Erika B. Johnston-MacAnanny, MD, &
Robert N. Taylor, MD, PhD
Disorders of the female reproductive system can occur as a result of disease in one of the many varied reproductive organs: the ovaries, the fallopian tubes, the uterus, the cervix, the vagina, or the breast. During the reproductive years, these disorders often present as altered menstruation, pelvic pain, or infertility. Cancers arising in these tissues occur more often in the late reproductive or menopausal years. Unfortunately, for several reasons, they often have high mortality rates and a high incidence of metastases when they are diagnosed. Some organs are located deep and are relatively inaccessible to palpation (ovaries). Others have few sensory nerves (ovary, fallopian tubes) and hence remain asymptomatic. Additionally, the breasts have large amounts of adipose tissue, which can make early detection of breast cancer difficult. The one exception is the uterine cervix. It has easy access to surveillance with use of the Papanicolaou smear and human papillomavirus (HPV) screening, which have led to a dramatically reduced mortality rate of cervical cancer.
Disorders of the female reproductive system can also occur as a result of disease in other organs whose function affects reproductive organs (eg, the brain, hypothalamus, pituitary, thyroid, adrenals, kidney, and liver). Presentation of these disorders is typically painless.
Conversely, disorders of the reproductive system can cause disorders in other tissues. Ovarian hormones are necessary for the maintenance and health of most tissues in women. Alterations in these hormones can lead to osteoporosis(loss of bone mass), atrophy and inflammation of estrogen-deprived tissues (eg, atrophic vaginitis), atherogenesis and alterations in cardiovascular compliance, and an increased risk of some forms of cancer (eg, endometrial carcinoma as a consequence of estrogen excess and progesterone deficiency). Dysfunction of the reproductive system also can contribute to unique variants of systemic disorders, such as gestational diabetes and the hypertensive syndrome of preeclampsia-eclampsia.
CHECKPOINT
1. How do female reproductive system disorders present during the reproductive years?
2. To what might you ascribe the lack of reduction in mortality rate from ovarian cancer in contrast to cervical cancer?
3. What are some consequences of reproductive system dysfunction?
NORMAL STRUCTURE & FUNCTION OF THE FEMALE REPRODUCTIVE TRACT
ANATOMY
The reproductive pelvic organs include the vagina, cervix, uterus, fallopian tubes, and ovaries (Figure 22-1). The two ovaries contain thousands of follicles, each with an oocyte surrounded by a layer of granulosa cells and thecal cells. These supporting cells produce steroids and paracrine products important in follicular maturation and coordination of events in reproduction. The fallopian tubes, which are open to the peritoneal space, connect the ovaries to the uterus. The uterus contains an internal hormone-sensitive mucosal lining, the endometrium. During nonpregnant cycles, menstrual bleeding occurs as the monthly culmination of endometrial growth, differentiation, and sloughing in response to changes in blood levels of estrogen and progesterone (Figure 22-2). During pregnancy, the endometrium produces a wide variety of endocrine and paracrine products, which promote embryonic implantation (Table 22-1). Surrounding the endometrium is the smooth muscle layer of the uterus, the myometrium. Contractions of the myometrium lead to menstrual cramps or expel the fetus at parturition. The cervix is contiguous with the uterus and is the conduit for passage of menses or the fetus into the vagina, the muscular tube opening into the vulva.
FIGURE 22-1 Anatomic landmarks of the uterus and adjacent organs. (Redrawn, with permission, from Chandrasoma P et al. Concise Pathology, 3rd ed. Originally published by Appleton & Lange. Copyright © 1998 by The McGraw-Hill Companies, Inc.)
FIGURE 22-2 Changes in the ovary, endometrium, and blood hormone levels during the menstrual cycle. Anti-müllerian hormone levels stay constant during the cycle. FSH, follicle-stimulating hormone; LH, luteinizing hormone. (Redrawn, with permission, from Chandrasoma P et al. Concise Pathology, 3rd ed. Originally published by Appleton & Lange. Copyright © 1998 by The McGraw-Hill Companies, Inc.)
TABLE 22-1 Endocrine and paracrine products of the endometrium.
The breasts (Figure 22-3) produce, store, and eject milk upon appropriate hormonal and physical stimulation.
FIGURE 22-3 Schematic drawing of female breast showing the mammary glands with ducts that open in the nipple. The outlines of the lobules do not exist in vivo but are shown for instructional purposes. The stippling indicates loose intralobular connective tissue. (Redrawn, with permission, from Junqueira LC et al. Basic Histology, 10th ed. McGraw-Hill, 2003.)
SEXUAL DIFFERENTIATION & MATURATION OF ESTROGEN-DEPENDENT TISSUES
Embryonic Sexual Differentiation
During embryonic development, the primordial gametes originate in the endoderm of the yolk sac, allantois, and hindgut and migrate to the genital ridge by week 5 or 6 of gestation. Once at the genital ridge, they multiply and induce male or female gonads depending on the identity of the sex chromosomes.
Until week 8 of gestation, the sex of the embryo cannot be determined morphologically; therefore, this period is termed the indifferent phase of sexual development. After this time, differentiation of the internal and external genitalia occurs, determining the phenotypic sex of the individual, which becomes fully developed after puberty. During embryogenesis, the internal genitalia are formed from a dual genital duct system within the urogenital ridge. The first to form is the wolffian duct, followed by the müllerian duct, which is dependent on prior wolffian duct development. After 8 weeks of gestation, production of anti-müllerian hormone by Sertoli cells in the fetal testes leads to regression of the müllerian ducts, whereas production of testosterone by the Leydig cells leads to persistence of the wolffian duct and subsequent development of the prostate, epididymis, and seminal vesicles. In the absence of these secretions, female internal reproductive organs are formed from the müllerian ducts, and the wolffian structures degenerate. Similarly, the external genitalia of males develop in the presence of dihydrotestosterone; in the absence of this hormone, the common embryologic structures give rise to female external genitalia. Exposure to androgens can result in virilization of the external genitalia of female embryos, whereas androgen deficiency results in defective male development (Figure 22-4). Therefore, the male phenotype is induced while no ovarian secretions are necessary for expression of the female phenotype.
FIGURE 22-4 Timing of male and female human sexual differentiation. (Redrawn, with permission, from Griffin JE et al. Textbook of Endocrine Physiology, 4th ed. Oxford University Press, 2000.)
During female development, the female ovaries contain about 7 million oogonia by 24 weeks of gestation. The majority of these cells die during intrauterine life, leaving only about 1 million primary oocytes at birth. This decreases to about 400,000 by puberty. The surviving oogonia are arrested at the prophase of meiosis I. Completion of the first meiotic division does not occur until the time of ovulation, and the second meiosis is completed with fertilization. Only about 400 of these oocytes mature and are released by ovulation during a woman’s lifetime; the others undergo atresia at various stages of development.
PUBERTY
Secondary sexual characteristics develop at puberty, when maturation of the capacity for adult reproductive function occurs. The changes that occur in the brain and hypothalamus that initiate the onset of puberty involve the establishment of sleep-dependent (first) and the later truly pulsatile release of gonadotropin-releasing hormone (GnRH) from the hypothalamus. The hypothalamic kisspeptin/GPR54 ligand/receptor pair appears to be the key mediator of the onset of puberty.
The increase in GnRH leads to an increase in and a pulsatile pattern of luteinizing hormone (LH) and then follicle-stimulating hormone (FSH) secretion, hormones collectively termed gonadotropins. Before about age 10 years in girls, gonadotropin secretion is at low levels and does not display a pulsatile character. After this age, pulsatile release of GnRH begins and initiates folliculogenesis, leading to cyclic changes in estrogen and progesterone production. These changes allow estrogen-dependent tissues, such as the breasts and the endometrium, to begin their maturation. The appearance of breast development is referred to as thelarche, and the first menstrual period is termed menarche.
CHECKPOINT
4. What is the difference between the chromosomal, gonadal, and phenotypic sex of an individual?
5. Approximately what percentage of the total number of oocytes present in the ovaries of a female at birth completes their maturation and is released upon ovulation over the course of her reproductive life?
6. Describe some changes that occur in the female with the onset of puberty.
THE MENSTRUAL CYCLE
Normal female reproductive function involves coordinated interaction between the brain and ovaries under the influence of other organs such as the liver (which metabolizes hormones and makes steroid-binding globulins), adrenals, and thyroid. With this coordination, cyclic changes during the course of the menstrual cycle allow the reproductive organs to perform specific functions at different points in time to optimize the chances for successful reproduction. When these mechanisms malfunction, the result may be infertility, altered menstrual bleeding, amenorrhea, or even cancer.
