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Effects of testosterone supplementation therapy on lipid metabolism in hypogonadal men with T2DM: a meta-analysis of randomized controlled trials.
Zhang, KS, Zhao, MJ, An, Q, Jia, YF, Fu, LL, Xu, JF, Gu, YQ
Andrology. 2018;(1):37-46
Abstract
Testosterone supplementation may be effective for the treatment of hypogonadism in men with type 2 diabetes mellitus (T2DM), but the evidence from randomized controlled trials (RCTs) is inconclusive. We aimed to systematically summarize results from intervention studies and assess the effects of testosterone supplementation therapy (TST) on lipid metabolism in RCTs of hypogonadal men with T2DM by meta-analysis. PubMed, Embase, and Cochrane Library databases were searched for studies reporting the effect of TST on lipid metabolism in hypogonadal men with T2DM until December 31, 2016. Seven RCTs from 252 trials, enrolling a total of 612 patients in the experimental and control groups with a mean age of 58.5 years, were included in this study. The pooled results of the meta-analysis demonstrated that TST significantly decreased TC and TG levels in hypogonadal men with T2DM compared with the control group, with mean differences (MDs) of -6.44 (95% CI: -11.82 to -1.06; I2 = 28%; p = 0.02) and -27.94 (95% CI: -52.33 to -3.54; I2 = 76%; p = 0.02). Subgroup analyses revealed that the heterogeneity (I2 = 76%) of TG originated from different economic regions, in which economic development, genetic and environmental factors, and dietary habits affect lipid metabolism of human, with a decrease (I2 = 45%) in developed countries. Additionally, subgroup analyses showed that TST increased HDL-C level in developing countries compared with the control group (MD = 2.79; 95% CI: 0.73 to 4.86; I2 = 0%; p = 0.008), but there was no improvement in developed countries (MD = 1.02; 95% CI: -4.55 to 6.60; I2 = 91%; p = 0.72). However, LDL-C levels were not improved consistently. Because the relationship between lipid metabolism and atherosclerosis is unequivocal, TST, which ameliorates lipid metabolism, may decrease the morbidity and mortality of cardiovascular disease in hypogonadal men with T2DM by preventing atherogenesis.
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11-Ketotestosterone Is the Dominant Circulating Bioactive Androgen During Normal and Premature Adrenarche.
Rege, J, Turcu, AF, Kasa-Vubu, JZ, Lerario, AM, Auchus, GC, Auchus, RJ, Smith, JM, White, PC, Rainey, WE
The Journal of clinical endocrinology and metabolism. 2018;(12):4589-4598
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Abstract
CONTEXT Adrenarche refers to the rise of dehydroepiandrosterone sulfate (DHEA-S) associated with the development of a functional adrenal zona reticularis. Clinical features of adrenarche include onset of body odor, axillary hair, and pubic hair, which reflect increased androgen action. An early rise in adrenal androgens, or premature adrenarche (PremA), is a risk factor for adverse metabolic profiles in adolescence and adulthood. The bioactive androgens associated with adrenarche and PremA remain poorly understood. The adrenal gland is a potential source of testosterone (T) and the 11-oxygenated derivatives 11β-hydroxytestosterone (11OHT) and 11-ketotestosterone (11KT). OBJECTIVE The objective of this study was to characterize the adrenal androgen biome contributing to adrenarche and PremA. PARTICIPANTS AND METHODS With the use of mass spectrometry, 19 steroids including the 11-oxygenated derivatives of T were measured in sera obtained from girls with PremA (n = 37; 4 to 7 years) and age-matched girls (n = 83; 4 to 10 years). RESULTS In reference population girls, dehydroepiandrosterone, DHEA-S, androstenediol-3-sulfate, T, and 11KT all increased at the onset of adrenarche (6 to 8 years) and beyond (9 to 10 years) (P < 0.05 vs younger subjects 4 to 5 years). T, 11OHT, and 11KT were further elevated in PremA vs age-matched girls (P < 0.001). Circulating concentrations of 11KT during adrenarche and PremA exceeded those of T and 11OHT (11KT > T ≥ 11OHT). Androgen receptor activity and nuclear translocation studies demonstrated that 11KT is a potent androgen similar to T. CONCLUSIONS Our findings suggest that 11KT is the dominant bioactive androgen in children during adrenarche and PremA. Its androgenic capacity suggests that it may be responsible for the phenotypic changes seen in these phenomena.
