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InternalMed_Harrison. Disorders of the female Reproductive System Janet E. Hall The female reproductive system regulates the hormonal changes respon-sible for puberty and adult reproductive function. Normal reproductive function in women requires the dynamic integration of hormonal sig-412 nals from the hypothalamus, pituitary, and ovary, resulting in repetitive cycles of follicle development, ovulation, and preparation of the endometrial lining of the uterus for implantation should conception occur. It is critical to understand pubertal development in normal girls (and boys) as a yardstick for identifying precocious and delayed puberty. For further discussion of related topics, see the following chapters: amenorrhea and pelvic pain (Chap. 69), infertility and contraception (Chap. 414), menopause (Chap. 413), disorders of sex development (Chap. 410), and disorders of the male reproductive system (Chap. 411).


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InternalMed_Harrison. The ovary orchestrates the development and release of a mature oocyte and also elaborates hormones (e.g., estrogen, progesterone, inhibin, relaxin) that are critical for pubertal development and preparation of the uterus for conception, implantation, and the early stages of pregnancy. To achieve these functions in repeated monthly cycles, the ovary undergoes some of the most dynamic changes of any organ in the body. Primordial germ cells can be identified by the third week of gestation, and their migration to the genital ridge is complete by 6 weeks of gestation. Germ cells persist within the genital ridge, are then referred to as oogonia, and are essential for induction of ovarian development. Although one X chromosome undergoes X inactivation in somatic cells, it is reactivated in oogonia and genes on both X chromosomes are required for normal ovarian development. A 2375 streak ovary containing only stromal cells is found in patients with 45,X Turner’s syndrome (Chap. 410).


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InternalMed_Harrison. The germ cell population expands, and starting at ~8 weeks of gestation, oogonia begin to enter prophase of the first meiotic division and become primary oocytes. This allows the oocyte to be surrounded by a single layer of flattened granulosa cells to form a primordial follicle (Fig. 412-1). Granulosa cells are derived from mesonephric cells that invade the ovary early in its development, pushing the germ cells to the periphery. The weight of evidence supports the concept that for the most part, the ovary contains a nonrenewable pool of germ cells. Through the combined processes of mitosis, meiosis, and atresia, the population of oogonia reaches its maximum of 6–7 million by 20 weeks of gestation, after which there is a progressive loss of both oogonia and primordial follicles through the process of atresia. At birth, oogonia are no longer present in the ovary, and only 1–2 million germ cells remain in the form of primordial follicles (Fig. 412-2). The oocyte persists in prophase of


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InternalMed_Harrison. process of atresia. At birth, oogonia are no longer present in the ovary, and only 1–2 million germ cells remain in the form of primordial follicles (Fig. 412-2). The oocyte persists in prophase of the first meiotic division until just before ovulation, when meiosis resumes.


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InternalMed_Harrison. The quiescent primordial follicles are recruited to further growth and differentiation through a highly regulated process that limits the size of the developing cohort to ensure that folliculogenesis can continue throughout the reproductive life span. This initial recruitment of primordial follicles to form primary follicles (Fig. 412-1) is characterized by growth of the oocyte and the transition from squamous to cuboidal granulosa cells. The theca interna cells that surround the developing follicle begin to form as the primary follicle grows. Acquisition of a zona pellucida by the oocyte and the presence of several layers of surrounding cuboidal granulosa cells mark the development of secondary follicles. It is at this stage that granulosa cells develop follicle-stimulating hormone (FSH), estradiol, and androgen receptors and communicate with one another through the development of gap junctions.


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InternalMed_Harrison. Bidirectional signaling between the germ cells and the somatic cells in the ovary is a necessary component underlying the maturation Prophase of first Disorders of the Female Reproductive System Resumption of meiosis FIGURE 412-1 Stages of ovarian development from the arrival of the migratory germ cells at the genital ridge through gonadotropinindependent and gonadotropin-dependent phases that ultimately result in ovulation of a mature oocyte. FSH, follicle-stimulating hormone; LH, luteinizing hormone. FIGURE 412-2 Ovarian germ cell number is maximal at mid-gestation and then decreases precipitously.


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InternalMed_Harrison. FIGURE 412-2 Ovarian germ cell number is maximal at mid-gestation and then decreases precipitously. of the oocyte and the capacity for hormone secretion. For example, oocyte-derived growth differentiation factor 9 (GDF-9) and bone morphogenic protein-15 (BMP-15), also known as GDF-9b, are required for migration of pregranulosa and pretheca cells to the outer surface of the developing follicle and, hence, initial follicle formation. GDF-9 is also required for formation of secondary follicles, as are granulosa cell–derived KIT ligand (KITL) and the forkhead transcription factor (FOXL2). All of these genes are potential candidates for premature ovarian failure in women, and mutations in the human FOXL2 gene have been shown to cause the syndrome of blepharophimosis/ptosis/ epicanthus inversus, which is associated with ovarian failure.


