Testosterone, Diabetes, Metabolic Syndrome

Recent research in the International Journal of Impotence Research say testosterone may have a protective role in the development of metabolic syndrome and subsequent diabetes mellitus and cardiovascular disease in aging men. However, clinical trials are needed to confirm this assumption.

Svartberg J.Epidemiology: testosterone and the metabolic syndrome.Int J Impot Res. 2007 Mar-Apr;19(2):124-8.

Low levels of testosterone, hypogonadism, have several common features with the metabolic syndrome. In the Tromso Study, a population-based health survey, testosterone levels were inversely associated with anthropometrical measurements, and the lowest levels of total and free testosterone were found in men with the most pronounced central obesity.

Total testosterone was inversely associated with systolic blood pressure, and men with hypertension had lower levels of both total and free testosterone.

Furthermore, men with diabetes had lower testosterone levels compared to men without a history of diabetes, and an inverse association between testosterone levels and glycosylated hemoglobin was found. Thus, there are strong associations between low levels of testosterone and the different components of the metabolic syndrome. In addition, an independent association between low testosterone levels and the metabolic syndrome itself has recently been presented in both cross-sectional and prospective population-based studies. Thus, testosterone may have a protective role in the development of metabolic syndrome and subsequent diabetes mellitus and cardiovascular disease in aging men. However, clinical trials are needed to confirm this assumption.

Insulin Sensitivity and Men with Heart Failure

Researchers writing in the European Journal of Heart Failure say “Testosterone improves fasting insulin sensitivity in men with chronic heart failure and may also increase lean body mass, these data suggest a favourable effect of testosterone on an important metabolic component of chronic heart failure”

Malkin CJ, Jones TH, Channer KS. The effect of testosterone on insulin sensitivity in men with heart failure.European Journal of Heart Failure 2007 Jan;9(1):44-50.
Resistance to insulin occurs in chronic heart failure (CHF) and is related to prognosis.

Studies of testosterone in non-(CHF) males suggest that physiological testosterone therapy improves insulin sensitivity.

This was a single-blind placebo controlled crossover trial to determine the effect of testosterone replacement on insulin sensitivity in 13 men with moderate to severe CHF (ejection fraction 30.5+/-1.3). The primary outcome was the homeostatic model index (HOMA-IR) of fasting insulin sensitivity and secondary outcomes were body composition as measured by bioelectrical impedance and glucose tolerance to a standard 75 g oral glucose load. Analysis was performed on the delta values with the treatment effect of placebo compared with that of testosterone. At baseline HOMA-IR correlated with measures of body fat [% fat mass (rP=0.84, p=0.0001) and body mass index (rP=0.79, p=0.01)] but not with CHF severity.

Testosterone reduced HOMA-IR (-1.9+/-0.8, p=0.03) indicating improved fasting insulin sensitivity. Testosterone also increased total mass (+1.5+/-0.5 kg, p=0.008) and decreased body fat (-0.8+/-0.3%, p=0.02).

Testosterone improves fasting insulin sensitivity in men with CHF and may also increase lean body mass, these data suggest a favourable effect of testosterone on an important metabolic component of CHF.

Testosterone and the Aging Male

A published report in the medical journal Aging Male says “The wide-ranging benefits of testosterone therapy in young and old men are clear and it appears that the route of administration (intramuscular, oral, or transdermal) does not alter this fact, but future work could illustrate even more profound effects of testosterone (e.g., in reducing cardiovascular risk) that could result in its recommended use in a wider range of patients.”

Abstratct:

Kohn FM. Testosterone and body functions. Aging Male. 2006 Dec;9(4):183-8

Testosterone supplementation can help reduce many of the symptoms associated with androgen deficiency in the aging male by its effects on various parts of the body.

Bone mineral density can decrease in the hypogonadal man and this may contribute to the increased fracture rate in the elderly. Testosterone therapy can improve bone mineral density and bone architecture by increasing bone formation and decreasing bone resorption – the possible benefits on fracture rate are unknown.

Testosterone also improves body composition by reducing body fat mass and increasing lean body mass, and by increasing epidermal thickness, but its effects on muscle strength are still debated.

In patients with diabetes and androgen deficiency, testosterone supplementation appears to reduce blood glucose and this could have important implications for cardiovascular risk reduction in patients with diabetes or the metabolic syndrome.

