Lecture 5: Menstruation
Normal Menstrual cycle
The normal human menstrual cycle can be divided into two segments: the ovarian cycle and the uterine cycle, based on the organ under examination.
The ovarian cycle may be further divided into follicular and luteal phases, whereas the uterine cycle is
divided into corresponding proliferative and secretory phases
1. Follicular phase—hormonal feedback promotes the orderly development of a single dominant follicle, which should be mature at midcycle and prepared for ovulation. The average length of the human follicular phase ranges from 10 to 14 days, and variability in this length is responsible for most variations in total cycle length.
2. Luteal phase—the time from ovulation to the onset of menses has an average length of 14 days.
A normal menstrual cycle lasts from 21 to 35 days, with 2 to 6 days of flow and an average blood loss of 20 to 60 mL. However, studies of large numbers of women with normal menstrual cycles have shown that only approximately two-thirds of adult women have cycles lasting 21 to 35 days.
The extremes of reproductive life (after menarche and perimenopause) are characterized by a higher percentage of anovulatory or irregularly timed cycles.
Hormonal Variations The relative pattern of ovarian, uterine, and hormonal variation along the normal menstrual cycle is shown in 5.1
1. At the beginning of each monthly menstrual cycle, levels of gonadal steroids are low and have been decreasing since the end of the luteal phase of the previous cycle.
2. With the demise of the corpus luteum, FSH levels begin to rise, and a cohort of growing follicles is recruited. These follicles each secrete increasing levels of estrogen as they grow in the follicular phase. The increase in estrogen, in turn, is the stimulus for uterine endometrial proliferation.
3. Rising estrogen levels provide negative feedback on pituitary FSH secretion, which begins to wane by the midpoint of the follicular phase. In addition, the growing follicles produce inhibin-B, which also suppresses FSH secretion by the
pituitary. Conversely, LH initially decreases in response to rising estradiol levels, but late in the follicular phase, the LH level is increased dramatically (biphasic response).
4. At the end of the follicular phase (just before ovulation), FSH-induced LH receptors are present on granulosa cells and, with LH stimulation, modulate the secretion of progesterone.
5. After a sufficient degree of estrogenic stimulation, the pituitary LH surge is triggered, which is the proximate cause of ovulation that occurs 24 to 36 hours later. Ovulation heralds the transition to the luteal–secretory phase.
6. The estrogen level decreases through the early luteal phase from just before ovulation until the mid-luteal phase when it begins to rise again as a result of corpus luteum secretion. Similarly, inhibin-A is secreted by the corpus luteum.
7. Progesterone levels rise precipitously after ovulation and can be used as a presumptive sign that ovulation has occurred.
8. Progesterone, estrogen, and inhibin-A act centrally to suppress gonadotropin secretion and new follicular growth. These hormones remain elevated through the lifespan of the corpus luteum and then wane with its demise, thereby setting the stage for the next cycle.
Uterus
Cyclic Changes of the Endometrium
This cycling portion of the endometrium is known as the decidua functionalis and is composed of a deeply situated intermediate zone (stratum spongiosum) and a superficial compact zone (stratum compactum).
The decidua basalis is the deepest region of the endometrium. It does not undergo significant monthly proliferation but, instead, is the source of endometrial regeneration after each menses.
In the typical 28-day cycle, ovulation occurs on cycle day 14. Within 48 to 72 hours following ovulation, the onset of progesterone secretion produces a shift in the histologic appearance of the endometrium to the secretory phase, so named for the clear presence of eosinophilic protein-rich secretory products in the glandular lumen.
In contrast to the proliferative phase, the secretory phase of the menstrual cycle is characterized by the cellular effects of progesterone in addition to estrogen.
During the secretory phase, the endometrial glands form characteristic periodic acid–Schiff positive–staining, glycogen-containing vacuoles.
Menses
In the absence of implantation, glandular secretion ceases, and an irregular breakdown of the decidua functionalis occurs. The resultant shedding of this layer of the endometrium is termed menses. The destruction of the corpus luteum and its production of estrogen and progesterone is the presumed cause of the shedding.
Ovarian Follicular Development The number of oocytes peaks in the fetus at 6 to 7 million by 20 weeks of gestation. Simultaneously (and peaking at the fifth month of gestation), atresia of the oogonia occurs, rapidly followed by follicular atresia. At birth, only 1 to 2 million oocytes remain in the ovaries, and at puberty, only 300,000 of the original 6 to 7 million oocytes are available for ovulation. Of these, only 400 to 500 will ultimately be released during ovulation. By the time of menopause, the ovary will be composed primarily of dense stromal tissue with only rare interspersed oocytes remaining.
