This chapter deals primarily with APGO Educational Topic Area:
TOPIC 45 NORMAL AND ABNORMAL UTERINE BLEEDING
Students should be able to describe endocrinologic and physiologic characteristics of a normal menstrual cycle.
Clinical Case
A 42-year-old woman presents with concerns that there may be something wrong with her “hormones” and she fears that she may be going through menopause. Her menstrual periods began at the age of 13 years and were moderately regular except when interrupted for her two pregnancies. Periods lately have been roughly 32 days apart, are preceded by breast tenderness and bloating, and generally have 3–4 days of flow. She underwent a tubal ligation following the birth of her last child. The patient’s concern centers on a lack of energy, loss of libido, and moderate weight gain. She reports that this is how all the other women in her family “went through the change.”
In the female reproductive cycle, ovulation is followed by menstrual bleeding in a cyclic, predictable sequence. This recurring process is established during puberty (average age of menarche is 12 years) and continues until the years prior to menopause (average age is 51 years). Regular ovulatory cycles are usually established by the third year after menarche, and continue until the perimenopause. Therefore, between ages 15 and 45 years, a woman has approximately 30 years of ovulatory reproductive cycles. The reproductive cycles may be interrupted by conditions, including pregnancy, lactation, illness, gynecologic disorders and endocrine disorders, and exogenous factors, such as hormone-based contraceptives and various other medications.
The duration of an adult reproductive cycle, from the beginning of one menses (Day 1) to the beginning of the next menses (Day 1), averages approximately 28 days (±7 days) and comprises three distinct phases. The follicular phase begins with the onset of menses (the first day of the menstrual cycle) and ends on the day of the luteinizing hormone (LH) surge. Ovulation occurs within 30 to 36 hours of the LH surge. The luteal phase begins on the day of the LH surge and ends with the onset of menses. The follicular and luteal phases each last approximately 14 days in regularly menstruating reproductive age women; however, variability in cycle length is more frequent at the extremes of reproductive ages. The duration of the luteal phase remains relatively constant, whereas the duration of the follicular phase can vary.
HYPOTHALAMIC–PITUITARY–GONADAL AXIS
Hypothalamic–pituitary–gonadal axis refers to the complex interactions between the hypothalamus, pituitary, and ovaries that regulate the reproductive cycle. These interactions are based on the interplay of the hormones released by these structures: gonadotropin-releasing hormone (GnRH); the gonadotropins follicle-stimulating hormone (FSH) and LH; and the ovarian sex steroid hormones, estrogen and progesterone. Through stimulatory and inhibitory actions, these hormones directly and indirectly stimulate oocyte development and ovulation, endometrial development to facilitate embryo implantation, and menstruation. Feedback loops between the hypothalamus, pituitary, and ovaries are presented in Figure 37.1.
Disruption of any of these communication and feedback loops results in alterations of hormone levels, which can lead to disorders of the reproductive cycle; ultimately, ovulation, reproduction, and menstruation can be affected.
FIGURE 37.1. The reproductive cycle requires complex interactions and feedback between the hypothalamus, pituitary, and ovaries, which are simplified in this diagram. GnRH, gonadotropin-releasing hormone; FSH, follicle-stimulating hormone; LH, luteinizing hormone.
Hypothalamic Gonadotropin-Releasing Hormone Secretion
The GnRH is secreted in a pulsatile fashion from the arcuate nucleus of the hypothalamus. GnRH reaches the anterior pituitary through the hypothalamic–pituitary portal vascular system. The pulsatile secretion of GnRH stimulates and modulates pituitary gonadotropin secretion. Due to its remote location and a half-life of 2 to 4 minutes, GnRH cannot be directly measured; therefore, measurements of LH pulses are used to indicate GnRH pulsatile secretion.Ovarian function requires the pulsatile secretion of GnRH in a specific pattern that ranges from 60-minute to 4-hour intervals. Therefore, the hypothalamus serves as the pulse generator of the reproductive cycle. Coordinated GnRH release is stimulated by various neurotransmitters and catecholamines as well as by the inherent pulsatility of the GnRH neurons.
