Preferential Release of Bioactive Luteinizing Hormone in Response to Endogenous and Low Dose Exogenous Gonadotropin-Releasing Hormone Pulses in Man

We used the rat interstitial cell testosterone (RICT) bioassay to assess biological LH activity secreted in response to endogenous and low dose exogenous GnRH pulses i n normal men. The absence of nonspecific plasma effects in the LH bioassay was demonstrated by the finding of undetectable levels of LH bioactivity despite low but measurable immunoac-tivity in 10 hypogonadotropic men. Moreover, bolus injections of human LH in 6 hypogonadotropic men defined a curvilinear relationship between plasma bioactive and immunoactive LH concentrations, in which the extrapolated concentration of plasma bioactive LH at a zero dose of immunoactive LH was indistinguishable from zero. Zero bioactive LH intercepts were also found when physiological bio- and immunoactive LH concentrations derived from 7 intensively sampled normal men were subjected to linear regression using 2-dimensional error fitting. In these men, exogenous low dose (10 μg) iv GnRH administration resulted in preferential release of bioactive LH, with a consequent significant increase in the median plasma bio- to immunoactive (bio:immuno) LH ratio. This pattern mimicked that of endogenous LH pulsatility, in which median intrapulse bio:immuno LH ratios were significantly higher than median interpulse ratios in the same individuals (P = 0.006). Increases in spontaneous plasma bio:immuno LH ratios were not attributable to spurious rises in bioactive LH concentrations associated with decreases in serum immunoactive LH levels. Rather, sample cross-correlation analyses demonstrated positive correlations between bio- and immunoactive LH at lags of 0-40 min, indicating that both hormones increased or decreased concomitantly. These results demonstrate that LH is secreted physiologically in pulses of increased biological activity, presumably reflecting the release of a functionally compartmentalized LH pool relatively enriched in biologically active hormone. Accordingly, evaluation of the plasma bio:immuno LH ratio can provide a useful and sensitive index of qualitative changes in the LH molecule in response to endogenous (spontaneous) and exogenous GnRH stimulation.