Regulation of Granulosa Cell Proliferation in the Rat

Abstract

The growth and maturation of the ovarian follicle is central to reproductive cyclicity in females and is under the endocrine control of the pituitary gonadotropins FSH and LH, as well as locally produced steroids and growth factors. A fundamental aspect of follicle development is proliferation and differentiation of granulosa cells, although the precise temporal dynamics and regulation remain largely unknown. FSH acts through its receptor to stimulate estradiol synthesis, which together with FSH induces proliferation of the granulosa cells in preantral and small antral follicles (95). In contrast, the LH surge initiates ovulation and formation of the corpus luteum (luteinization) in preovulatory follicles. Luteinization has been considered the terminal differentiation of granulosa to luteal cells and has been associated with a rapid reduction in granulosa cell proliferation (36, 114). However, more recent evidence suggests that (a) cell cycle control and luteinization are not functionally and/or mechanistically linked (113, 137), and (b) luteinization is associated with additional granulosa cell proliferation (100, 124, 126-128). The data presented herein challenge the dogma that granulosa cell proliferation is strictly associated with follicle growth and exit from the cell cycle is strictly associated with the LH surge and luteinization. The role of granulosa cell proliferation and differentiation in follicular development and luteinization is only just now beginning to be elucidated. Several ovarian pathologies are associated with defects in these processes, including luteinized unruptured follicle syndrome and polycystic ovarian syndrome (PCOS). PCOS, in particular, is a serious public health issue, affecting anywhere from 3.4% to 6.8% of women (138). Among females undergoing assisted reproductive technology (ART) cycles in the United States in 2003, 6% had been diagnosed with ovulatory dysfunction (139). Thus, pathologies associated with follicular development and luteinization have the potential to afflict large numbers of reproductive-age women. Further, the use of controlled ovarian stimulation (COS) cycles to generate large numbers of oocytes for use in ART procedures is fraught with problems, such as a shortened luteal phase as well as a heterogeneous population of antral follicles likely differing in size, health, and oocyte quality (140) all affecting the rate of pregnancy from these procedures. For example, of the 122,872 ART cycles performed in 2003, only 35, 785 (-30%) resulted in a live birth (139). Finally, a better understanding of the processes that govern granulosa cell proliferation has important ramifications for ovarian cancer, especially rare juvenile granulosa cell tumors that are nevertheless associated with a high mortality (141).