The menstrual cycle has three phases. The follicular phase typically lasts 12-14 days and culminates in the production of a mature oocyte. Initially, a cohort of follicles begins to grow, but ultimately a single dominant follicle is selected and the rest undergo a process of degeneration and apoptotic death, termed atresia (Figure 22-5). The follicular phase is followed by ovulation, in which the dominant follicle releases its mature oocyte to be transported through the uterine tubes for fertilization and subsequent implantation in a receptive uterus. The third, luteal, phase also averages 14 days and is characterized by luteinization of the ruptured follicle to produce the corpus luteum. The physiology of each of these phases in the menstrual cycle is best understood by considering different compartments: neuroendocrine, ovarian, and target tissues, most notably the uterus (Figure 22-6).
FIGURE 22-5 Diagram of the ovary, showing the sequential development of a follicle and the formation of a corpus luteum. An atretic follicle is shown in the center, and the structure of the wall of the mature follicle is detailed at the upper right. (Redrawn, with permission, from Gorbman A et al. Textbook of Comparative Endocrinology. Wiley, 1962.)
FIGURE 22-6 Female reproductive neuroendocrine feedback axis. Solid arrows indicate stimulation; dashed arrows indicate inhibition.
The neuroendocrine axis involves the brain, hypothalamus, pituitary, and the ovary. Neurons within the hypothalamus synthesize the peptide GnRH, and its secretion is modulated by endogenous opioids and corticotropin-releasing hormone (CRH). GnRH is secreted directly into the portal circulation of the pituitary in a pulsatile fashion. This pulsatility is required for proper activation of its receptor located on the gonadotropes, which are cells located in the anterior pituitary. In response, the gonadotropes secrete the polypeptides FSH and LH, collectively called gonadotropins, which stimulate the ovary to produce estrogen and inhibin. Inhibin feeds back to suppress FSH secretion but has no effect on LH. Estrogen also affects the pituitary by increasing the number of GnRH receptors and its sensitivity to GnRH stimulation. With estradiol production by the ovaries, a critical concentration is reached for a sufficient time to induce a midcycle LH surge and subsequent ovulation. After this surge, high levels of progesterone produced by the corpus luteum suppress gonadotropin release for the duration of the luteal phase.
Within the ovary, LH and FSH lead to the synthesis and secretion of steroid hormones and other paracrine/autocrine proteins, directing the maturation of a single oocyte for ovulation. During the early follicular phase, FSH stimulates growth of a cohort of follicles and increases the production of inhibin and activin in granulosa cells. Activin acts in the ovary to augment the effect of FSH, increasing aromatase activity and increasing production of FSH and LH receptors. LH stimulates the production of androgens in the thecal cells, which is augmented by inhibin. Androgens diffuse into the granulosa cells to be converted to estrogens through the enzymatic reaction of aromatization. As the follicular phase progresses, inhibin production comes under the control of LH, and the increasing amounts of inhibin lead to further conversion of androgens to produce the high levels of estrogen needed for the LH surge.
The midcycle LH surge triggers the final steps of oocyte maturation and resumption of meiosis within the dominant oocyte. Changes in prostaglandins and proteases allow digestion of the follicular wall leading to oocyte extrusion and ovulation. The follicular cells remaining after ovulation develop into a structure called the corpus luteum, which synthesizes and releases large amounts of both estradiol and progesterone. Continued secretion from the corpus luteum requires LH (or human chorionic gonadotropin [hCG], as discussed below) stimulation; in its absence, degeneration occurs.
The uterine compartment reacts to the steroids produced from the ovaries throughout the menstrual cycle. During the follicular phase, the endometrium proliferates under the influence of estrogen, creating straight glands with thin secretions and microvascular proliferation. During the luteal phase, the high levels of estradiol and progesterone promote maturation of the endometrium, which develops tortuous glands engorged with thick secretions and proteins (Figure 22-2). Additionally, the endometrium secretes a number of endocrine and paracrine factors (Table 22-1). These changes optimize the environment for implantation. In the absence of pregnancy, the corpus luteum cannot sustain the high levels of progesterone production and the endometrial vasculature cannot be maintained. This leads to sloughing of the endometrium and the onset of menstruation, which is marked by the nadir of estradiol and progesterone levels, ending the cycle (Figure 22-2).
Contraception
Birth control pills are a pharmacologic means of preventing pregnancy by disrupting the precise timing of hormone-directed events necessary for reproduction. Current formulations include progestins alone as well as combinations of estrogens and progestins. Most preparations of estrogen and progestin block the LH surge at midcycle, thereby preventing ovulation. However, other contraceptive actions include effects on estrogen- and progesterone-sensitive tissues, such as inducing antifertility changes in cervical mucus and the endometrial lining that are unfavorable to sperm transport and embryonic implantation, respectively.
In order to mitigate the unpleasant side effects of nausea and bloating, as well as the dangerous side effect of thrombosis, the doses of estrogen and progestin have been decreased over the years. Non-oral formulations also have been developed, including long-term intrauterine and subdermal systems that deliver progestins. A transdermal patch allows absorption of estrogen and progestin without “first-pass” metabolism in the liver. Transvaginal absorption is also available with a soft ring placed monthly in the vagina. Each of these formulations provides contraceptive efficacy equal to or better than oral contraceptive pills.
PHYSIOLOGY OF OVARIAN STEROIDS
Like the adrenal gland, the ovary is a steroid factory. The ovary secretes three types of steroids: progesterone, containing 21 carbons; androgens, containing 19 carbons; and estrogens, containing 18 carbons. Steroid synthesis occurs by conversion from cholesterol in a series of oxidative biochemical reactions catalyzed by enzymes in the mitochondria and the endoplasmic reticulum (see Chapter 21). The rate-limiting steps in steroid production involve the transport (StAR) and side chain cleavage of cholesterol within the mitochondrion by the enzyme cytochrome P450, family 11, subfamily A, polypeptide 1 (CYP11A1) to generate the basic steroid backbone, pregnenolone. This steroid is further modified in the endoplasmic reticulum to generate the various steroid hormones. Because steroids are synthesized by a cascade of enzyme reactions in various pathways, a block in one step (eg, resulting from a congenital enzyme defect or inhibition by certain drugs) can result in lack of synthesis of downstream products and “spillover” of precursors. Such defects are the hallmark of congenital adrenal hyperplasia (discussed in Chapter 21).
The classical mechanism of steroid hormone action involves diffusion across the plasma membrane, binding of the steroid to receptor proteins in the cytoplasm or nucleus, and, after association with chromatin, activation of transcription of selected genes by binding of the steroid-receptor complex to specific regions of DNA. In this way, the pattern of gene expression is changed in the various steroid-responsive tissues (ie, those that contain steroid receptors). Membrane-bound steroid receptors also have been shown to activate phosphorylation cascades typically regulated by growth factors.
CHECKPOINT
7. What are the primary target tissues for GnRH? For gonadotropins? For ovarian steroids?
8. Why is pulsatile secretion of GnRH important?
9. What are some specialized features of GnRH action?
10. What are the specific effects of gonadotropins on the ovary?
11. How does the structure of the uterine lining differ in the midfollicular versus the midluteal stages, and for what reproduction-related events is each stage optimized?
12. What products are made by a granulosa cell in the dominant follicle over the course of its lifetime?
PREGNANCY
Prerequisites for a Successful Pregnancy
A number of changes must occur in reproductive and other organs for establishment and successful completion of a pregnancy. Fertilization requires successful ovulation, capture of the mature oocyte by the fimbria of the fallopian tubes, and transport of the zygote to the uterus. Because fertilization usually occurs in the ampulla, it also requires effective transport of viable sperm into the distal tube.
After implantation, a placenta forms consisting of two functional epithelial layers, the cytotrophoblast and the syncytiotrophoblast, as well as an adjacent maternal layer, the endometrial decidua, with its underlying mesenchymal core (Figure 22-7). The placenta allows intimate apposition of maternal and fetal circulations for exchange of nutrients, oxygen, and waste products. In addition, the placenta secretes a variety of important hormones, including an LH-like hormone termed human chorionic gonadotropin (hCG). Unlike LH secretion by the gonadotrophs of the anterior pituitary, placental secretion of hCG is neither pulsatile nor inhibited by the high levels of estrogen and progesterone. hCG maintains the corpus luteum for a period of 8–10 weeks until the full progesterone-producing capacity of the placenta has developed. At that point, hCG levels fall and the mature placenta produces progesterone from maternal cholesterol (Figure 22-8). Other factors produced by the placenta include a growth hormone–like protein human chorionic somatomammotropin (hCS), also known as placental lactogen (hPL) (Table 22-2).
FIGURE 22-7 Placental anatomy.
FIGURE 22-8 Hormone production during pregnancy. (FSH, follicle-stimulating hormone; LH, luteinizing hormone; hCG, human chorionic gonadotropin.) (Redrawn and modified, with permission, from Fritz M et al. Regulation of the menstrual cycle. In: Clinical Gynecologic Endocrinology and Infertility, 8th ed. Lippincott Williams & Wilkins, 2011.)
