Chronic elevation of androgens suppresses hypothalamic–pituitary secretion of FSH, a detriment to the development and maturation of a dominant follicle (81). Clinically, androgen excess results in chronic anovulation, as is seen in polycystic ovarian syndrome.
Preovulatory follicles are characterized by a ﬂuid-filled antrum that is composed of plasma with granulosa cell secretions. The granulosa cells at this point have further differentiated into a heterogenous population. The oocyte remains connected to the follicle by a stalk of specialized granulosa known as the cumulus oophorus.
Rising estrogen levels have a negative feedback effect on FSH secretion. Conversely, LH undergoes biphasic regulation by circulating estrogens. At lower concentrations, estrogens inhibit LH secretion. At higher levels, estrogen enhances LH release. This stimulation requires a sustained high level of estrogen (200 pg/mL) for more than 48 hours (84). Once the rising estrogen level produces positive feedback, a substantial surge in LH secretion occurs. Concomitant to these events, the local estrogen–FSH interactions in the dominant follicle induce LH receptors on the granulosa cells. Exposure to high levels of LH results in a specific response by the dominant follicle—the result is luteinization of the granulosa cells, production of progesterone, and initiation of ovulation. Ovulation will occur in the single mature, or Graafian, follicle 10 to 12 hours after the LH peak or 34 to 36 hours after the initial rise in midcycle LH (85–87).
As suggested previously, the sex steroids are not the only gonadotropin regulators of follicular development. Two related granulosa cell–derived peptides were identified that play opposing roles in pituitary feedback (88). The first of these peptides, inhibin, is secreted in two forms: inhibin-A and inhibin-B. Inhibin-B is secreted primarily in the follicular phase and is stimulated by FSH, whereas inhibin-A is mainly active in the luteal phase (89). Both forms of inhibin act to inhibit FSH synthesis and release (90,91). The second peptide, activin, stimulates FSH release from the pituitary gland and potentiates its action in the ovary (92,93). It is likely that there are numerous other intraovarian regulators similar to inhibin and activin, each of which may play a key role in promoting the normal ovulatory process (94). Some of these include follistatin, insulinlike growth factor-1 (ILGF-1), epidermal growth factor (EGF)/transforming growth factor-α (TGF-α), TGF-β1, fibroblast growth factor-β (FGF-β), interleukin-1, tissue necrosis factor-α, OMI, and renin–angiotensin.
The midcycle LH surge is responsible for a dramatic increase in local concentrations of prostaglandins and proteolytic enzymes in the follicular wall (95). These substances progressively weaken the follicular wall and ultimately allow a perforation to form. Ovulation most likely represents a slow extrusion of the oocyte through this opening in the follicle rather than a rupture of the follicular structure (96). Direct measurements of intrafollicular pressures were recorded and failed to demonstrate an explosive event.