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Life Extension Magazine


October 2010

Metabolic syndrome, testosterone deficiency and erectile dysfunction never come alone.

Until a decade ago the ailments of elderly men, such as atherosclerosis, hypertension, diabetes mellitus, lower urinary tract symptoms and erectile dysfunction (ED), were regarded as distinct diagnostic/therapeutic entities but there is a growing awareness that these entities are not disparate and, to improve the health of the ageing male, require an integral approach. There is an inter-dependence between the metabolic syndrome, ED and patterns of testosterone in ageing men. The main features of the metabolic syndrome are abdominal obesity, insulin resistance, hypertension and dyslipidaemia, significant factors in the aetiology of erectile function. The metabolic syndrome is associated with lower-than-normal testosterone levels. A new concept of the role of testosterone in male physiology suggests that testosterone plays also a significant role in the development and maintenance of bone and muscle mass and is a determinant of glucose homeostasis and lipid metabolism. Testosterone is not only a factor in libido but exerts also essential effects on the anatomical and physiological substrate of penile erection. With these recent insights, the health problems of elderly men must be placed in a context that allows an integral approach. Treatment of testosterone deficiency is to become part and parcel of this approach.

Andrologia. 2008 Aug;40(4):259-64

Androgens, insulin resistance and vascular disease in men.

Type 2 diabetes mellitus is increasing globally and is an established risk factor for the development of atherosclerotic vascular disease. Insulin resistance is the hallmark feature of type 2 diabetes and is also an important component of the metabolic syndrome. There is evidence to suggest that testosterone is an important regulator of insulin sensitivity in men. Observational studies have shown that testosterone levels are low in men with diabetes, visceral obesity (which is strongly associated with insulin resistance), coronary artery disease and metabolic syndrome. Short-term interventional studies have also demonstrated that testosterone replacement therapy produces an improvement in insulin sensitivity in men. Thus hypotestosteronaemia may have a role in the pathogenesis of insulin-resistant states and androgen replacement therapy could be a potential treatment that could be offered for improvements in glycaemic control and reduction in cardiovascular risk, particularly in diabetic men.

Clin Endocrinol (Oxf). 2005 Sep;63(3):239-50

Testosterone in obesity, metabolic syndrome and type 2 diabetes.

Testosterone levels are reduced in obesity, the metabolic syndrome and type 2 diabetes. Low testosterone levels are now being recognised as an independent risk factors for these conditions. Findings from men undergoing androgen suppression as treatment for prostate cancer confirm that the hypogonadal state increases body fat mass and serum insulin and there is a high rate of developing new diabetes in this population. Clinical trial data are consistent in showing reductions in body fat mass during testosterone replacement therapy. There are also trials showing improvements in insulin resistance and glycaemic control with testosterone. Most of the trials in this area to date have been of small size and the promising results require confirmation in larger trials, which are underway. In the longer term, large trials should be conducted to assess the potentially beneficial effects of testosterone on cardiovascular risk in this and other patient groups. In the meantime physicians involved in the care of men with diabetes should remain vigilant for the symptoms and signs of hypogonadism. Testosterone replacement therapy should be considered for those men with subsequently confirmed hypogonadism.

Front Horm Res. 2009;37:74-90

Men’s health, low testosterone, and diabetes: individualized treatment and a multidisciplinary approach.

Testosterone plays a critical role in male reproductive and metabolic functioning. Serum testosterone levels decrease with age, and low testosterone is associated with a variety of comorbidities, including insulin resistance, type 2 diabetes, obesity, metabolic syndrome, and cardiovascular disease. Men with type 2 diabetes have been shown to have significantly lower testosterone levels than men without diabetes. Several forms of testosterone replacement therapy (eg, oral, injectable, buccal, transdermal preparations) are available for use in the United States. The primary goals of testosterone therapy are to restore physiologic testosterone levels and reduce the symptoms of hypogonadism. Testosterone therapy may be a viable option in some men with diabetes and low testosterone; however, clinicians must be aware of contraindications to therapy (eg, prostate cancer and male breast cancer), implement appropriate monitoring procedures, and ensure that patient expectations are realistic regarding treatment outcome. Data suggest that testosterone therapy may have a positive effect on bones, muscles, erythropoiesis and anemia, libido, mood and cognition, penile erection, cholesterol, fasting blood glucose, glycated hemoglobin, insulin resistance, visceral adiposity, and quality of life. Sexual health may be a window into men’s health; thus, more effective communication strategies are needed between clinicians and men with diabetes to ensure that sexual health topics are adequately addressed. Diabetes educators can play a key role in screening for low testosterone, providing relevant information to patients, and increasing clinician awareness of the need to address men’s sexual health and implement appropriate strategies. Multidisciplinary care and individualized treatment are needed to optimize outcome.