Pituitary Gonadotropin Secretion
The pituitary gonadotropins FSH and LH are glycoprotein hormones secreted by the anterior pituitary gland. FSH and LH are also secreted in pulsatile fashion in response to the pulsatile release of GnRH; the magnitude of secretion and the rates of secretion of FSH and/or LH are determined largely by the levels of ovarian steroid hormones, estrogen and progesterone, and other ovarian factors (such as inhibin, activin, and follistatin).
When a woman is in a state of relative estrogen deficiency, as in the early follicular phase, the principal gonadotropin secreted is FSH. The ovary responds to FSH secretion with estradiol production, with subsequent negative feedback on the pituitary inhibiting FSH secretion and positive feedback facilitating LH secretion.
Ovarian Steroid Hormone Secretion
At midcycle, there is a marked increase in LH secretion (the LH surge), which triggers ovulation. With ovulation, the ovarian follicle is converted into a corpus luteum and begins secreting progesterone.
At birth, the human ovary contains approximately 1 to 2 million primordial follicles. Each follicle contains an oocyte that is arrested in prophase of the first meiotic division. A large number of these inactive primordial follicles undergo a degenerative process known as atresia during childhood; thus, at menarche, 300,000 to 500,000 oocytes remain.
The immature oocyte is encircled by a single layer of granulosa cells, followed by a thin basement membrane that separates the follicle from the surrounding ovarian stroma. Early follicular maturation occurs independently of gonadotropins, the granulosa cells proliferate into multiple layers, and the surrounding stromal cells differentiate into theca cells. Granulosa cells produce estrogens, including estrone and estradiol, the latter being the more potent of the two. Theca cells produce androgens, which serve as the precursors required for granulosa cell estrogen production. Androgens (androstenedione and testosterone) enter the granulosa cells by diffusion and are converted to estrogen. The two-cell theory of estrogen synthesis is diagrammed in Figure 37.2.
During follicular development, FSH binds to FSH receptors on the granulosa cells, causing cellular proliferation and increased binding of FSH, thereby increasing production of estradiol. Estradiol stimulates the proliferation of LH receptors on theca and granulosa cells, and LH stimulates the theca cells to produce androgens. Greater androgen production leads to increased estradiol production. Rising estrogen levels influence the pituitary gland through negative feedback and result in suppression of FSH and LH secretion. In the late follicular phase, peak estradiol concentrations from the dominant follicle have positive feedback on the pituitary, which stimulates the midcycle surge of LH secretion that is necessary for ovulation. With ovulation, the dominant ovarian follicle releases its oocyte and transitions to a progesterone-secreting ovarian cyst, the corpus luteum. The process of follicular maturation is presented in Figure 37.3.
REPRODUCTIVE CYCLE
As discussed, the reproductive cycle is divided into three phases: menstruation and the follicular phase, ovulation, and the luteal phase. These three phases refer to the status of the ovary during the reproductive cycle. In contrast, when referring to the endometrium, the phases of the menstrual cycle are termed the proliferative and secretory phases.
FIGURE 37.2. The two-cell theory of estrogen production. cAMP, cyclic adenosine monophosphate; LH, luteinizing hormone; FSH, follicle-stimulating hormone.
Phase I: Menstruation and the Follicular Phase
The first day of menstrual bleeding is considered day 1 of the menstrual cycle. When conception does not occur, the involution of the corpus luteum and, hence, the decline of progesterone and estrogen levels cause menstruation. Normal menstruation lasts 3 to 7 days, during which women lose 20 to 60 mL of dark, nonclotting blood. Menstruation consists of blood and desquamated superficial endometrial tissues. Prostaglandins in the secretory endometrium and menstrual blood produce contractions of the uterine vasculature and musculature, which in turn cause endometrial ischemia and uterine cramping. These prostaglandin-associated uterine contractions also aid in expulsion of the menstrual blood and tissue. Rising estrogen levels in the early follicular phase induce endometrial healing which leads to cessation of menstruation.
At the end of the luteal phase, serum concentrations of estradiol, progesterone, and LH reach their lowest levels. In response to low hormone levels, FSH begins to rise in the late luteal phase before the onset of menstruation to recruit the next cohort of follicles. Thus, during menstruation, follicular growth has already been initiated for the new reproductive cycle. Estradiol levels rise during the follicular phase, causing a decline in FSH. LH remains low in the early follicular phase, but increasing estrogen levels have positive feedback on LH release, and LH starts to rise by the midfollicular phase. Although several follicles begin the maturation process, only the follicle with the greatest number of granulosa cells and FSH receptors and the highest estradiol production becomes the dominant follicle; the nondominant follicles undergo atresia.
