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Effect of clomiphene citrate treatment on the Sertoli cells of dysmetabolic obese men with low testosterone levels.
Pelusi, C, Fanelli, F, Baccini, M, Triggiani, V, Bartolomeo, N, Carbone, MD, De Pergola, G, Di Dalmazi, G, Pagotto, U, Pasquali, R, et al
Clinical endocrinology. 2020;(1):38-45
Abstract
BACKGROUND Clomiphene citrate (CC) has been shown to restore the hypothalamic-pituitary-gonadal (HPG) axis by increasing testosterone (T) levels to physiological levels in patients with dysmetabolic conditions such as obesity, metabolic syndrome and type 2 diabetes mellitus (T2DM). However, the data are unclear regarding the effects on Sertoli cell (SC) function. AIM: To study SC function by assessing Inhibin B (IB) and anti-Mullerian hormone (AMH) levels at baseline and after 3 months of CC treatment. MATERIALS AND METHODS This is an ancillary study of a cross-over, randomised, double-blind, placebo-controlled trial performed to evaluate androgen response to CC treatment in dysmetabolic obese subjects with low T levels treated with metformin. We evaluated SC function by assessing IB and AMH levels at baseline and after 3 months of each treatment in ten dysmetabolic obese subjects with low T levels. In all subjects, the influence of the clinical characteristics, metabolic and hormonal baseline parameters on SC and Leydig (LC) function, evaluated respectively with AMH, IB, follicle-stimulating hormone (FSH) and T levels, was tested. RESULTS No significant changes were observed for IB and AMH concentrations after each treatment period. Whereas T and oestradiol (E2) levels were shown to be significantly higher in the CC plus metformin phase (CC/Met) only. No clinical, metabolic or hormonal parameters showed significant effects on serum AMH at baseline or after treatments. However, baseline T, dihydrotestosterone (DHT) and E2 positively affected IB levels during CC/Met therapy (P = .003, P = .038 and P = .049, respectively). Baseline leptin and FSH had a negative (P = 031) and positive (P = .048) respectively role on T levels during CC/Met, as they were statistically significant compared to the placebo period (Plac/Met). CONCLUSION Unlike the LC activity, CC was unable to influence SC function, as shown by the lack of IB and AMH serum modifications, thus suggesting an intrinsic nonreversible defect of SC cells in patients with dysmetabolic conditions.
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Testosterone concentrations and risk of cardiovascular events in androgen-deficient men with atherosclerotic cardiovascular disease.
Boden, WE, Miller, MG, McBride, R, Harvey, C, Snabes, MC, Schmidt, J, McGovern, ME, Fleg, JL, Desvigne-Nickens, P, Anderson, T, et al
American heart journal. 2020;:65-76
Abstract
BACKGROUND Whether androgen deficiency among men increases the risk of cardiovascular (CV) events or is merely a disease marker remains a subject of intense scientific interest. OBJECTIVES Among male subjects in the AIM-HIGH Trial with metabolic syndrome and low baseline levels of high-density lipoprotein (HDL)-cholesterol who were randomized to niacin or placebo plus simvastatin, we examined the relationship between low baseline testosterone (T) concentrations and subsequent CV outcomes during a mean 3-year follow-up. METHODS In this post hoc analysis of men with available baseline plasma T concentrations, we examined the relationship between clinical/demographic characteristics and T concentrations both as a continuous and dichotomous variable (<300 ng/dL ["low T"] vs. ≥300 ng/dL ["normal T"]) on rates of pre-specified CV outcomes, using Cox proportional hazards models. RESULTS Among 2118 male participants in whom T concentrations were measured, 643 (30%) had low T and 1475 had normal T concentrations at baseline. The low T group had higher rates of diabetes mellitus, hypertension, elevated body mass index, metabolic syndrome, higher blood glucose, hemoglobin A1c, and triglyceride levels, but lower levels of both low-density lipoprotein and HDL-cholesterol, and a lower rate of prior myocardial infarction (MI). Men with low T had a higher risk of the primary composite outcome of coronary heart disease (CHD) death, MI, stroke, hospitalization for acute coronary syndrome, or coronary or cerebral revascularization (20.1%) compared with the normal T group (15.2%); final adjusted HR 1.23, P = .07, and a higher risk of the CHD death, MI, and stroke composite endpoint (11.8% vs. 8.2%; final adjusted HR 1.37, P = .04), respectively. CONCLUSIONS In this post hoc analysis, there was an association between low baseline testosterone concentrations and increased risk of subsequent CV events in androgen-deficient men with established CV disease and metabolic syndrome, particularly for the composite secondary endpoint of CHD death, MI, and stroke. CONDENSED ABSTRACT In this AIM-HIGH Trial post hoc analysis of 2118 men with metabolic syndrome and low HDL-cholesterol with available baseline plasma testosterone (T) samples, 643 males (30%) had low T (mean: 229 ng/dL) and 1475 (70%) had normal T (mean: 444 ng/dL) concentrations. The "low T" group had a 24% higher risk of the primary 5-component endpoint (20.1%) compared with the normal T group (15.2%); final adjusted HR 1.23, P = .07). There was also a 31% higher risk of the secondary composite endpoint: coronary heart disease death, myocardial infarction, and stroke (11.8% vs. 8.2%, final adjusted HR 1.37, P = .04) in the low vs. normal T group, respectively.
