The Menstrual Cycle
Gametogenesis and steroidogenesis proceed in a continuous fashion in the postpubertal human male. In contrast, the postpubertal human female exhibits repetitive cyclic changes in the hypothalamic–pituitary–ovarian axis that allow: (i) the maturation and release of gametes from the ovary; and (ii) the development of a uterine environment prepared to support a pregnancy should fertilization occur. In the absence of conception, each cycle ends in menstrual bleeding. The pituitary gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH), link the hypothalamus and the ovary and mediate these cyclic changes.
The menstrual cycle is best understood if divided into the four phases of functional and morphologic changes in the ovary and endometrium: (i) follicular, (ii) ovulatory, (iii) luteal and (iv) menstrual (Fig. 14.1).
Conventionally considered the first phase, this is the phase of the menstrual cycle leading up to ovulation. In a typical 28-day menstrual cycle, it comprises the first 14 days. In ovulatory cycles of more or less than 28 days’ duration, the deviation from the average is largely caused by differences in the length of the follicular phase.
During this phase of the menstrual cycle, a cohort of ovarian follicles will rapidly mature, although only one typically becomes the dominant follicle, called the Graafian follicle. Those follicles that undergo final maturation in a given cycle have likely been growing for several months prior to that cycle. Progression from the primordial or resting state to the small antral stage is largely gonadotropin-independent. During the few days prior to the start of menstruation, a small cohort of these growing follicles, now at the small antral stage, is recruited for further gonadotropin-dependent growth. As one cycle ends, the scheduled demise of the corpus luteum results in a rapid decline in its hormonal secretion. The resultant fall in serum estradiol releases the central negative feedback inhibition on FSH secretion. Associated declines in progesterone and inhibin Aare involved to a lesser degree. Increases in FSH secretion during the late luteal phase are accompanied by an increase in the pulse frequency of LH secretion.
Day 1 of menstrual bleeding is considered the first day of the follicular phase. During days 4–5 of this phase, development of the recruited ovarian follicle cohort is characterized by FSH-induced granulosa cell proliferation and aromatase activity. The theca cells of the developing follicle produce androgen precursors. These are converted into estradiol within neighboring granulosa cells. The process has been called the two-cell hypothesis (Chapter 2). Estradiol levels increase. The recruited follicles have several layers of granulosa cells surrounding their oocytes and a small accumulation of follicular fluid. FSH induces synthesis of additional FSH receptors on granulosa cells, expanding its own effects. FSH also stimulates synthesis of new LH receptors on the granulosa cells, thereby initiating LH responsiveness.
By days 5–7 of the menstrual cycle, a single, selected follicle pre- dominates to the detriment of the others in the selected cohort, and will mature and ovulate between days 13 and 15. The predominant follicle is characterized by the highest mitotic index of all the recruited follicles, an optimal capacity for FSH retention in its follicular fluid, and high estradiol and inhibin B synthesis. Nondominant follicles have elevated androgen : estrogen ratios in their follicular fluid, suggesting suboptimal induction of aromatase activity, and will undergo atresia. Androgens appear to be key to the atresia process, as granulosa cells treated with androgen in vitro undergo apoptosis.
During the mid to late follicular phase, continued elevations in circulating estradiol and inhibin B suppress FSH secretion, so preventing new follicular recruitment. Continuous high elevations of circulating estradiol exert a somewhat unexpected effect on the pituitary gland; exponential increases in LH secretion. The ovary also exhibits increased responsiveness to the gonadotropins. Lastly, high estrogen levels cause growth of the endometrial tissue lining the uterus. These changes in the endometrium can be distinguished microscopically and are defined as the “proliferative phase” (Chapter 10).
This phase of the menstrual cycle is characterized by a surge in pituitary LH secretion, culminating in extrusion of the mature ovum through the capsule of the ovary. In the 2–3 days preceding the onset of the LH surge, circulating estradiol and inhibin B rise rapidly and in parallel. Estradiol synthesis is at a maximum and no longer dependent on FSH. Progesterone begins to rise as the surging LH induces progesterone synthesis by the granulosa cells.
