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Sex Hormones journal articles on benefits

 

Current Urology Reports  http://www.springerlink.com/content/511756m02x4n133m/  

Volume 8, Number 6 (2007), 467-471, DOI: 10.1007/s11934-007-0050-4

Testosterone, diabetes mellitus, and the metabolic syndrome

Abstract

Metabolic syndrome is characterized by insulin insensitivity, central obesity dyslipidemia, and hypertension. It is recognized as a risk factor for cardiovascular disease in men; by the time metabolic syndrome is diagnosed, however, most men already have entrenched cardiovascular disease. A reliable early warning sign is needed to alert physicians to those at risk for metabolic syndrome and cardiovascular disease. Low serum testosterone level has emerged as a reliable prognosticator of metabolic syndrome in men whose testosterone deficiency is genetic (Klinefelter syndrome), iatrogenic following surgery for testicular cancer, pharmacologically induced by gonadotropin-releasing hormone during prostate cancer treatment, or a natural consequence of aging. One third of men with type 2 diabetes mellitus are now recognized as testosterone deficient. Emerging evidence suggests that testosterone therapy may be able to reverse some aspects of metabolic syndrome.

Fulltext at http://resources.metapress.com/pdf-preview.axd?code=511756m02x4n133m&size=largest

“In on pivotal 2005 study, Laakxonen et at measured hormone levels in 702 Finnish men without evidence of diabetes or MetS at baseline and after 11 years of regular follow-up.  Of the original cohort, 57 men had diabetes and 127 with the lowest serum testosterone levels developed on or more MetS manifestations….  [Another study found] higher levels of serum testosterone and sex hormone-binding globulin (SHBG) in these middle-aged and aging men conferred a protective benefit against METS development….a finding that was surprisingly independent of baseline insulin level, body weight, and body fat.”

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http://care.diabetesjournals.org/content/27/5/1036.short

American Diabetes Association, Diabetes Care

doi: 10.2337/diacare.27.5.1036 Diabetes Care May 2004 vol. 27 no. 5 1036-1041

Testosterone and Sex Hormone–Binding Globulin Predict the Metabolic Syndrome and Diabetes in Middle-Aged Men

Abstract

OBJECTIVE—In men, hypoandrogenism is associated with features of the metabolic syndrome, but the role of sex hormones in the pathogenesis of the metabolic syndrome and diabetes is not well understood. We assessed the association of low levels of testosterone and sex hormone–binding globulin (SHBG) with the development of the metabolic syndrome and diabetes in men.

RESEARCH DESIGN AND METHODS—Concentrations of SHBG and total and calculated free testosterone and factors related to insulin resistance were determined at baseline in 702 middle-aged Finnish men participating in a population-based cohort study. These men had neither diabetes nor the metabolic syndrome.

RESULTS—After 11 years of follow-up, 147 men had developed the metabolic syndrome (National Cholesterol Education Program criteria) and 57 men diabetes. Men with total testosterone, calculated free testosterone, and SHBG levels in the lower fourth had a severalfold increased risk of developing the metabolic syndrome (odds ratio [OR] 2.3, 95% CI 1.5–3.4; 1.7, 1.2–2.5; and 2.8, 1.9–4.1, respectively) and diabetes (2.3, 1.3–4.1; 1.7, 0.9–3.0; and 4.3, 2.4–7.7, respectively) after adjustment for age. Adjustment for potential confounders such as cardiovascular disease, smoking, alcohol intake, and socioeconomic status did not alter the associations. Factors related to insulin resistance attenuated the associations, but they remained significant, except for free testosterone.

CONCLUSIONSLow total testosterone and SHBG levels independently predict development of the metabolic syndrome and diabetes in middle-aged men. Thus, hypoandrogenism is an early marker for disturbances in insulin and glucose metabolism that may progress to the metabolic syndrome or frank diabetes and may contribute to their pathogenesis.

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This subject is thinly researched with a lack of appropriate population studies. However based on animal studies and 1 trial, there is a positive effects of estrogen in the brain. 

The Journal of Clinical Endrocrinology & Metabolism   Doi: 10.1210/jc.82.2.638 February 1, 1997 vol. 82 no. 2 638-643

http://jcem.endojournals.org/content/82/2/638.short

 

Estrogen Replacement Therapy Decreases Hyperandrogenicity and Improves Glucose Homeostasis and Plasma Lipids in Postmenopausal Women With Noninsulin-Dependent Diabetes Mellitus1

 

Abstract

Hyperandrogenicity in women is closely associated with insulin resistance and a risk factor for cardiovascular disease and noninsulin-dependent diabetes mellitus (NIDDM). Therefore, 25 postmenopausal women with NIDDM and sex hormone-binding globulin values less than 60 nmol/L, as an indicator of a moderate hyperandrogenicity, were treated with 2 mg 17-β-estradiol orally for 3 months in a double-blind, cross-over, placebo-controlled trial. During the last 16 days of active treatment, 1 mg norethisterone acetate was added for 10 days for endometrial protection.