TABLE 22-2 Endocrine and paracrine products in pregnancy other than steroids.
During most of pregnancy, the fetus provides the placenta with androgens, which are aromatized to make estrogens secreted into the maternal circulation (Figure 22-9). This reflects the action of a special zone in the fetal adrenal cortex engaged in androgen production. Toward the end of pregnancy, increasing ACTH secretion by the fetal pituitary triggers the fetal adrenal to produce cortisol in addition to androgen. This switch may play a role in triggering the onset of labor by modulating the expression of progesterone receptors in the myometrium.
FIGURE 22-9 Fetal-placental-maternal cooperation in steroidogenesis. LDL, low-density lipoprotein; 3β-Hydroxysteroid dehydrogenase, hydroxy-Δ-5-steroid dehydrogenase, 3 β- and steroid Δ-isomerase (HSD3β); 17β-Hydroxylase, 17α-hydroxylase activity of cytochrome P450, family 17, subfamily A, polypeptide 1 (CYP17A1). (Reproduced from Fritz M et al. The endocrinology of pregnancy. In: Clinical Gynecologic Endocrinology and Infertility, 8th ed. Lippincott Williams & Wilkins, 2011.)
In addition to the changes in organs with pregnancy-specific functions, physiologic changes occur in essentially every maternal organ system. These include increased blood volume (increased by more than 40% by the middle of the third trimester), increased total body water (increased by 6–8 L), and increased cardiac output because of increased stroke volume (increased by 30%) and heart rate (increased by 15%). A striking increase in minute ventilation (increased by 50% compared with nonpregnant state) without any change in respiratory rate is observed as a result of increased tidal volume (Chapter 9). Dramatic increases in renal blood flow and glomerular filtration rate (increased by 40%) are also seen. Most of these alterations are related in complex ways to the effects of hormones produced in pregnancy.
Effects of Ovarian Steroids in Pregnancy
The physiological effects of various sex steroids in pregnancy are incompletely understood. The demonstrated and proposed roles of progesterone in pregnancy include (1) promotion of implantation; (2) suppression of the maternal immune response to fetal antigens, thus preventing rejection of the allogeneic fetus; (3) increased cardiovascular compliance; (4) provision of substrate for manufacture by the fetal adrenal of glucocorticoids and mineralocorticoids; (5) maintenance of myometrial quiescence through gestation; and (6) a role in parturition. Estrogens contribute to (1) volume expansion; (2) cardiac remodeling; and (3) preparative production of clotting factors, anticipating blood loss that commonly follows delivery.
Human Chorionic Somatomammotropin & Fuel Homeostasis in Pregnancy
Another example of fetal-placental-maternal interactions is seen in the actions of hCS (Figure 22-10). This “counterregulatory” hormone (ie, a hormone whose actions oppose those of insulin) appears to serve as a defense against fetal hypoglycemia. From a metabolic standpoint, pregnancy is a form of “accelerated starvation” characterized by fasting hypoglycemia, as fuel substrates produced by the mother are consumed by the growing fetus. The hCS produced by the placenta in response to hypoglycemia serves to increase lipolysis, thereby raising maternal free fatty acid levels and ultimately blood glucose and ketone levels. This “diabetogenic” role of hCS is a major burden on the maternal compartment and contributes to the tendency for diabetes mellitus to emerge in susceptible individuals during pregnancy. Normally, glucose is the major fuel source for the fetus. However, in the event of glucose deprivation, ketones provide a ready emergency fuel supply (as they do in starvation) for both the mother and, via the placenta, for the fetus.
FIGURE 22-10 Fetal-placental-maternal cooperation in fuel homeostasis. hCS, human chorionic somatomammotropin; FFA, free fatty acids. (Reproduced from Fritz M et al. The endocrinology of pregnancy. In: Clinical Gynecologic Endocrinology and Infertility, 8th ed. Lippincott Williams & Wilkins, 2011.)
CHECKPOINT
13. How is the corpus luteum maintained until the placenta has developed adequately?
14. What are some possible roles of steroids during pregnancy?
15. Why is new-onset diabetes mellitus a common complication of pregnancy?
LACTATION
Breast Structure & Development
The rudiments for breast development are established during embryonic development. During puberty, rising estrogen levels stimulate breast growth as one of a number of female secondary sexual characteristics. Breast growth involves both proliferation and branching of lactiferous ducts as well as accumulation of adipose and connective tissue. In the mature breast, each terminal lactiferous duct drains clusters of tubuloalveolar secretory units lined by milk-secreting epithelial cells and is suspended in connective and adipose tissue well populated with lymphocytes. The mature female breast consists of a cluster of 15–25 lactiferous ducts, each emerging independently at the nipple (Figure 22-3). Both the pubertal and pregnant phases of breast growth require the permissive influence of glucocorticoids, thyroxine, and insulin for full development, and their actions are potentiated by estrogen and progesterone.
Initiation & Maintenance of Milk Synthesis & Secretion
During pregnancy, prolactin, progesterone, and hCS play a dominant role in stimulating breast growth and the capacity for milk production. Actual lactation, or milk release, however, is inhibited by the high levels of placental steroids present before birth. After delivery of the placenta, estrogen and progesterone levels fall dramatically, removing this block. Maintenance of milk secretion requires the integrated action of both anterior and posterior pituitary factors (Figure 22-11) as well as interaction between the mother and infant. Suckling stimulates afferent neural pathways that suppress dopamine levels in the hypothalamus, thereby maintaining high levels of prolactin necessary for milk synthesis. At the same time, afferent sensory nerve fibers in the breast (as well as other stimuli such as the infant’s cry) stimulate synthesis, transport, and secretion of oxytocin from the posterior pituitary. Oxytocin promotes contraction of mammary myoepithelial cells, thereby triggering ejection of milk from the mammary epithelial alveoli and out the nipple.
FIGURE 22-11 The role of anterior and posterior pituitary factors in milk synthesis and secretion. SO, supraoptic nucleus; PV, paraventricular nucleus. (Redrawn, with permission, from Rebar RW. The breast and physiology of lactation. In: Creasy RK et al, eds. Maternal-Fetal Medicine: Principles and Practice, 4th ed. Saunders, 1999.)
Toward the end of pregnancy, there is an increase in the lymphocyte population in the vasculature and connective tissue of the breast. These lymphocytes secrete immunoglobulin A (IgA) into the local bloodstream, from which it is taken up by the mammary epithelial cells. By the process of transcytosis, IgA crosses the mammary epithelial cells into the luminal secretion (milk). This mechanism, coupled with the transplacental transport of maternal IgG, is responsible for conferring passive immunity on the newborn. The earliest mammary gland secretion after birth, termed colostrum, has particularly high immunoglobulin content.
The high level of prolactin maintained during lactation also has a contraceptive effect, primarily by inhibition of pulsatile secretion of GnRH. The precise mechanism is not known but may involve a short feedback loop by which prolactin stimulates dopamine release, which, in turn, elevates endogenous opioid release and inhibits GnRH secretion. There may also be effects of prolactin directly on the ovary that contribute to lactational anovulation and amenorrhea. However, it should be noted that the contraceptive effect of prolactin is only moderate and, therefore, of low reliability.
CHECKPOINT
16. Which hormones are involved in breast development?
17. Why is milk rarely secreted before parturition?
18. What is the probable mechanism of lactational amenorrhea?
Menopause
Menopause is the point in a woman’s life when, as a result of exhaustion of the supply of functioning ovarian follicles, menstrual cycles cease. Ten years before menopause, at approximately age 40 years, reproductive function starts to diminish. This is manifested as a decreased frequency of ovulation and alterations in menstrual patterns. During this time, in the setting of few remaining follicles, increased GnRH-stimulated LH and FSH secretion is observed. Higher levels of estradiol circulate, particularly in the follicular phase from ages 35–48 years, and then estradiol levels sharply decline just prior to menopause. This transitory period of diminishing reproductive function approaching menopause is termed the climacteric.
During the climacteric transition, the hormonal status of women changes from a cyclic high-estrogen state to a steady-state low-estrogen postmenopausal state. This leads to vasomotor symptoms such as hot flushes (“hot flashes”), sweating, and chills. Psychologic symptoms such as irritability, tension, anxiety, and depression may also be observed. After menopause, other more gradual changes can appear. In addition to atrophy of estrogen-dependent tissues such as the vaginal epithelium, a gradual loss in bone density leading to osteoporosis can occur.
