At any given time, a small group of follicles is maturing. However, after progressing to a certain stage, most oocytes and their follicles die. To survive, the follicle must be exposed to a wave of gonadotropic hormone release, icatch the wavei at the right time, and ride it until it peaks. Thus, for oocyte maturation to occur, the follicle needs to be at a certain stage of development when the waves of gonadotropin arise.
The first day of vaginal bleeding is considered to be day 1 of the menstrual cycle (Figure 1). This bleeding represents the sloughing off of endometrial tissue and blood vessels that would have aided the implantation of the blastocyst. In the first part of the cycle (called the proliferative or follicular phase), the pituitary starts secreting increasingly large amounts of FSH. Any maturing follicles that have reached a certain stage of development respond to this hormone with further growth and cellular proliferation. FSH also induces the formation of LH receptors on the granulosa cells. Shortly after this period of initial follicle growth, the pituitary begins secreting LH. In response to LH, the dictyate meiotic block is broken. The nuclear membranes of competent oocytes break down, and the chromosomes assemble to undergo the first meiotic division. One set of chromosomes is kept inside the oocyte, and the other ends up in the small polar body. Both are encased by the zona pellucida, which has been synthesized by the growing oocyte. It is at this stage that the egg will be ovulated.
The two gonadotropins, acting together, cause the follicle cells to produce increasing amounts of estrogen, which has at least five major activities in regulating the further progression of the menstrual cycle:
- It causes the uterine endometrium to begin its proliferation and to become enriched with blood vessels.
- It causes the cervical mucus to thin, thereby permitting sperm to enter the inner portions of the reproductive tract.
- It causes an increase in the number of FSH receptors on the granulosa cells of the mature follicles while causing the pituitary to lower its FSH production. It also stimulates the granulosa cells to secrete the peptide hormone inhibin, which also suppresses pituitary FSH secretion.
- At low concentrations, it inhibits LH production, but at high concentrations, it stimulates it.
- At very high concentrations and over long durations, estrogen interacts with the hypothalamus, causing it to secrete gonadotropin-releasing hormone.
As estrogen levels increase as a result of follicular production, FSH levels decline. LH levels, however, continue to rise as more estrogen is secreted. As estrogen continues to be made (days 7n10), the granulosa cells continue to grow.
Starting on day 10, estrogen secretion rises sharply. This rise is followed at midcycle by an enormous surge of LH and a smaller burst of FSH. Experiments with female monkeys have shown that exposure of the hypothalamus to greater than 200 picograms of estrogen per milliliter of blood for more than 50 hours results in hypothalamic secretion of gonadotropin-releasing hormone. This factor causes the subsequent release of FSH and LH from the pituitary. Within 10 to12 hours after the gonadotropin peak, the egg is ovulated (Garcia et al. 1981).
Although the detailed mechanism of ovulation is not yet known, the physical expulsion of the mature oocyte from the follicle appears to be the result of an LH-induced increase in collagenase, plasminogen activator, and prostaglandins within the follicle (Lemaire et al. 1973). Prostaglandins may cause localized contractions in the smooth muscles of the ovary and may also increase the flow of water from the ovarian capillaries, increasing fluid pressure in the antrum (Diaz-Infante et al. 1974; Koos and Clark 1982). If ovarian prostaglandin synthesis is inhibited, ovulation does not take place. In addition, collagenase and the plasminogen activator protease loosen and digest the extracellular matrix of the follicle (Beers et al. 1975; Downs and Longo 1983). The mRNA for plasminogen activator has been dormant in the oocyte cytoplasm. LH causes this message to be polyadenylated and translated into this powerful protease (Huarte et al. 1987). The result of LH, then, is increased follicular pressure coupled with the degradation of the follicle wall. A hole is digested through which the ovum can burst.
Following ovulation, the luteal phase of the menstrual cycle begins. The remaining cells of the ruptured follicle, under the continued influence of LH, become the corpus luteum. (They are able to respond to this LH because the surge in FSH stimulates them to develop even more LH receptors.) The corpus luteum secretes some estrogen, but its predominant secretion is progesterone. This steroid hormone circulates to the uterus, where it completes the job of preparing the uterine tissue for blastocyst implantation, stimulating the growth of the uterine wall and its blood vessels. Blocking the progesterone receptor with the synthetic steroid mifepristone (RU486) stops the uterine wall from thickening and prevents the implantation of a blastocyst* (Couzinet et al. 1986; Greb et al. 1999).
Progesterone also inhibits the production of FSH, thereby preventing the maturation of any more follicles and ova. (For this reason, a combination of estrogen and progesterone has been used in birth control pills. The growth and maturation of new ova are prevented as long as FSH is inhibited.)
If the ovum is not fertilized, the corpus luteum degenerates, progesterone secretion ceases, and the uterine wall is sloughed off. With the decline in serum progesterone levels, the pituitary secretes FSH again, and the cycle is repeated. However, if fertilization occurs, the trophoblast secretes a new hormone, luteotropin, which causes the corpus luteum to remain active and serum progesterone levels to remain high. Thus, the menstrual cycle enables the periodic maturation and ovulation of human eggs and allows the uterus to periodically develop into an organ capable of nurturing a developing organism for 9 months.
*This is why RU486 is used for postconception birth control. RU486 is thought to compete for the progesterone receptor inside the nucleus. RU486 can bind to the progesterone site in the receptor, and the receptor-RU486 complex appears to form heterodimers with the normal progesterone-carrying progesterone receptor. When this RU486-progesterone complex binds to progesterone-responsive enhancer elements on the DNA, transcription from these sites is inhibited (Vegeto et al. 1992; Spitz and Bardin 1993).
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Diaz-Infante, A., K. H. Wright and E. E. Wallach. 1974. Effects of indomethacin and PGF2a on ovulation and ovarian contraction in the rabbit. Prostaglandins 5: 567n581.
Downs, S. and F. J. Longo. 1983. Prostaglandins and preovulatory follicular maturation in mice. J. Exp. Zool.228: 99n108.
Garcia, J. E., G. S. Jones and G. L. Wright. 1981. Prediction of the time of ovulation. Fertil. Steril. 36: 308n315.
Greb, R. R., L. Kiesel, A. K. Selbmann, M. Wehrmann, G. D. Hodgen, A. L. Goodman and D. Wallwiener. 1999. Disparate actions of mifepristone (RU 486) on glands and stroma in the primate endometrium. Hum. Reprod. 14: 198n206.
Huarte, J., D. Belin, A. Vassalli, S. Strickland and J.-D. Vassalli. 1987. Meiotic maturation of mouse oocytes triggers the translation and polyadenylation of dormant tissue-type plasminogen activator mRNA. Genes Dev. 1: 1201n1211.
Koos, R. D. and M. R. Clark. 1982. Production of 6-keto-prostaglandin F1a by rat granulosa cells in vitro. Endocrinology 111: 1513n1518.
Lemaire, W. J., N. S. T. Yang, H. H. Behram and J. M. Marsh. 1973. Preovulatory changes in concentration of prostaglandin in rabbit Graafian follicles. Prostaglandins 3: 367n376.
Spitz, I. M. and C. W. Bardin. 1993. Mifepristone (RU486): A modulator of progestin and glucocorticoid action. N. Engl. J. Med. 329: 404n412.
Vegeto, E., G. F. Allan, W. T. Schrader, M.-J. Tsai, D. P. McDonnell and B. W. OiMalley. 1992. The mechanism of RU486 antagonism is dependent on the conformation of the carboxy-terminal tail of the human progesterone receptor. Cell 69: 703n713.