Blood glucose, glycosylated hemoglobin, insulin, c-peptide, lipoprotein profile, sex steroid hormones, GH, and insulin-like growth factor I (IGF-I) were measured, and insulin sensitivity was determined by the euglycemic hyperinsulinemic clamp method. All metabolic measurements were taken at baseline and after 68 days of active or placebo treatment.

Estradiol treatment, compared with the placebo period, was followed by a marked increase of sex hormone-binding globulin and a decrease of free testosterone. Blood glucose, glycosylated hemoglobin, c-peptide, total cholesterol, low-density lipoprotein cholesterol, and IGF-1 decreased significantly (P < 0.01–P < 0.001), whereas high-density lipoprotein cholesterol rose (P < 0.001).

In conclusion, estrogen replacement therapy in postmenopausal women with NIDDM ameliorated hyperandrogenicity, and this was accompanied by marked improvements in glucose homeostasis and lipoprotein profile.

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Low testosterone was associated with 2.3 higher rate of mortality.  This was a low dose, as is currently marketed.  Unfortunately the level of the treated with testosterone group is no given here.  In the full text, 60 patients received TRT (testosterone replacement therapy) for one year, and 51 for more than 2 years.  Thus those treated few received treatment for the duration of the study.  If so there would surely had been an even greater divergence between the tow groups.

http://www.eje-online.org/content/169/6/725.abstract    EJE-13-0321v1, 159/6/725  

2013 European Society of Endocrinology, Made available on line 9/2/13

Testosterone deficiency is associated with increased risk of mortality and testosterone replacement improves survival in men with type 2 diabetes

Abstract

Objective Men with type 2 diabetes are known to have a high prevalence of testosterone deficiency. No long-term data are available regarding testosterone and mortality in men with type 2 diabetes or any effect of testosterone replacement therapy (TRT). We report a 6-year follow-up study to examine the effect of baseline testosterone and TRT on all-cause mortality in men with type 2 diabetes and low testosterone.

Research design and methods A total of 581 men with type 2 diabetes who had testosterone levels performed between 2002 and 2005 were followed up for a mean period of 5.81.3 S.D. years. Mortality rates were compared between total testosterone >10.4 nmol/l (300 ng/dl; n=343) and testosterone ≤10.4 nmol/l (n=238). The effect of TRT (as per normal clinical practise: 85.9% testosterone gel and 14.1% intramuscular testosterone undecanoate) was assessed retrospectively within the low testosterone group.

Results Mortality was increased in the low testosterone group (17.2%) compared with the normal testosterone group (9%; P=0.003) when controlled for covariates. In the Cox regression model, multivariate-adjusted hazard ratio (HR) for decreased survival was 2.02 (P=0.009, 95% CI 1.2–3.4). TRT (mean duration 41.620.7 months; n=64) was associated with a reduced mortality of 8.4% compared with 19.2% (P=0.002) in the untreated group (n=174). The multivariate-adjusted HR for decreased survival in the untreated group was 2.3 (95% CI 1.3–3.9, P=0.004).

Conclusions Low testosterone levels predict an increase in all-cause mortality during long-term follow-up. Testosterone replacement may improve survival in hypogonadal men with type 2 diabetes.

 

From Full text at http://www.eje-online.org/content/169/6/725.full

Several longitudinal population studies have reported that a low testosterone at baseline is associated with an increase in all-cause mortality (1). Some individual studies have specifically identified increases in cardiovascular, respiratory and cancer deaths (2, 3, 4).   A meta-analysis of published research papers with a mean follow-up period of 9.7 years confirmed that low testosterone was associated with increased risk of all-cause and cardiovascular mortality in community based studies.  Men with specific co-morbidities such as proven coronary artery disease and renal failure have also found that low testosterone predicts an increased risk of earlier death than those with the same condition and are testosterone replete. There is a high prevalence of low serum testosterone levels and clinical hypogonadism in men with type 2 diabetes.   The major cause of death in men with type 2 diabetes is cardiovascular disease (CVD). Low testosterone has in several studies been linked with CVD (12). There is also evidence which has shown that the degree of atherosclerosis as assessed by the degree of carotid intimal media thickness (CIMT) is inversely associated with testosterone levels (13, 14, 15). One study found that a low testosterone status was associated with greater progression of atherosclerosis as assessed by CIMT over a 4-year follow-up period (14). Furthermore, low testosterone is associated with a pro-inflammatory milieu and testosterone replacement suppresses circulating cytokines (16, 17).  Our previous study found a high prevalence of symptomatic hypogonadism in men with type 2 diabetes; 17% had TT <8nmol/l whereas a further 25% had testosterone levels between 8 and 12nmol/l . 

