Infusion of Progestins into the Hypothalamus of Female New Zealand White Rabbits: Effect onin VivoLuteinizing Hormone-Releasing Hormone Release as Determined with Push-Pull Perfusion*

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Abstract
Previously, we have reported that intermittent infusion of progesterone (P4; 10ng/ml) into the hypothalamus of conscious unrestrained female New Zealand White rabbits stimulates LHRH release in vivo. To further investigate this phenomenon, in the present studies, the effect of pulsatile (six pulses; 10 min on, 30 min off) and continuous infusion of P4 (Exp I) and 4-pregnen-20.alpha.-ol-3-one or 20.alpha.-hydroxyprogesterone (20.alpha.-OH-P; Exp II) on LHRH release were studied in vivo using push-pull cannulae. Furthermore, the effect of pulsatile infusion (six pulses; 10 min on, 30 min off) of low doses of the following three pregestins [5.beta.-pregnan-3.beta.-ol-20-one (pregnanolone), 5.alpha.-pregnan-3.alpha.-ol-20-one (3.alpha.-5.alpha.-P), and 20.alpha.-OH-P] into the hypothalamus of does using push-pull cannulae were examined in Exp III. In Exp I, continuous infusion of P4 at 10 ng/ml was unable to stimulate mean LHRH release. However, pulses of P4 at 0.01 ng/ml (n = 4) were found to significantly increase the amplitude of the largest LHRH pulse (control period, 1.18 .+-. 0.41; versus treatment period, 3.15 .+-. 0.75 pg; P < 0.035) as well as the frequency of LHRH pulses (control period, 0.72 .+-. 0.26; treatment period, 1.37 .+-. 0.12 pulses/h; P < 0.035). On the other hand, there was no effect of pulses of P4 at 0.001 ng/ml (n = 4) on the activity of the LHRH neural apparatus. In Exp II, pulses of 20.alpha.-OH-P at 10 ng/ml (n = 4) were found to significantly increase the mean LHRH release (control period, 1.24 .+-. 0.10; treatment period, 2.07 .+-. 0.52 pg/10 min) as well as the amplitude of the largest LHRH pulse (control period, 0.99 .+-. 0.36; treatment period, 8.15 .+-. 3.75 pg). Interestingly, continuous infusion of 20.alpha.-OH-P (10 ng/ml) also significantly increased the mean amplitude (control period, 0.58 .+-. 0.34; treatment period, 1.90 .+-. 0.29 pg) as well as the amplitude of the largest LHRH pulse (control period, 0.64 .+-. 0.37; treatment period, 4.30 .+-. 1.97 pg). In contrast, in Exp III, pregnanolone, but neither 3.alpha.-5.alpha.-P nor 20.alpha.-OH-P, infused at 0.001 ng/ml significantly increased the mean LHRH release (control period, 0.92 .+-. 0.31; treatment period, 1.80 .+-. 0.99 pg/10 min; P < 0.035) as well as the mean amplitude (0.86 .+-. 0.52 to 2.32 .+-. 1.30 pg; P < 0.035) and frequency of the LHRH pulses (0.70 .+-. 0.32 to 1.15 .+-. 0.18 pulses/h; P < 0.035). In addition, there was a significant increase in the amplitude of the largest LHRH pulse amplitude (1.13 .+-. 0.58 to 4.93 .+-. 3.35 pg). Overall, these results confirm that pulsatile and not continuous infusion of P4 is able to stimulate LHRH release at 10 ng/ml. In addition, pulsatile infusion of 20.alpha.-OH-P was also quite effective in stimulating LHRH release at 10 ng/ml. More importantly, pregnanolone, but not 3.alpha.-5.alpha.-P, is the most potent stimulator of all the progestins tested including P4, since concentrations of 0.001 ng/ml were highly effective. These data indicate that pregnanolone may be playing an important role in regulating the activity of the LHRH neural apparatus either as a metabolite of P4 or through a direct effect.