Contraceptive progestins and gonadotropin secretion in vitro.
In an in vitro bioassay using rat pituitary cell cultures the effect of contraceptive progestins was tested on basal and gonadotropin-releasing hormone (GnRH)-induced luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion in vitro. Progestins diminished gonadotropin release in pituitary cells stimulated with GnRH, but did not alter basal values. This inhibitory effect was dose dependent in a range of 10(-10)-10(-5) M tested and the inhibitory action of most of the progestins examined was more potent than that of progesterone. The maximal reduction of LH and FSH values was by 60% of GnRH-induced control levels. Progestins also caused a shift in sensitivity of cells to GnRh (10(-12)-10(-6) M). When time dependence was investigated, some progestins potentiated GnRH effect on gonadotropins in pituitary cell cultures pre-incubated for a short time (4 h) with steroids. More prolonged pre-incubations from 23 to 71 h resulted in a progressive suppression of LH and FSH response to GnRH (10(-7) M). In order to examine intracellular effects, cells were pretreated with progestins and inositol phosphate metabolism was investigated. The data obtained in pituitary cells give evidence that polyphosphoinositide breakdown is potentially an early step in the action of GnRH on gonadotropin secretion by providing diacylglycerol and inositol phosphates. Addition of gonadotropin-releasing hormone to myo-2[3H]inositol-prelabeled rat pituitary cells in primary culture evoked a dose-dependent increase of the accumulation of [3H]inositol phosphates with a rise of inositol triphosphate, inositol diphosphate and inositol monophosphate within 1 min. Using one contraceptive progestin, gestoden, inositol phosphate production was inhibited by 80% compared to controls of GnRH-treated cells without the addition of steroids. The data obtained in this study suggest that this in vitro bioassay using rat pituitary cells is a useful tool in testing progestational compounds regarding their potency on gonadotropin release. In addition, these results show that one possible site of interference of progestins with GnRH-induced gonadotropin secretion may involve polyphosphoinositide breakdown.
D000818:Animals; D004305:Dose-Response Relationship, Drug; D005260:Female; D005640:Follicle Stimulating Hormone / Q000378:metabolism*; D007987:Gonadotropin-Releasing Hormone / Q000494:pharmacology; D007295:Inositol Phosphates / Q000378:metabolism; D007700:Kinetics; D007986:Luteinizing Hormone / Q000378:metabolism*; D010903:Pituitary Gland, Anterior / Q000187:drug effects / Q000378:metabolism*; D011374:Progesterone / Q000494:pharmacology; D045167:Progesterone Congeners / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains
D007295:Inositol Phosphates; D045167:Progesterone Congeners; D007987:Gonadotropin-Releasing Hormone; D011374:Progesterone; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone