In the early follicular phase of the cycle, (1) the pulse generator produces bursts of neuronal activity with a frequency of about one per hour that correspond with pulses of GnRH secretion, (2) these cause a corresponding pulsatile release of LH and FSH from pituitary gonadotropes, and (3) FSH in particular causes the graafian follicle to mature and secrete estrogen. The effects of estrogens on the pituitary are inhibitory at this time and cause the amount of LH and FSH released from the pituitary to decline (i.e., the amplitude of the LH pulse decreases), so gonadotropin levels gradually fall, as seen in Figure 40–3. Inhibin, produced by the ovary, also exerts a negative feedback to selectively decrease serum FSH at this time (Chapter 38). Activin and follistatin, two other peptides released from the ovary, may also regulate FSH production and secretion to a lesser extent, although their levels do not vary appreciably during the menstrual cycle.
At mid-cycle, serum estradiol rises above a threshold level of 150-200 pg/mL for ∼36 hours. This sustained elevation of estrogen no longer inhibits gonadotropin release but exerts a brief positive feedback effect on the pituitary to trigger the preovulatory surge of LH and FSH. This effect primarily involves a change in pituitary responsiveness to GnRH. In some species, estrogens may also exert a positive effect on hypothalamic neurons that contributes to a mid-cycle "surge" of GnRH release; this is not yet established in humans. Progesterone may contribute to the mid-cycle LH surge.
The mid-cycle surge in gonadotropins stimulates follicular rupture and ovulation within 1-2 days. The ruptured follicle then develops into the corpus luteum, which produces large amounts of progesterone and lesser amounts of estrogen under the influence of LH during the second half of the cycle. In the absence of pregnancy, the corpus luteum ceases to function, steroid levels drop, and menstruation occurs. When steroid levels drop, the pulse generator reverts to a firing pattern characteristic of the follicular phase, the entire system then resets, and a new ovarian cycle occurs.
Regulation of the frequency and amplitude of gonadotropin secretions by steroids may be summarized as follows: Estrogens act primarily on the pituitary to control the amplitude of gonadotropin pulses, and they may also contribute to the amplitude of GnRH pulses secreted by the hypothalamus.
In the follicular phase of the cycle, estrogens inhibit gonadotropin release but then have a brief mid-cycle stimulatory action that increases the amount released and causes the LH surge. Progesterone, acting on the hypothalamus, exerts the predominant control of the frequency of LH release. It decreases the firing rate of the hypothalamic pulse generator, an action thought to be mediated largely via inhibitory opioid neurons (containing progesterone receptors) that synapse with GnRH neurons. Progesterone also exerts a direct effect on the pituitary to oppose the inhibitory actions of estrogens and thus enhance the amount of LH released (i.e., to increase the amplitude of the LH pulses). These steroid feedback effects, coupled with the intrinsic activity of the hypothalamic GnRH pulse generator, lead to relatively frequent LH pulses of small amplitude in the follicular phase of the cycle, and less frequent pulses of larger amplitude in the luteal phase. Studies in knockout mice indicate that ERα (Hewitt and Korach, 2003) and the progesterone receptor PR-A (Conneely et al., 2002) mediate the major actions of estrogens and progestins, respectively, on the hypothalamic-pituitary axis.
In males, testosterone regulates the hypothalamic-pituitary-gonadal axis at both the hypothalamic and pituitary levels, and its negative feedback effect is mediated to a substantial degree by estrogen formed via aromatization. Thus, exogenous estrogen administration decreases LH and testosterone levels in men, and anti-estrogens such as clomiphene cause an elevation of serum LH, which can be used to evaluate the male reproductive axis.
When the ovaries are removed or cease to function, there is overproduction of FSH and LH, which are excreted in the urine. Measurement of urinary or plasma LH is valuable to assess pituitary function and the effectiveness of therapeutic doses of estrogen. Although FSH levels will also decline upon estrogen administration, they do not return to normal, secondary to production of inhibin by the ovary (Chapter 38). Consequently, the measurement of FSH levels as a means to monitor the effectiveness of hormone therapy is not clinically useful. Additional features of the regulation of gonadotropin secretion and actions are discussed in Chapters 38 and 66.
