The anatomy of the reproductive system of adult women is described in Chapter 1. Unlike the reproductive system of men, this system shows regular cyclic changes that teleologically may be regarded as periodic preparation for fertilization and pregnancy. In primates, the cycle is a menstrual cycle, and its most conspicuous feature is the cyclic vaginal bleeding that occurs with shedding of the uterine mucosa (menstruation). The length of the cycle is notoriously variable, but the average figure is 28 days from the start of one menstrual period to the start of the next. By common usage, the days of the cycle are identified by number, starting with the first day of menstruation.
From the time of birth, there are many primordial follicles under the ovarian capsule. Each contains an immature ovum (Fig. 4–4). At the start of each cycle, several of these follicles enlarge and a cavity forms around the ovum (antrum formation). This cavity is filled with follicular fluid. In humans, 1 of the follicles in 1 ovary starts to grow rapidly on about the sixth day and becomes the dominant follicle. The others regress, forming atretic follicles. It is not known how 1 follicle is singled out for development during this follicular phase of the menstrual cycle, but it seems to be related to the follicle's ability to produce estrogen, which is necessary for final maturation. The secretion of estrogen, in animal models, has been demonstrated even before the dominant follicle has emerged as morphologically dominant. Theoretically, depending on the position of the follicle to the blood supply, there is a gradient of exposure to different amounts of hormones, growth factors, and other signaling molecules. Therefore, the follicle most responsive to follicle-stimulating hormone (FSH) is likely to be the first to produce estradiol.
Diagram of a mammalian ovary, showing the sequential development of a follicle, formation of a corpus luteum, and, in the center, follicular atresia. A section of the wall of a mature follicle is enlarged at the upper right. The interstitial cell mass is not prominent in primates.
The structure of a mature ovarian follicle (graafian follicle) is shown in Figure 4–4. The cells of the theca interna of the follicle are the primary source of circulating estrogens. The follicular fluid has a high estrogen content, and much of this estrogen comes from the granulosa cells.
At about the 14th day of the cycle, the distended follicle ruptures, and the ovum is extruded into the abdominal cavity. This is the process of ovulation. The ovum is picked up by the fimbriated ends of the uterine tubes (oviducts) and transported to the uterus. Unless fertilization occurs, the ovum degenerates or passes on through the uterus and out of the vagina.
The follicle that ruptures at the time of ovulation promptly fills with blood, forming what is sometimes called a corpus hemorrhagicum. Minor bleeding from the follicle into the abdominal cavity may cause peritoneal irritation and fleeting lower abdominal pain (“mittelschmerz”). The granulosa and theca cells of the follicle lining promptly begin to proliferate, and the clotted blood is rapidly replaced with yellowish, lipid-rich luteal cells, forming the corpus luteum. This is the luteal phase of the menstrual cycle, during which the luteal cells secrete estrogen and progesterone. Growth of the corpus luteum depends on its developing an adequate blood supply. There is evidence that vascular endothelial growth factor (VEGF) is essential for this process through regulation by the transcription factor, HIF-1α, under hypoxic conditions or by gonadotropin-stimulated conditions. If pregnancy occurs, the corpus luteum persists, and there are usually no more menstrual cycles until after delivery. If there is no pregnancy, the corpus luteum begins to degenerate about 4 days before the next menses (day 24 of the cycle) and is eventually replaced by fibrous tissue, forming a corpus albicans.
In humans, no new ova are formed after birth. During fetal development, the ovaries contain over 7 million germ cells; however, many undergo involution before birth, and others are lost after birth. At the time of birth, there are approximately 2 million primordial follicles containing ova, but approximately 50% of these are atretic. The remaining million ova undergo the first meiotic division at this time and arrest in prophase until adulthood. Atresia continues during development, and the number of ova in both the ovaries at the time of puberty is less than 300,000 (Fig. 4–5). Normally, only 1 of these ova per cycle (or about 400–500 in the course of a normal reproductive life) is stimulated to mature; the remainder degenerate. Just before ovulation, the first meiotic division is completed. One of the daughter cells, the secondary oocyte, receives most of the cytoplasm, while the other, the first polar body, fragments and disappears. The secondary oocyte immediately begins the second meiotic division, but this division stops at metaphase and is completed only when a sperm penetrates the oocyte. At that time, the second polar body is cast off, and the fertilized ovum proceeds to form a new individual.
Number of primordial follicles per ovary in women at various ages. □, premenopausal women (regular menses); ▪, perimenopausal women (irregular menses for at least 1 year); ▴, postmenopausal women (no menses for at least 1 year). Note that the vertical scale is a log scale and that the values are from 1 rather than 2 ovaries. (Reproduced, with permission, from Richardson SJ, Senikas V, Nelson JF. Follicular depletion during the menopausal transition: evidence for accelerated loss and ultimate exhaustion. J Clin Endocrinol Metab 1987;65:1231.)