Preovulatory Follicle
Preovulatory follicles are characterized by a fluid-filled antrum that is composed of plasma with granulosa-cell secretions.
The granulosa cells at this point have further differentiated into a heterogeneous population. The oocyte remains connected to the follicle by a stalk of specialized granulosa known as the cumulus oophorus.
Rising estrogen levels have a negative feedback effect on FSH secretion. Conversely, LH undergoes biphasic regulation by circulating estrogens. At lower concentrations, estrogens inhibit LH secretion. At higher levels, however, estrogen enhances LH release.
This stimulation requires a sustained high level of estrogen (200 pg/mL) for more than 48 hours (78). Once the rising estrogen level produces positive feedback, a substantial surge in LH secretion occurs. Concomitant to these events, the local estrogen-FSH interactions in the dominant follicle induce LH receptors on the granulosa cells. Thus, exposure to high levels of LH results in a specific response by the dominant follicle—the result is luteinization of the granulosa cells, production of progesterone, and initiation of ovulation. In general, ovulation will occur in the single mature, or Graafian, follicle 10 to 12 hours after the LH peak or 34 to 36 hours after the initial rise in midcycle LH
Ovulation
The midcycle LH surge is responsible for a dramatic increase in local concentrations of prostaglandins and proteolytic enzymes in the follicular wall
Luteal Phase
Structure of Corpus Luteum After ovulation, the remaining follicular shell is transformed into the primary regulator of the luteal phase: the corpus luteum.
Hormonal Function and Regulation The hormonal changes of the luteal phase are characterized by a series of negative feedback interactions designed to lead to regression of the corpus luteum if pregnancy does not occur. Corpus luteum steroids (estradiol and progesterone) provide negative central feedback and cause a decrease in FSH and LH secretion. Continued secretion of both steroids will decrease the stimuli for subsequent follicular recruitment. Similarly, luteal secretion of inhibin also potentiates FSH withdrawal. In the ovary, local production of progesterone inhibits the further development and recruitment of additional follicles.
Continued corpus luteum function depends on continued LH production. In the absence of this stimulation, the corpus luteum will invariably regress after 12 to 16 days and form the scarlike corpora Albicans
Summary of Menstrual Cycle Regulation
Following is a summary of the regulation of the menstrual cycle:
1. GnRH is produced in the arcuate nucleus of the hypothalamus and secreted in a pulsatile fashion into the portal circulation, where it travels to the anterior pituitary
2. Ovarian follicular development moves from a period of gonadotropin independence to a phase of FSH dependence.
3. As the corpus luteum of the previous cycle fades, luteal production of progesterone and inhibin A decreases, allowing FSH levels to rise.
4. In response to FSH stimulus, the follicles grow and differentiate, and secrete increasing amounts of estrogen and inhibin-B.
5. Estrogen stimulates growth and differentiation of the functional layer of the endometrium, which prepares for implantation. Estrogens work with FSH in stimulating follicular development.
6. The two-cell two-gonadotropin theory dictates that with LH stimulation, the ovarian theca cells will produce androgens that are converted by the granulosa cells into estrogens under the stimulus of FSH.
7. Rising estrogen and inhibin levels negatively feedback the pituitary gland and hypothalamus and decrease the secretion of FSH.
8. The one follicle destined to ovulate each cycle is called the dominant follicle. It has relatively more FSH receptors and produces a larger concentration of estrogens than the follicles that will undergo atresia. It can continue to grow despite falling FSH levels.
9. Sustained high estrogen levels cause a surge in pituitary LH secretion that triggers ovulation, progesterone production, and the shift to the secretory, or luteal, phase.
10. Luteal function is dependent on the presence of LH. However, the corpus luteum secretes estrogen, progesterone, and inhibin-A, which serve to maintain gonadotropin suppression. Without continued LH secretion, the corpus luteum will regress after 12 to 16 days. The resulting loss of progesterone secretion results in menstruation.
11. If pregnancy occurs, the embryo secretes hCG, which mimics the action of LH by sustaining the corpus luteum. The corpus luteum continues to secrete progesterone and supports the secretory endometrium, allowing the pregnancy to continue to develop.
The decidua is classified into three parts based on anatomical location.
1. Decidua directly beneath blastocyst implantation is modified by trophoblast invasion and becomes the decidua basalis.
2. The decidua capsularis overlies the enlarging blastocyst and initially separates it from the rest of the uterine cavity.
This portion is most prominent during the second month of pregnancy, consisting of decidual cells covered by a single layer of flattened epithelial cells. Internally, it contacts the avascular, extraembryonic fetal membrane—the chorion laeve.
3. The remainder of the uterus is lined by decidua parietalis—sometimes called decidua vera when decidua capsularis and parietalis are joined.
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