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LE Magazine May 2003

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Testosterone

Testosterone supplementation therapy for older men: potential benefits and risks.

Serum testosterone levels decline gradually and progressively with aging in men. Many manifestations associated with aging in men, including muscle atrophy and weakness, osteoporosis, reduced sexual functioning and increased fat mass, are similar to changes associated with testosterone deficiency in young men. These similarities suggest that testosterone supplementation may prevent or reverse the effects of aging. A MEDLINE search was performed to identify studies of testosterone supplementation therapy in older men. A structured, qualitative review was performed of placebo-controlled trials that included men aged 60 and older and evaluated one or more physical, cognitive, affective, functional or quality-of-life outcomes. Studies focusing on patients with severe systemic diseases and hormone deficiencies related to specific diseases were excluded. In healthy older men with low-normal to mildly decreased testosterone levels, testosterone supplementation increased lean body mass and decreased fat mass. Upper and lower body strength, functional performance, sexual functioning and mood were improved or unchanged with testosterone replacement. Variable effects on cognitive function were reported, with improvements in some cognitive domains (e.g., spatial, working and verbal memory). Testosterone supplementation improved exercise-induced coronary ischemia in men with coronary heart disease, whereas angina pectoris was improved or unchanged. In a few studies, men with low testosterone levels were more likely to experience improvements in lumbar bone mineral density, self-perceived functional status, libido, erectile function and exercise-induced coronary ischemia with testosterone replacement than men with less marked testosterone deficiency. No major unfavorable effects on lipids were reported, but hematocrit and prostate specific antigen levels often increased. Based on these results, testosterone supplementation cannot be recommended at this time for older men with normal or low-normal testosterone levels and no clinical manifestations of hypogonadism. However, testosterone replacement may be warranted in older men with markedly decreased testosterone levels, regardless of symptoms, and in men with mildly decreased testosterone levels and symptoms or signs suggesting hypogonadism. The long-term safety and efficacy of testosterone supplementation remain uncertain. Establishment of evidence-based indications will depend on further demonstrations of favorable clinical outcomes and symptomatic, functional and quality-of-life benefits in carefully performed, long-term, randomized, placebo-controlled clinical trials.

J Am Geriatr Soc 2003 Jan;51(1):101-115

Testosterone, cytochrome P450 and cardiac hypertrophy.

Cytochrome P450 mono-oxygenases (CYP) play an essential role in steroid metabolism, and there is speculation that sex hormones might influence cardiac mass and physiology. As CYP mono-oxygenases activity is frequently altered during disease, we tested our hypothesis that CYP mono-oxygenase expression and testosterone metabolism are altered in cardiac hypertrophy. We investigate major CYP mono-oxygenase isoforms and other steroid-metabolizing enzymes and the androgen receptor in normal, hypertrophic, and assist device-supported human hearts and in spontaneously hypertensive rats (SHR). We show increased and idiosyncratic metabolism of testosterone in hypertrophic heart and link these changes to altered CYP mono-oxygenase expression. We show significant induction of 5-alpha steroid reductase and P450 aromatase gene expression and enhanced production of dihydrotestosterone, which can be inhibited by the 5-alpha reductase inhibitor finasteride. We show increased gene expression of the androgen receptor and increased levels of lipid peroxidation in diseased hearts, the latter being markedly inhibited by CYP mono-oxygenase inactivation. We show alpha-MHC to be significantly repressed in cardiac hypertrophy and restored to normal on testosterone supplementation. We conclude that heart-specific steroid metabolism is of critical importance in cardiac hypertrophy.

FASEB J 2002 Oct;16(12):1537-49

The effect of testosterone on regional blood flow in prepubertal anaesthetized pigs.