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Effects of testosterone supplement treatment in hypogonadal adult males with T2DM: a meta-analysis and systematic review.
Zhang, J, Yang, B, Xiao, W, Li, X, Li, H
World journal of urology. 2018;(8):1315-1326
Abstract
PURPOSE Testosterone supplement treatment (TST) is a classic therapy for hypogonadal men with type 2 diabetes mellitus (T2DM), but the effects of TST in different studies are inconsistent. We conducted this meta-analysis to evaluate the precise role of TST in hypogonadal men with T2DM. METHODS PubMed, Embase, Cochrane Library and Web of Science were searched to identify qualified randomized controlled trials (RCTs). Pooled mean differences (MDs) with 95% confidence intervals (CIs) were calculated to measure the specific effects of TST. Trial sequential analysis was performed to verify the pooled results. RESULTS A total of eight RCTs were enrolled in our meta-analysis, including 596 hypogonadal participants with T2DM. Compared with comparators, TST can significantly improve glycemic control by reducing homeostatic model assessment of insulin resistance (MD - 0.79, 95% CI - 1.23 to - 0.34), fasting glucose (MD - 0.98, 95% CI - 1.13 to - 0.54), fasting insulin (MD - 2.47, 95% CI - 3.99 to - 0.95) and HbA1c% (MD - 0.45, 95% CI - 0.73 to - 0.16). In addition, TST can result in a decline in cholesterol (MD - 0.29, 95% CI - 0.38 to - 0.19) and triglyceride (MD - 0.37, 95% CI - 0.59 to - 0.15). CONCLUSION Our results indicated that TST can improve glycemic control and decrease TC and TG in hypogonadal patients with T2DM. We recommend TST during the anti-diabetic therapy in these patients.
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Androgens and the Regulation of Adiposity and Body Fat Distribution in Humans.
Tchernof, A, Brochu, D, Maltais-Payette, I, Mansour, MF, Marchand, GB, Carreau, AM, Kapeluto, J
Comprehensive Physiology. 2018;(4):1253-1290
Abstract
The sexual dimorphism in human body fat distribution suggests a causal role for sex hormones. This is of particular importance when considering the role of excess visceral adipose tissue accumulation as a critical determinant of obesity-related cardiometabolic alterations. Scientific literature on the modulation of body fat distribution by androgens in humans is abundant, remarkably inconsistent and difficult to summarize. We reviewed relevant literature on this topic, with a particular emphasis on androgen replacement, androgen effects on selected parameters of adipose tissue function and adipose tissue steroid-converting enzymes. In men, low androgenic status mostly reflected by reduced total testosterone is a frequent feature of visceral obesity and the metabolic syndrome. Regarding testosterone therapy, however, studies must be appreciated in the context of current controversies on their cardiovascular effects. Analyses of available studies suggest that decreases in waist circumference in response to testosterone are more likely observed in men with low levels of testosterone and high BMI at study onset. In women with androgen excess, higher testosterone and free testosterone levels are fairly consistent predictors of increased abdominal and/or visceral adipose tissue accumulation, which is not the case in nonhyperandrogenic women. Regarding mechanisms, androgens decrease adipogenesis and markers of lipid storage in vitro in men and women. Evidence also suggest that local steroid transformations by adipose tissue steroid-converting enzymes expressed in a depot-specific fashion may play a role in androgen-mediated modulation of body fat distribution. Accumulating evidence shows that androgens are critical modulators of body fat distribution in both men and women. © 2018 American Physiological Society. Compr Physiol 8:1253-1290, 2018.
