectly by increasing HNF-4alpha gene expression, and by reducing cellular palmitate levels that further contribute to increased HNF-4alpha levels in hepatocytes.

Heart rate recovery improves after weight loss in overweight and obese women with polycystic ovary syndrome

To determine the effects of weight loss on heart rate recovery (HRR) in overweight women with polycystic ovary syndrome (PCOS). A 10-week prospective clinical intervention. Clinical research unit. Fifty-seven overweight and obese women with PCOS (age: 29.8 +/- 0.8 years; body mass index [BMI] 36.2 +/- 0.7 kg/m(2)). A dietary plan of 5-6 MJ/day ( approximately 30% energy restricted). Heart rate recovery (defined as the reduction in heart rate after 1 minute from peak heart rate after a graded treadmill test to exhaustion), weight, waist circumference, blood pressure, glucose, insulin, homeostasis model assessment of insulin resistance, and sex steroids before and after the intervention. The mean percentage of weight loss was (-6.7 +/- 0.4%). There were significant reductions in waist circumference (-6.9 +/- 0.6 cm), blood pressure (-4.9/-2.5 +/- 1.2/1.2 mm Hg), fasting insulin (-3.4 +/- 0.7 mU/L), fasting glucose (-0.17 +/- 0.05 mmol/L), homeostasis model assessment of insulin resistance (-0.43 +/- 0.09), T (-0.38 +/- 0.07 nmol/L), free androgen index (-2.86 +/- 0.58), and an increase in sex hormone-binding globulin [SHBG] (5.86 +/- 1.12 nmol/L). The HRR improved from 30.9 +/- 1.1 to 38.0 +/- 1.1 beats/min and that was related to the reduction in body weight (r = -0.34) and waist circumference (r = -0.27). Weight loss in overweight and obese women with PCOS is associated with improvements in HRR, which suggests improved autonomic function. This highlights the importance of weight loss to reduce the cardiovascular disease risk in these women.

Comparison of corticoid substitution versus combined oral contraception administration in the treatment of non-classic adrenal hyperplasia: A prospective study

Objective.The clinical symptoms of non-classic adrenal hyperplasia (NCAH) are the same as those in patients with polycystic ovary syndrome (PCOS). The aim of our study was to compare conventional corticoid treatment of NCAH with the effect of combined oral contraception (COC) administration (used in treatment of PCOS) on clinical and laboratory parameters of NCAH.Design.A prospective clinical study, cross-over design.Material and methods.Since 1999 from 298 hyperandrogenic women, eight patients having 21-hydroxylase deficient NCAH have been identified. They were divided equally into two groups according to the order of application treatment modality (hydrocortison vs. COC). Effect of treatment of both modalities on clinical symptoms (hirsutism – FG score, acne, menstrual cycle) and laboratory parameters (testosterone, androstenedione, dehydroepiandrosterone, dehydroepiandrosterone sulphate, sex hormone binding globulin (SHBG)) were evaluated.Results.We observed the decrease of plasma androgens in both groups, which did not differ significantly. Significant increase of SHBG (i.e. decrease of free androgens) was, however, documented in each period with COC administration. Not surprisingly, improvement of the most frequent clinical symptom of NCAH in our study group, oligomenorrhea, was also more apparent in COC. Hirsutism was only a minor problem in our group that did not allow to evaluate treatment effect of both the modalitiesConclusion.Our results indicate that ovarian suppression by COC administration can effectively suppress androgen production and improve the most frequent clinical symptom (irregular cycle) in patients with NCAH, so can be successfully used for the treatment at least under basal conditions. Whether corticosteroid substitution can be limited to patients with inadequate response to COC on plasma androgen levels or with signs of adrenal insufficiency requires further data.

