Factors Determining the Diurnal Variation in Progesterone-Induced Gonadotropin Release in the Ovariectomized Rat*

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Abstract
Mechanisms underlying the diurnal variation in the gonadotropin-releasing effect of progesterone (P) in the estrogen-primed ovariectomized rat were investigated. As large amounts of LH and FSH are released in the afternoon and evening but not in the morning, the following possibilities were tested: 1) active P metabolites are not available in the morning; 2) central monoaminergic pathways mediating the P response are inactive in the morning; and 3) pituitary sensitivity to LHRH is enhanced in the afternoon. All P metabolites tested (as well as ACTH) led to significant LH surges in the early afternoon but not in the morning. The serotonin precursor, 5-hydroxytryptophan, administered in conjunction with P in the morning caused a significant, increase of LH and FSH, whereas the noradrenaline precursor, DL-threo-dihydroxyphenyl-serine, and the a-noradrenaline receptor agonist, clonidine, were without effect. The serotonin antagonist Sandoz 26-921 administered simultaneously with P at 1200 h blocked the P-induced LH surge but not the FSH surge in the afternoon. Peak values of both LH and FSH obtained in response to a LHRH analog were significantly greater in the afternoon, but the overall response (expressed as the area under the curve) failed to reflect this difference. The absence of the P response in the morning may thus be caused, at least in part, by reduced activity of central serotoninergic neurons. In contrast, neither the availability of P metabolites in the morning nor pituitary responsiveness appears to be rate limiting.