Aging Men, Obesity, Metabolic Syndrome, Decrease in Total Serum Testosterone Levels

Researchers writing in the Journal of Urology say that their study “…demonstrated that aging men with obesity and the metabolic syndrome have a significant decrease in total serum testosterone levels compared to aging, metabolically healthy men.”

Kaplan SA, Meehan AG, Shah A. The Age Related Decrease in Testosterone is Significantly Exacerbated in Obese Men With the Metabolic Syndrome. What are the Implications for the Relatively High Incidence of Erectile Dysfunction Observed in These Men? J Urol. 2006 Oct;176(4):1524-8
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Osteoporosis in Men

Testosterone and Estradiol Deficiency
Researchers writing in the Journal of Clinical Endocrinology & Metabolism say that: Older men with total testosterone or estradiol deficiency were more likely to be osteoporotic. Those with osteoporosis were more likely to be total testosterone or estradiol deficient. Rapid hip bone loss was more likely in men with total testosterone deficiency.

Fink HA, Ewing SK, Ensrud KE, Barrett-Connor E, Taylor BC, Cauley JA, Orwoll ES. Association of Testosterone and Estradiol Deficiency with Osteoporosis and Rapid Bone Loss in Older Men. J Clin Endocrinol Metab. 2006 Jul 18

From the article abstract:
Context: The clinical value of measuring testosterone and estradiol in older men with osteoporosis and of measuring bone mineral density (BMD) in older men with testosterone or estradiol deficiency is uncertain.

Objective: To examine the association of testosterone and estradiol deficiency with osteoporosis and rapid bone loss in older men.

Participants: 2447 community-dwelling men aged >/=65.

Main Outcome Measures: Total testosterone deficiency defined as <200 ng/dl.

Total estradiol deficiency defined as <10 pg/ml.

Results: Prevalence of osteoporosis in men with deficient and normal total testosterone was 12.3% and 6.0% (P = 0.003), and in those with deficient and normal total estradiol was 15.4% and 2.8% (P < 0.0001).

Among osteoporotic men and those with normal BMD, prevalence of total testosterone deficiency was 6.9% and 3.2% (P = 0.01) and prevalence of total estradiol deficiency was 9.2% and 2.4% (P = 0.0001). Incidence of rapid hip bone loss in men with deficient and normal total testosterone was 22.5% and 8.6% (P = 0.007), and in those with deficient and normal total estradiol was 14.3% and 6.3% (P = 0.08).

Conclusions: Older men with total testosterone or estradiol deficiency were more likely to be osteoporotic. Those with osteoporosis were more likely to be total testosterone or estradiol deficient. Rapid hip bone loss was more likely in men with total testosterone deficiency. BMD testing of older men with sex steroid deficiency may be clinically warranted.

Testosterone and Ischemic Heart Disease

Researchers writing in Cardiovascular & Hematological Disorders Drug Targets examined lower testosterone levels in patients with ischemic heart disease. The researchers noted recent studies showing that testosterone level is lower in patients with ischemic heart diseases, and testosterone treatment alleviates the symptoms and there is increasing evidence to suggest testosterone confers cardioprotection by direct action on the myocardium.

Tsang S, Liu J, Wong TM. Testosterone and cardioprotection against myocardial ischemia. Cardiovasc Hematol Disord Drug Targets. 2007 Jun;7(2):119-25.

The researchers noted recent studies showing that testosterone level is lower in patients with ischemic heart diseases, and testosterone treatment alleviates the symptoms and there is increasing evidence to suggest testosterone confers cardioprotection by direct action on the myocardium.

Hypoandrogen-Metabolic Syndrome in Men

Gould DC, Kirby RS, Amoroso P. Hypoandrogen-metabolic syndrome: a potentially common and underdiagnosed condition in men. Int J Clin Pract. 2007 Feb;61(2):341-4.

Researchers writing in the International Journal of Clinical Practice say Men with (Hypoandrogen-metabolic syndrome) and symptoms of androgen deficiency may be managed by, in the absence of contraindications, testosterone replacement therapy along with weight reduction and other measures to normalize glucose, lipid and blood pressure control.

The researchers noted that symptoms of androgen deficiency (hypoandrogenaemia (hypogonadism, hypotestosteronaemia) may be a common accompanying factor in men with the metabolic syndrome and when androgen deficiency and metabolic syndrome are present together “they may be considered as a specific entity, the hypoandrogen-metabolic (HAM) syndrome.”

The researchers concluded: “The prevalence of both hypoandrogenaemia and the metabolic syndrome increases with age and the clinician will frequently attend to men in their middle to advanced years with obesity, low androgen levels and metabolic syndrome.

These conditions place men at an increased risk of cardiovascular and coronary heart disease and type 2 diabetes and can be simply investigated with weight, waist and blood pressure measurement and blood sample analyses.

Men with HAM and symptoms of androgen deficiency may be managed by, in the absence of contraindications, testosterone replacement therapy along with weight reduction and other measures to normalise glucose, lipid and blood pressure control.”

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.

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