EVIDENCE FOR ATTENUATION OF HYPOTHALAMIC GONADOTROPIN-RELEASING-HORMONE (GNRH) IMPULSE STRENGTH WITH PRESERVATION OF GNRH PULSE FREQUENCY IN MEN WITH CHRONIC-RENAL-FAILURE

To investigate the nature of putative disturbances in pulsatile gonadotropin ( LH) secretion in men with chronic renal failure, we undertook blood sampling at 10-min intervals for 24 h in 9 hemodialysis-dependent uremic men and 16 community- and age-matched controls. Serum LH concentrations were measured in a 2-site immunoradiometric assay, which does not cross-react with free a or LH beta-subunit and correlates well with an in vitro Leydig cell bioassay. Deconvolution analysis was applied to calculate the number, amplitude, mass, and duration of spontaneous LH release episodes and simultaneously estimate the half-life of endogenous LH in each subject. We observed that: 1) the estimated half-life of immunoradiometric LH removal from plasma averaged 103 +/- 11 min in normal and 207 +/- 29 min in uremic men (P < 0.01); 2) the number of LH secretory bursts was slightly higher in uremic than healthy men (e.g. 20 +/- 2.2 vs. 15 +/- 1.0 secretory bursts/24 h, respectively; P = 0.05); 3) the mass of LH secreted per burst was approximately 50% lower in chronic renal failure than in health, namely 1.4 +/- 0.18 vs. 2.8 +/- 0.42 IU/L (P < 0.01); 4) the decrease in the mass of LH secreted per burst was not due to a decline in LH secretory burst amplitude, but rather an attenuation of LH secretory burst duration (4.8 +/- 0.35 min in uremic vs. 11 +/- 1.3 min in normal men; P < 0.001); 5) the mean 24-h serum immunoradiometric LH concentration was significantly higher in uremia at 5.7 +/- 0.68 vs. 3.6 +/-0.41 IU/L in controls (P = 0.017); and 6) serum estradiol concentrations were increased in uremia, but total and free testosterone concentrations did not differ significantly between the two subject groups. In response to synthetic GnRH (10 gg, administered iv after the 24-h basal sampling period), the mean mass of immunoradiometric LH released within each calculated LH secretory burst was similar in uremic (n = 8) and normal (n = 21) individuals. We conclude that uremia is accompanied by a specific defect in the pulsatile mode of LH secretion, which is marked by an abbreviation of LH secretory burst duration and a consequent fall in the mass of LH secreted per spontaneous release episode. There is no overall decline in LH secretory pulse frequency or gonadotroph responsiveness to a submaximally effective dose of exogenous GNRH. Such findings are consistent with diminished hypothalamic GnRH impulse strength. Attenuated release of LH occurs in the presence of a significant prolongation of LH half-life, which results in an overall rise in mean and integrated serum LH concentrations. Since increased serum LH concentrations are sustained without an increase in total or free serum testosterone concentrations, the possibility of diminished negative feed-back effects of androgen on the hypothalamo-pituitary unit and/or a coexistent Leydig cell defect must also be considered.