This work was undertaken to study the effects of testosterone on the coronary, mesenteric, renal and iliac circulations and to determine the mechanisms of action involved. In prepubertal pigs of both sexes anaesthetized with sodium pentobarbitone, changes in left circumflex or anterior descending coronary, superior mesenteric, left renal and left external iliac blood flow caused by intra-arterial infusion of testosterone were assessed using electromagnetic flowmeters. Changes in heart rate and arterial blood pressure were prevented by atrial pacing and by connecting the arterial system to a pressurized reservoir containing Ringer solution. In 12 pigs, intra-arterial infusion of testosterone for five minutes to achieve a stable intra-arterial concentration of 1 microg l(-1) increased coronary, mesenteric, renal and iliac blood flow without affecting the maximum rate of change of left ventricular systolic pressure (left ventricular dP/dt(max)) and filling pressures of the heart. In a further five pigs, a concentration-response curve was obtained by graded increases in the intra-arterial concentration of the hormone between 0.125 and 8 microg l(-1). The mechanisms of these responses were studied in the 12 pigs by repeating the experiment after haemodynamic variables had returned to the control values before infusions. In six pigs, blockade of muscarinic cholinoceptors and adrenoceptors with atropine, propranolol and phentolamine did not affect the responses caused by intra-arterial infusion of testosterone performed to achieve a stable intra-arterial concentration of 1 microg l(-1). In the same pigs and in the remaining six pigs, the increases in coronary, mesenteric, renal and iliac blood flow caused by intra-arterial infusion of testosterone performed to achieve a stable intra-arterial concentration of 1 microg l(-1) were prevented by intra-arterial injection of N(omega)-nitro-L-arginine methyl ester. The present study shows that intra-arterial infusion of testosterone dilated coronary, mesenteric, renal and iliac circulations. The mechanism of this response involved the release of nitric oxide.

J Physiol 2002 Aug 15;543(Pt 1):365-72

Cyclosporine adversely affects baroreflexes via inhibition of testosterone modulation of cardiac vagal control.

Previous studies have shown that the immunosuppressant drug cyclosporine A attenuates arterial baroreceptor function. This study investigated whether the modulatory effect of cyclosporine on baroreceptor function involves inhibition of the baroreflex-facilitatory effect of testosterone. The role of cardiac autonomic control in cyclosporine-testosterone baroreflex interaction was also investigated. Baroreflex curves relating bradycardic responses to increments in blood pressure evoked by phenylephrine were constructed in conscious, sham-operated, castrated rats and in testosterone-replaced castrated (CAS + T) rats in the absence and presence of cyclosporine. The slopes of the curves were taken as an index of the baroreflex sensitivity (BRS). Short-term (11 to 13 days) cyclosporine treatment or castration reduced plasma testosterone levels and caused similar attenuation of the reflex bradycardia, as indicated by the significantly smaller BRS compared with sham-operated values (-0.97 +/- 0.07, -0.86 +/- 0.06, and -1.47 +/- 0.10 beats/min/mm Hg, respectively). The notion that androgens facilitate baroreflexes is further confirmed by the observation that testosterone replacement of castrated rats restored plasma testosterone and BRS to sham-operated levels. Cyclosporine had no effect on BRS in castrated rats but caused a significant reduction in CAS + T rats. Muscarinic blockade by atropine caused approximately 60% reduction in the BRS in sham-operated rats, an effect that was significantly and similarly diminished by castration, cyclosporine, or their combination. beta-Adrenergic blockade by propranolol caused no significant changes in BRS. These findings suggest that cyclosporine attenuates baroreflex responsiveness via, at least partly, inhibition of the testosterone-induced facilitation of cardiomotor vagal control.

J Pharmacol Exp Ther 2002 Apr;301(1):346-54

Sex hormone-binding globulin levels and cardiovascular risk factors in morbidly obese subjects before and after weight reduction induced by diet or malabsorptive surgery.

