Follicular phase

Conventionally considered the first phase, this is the phase of the menstrual cycle leading up to ovulation. In a typical 28-day menstrual cycle, it comprises the first 14 days. In ovulatory cycles of more or less than 28 days’ duration, the deviation from the average is largely caused by differences in the length of the follicular phase.

During this phase of the menstrual cycle, a cohort of ovarian follicles will rapidly mature, although only one typically becomes the dominant follicle, called the Graafian follicle. Those follicles that undergo final maturation in a given cycle have likely been growing for several months prior to that cycle. Progression from the primordial or resting state to the small antral stage is largely gonadotropin-independent. During the few days prior to the start of menstruation, a small cohort of these growing follicles, now at the small antral stage, is recruited for further gonadotropin-dependent growth. As one cycle ends, the scheduled demise of the corpus luteum results in a rapid decline in its hormonal secretion. The resultant fall in serum estradiol releases the central negative feedback inhibition on FSH secretion. Associated declines in progesterone and inhibin A are involved to a lesser degree. Increases in FSH secretion during the late luteal phase are accompanied by an increase in the pulse frequency of LH secretion.

Day 1 of menstrual bleeding is considered the first day of the follicular phase. During days 4–5 of this phase, development of the recruited ovarian follicle cohort is characterized by FSH-induced granulosa cell proliferation and aromatase activity. The theca cells of the developing follicle produce androgen precursors. These are converted into estradiol within neighboring granulosa cells. The process has been called the two-cell hypothesis (Chapter 2). Estradiol levels increase. The recruited follicles have several layers of granulosa cells surrounding their oocytes and a small accumulation of follicular fluid. FSH induces synthesis of additional FSH receptors on granulosa cells, expanding its own effects. FSH also stimulates synthesis of new LH receptors on the granulosa cells, thereby initiating LH responsiveness.

By days 5–7 of the menstrual cycle, a single, selected follicle predominates to the detriment of the others in the selected cohort, and will mature and ovulate between days 13 and 15. The predominant follicle is characterized by the highest mitotic index of all the recruited follicles, an optimal capacity for FSH retention in its follicular fluid, and high estradiol and inhibin B synthesis. Nondominant follicles have elevated androgen : estrogen ratios in their follicular fluid, suggesting suboptimal induction of aromatase activity, and will undergo atresia. Androgens appear to be key to the atresia process, as granulosa cells treated with androgen in vitro undergo apoptosis.

During the mid to late follicular phase, continued elevations in circulating estradiol and inhibin B suppress FSH secretion, so preventing new follicular recruitment. Continuous high elevations of circulating estradiol exert a somewhat unexpected effect on the pituitary gland; exponential increases in LH secretion. The ovary also exhibits increased responsiveness to the gonadotropins. Lastly, high estrogen levels cause growth of the endometrial tissue lining the uterus. These changes in the endometrium can be distinguished microscopically and are defined as the “proliferative phase” (Chapter 10).