A modest degree of androgen production from thecal cells of the residual ovarian stroma continues even in the absence of follicular growth. In postmenopausal women, ovarian and adrenal androgens continue to be aromatized into estrogens by the enzyme aromatase (cytochrome P450, CYP19A1) in adipose tissue and hair follicles. The significance of peripheral aromatization in relation to severity of symptoms of menopause varies in different individuals.
In the medical literature, menopause was often viewed as an “endocrinopathy,” specifically as a disorder of estrogen deficiency. To treat the vasomotor symptoms and osteoporosis, hormone therapy (HT) was often prescribed. Given the interaction of estrogen on the cardiovascular system, HT had also been thought to improve cardiovascular events, and several trials suggested its usefulness in primary and secondary prevention of coronary heart disease. Results of prospective studies, however, showed no benefit in cardiovascular protection with HT. The Women’s Health Initiative showed that the increased risk of thromboembolic disease and invasive breast cancer associated with estrogen and progesterone replacement outweighed the benefit of fewer events of colon cancer and hip fractures. Treatment with estrogen replacement therapy without progesterone in women who had undergone hysterectomy did not show any increase in breast cancer but instead suggested possible breast cancer prevention. The other risks and benefits were similar. From these studies, it is recognized that HT should not be used for cardiovascular prevention or initiated in women older than 60 years. Use for symptomatic relief of menopausal symptoms is still appropriate after counseling the patient about the global risks and benefits of treatment.
CHECKPOINT
19. What are the symptoms of menopause?
20. What is the primary source of the estrogen found in the bloodstream of postmenopausal women not on estrogen replacement therapy?
21. Compare LH and FSH levels before puberty, during the reproductive years, and after the menopause.
OVERVIEW OF FEMALE REPRODUCTIVE TRACT DISORDERS
Many female reproductive disorders can be traced to a particular level of the neuroendocrine feedback axis and thus can be categorized as resulting from central (pituitary, hypothalamus, or other brain centers which influence the hypothalamus), ovarian or end-organ (target tissue, eg, uterine) dysfunction.
DISORDERS OF CENTRAL HYPOTHALAMIC-PITUITARY FUNCTION
Any change in the precise rate or amplitude of GnRH secretion by the hypothalamus can result in altered pituitary responsiveness (eg, downregulation of GnRH receptors or altered gonadotropin secretion). This altered pituitary function, in turn, results in disordered ovarian function (eg, inadequate steroidogenesis with or without anovulation) and altered target tissue response (eg, endometrial atrophy and menstrual abnormalities). Many central (eg, psychic stress) and peripheral (eg, body fat content) inputs affecting pulsatile GnRH release are integrated in the hypothalamus. Thus, altered GnRH release from the hypothalamus is a common cause of amenorrhea (eg, in athletic young women).
DISORDERS OF THE OVARY
Proper ovarian function involves responsiveness to gonadotropins, intrinsic viability of follicles, and a host of paracrine interactions within and between individual follicles. Polycystic ovary syndrome (PCOS) is an example of ovarian dysfunction resulting from a self-perpetuating cycle of altered feedback relationships (see later discussion). PCOS is manifested by anovulation, hirsutism, infertility, dyslipidemia, and either abnormal uterine bleeding or amenorrhea.
DISORDERS OF THE UTERUS, FALLOPIAN TUBES, & VAGINA
Because normal menstrual bleeding is most directly a function of the growth state of the uterine endometrium, disorders of the uterus, including hormonal dysfunction, myomas (fibroids, benign tumors of the underlying myometrium), and cancer of the endometrium itself, often present with abnormal vaginal bleeding.
Pelvic infections can produce adhesions and scarring of the endometrium or fallopian tubes that may result in infertility. The initial presentation typically includes abdominal and pelvic (cervical and adnexal) pain and with fever, an elevated white blood cell count, or a positive endocervical culture. Common infectious agents include gonorrhea, anaerobic bacteria, and Chlamydia. Multiple organisms are usually involved, and symptoms may be minimal or absent in as many as half of infected women. Aggressive screening programs and prompt antibiotic therapy are important in treating these infections to limit permanent damage to sensitive reproductive structures. Pelvic infections can develop into tubo-ovarian abscesses requiring surgical drainage.
DISORDERS OF PREGNANCY
The normal events of pregnancy potentially set the stage for a wide array of localized and systemic disorders. Abnormalities in the process of implantation, for example, appear to predispose to recurrent miscarriage and preeclampsia-eclampsia (see later). In addition, genetic predisposition to diseases that might otherwise remain latent for decades may be manifested first—often transiently—during pregnancy.
A good example of the latter is the genetic predisposition to development of diabetes mellitus. As discussed, pregnancy is a counterregulatory state, with elevation of multiple blood glucose-elevating hormones, especially hCS. Because of the insulin-resistant features of pregnancy, blood glucose control in diabetics who become pregnant is more difficult. Nondiabetic patients can also develop diabetes transiently during pregnancy (gestational diabetes mellitus). Gestational diabetes mellitus is common and involves 2–5% of all pregnancies in the United States. Many of these individuals go on to manifest type 2 diabetes mellitus later in life.
Poor control of blood glucose during pregnancy has effects on the mother, on the course of the pregnancy, and on the fetus. Maternal retinopathy and nephropathy may appear during the course of the pregnancy, although the long-term severity of the mother’s disease is probably not altered by pregnancy. There is a higher incidence of acute complications of diabetes, including ketoacidosis, hypoglycemia, and infections during pregnancy. Patients with gestational and pregestational diabetes mellitus are at greater risk for preeclampsia-eclampsia. Poor glucose control also increases the rate and risk of cesarean section with associated anesthetic and surgical morbidity.
The effects of poor glucose control on the fetus are even more profound. Unexplained fetal deaths, spontaneous abortions, and congenital anomalies are increased. Just how gestational diabetes increases the risk of congenital anomalies is not well understood. Some studies have implicated altered myoinositol and prostaglandin metabolism. Other studies have demonstrated embryopathic effects of oxygen free radicals generated at elevated levels in diabetic pregnancies.
Fetal macrosomia (large body size) is often the result of gestational diabetes. High maternal blood glucose triggers increased fetal insulin secretion and, therefore, results in a larger fetus. As the fetus becomes larger, the risk of fetopelvic disproportion increases, which contributes to traumatic vaginal deliveries or an increased frequency of cesarean section. Neonatal hypoglycemia, hypocalcemia, polycythemia, and hyperbilirubinemia also may occur.
The high levels of steroids and other products in the pregnant state can lead to a range of other serious medical complications. Pregnancy is paradoxically associated with both hemorrhage and thrombosis (Table 22-3). Both are related to the special functions of the placenta and its adaptations in the course of mammalian evolution.
TABLE 22-3 Factors predisposing to thrombosis in pregnancy.
Separation of the placenta from the wall of the uterus at birth poses a threat of massive, life-threatening hemorrhage given the intimate apposition of the placenta and the maternal blood supply, 10% of which is funneled to the uterus at term. As an adaptation to this risk, pregnancy is a hypercoagulable state established in part by estrogen stimulation of hepatic coagulation proteins. Physiologically, this increased tendency toward coagulation and decreased activity of the fibrinolytic system may serve to control postpartum hemorrhage. Pathologically, these same factors pose a risk of inappropriate thrombosis. It has been calculated that the risk of thrombophlebitis is increased nearly 50 times in the first month postpartum compared with the nonpregnant state. When thrombosis does occur, therapy is complicated by the teratogenic risks associated with warfarin. Therefore, pregnant patients with thrombosis are given subcutaneous heparin therapy.
Miscarriage, Ectopic Pregnancy, & Placental Disorders
At least 15% of all pregnancies terminate in spontaneous abortions as a result of genetic or environmental factors before the period when extrauterine life is possible (about 24 weeks of gestation and 750 g body weight). Inevitable abortion presents with heavy bleeding, pain, and dilation of the internal os. Threatened abortion is considered when painless uterine bleeding occurs with a closed, uneffaced cervix.
For patients presenting with vaginal bleeding and pain in the first trimester, miscarriage must be distinguished from molar and ectopic pregnancy. Ectopic pregnancy typically results from implantation of the blastocyst into the lining of the tube rather than the endometrium. Damaged or scarred fallopian tubes, from previous pelvic infections or endometriosis, impede transit of the zygote, leading to a predisposition for ectopic pregnancies. In this location, the embryo is not viable, but its growth results in rupture and potentially life-threatening hemorrhage unless it is surgically or medically eliminated. Diagnosis is made by a failure of serum β-hCG to rise appropriately in the first several weeks of pregnancy and failure to localize an intrauterine pregnancy by ultrasonography.
Third-trimester bleeding is typically associated with placenta previa (placental obstruction of all or part of the internal cervical os) or placental abruption (premature separation of a normally implanted placenta). Women who have had multiple prior pregnancies, and particularly those with multiple Caesarean section deliveries, are at increased risk of placenta previa, which is believed to be due to scar tissue formation from previous implantations. Hypertension, smoking, and multiple pregnancies increase the risk of hemorrhage into the decidual plate and subsequent placental abruption. Hemorrhage can be massive and life-threatening.
