Gonadotropin-Releasing Hormone (GnRH) Agonists and GnRH Antagonists Do Not Alter Endogenous GnRH Secretion in Short-Term Castrated Rams

The administration of GnRH agonists and antagonists suppresses pituitary LH secretion. However little is known about their effects on endogenous GnRH secretion. To determine if GnRH analogs act on GnRH secretion through a short or ultrashort loop feedback mechanism, experiments were performed to analyze GnRH secretion in hypophyseal portal blood of conscious short-term castrated rams under both agonist or antagonist treatment. In Study 1, six rams were castrated and surgically prepared for portal blood collection on day –7. Portal and peripheral blood were collected simultaneously every 10 min for 14–15 h on day 0. Five hours after the beginning of the portal blood collection, animals were injected im with 5 mg potent GnRH antagonist (Nal-Glu). In Study 2, six rams were treated daily from day –11 to day 0 with the GnRH agonist D-Trp6 GnRH (0.5 mg im). Castration and surgical preparation for portal blood collection were performed on day –7. On day 0 portal and peripheral blood were collected simultaneously every 10 min for 10–11 h. In both studies, to determine whether an increase in GnRH concentration in hypophyseal portal blood can overcome the inhibitory effect of the GnRH analogs, between 5 and 5.5 h after the injection of the analogs, endogenous GnRH secretion was stimulated by Naloxone administration (3 × 100 mg, iv, at 30-min intervals) followed by a bolus of eogenous GnRH (2 × 10 μg, iv at 30-min intervals). In Study 1, Nal- Glu administration led to a rapid cessation of pulsatile LH secretion for the duration of blood collection while GnRH pulse frequency and amplitude were not affected. GnRH and LH pulse frequency before and after Nal-Glu administration were, 6.2 ± 0.6 us. 5.7 ± 0.8 (NS) and 5.3 ± 0.3 vs. 0.3 ± 0.2 pulses/6 h (P < 0.001) respectively. In Study 2, peripheral LH secretion was completely suppressed while GnRH secretion (portal blood) remained pulsatile. GnRH pulses frequency and pulse amplitude were 4.3 ± 0.3 pulses/6 h and 43.0 ± 4.7 pg/ml, respectively. In both experiments, neither stimulation of endogenous GnRH secretion by naloxone nor administration of exogenous GnRH allowed reinitiation of LH secretion. However, additional studies in two animals of each treatment group (study III) showed that this was clearly a dose related effect in antagonist treated but not in agonist-treated animals since higher doses of exogenous GnRH (i.e. 100 μg or 1000 μg) can increase significantly LH levels. Our results demonstrate that in short-term castrated ram, neither GnRH agonist nor GnRH antagonist administration affect endogenous GnRH secretion either directly by an action on GnRH neurones or indirectly by a decrease in LH secretion. Our results, therefore, do not support a role for both a short loop and ultrashort loop feedback mechanism in castrated rams. (Endocrinology127: 2523–2529,1990)