Interventional trials have reported that testosterone replacement improves insulin resistance, glycaemic control, visceral obesity and lipid profile in the short term (18, 19, 20, 21, 22, 23). A large multi-centre, randomised, double-blind, placebo-controlled study was recently undertaken in eight European countries, the TIMES2 study, which showed that testosterone replacement therapy (TRT) improves certain cardiovascular risk factors which included insulin resistance, cholesterol, lipoprotein(a), body fat composition and sexual function in men with type 2 diabetes and/or the metabolic syndrome (21). 

Results

The mean TT level was 15.74.5nmol/l in the normal testosterone group as compared with 7.52nmol/l in the low testosterone group (P≤0.001). The weight (102.121.4 (low testosterone) vs 95.218.5kg (normal testosterone),P<0.001) and BMI (33.66.1 vs 31.25.3kg/m2, P<0.001) were higher in the low testosterone group and they were more likely to have poorer diabetes control than the normal testosterone group (HbA1c, 7.51.3 vs 7.21.4;P=0.002). Both groups were matched for age, smoking status, pre-existing CVD, statin and ACE inhibitors or ARB therapy.  [See table 1 for HbA1c, age, statin use etc. at http://www.eje-online.org/content/169/6/725/T1.expansion.html ]. 

Effect of TRT

Of the 238 men with low testosterone, 64 patients (27%) received TRT and 174 did not. Mean duration of TRT was 41.620.7 (S.D.) months. A total of 60 patients received TRT for 12 months or more and 51 had treatment for 2 years or more. [This entails that the results significantly under report the benefit of TTT—jk]. 

Discussion

It is important to note that all patients treated with testosterone had careful adjustment of testosterone to achieve levels within the mid to upper normal range for healthy men. [This is contradicted by the line above which states that 60 patients received TRT for 1 year, not the duration of the study.  It is unlikely that their level would remain high, since other studies have shown a return to an even lower level after discontinuation of treatment.  Also troubling is the lack in this article of the testosterone level for both groups at end of study.—jk]

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http://diabetes.diabetesjournals.org/content/62/2/411.full.pdf+html

http://diabetes.diabetesjournals.org/content/62/2/411.abstract

Neuronal Androgen Receptor Regulates Insulin Sensitivity via Suppression of Hypothalamic NF-κB–Mediated PTP1B Expression

 

Abstract

Clinical investigations highlight the increased incidence of metabolic syndrome in prostate cancer (PCa) patients receiving androgen deprivation therapy (ADT). Studies using global androgen receptor (AR) knockout mice demonstrate that AR deficiency results in the development of insulin resistance in males. However, mechanisms by which AR in individual organs coordinately regulates insulin sensitivity remain unexplored. Here we tested the hypothesis that functional AR in the brain contributes to whole-body insulin sensitivity regulation and to the metabolic abnormalities developed in AR-deficient male mice. The mouse model selectively lacking AR in the central nervous system and AR-expressing GT1-7 neuronal cells were established and used to delineate molecular mechanisms in insulin signaling modulated by AR. Neuronal AR deficiency leads to reduced insulin sensitivity in middle-aged mice. Neuronal AR regulates hypothalamic insulin signaling by repressing nuclear factor-κB (NF-κB)–mediated induction of protein-tyrosine phosphatase 1B (PTP1B). Hypothalamic insulin resistance leads to hepatic insulin resistance, lipid accumulation, and visceral obesity. The functional deficiency of AR in the hypothalamus leads to male mice being more susceptible to the effects of high-fat diet consumption on PTP1B expression and NF-κB activation. These findings suggest that in men with PCa undergoing ADT, reduction of AR function in the brain may contribute to insulin resistance and visceral obesity. Pharmacotherapies targeting neuronal AR and NF-κB may be developed to combat the metabolic syndrome in men receiving ADT and in elderly men with age-associated hypogonadism.


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