Diabetes Educ. 2008 Nov-Dec;34 Suppl 5:97S-112S

The role of testosterone in type 2 diabetes and metabolic syndrome in men.

Over the last three decades, it has become apparent that testosterone plays a significant role in glucose homeostasis and lipid metabolism. The metabolic syndrome is a clustering of risk factors predisposing to diabetes mellitus type 2, atherosclerosis and cardiovascular morbidity and mortality. The main components of the syndrome are visceral obesity, insulin resistance, glucose intolerance, raised blood pressure and dyslipidemia (elevated triglycerides, low levels of high-density lipoprotein cholesterol), and a pro-inflammatory and thrombogenic state. Cross-sectional epidemiological studies have reported a direct correlation between plasma testosterone and insulin sensitivity, and low testosterone levels are associated with an increased risk of type 2 diabetes mellitus, dramatically illustrated by androgen deprivation in men with prostate carcinoma. Lower total testosterone and sex hormone-binding globulin (SHBG) predict a higher incidence of the metabolic syndrome. There is evidence that hypotestosteronemia should be an element in the definition of the metabolic syndrome since low levels of testosterone are associated with or predict the development of the metabolic syndrome and of diabetes mellitus. Administration of testosterone to hypogonadal men reverses part of the unfavorable risk profile for the development of diabetes and atherosclerosis. So far, studies on the effects of normalization of testosterone in hypogonadal men on glucose homeostasis are limited, but convincing, and if diabetes mellitus is viewed in the context of the metabolic syndrome, the present results of testosterone treatment are very encouraging.

Arq Bras Endocrinol Metabol. 2009 Nov;53(8):901-7

Lower sex hormone-binding globulin is more strongly associated with metabolic syndrome than lower total testosterone in older men: the Health in Men Study.

BACKGROUND: Reduced circulating testosterone and sex hormone-binding globulin (SHBG) are implicated as risk factors for metabolic syndrome. As SHBG increases with age while testosterone declines, we examined the relative contributions of SHBG and testosterone to the risk of metabolic syndrome in older men. METHODS: We conducted a cross-sectional study of 2,502 community-dwelling men aged > or = 70 years without known diabetes. Metabolic syndrome was defined using the National Cholesterol Education Program-Third Adult Treatment Panel (NCEP-ATPIII) criteria. Early morning fasting sera were assayed for total testosterone, SHBG and LH. Free testosterone was calculated using mass action equations. RESULTS: There were 602 men with metabolic syndrome (24.1%). The risk of metabolic syndrome increased for total testosterone < 20 nmol/l, SHBG < 50 nmol/l and free testosterone < 300 pmol/l. In univariate analyses SHBG was associated with all five components of metabolic syndrome, total testosterone was associated with all except hypertension, and free testosterone was associated only with waist circumference and triglycerides. In multivariate analysis, both total testosterone and especially SHBG remained associated with metabolic syndrome, with odds ratios of 1.34 (95% confidence interval (CI): 1.18-1.52) and 1.77 (95% CI: 1.53-2.06) respectively. Men with hypogonadotrophic hypogonadism (total testosterone < 8 nmol/l, LH < or = 12 IU/l) had the highest prevalence of metabolic syndrome (53%, P<0.001). CONCLUSIONS: Lower SHBG is more strongly associated with metabolic syndrome than lower total testosterone in community-dwelling older men. SHBG may be the primary driver of these relationships, possibly reflecting its relationship with insulin sensitivity. Further studies should examine whether measures that raise SHBG protect against the development of metabolic syndrome in older men.

Eur J Endocrinol. 2008 Jun;158(6):785-92

Hypogonadotrophic hypogonadism in type 2 diabetes, obesity and the metabolic syndrome.