The wide-ranging benefits of testosterone therapy in young and old men are clear and it appears that the route of administration (intramuscular, oral, or transdermal) does not alter this fact, but future work could illustrate even more profound effects of testosterone (e.g., in reducing cardiovascular risk) that could result in its recommended use in a wider range of patients.

Testosterone and Muscle Strength in the Elderly

Researchers writing in the Journal of the American Geriatric Society suggest that testosterone/DHT therapy may produce a moderate increase in muscle strength in men age 65 and over.

Ottenbacher KJ, Ottenbacher ME, Ottenbacher AJ, Acha AA, Ostir GV. Androgen treatment and muscle strength in elderly men: A meta-analysis. J Am Geriatr Soc. 2006 Nov;54(11):1666-73

The researchers reviewed published, randomized trials examining the effect of androgen treatment (Testosterone or dihydrotestosterone (DHT)) on muscle strength in older men age 65 and over.

What they found was: “larger effects for measures of lower extremity muscle strength than for upper extremity muscle strength” and “injected than topical or oral administration of testosterone/DHT.”

Testosterone and Cognitive Function

A study in the European Journal of Endocrinology says “Low endogenous levels of testosterone may be related to reduced cognitive ability, and testosterone substitution may improve some aspects of cognitive ability.”

Beauchet O. Testosterone and cognitive function: current clinical evidence of a relationship. Beauchet O. Eur J Endocrinol. 2006 Dec;155(6):773-81.

BACKGROUND: Testosterone levels decline as men age, as does cognitive function. Whether there is more than a temporal relationship between testosterone and cognitive function is unclear. Chemical castration studies in men with prostate cancer suggest that low serum testosterone may be associated with cognitive dysfunction. Low testosterone levels have also been observed in patients with Alzheimer’s disease (AD) and mild cognitive impairment (MCI). This paper reviews the current clinical evidence of the relationship between serum testosterone levels and cognitive function in older men.

METHODS: A systematic literature search was conducted using PubMed and EMBASE to identify clinical studies and relevant reviews that evaluated cognitive function and endogenous testosterone levels or the effects of testosterone substitution in older men.

RESULTS: Low levels of endogenous testosterone in healthy older men may be associated with poor performance on at least some cognitive tests. The results of randomized, placebo-controlled studies have been mixed, but generally indicate that testosterone substitution may have moderate positive effects on selective cognitive domains (e.g. spatial ability) in older men with and without hypogonadism. Similar results have been found in studies in patients with existing AD or MCI.

CONCLUSIONS: Low endogenous levels of testosterone may be related to reduced cognitive ability, and testosterone substitution may improve some aspects of cognitive ability. Measurement of serum testosterone should be considered in older men with cognitive dysfunction. For men with both cognitive impairment and low testosterone, testosterone substitution may be considered. Large, long-term studies evaluating the effects of testosterone substitution on cognitive function in older men are warranted.

Testosterone and Prostate

Research published in the Journal of Steroid Biochemistry and Molecular Biology says “Data from all published prospective studies on circulating level of total and free testosterone do not support the hypothesis that high levels of circulating androgens are associated with an increased risk of prostate cancer.”

Raynaud JP. Prostate cancer risk in testosterone-treated men.
J Steroid Biochem Mol Biol. 2006 Dec;102(1-5):261-6.

Men with classical androgen deficiency have reduced prostate volume and blood prostate-specific antigen (PSA) levels compared with their age peers. As it is plausible that androgen deficiency partially protects against prostate disease, and that restoring androgen exposure increases risk to that of eugonadal men of the same age, men using ART should have age-appropriate surveillance for prostate disease. This should comprise rectal examination and blood PSA measurement at regular intervals (determined by age and family history) according to the recommendations, permanently revisited, published by ISSAM, EAU, Endocrine Society….

Testosterone replacement therapy is now being prescribed more often for aging men, the same population in which prostate cancer incidence increases; it has been suggested that administration in men with unrecognised prostate cancer might promote the development of clinically significant disease.

In hypogonadal men who were candidates for testosterone therapy, a 14% incidence of occult cancer was found. A percentage (15.2%) of prostate cancer has been found in the placebo group (with normal DRE and PSA) in the prostate cancer prevention study investigating the chemoprevention potential of finasteride.