FIGURE 37.3. Ovarian follicle development during the reproductive cycle.
Phase II: Ovulation
As the dominant follicle secretes an increasing amount of estradiol, there is marked positive feedback to the pituitary gland to secrete LH. By days 11 to 13 of the cycle, the LH surge occurs, which triggers ovulation. The LH surge begins 34 to 36 hours prior to ovulation, and peak LH secretion occurs 10 to 12 hours prior to ovulation. With the LH surge, the granulosa and theca cells undergo distinct changes and begin production of progesterone. Meiosis of the primary follicle resumes after the LH surge and the first polar body is released; the oocyte then arrests in metaphase of the second meiotic division until fertilization occurs. During ovulation, the oocyte is expelled from the follicle, and the follicle is converted into the corpus luteum.
Some women experience a twinge of pain (“mittelschmerz”) at the time of ovulation and can precisely identify the time of ovulation. Other women do not experience this brief discomfort but can recognize characteristic symptoms that occur due to progesterone production after ovulation.
Phase III: Luteal Phase
The luteal phase of the menstrual cycle is characterized by an alteration in the balance of sex steroid secretion from predominance of estrogen to predominance of progesterone. The process of follicular development has led to increased numbers of LH receptors on the granulosa and theca cells. The midcycle LH surge stimulates these LH receptors and converts the enzymatic machinery of these cells to produce and secrete progesterone; this process is called luteinization. Progesterone has negative feedback on pituitary secretion of FSH and LH; therefore, both hormones are suppressed during the luteal phase. The corpus luteum also produces estradiol in a pattern that parallels progesterone secretion.
The production of progesterone begins approximately 24 hours before ovulation and rises rapidly thereafter. Maximal progesterone production occurs 3 to 4 days after ovulation. The lifespan of the corpus luteum ends approximately 9 to 11 days after ovulation; if conception does not occur, the corpus luteum undergoes involution (a progressive decrease in size), and progesterone production sharply declines. This withdrawal of progesterone releases FSH from negative feedback; thus, FSH levels begin to rise prior to menstruation and the initiation of a new cycle.
The carefully orchestrated sequence of estrogen production and then progesterone production is essential for proper endometrial development to allow implantation of an embryo. If the oocyte becomes fertilized and implantation occurs, the resulting zygote begins secreting human chorionic gonadotropin, which sustains the corpus luteum for another 6 to 7 weeks. Adequate progesterone production by the corpus luteum is necessary to sustain the early pregnancy. By 9 to 10 weeks of pregnancy, placental steroidogenesis is well established, and the placenta assumes progesterone production.
The corpus luteum measures approximately 2.5 cm in diameter, has a characteristic deep yellow color, and can be seen on gross inspection of the ovary if surgery is performed during the luteal phase of the cycle. As the function of the corpus luteum declines, it decreases in volume and loses its yellow color. After a few months, the corpus luteum becomes a white fibrous streak within the ovary, called the corpus albicans.
Reproductive cycle changes in gonadotropins, steroid hormones, ovarian follicles, and the endometrium are summarized in Figure 37.4.
CLINICAL MANIFESTATIONS OF HORMONAL CHANGES
Hormonal changes induced by the hypothalamic–pituitary– gonadal axis and the adrenal gland trigger puberty, and hormones continue to exert a cyclic influence until a woman reaches menopause. At that time, the lack of cyclic ovarian function results in the permanent cessation of menstruation.
Various female structures undergo changes in response to the reproductive cycle hormones: the endometrium and endocervix, breasts, vagina, and the hypothalamus. Changes in the endocervix and breasts can be directly observed. Daily assessment of basal body temperature can identify changes in the hypothalamic thermoregulation center. Other changes can be assessed by cytologic examination of a sample from the vaginal epithelium or histologic evaluation of an endometrial biopsy. A careful history may identify symptoms associated with hormone effects, such as abdominal bloating, fluid retention, mood and appetite changes, and uterine cramps at the onset of menstruation.