Recent work shows a high prevalence of low testosterone and inappropriately low LH and FSH concentrations in type 2 diabetes. This syndrome of hypogonadotrophic hypogonadism (HH) is associated with obesity, and other features of the metabolic syndrome (obesity and overweight, hypertension and hyperlipidemia) in patients with type 2 diabetes. However, the duration of diabetes or HbA1c were not related to HH. Furthermore, recent data show that HH is also observed frequently in patients with the metabolic syndrome without diabetes but is not associated with type 1 diabetes. Thus, HH appears be related to the two major conditions associated with insulin resistance: type 2 diabetes and the metabolic syndrome. CRP concentrations have been shown to be elevated in patients with HH and are inversely related to plasma testosterone concentrations. This inverse relationship between plasma free testosterone and CRP concentrations in patients with type 2 diabetes suggests that inflammation may play an important role in the pathogenesis of this syndrome. This is of interest since inflammatory mechanisms may have a cardinal role in the pathogenesis of insulin resistance. It is relevant that in the mouse, deletion of the insulin receptor in neurons leads to HH in addition to a state of systemic insulin resistance. It has also been shown that insulin facilitates the secretion of gonadotrophin releasing hormone (GnRH) from neuronal cell cultures. Thus, HH may be the result of insulin resistance at the level of the GnRH secreting neuron. Low testosterone concentrations in type 2 diabetic men have also been related to a significantly lower hematocrit and thus to an increased frequency of mild anemia. Low testosterone concentrations are also related to an increase in total and regional adiposity, and to lower bone density. This review discusses these issues and attempts to make the syndrome relevant as a clinical entity. Clinical trials are required to determine whether testosterone replacement alleviates symptoms related to sexual dysfunction, and features of the metabolic syndrome, insulin resistance and inflammation.

Curr Mol Med. 2008 Dec;8(8):816-28

The dark side of testosterone deficiency: III. Cardiovascular disease.

A considerable body of evidence exists suggesting that androgen deficiency contributes to the onset, progression, or both of cardiovascular disease (CVD). The aim of this review is to evaluate the relationships between testosterone (T) deficiency and risk factors of CVD and to discuss the implications of androgen deficiency in men with cardiovascular risk factors. The relationship between androgen deficiency and endothelial function, lipid profiles, inflammatory responses, altered vascular smooth muscle reactivity, and hypertension are discussed with regard to CVD. A comprehensive literature search was carried out with the use of Pub Med from 1980 through 2009, and relevant articles pertinent to androgen deficiency and vascular disease were evaluated and discussed. Low T, whether attributed to hypogonadism or androgen deprivation therapy, in men with prostate carcinoma, produces adverse effects on cardiovascular health. Androgen deficiency is associated with increased levels of total cholesterol, low-density lipoprotein, increased production of proinflammatory factors, and increased thickness of the arterial wall and contributes to endothelial dysfunction. Testosterone supplementation restores arterial vasoreactivity; reduces proinflammatory cytokines, total cholesterol, and triglyceride levels; and improves endothelial function but also might reduce high-density lipoprotein levels. Testosterone is an anabolic hormone with a wide range of beneficial effects on men’s health. The therapeutic role of T in men’s health, however, remains a hotly debated issue for a number of reasons, including the purported risk of prostate cancer. In view of the emerging evidence suggesting that androgen deficiency is a risk factor for CVD, androgen replacement therapy could potentially reduce CVD risk in hypogonadal men. It should be emphasized, however, that androgen replacement therapy should be done with very thorough and careful monitoring for prostate diseases.

J Androl. 2009 Sep-Oct;30(5):477-94

The relationship between androgens concentrations (testosterone and dehydroepiandrosterone sulfate) and metabolic syndrome in non-obese elderly men.

