Throughout her reproductive life, a woman’s reserve of primordial follicles declines with advancing age, from some 200,000 at puberty to less than 1,000 at menopause. Each primordial follicle contains an oocyte resting in meiotic prophase I. The fate of a follicle destined for ovulation is actually decided 3 months earlier, when it is “awakened” from this primordial pool. Together with several others, it commences a slow maturation process under the influence of paracrine factors until arriving at the pre-antral stage, a crossing point controlled by anti-Müllerian hormone (AMH). At this point the targeted follicles acquire FSH receptors for the first time. Whereas previous growth was FSH-independent, the structures now become hormonally dependent. By the start of a menstrual cycle, several pre-antral follicles, each 2–5 mm in diameter, have survived the sequence of events during this “awakening” period (Fig. 2.1).

As the menstrual cycle terminates, corpus luteal decay results in a fall of estrogen and progestin secretion that triggers a chain of endometrial changes leading to menstruation. This decline of steroids and inhibin A removes their inhibitory effects on the hypothalamic-pituitary axis and permits a rise of FSH that is perceptible in plasma even before the first day of the menstruation.

Enhanced secretion of FSH, at the end of the previous cycle and during the subsequent early follicular phase, stimulates pre-antral follicles inconsistently because the sensitivity of each follicle is correlated with its respective endowment of FSH receptors. As the growing wave of FSH surpasses the threshold of the most hormone-sensitive follicles, a period of rapid growth ensues for those recruited early, and an “FSH window” opens. With concomitant stimulation by pituitary LH, cells of the theca interna deliver an androgen substrate to the aromatase complex of adjacent granulosa cells that will synthetize increasing amounts of estradiol and also the protein hormone inhibin B. Estradiol in turn furthers the synthesis of additional FSH receptors, with assistance from FSH itself. This “snowballing” effect amplifies follicular sensitivity to both gonadotropins and enhances growth of follicles to the antral stage that is evidenced by accumulating follicular fluid. At the same time, estradiol and FSH induce the synthesis of LH receptors on the granulosa cells, thereby promoting still more estrogen secretion.

The few follicles recruited at the beginning of the cycle are asynchronous with the others as a result of their unique sensitivity to FSH. Although initially indistinguishable morphologically from other follicles, the one whose FSH threshold is lowest begins to grow before the others. Its aromatase complex is the first to be aroused by FSH, and it begins to secrete estrogens before the others. This follicle is then enabled to enter the “snowball” phase ahead of the remaining cohort and is becoming the “selected one” to yield a gamete. As the other follicles join to secrete increasing amounts of estradiol and inhibin B, a negative feedback begins to impact pulsatile FSH release at the hypothalamic-pituitary level. On about the seventh day of the menstrual cycle, FSH secretion falls and the “FSH window” closes. Only the selected follicle continues growing, thanks to its rich population of FSH receptors that permits development even in the face of declining FSH. Whereas growth of all the remaining less sensitive follicles diminishes or stops altogether during the late follicular phase, the lead follicle, now 1 cm in diameter, expands due to additional stimulation from an FSH-like effect of LH. The aromatase complex also becomes functionally coupled to LH receptors, permitting additional LH participation in the selected follicle’s primacy and its late follicular phase maturation. By this time all of the other irregularly stimulated follicles that were initially recruited at the beginning of the cycle have undergone atresia and vanish within the ovarian stroma.

When plasma estradiol levels have been maintained in excess of 100 pg/ml for more than 48 h, and when the selected follicular diameter begins to exceed 16 mm, a large release of hypothalamic GnRH elicits a surge of pituitary FSH and LH. This final gonadotropin wave initiates a stream of follicular events leading to an initial erosion of the follicular wall accompanied by an increase of follicular fluid osmotic pressure that provokes a triad of events: a follicular rupture at the apex, a differentiation of the cumulus, and a final maturation of the oocyte itself. The oocyte’s meiotic process is awakened from prophase I through metaphase II, where maturation is again halted to await arrival of a haploid spermatozoon.

Following expulsion of the ovum, the follicle’s remaining granulosa cells become heavily vascularized and join with remaining theca interna to be transformed into luteinized cells. The corpus luteum actively secretes estradiol accompanied by a large output of progesterone, all being directed by a pulsatile signal from pituitary LH. Luteal lifespan is already programmed for 12–14 days unless its function can be rescued and maintained by exponentially rising chorionic gonadotropin (hCG) levels from trophoblast of an implanting embryo. While the menstrual cycle progressively develops under the influence of two pituitary gonadotropins, FSH and LH, the third gonadotropin, hCG, of placental origin, appears once the embryo implants. This signals the transformation of a menstrual cycle into a beginning pregnancy.

Throughout the menstrual cycle, follicle-stimulating hormone is secreted in a pulsatile manner by gonadotrophs in the adenohypophysis, a process that is itself controlled through a pulsatile release of hypothalamic gonadorelin (GnRH). FSH is delivered through blood to specific receptors on the surface of the ovarian granulosa cells and act to promote follicular growth and development. Despite a modest degradation by the liver, and elimination from the body by the kidneys, urinary FSH retains its biological activity (i.e., it is still able to bind to, and activate, ovarian receptors).

The evolution of ovarian follicles is directed by substantial changes of plasma FSH levels throughout the menstrual cycle. Levels are highest during the end of the luteal phase and early follicular phase (the recruitment period). Then FSH begins to decrease in mid-follicular phase (the selection-leadership period) due to the negative feedback effect of rising levels of estradiol and inhibin B (Fig. 2.2). There is a pre-ovulatory surge of FSH, synchronous with the LH surge, and then levels enter a declining period, only to rise again at the end of the luteal phase.

The physiologic role of FSH is directed solely toward proliferation and development of ovarian granulosa cells, thereby to control follicular growth. FSH also induces secretion of inhibin B and, together with estradiol, the appearance and proliferation of LH receptors in the follicle. Finally the pre-ovulatory FSH peak participates importantly in the maturation of the cumulus-oocyte complex.