Studies on the mechanism of PGF2alpha and gonadotropin interactions on LH receptor function in corpora lutea during luteolysis.

1. In the present experiments evidence was shown which demonstrates that PGF2alpha treatment of the rat produces a rapid fall in circulating progesterone in the latter part of pseudopregnancy but not shortly after corpus luteum formation. This refractory period of at least 3 days following ovulation is similar to that which occurs in large animals, such as the cow. 2. Loss of luteal LH receptors was associated with a loss in LH-stimulated progesterone synthesis and an attenuation of LH-stimulated cyclic AMP synthesis in vitro, a finding which supports a functional loss of LH activity in such tissues exposed in vivo to PGF2alpha. Tissue levels of cyclic GMP were generally decreased by both LH, PGF2alpha, and incubation and the relevance of the latter cyclic nucleotide remains obscure in luteolysis and corpus luteum function. 3. The depression of progesterone induced by PGF2alpha precedes a marked drop in corpus luteum LH receptors but no change in reeptor affinity was seen. For example, the first significant drop in LH receptors was observed 8 hr after PGF2alpha treatment whereas serum progesterone was depressed within 2 hr. 4. Prolactin administration to animals simultaneously with PGF2alpha blocked the loss in LH receptors and serum progesterone observed with PGF2alpha treatment alone. In one experiment, but not in the other, prolactin treatment alone produced an elevation in corpus luteum LH receptors. Suppression of endogenous prolactin secretion with ergocryptine mimicked the effect of PGF2alpha on both the LH receptor and serum progesterone and this effect was also blocked with simultaneous prolactin treatment. It is concluded that the mechanism of PGF2alpha-induced luteolysis has several components. The initial event appears to be due to direct gonadotropin antagonism which occurs independently from a change in quantity of luteal LH receptors. This effect has been shown in vitro (10) as well as in vivo (3) and the mechanism appears not to be related to changes in ovarian hemodynamics and not to direct antagonism of LH binding to its receptor (23). Possibly the early effect of PGF2alpha may be due to elevation of cGMP which then antagonizes cyclic AMP action, but our studies to date have been unsuccessful in demonstrating such a response. Eight hours following PGF2alpha administration, the first measurable decrease in LH receptors was seen and this response was correlated with the first sign of functional luteolysis, elevation of serum 20alpha-ol. The latter response is correlated with a loss of prolactin action on the corpus luteum; it was therefore interesting to observe that prolactin blocked, and ergocryptine mimicked, the PGF2alpha effect on the LH receptor and serum progesterone. Thus, one is lead to the conclusion that the mechanism of luteolysis produced by PGF2alpha in the rat is closely associated with a loss in prolactin activity...