TROPHOBLASTIC DISEASES
Complete molar pregnancies are abnormal growths resulting from trophoblastic proliferation. Rarely, they coexist with a fetus (partial mole). The prevalence in the United States is approximately 1 per 1500 pregnancies, but in certain areas of Asia it is as high as 1 per 125 pregnancies. The tissue in complete moles has higher malignant potential and is purely of paternal origin, whereas that of partial moles is usually benign and typically contains an extra set of paternal chromosomes (triploidy). Most moles present with vaginal bleeding and are diagnosed during evaluation of threatened abortion by (1) lack of a fetus and (2) presence of hydropic trophoblastic tissue on ultrasound imaging. Particularly severe nausea of pregnancy, a uterus larger than expected for gestational age, and an extremely elevated hCG level are suggestive, but not diagnostic, of molar pregnancy.
The complications of hydatidiform mole include high risks of (1) choriocarcinoma, a malignant, trophoblastic neoplasm with high potential for metastasis, especially to lung and brain; (2) hyperthyroidism with added risk of thyroid storm during induction of anesthesia; and (3) severe hemorrhage or trophoblastic tissue pulmonary embolism during suction curettage to remove the molar products. The extremely high levels of hCG that occur with molar pregnancy and choriocarcinoma can result in cross-activation of the thyroid-stimulating hormone (TSH) receptor and trigger hyperthyroidism in some patients. Approximately 5% of women with hydatidiform mole subsequently develop choriocarcinoma. The serum β-hCG can be used as a sensitive test to detect the continued presence of malignant tissue. The exquisite sensitivity of choriocarcinoma to chemotherapy has made it a readily curable malignancy if detected early.
DISORDERS OF THE BREAST
Intrinsic disorders of the breast are either malignant (breast cancer) or benign (eg, fibrocystic disease). Breast disease also can occur as a result of the effects of other disorders or drug therapy, as in galactorrhea. The breast, like other estrogen- and progesterone-target tissues, displays cyclic changes through the menstrual cycle. Subtle imbalances in the relative levels of estrogen and progesterone may be the cause of benign breast disease. This term refers to abnormalities ranging from normal premenstrual breast tenderness relieved with menstruation at one extreme to so-called fibrocystic disease at the other. In fibrocystic disease, breast fibrosis and cysts are associated with mammary epithelial hyperplasia. True fibrocystic disease with epithelial cell hyperplasia is a risk factor for breast cancer in much the same way that endometrial hyperplasia resulting from unopposed estrogen action is a risk factor for endometrial cancer.
CHECKPOINT
22. What are some central causes of menstrual disorders?
23. Why might you suspect some patients with choriocarcinoma to develop hyperthyroidism?
24. Are fibrocystic changes a risk factor for breast cancer?
DISORDERS OF SEXUAL DEVELOPMENT (DSD) [FORMERLY PSEUDOHERMAPHRODITISM]
Under certain circumstances, aberrations can occur during embryogenesis that alter the normal course of events in chromosomal, gonadal, or phenotypic sexual development. An example of such an aberration in chromosomal sex is Turner syndrome (45,X). Individuals with Turner syndrome are phenotypic females with primary amenorrhea, absent secondary sexual characteristics, short stature, webbed neck, shield chest, and bilateral streak gonads.
An example of altered gonadal sex is the syndrome of pure gonadal dysgenesis. Affected individuals have bilateral streak gonads and an immature female phenotype, but unlike those with Turner syndrome, they are of normal height, have no associated somatic defects, and have a normal female karyotype.
Disorders of phenotypic sex include disorders that result from exposure of female embryos to excessive maternal or exogenous androgens (eg, congenital adrenal hyperplasia) (see Chapter 21) during sexual differentiation or from defects in androgen synthesis or tissue sensitivity in the embryo (eg, testicular feminization).
PATHOPHYSIOLOGY OF SELECTED FEMALE REPRODUCTIVE TRACT DISORDERS
MENSTRUAL DISORDERS
Disorders of the menstrual cycle include (1) amenorrhea (lack of menstrual bleeding), which may be primary amenorrhea (ie, the failure of onset of menstrual periods by age 16) or secondary amenorrhea (ie, the lack of menstrual periods for 6 months in a previously menstruating woman); (2) dysmenorrhea (pain and other symptoms accompanying menstruation); or (3) menorrhagia (excessive vaginal bleeding) or metrorrhagia (irregular or abnormally protracted vaginal bleeding).
Etiology
A. Amenorrhea
The cause of amenorrhea can be traced to one of four broad categories of conditions (Table 22-4):
1. Normal physiologic processes such as pregnancy and menopause.
2. Disorders of the uterus or the pathway of menstrual flow such as destruction of the endometrium after curettage coupled with infection, which can cause within the uterus (Asherman syndrome).
3. Disorders of the ovary such as gonadal failure resulting from a range of chromosomal, developmental, and structural abnormalities, autoimmune disorders, premature loss of follicles, and poorly understood syndromes in which ovaries with follicles are resistant to gonadotropin stimulation.
4. Disorders of the hypothalamus or pituitary resulting in either lack of or disordered GnRH secretion and, as a consequence, insufficient gonadotropin secretion to maintain ovarian steroid production. The causes of hypothalamic and pituitary dysfunction include prolactin-secreting tumors, hypothyroidism, excessive stress and exercise, and weight loss.
TABLE 22-4 Causes of amenorrhea.
Within these categories, amenorrhea can have very diverse specific causes.
B. Dysmenorrhea
Dysmenorrhea is pain, typically cramping in character and lower abdominal in location, occurring in the days just before and during menstrual flow. Dysmenorrhea can occur as a primary disorder in the absence of identifiable pelvic disease or may be secondary to underlying pelvic disease such as endometriosis and leiomyomas (Table 22-5).
TABLE 22-5 Categories of dysmenorrhea.
C. Abnormal Vaginal Bleeding
Vaginal bleeding is abnormal if it occurs (1) prepubertally, (2) at the time of usual menses but is of longer than usual duration, (3) at the time of usual menses but is heavier than usual, (4) between menstrual periods, or (5) after menopause in the absence of pharmacologic hormone treatment with (postmenopausal bleeding). The categories of abnormal vaginal bleeding and some specific causes are presented in Table 22-6.
TABLE 22-6 Causes of abnormal vaginal bleeding.
Pathology & Pathogenesis
A. Amenorrhea
The pathogenesis of amenorrhea depends on the level of the neuroendocrine reproductive axis from which the disorder stems and whether it is due to a structural problem or to a functional problem of hormonal control. In a previously menstruating patient presenting with amenorrhea, it is important first to rule out pregnancy and then to assess thyroid (serum TSH level) and pituitary (serum prolactin level) function before approaching the workup of amenorrhea.
1. Uterine Disorders—Damage to the underlying stem cells from which the endometrium proliferates can lead to amenorrhea. In most cases, this occurs in the setting of endometritis after curettage(scraping of the endometrium) either for postpartum bleeding or dysfunctional uterine bleeding and subsequent failure of the endometrium to regenerate. Ultrasound typically reveals a thin lining (?5 mm).
To establish a functional endometrium, an amenorrheic patient is given either progesterone alone or the sequential combination of estrogen and progesterone. Renewed vaginal bleeding after cessation of the hormonal therapy suggests that the endometrium is intact. This response also indicates that the cause of amenorrhea lies elsewhere (ie, is due to an endocrine defect causing lack or insufficiency of cyclic estrogen and progesterone stimulation).
2. Ovarian Insufficiency—Amenorrhea resulting from ovarian insufficiency can be either primary or secondary to dysfunction higher in the neuroendocrine reproductive axis. Primary (or premature) ovarian insufficiency occurs with a premature loss of follicles. This can result from genetic disorders, autoimmune disorders (lymphocytic oophoritis), metabolic problems (galactosemia), or exogenous insults such as chemotherapy, toxins, or radiation. Secondary ovarian insufficiency is caused by a lack of gonadotropin stimulation of otherwise normal ovaries, resulting in failure to produce the estrogen and progesterone needed for menstrual cycles.
a. Primary ovarian insufficiency—Primary ovarian insufficiency occurs when atresia of follicles is accelerated in an ovary of a woman of reproductive age. It presents with symptoms and signs of menopause resulting from estrogen deficiency in patients younger than 40 years. Serum LH and FSH levels are elevated. There is a lack of estrogen production and an absence of viable follicles. In some instances, primary ovarian insufficiency is just one manifestation of an autoimmune polyglandular failure syndrome in which autoantibodies destroy a number of endocrine tissues. These patients also may have associated diabetes mellitus, hypothyroidism, or adrenal insufficiency, as discussed elsewhere (see Chapters 18, 20, and 21).
