Context. Aging is associated with diminished testosterone (Te) secretion, which could be attributed to Leydig cell dysfunction, decreased pituitary stimulation and altered Te feedback. Objective. The goal was to quantify all three regulatory nodes of the GnRH-LH-Leydig cell- axis in the same cohort of healthy men, by measuring (1) indirectly the strength of the endogenous GnRH signal on the gonadotrope, (2) the strength of Te feedback on LH by ketoconazole (KTCZ), and (3) the effect of LH infusions on Te secretion, in relation to age and body composition.
Design. This was a placebo-controlled, blinded, prospectively randomized cross-over study in 40 men, age 19–73 yr, BMI 20–34.3 kg/m2. A submaximal dose of ganirelix (GnRH antagonist) was used to assess outflow of GnRH, by calculating the difference between LH output during the control and ganirelix arm. Ketoconazole (steroidogenic inhibitor) was used to estimate feedback, by the difference in LH output during ketoconazole and control arm. High-dose ganirelix and repeated 6-min LH (18.75 IU) infusions were used to measure testicular responsivity. Blood sampling was at 10-min intervals. The 4 sessions were concluded with, a single submaximally GnRH stimulus to assess the responsiveness of the gonadotrope during ganirelix inhibition.
Interventions. In 3 of the 4 experiments subjects underwent 5 h of blood sampling at 10-min intervals, starting at 0800 h. At 1100 h GnRH was injected and sampling was continued for another 2 h. Admission was at 1700 h the day before. At 2000 h they received KTCZ, dexamethasone or ganirelix and/or placebo. KTCZ and dexamethasone (or placebo) were administered again at 0700 when the IV catheter was placed. High-dose ganirelix was used to test the testicular responsiveness, and 7 LH pulses (90 min intervals) were given., with blood sampling from 1500 till 1300 h next day.
Outcome measures. Mean concentrations of LH and (bio)Te, deconvolution analysis, endogenous dose-response LH-bioTe relation, and approximate entropy. Abdominal visceral fat (AVF) was calculated from single slice CT.
Results. There were age-, but not body composition-related decreases in estimated endogenous GnRH secretion, Te’s feedback strength on LH, and Leydig cell responsivity to LH, accompanied by changes in approximate entropy. Bioavailable Te levels were negatively related to both age and AVF, without interaction between these variables. The LH response to a submaximal dose of GnRH was independent of age and AVF.
Conclusion. Advancing age is associated with 1) attenuated bioavailable Te secretion caused by diminished GnRH outflow and not by decreased GnRH responsivity of the gonadotrope, 2) diminished testicular responsivity to infused LH pulses, and 3) partial compensation by diminished Te feedback on central gonadotropic regulation.