During the first few days of the follicular phase, multiple follicles have the potential to ovulate and can be rescued from atresia by treatment with supraphysiological amounts of FSH. This accounts for the high frequency of multiple births following therapies for infertility that involve administration of gonadotropins or agents such as clomiphene that stimulate endogenous gonadotropin secretion. Production of multiple ova (superovulation) induced in this way is used for harvesting eggs for in vitro fertilization technologies.
by the corpus luteum and is called the luteal phase. It also lasts about 14 days. Ovulation occurs at midcycle and requires only about a day. These events are orchestrated by a complex pattern of pituitary and ovarian hormonal changes. Even as the ripening follicle is prepared for ovulation, preparations are underway in the background to set the stage for the next cycle in the event that fertilization does not occur.
Early growth of follicles from the primordial to the preantral stage is independent of pituitary hormones and is likely governed by paracrine factors produced by the ovum itself as well as by granulosa and thecal cells. Follicular sensitivity to gonadotropins becomes evident at the early antral stage and gradually increases as individual follicles in each cohort slowly increase from about 0.2 to 2 mm in diameter, at which time they are capable of undergoing the rapid growth and development that lead to ovulation. Approximately 85 days elapse between entry of a cohort of follicles into the gonadotropin-responsive stage and ovulation of one of them. During this time all follicles in both ovaries are exposed to wide swings in gonadotropin concentrations, but their capacity to respond is limited by their degree of development. Ovulation occurs at the midpoint of the fourth cycle after a cohort of follicles reaches the antral stage and has been growing in response to gonadotropins; consequently, the next three cohorts are already being prepared to ovulate. The number of follicles with the potential to ovulate in each cohort is reduced by atresia at all stages of development.
Under normal circumstances, only one follicle ovulates in each cycle. The ovulatory follicle is randomly located on either the right or left ovary. Usually 6 to 12 follicles are mature enough to enter into the final preovulatory growth period near the end of the luteal phase of the preceding cycle and begin to grow rapidly in response to the increase in FSH that occurs at that time. The ovulatory or "dominant" follicle is selected from this group early in the follicular phase that leads to its ovulation. The physiological mechanisms for selection of a single dominant follicle are not understood. Recruitment of the next cohort of follicles does not begin as long as the dominant follicle or its resultant corpus luteum is present and functional. Experimental destruction of either the dominant follicle or the corpus luteum is promptly followed by selection and development of a new ovulatory follicle from the next cohort.
Granulosa cells in antral follicles are the only targets for FSH. No other ovarian cells are known to have FSH receptors. Granulosa cells of the ovulatory follicle are the major and virtually only source of estradiol in the follicular phase of the ovarian cycle and secrete estrogens in response to FSH. Until about the middle of the follicular phase, LH receptors are found only in cells of the theca interna and the stroma. LH stimulates thecal cells to produce androstenedione. Follicular synthesis of estrogen depends on complex interactions between the two gonadotropins and between theca and granulosa cells. Although isolated theca and granulosa cells may be able to synthesize some estrogens, cooperative interaction of both cell types is required for physiologically relevant rates of estradiol production in the follicular phase. Neither granulosa nor theca cells express the full complement of enzymes needed for synthesis of estradiol. Granulosa cells are limited in their capacity to produce pregnenolone because they have little access to cholesterol delivered by the circulation in the form of low-density lipoproteins (LDLs), express few LDL receptors, and have minimal levels of the P450scc necessary to convert cholesterol to pregnenolone (Fig. 6). Theca cells, which have a direct capillary blood supply, express high levels of LDL receptors, as well as high levels of P450scc and P450c17. Theca cells thus can metabolize the 21-carbon pregnenolone to the 19-carbon androstenedione but lack aromatase and hence cannot synthesize estrogens. Granulosa cells, on the other hand, express ample aromatase but cannot produce its 19-carbon substrate because they lack P450c17; however, granulosa cells readily aromatize androgens provided by diffusion from the theca interna. This two-cell interaction is illustrated in Fig. 7. The participation of two different
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