1) Previous studies in human and experimental animals have suggested that sex steroid hormones may modulate the pituitary secretion of biologically active gonadotropin. We examine the role of E2 in biologically active LH secretion, in men subjected to steady state E2 infusion and feedback actions of endogenous E2 on spontaneous and exogenous GnRH stimulated pulsatile bioactive LH release. E2 suppressed mean circulating bioactive LH concentrations, with a consequent significant decline in the plasma bio/immune LH ratio. Conversely, antiestrogen treatment enhanced spontaneous bioactive LH pulse frequency, pulse amplitude, and intrapulse and interpulse bio/immune LH ratios. Low-dose pulsed injections of exogenous GnRH also increased plasma bio/immune LH ratios. However, tamoxifen attenuated the ability of exogenous GnRH to further enhance the bio/immune LH ratio, which suggests that endogenous LH release was already maximally enriched in LH bioactivity during antiestrogen administration. The ability of E2 to modulate specific properties of the LH pulse signal as well as its frequency may have significant implications in relation to target tissue function, and also reflect direct actions of estradiol on gonadotrope function, through influence the cellular processing and/or one or more aspects of terminal glycosylation of LH molecules. 2) In our early studies using a single large bolus of GnRH and/or continuous GnRH infusions were not able to disclose a stimulatory effect of exogenous GnRH on the plasma bio/immune LH ratio. In contrast, a schedule of two consecutive submaximal pulses (10 micrograms one hour apart) of exogenous GnRH did result in an immediate and preferential release of bioactive LH with a consequent increase in the plasma bio/immuno LH ratio. These findings might be explained by functional compartmentalization of releasable LH pools. 3) The dynamics of bioactive LH release in healthy older men (ages 60-75) have revealed significant attenuation of the pituitary's capacity to release biologically active gonadotropic hormone. The diminution of bioactive LH release could be unmasked by low-dose (10 micrograms) exogenous GnRH, or by antiestrogen treatment. Young and older healthy men exhibit similar mean basal plasma bioactive LH concentrations and spontaneous LH pulse properties. However, pituitary bioactive LH reserve is markedly attenuated in older men challenged with either exogenous GnRH or antiestrogen, indicating that healthy aging men manifest an impaired secretory reserve for biologically active LH release.
