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The stimulatory effects of testosterone on erythropoiesis are very well known, but the mechanisms underlying the erythropoietic action of testosterone are still poorly understood, although erythropoietin has long been considered a potential mediator. A total of 108 healthy men >65 years old with serum testosterone concentration <475 ng/dL were recruited by direct mailings to alumni of the University of Pennsylvania and Temple University, and randomized to receive a 60-cm(2) testosterone or placebo patch for 36 months. Ninety-six subjects completed the trial. We used information and stored serum specimens from this trial to test the hypothesis that increasing testosterone increases haemoglobin by stimulating erythropoietin production. We used information of 67 men, 43 in the testosterone group and 24 in the placebo group who had banked specimens available for assays of testosterone, haemoglobin and erythropoietin at baseline and after 36 months. The original randomized clinical study was primarily designed to verify the effects of testosterone on bone mineral density. The primary outcome of this report was to investigate whether or not transdermal testosterone increases haemoglobin by increasing erythropoietin levels. The mean age ± SD of the 67 subjects at baseline was 71.8 ± 4.9 years. Testosterone replacement therapy for 36 months, as compared with placebo, induced a significant increase in haemoglobin (0.86 ± 0.31 g/dL, p = 0.01), but no change in erythropoietin levels (-0.24 ± 2.16 mIU/mL, p = 0.91). Included time-varying measure of erythropoietin did not significantly account for the effect of testosterone on haemoglobin (Treatment-by-time: β = 0.93, SE = 0.33, p = 0.01). No serious adverse effect was observed. Transdermal testosterone treatment of older men for 36 months significantly increased haemoglobin, but not erythropoietin levels. The haematopoietic effect of testosterone does not appear to be mediated by stimulation of erythropoietin production., (© 2012 American Society of Andrology and European Academy of Andrology.)

Objective: The prevalence of peripheral artery disease (PAD) increases with aging and is higher in persons with metabolic syndrome and diabetes. PAD is associated with adverse outcomes, including frailty and disability. The protective effect of testosterone and sex hormone binding globulin (SHBG) for diabetes in men suggests that the biological activity of sex hormones may affect PAD, especially in older populations., Methods: Nine hundred and twenty-one elderly subjects with data on SHBG, testosterone (T), estradiol (E2) were selected from InCHIANTI study. PAD was defined as an Ankle-Brachial Index (ABI) < 0.90. Logistic regression models adjusted for age (Model 1), age, BMI, insulin, interleukin-6, physical activity, smoking, chronic diseases including metabolic syndrome (Model 2), and a final model including also sex hormones (Model 3) were performed to test the relationship between SHBG, sex hormones and PAD., Results: The mean age (±SD) of the 419 men and 502 women was 75.0 ± 6.8 years. Sixty two participants (41 men, 21 women) had ABI < 0.90. Men with PAD had SHBG levels lower than men without PAD (p = 0.03). SHBG was negatively and independently associated with PAD in men (p = 0.028) but not in women. The relationship was however attenuated after adjusting for sex hormones (p = 0.07). The E2 was not significantly associated with PAD in both men and women. In women, but not in men, T was positively associated with PAD, even after adjusting for multiple confounders, including E2 (p = 0.01)., Conclusions: Low SHBG and high T levels are significantly and independently associated with the presence of PAD in older men and women, respectively., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Classic male hypogonadism is associated with known adverse effects including decreased libido, erectile dysfunction, osteoporosis, and changes in body composition. Recently, we have come to appreciate that reduction in serum testosterone (T) levels resulting from aging or chronic disease or androgen deprivation therapy (ADT) have consequences similar to those seen in classic male hypogonadism which include increased fat mass, decreased lean body mass, decreased muscle strength, and sexual dysfunction. These data suggest that low T levels may represent a newly recognized cardiometabolic risk factor. Therefore, we carried out a careful review of the literature, focusing on major turning points of research and studies which gave more important and controversial contribution to the cardiovascular role of T. Observational studies and clinical trials investigating the relationship between T levels and cardiovascular disease and mortality were identified byMedline search. The results were synthesized, tabulated, and interpreted. The aim of this review is to discuss the association between low T levels and adverse metabolic profile such as insulin resistance, metabolic syndrome, and diabetes. We will also investigate the potential mechanisms by which male hypogonadism, especially age related or induced by ADT, may increase cardio-metabolic risk. Finally we will detail the emerging relationship between low T and mortality in men addressing also the reverse hypothesis that low T has a protective role by turning off T-dependent functions.