One of the main goals of weight reduction in morbidly obese subjects is its benefit on coronary heart disease (CHD) risk. A cross-sectional study was designed to randomly assign 79 morbidly obese subjects (27 men and 52 women; age: 30 to 45 years) either to a diet protocol (20 kcal per kg fat-free mass (FFM); 55% carbohydrates, 30% fat and 15% proteins) or to malabsorptive surgery (biliopancreatic diversion). Fatness parameters, measured by dual-energy X-ray absorptiometry, lipid profile, insulin, leptin, sex steroid hormones and sex hormone-binding globulin (SHBG) levels were compared at baseline and one year after the beginning of the study. The data showed that plasma SHBG levels, but not testosterone levels, correlated negatively to fasting insulin levels and positively to HDL-cholesterol in both men and women. Total leptin levels were significantly lower (P<0.0001) in post-BPD subjects of both sexes compared to dietary treated obese subjects. The logarithm of plasma leptin correlated significantly and positively with insulin but negatively with SHBG. A step-down regression analysis showed that FFM and SHBG, but not insulin levels, were the most powerful independent variables for predicting HDL-cholesterol levels in morbidly obese patients. The negative relationship between SHBG levels and CHD risk appears to be mediated by a concomitant variation in body fatness. Finally, in obese patients, SHBG levels seem to be an indicator of total adiposity rather than an index of an altered insulin/glucose homeostasis.

Atherosclerosis 2002 Apr;161(2):455-62

Effect of intravenous testosterone on myocardial ischemia in men with coronary artery disease.

BACKGROUND: Studies on the effect of estrogen on atherosclerotic coronary artery disease (CAD) risk in women have produced conflicting results. Similar confusion, but fewer data, exists on the effect of testosterone on CAD risk in men. METHODS: We used 99mTc sestamibi single-photon emission computed tomography (SPECT) myocardial perfusion imaging to examine the acute effect of intravenous testosterone in 32 men (mean age, 69.1 +/- 6.4 years) with provocable myocardial ischemia on standard medical therapy. Patients performed three exercise (n = 18) or adenosine (n = 16) stress tests during the infusion of placebo or two doses of testosterone designed to increase testosterone two or six times baseline. RESULTS: Serum testosterone increased 137 +/- 58% and 488 +/- 113%, and estradiol levels increased 27 +/- 46% and 76 +/- 57%, (P <.001 for all) during the two testosterone infusions. There were no differences among the placebo or testosterone groups in peak heart rate, systolic blood pressure, maximal rate pressure product, perfusion imaging scores or the onset of ST-segment depression. CONCLUSIONS: Acute testosterone infusion has neither a beneficial nor a deleterious effect on the onset and magnitude of stress-induced myocardial ischemia in men with stable CAD.

Am Heart J 2002 Feb;143(2):249-56

Testosterone increases blood pressure and cardiovascular and renal pathology in spontaneously hypertensive rats.

The objective of this paper was to test the hypothesis that testosterone (T) raises blood pressure (BP), which is associated with increased coronary adventitial collagen, whereas the hemodynamic force of BP increases the coronary media:lumen ratio. Five treatment groups of spontaneously hypertensive rat (SHR) were established (n = 8-10 per group): controls; hydralazine (HYZ); castration; castration + HYZ; and castration + HYZ + T + captopril. At 12 weeks of age, the castrate + HYZ group was divided so that the mean BP was the same in both groups (162 mmHg). Both groups continued to receive HYZ treatment; however one group received T implants. Also, at 12 weeks of age the castrate + HYZ + T + captopril group received T implants. BP in the HYZ group was reduced compared with controls (192 mmHg vs 218 mmHg, p < 0.01). Castration lowered BP to 170 mmHg (p < 0.01) compared with controls. However, T implants increased BP by 15 mmHg (p < 0.02) in the castrate + HYZ group and by 44 mmHg in the castrate + HYZ + captopril group (p < 0.01). Captopril in combination with HYZ significantly reduced BP compared with controls but T replacement increased BP and coronary collagen deposition in spite of HYZ and captopril treatment.

Blood Press 2000;9(4):227-38

Effect of testosterone replacement on whole body glucose utilization and other cardiovascular risk factors in males with idiopathic hypogonadotrophic hypogonadism.