Endometrium
Within the uterus, the endometrium undergoes dramatic histologic changes during the reproductive cycle. During menstruation, the entire endometrium is expelled, and only the basal layer remains. During the follicular phase, the rise in estrogen levels stimulates endometrial cell growth: The endometrial stroma thickens and the endometrial glands become elongated to form the proliferative endometrium. In an ovulatory cycle, the endometrium reaches maximal thickness at the time of ovulation.
When ovulation occurs, the predominant hormone shifts from estrogen to progesterone, and distinct changes occur within the endometrium at almost daily intervals. Progesterone causes differentiation of the endometrial components and converts the proliferative endometrium into a secretory endometrium. The endometrial stroma becomes loose and edematous, while blood vessels entering the endometrium become thickened and twisted. The endometrial glands, which were straight and tubular during the proliferative phase, become tortuous and contain secretory material within the lumen. With the withdrawal of progesterone at the end of the luteal phase, the endometrium breaks down and is sloughed during menses.
FIGURE 37.4. A summary of pituitary, ovarian, uterine, and vaginal changes during the reproductive cycle. FSH, follicle-stimulating hormone; LH, luteinizing hormone; E2, estrodial; P, progesterone.
If ovulation does not occur, and estrogen continues to be produced, the endometrial stroma continues to thicken, and the endometrial glands continue to elongate. Only an endometrial biopsy will identify proliferative endometrium.The endometrium eventually outgrows its blood supply and sections of the endometrium slough intermittently. Without progesterone withdrawal to initiate desquamation of the entire endometrium, bleeding is acyclic and occurs outside of hormonal control irregularly and for prolonged periods of time. When women present with abnormal uterine bleeding, anovulatory bleeding is a common diagnosis (see Chapter 39).
Endocervix
The endocervix contains glands that secrete mucus in response to hormonal stimulation. Under the influence of estrogens, the endocervical glands secrete large quantities of thin, clear, watery mucus. Endocervical mucus production is maximal at the time of ovulation. This mucus facilitates sperm capture, storage, and transport. With ovulation, progesterone reverses the effect of estrogen on the endocervical mucus, and mucus production diminishes.
Some women monitor their cervical mucus to optimize the timing of intercourse when trying to conceive or in order to avoid conception. However, the timing of these changes is nonspecific and is one of the less reliable methods of contraception recognized by the American College of Obstetricians and Gynecologists.
Breasts
Estrogen exposure is necessary for pubertal breast development; however, reproductive cycle changes in the breast occur primarily due to progesterone effect. The ductal elements of the breast, nipple, and areola respond to progesterone secretion. Some women will notice more breast tenderness and fullness in the luteal phase due to progesterone-mediated changes.
Vagina
Estrogen promotes growth of the vaginal epithelium and maturation of the superficial epithelial cells of the mucosa. During sexual stimulation, the presence of estrogen aids vaginal transudation and lubrication, which facilitates intercourse. During the luteal phase of the reproductive cycle, the vaginal epithelium retains its thickness, but the secretions are markedly diminished.
Hypothalamic Thermoregulation Center
Progesterone is a hormone with thermogenic effects; under the influence of progesterone, the hypothalamus shifts the basal body temperature upward by 0.5°F to 1.0°F over the average preovulatory temperature. This shift occurs abruptly with the beginning of progesterone secretion and quickly returns to baseline with the decline in progesterone secretion. Therefore, these changes in basal body temperature reflect changes in plasma progesterone concentration.
Because the basal body temperature assumes basal conditions at rest, it should be performed immediately in the morning upon awakening, prior to any activity.
Special thermometers with an expanded scale are available for this purpose. Identification of this characteristic biphasic curve provides retrospective, indirect evidence of ovulation; however, some ovulatory women do not demonstrate these changes.
Clinical Follow-Up
Although there may be some familial element to when a woman undergoes menopause, this patient would seem to have a normal reproductive cycle with melasma that suggests that she continues to ovulate. She is reassured when told this information and that her prior tubal ligation would have no effect on the age of menopause. Further exploration of her history and symptoms suggested mild depression, which was further confirmed when a test of thyroid function returned normal values.
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