Key to ovulation is the midcycle positive feedback effect of estrogen on LH secretion. Proof that rising ovarian estrogens are central to ovulation lies in the observation that a gonadotropin surge can be elicited when prolonged elevated circulating estradiol concentrations are produced experimentally by 2–3 days of exogenous estrogen administration in women. The effects of elevated circulating estrogen are further augmented by the presence of ovarian progesterone. The site of the positive feedback actions of midcycle estrogen on LH secretion appears to be in both the hypothalamic neuroendocrine cells and the pituitary gonadotropes. The exact mechanism by which estrogen induces the midcycle LH surge is uncertain, but dopaminergic and β-endorphinergic neuronal modulation of the gonadotropin-releasing hormone (GnRH) pulse generator are involved. In fact, at midcycle, there is a 20-fold increase in sensitivity of the pituitary gonadotropes to GnRH. Further, the GnRH pulse generator can be inhibited by both synthetic and naturally occurring opioids, suggesting that opioids have a pivotal role in the neuronal control of the midcycle LH surge. A small rise in FSH occurs simultaneously with the pronounced rise in LH at midcycle, presumably in response to the GnRH signal.
Ovulation appears to require LH. The exact mechanism of this effect is unknown, although prostaglandins are thought to be at least one of the mediators. To this point, LH has been shown to stimulate prostaglandin biosynthesis by ovarian cells and inhibitors of prostaglandin synthesis inhibit ovulation in animals.
After ovulation, the dominant morphologic and functional feature of the ovary is the formation and maintenance of the corpus luteum. In humans, the luteal cells make large amounts of estrogen and inhibin. In fact, the circulating estrogen concentrations during the luteal phase are in the preovulatory, positive feedback range. Characteristic of the luteal phase, however, are the uniquely high concentrations of progesterone and 17-hydroxyprogestrone secreted by the corpus luteum. Progesterone at these elevated levels prevents estrogen from stimulating another LH surge from the pituitary. Instead, in the presence of the combination of high concentrations of progesterone and estrogen, the preovulatory GnRH pulses are reduced in frequency, resulting in only baseline FSH and LH secretion.
The length of the luteal phase is more consistent than that of the follicular phase, normally 14 ± 2 days. If pregnancy does not ensue, the corpus luteum spontaneously regresses and follicular development proceeds for the next cycle. Only small amounts of LH are necessary to maintain the corpus luteum in a normal cycle. However, after 14 days, even basal LH secretion will not support the endocrine function of the gland. If pregnancy ensues, maintenance of the corpus luteum and progesterone production is critical to the success of the early gestation. Human chorionic gonadotropin (hCG) is a hormone homologous to LH. hCG is secreted by the placental tissues (trophoblast) of a developing pregnancy. Therefore, in the presence of pregnancy, hCG secreted by gestational trophoblast can maintain the corpus luteum until the trophoblast assumes the role of progesterone secretion (Chapter 18). High progesterone elevelsal so create the“secretoryphase” of theen dometrium, which is marked by endometrial maturation that can allow implantation of the embryo (Chapter 16). The exact trigger for the demise of the corpus luteum in a cycle that does not result in pregnancy is unknown. DNA fragmentation patterns characteristic of apoptosis appear in the corpus luteum as early as the mid to late luteal phase.
The rise in FSH secretion near the end of the luteal phase is reliant on a concomitant drop in the high circulating levels of progesterone, estradiol and inhibin. It is clinically significant that an estrogen antagonist such as clomiphene citrate, administered in the luteal phase, causes a rise in circulating FSH levels and initiation of follicular recruitment.
The first day of menstruation marks the beginning of the next cycle. A new wave of follicles has been recruited and will progress toward maturation and, for one, ovulation. The phenomenon known as menstruation is largely an endometrial event, triggered by the loss of progesterone support from the corpus luteum in nonconception cycles. Dramatic structural changes occur in the endometrium during menstruation, driven by complex and only partially understood mechanisms. Hormonally regulated matrix-degrading proteases and lysosomes appear to be involved. Matrix-degrading proteases are part of the metalloproteinase (MMP) family of enzymes whose substrates include collagen and other matrix proteins. Of the MMP family, seven members are expressed in cell- and menstrual cycle-specific patterns. Also, the endothelins, which are potent vasoconstrictors, appear to have maximum activity at the end of the luteal phase. Finally, the premenstrual fall in progesterone is associated with a decline in 15-hydroxyprostaglandin dehydrogenase activity. This results in an increase in the availability of prostaglandin PGF2α, a potent stimulator of myometrial contractility. Prostaglandin and thromboxane homeostasis direct myometrial and vascular contractions within the uterus. Control of such contractility is central to the creation of endometrial ischemia, the promotion of endometrial sloughing and the cessation of menstrual bleeding.