Regulation of the human menstrual cycle.

Our understanding of the regulation of the menstrual cycle has recently improved with the development of various tools of investigation. The cycle is now thought to be determined mainly by the ovary itself, which sends various signals to the pituitary and the hypothalamus. The aim of the cycle is to produce a single mature oocyte each month from puberty to menopause. However, the most common evolution of a follicle is atresia, a consequence of the genetically controlled, ovarian apotosis (or "programmed cell death"). Follicular growth and maturation are mostly independent of gonadotropins, from the stage of primordial follicles to antral follicles. A complete intraovarian paracrine system is implied in this gonadotropin-independent follicular growth, and in the modulation of the actions of the gonadotropins in the ovary. FSH allows the rescue of a minority of follicles from atresia and is indispensable to only the final maturation of the preovulatory follicle. The cyclical variations of the gonadotropins are under the control of ovarian steroids (estradiol and progesterone) and peptides (inhibin). The cycle length is determined by follicular growth and by the fixed life span of the corpus luteum. The mechanism of action of gonadotropins is much better understood since the gonadotropins and their receptor cDNA have been cloned. The recent description of naturally occurring mutations has lead to a better understanding of the role of each gonadotropin, demonstrating the crucial role of FSH in the terminal maturation of the follicles. The ovarian cycle can also be monitored at the level of target tissues of steroids such as the endometrium. The cellular mechanisms of endometrial maturation, under the control of estradiol and progesterone, are better understood. The endometrial maturation is synchronized to follicular development and allows implantation of the conceptus. The genes implied in the implantation of the embryo are being identified (e.g., integrins). Last but not least, the mechanisms of endometrial shedding are being elucidated, especially the role of metalloproteases and angiogenic factors. These concepts will allow the development of new treatments for infertility, the design of new contraceptive techniques, and a better tolerance of treatments using sex steroids, particularly progestin-only pill.