The events that occur in the uterus during the menstrual cycle terminate with the menstrual flow. By the end of each menstrual period, all but the deep layer of the endometrium has sloughed. Under the influence of estrogen secreted from the developing follicles, the endometrium regenerates from the deep layer and increases rapidly in thickness during the period from the fifth to 16th days of the menstrual cycle. As the thickness increases, the uterine glands are drawn out so that they lengthen (Fig. 4–6), but they do not become convoluted or secrete to any degree. These endometrial changes are called proliferative, and this part of the menstrual cycle is sometimes called the proliferative phase. It is also called the preovulatory or follicular phase of the cycle. After ovulation, the endometrium becomes more highly vascularized and slightly edematous under the influence of estrogen and progesterone from the corpus luteum. The glands become coiled and tortuous (Fig. 4–6), and they begin to secrete clear fluid. Consequently, this phase of the cycle is called the secretory or luteal phase. Late in the luteal phase, the endometrium, like the anterior pituitary, produces prolactin. The function of this endometrial prolactin has yet to be determined, though it has been suggested that prolactin may play a role in implantation.
Changes in the endometrium during the menstrual cycle. (Reproduced, with permission, from Ganong WF. Review of Medical Physiology. 22nd ed. New York, NY: McGraw-Hill; 2005.)
The endometrium is supplied by 2 types of arteries. The superficial two-thirds of the endometrium, the stratum functionale, is shed during menstruation and is supplied by the long, coiled spiral arteries. The deep layer, which is not shed, is called the stratum basale and is supplied by short, straight basilar arteries.
When the corpus luteum regresses, hormonal support for the endometrium is withdrawn, causing vascular spasms in the spiral artery, ultimately leading to endometrial ischemia. The endometrium becomes thinner, which adds to the coiling of the spiral arteries. Leukocyte infiltration into the endometrial stroma initiates the breakdown of the extracellular matrix in the functionalis layer. Foci of necrosis appear in the endometrium and walls of the spiral arteries, which coalesce and lead to spotty hemorrhages that become confluent and ultimately produce menstrual flow.
Spiral artery vasospasm serves to limit blood loss during menstruation and probably is produced by locally released prostaglandins. There are large quantities of prostaglandins in the secretory endometrium and in menstrual blood. Infusions of prostaglandin F2a (PGF2a) produce endometrial necrosis and bleeding. One theory of the onset of menstruation holds that in necrotic endometrial cells, lysosomal membranes break down and release proteolytic enzymes that foster the formation of prostaglandins from cellular phospholipids while promoting further local tissue destruction.
From the point of view of endometrial function, the proliferative phase of the menstrual cycle represents the restoration of the epithelium from the preceding menstruation, while the secretory phase represents the preparation of the uterus for implantation of the fertilized ovum. The length of the secretory phase is remarkably constant, about 14 days. The variations seen in the length of the menstrual cycle are mostly due to variations in the length of the proliferative phase. When fertilization fails to occur during the secretory phase, the endometrium is shed, and a new cycle begins.
Menstrual blood is predominantly arterial, with only 25% of the blood being of venous origin. It contains tissue debris, prostaglandins, and relatively large amounts of fibrinolysin from the endometrial tissue. The fibrinolysin lyses clots, so menstrual blood does not normally contain clots unless the flow is excessive.
The usual duration of the menstrual cycle is 3–5 days, but flow as short as 1 day and as long as 8 days can occur in normal women. The average amount of blood loss is 30 mL but normally may range from slight spotting to 80 mL. Loss of more than 80 mL is abnormal. Obviously, the amount of flow can be affected by various factors, including not only the thickness of the endometrium, but also the medications and diseases that affect clotting mechanisms. After menstruation, the endometrium regenerates from the stratum basale.
In some instances, ovulation fails to occur during the menstrual cycle. Such anovulatory cycles are common for the first 12–18 months after menarche and again before the onset of menopause. When ovulation does not occur, no corpus luteum is formed, and the effects of progesterone on the endometrium are absent. Estrogens continue to cause growth, however, and the proliferative endometrium becomes thick enough to break down and begin to slough. The time it takes for bleeding to occur is variable, but it usually occurs less than 28 days from the last menstrual period. The flow is also variable and ranges from scanty to relatively profuse.
Cyclic Changes in the Uterine Cervix
Although it is contiguous with the body of the uterus, the cervix of the uterus is different in a number of ways. The mucosa of the uterine cervix does not undergo cyclic desquamation, but there are regular changes in the cervical mucus. Estrogen makes the mucus much thinner and more alkaline, changes that promote the survival and transport of sperm. Progesterone makes it thick, tenacious, and cellular. The mucus is thinnest at the time of ovulation, and its elasticity, or spinnbarkeit, increases so that by midcycle a drop can be stretched into a long, thin thread that may be 8–12 cm or more in length. In addition, it dries in an arborizing, fernlike pattern when a thin layer is spread on a slide (Fig. 4–7). After ovulation and during pregnancy, it becomes thick and fails to form the fern pattern.