Genetic causes of primary ovarian insufficiency include abnormalities of the FMR1 gene. Expansion of CGG trinucleotide repeats between 55 and 200 copies is defined as the fragile X premutation and is associated with premature depletion of ovarian function (see Chapter 2), Turner syndrome (absence of, or abnormality in, an X chromosome, [ie, 45,X]), and Turner mosaicism (ie, multiple cell lines of varying sex chromosome composition). Approximately 40% of patients who appear to have Turner syndrome prove to be mosaics. The presence of any Y chromosome in the karyotype of these individuals carries a high risk for gonadal germ cell tumors and is an indication for gonadectomy. Thus, a karyotype should be performed on any amenorrheic individual younger than 30 years with high serum FSH and LH levels.
b. Chronic anovulation—Other patients are found to have adequate numbers of follicles, but these fail to mature and ovulate. This condition is known as chronic anovulation and is manifested as amenorrhea with intermittent bleeding (caused by uncoordinated overgrowth of the endometrium in response to stimulation by estrogen alone). Left untreated, the high estrogen level places these women at increased risk for endometrial carcinoma. Among the causes of chronic anovulation is thyroid dysfunction (Table 22-7). Both hyperthyroidism and hypothyroidism can alter ovarian function and the metabolism of androgens and estrogens, resulting in a variety of menstrual disorders. Another cause of chronic anovulation is hyperprolactinemia. It has been proposed that progressively more severe hyperprolactinemia presents first as an inadequate luteal phase with recurrent abortion, then as anovulation with intermittent bleeding, and finally as amenorrhea. Clinical consequences of chronic anovulation are summarized in Table 22-8.
c. Hormonal feedback disorders—PCOS affects 2–5% of reproductive age women and presents with amenorrhea and hirsutism (Table 22-9). Patients are often obese with hyperinsulinemia, insulin resistance and dyslipidemia. In addition, they have elevated plasma androgens, together with elevated plasma estrogens that are predominantly estrone derived from peripheral aromatization of adrenal androgens in the granulosa cell by the enzyme aromatase (cytochrome P450, CYP19A1).
The hyperinsulinemia is believed to be a key etiologic factor. Insulin results in decreased hepatic synthesis of steroid hormone-binding globulin (SHBG) and insulin-like growth factor binding protein-1 (IGFBP-1) (Figure 22-12). The decreased levels of binding proteins results in an increase in free androgens, estrogens, and IGF-1. IGF-1 and high levels of insulin stimulate the IGF-1 receptor, leading to increased thecal androgen production in response to LH, contributing to the hyperandrogenemic state. The high androgens impede developing follicles and disrupt the feedback relationships that normally result in selection of a dominant follicle for ovulation (Figure 22-12). The resulting anovulation is associated with amenorrhea and estrogen-induced endometrial hyperplasia with breakthrough bleeding. The elevated estrogen levels also are implicated in the development of endometrial cancer. Thus, events occurring in the brain, ovary, and bloodstream of these patients work together to constitute a vicious cycle that maintains the aberrant feedback relationships.
The high levels of androgens in the bloodstream are responsible for hirsutism. Patients with elevated androgens from totally different causes (eg, Cushing disease and congenital adrenal hyperplasia) also display amenorrhea associated with polycystic ovaries, suggesting that the structural changes in the ovaries are secondary to the disordered feedback.
d. Pituitary disorders—Head trauma resulting in pituitary stalk transection with loss of hypothalamic-pituitary communication should be considered in patients with new-onset infertility with amenorrhea. The same is true of vascular accidents such as Sheehan syndrome, in which postpartum hemorrhage causes hypotension and consequent ischemic necrosis of the pituitary. Enlargement of the anterior pituitary during pregnancy may predispose to ischemia under conditions of hypotension. The pituitary approximately doubles in size during normal pregnancy, largely as a result of hypertrophy and hyperplasia of prolactin-secreting lactotrophs.
e. Hypothalamic disorders—Inputs from various central pathways impinge on the mediobasal portion of the hypothalamus, including the arcuate nucleus, from which GnRH pulses originate. Medications and illicit drugs that affect the neurotransmitters used in these pathways (opioids, dopamine, and norepinephrine) can affect GnRH secretion as well. This underscores the importance of a taking a detailed medication and social history in the workup of amenorrhea.
Also important is a detailed history of behavioral patterns or any recent life changes. Psychic stress (eg, that associated with moving to a different country) can lead to altered GnRH secretion and subsequent amenorrhea that lasts up to 1 year. Vigorous exercise and excessive weight loss can also lead to impaired GnRH pulsatility, accounting for the amenorrhea seen in competitive athletes and in anorexia nervosa.
Thus, a wide range of factors that alter pulsatile release of GnRH can influence female reproductive physiology. Lack of menstrual periods because of a change in one of these factors is termed hypothalamic amenorrheaand is a common cause of infertility. Correction of the underlying cause often leads to a return of normal cyclic ovulation.
f. Indirect influences—In addition to factors that work directly on the GnRH-secreting neurons, indirect influences must be considered. Primary hypothyroidism, as well as primary or secondary hyperprolactinemia, can result in altered GnRH pulse frequency and amplitude. The subsequent diminished gonadotropin secretion produces a secondary ovarian failure and amenorrhea. Examples of conditions that result in secondary hyperprolactinemia include lactation and treatment with drugs that have dopamine-blocking effects (eg, antipsychotic agents).
TABLE 22-7 Causes and mechanisms of chronic anovulation.
TABLE 22-8 Clinical consequences of chronic anovulation in polycystic ovary syndrome.
TABLE 22-9 Manifestations of polycystic ovary syndrome.1
FIGURE 22-12 Pathogenesis of the various clinical manifestations of the polycystic ovary syndrome. SHBG, steroid hormone-binding globulin; IGFBP-1, insulin-like growth factor binding protein-1; IGF, insulin-like growth factor; FSH, follicle-stimulating hormone; LH, luteinizing hormone. (Redrawn, with permission, from Barnes HV. Clinical Medicine: Selected Problems with Pathophysiologic Correlations. Year Book Medical Publishers, 1988.)
CHECKPOINT
25. Identify environmental and lifestyle factors that cause altered GnRH secretion and hypothalamic amenorrhea.
26. What are the consequences of untreated amenorrhea?
B. Dysmenorrhea
Primary dysmenorrhea is thought to be due to disordered prostaglandin production by the secretory endometrium. Prostaglandin F2? (PGF2?) stimulates myometrial contractions of the nonpregnant uterus, whereas prostaglandins of the E series tend to inhibit its contraction. It appears that patients with severe dysmenorrhea generally have excessive production of PGF2? rather than increased sensitivity to this prostaglandin. Unabated contractions of the myometrium result in ischemia of uterine muscle, which stimulates uterine pain fibers of the autonomic nervous system. Anxiety, fear, and stress may lower the pain threshold and thereby exaggerate the prominence of these symptoms.
Among the secondary causes of dysmenorrhea is endometriosis, a disorder in which extrauterine implants of ectopic endometrial tissue respond cyclically to estrogen and progesterone production (Table 22-5). This is a common disorder affecting 10–25% of women of reproductive age. The presenting symptoms of patients with endometriosis can range from pain and cramping during menstruation to adhesions with bowel obstruction in severe cases. Typical locations for ectopic endometrial tissue include the pelvic portion of the peritoneal cavity and ovaries. Establishment of endometrial tissue in these locations is believed to occur by either or both of two mechanisms: (1) transport of sloughed endometrial tissue by retrograde menstruation through the fallopian tubes or (2) metaplasia of undifferentiated celomic mesenchyme in the peritoneum, perhaps under the influence of growth factors present in retrograde menstrual efflux. Research findings support the hypothesis of a vicious cycle involving peritoneal inflammation with elevated cytokines in peritoneal fluid and secretion of angiogenic factors that maintain ectopic endometrial tissue. A characteristic feature of endometriosis is amelioration after pregnancy and after menopause. These observations provide a therapeutic rationale for the most common modes of medical therapy, which include birth control pills; synthetic progestins (medroxyprogesterone acetate) or androgens (danazol), which block gonadotropin production; and long-acting GnRH analogs that downregulate the reproductive neuroendocrine axis. Some of these drugs may also work by downregulation of cytokine production. It is unclear how endometriosis causes infertility, although inflammatory cytokines have been invoked.
C. Abnormal Vaginal Bleeding
The pathogenesis of abnormal vaginal bleeding depends on its cause, as outlined next.
1. Functional disorders—Endocrine disorders, as described previously, can sometimes result in altered amounts and timing of hormonal stimulation of the genital tract, at times causing a complete cessation of menses.