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Subclinical Hypothyroidism Impact on the Characteristics of Patients with Polycystic Ovary Syndrome. A Meta-Analysis of Observational Studies.
de Medeiros, SF, de Medeiros, MAS, Ormond, CM, Barbosa, JS, Yamamoto, MMW
Gynecologic and obstetric investigation. 2018;(2):105-115
Abstract
BACKGROUND/AIMS: Definitive polycystic ovary syndrome (PCOS) diagnosis should exclude thyroid dysfunctions. The purpose of the study is to examine the impact of subclinical hypothyroidism on the characteristics of PCOS patients. METHODS A meta-analysis of the published observational studies was conducted. Medline, Scopus, and Cochrane database search was performed to identify the studies that compared euthyroid PCOS and subclinical hypothyroidism (SCH)-PCOS patients. A total of 9 studies were selected, totalizing the inclusion of 1,537 euthyroid PCOS and 301 SCH-PCOS. The data were expressed as raw mean difference and standard error, using the random-effects model. Heterogeneity among studies was examined using the Cochran's test (Q) and I2 statistics. RESULTS Anthropometrical parameters were similar in both groups. Total cholesterol (TC) and triglyceride (TG) were higher in SCH-PCOS (p = 0.036 and p = 0.012). High-density lipoprotein cholesterol was lower in the SCH-PCOS group (p = 0.018). Fasting glucose was lower in euthyroid PCOS (p = 0.022). All androgen levels were similar in both group (p > 0.05 for all). CONCLUSION TC, TG and fasting glucose were higher in SCH-PCOS patients. Because of the heterogeneity among studies, some summarized results should be interpreted with caution. Consistent data for future studies addressing PCOS diagnosis are provided.
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Randomized controlled trials - mechanistic studies of testosterone and the cardiovascular system.
Jones, TH, Kelly, DM
Asian journal of andrology. 2018;(2):120-130
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Testosterone deficiency is common in men with cardiovascular disease (CVD), and randomized placebo-controlled trials (RCTs) have reported beneficial effects of testosterone therapy on exercise-induced cardiac ischemia in chronic stable angina, functional exercise capacity, maximum oxygen consumption during exercise (VO2max) and muscle strength in chronic heart failure (CHF), shortening of the Q-T interval, and improvement of some cardiovascular risk factors. Testosterone deficiency is associated with an adverse CV risk profile and mortality. Clinical and scientific studies have provided mechanistic evidence to support and explain the findings of the RCTs. Testosterone is a rapid-onset arterial vasodilator within the coronary circulation and other vascular beds including the pulmonary vasculature and can reduce the overall peripheral systemic vascular resistance. Evidence has demonstrated that testosterone mediates this effect on vascular reactivity through calcium channel blockade (L-calcium channel) and stimulates potassium channel opening by direct nongenomic mechanisms. Testosterone also stimulates repolarization of cardiac myocytes by stimulating the ultra-rapid potassium channel-operated current. Testosterone improves cardiac output, functional exercise capacity, VO2maxand vagally mediated arterial baroreceptor cardiac reflex sensitivity in CHF, and other mechanisms. Independent of the benefit of testosterone on cardiac function, testosterone substitution may also increase skeletal muscle glucose metabolism and enhance muscular strength, both factors that could contribute to the improvement in functional exercise capacity may include improved glucose metabolism and muscle strength. Testosterone improves metabolic CV risk factors including body composition, insulin resistance, and hypercholesterolemia by improving both glucose utilization and lipid metabolism by a combination of genomic and nongenomic actions of glucose uptake and utilization expression of the insulin receptor, glucose transporters, and expression on regulatory enzymes of key metabolic pathways. The effect on high-density lipoprotein-cholesterol (HDL-C) differs between studies in that it has been found to fall, rise, or have no change in levels. Testosterone replacement can suppress the levels of circulating pro-inflammatory cytokines and stimulate the production of interleukin-10 (IL-10) which has anti-inflammatory and anti-atherogenic actions in men with CVD. No effect on C-reactive protein has been detected. No adverse effects on clotting factors have been detected. RCTs have not clearly demonstrated any significant evidence that testosterone improves or adversely affects the surrogate markers of atherosclerosis such as reduction in carotid intima thickness or coronary calcium deposition. Any effect of testosterone on prevention or amelioration of atherosclerosis is likely to occur over years as shown in statin therapy trials and not months as used in testosterone RCTs. The weight of evidence from long-term epidemiological studies supports a protective effect as evidenced by a reduction in major adverse CV events (MACEs) and mortality in studies which have treated men with testosterone deficiency. No RCT where testosterone has been replaced to the normal healthy range has reported a significant benefit or adverse effect on MACE nor has any recent meta-analysis.
