Michael, Anthony Edwin; (1992) Intracellular mechanisms involved in the hormonal control of luteal regression in primates. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Although prostaglandin F2α [PGF2α] is luteolytic in non-primates, its role in inducing functional regression of the primate corpus luteum remains unclear. In the marmoset monkey, cloprostenol {a PGF2α analogue} induces luteolysis if injected during the mid-luteal phase. The present study investigated the intracellular mechanisms of this luteolytic action in marmoset luteal tissue and human granulosa cells luteinized in vitro. Cloprostenol inhibited progesterone and cyclic AMP [cAMP] responses to human chorionic gonadotrophin [hCG] and dibutyryl-cAMP [dbcAMP] by marmoset luteal tissue obtained during the mid-luteal phase, but had no effect on gonadotrophin-stimulated progesterone production in the early luteal phase. Conversely, cloprostenol stimulated the generation of [3H]-inositol phosphates by luteal tissue obtained in the early luteal phase, but had no effect on inositol phosphate production by mid-luteal phase tissue. In cultured human granulosa cells, PGF2α and cloprostenol inhibited the progesterone and cAMP responses to hCG, luteinizing hormone [LH] and dbcAMP in a dose-dependent manner. These antigonadotrophic actions were mimicked by a protein kinase C [PKC] activator, 4β-PMA, but were prevented by: (1) inhibition of PKC with staurosporine; (2) PMA-induced down-regulation of PKC; (3) inhibition of cAMP phosphodiesterase with isobutyl methylxanthine; (4) pretreatment with hCG, LH or cAMP analogues. The hydrolysis of [3H]-cAMP was stimulated by PGF2α, cloprostenol and 4β-PMA, although not in PKC down-regulated cells. In conclusion, the luteolytic action of PGF2α/cloprostenol in the primate corpus luteum results from the inhibition of gonadotrophin-induced cAMP generation and action, and involves a stimulation of cAMP phosphodiesterase. These effects are mediated via protein kinase C, although not through increased phosphoinositide turnover. Pre-exposure to gonadotrophin may account for the insensitivity of the corpus luteum to cloprostenol in the early luteal phase and for the suppression of luteolysis in early pregnancy by CG from the implanting embryo.

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