2. Structural lesions—Structural lesions that alter the contour of the endometrial cavity often lead to uterine bleeding. Endometrial polyps present with premenstrual or intermenstrual spotting. Fibroids, however, more often lead to menometrorrhagia. When these benign tumors are located within the endometrial cavity or within the wall of the uterus, they can disrupt the endometrial vasculature. Very heavy prolonged or sporadic bleeding can occur.
3. Malignancy—Both precancerous and cancerous lesions of the uterus or cervix can produce abnormal vaginal bleeding. Endometrial hyperplasia is often the consequence of excessive estrogen production and stimulation without progesterone exposure. It can progress to endometrial cancer with continued estrogen excess. Unopposed estrogen stimulation can occur because of 1) an ovarian disorder (eg, chronic anovulation), 2) enhanced peripheral aromatization of adrenal androgens by CYP19A1 or 3) estrogen therapy without adequate progestin supplementation. Endometrial cancer is largely a perimenopausal and postmenopausal disease; only 5% of cases occur during the reproductive years. Endometrial cancer spreads by direct involvement of lymphatics with distant metastases to the lung, brain, skeleton, and abdominal organs. Patients with endometrial cancer typically present with abnormal vaginal bleeding. As with ovarian cancer, ascites, bowel obstruction, and associated pleural effusions occur in widespread disease.
Dysplasia of the cervix and cervical cancer can also present with abnormal vaginal bleeding. Carcinogens in tobacco as well as persistent infection with certain subtypes of human papillomavirus (HPV) have been shown to increase the risk of cervical cancer. If untreated, cervical cancer spreads directly to the other pelvic organs; death often occurs through hemorrhage, infection, or renal failure secondary to ureteral obstruction. Currently, the American College of Obstetricians and Gynecologists recommends that uninfected girls and women between the ages of 9 and 26 years (and, as their potential sexual partners, boys and men between the ages of 11 and 26 years) be vaccinated against HPV in order to prevent cervical cancer.
4. Systemic conditions with altered coagulation—Normal blood clotting involves both coagulation factors and platelets. Disorders affecting the production, quality, and survival of either clotting factors or platelets can cause abnormal vaginal bleeding (Table 22-10).
TABLE 22-10 Disorders of coagulation.
CHECKPOINT
27. What are effective medical therapies for endometriosis, and how do they work?
28. What factors predispose to cervical cancer?
Clinical Manifestations
A. Amenorrhea
The clinical symptoms and signs that accompany amenorrhea depend on its category (Table 22-4). In genetic disorders, particularly disorders of ovarian development, various degrees of delayed puberty, such as lack of breast development and absence of pubic hair, may accompany amenorrhea. In outflow tract disorders (eg, imperforate hymen), pain from occult, obstructed menstruation may occur on a cyclic basis. Generally, disorders of the uterus and the hypothalamic-pituitary axis that result in amenorrhea are painless. Ovarian insufficiency resulting in amenorrhea is often preceded by symptoms referable to decreased estrogen and progesterone production. These include hot flushes and other vasomotor symptoms.
The most common complication in the nonpregnant patient with amenorrhea is infertility. Additional complications depend on the specific cause of lack of menstruation. Osteoporosis is a major potential long-term complication of inadequate estrogen production. Inadequate estrogen can also be associated with thinning of estrogen-dependent epithelia, such as that of the vagina, resulting in atrophic vaginitis. This symptom usually responds to topical estrogen cream. In the case of inadequate progesterone production—typically associated with irregular vaginal bleeding but seen also in some cases of amenorrhea—the risk of endometrial cancer is greatly increased. Endometrial cancer is the most common cancer of the female genital tract; 34,000 new cases are identified annually in the United States. Risk factors for endometrial cancer include early menarche, late menopause, nulliparity, obesity, hypertension, and diabetes mellitus.
B. Dysmenorrhea
Dysmenorrhea may be accompanied by a variable constellation of symptoms, including sweating, weakness and fatigue, insomnia, nausea, vomiting, diarrhea, back pain, headache (including both migraine and tension headaches; see Chapter 7), dizziness, and syncope. Prostaglandin synthesis inhibitors (nonsteroidal anti-inflammatory agents) often alleviate many of these symptoms if treatment is initiated prior to menses and averts the cascade of events that occur with production of prostaglandins.
With premenstrual syndrome (PMS), dysmenorrhea is accompanied by additional symptoms, including a sensation of bloating, weight gain, edema of the hands and feet, breast tenderness, acne, anxiety, aggression, mood irritability, food cravings, and change in libido. An initial approach should be to encourage changes in lifestyle if indicated by the history (eg, more sleep, exercise, improved diet, and less tobacco, alcohol, and caffeine). Pharmacologic therapy with serotonin-reuptake inhibitors (SSRIs) has proven beneficial in addition to behavioral modification.
C. Abnormal Vaginal Bleeding
The symptoms and signs that accompany abnormal vaginal bleeding vary with the cause. In children, vulvovaginitis is the most frequent disorder, accompanied by a mucopurulent discharge that may become bloody with mucosal erosion. Other prominent causes, including foreign objects and tumors, can be assessed by physical examination. In adolescents and adults, dysfunctional uterine bleeding is most common, but other causes must be considered. These include pregnancy (assessed by serial serum hCG determinations and ultrasound examination), trauma (by history and physical examination), cancer (by colposcopy and hysteroscopy), and systemic disorders such as a hemorrhagic diathesis (by platelet, prothrombin, and partial thromboplastin time determinations) and thyroid disease (by serum TSH, total and free thyroxine determinations). In postmenopausal women, one fifth of cases of vaginal bleeding prove to be endometrial cancer.
INFERTILITY
Infertility is defined as the absence of conception after at least 1 year of regular sexual intercourse.
Etiology
In approximately 30% of cases, infertility is due to male factors (eg, inadequate sperm count) (see Chapter 23). For female infertility, about 40% of cases are due to ovulatory failure, about 40% are due to endometrial or tubal disease, about 10% are due to rarer causes (eg, thyroid disease or hyperprolactinemia), and about 10% remain unexplained after full workup (Table 22-11).
TABLE 22-11 Causes of female infertility.1
Pathology & Pathogenesis
A. Ovulatory Causes
Infertility due to ovarian dysfunction can result from disorders of the hypothalamus or pituitary, resulting in inadequate gonadotropic stimulation of the ovary; from ovarian disorders, resulting either in inadequate secretory products or failure to ovulate; and occasionally from both types of disorders occurring at the same time. Correction of the underlying cause will often restore fertility. In many cases, administration of exogenous gonadotropins will stimulate the ovaries to produce follicular growth. The oocytes can then be released in vivo and fertilized by intercourse or by artificial insemination. Alternatively, the mature oocytes can be removed via transvaginal aspiration and subsequently fertilized utilizing in vitro fertilization (IVF) in the laboratory followed by return of the resultant embryos to the uterus transcervically.
One of the most common ovarian disorders, called diminished ovarian reserve, is age related and can involve both the oocytes themselves and the secretory products of the ovary. There is accelerated loss of follicles with the approach of menopause. With follicular depletion, FSH levels tend to rise, reflecting inadequate production of inhibin, and anti-müllerian hormone levels fall. This could result from an inadequate number of follicles, diminished competence of the remaining follicles, diminished steroidogenesis by the aging ovary, or some combination of these factors. Regardless of the specific reason, the net effect is a shortened follicular phase and is associated with increased rates of infertility. Treatment with clomiphene citrate, a weak estrogen antagonist, is a means of diminishing negative feedback and increasing endogenous gonadotropin stimulation of the ovary and restoring ovulation.
Other etiologies of ovulation dysfunction include conditions that alter the coordination between ovary and hypothalamus, such as PCOS and hypothalamic amenorrhea. In these scenarios, the oocytes do not undergo the appropriate development and maturation to lead to regular ovulation.
B. Tubal and Pelvic Causes
With normal follicles and reproductive neuroendocrine axis function, the major cause of infertility is abnormality of the endometrium or fallopian tubes. Prior or ongoing pelvic infections, with adhesions or inflammation, can result in failure of sperm or egg transport, failure of implantation, or implantation in an inappropriate location (ectopic pregnancy).
Endometriosis, presumably occurring due to the cyclic proliferation and sloughing of ectopic endometrial tissue, results in inflammation and adhesion formation. New data suggest that endometriosis may arise from a circulating endometrial stem cell population. This condition should be suspected when infertility is associated with severe dysmenorrhea. Surgical and medical therapies are efficacious in the reduction of endometriosis-associated pain.
C. Other Causes of Female Infertility
Most of the less common causes of infertility can be grouped into those disorders that affect the production of GnRH by the hypothalamus or the hormone’s effect on the pituitary (eg, thyroid disease and hyperprolactinemia).
