During the several days following the breakdown of the corpus luteum, growth of the cohort of follicles continues, driven by the stimulus of FSH. The enlarging oocyte secretes a glycoprotein-rich substance, the zona pellucida, which separates it from the surrounding granulosa cells (except for the aforementioned gap junction). With transformation from a primordial to a preantral follicle, there is continued mitotic proliferation of the encompassing granulosa cells. Simultaneously, theca cells in the stroma bordering the granulosa cells proliferate. Both cell types function synergistically to produce estrogens that are secreted into the systemic circulation. At this stage of development, each of the seemingly identical cohort members must either be selected for dominance or undergo atresia. It is likely that the follicle destined to ovulate was selected before this point, although the mechanism for selection remains obscure.
Two-Cell, Two-Gonadotropin Theory
The fundamental tenet of follicular development is the two-cell, two-gonadotropin theory (73,75,76) (Fig. 7.11). This theory states that there is a subdivision and compartmentalization of steroid hormone synthesis activity in the developing follicle. Most aromatase activity (for estrogen production) is in the granulosa cells (77). Aromatase activity is enhanced by FSH stimulation of specific receptors on these cells (78,79). Granulosa cells lack several enzymes that
Figure 7.11 The two-cell, two-gonadotropin theory of follicular development in which there is compartmentalization of steroid hormone synthesis in the developing follicle. LH, luteinizing hormone; FSH, follicle-stimulating hormone.
occur earlier in the steroidogenic pathway and require androgens as a substrate for aromatization. Androgens, in turn, are synthesized primarily in response to stimulation by LH, and the theca cells possess most of the LH receptors at this stage (78,79). Therefore, a synergistic relationship must exist: LH stimulates the theca cells to produce androgens (primarily androstenedione), which in turn are transferred to the granulosa cells for FSH-stimulated aromatization into estrogens. These locally produced estrogens create a microenvironment within the follicle that is favorable for continued growth and nutrition (80). Both FSH and local estrogens serve to further stimulate estrogen production, FSH receptor synthesis and expression, and granulosa cell proliferation and differentiation.
Androgens have two positive regulatory roles in follicular development. Within the ovary, androgens promote granulose cell proliferation, aromatase activity, and inhibit programmed death of these cells (81).
As the peripheral estrogen level rises, it negatively feeds back on the pituitary and hypothalamus to decrease circulating FSH levels (82). Increased ovarian production of inhibin-B further decreases FSH production at this point.
The falling FSH level that occurs with the progression of the follicular phase represents a threat to continued follicular growth. The resulting adverse environment can be withstood only by follicles with a selective advantage for binding the diminishing FSH molecules; that is, those with the greatest number of FSH receptors. The dominant follicle, therefore, can be perceived as the one with a richly estrogenic microenvironment and the most FSH receptors (83). As it grows and develops, the follicle continues to produce estrogen, which results in further lowering of the circulating FSH and creates a more adverse environment for competing follicles. This process continues until all members of the initial cohort, with the exception of the single dominant follicle, have suffered atresia. The stage is then set for ovulation.