Molecular aspects of hormone action in ovarian follicular development, ovulation, and luteinization.

As stated earlier, the mammalian ovary maintains the continuous development of follicles, but only a few are selected to ovulate and form corpora lutea. These processes are regulated primarily by the gonadotropins and involve specific, sequential changes in the function of theca cells and granulosa cells. Data from recent studies (summarized in Figure 3) show that specific genes are turned on or off at different stages of follicular growth in response to estradiol and different amounts of gonadotropins and cAMP. For example, mRNA for RII51 in granulosa cells and theca cells increases in association with small increased in cAMP but is markedly reduced by the LH surge and high cAMP. The content of mRNA for other kinase subunits, RI and C alpha, show little or no change during similar hormonal changes. In theca cells, mRNA for 17 alpha-hydroxylase increased and decreased in a manner similar to that for RII51. In contrast, levels of mRNA for P450scc increased only gradually in follicles but were markedly increased by the LH surge and high concentrations of cAMP and then appeared to be constitutively expressed in rat corpora lutea in a cAMP-independent manner. PGS and t-PA appear to follow yet another pattern: rapid induction by the LH surge followed by a rapid decline in association with ovulation. One major task for reproductive endocrinologists and molecular biologists now is to determine how low and high concentrations of cAMP act to turn on and turn off the expression of these specific genes at specific times during follicular maturation. A working model of the molecular events occurring in theca and granulosa cells of PO follicles is shown in Figure 4. LH acts on theca cells via cAMP ro regulate both P450scc and P450(17) alpha mRNA levels, leading to increased biosynthesis of androstenedione. The mechanisms by which cAMP acts in theca cells remain to be determined but appear to involve an increase in the content of RII51, P450scc, and P450(17) alpha. In granulosa cells, androstenedione is converted to estradiol by the aromatase P450 enzyme system. Estradiol, in turn, binds to estradiol receptors present in these cells and may thereby regulate gene expression. However, despite the presence of estradiol and estradiol receptors, little or no effect of estradiol is observed unless FSH acts via the FSH receptor to increase intracellular concentrations of cAMP. In a manner not yet understood, cAMP appears to enhance the actions of estradiol.(ABSTRACT TRUNCATED AT 400 WORDS)