Aging is accompanied by a pro-inflammatory state expressed by the increasing levels of inflammatory cytokines, including interleukin-6 (IL- 6), tumor necrosis factor alpha (TNF-alpha) and interleukin- 1beta (IL-1beta). At the same time, aging is associated with a decrease in serum testosterone (T) levels. There is evidence from many experimental studies that IL-6, TNF-alpha and IL-1beta inhibit T secretion by their influence on the central (hypothalamic-pituitary) and peripheral (testicular) components of the gonadal axis. On the other hand, observational and interventional studies suggest that T supplementation reduces inflammatory markers in both young and old hypogonadal men. Preliminary data from 473 older male participants of the InCHIANTI population showed a significant inverse relationship between T and soluble IL-6 receptor (sIL-6r) levels (a soluble portion of the IL-6 receptor that may enhance the biological activity of IL-6) but not with other markers of inflammation. This study, together with previous observations, suggests that a close relationship exists between the development of a pro-inflammatory state and the decline in T levels, two trends that are often observed in aging men. In the context of this paradigm, we discuss androgen deprivation therapy, a treatment used in men with metastatic prostate cancer as an ideal model to improve our understanding of the relationship between T and inflammatory markers. We advocate the notion that changes in inflammatory markers and T in aging men are causally linked. However, longitudinal and interventional studies are needed to confirm that T can be used therapeutically, based on its anti-inflammatory properties.

Objective: To assess if androgen decline in physiological aging contributes to the concomitant changes in body composition and lipoprotein levels., Design: Cross-sectional, observational study., Setting: A university-based outpatient center., Subjects: The study comprised 206 healthy volunteers (aged 18-95 years)., Measurements: Blood samples were drawn after an overnight fast for the assay of hormones (free testosterone (FT), estradiol (E2), and sex hormone-binding globulin (SHBG)) and lipids (total cholesterol, triglycerides, high-density lipoprotein cholesterol, and lipoprotein Lp(a)). At the same time, body composition was assessed by both anthropometry (fat mass percentage (FM%) estimated from four measures of skinfold thickness using the Durnin and Womersley equation and the Siri equation) and by bioimpedance analysis (FM% estimated using the Segal or Deurenberg equations, respectively, for subjects younger or older than 62 years)., Results: A significant age-related decline was found for FT and E2 concentrations, whereas SHBG levels were related positively with age. No significant association was apparent between hormonal changes and the concomitant modifications of body composition and lipoproteins. Only SHBG showed a significant inverse association between FM% and the waist-to-hip ratio, independent of age. The comparison between older hypogonadal (with FT levels below the lower limit of the normality range assessed in younger subjects) and eugonadal men did not show any significant differences in body composition or lipid profile., Conclusions: This study suggests that, in men, androgen decline caused by normal aging does not significantly affect some targets of testosterone action, such as body composition and lipid metabolism. Therefore, androgen supplementation in hypogonadal older men cannot be expected to influence nutritional status and body composition to the same extent that it does other main targets of testosterone action, such as sexual activity and muscle strength. However, we cannot exclude that selected subsets of older patients with low testosterone levels, especially if affected by catabolic disease, could benefit from the effects of androgen administration on nutritional status.

To investigate the effects of aging on the secretion of the common alpha-subunit of the glycoprotein hormones, we measured basal levels of luteinizing hormone (LH), testosterone (T) and alpha-subunit in 176 normal men aged 19 to 89 years. In addition, in two groups of young (less than 65 years; n = 25) and old (greater than 65 years; n = 15) subjects, the effects of luteinizing hormone-releasing hormone (LHRH) on LH and alpha-subunit secretion were determined. Age-related increases in serum alpha-subunit and LH were noted only in the oldest men while T levels decreased progressively with advancing age. LHRH stimulation resulted in significantly greater secretion of alpha-subunit in the old subjects while no difference in LH release between young and old men was observed. Moreover, there was a delay to peak LH and alpha-subunit levels after LHRH in the old subjects. These data suggest that the aging process in males involves deficits in both testicular and gonadotroph functions as demonstrated by (1) the relative hypogonadotropic hypogonadism seen until the ninth decade; (2) the hypergonadotropic hypogonadism apparent in men greater than 80 years; (3) the delay in the timing of peak responses of LH and alpha-subunit after LHRH administration; and (4) the disproportionate increase in the secretion of alpha subunit relative to intact LH.