Sexual quality of life in epilepsy: Correlations with sex hormone blood levels

Seventy-nine consecutive inpatients of an epilepsy center (34 women, 45 men) who had either generalized epilepsy, temporal lobe epilepsy, focal epilepsy of other origin, or no epilepsy completed the Derogatis Interview for Sexual Function-Self-Report Inventory. Quantitative assessments of blood levels were performed for prolactin, total testosterone, sex hormone-binding globulin, estradiol, dehydroepiandrosterone sulfate, luteinizing hormone, and follicle-stimulating hormone. In men, increasing sex hormone-binding globulin levels and duration of epilepsy decreased sexual quality of life. Sex hormone-binding globulin level in men was related to enzyme-inducing antiepileptic drugs and age. In women, we found no associations between blood hormone levels and sexual quality of life. Our results suggest that sexual quality of life is affected by sexual hormone blood levels in men, but not in women with epilepsy. Avoiding enzyme-inducing antiepileptic drugs may lower the risk of raised sex hormone-binding globulin levels and, thus, of lowered sexual quality of life in men with epilepsy.

Low body mass index and declining sex steroids explain most age-related bone loss in Brazilian men

Osteoporosis in men is underestimated, but our data point to an increasing prevalence rate in those over 70 years old with body mass index (BMI) <25 kg/m(2), bioavailable testosterone <2.7 nmol/L, bioavailable estradiol <40 pmol/L, and high bone turnover, defined in this study as serum carboxyterminal cross-linked telopeptide of type I collagen (ICTP) >4.3 microg/L. The association of sex steroids and osteoporosis was evaluated in 104 men, aged 50-93 years old. Bone mineral density (BMD), bone turnover (ICTP), testosterone (T), and estradiol (E(2)) were measured; free and bioavailable hormones (free testosterone index [FTI], BioT, free estradiol index [FEI], and BioE(2)) were calculated from T, E(2), sex hormone-binding globulin (SHBG), and albumin. Nonparametric analysis and Poisson regression models were used. Significant increases in SHBG and ICTP and decreases in femoral neck BMD, FTI, FEI, BioT, and BioE(2) were observed with each additional decade of age. Femoral neck BMD was inversely correlated with ICTP, and both were significantly associated with SHBG, FTI, BioT, FEI, and BioE. There was a direct and graded association between age and osteoporosis prevalence rate (OP PR; p = 0.028). Compared to participants less than 70 years old, the crude OP PR of those 80 years and older was 3.2 (95%CI = 1.4-7.3). Adjusting sequentially for BMI and bioavailable sex hormones attenuated the association between age and osteoporosis prevalence by 55% and 77%, respectively. Our data support the view that low BMI and declining sex steroids explain most of the association between aging, increased bone turnover, and osteoporosis in men.

Annual reproductive phase-related profile of sex steroids and their carrier, SHBG, in the Indian major carp, Labeo rohita

This study reports annual cyclic changes in the plasma levels of sex hormone binding globulin (SHBG), sex steroids (E 2, estradiol; T, testosterone; P, progesterone) and protein (PRT) in correlation with reproductive phases in both sexes of an Indian major carp, Labeo rohita. Plasma SHBG, E 2, T and PRT levels in females and SHBG and T levels in males showed steady increases ( p < 0.005) in parallel with the gonadosomatic index (GSI) escalation in the preparatory and prespawning phases attaining peak levels before spawning. During the late spawning and early postspawning phases, E 2, T and SHBG levels revealed an abrupt and significant descent coincident with the GSI in both the sexes. The plasma P levels in females, attaining measurable quantities only in prespawning phase, underwent a rapid increase followed by a quick decline to undetectable levels in the spawning phase. This occurrence of P for a short duration suggests a limited role in ovarian function. During the resting phase, the E 2, T and SHBG levels in both sexes declined to minimum in conjunction with a decrease in the GSI, while PRT showed an increase. These data suggest that a significant increase in SHBG ( p < 0.005) prior to spawning enhances its binding capacity with sex steroids in both sexes synchronizing the reproductive activity. The significant increase of PRT in females during early spawning reflects its role in oocyte function, while PRT and E 2 in males may not significantly affect the testicular activity.