The hypothesis that high levels of circulating androgens is a risk factor for prostate cancer is supported by the dramatic regression, after castration, of tumour symptoms in men with advanced prostate cancer. However these effects, seen at a very late stage of cancer development, may not be relevant to reflect the effects of variations within a physiological range at an earlier stage. Data from all published prospective studies on circulating level of total and free testosterone do not support the hypothesis that high levels of circulating androgens are associated with an increased risk of prostate cancer.

A study on a large prospective cohort of 10,049 men, contributes to the gathering evidence that the long standing “androgen hypothesis” of increasing risk with increasing androgen levels can be rejected, suggesting instead that high levels within the reference range of androgens, estrogens and adrenal androgens decrease aggressive prostate cancer risk.

Indeed, high-grade prostate cancer has been associated with low plasma level of testosterone.

Furthermore, pre-treatment total testosterone was an independent predictor of extraprostatic disease in patients with localized prostate cancer; as testosterone decreases, patients have an increased likelihood of non-organ confined disease and low serum testosterone levels are associated with positive surgical margins in radical retropubic prostatectomy. A clinical implication of these results concerns androgen supplementation which has become easier to administer with the advent of transdermal preparations (patch or gel) that achieve physiological testosterone serum levels without supra physiological escape levels.

During the clinical development of a new testosterone patch in more than 200 primary or secondary hypogonadal patients, no prostate cancer was diagnosed.

Subclinical Hypothyroidism and Testosterone Deficiency

Researchers writing in the International Journal of Andrology say that there is “a direct association between subclinical hypothyroidism and hypoandrogenaemia. Testosterone deficiency and its symptoms should be kept in view while managing subclinical hypothyroidism in male patients.”

Kumar A, Chaturvedi PK, Mohanty BP. Hypoandrogenaemia is associated with subclinical hypothyroidism in men. Int J Androl. 2006 Jul 24

From the article abstract:
“Hypothyroidism has been shown to be associated with a reduction in serum testosterone level in males. This reduction in testosterone is reversible by thyroxine replacement therapy. However, to the best of our knowledge, it is not yet known, whether a similar reduction in serum testosterone level is observed in subclinically hypothyroid males [thyroid-stimulating hormone (TSH) < 10 mIU/L] in whom the benefits of thyroxine replacement therapy are still controversial.

Our goal was to investigate the putative connections between subclinical hypothyroidism and the circulating levels of gonadotrophins and gonadal steroids in males (ranging from 20 to 54 years).

The serum samples from patients showing normal euthyroid and subclinical hypothyroid profiles (TSH < 10 mIU/L) were further analysed for the levels of luteinizing hormone, follicle-stimulating hormone, prolactin, testosterone, sex hormone-binding globulin, progesterone and oestradiol.

Subclinical hypothyroidism was associated with a decrease in the levels of serum testosterone and its precursor progesterone. The data suggest that serum testosterone declines because of the non-availability of its precursor progesterone.

The level of oestradiol was similar in both the groups, suggesting a greater conversion rate of testosterone to oestradiol in subclinically hypothyroid males, in order to maintain the oestradiol levels.

Prolactin levels were slightly but significantly increased in subclinical hypothyroidism. To the best of our information this is a novel report, which shows a direct association between subclinical hypothyroidism and hypoandrogenaemia. Testosterone deficiency and its symptoms should be kept in view while managing subclinical hypothyroidism in male patients. Further studies are needed in order to reveal the physiological and molecular mechanisms leading to hypoandrogenaemia in subclinical hypothyroidism (TSH < 10 mIU/L).

Low Testosterone Levels and Mortality

Researchers writing in the Annals of Internal Medicine examined “whether low testosterone levels are a risk factor for mortality in male veterans.”

Shores MM, Matsumoto AM, Sloan KL, Kivlahan DR. Low serum testosterone and mortality in male veterans.
Arch Intern Med. 2006 Aug 14-28;166(15):1660-5.

BACKGROUND: Low serum testosterone is a common condition in aging associated with decreased muscle mass and insulin resistance. This study evaluated whether low testosterone levels are a risk factor for mortality in male veterans.