Patterns formed when cervical mucus is smeared on a slide, permitted to dry, and examined under the microscope. Progesterone makes the mucus thick and cellular. In the smear from a patient who failed to ovulate (bottom), there is no progesterone to inhibit the estrogen-induced fern pattern. (Reproduced, with permission, from Barrett KE. Ganong's Review of Medical Physiology. 23rd ed. New York, NY: McGraw-Hill; 2010.)
Under the influence of estrogens, the vaginal epithelium becomes cornified, and these cornified epithelial cells can be identified in a vaginal smear. Under the influence of progesterone, a thick mucus is secreted, and the epithelium proliferates and becomes infiltrated with leukocytes. The cyclic changes in the vaginal smear in rats are particularly well known. The changes in humans and other species are similar but unfortunately not so clear-cut. However, the increase in cornified epithelial cells is apparent when a vaginal smear from an adult woman in the follicular phase of the menstrual cycle is compared, for example, with a smear taken from a prepubescent female.
Cyclic Changes in the Breasts
Although lactation normally does not occur until the end of pregnancy, there are cyclic changes in the breasts during the menstrual cycle. Estrogens cause proliferation of mammary ducts, whereas progesterone causes growth of lobules and alveoli (see Actions of Progesterone). The breast swelling, tenderness, and pain experienced by many women during the 10 days preceding menstruation probably are due to distention of the ducts, hyperemia, and edema of the interstitial tissue of the breasts. All of these changes regress, along with the symptoms, during menstruation.
Cyclic Changes in Other Body Functions
In addition to cyclic breast swelling and tenderness, there is usually a small increase in body temperature during the luteal phase of the menstrual cycle. This change in body temperature (see Indicators of Ovulation) probably is due to the thermogenic effect of progesterone.
Changes during Sexual Intercourse
During sexual excitation, the vaginal walls become moist as a result of transudation of fluid through the mucus membrane. A lubricating mucus is secreted by the vestibular glands. The upper part of the vagina is sensitive to stretch, while tactile stimulation from the labia minora and clitoris adds to the sexual excitement. The stimuli are reinforced by tactile stimuli from the breasts and, as in men, by visual, auditory, and olfactory stimuli. Eventually, the crescendo or climax known as orgasm may be reached. During orgasm, there are autonomically mediated rhythmic contractions of the vaginal wall. Impulses also travel via the pudendal nerves and produce rhythmic contractions of the bulbocavernosus and ischiocavernosus muscles. The vaginal contractions may aid in the transport of spermatozoa but are not essential for it, as fertilization of the ovum is not dependent on orgasm.
Knowing when during the menstrual cycle ovulation occurs is important in increasing fertility or, conversely, in contraception. A convenient, but retrospective, indicator of the time of ovulation is a rise in the basal body temperature (Fig. 4–8). Accurate temperatures can be obtained by using a thermometer that is able to measure temperature precisely between 96 and 100°F. The woman should take her temperature orally, vaginally, or rectally in the morning before getting out of bed. The cause of temperature change at the time of ovulation is unknown but probably is due to the increase in progesterone secretion, as progesterone is thermogenic. A rise in urinary LH occurs during the rise in circulating LH that causes ovulation. This increase can be measured and used as another indicator of ovulation. Kits using dipsticks or simple color tests for detection of urinary LH are available for home use.
Basal body temperature and plasma hormone concentrations (mean ± standard error) during the normal human menstrual cycle. Values are aligned with respect to the day of the midcycle luteinizing hormone (LH) peak. FSH, follicle-stimulating hormone. (Reproduced, with permission, from Barrett KE. Ganong's Review of Medical Physiology. 23rd ed. New York, NY: McGraw-Hill; 2010.)
Ovulation normally occurs about 9 hours after the peak of the LH surge at midcycle (Fig. 4–8). The ovum lives approximately 72 hours after it is extruded from the follicle but probably is fertilizable for less than half this time. In a study of the relationship of isolated intercourse to pregnancy, 36% of women had a detected pregnancy following intercourse on the day of ovulation, but with intercourse on days after ovulation, the percentage was zero. Isolated intercourse of the first and second days before ovulation led to pregnancy in about 36% of the women. A few pregnancies resulted from isolated intercourse on day 3, 4, or 5 before ovulation, although the percentage was much lower, ie, 8% on day 5 before ovulation. Thus, some sperm can survive in the female genital tract and produce fertilization for up to 120 hours before ovulation, but the most fertile period is clearly the 48 hours before ovulation. However, for those interested in the “rhythm method” of contraception, if should be noted that there are rare but documented cases of pregnancy resulting from isolated coitus on every day of the cycle.