INTRODUCTION: The metabolic syndrome characterized by central obesity, insulin and lipid dysregulation, and hypertension, is a precursor state for atherosclerotic process and, in consequence, cardiovascular disease. Decline of both testicular and adrenal function with aging causes a decrease in androgen concentration in men. It has been postulated that low levels of total testosterone and dehydroepiandrosterone sulfate (DHEA-S) are associated with unfavorable levels of several strong cardiovascular disease risk factors, such as lipids and blood pleasure, which are components of the metabolic syndrome, and insulin levels. Both testosterone and DHEA-S deficiency are risk factors of obesity and insulin resistance, but it is not clear, whether this possible influence is independent. The aim of this study was to determined whether lower androgens (testosterone and DHEA-S) levels are associated with the development of metabolic syndrome in non-obese elderly men as well as analysis, whether these sex hormones influents on measured parameters separately. MATERIAL AND METHODS: Together 85 men age from 60 to 70 years (mean 66.3 +/- 1.5 years; mean +/- SEM) were analyzed. Testosterone levels < 4 ng/ml or DHEA levels < 2000 ng/ml and BMI < 30 kg/m(2) were including criteria. Patients were divided into three groups: 52 with testosterone deficiency (L-T), 32 with DHEA deficiency (L-DHEA-S) and 67 with deficiency of both sex hormones (L-T/DHEA-S). The influence of sex hormones deficiency in these groups on blood pressure, lipids, visceral obesity and fasting glucose were measured (according to metabolic syndrome definition NCEP III/IDF). RESULTS: Testosterone levels in L-T, L-DHEA and L-T/DHEA-S groups were respectively 3.19 +/- 0.23 ng/ml, 4.89 +/- 0.45 ng/ml and 3.25 +/- 0.34 g/ml (p < 0.002). While DHEA-S levels were respectively 2498 +/- 98 ng/ml, 1435 +/- 1010 ng/ml and 1501 +/- +/- 89 ng/ml). BMI values do not differ between groups. Waist circumference was significantly higher in L-T/DHEA-S group than in L-T i L-DHEA-S groups (respectively: 99.9 +/- 6,1 cm, 97.1 +/- 7.1 cm i 96.2 +/- 6.4 cm; mean +/- SD, p < 0.05 vs. L-T and L-DHEA-S groups). Mean triglycerides concentration in L-T/DHEA-S group was significantly higher than in L-T and L-DHEA-S groups (respectively: 188.2 +/- 13.3 mg/dl, 161.7 +/- 14.7 mg/dl and 152.2 +/- 12.8 mg/dl (mean +/- SD; p < 0.02 vs. L-T and L-DHEA-S groups). Analysis of prevalence of risk factors showed, that in L-T/DHEA-S group they were more frequent than in other groups. The most significant percentage difference was observed for triglycerides: concentration > or = 150 mg/dl was measured in 31% men in L-T group, 28% men in L-DHEA-S group and 42% men in L-T/DHEA-S group. According metabolic syndrome definition NCEP III/IDF prevalence of this syndrome was: 71% patients in L-T/DHEA-S group, 67% patients in L-T group and 64% patients in L-DHEA-S group. CONCLUSIONS: The DHEA-S and testosterone deficiency was a significant and independent risk factor of the metabolic syndrome in non-obese elderly men. It seems, that triglycerides concentration and waist circumference are more sensitive then others parameters to reflect the influence of sex hormones deficiency on risk of the metabolic syndrome in elderly men.

Endokrynol Pol. 2007 Nov-Dec;58(6):496-504

Changes in sex hormone-binding globulin and testosterone during weight loss and weight maintenance in abdominally obese men with the metabolic syndrome.

BACKGROUND: Mild hypoandrogenism in men, usually defined by low levels of testosterone, is a peculiar feature of abdominal obesity that independently predicts the development of insulin resistance and diabetes mellitus. Little is known about the short- and long-term effects of weight loss on sex steroids in abdominally obese men, however. OBJECTIVES: We assessed the effect of rapid weight loss and sustained weight maintenance on the plasma concentrations of testosterone and other sex hormones in 58 abdominally obese men (age, 46.3 +/- 7.5 years; body mass index, 36.1 +/- 3.8 kg/m(2); waist girth, 121 +/- 10 cm) with the metabolic syndrome. RESULTS: The men lost on average 16.3 +/- 4.5 kg during a 9-week very low-calorie diet (VLCD) and maintained 14.3 +/- 9.1 kg weight loss after a 12-month maintenance period (vs. baseline, p < 0.001). Sex hormone-binding globulin (SHBG) increased from 27.6 +/- 11.9 to 48.1 +/- 23.5 nmol/l during the VLCD but decreased to 32.6 +/- 12.9 nmol/l during weight maintenance, which was still higher than at baseline (p < 0.001). Free testosterone (fT) increased from 185 +/- 66 to 208 +/- 70 pmol/l (p = 0.002) during the VLCD and remained high after 1 year of weight maintenance (212 +/- 84 pmol/l, p = 0.002). Total testosterone levels followed a pattern intermediate between fT and SHBG. Plasma estradiol and dehydroepiandrosterone sulphate concentrations changed only transiently or not at all. CONCLUSIONS: Rapid weight loss with successful weight maintenance in abdominally obese men with the metabolic syndrome brings about a sustained increase in fT levels. The dramatic increase in SHBG attenuated initially during weight maintenance but remained elevated. These findings may be important with regard to prevention of progressive metabolic decompensation and cardiovascular disease associated with obesity and the metabolic syndrome.

Diabetes Obes Metab. 2004 May;6(3):208-15