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Effects of Resveratrol on Polycystic Ovary Syndrome: A Double-blind, Randomized, Placebo-controlled Trial.
Banaszewska, B, Wrotyńska-Barczyńska, J, Spaczynski, RZ, Pawelczyk, L, Duleba, AJ
The Journal of clinical endocrinology and metabolism. 2016;(11):4322-4328
Abstract
CONTEXT Polycystic ovary syndrome (PCOS) is the most common endocrinopathy affecting women of reproductive age. Hyperandrogenism is the central feature of PCOS. Studies on isolated ovarian theca-interstitial cells suggest that resveratrol, a natural polyphenol, reduces androgen production. OBJECTIVE This study was designed to evaluate endocrine and metabolic effects of resveratrol on PCOS. DESIGN AND SETTING This was a randomized (1:1) double-blind, placebo-controlled trial that evaluated the effects of resveratrol over a period of 3 months in an academic hospital. PATIENTS AND OTHER PARTICIPANTS Subjects with PCOS were identified according to the Rotterdam criteria. Thirty-four subjects were enrolled and 30 subjects completed the trial. Evaluations were performed at baseline and repeated after 3 months of treatment. INTERVENTION Resveratrol (1,500 mg p.o.) or placebo were administered daily. MAIN OUTCOME MEASURE Primary outcome was the change in the serum total T. RESULTS Resveratrol treatment led to a significant decrease of total T by 23.1% (P = .01). In parallel, resveratrol induced a 22.2% decrease of dehydroepiandrosterone sulfate (P = .01), a decrease of fasting insulin level by 31.8% (P = .007) and an increase of the Insulin Sensitivity Index (Matsuda and DeFronzo) by 66.3% (P = .04). Levels of gonadotropins, the lipid profile as well as markers of inflammation and endothelial function were not significantly altered. CONCLUSIONS Resveratrol significantly reduced ovarian and adrenal androgens. This effect may be, at least in part, related to an improvement of insulin sensitivity and a decline of insulin level.
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Effect of orlistat on weight loss, hormonal and metabolic profiles in women with polycystic ovarian syndrome: a randomized double-blind placebo-controlled trial.
Moini, A, Kanani, M, Kashani, L, Hosseini, R, Hosseini, L
Endocrine. 2015;(1):286-9
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Influence of testosterone replacement therapy on metabolic disorders in male patients with type 2 diabetes mellitus and androgen deficiency.
Janjgava, S, Zerekidze, T, Uchava, L, Giorgadze, E, Asatiani, K
European journal of medical research. 2014;(1):56
Abstract
BACKGROUND Multiple epidemiological studies have shown that low testosterone levels are associated with and predict the future development of type 2 diabetes mellitus and the metabolic syndrome. The aim of our study was to show the influence of testosterone replacement therapy on obesity, HbA1c level, hypertension and dyslipidemia in patients with diabetes mellitus and androgen deficiency. METHODS One hundred and twenty-five male patients with diabetes mellitus were screened; 85 subjects aged 41 to 65 years, with BMI from 27.0 to 48.0 kg/m(2), were randomized in a placebo-controlled study. They also underwent a routine physical examination and selected by free testosterone examination. We divided patients into two groups: 1) treatment group, where we used diet, physical activity, patient's antidiabetic therapy and testosterone replacement therapy; 2) placebo group, where we used diet, physical activity, patient's antidiabetic therapy and placebo. RESULTS After 6 months of treatment we repeated the diagnostic assessments: lipid profile was improved in both groups but in first group it was clinically significant. Free testosterone level increased in all groups, but in group I was clinically significant. HbA1c decreased in both groups, but in group I we obtained the best result. Leptin level after treatment was approximately the same in both groups. Also, blood pressure was reduced in both groups but results were similar. CONCLUSIONS Our study demonstrated that it is possible to break this metabolic vicious circle by raising testosterone levels in diabetic men with androgen deficiency. Re-instituting physiological levels of testosterone, as the study has shown, has an important role in reducing the prevalence of diabetic complications.