METHODS: We used a clinical database to identify men older than 40 years with repeated testosterone levels obtained from October 1, 1994, to December 31, 1999, and without diagnosed prostate cancer. A low testosterone level was a total testosterone level of less than 250 ng/dL (<8.7 nmol/L) or a free testosterone level of less than 0.75 ng/dL (<0.03 nmol/L). Men were classified as having a low testosterone level (166 [19.3%]), an equivocal testosterone level (equal number of low and normal levels) (240 [28.0%]), or a normal testosterone level (452 [52.7%]). The risk for all-cause mortality was estimated using Cox proportional hazards regression models, adjusting for demographic and clinical covariates over a follow-up of up to 8 years. RESULTS: Mortality in men with normal testosterone levels was 20.1% (95% confidence interval [CI], 16.2%-24.1%) vs 24.6% (95% CI, 19.2%-30.0%) in men with equivocal testosterone levels and 34.9% (95% CI, 28.5%-41.4%) in men with low testosterone levels. After adjusting for age, medical morbidity, and other clinical covariates, low testosterone levels continued to be associated with increased mortality (hazard ratio, 1.88; 95% CI, 1.34-2.63; P<.001) while equivocal testosterone levels were not significantly different from normal testosterone levels (hazard ratio, 1.38; 95% CI, 0.99%-1.92%; P=.06). In a sensitivity analysis, men who died within the first year (50 [5.8%]) were excluded to minimize the effect of acute illness, and low testosterone levels continued to be associated with elevated mortality.

CONCLUSIONS: Low testosterone levels were associated with increased mortality in male veterans. Further prospective studies are needed to examine the association between low testosterone levels and mortality.

Low Testosterone Levels are Associated with Coronary Artery Disease

Researchers say that low testosterone levels are associated with coronary artery disease in male patients with angina.
Rosano GM, Sheiban I, Massaro R, Pagnotta P, Marazzi G, Vitale C, Mercuro G, Volterrani M, Aversa A, Fini M. Low testosterone levels are associated with coronary artery disease in male patients with angina.Int J Impot Res. 2006 Aug 31

From the study abstract
Historically, high androgen levels have been linked with an increased risk for coronary artery disease (CAD.) However, more recent data suggest that low androgen levels are associated with adverse cardiovascular risk factors, including an atherogenic lipid profile, obesity and insulin resistance.

The aim of the present study was to evaluate the relationship between plasma sex hormone levels and presence and degree of CAD in patients undergoing coronary angiography and in matched controls.

We evaluated 129 consecutive male patients (mean age 58+/-4 years, range 43-72 years) referred for diagnostic coronary angiography because of symptoms suggestive of CAD, but without acute coronary syndromes or prior diagnosis of hypogonadism. Patients were matched with healthy volunteers. Out of 129 patients, 119 had proven CAD; in particular, 32 of them had one, 63 had two and 24 had three vessel disease, respectively. Patients had significantly lower levels of testosterone than controls (9.8+/-6.5 and 13.5+/-5.4 nmol/l, P<0.01) and higher levels of gonadotrophin (12.0+/-1.5 vs 6.6+/-1.9 IU/l and 7.9+/-2.1 vs 4.4+/-1.4, P<0.01 for follicle-stimulating hormone and luteinizing hormone, respectively). Also, both bioavailable testosterone and plasma oestradiol levels were lower in patients as compared to controls (0.84+/-0.45 vs 1.19+/-0.74 nmol/l, P<0.01 and 10.7+/-1.4 vs 13.3+/-3.5 pg/ml, P<0.05). Hormone levels were compared in cases with one, two or three vessel disease showing significant differences associated with increasing severity of coronary disease. An inverse relationship between the degree of CAD and plasma testosterone levels was found (r=-0.52, P<0.01).

In conclusion, patients with CAD have lower testosterone and oestradiol levels than healthy controls. These changes are inversely correlated to the degree of CAD, suggesting that low plasma testosterone may be involved with the increased risk of CAD in men.

Testosterone and Prostate Cancer: An Historical Perspective on a Modern Myth

Morgentaler A.

Eur Urol. 2006 Jul 26

CONCLUSIONS: This historical perspective reveals that there is not now-nor has there ever been-a scientific basis for the belief that T causes pCA to grow. Discarding this modern myth will allow exploration of alternative hypotheses regarding the relationship of T and pCA that may be clinically and scientifically rewarding.

Read More
Testosterone replacement therapy and the risk of prostate cancer
The article says “The belief that testosterone increases the risk of prostate cancer is so widely accepted that study after study that tries to show it and can’t keeps getting repeated over and over,” says Dr. Abraham Morgentaler, a Boston urologist and author of the 2004 review. “People don’t believe it.”

« Previous Page — Next Page »