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The impact of testosterone replacement therapy on glycemic control, vascular function, and components of the metabolic syndrome in obese hypogonadal men with type 2 diabetes.
Groti, K, Žuran, I, Antonič, B, Foršnarič, L, Pfeifer, M
The aging male : the official journal of the International Society for the Study of the Aging Male. 2018;(3):158-169
Abstract
OBJECTIVE This study set out to assess effects of testosterone replacement therapy (TRT) on parameters of metabolic syndrome and vascular function in obese hypogonadal males with type 2 diabetes mellitus (DM2). STUDY DESIGN Fifty-five obese hypogonadal diabetic males on oral hypoglycemic treatment were enrolled into this one-year, double-blind, randomized, placebo-controlled clinical study. Group T (n = 28) was treated with testosterone undecanoate (1000 mg i.m. every 10 weeks) while group P (n = 27) received placebo. METHODS Anthropometrical and vascular measurements - flow-mediated dilatation (FMD) and intima media thickness (IMT) - biochemical and hormonal blood sample analyses were performed at the start of the study and after one year. Derived parameters (BMI, HOMA-IR, calculated free testosterone (cFT) and bioavailable testosterone (BT)) were calculated. RESULTS TRT resulted in reduction of HOMA-IR by 4.64 ± 4.25 (p < .001), HbA1c by 0.94 ± 0.88% points (p < .001), and an increase in FMD by 2.40 ± 4.16% points (p = .005). CONCLUSION TRT normalized serum testosterone levels, improved glycemic control and endothelial function while exerting no ill effects on the study population.
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The effect of vitamin D supplementation in combination with low-calorie diet on anthropometric indices and androgen hormones in women with polycystic ovary syndrome: a double-blind, randomized, placebo-controlled trial.
Jafari-Sfidvajani, S, Ahangari, R, Hozoori, M, Mozaffari-Khosravi, H, Fallahzadeh, H, Nadjarzadeh, A
Journal of endocrinological investigation. 2018;(5):597-607
Abstract
PURPOSE Polycystic ovary syndrome (PCOS) is known as the most common endocrine disorder in reproductive age women. The aim of this studywas to evaluate the effects of vitamin D supplementation in combination with low-calorie diet on anthropometric indices, reproductive hormones and menstrual regularity in overweight and obese PCOS women. METHODS In this randomized controlled clinical trial, 60 PCOS women with vitamin D insufficiency were randomly assigned to 12 weeks of either (1) weight-loss intervention + 50,000 IU/week oral vitamin D3 or (2) weight-loss intervention + placebo. At the beginning and end of the study, the anthropometric indices, body composition, 25-hydroxyvitamin D, total testosterone, dehydroepiandrosterone sulfate (DHEAS), sex hormone-binding globulin (SHBG) and free androgen index (FAI) were measured and regularity of menses was compared among the two groups. RESULT After 12-week intervention, median of serum 25-hydroxyvitamin D3 significantly increased from 18.5 (10.75-20) ng/ml to 42.69 (34-53.25) ng/ml in vitamin D group compared to placebo group (p < 001). Moreover, there was a significant improvement in frequency regular menstrual cycle (p = 0.01). Mean of weight, body mass index, fat mass, waist and hip circumference and waist-to-hip ratio significantly decreased in both groups, but was not different between two groups. Mean of total testosterone insignificantly decreased from 0.7 to 0.5 ng/ml in vitamin D group (p = 0.18). In addition, we did not observe significant differences regarding DHEAS, FAI and SHBG between two groups. CONCLUSIONS In women with PCOS, androgen profile did not change with vitamin D supplementation when combined with low-calorie diet, but menstrual frequency significantly improved. CLINICAL TRIAL REGISTRATION NUMBER IRCT2016062710826N19.
