Biomarkers and Noncalcified Coronary Artery Plaque Progression in Older Men Treated With Testosterone.

ObjectiveRecent results from the Cardiovascular Trial of the Testosterone Trials showed that testosterone treatment of older men with low testosterone was associated with greater progression of noncalcified plaque (NCP). We evaluated the effect of anthropometric measures and cardiovascular biomarkers on plaque progression in individuals in the Testosterone Trial.MethodsThe Cardiovascular part of the trial included 170 men aged 65 years or older with low testosterone. Participants received testosterone gel or placebo gel for 12 months. The primary outcome was change in NCP volume from baseline to 12 months, as determined by coronary computed tomography angiography (CCTA). We assayed several markers of cardiovascular risk and analyzed each marker individually in a model as predictive variables and change in NCP as the dependent variable.ResultsOf 170 enrollees, 138 (73 testosterone, 65 placebo) completed the study and were available for the primary analysis. Of 10 markers evaluated, none showed a significant association with the change in NCP volume, but a significant interaction between treatment assignment and waist-hip ratio (WHR) (P = 0.0014) indicated that this variable impacted the testosterone effect on NCP volume. The statistical model indicated that for every 0.1 change in the WHR, the testosterone-induced 12-month change in NCP volume increased by 26.96 mm3 (95% confidence interval, 7.72-46.20).ConclusionAmong older men with low testosterone treated for 1 year, greater WHR was associated with greater NCP progression, as measured by CCTA. Other biomarkers and anthropometric measures did not show statistically significant association with plaque progression

Stimulation of sperm production by human luteinizing hormone in gonadotropin-suppressed normal men

The relative roles of FSH and LH in the control of human spermatogenesis are not well established. We previously reported that supraphysiological doses of hCG can stimulate sperm production in gonadotropin-suppressed normal men despite prepubertal FSH levels. To determine whether more nearly physiological levels of human LH (hLH) also can stimulate spermatogenesis when FSH levels are suppressed, we administered hLH to normal men whose endogenous gonadotropin levels and sperm production were suppressed by exogenous testosterone enanthate (T). After a 3-month control period, 11 normal men received 200 mg T, im, weekly to suppress LH and FSH. T administration alone was continued for 3-4 months until 3 successive sperm concentrations (performed twice monthly) revealed azoospermia or severe oligospermia (sperm concentrations, less than 4 million/ml). Then, while continuing T, 4 of the 11 men (experimental subjects) simultaneously received 1100 IU hLH, sc, daily for 4-6 months to replace LH activity, leaving FSH activity suppressed. The effect on sperm production of the selective FSH deficiency produced by hLH plus T administration was determined. The remaining 7 men (control subjects) continued to receive T alone at the same dosage, without gonadotropin replacement, for an additional 6 months. In the four experimental subjects, sperm concentrations increased significantly from 0.7 +/- 0.7 million/ml (mean +/- SEM) during T treatment alone to 19 +/- 4 million/ml during hLH plus T administration (P less than 0.001). However, none of the men achieved sperm concentrations consistently in their own pretreatment range. Sperm motilities and morphologies were normal in all four subjects by the end of hLH plus T administration. In contrast, sperm concentrations in the seven control subjects remained suppressed (less than 3 million/ml) throughout the entire period of prolonged T administration alone. Serum LH bioactivity, determined monthly by in vitro mouse Leydig cell bioassay in all four experimental subjects, was markedly suppressed during T administration alone (120 +/- 10 ng/ml) compared to that during the control period (390 +/- 20 ng/ml; P less than 0.001). With the addition of hLH to T, LH bioactivity returned to control levels (400 +/- 40 ng/ml; P = NS compared to control value). Serum FSH levels determined monthly by RIA were reduced from 98 +/- 12 ng/ml during the control period to undetectable levels (less than 25 ng/ml) during the T alone and the hLH plus T periods (P less than 0.01).(ABSTRACT TRUNCATED AT 400 WORDS

Modulation of pulsatile gonadotropin secretion by testosterone in man

In experimental animals, primary testicular deficiency leads to increased LH pulse frequency. Pulsatile FSH secretion has not been well characterized in any species. To determine the effect of testosterone (T) on the pattern of pulsatile gonadotropin secretion in man, we performed frequent blood-sampling studies in six normal men and six men with primary hypogonadism. All primary hypogonadal men were studied 6-8 weeks after stopping T replacement therapy. Five of the six hypogonadal men were restudied 6-8 weeks after treatment with T enanthate (200 mg, im, every 2 weeks; sampling in this group was 2 weeks after their last T injection). Blood sampling was done at 10-min intervals for 12 h in all subjects, and the pattern of episodic LH and FSH secretion was determined. Normal men had a serum T level of 6.3 +/- 0.3 ng/ml (mean +/- SEM), a LH level of 34 +/- 3 ng/ml, and a LH pulse pattern characterized by low frequency (7.6 +/- 0.7 pulses/12 h) and low amplitude (16 +/- 1 ng/ml). Compared to normal men, primary hypogonadal men had a significantly lower T level (2.9 +/- 0.4 ng/ml) and significantly higher LH pulse frequency (13.0 +/- 1.3 pulses/12 h), amplitude (51 +/- 7 ng/ml), and mean level (222 +/- 26 ng/ml). Reinstitution of T replacement therapy in hypogonadal men resulted in a significant increase in the T level (4.7 +/- 0.5 ng/ml) and significant decreases in LH pulse frequency (7.2 +/- 1.6 pulses/12 h) and amplitude (41 +/- 5 ng/ml) as well as mean LH level (75 +/- 15 ng/ml). FSH levels fluctuated in a distinctly pulsatile pattern in all three groups. Differences in pulsatile FSH secretion between primary hypogonadal men before and during T therapy and normal men paralleled those in pulsatile LH secretion in both frequency and amplitude. These results demonstrate that in man 1) diminished T negative feedback results in high frequency (circhoral), high amplitude LH and FSH pulses; 2) T replacement decreased LH and FSH pulse frequency and amplitude as well as mean levels; and 3) the decreased LH and FSH pulse frequency with T treatment implies that T or a metabolite of T acts on the central nervous system to slow the hypothalamic LHRH pulse generator