Divalproex Extended‐Release in Adolescent Migraine Prophylaxis: Results of a Randomized, Double‐Blind, Placebo‐Controlled Study

To evaluate the efficacy, tolerability, and safety of 3 different doses of divalproex sodium extended-release vs placebo in the prophylaxis of migraine headaches in adolescents. Divalproex sodium has been approved for migraine prophylaxis in adults, and previous uncontrolled data suggest divalproex sodium may be effective in preventing migraine in children and adolescents with acceptable tolerability. This was a 12-week, phase 3, randomized, placebo-controlled, double-blind, parallel-group, multicenter study in approximately 300 adolescents aged 12 to 17 years with migraine headaches. At the end of the baseline phase, subjects still meeting study criteria were randomized in a 1:1:1:1 ratio to receive divalproex sodium extended-release 250 mg, 500 mg, or 1000 mg once daily, or placebo. The primary efficacy variable was reduction from baseline in 4-week migraine headache rate for each active treatment group vs placebo. Standard safety assessments were conducted and testosterone and sex hormone-binding globulin levels were collected for postmenarchal females. There was no statistically significant treatment difference between any divalproex sodium extended-release dose group and placebo for the primary efficacy variable, reduction from baseline in 4-week migraine headache rate. There were no statistically significant differences in adverse events between any active treatment group and placebo. A notable dose-related decrease in platelets was observed, and individuals in all 4 treatment groups had increases in ammonia levels; treatment differences in other laboratory variables were generally small. Among postmenarchal female subjects who were not taking hormonal contraceptives or other steroids, there was no statistically significant change in testosterone levels, but a statistically significant dose-related increase in sex hormone-binding globulin was observed. In the current study, divalproex sodium extended-release did not differentiate from placebo in the prophylactic treatment of migraine headaches but was generally well-tolerated in adolescents aged 12 to 17 years.

Dehydroepiandrosterone sulfate and insulin resistance in patients with polycystic ovary syndrome

To test the hypothesis that increasing DHEAS levels is associated with improved insulin resistance in patients with polycystic ovary syndrome (PCOS). Cross-sectional cohort analysis. Academic medical center. Three hundred fifty-two women with PCOS. Patients presenting for evaluation of symptoms related to androgen excess were evaluated physically and biochemically through laboratory analysis. Circulating DHEAS, total T, free T, sex hormone-binding globulin (SHBG), and 17-hydroxyprogesterone (17-OHP) levels, and calculated homeostasis model assessment of insulin resistance (HOMA-IR). Bivariate analysis indicated that all parameters were associated with HOMA-IR, except 17-OHP and age, and confirmed a negative correlation between DHEAS and HOMA-IR. Multivariate analysis indicated that increases in DHEAS, SHBG, 17-OHP, and age were associated with decreasing HOMA-IR, whereas increases in free T, body mass index (BMI), and waist-to-hip ratio (WHR) were associated with increasing HOMA-IR. In decreasing order of importance, the following variables predicted insulin resistance: BMI > WHR > age > DHEAS > free T > SHBG > 17-OHP. DHEAS is negatively correlated to insulin resistance in patients with PCOS, and in our model ranked just behind other well-established predictors including BMI, WHR, and age. Whether this is due to a direct beneficial effect on insulin action by adrenal androgens such as DHEA, or whether DHEAS simply reflects the circulating levels of hyperinsulinemia, remains to be determined.

Hypoactive sexual desire in transsexual women: prevalence and association with testosterone levels

