The Dynamics of Gonadotropin Inhibition in Women Induced by an Antagonistic Analog of Gonadotropin-releasing Hormone

The inhibitory effect of a GnRH antagonist, [AC-delta 2-Pro1, p-F-D-Phe 2, D-Trp3,6]GnRH (4F-Antag), on gonadotropin secretion was determined by four sequential studies in five hypergonadotropic postmenopausal women. In response to an iv (80 micrograms/kg) dose of 4F-Antag, a progressive decline in basal gonadotropin levels with a marked attenuation of pulse amplitude was observed. Mean serum LH and FSH concentrations were maximally reduced by 46% and 26%, respectively, 4 and 9 h after the iv bolus. A similar pattern of suppression was found with sc and im routes of administration, with maximal effects occurring at 6.0 h for LH and 8.5 h for FSH. This was followed by the resumption of pulsatile release and a return to basal levels between 10 and 24 h for both gonadotropins. When 4F-Antag was superimposed during an iv infusion of GnRH (0.2 micrograms/min) at the time (2 h) of maximal LH release (231% above basal values), a 47.1% decrease in GnRH-stimulated LH levels and a 15.8% decrease in FSH values occurred at 1.75 h. A positive linear correlation was found between basal and exogenous GnRH-stimulated LH and FSH concentrations and the inhibitory effect of the 4F-antagonist. The dynamics of the antagonistic effect demonstrated by this analog provide an important reference for future investigations of endogenous GnRH control of gonadotropin secretion as well as for exploring contraceptive potential.