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Plasma sex steroid hormones and risk of developing type 2 diabetes in women: a prospective study.
Ding, EL, Song, Y, Manson, JE, Rifai, N, Buring, JE, Liu, S
Diabetologia. 2007;(10):2076-84
Abstract
AIMS/HYPOTHESIS Prospective data directly investigating the role of endogenous sex hormones in diabetes risk have been scant, particularly in women. We aimed to examine comprehensively plasma sex hormones in connection with risk of developing type 2 diabetes in postmenopausal women. METHODS We conducted a prospective, nested case-control study of plasma oestradiol, testosterone and dehydroepiandrosterone sulfate and risk of type 2 diabetes in a cohort of women health professionals with a mean age of 60.3 and 12.2 years since menopause. Among women not using hormone therapy and free of baseline cardiovascular disease, cancer and diabetes, 359 incident cases of type 2 diabetes were matched with 359 controls during an average follow-up of 10 years. RESULTS Oestradiol and testosterone were each strongly and positively associated with risk of type 2 diabetes. After adjustment for BMI, family history, lifestyle and reproductive variables, the multivariable relative risks (95% CI) comparing the highest vs lowest quintile were 12.6 (2.83-56.3) for total oestradiol (p = 0.002 for trend), 13.1 (4.18-40.8) for free oestradiol (p < 0.001 for trend), 4.15 (1.21-14.2) for total testosterone (p = 0.019 for trend) and 14.8 (4.44-49.2) for free testosterone (p < 0.001 for trend). These associations remained robust after adjusting and accounting for other metabolic syndrome components and baseline HbA(1c) levels. CONCLUSIONS/INTERPRETATION In postmenopausal women, higher plasma levels of oestradiol and testosterone were strongly and prospectively related to increased risk of developing type 2 diabetes. These prospective data indicate that endogenous levels of sex hormones may play important roles in the pathogenesis of type 2 diabetes. ClinicalTrials.gov ID no.: NCT00000479.
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Testosterone replacement therapy improves insulin resistance, glycaemic control, visceral adiposity and hypercholesterolaemia in hypogonadal men with type 2 diabetes.
Kapoor, D, Goodwin, E, Channer, KS, Jones, TH
European journal of endocrinology. 2006;(6):899-906
Abstract
OBJECTIVE Low levels of testosterone in men have been shown to be associated with type 2 diabetes, visceral adiposity, dyslipidaemia and metabolic syndrome. We investigated the effect of testosterone treatment on insulin resistance and glycaemic control in hypogonadal men with type 2 diabetes. DESIGN This was a double-blind placebo-controlled crossover study in 24 hypogonadal men (10 treated with insulin) over the age of 30 years with type 2 diabetes. METHODS Patients were treated with i.m. testosterone 200 mg every 2 weeks or placebo for 3 months in random order, followed by a washout period of 1 month before the alternate treatment phase. The primary outcomes were changes in fasting insulin sensitivity (as measured by homeostatic model index (HOMA) in those not on insulin), fasting blood glucose and glycated haemoglobin. The secondary outcomes were changes in body composition, fasting lipids and blood pressure. Statistical analysis was performed on the delta values, with the treatment effect of placebo compared against the treatment effect of testosterone. RESULTS Testosterone therapy reduced the HOMA index (-1.73 +/- 0.67, P = 0.02, n = 14), indicating an improved fasting insulin sensitivity. Glycated haemoglobin was also reduced (-0.37 +/- 0.17%, P = 0.03), as was the fasting blood glucose (-1.58 +/- 0.68 mmol/l, P = 0.03). Testosterone treatment resulted in a reduction in visceral adiposity as assessed by waist circumference (-1.63 +/- 0.71 cm, P = 0.03) and waist/hip ratio (-0.03 +/- 0.01, P = 0.01). Total cholesterol decreased with testosterone therapy (-0.4 +/- 0.17 mmol/l, P = 0.03) but no effect on blood pressure was observed. CONCLUSIONS Testosterone replacement therapy reduces insulin resistance and improves glycaemic control in hypogonadal men with type 2 diabetes. Improvements in glycaemic control, insulin resistance, cholesterol and visceral adiposity together represent an overall reduction in cardiovascular risk.