Effects of Cyclical Gonadal Steroids on the Reproductive Tract. The cyclical changes in estrogen and progesterone production by the ovaries regulate corresponding events in the fallopian tubes, uterus, cervix, and vagina. Physiologically, these changes prepare the uterus for implantation, and the proper timing of events in these tissues is essential for pregnancy. If pregnancy does not occur, the endometrium is shed as the menstrual discharge.
The uterus is composed of an endometrium and a myometrium. The endometrium contains an epithelium lining the uterine cavity and an underlying stroma; the myometrium is the smooth muscle component responsible for uterine contractions. These cell layers, the fallopian tubes, cervix, and vagina display a characteristic set of responses to both estrogens and progestins. The changes typically associated with menstruation occur largely in the endometrium (Figure 40–3).
The luminal surface of the endometrium is a layer of simple columnar epithelial secretory and ciliated cells that is continuous with the openings of numerous glands that extend through the underlying stroma to the myometrial border. Fertilization normally occurs in the fallopian tubes, so ovulation, transport of the fertilized ovum through the fallopian tube, and preparation of the endometrial surface must be temporally coordinated for successful implantation.
The endometrial stroma is a highly cellular connective-tissue layer containing a variety of blood vessels that undergo cyclic changes associated with menstruation. The predominant cells are fibroblasts, but macrophages, lymphocytes, and other resident and migratory cell types also are present.
Menstruation marks the start of the menstrual cycle. During the follicular (or proliferative) phase of the cycle, estrogen begins the rebuilding of the endometrium by stimulating proliferation and differentiation. Numerous mitoses become visible, the thickness of the layer increases, and characteristic changes occur in the glands and blood vessels. In rodent models, ERα mediates the uterotrophic effects of estrogens (Hewitt and Korach, 2003). The overall endometrial response involves estrogen- and progesterone-mediated expression of peptide growth factors and receptors, cell cycle genes, and other regulatory signals. An important response to estrogen in the endometrium and other tissues is induction of the progesterone receptor (PR), which enables cells to respond to this hormone during the second half of the cycle.
In the luteal (or secretory) phase of the cycle, elevated progesterone limits the proliferative effect of estrogens on the endometrium by stimulating differentiation. Major effects include stimulation of epithelial secretions important for implantation of the blastocyst and the characteristic growth of the endometrial blood vessels seen at this time. These effects are mediated by PR-A in animal models (Conneely et al., 2002). Progesterone is thus important in preparation for implantation and for the changes that take place in the uterus at the implantation site (i.e., the decidual response). There is a narrow "window of implantation," spanning days 19-24 of the endometrial cycle, when the epithelial cells of the endometrium are receptive to blastocyst implantation. Because endometrial status is regulated by estrogens and progestins, the efficacy of some contraceptives may be due in part to production of an endometrial surface that is not receptive to implantation. If pregnancy does not occur, the corpus luteum regresses due to lack of continued LH secretion, estrogen and progesterone levels fall, and the endometrium is shed (Figure 40–3).
If implantation occurs, human chorionic gonadotropin (hCG) (Chapter 38), produced initially by the trophoblast and later by the placenta, interacts with the LH receptor of the corpus luteum to maintain steroid hormone synthesis during the early stages of pregnancy. In later stages the placenta itself becomes the major site of estrogen and progesterone synthesis.
Estrogens and progesterone have important effects on the fallopian tube, myometrium, and cervix. In the fallopian tube, estrogens stimulate proliferation and differentiation, whereas progesterone inhibits these processes. Also, estrogens increase and progesterone decreases tubal muscular contractility, which affects transit time of the ovum to the uterus. Estrogens increase the amount of cervical mucus and its water content to facilitate sperm penetration of the cervix, whereas progesterone generally has opposite effects. Estrogens favor rhythmic contractions of the uterine myometrium, and progesterone diminishes contractions. These effects are physiologically important and may also play a role in the action of some contraceptives.