No abstract

As men age, their serum testosterone concentrations decrease, as do their bone densities. Because bone density is also low in hypogonadal men, we hypothesized that increasing the serum testosterone concentrations of men over 65 yr to those found in young men would increase their bone densities. We randomized 108 men over 65 yr of age to wear either a testosterone patch or a placebo patch double blindly for 36 months. We measured bone mineral density by dual energy x-ray absorptiometry before and during treatment. Ninety-six men completed the entire 36-month protocol. The mean serum testosterone concentration in the men treated with testosterone increased from 367 +/- 79 ng/dL (+/-SD; 12.7 +/- 2.7 nmol/L) before treatment to 625 +/- 249 ng/dL (21.7 +/- 8.6 nmol/L; P < 0.001) at 6 months of treatment and remained at that level for the duration of the study. The mean bone mineral density of the lumbar spine increased (P < 0.001) in both the placebo-treated (2.5 +/- 0.6%) and testosterone-treated (4.2 +/- 0.8%) groups, but the mean changes did not differ between the groups. Linear regression analysis, however, demonstrated that the lower the pretreatment serum testosterone concentration, the greater the effect of testosterone treatment on lumbar spine bone density from 0-36 months (P = 0.02). This analysis showed a minimal effect (0.9 +/- 1.0%) of testosterone treatment on bone mineral density for a pretreatment serum testosterone concentration of 400 ng/dL (13.9 nmol/L), but an increase of 5.9 +/- 2.2% for a pretreatment testosterone concentration of 200 ng/dL (6.9 nmol/L). Increasing the serum testosterone concentrations of normal men over 65 yr of age to the midnormal range for young men did not increase lumbar spine bone density overall, but did increase it in those men with low pretreatment serum testosterone concentrations.

As men age, serum testosterone concentrations decrease, the percentage of body mass that is fat increases, the percentage of lean body mass decreases, and muscle strength decreases. Because these changes are similar to those that occur in hypogonadal men, we hypothesized that increasing the serum testosterone concentration of men over 65 yr of age to that in young men would decrease their fat mass, increase their lean mass, and increase their muscle strength. We randomized 108 men over 65 yr of age to wear either a testosterone patch or a placebo patch in a double blind study for 36 months. We measured body composition by dual energy x-ray absorptiometry and muscle strength by dynamometer before and during treatment. Ninety-six men completed the entire 36-month protocol. Fat mass decreased (-3.0+/-0.5 kg) in the testosterone-treated men during the 36 months of treatment, which was significantly different (P = 0.001) from the decrease (-0.7+/-0.5 kg) in the placebo-treated men. Lean mass increased (1.9+/-0.3 kg) in the testosterone-treated men, which was significantly different (P < 0.001) from that (0.2+/-0.2 kg) in the placebo-treated men. The decrease in fat mass in the testosterone-treated men was principally in the arms (-0.7+/-0.1 kg; P < 0.001 compared to the placebo group) and legs (-1.1+/-0.2 kg; P < 0.001), and the increase in lean mass was principally in the trunk (1.9+/-0.3 kg; P < 0.001). The change in strength of knee extension and flexion at 60 degrees and 180 degrees angular velocity during treatment, however, was not significantly different between the two groups. We conclude that increasing the serum testosterone concentrations of normal men over 65 yr of age to the midnormal range for young men decreased fat mass, principally in the arms and legs, and increased lean mass, principally in the trunk, but did not increase the strength of knee extension and flexion, as measured by dynamometer.

Treatment of hypogonadal men with testosterone has been shown to ameliorate the effects of testosterone deficiency on bone, muscle, erythropoiesis, and the prostate. Most previous studies, however, have employed somewhat pharmacological doses of testosterone esters, which could result in exaggerated effects, and/or have been of relatively short duration or employed previously treated men, which could result in dampened effects. The goal of this study was to determine the magnitude and time course of the effects of physiological testosterone replacement for 3 yr on bone density, muscle mass and strength, erythropoiesis, prostate volume, energy, sexual function, and lipids in previously untreated hypogonadal men. We selected 18 men who were hypogonadal (mean serum testosterone +/- SD, 78 +/- 77 ng/dL; 2.7 +/- 2.7 nmol/L) due to organic disease and had never previously been treated for hypogonadism. We treated them with testosterone transdermally for 3 yr. Sixteen men completed 12 months of the protocol, and 14 men completed 36 months. The mean serum testosterone concentration reached the normal range by 3 months of treatment and remained there for the duration of treatment. Bone mineral density of the lumbar spine (L2-L4) increased by 7.7 +/- 7.6% (P < 0.001), and that of the femoral trochanter increased by 4.0 +/- 5.4% (P = 0.02); both reached maximum values by 24 months. Fat-free mass increased 3.1 kg (P = 0.004), and fat-free mass of the arms and legs individually increased, principally within the first 6 months. The decrease in fat mass was not statistically significant. Strength of knee flexion and extension did not change. Hematocrit increased dramatically, from mildly anemic (38.0 +/- 3.0%) to midnormal (43.1 +/- 4.0%; P = 0.002) within 3 months, and remained at that level for the duration of treatment. Prostate volume also increased dramatically, from subnormal (12.0 +/- 6.0 mL) before treatment to normal (22.4 +/- 8.4 mL; P = 0.004), principally during the first 6 months. Self-reported sense of energy (49 +/- 19% to 66 +/- 24%; P = 0.01) and sexual function (24 +/- 20% to 66 +/- 24%; P < 0.001) also increased, principally within the first 3 months. Lipids did not change. We conclude from this study that replacing testosterone in hypogonadal men increases bone mineral density of the spine and hip, fat-free mass, prostate volume, erythropoiesis, energy, and sexual function. The full effect of testosterone on bone mineral density took 24 months, but the full effects on the other tissues took only 3-6 months. These results provide the basis for monitoring the magnitude and the time course of the effects of testosterone replacement in hypogonadal men.

The present study was carried out to perform a dose-response analysis of the effect of fenoldopam, a DA-1 receptor agonist, on renal sodium excretion. Infusions of fenoldopam for 30 min at doses of 0.125, 0.25, 0.5, and 1.0 pg/kg/min in four separate groups of pentobarbital-anesthetized dogs caused dose-dependent hypotension and renal vasodilation. The reflex tachycardic response was not dose-dependent and seen only with the three higher doses. There was no change in glomerular filtration with any of the four doses of fenoldopam. At the doses of 0.25 and 0.5 pg/kg/min fenoldopam caused significant increases in urine volume, urinary sodium excretion, and fractional excretion of sodium during the infusion as well as during the first recovery period of 30 min. At the highest dose of 1 pg/kg/min no diuresis or natriuresis was seen during the infusion: however, significant increases in urine volume and sodium excretion were seen during the two recovery periods. At the lowest dose (0.125 pg/kg/min) fenoldopam caused minimal hemodynamic changes but produced maximum increases in urine volume and urinary sodium excretion. These effects of fenoldopam were antagonized by the DA-I receptor antagonist, SCH 23390. The results of our study show that the tubular effects of fenoldopam leading to increased renal sodium excretion are evident at doses lower than those required to cause changes in systemic and renal hemodynamics. In addition, at higher doses when the magnitude of hypotension is very pronounced, this effect may limit the increase in sodium excretion produced by fenoldopam.