An unknown proportion of transsexual women (defined as post-operative male-to-female transsexuals on oestrogen replacement) experience hypoactive sexual desire disorder (HSDD). It has been suggested that the absence of ovarian androgen production together with oestrogen treatment-related increase in sex hormone-binding globulin (SHBG) levels could be leading to HSDD, due to low levels of biologically available testosterone. This study wishes to document the HSDD prevalence among transsexual women and the possible association to androgen levels. Cross-sectional study. Transsexual women (n=62) and a control group of ovulating women (n=30) participated in this study. Questionnaires measuring sexual desire (sexual desire inventory) and relationship and sexual satisfaction (Maudsley Marital Questionnaire) were completed. Serum levels of total testosterone, LH and SHBG were measured in blood samples obtained at random in transsexual women and in the early follicular phase in ovulating women. The transsexual group had lower levels of total and calculated free testosterone (both P<0.001) than the ovulating women. HSDD was reported in 34% of the transsexual and 23% of the ovulating women (P=0.30). Both groups reported similar levels of sexual desire (P=0.97). For transsexual women, no significant correlation was found between sexual desire and total (P=0.64) or free testosterone (P=0.82). In ovulating women, these correlations were significant (P=0.006, resp. P=0.003). HSDD is reported in one-third of transsexual women. This prevalence is not substantially different from controls, despite markedly lower (free) testosterone levels, which argues against a major role of testosterone in this specific group.

Association of bioavailable estradiol levels and testosterone levels with serum albumin levels in elderly men

Estrogens are reported to be the essential sex steroid acting on some male physiological functions, and bioavailable estrogens comprise the free and albumin-bound fractions. Moreover, most of the bioavailable sex steroid is made up of albumin-bound fraction. We examined the age-related change in serum free, albumin-bound and bioavailable estradiol levels in comparison with each fraction of testosterone and its relationship with serum albumin level in elderly men. Albumin-bound as well as bioavailable estradiol levels declined with age, and their decreases were associated much more with the decrease of albumin level than the increase of sex-hormone binding globulin (SHBG) level in sixties and seventies, and similar results were recognized in the level of each fraction of testosterone, suggesting albumin levels have an important role for maintaining bioavailable sex steroid levels in males aged over sixty. Moreover, our study showed that SHBG levels associated inversely with bioavailable sex steroid levels particularly when serum albumin level was low. It seems likely that the decrease of bioavailable estradiol as well as testosterone is induced by the decrease of albumin-bound fractions in combination with the increase of SHBG-bound fractions in males aged over sixty, and that their physical characteristics of aging could be induced by the decrease of albumin-bound fractions caused by the decrease of serum albumin regardless of total sex steroid levels.

Low Sex Hormone-Binding Globulin and Testosterone Levels in Association with Erectile Dysfunction among Human Immunodeficiency Virus-Infected Men Receiving Testosterone and Oxandrolone

Men with acquired immunodeficiency syndrome (AIDS) wasting and hypogonadism are frequently treated with testosterone and oxandrolone, an orally administered anabolic-androgenic steroid hormone. We observed reductions in testosterone and sex hormone-binding globulin (SHBG) levels, in association with complaints of erectile dysfunction, after prolonged exposure to this therapeutic regimen. First description of an association between long-term receipt of oxandrolone with erectile dysfunction, low SHBG and testosterone. Case report of three human immunodeficiency virus-infected hypogonadal male patients receiving treatment for wasting syndrome and hypogonadism, and highly active antiretroviral therapy. All three patients received long-term oxandrolone in addition to testosterone replacement therapy. Testosterone and SHBG levels for patients 1, 2, and 3, respectively: total testosterone 183, 71, and 151 ng/dL (260-1,000 ng/dL); free testosterone (not done for patient 3) 58.3 and 26.9 pg/mL (50-210 pg/mL); SHBG 6, 9, and 6 nmol/L (7-50 nmol/L). No other hormonal abnormalities were detected. Following discontinuation of oxandrolone, levels of total testosterone rose, consistent with increase in SHBG. One patient received repeat SHBG assay documenting rise in SHBG level. Patient 2 reported return of libido and early morning erections several weeks after discontinuation of oxandrolone. Patients had erectile dysfunction in association with low testosterone and SHBG, in spite of exogenous testosterone replacement. Discontinuation of oxandrolone led to the normalization or improvement of testosterone levels in all three patients with symptomatic improvement in one patient. First pass metabolism of orally administered oxandrolone may decrease hepatic synthesis of SHBG, allowing exogenously supplied testosterone to be excreted. Further work is necessary to elucidate the relationship.