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Source and amount of carbohydrate in the diet and inflammation in women with polycystic ovary syndrome.
Barrea, L, Marzullo, P, Muscogiuri, G, Di Somma, C, Scacchi, M, Orio, F, Aimaretti, G, Colao, A, Savastano, S
Nutrition research reviews. 2018;(2):291-301
Abstract
High carbohydrate intake and low-grade inflammation cooperate with insulin resistance and hyperandrogenism to constitute an interactive continuum acting on the pathophysiology of polycystic ovary syndrome (PCOS), the most common endocrine disorder in women of reproductive age characterised by oligo-anovulatory infertility and cardiometabolic disorders. The role of insulin in PCOS is pivotal both in regulating the activity of ovarian and liver enzymes, respectively involved in androgen production and in triggering low-grade inflammation usually reported to be associated with an insulin resistance, dyslipidaemia and cardiometabolic diseases. Although an acute hyperglycaemia induced by oral glucose loading may increase inflammation and oxidative stress by generating reactive oxygen species through different mechanisms, the postprandial glucose increment, commonly associated with the Western diet, represents the major contributor of chronic sustained hyperglycaemia and pro-inflammatory state. Together with hyperinsulinaemia, hyperandrogenism and low-grade inflammation, unhealthy diet should be viewed as a key component of the 'deadly quartet' of metabolic risk factors associated with PCOS pathophysiology. The identification of a tight diet-inflammation-health association makes the adoption of healthy nutritional approaches a primary preventive and therapeutic tool in women with PCOS, weakening insulin resistance and eventually promoting improvements of reproductive life and endocrine outcomes. The intriguing nutritional-endocrine connections operating in PCOS underline the role of expert nutritionists in the management of this syndrome. The aim of the present review is to provide an at-a-glance overview of the possible bi-directional mechanisms linking inflammation, androgen excess and carbohydrate intake in women with PCOS.
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Testosterone a key factor in gender related metabolic syndrome.
Bianchi, VE, Locatelli, V
Obesity reviews : an official journal of the International Association for the Study of Obesity. 2018;(4):557-575
Abstract
Metabolic syndrome (MetS) is highly correlated with cardiovascular diseases. Although an excess of body fat is a determinant factor for MetS development, a reduced level of testosterone plays a fundamental role in its regulation. Low testosterone level is highly related to insulin resistance, visceral obesity and MetS. We have searched in Pubmed clinical trial with the password: testosterone and insulin resistance, and testosterone and MetS. We found 19 studies on the correlation between testosterone level with insulin resistance and 18 on the effect of testosterone therapy on MetS. A high correlation between low testosterone and insulin resistance has been found in men, but not in women. Testosterone administration in hypogonadal men improved MetS and reduced the mortality risk. Androgen and oestrogen receptors are expressed in adipocytes, muscle and liver tissue, and their activation is necessary to improve metabolic control. Normalization of testosterone level should be the primary treatment in men, along with caloric restriction and physical exercise. These findings come mainly from correlative data, and there remains a need for randomized trials to strengthen this evidence. This review will consider the effects of testosterone on the regulation and development of MetS in men and women.