BACKGROUND: Excessive testosterone in males or estrogens in females could explain their differences in coronary heart disease event rates. As a contraceptive testosterone is likely to be used at large scale. The role of testosterone in increasing the risks of coronary heart disease needs investigation. AIM: To look at the role of testosterone in development of insulin resistance and other cardiovascular risk factors. DESIGN: Prospective, before-after study on 10 male subjects with idiopathic hypogonadotrophic hypogonadism pre- and post-testosterone replacement therapy; outcome measures: anthropometry, lipoprotein profile and M value (whole body glucose disposal rates on standard hyperinsulinemic euglycemic clamp; at insulin infusion rate: 40 mU x (m-2)). RESULTS: Pre-treatment serum testosterone was 0.43 (0.515) ng x mL(-1), LH was 1.29 (0.08) IU x L(-1), and FSH was 1.54 (0.08) IU x L(-1). None had glucose intolerance. After replacement testosterone levels increased to 9.4 ng x mL(-1) (p=0.0005); weight increase of 5.0 kg (p=0.140), body mass index increase of 1.2 kg x m(-2) (p=0.28), and the change in waist to hip ratio (p=0.31) were not statistically significant. M-value (mg x kg x min(-1)) did not change after testosterone therapy (5.86 [0.72] vs 5.29 [0.82], p=0.62). Insulin levels (mU x L(-1)) achieved during the clamps were 89.5 (14.2) before and 146 (32.2) after androgen therapy (p=0.127). There was no change in glucose area under curve (mg x min x dL(-1)) (14406 [502.2] vs 12557 [826.5], p=0.312). On testosterone replacement therapy total and LDL cholesterol levels (mg x dL(-1)) declined (122.5 [13.4] vs 91.6 [5.0], p=0.04; 65.9 [9.9] vs 39.4 [7.3], p=0.05); Ratio of total cholesterol to HDL ratio also decreased significantly (p=0.05). Changes of serum triglycerides (p=0.25) and HDL cholesterol (p=0.19) did not attain statistical significance. CONCLUSIONS: Insulin sensitivity does not decrease on testosterone replacement therapy of male subjects with idiopathic hypogonadotrophic hypogonadism. Testosterone replacement was associated with decrease in other cardiovascular risk factors.

Horm Metab Res 1998 Oct;30(10):642-5

Testosterone-propionate impairs the response of the cardiac capillary bed to exercise.

OBJECTIVE: Experimental application of anabolic-androgenic steroids and exercise training induce cardiac hypertrophy. This study quantifies for the first time, on microscopical level, the adaptation of the cardiac capillaries and myocytes to the concomitant application of testosterone-propionate and exercise training. METHODS: Female SPF-NMRI mice were studied over three and six week Experimental groups: (i) sedentary control (C); (ii) exercise (treadmill running, E); (iii) testosterone-propionate (TP); and (iv) testosterone-propionate+exercise (TPE). Morphometric parameters: 1) papillary muscles: capillary density, intercapillary distance, number of capillaries around a myocyte, and minimal myocyte diameter; and 2) left ventricular wall: capillary density and intercapillary distance. RESULTS: Papillary muscle: A striking suppression of the exercise-induced improvement in capillary supply occurs in the testosterone-propionate+exercise groups over three and six week Exercise without drugs increases significantly (P < 0.05) the capillary density, shortens significantly (P < 0.05) the intercapillary distance, whereas it increases the number of capillaries around a myocyte. These alterations are not observed in the testosterone-propionate treated sedentary animals; e.g., capillary density after 6 week (mean values +/- standard deviation, capillaries x mm(-2)): C: 4272 +/- 287, E: 5411 +/- 758, TP: 4221 +/- 364, and TPE: 3997 +/- 397. Moreover, only in the testosterone-propionate+exercise groups occurs a mild myocyte hypertrophy after both time periods: there is a trend toward hypertrophy (P < 0.1) in comparison with the C groups and a significant hypertrophy (P < 0.05) in comparison with the E groups. CONCLUSIONS: Testosterone-propionate profoundly inhibits the exercise-induced augmented capillarization, whereas (under training conditions) it leads to a mild myocyte hypertrophy. The microvascular impairment could trigger an imbalance between the myocardial oxygen supply and demand, especially during physical exercise.

Med Sci Sports Exerc 2000 May;32(5):946-53

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