Intraovarian factors in ovulation: determinants of follicular response to gonadotrophins

Abstract

Summary. (1) Follicles vary greatly in their response to a hormonal stimulus. Some of the factors that influence the sensitivity of the rat follicle to ovulatory hormones are discussed in this review. (2) The responsiveness of the rat ovary to gonadotrophins undergoes striking augmentation during the 2nd week of postnatal development with respect to cyclic AMP formation, cAMP-stimulated protein kinase activity, inducibility of ornithine decarboxylase and oestrogen secretion. (3) FSH, probably in concert with oestrogen, sensitizes the follicle to subsequent stimulation of adenylyl cyclase by LH. This synergism, based on heterologous receptor induction, operates during prepubertal as well as cyclic follicular maturation. (4) The ovarian LH-stimulated adenylyl cyclase possesses a guanine nucleotide regulatory site. Occupation of this site by GTP or Gpp(NH)p reduces the concentration of LH required for half-maximal stimulation of the enzyme and increases its activity (Vmax). (5) Androgen synergizes FSH in stimulating progestin secretion by cultured immature granulosa cells, though the steroid is known to antagonize the FSH action on granulosa cell proliferation. Thecal androgen may be required for the maturation of the FSH response mechanism in granulosa cells of preantral follicles, while promoting atresia in large antral follicles. (6) Continued exposure of the follicle to high concentrations of LH, FSH, or PGE-2 results in refractoriness of adenylyl cyclase to further stimulation by the same hormone. Desensitization may be transient (PGE-2) or protracted (LH) and seems to depend on the synthesis of a macromolecular inhibitor that affects the coupling between hormone receptor and adenylyl cyclase. This mechanism may account for the shut-down of follicular steroid production at ovulation, which depends on cAMP, and permit the expression of processes that are inhibited by cAMP. (7) Granulosa cells exert a restraining influence on oocyte maturation which may be transmitted by direct contact and perhaps by substances released into the follicular fluid; this inhibition is reversed by LH. The sensitivity of the oocyte to the meiosis-triggering action of LH increases, and its susceptibility to inhibition by follicular fluid extracts decreases, during the final stages of preovulatory development. (8) Specific binding sites for LH are restricted to the theca interna and the peripheral layers of the membrana granulosa of the preovulatory follicle. Extensive gap junctions between granulosa cells provide an anatomical basis for the propagation of the signal generated by LH to the interior of the follicle. The presence of such gap junctions between cytoplasmic extensions of the coronal cells and the oocyte may serve to control the membrane potential of the oocyte by electrical coupling. Depolarization of this membrane precedes ovum maturation in non-mam-malian species. (9) Prostaglandin synthesis within the follicle is stimulated by LH and is essential for LH-induced follicular rupture. Cells of the external theca contain abundant microfilaments and are rich in actin and smooth-muscle myosin, demonstrable by immunofluorescence. These smooth muscle-like cells may be a target for prostaglandins and/or adrenergic neurotransmitters during ovulation and assist extrusion of the cumulus mass. (10) Actin and myosin occur beneath the oolemma of the mammalian oocyte and may play a part in the dynamics of the maturation divisions. (11) Thecal and granulosa cells in ovarian slices incorporate 35SO4 into chondroitin sulphates and heparin-like substances and rapidly secrete these into the antral fluid. LH suppresses the synthesis of these sulphated glycosaminoglycans; progesterone probably mediates this inhibition. Since the antral S-GAGs include heparin, this secretion may have regulatory actions within the follicle beyond the hydrodynamic effects postulated earlier. (12) Delayed effects of hormones on the sensitivity of the follicle to the same hormone or to the action of a heterologous hormone, and the successive appearance and redistribution of different hormone receptors and specialized membrane components may be significant elements in the programming of a precisely timed developmental sequence that is a characteristic feature of the life history of the follicle.