The growth of ovarian follicles, ovulation, and the formation of the corpus luteum are complex processes that involve dramatic changes in granulosa cell function. The changes are sequential and are dictated by specific, tightly regulated responses to gonadotropins, steroids, and growth factors. One of the most dramatic changes in granulosa cell function is the rapid switch from the highly proliferative stage characterizing granulosa cells of preovulatory follicles to the nonproliferative, terminally differentiated phase of luteal cells. Some of the cell cycle regulatory mechanisms mediating this switch, as well as their control by hormones, are the topics of this minireview. buy ortho tri-cyclen
In primordial follicles, the oocyte is surrounded by a single layer of nondividing granulosa cells arrested in Go phase of the cell cycle. Primordial follicles leave this quiescent state and initiate a phase of slow growth in which the granulosa cells have entered the cell cycle but proliferation is exceedingly slow. However, as these slowly dividing granulosa cells acquire enhanced responsiveness to FSH and LH and begin producing estradiol, exposure to these hormones triggers a rapid burst of proliferation that results in the formation of large preovulatory follicles. This rapid phase of growth is characterized by a marked increase in the labeling of granulosa cells by tri-tiated thymidine, as well as by 5-bromodeoxyuridine (BrdU). Granulosa cells of these preovulatory follicles not only are highly proliferative but are also differentiating and acquire LH receptors. The LH surge then triggers dramatic changes in both follicular structure and function. LH terminates follicular growth by causing granulosa cells of preovulatory follicles to exit the cell cycle and rapidly initiates a program of terminal differentiation (lu-teinization) in which the cells cease to divide. As shown herein, the exit of preovulatory granulosa cells from the cell cycle occurs within about 4 h after the LH surge (Fig. 1), and this related to dramatic changes in specific molecules regulating cell cycle progression (see Figs. 4 and 5). In addition, follicular rupture (ovulation) occurs and granulosa cells luteinize to form mature corpora lutea. Interestingly, granulosa cells are completely reprogrammed to luteinize by 7 h after exposure to the LH surge.
FIG. 1. Changes in granulosa cell proliferation in the ovary detected by BrdU labeling. Preovulatory follicles in mice 48 h after treatment with 4 IU eCG have many proliferating granulosa cells, seen as cells with black nuclei. In response to the LH surge (5 IU hCG), these cells exit the cell cycle, as seen by the absence of labeled granulosa cells in large preovulatory follicles. Methods as described previously. X200 (reproduced at 88%).