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The action of progesterone (P) to block estradiol-induced gonadotropin surges in the rhesus monkey requires an intact hypothalamus. The present study was performed to determine whether the blocking action of P is the result of an inhibition in hypothalamic GnRH secretion or of some other mechanism. Ovulatory menstrual cycles were initiated in acyclic rhesus monkeys with intact nervous systems by a pulsatile GnRH replacement regimen previously shown to be effective in sustaining normal ovarian cycles in monkeys with hypothalamic lesions. Whereas unambiguous surges of LH and FSH were elicited by estradiol benzoate during the follicular phase of these cycles, no such gonadotropin discharges were obtained in the presence of luteal phase levels of P generated by sc P-containing Silastic capsules. Because exogenous GnRH replacement was provided throughout these experiments, it is concluded that P blockade of estradiol-induced gonadotropin surges is not the consequence of an interruption in GnRH release. The results suggest, rather, that P may cause the production of an inhibitory factor from the central nervous system which blocks the positive feedback action of estradiol on the pituitary gland.

The site of action of progesterone (P) in the blockade of estradiol-induced gonadotropin discharges was examined in rhesus monkeys bearing hypothalamic lesions which abolish endogenous GnRH production. Normal ovulatory menstrual cycles were re-established in these animals by the pulsatile, hourly administration of GnRH. In the follicular phase of these induced menstrual cycles, P-containing Silastic capsules were implanted sc yielding luteal phase plasma P concentrations which normally block estradiol-induced gonadotropin surges. P failed to block estradiol-induced surges in lesioned animals on GnRH replacement. In such animals, however, P advanced the initiation of these surges. While estradiol acts on the pituitary to cause gonadotropin discharges, P appears to block this effect by acting on the central nervous system. On the other hand, the results also suggest that the site of facilitatory action of P on gonadotropin release is at the level of the pituitary gland.

The suppression during lactation of pulsatile LH release and pituitary GnRH receptors has been attributed to a primary deficit in hypothalamic GnRH release. In the present investigation we have attempted to characterize the responsiveness of the lactational hypothalamus using the excitatory amino acid receptor agonist N-methyl-aspartic acid (NMA) to stimulate LH and PRL secretion. Lactating rats were ovariectomized on day 2 postpartum, and their litters were adjusted to eight pups. Dual venous catheters were implanted 6-7 days later, and rats were fitted with protective tethers and jackets for chronic pulsatile infusions of GnRH and NMA. GnRH pulses (5 or 10 ng/pulse once every 50 min) were administered for 20 h to up-regulate GnRH receptors and restore pituitary responsiveness to GnRH. Rats were then infused with NMA (40 mg/kg BW.pulse) once every 50 min for four pulses or once every 2 h over a 24-h period. Blood samples were collected at 10-min intervals at times surrounding the final two GnRH pulses, the first several NMA pulses, and the final three NMA pulses 24 h later. Samples were analyzed for LH and PRL by RIA. Procedural control experiments were performed in normal adult rats with NMA administered at 20 mg/kg BW.pulse in males and at 20 and 40 mg/kg BW.pulse in females. Whereas normal rats responded to NMA pulses with unambiguous LH and PRL peaks, lactating rats failed to show LH responses either acutely or after 24 h of treatment. PRL responses to the drug depended upon the circulating levels of the hormone immediately preceding each NMA pulse. When levels were elevated (presumably due to intermittent suckling by the pups), NMA infusion resulted in an acute suppression of PRL. When PRL levels were low, NMA appeared to neither stimulate nor inhibit this hormone. These data suggest that GnRH release from the hypothalamus of the lactating rat is refractory to NMA stimulation, perhaps due to suckling-induced activation of endogenous opioid peptide or gamma-aminobutyric acid systems that could suppress GnRH neurons. Conversion of the PRL response from stimulation by NMA in normal animals to inhibition during lactation might be attributed to simultaneous activation of both dopamine neurons and the PRL-releasing factor system. According to this hypothesis, the response to NMA would be dominated by PRL-releasing factor in normal rats and by dopamine in lactating animals, which have a lower dopamine turnover rate and thus a greater potential for becoming activated by NMA.