Adenylyl cyclase activities in ovarian tissues. II. Regulation of responsiveness to LH, FSH, and PGE1 in the rabbit.

We conducted a study to determine whether a decline in the capacity of preovulatory follicles to accumulate cAMP in response to in vitro LH exposure, reported by Marsh et al. (1), is due to direct desensitization of the LH-hCG-responsive adenylyl cyclase (AC) system. Enzyme activity was determined in the absence and in the presence of 10 mug/ml of LH, FSH, and prostaglandin (PG) E1 in homogenates prepared from Graafian follicles dissected before and at various times after rendering them preovulatory either by mating (endogenous LH release) or by injection of hCG (100 IU/3.5-4.5 g rabbit, iv). Both of these treatments resulted in desensitization of the AC to LH and FSH stimulation, so that by the time of ovulation these responses were absent. hCG-induced desensitization was rapid (50% loss of LH-stimulated activity was obtained within 5 min of injection), was dose-dependent, requiring an ovulatory dose; was selective for LH- and FSH-stimulated activity, being without effect on basal and PGE1 as well as NaF-stimulated activities; and was induced specifically by LH (mating) and hCG-FSH and PRL being without effect. Desensitization of follicular AC does not seem to be mediated by PG, for doses of indomethacin that inhibited ovulation did not interfere with the loss of LH responsiveness. The incubation in vitro of dissected Graafian (estrous) follicles with LH (2 h) also resulted in desensitization to LH stimulation and indicated that this phenomenon was due to a direct effect of LH on the follicles and was not mediated by hormones derived from other endocrine structures. Newly formed corpora lutea (CL) in either pregnancy or pseudopregnancy (PSP) developed a new AC system that was highly responsive to LH and less responsive to FSH and PGE1. This new system persisted for the duration of pregnancy and PSP, and became inactive with regression of CL. The prolongation of PSP by hysterectomy was accompanied by the persistence of an active LH-responsive AC system. The injection of ovulatory doses of hCG into 6-day PSP rabbits produced, within 2 h, a 50% desensitization of the luteal AC systems to LH stimulation. After day 10 of pregnancy, the levels of LH-stimulated AC activity in CL and the levels of progesterone in serum, reported by Challis et al. (2), were found to parallel each other, suggesting that this enzyme activity may be a physiologic regulatory step in progesterone synthesis by the normal CL throughout most of the animal's pregnancy. This finding is discussed in the light of compelling evidence that estrogens are luteotrophic in the rabbit.