CHECKPOINT
29. What are the most common causes of infertility in couples?
30. How do postcoital high-dose estrogens work as a contraceptive?
31. What feature of the history suggests a tubal or uterine cause of infertility?
PREECLAMPSIA-ECLAMPSIA
Pregnancy is associated with a host of medical complications in which clinical management requires an understanding of both the underlying physiology of pregnancy and the pathophysiology of the particular disorder. The syndrome of preeclampsia-eclampsia, characterized by hypertension, proteinuria, and edema, is chosen for focus for several reasons. First, preeclampsia-eclampsia is one of the most common causes of maternal death in the United States and the developed world. Second, it illustrates how pathophysiologic mechanisms in pregnancy may be far more complex—and the clinical consequences far more serious—than would have been expected from a simple consideration of each of the presenting symptoms in isolation. Third, advances have significantly altered current thinking about the pathogenesis of this disorder.
Clinical Presentation
Hypertension can develop during pregnancy as an isolated finding, pregnancy-induced hypertension (PIH), or as a component of a dangerous syndrome, preeclampsia-eclampsia. Treatment guidelines for PIH are different than those for essential hypertension in the nonpregnant patient; elevated maternal blood pressure is often left untreated unless symptomatic or if severe hypertension develops. Because placental perfusion is dependent on a pressure difference between the maternal and fetal circulations, decreases in maternal blood pressure can lead to underperfusion of the placenta. This can result in placental insufficiency with fetal growth restriction and distress.
The hypertension seen in preeclampsia is associated with proteinuria and edema. This syndrome occurs in approximately 5% of pregnancies in the United States. Eclampsia, the superimposition of generalized tonic-clonic seizures on pregnancy-induced hypertension, can occur as the initial presenting sign of this syndrome or during its progression and is life-threatening. Table 22-12 summarizes the symptoms and signs of preeclampsia-eclampsia.
TABLE 22-12 Symptoms and signs of preeclampsia-eclampsia.
Etiology
Preeclampsia-eclampsia is thought to derive from faulty implantation, resulting in a systemic disorder of endothelial cell activation (see later discussion). Predisposing factors for the development of preeclampsia include first pregnancy, obesity, preexisting diabetes or hypertension, hydatidiform mole, malnutrition, and a family history of preeclampsia.
Pathology & Pathogenesis
The placenta of a preeclamptic patient shows signs of premature aging, including apoptosis, hyaline deposition, calcification, and congestion. The maternal decidua also shows hemorrhage and necrosis with thrombosis of spiral arteries and diffuse infarcts.
Normally, blood vessels of the uterine wall undergo striking morphologic changes at the site of implantation, facilitating placental perfusion. The diameters of the spiral arteries increase and the muscular and elastic components are lost. However, for unknown (perhaps immune-mediated) reasons, these early angiogenic changes of implantation do not occur—or at least not fully—in patients who will develop preeclampsia-eclampsia later in gestation. As a result, a condition of relative placental ischemia is established, with the release of lipid and protein factors that damage the maternal vascular endothelium, at first within the decidua and later systemically. Oxidative injury is believed to potentiate the effects of maternal factors (eg, obesity, diabetes, diet, genes) to cause generalized endothelial cell damage.
Endothelial activation has two important pathophysiologic consequences. First, the balance between vasodilation and vasoconstriction is altered, specifically by diminished production of vasodilator products such as prostacyclin and nitric oxide, increased production of vasoconstrictive thromboxane, endothelin and platelet-derived growth factor. As a result, there is increased vasoconstriction of placental bed arterioles, with hypoperfusion and ischemia of downstream tissues and systemic hypertension. Second, the endothelial cell barrier between platelets and the collagen of basement membranes is breached, promoting thrombosis.
As a result of the latter changes, platelet aggregation, activation of the clotting cascade, and production of vasoactive substances cause capillary leak. This results in further tissue hypoperfusion, edema formation, and proteinuria, the hallmarks of preeclampsia-eclampsia. Because these processes result in further vascular endothelial damage, a vicious circle is established.
Recent speculation has centered on the potential of serotonin to modulate vasodilation and angiogenic growth factors. New data also invoke a role for agonistic autoantibodies directed against the second extracellular loop of the angiotensin II AT1 receptor, resulting in the vasospasm associated with preeclampsia. A short angiotensin peptide (Ang 1-7) with vasodilator activity is reported to be reduced in preeclampsia.
Clinical Manifestations
Preeclampsia has a plethora of manifestations (Table 22-12). Beyond the clinical triad of hypertension, edema, and proteinuria, patients also can have increased deep tendon reflexes, or placental abruption. Hepatic periportal congestion, hemorrhage, and necrosis can lead to elevated liver function tests and ultimately result in rupture of the hepatic capsule. Severe preeclampsia also can produce renal changes, including glomerular endothelial cell swelling, mesangial proliferation, and marked narrowing of glomerular capillary lumens. The renal cortex displays significant cortical ischemia that may progress to frank necrosis and acute kidney injury. Thrombocytopenia and disseminated intravascular coagulopathy (DIC) as well as cerebral vascular accidents also may occur (Table 22-13). Eclampsia, or maternal seizure resulting from cerebral ischemia and petechial hemorrhage, can occur in this setting or can appear as the first manifestation of this disease. Preeclampsia-eclampsia also carries risks for the fetus. Placental deterioration and insufficiency can result in intrauterine growth restriction (IUGR) and fetal hypoxia. Delivery of the fetus and placenta is the only definitive cure for this syndrome, which carries a high morbidity and mortality for both mother and child (Table 22-13).
TABLE 22-13 Complications of preeclampsia-eclampsia.
CHECKPOINT
32. What are the hallmarks of preeclampsia-eclampsia?
33. What are the risks to the fetus of untreated maternal hypertension?
34. What are some of the maternal sequelae of preeclampsia-eclampsia?
CASE STUDIES
Yeong Kwok, MD
(See Chapter 25, p. 738 for Answers)
CASE 110
A 24-year-old woman presents to the clinic complaining of painful menses. She states that for the last several years she has had cramping pain in the days preceding her menses as well as during her menses. In addition, she notes bloating and weight gain in the week before her menses, with swelling of her hands and feet. She has irritability and severe mood swings during that time such that she cries easily and for no reason seems to become enraged at her family or boyfriend. On review of systems, she denies urinary symptoms, vaginal discharge, or GI symptoms. She has no significant medical history. She has never been pregnant. She has never had a sexually transmitted disease. She is sexually active only with her long-standing boyfriend and states that they always use condoms. She takes no medications. Her physical examination is unremarkable.
Questions
A. What are some possible causes of this woman’s dysmenorrhea? Which do you think is most likely? Why?
B. What is the pathophysiologic mechanism responsible for her dysmenorrhea?
C. How would you treat her symptoms?
CASE 111
A 28-year-old woman presents to the clinic with a complaint of infertility. She states that she and her husband have been trying to get pregnant for approximately 1 year without success. She had menarche at age 14 years. Since that time, she has had regular menses lasting 5 days, without significant dysmenorrhea or abnormal bleeding. She has never been pregnant. Medical history is notable for gonorrhea and trichomoniasis at age 18 years. In addition, she has had an abnormal Pap smear consistent with human papillomavirus at age 20 years, with normal Pap smears since that time. She takes no medications. She has been married for 2 years and is sexually active only with her husband. Before her marriage, she had approximately 25 sexual partners, most during her college years. Her physical examination is unremarkable.
Questions
A. What are the most common causes of female infertility?
B. What do you suspect is the cause of this patient’s infertility? Why?
CASE 112
A 28-year-old woman presents to her obstetrician for her regularly scheduled prenatal examination. She is 30 weeks pregnant. She has noted some swelling of her hands and feet in the last 2 weeks that seems to be getting progressively worse, such that she is no longer able to wear her rings and can only wear open-heeled shoes. She is otherwise without complaints. She has no past medical problems. This is her first pregnancy. She has had regular prenatal care and, thus far, with no complications. She is taking only prenatal multivitamins. Family history is notable for maternal hypertension and diabetes. She is married and works as a schoolteacher. She denies alcohol, tobacco, and drug use. On examination she appears to be well, with blood pressure of 152/95 mm Hg. Fundal height is consistent with gestational age. Fetal heart rate is 140 bpm. Extremities have 1+ lower extremity edema to the knees and trace edema of the hands. Urine dipstick reveals 3+ protein.
Questions
A. What is the likely diagnosis?
B. What are some risk factors for developing this condition?
C. How does this condition develop? How does it result in maternal hypertension, edema, and proteinuria?
D. What are the risks to the fetus if this condition is left untreated?
E. What are the maternal sequelae of leaving this condition untreated? What is the treatment?
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