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InternalMed_Harrison. The early stages of follicle growth are primarily driven by intraovarian factors and may take up to a year from development of the primary follicle to the dominant follicle stage. Further maturation to the preovulatory state, including the resumption of meiosis in the oocyte, requires the combined stimulus of FSH and luteinizing hormone (LH) (Fig. 412-1) and can be accomplished within weeks. Recruitment of secondary follicles from the resting follicle pool requires the direct action of FSH, whereas anti-müllerian hormone (AMH) produced from small growing follicles, restrains this effect of FSH. Accumulation of follicular fluid between the layers of granulosa cells creates an antrum that divides the granulosa cells into two functionally distinct groups: mural cells that line the follicle wall and cumulus cells that surround the oocyte (Fig. 412-3). Recent evidence suggests that, in addition to its role in normal development of the müllerian system, the WNT signaling pathway is required


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InternalMed_Harrison. and cumulus cells that surround the oocyte (Fig. 412-3). Recent evidence suggests that, in addition to its role in normal development of the müllerian system, the WNT signaling pathway is required for normal antral follicle development and may also play a role in ovarian steroidogenesis. A single dominant follicle emerges from the growing follicle pool within the first 5–7 days after the onset of menses, and the majority of follicles fall off their growth trajectory and become atretic. Autocrine actions of activin and BMP-6, derived from the granulosa cells, and paracrine actions of GDF-9, BMP-15, BMP-6, and Gpr149, derived from the oocyte, are involved in granulosa cell proliferation and modulation of FSH responsiveness. Differential exposure to these factors may explain the mechanism whereby a given follicle is selected for continued growth to the preovulatory stage. The dominant follicle can be distinguished by its size, evidence of granulosa cell proliferation, large number of FSH


InternalMed_Harrison

InternalMed_Harrison. a given follicle is selected for continued growth to the preovulatory stage. The dominant follicle can be distinguished by its size, evidence of granulosa cell proliferation, large number of FSH receptors, high aromatase activity, and elevated concentrations of estradiol and inhibin A in follicular fluid.


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InternalMed_Harrison. FIGURE 412-3 Development of ovarian follicles. The Graafian follicle is also known as a tertiary or preovulatory follicle. (Courtesy of JH Eichhorn and D. Roberts, Massachusetts General Hospital; with permission.)


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InternalMed_Harrison. The dominant follicle undergoes rapid expansion during the 5–6 days prior to ovulation, reflecting granulosa cell proliferation and accumulation of follicular fluid. FSH induces LH receptors on the granulosa cells, and the preovulatory, or Graafian, follicle moves to the outer ovarian surface in preparation for ovulation. The LH surge triggers the resumption of meiosis, the suppression of granulosa cell proliferation, and the induction of cyclooxygenase 2 (COX-2), prostaglandins, the progesterone receptor, and the epidermal growth factor (EGF)-like growth factors amphiregulin, epiregulin, betacellulin, and neuroregulin 1, all of which are required for ovulation. EGF-like factors are thought to mediate these follicular responses to LH. Ovulation also involves production of extracellular matrix leading to expansion of the cumulus cell population that surrounds the oocyte and the controlled expulsion of the egg and follicular fluid. Both progesterone and prostaglandins (induced by the


InternalMed_Harrison

InternalMed_Harrison. matrix leading to expansion of the cumulus cell population that surrounds the oocyte and the controlled expulsion of the egg and follicular fluid. Both progesterone and prostaglandins (induced by the ovulatory stimulus) are essential for this process. After ovulation, luteinization is induced by LH in conjunction with the acquisition of a rich vascular network in response to vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (FGF). Traditional regulators of central reproductive control, gonadotropin-releasing hormone (GnRH) and its receptor (GnRHR), are also produced in the ovary and may be involved in corpus luteum function.


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InternalMed_Harrison. GnRH neurons develop from epithelial cells outside the central nervous system and migrate, initially alongside the olfactory neurons, to the medial basal hypothalamus. Studies in GnRH-deficient patients who fail to undergo puberty have provided insights into genes that control the ontogeny and function of GnRH neurons (Fig. 412-4). KAL1, FGF8/FGFR1, PROK2/PROKR2, NSMF, and CDH7, among others (Chap. 411), have been implicated in the migration of GnRH neurons to the hypothalamus. Approximately 7000 GnRH neurons, scattered throughout the medial basal hypothalamus, establish contacts with capillaries of the pituitary portal system in the median eminence. GnRH is secreted into the pituitary portal system in discrete pulses to stimulate synthesis and secretion of LH and FSH from pituitary gonadotropes, which comprise ~10% of cells in the pituitary (Chap. 401e). Functional connections of GnRH neurons with the portal system are established by the end of the first trimester, coinciding with


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InternalMed_Harrison. which comprise ~10% of cells in the pituitary (Chap. 401e). Functional connections of GnRH neurons with the portal system are established by the end of the first trimester, coinciding with the production of pituitary gonadotropins. Thus, like the ovary, the hypothalamic and pituitary components of the reproductive system are present before birth. However, the high levels of estradiol and progesterone produced by the placenta suppress hypothalamic-pituitary stimulation of ovarian hormonal secretion in the fetus.


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InternalMed_Harrison. After birth and the loss of placenta-derived steroids, gonadotropin levels rise. FSH levels are much higher in girls than in boys. This rise in FSH results in ovarian activation (evident on ultrasound) and increased inhibin B and estradiol levels. Studies that have identified mutations in TAC3, which encodes neurokinin B, and its receptor, TAC3R, in patients with GnRH deficiency indicate that both are involved in control of GnRH secretion and may be particularly important at this early stage of development. By 12–20 months of age, the reproductive axis is again suppressed, and a period of relative quiescence persists until puberty (Fig. 412-5). At the onset of puberty, pulsatile GnRH secretion induces pituitary gonadotropin production. In the early stages of puberty, LH and FSH secretion are apparent only during sleep, but as puberty develops, pulsatile gonadotropin secretion occurs throughout the day and night.


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InternalMed_Harrison. FIGURE 412-4 Establishment of a functional gonadotropin-releasing hormone (GnRH) system requires the participation of a number of genes that are essential for development and migration of GnRH neurons from the olfactory placode to the hypothalamus in addition to genes involved in the functional control of GnRH secretion and action. KAL 1 FGR8/FGFR1 NSMF PROK2/PROKR2 OlfactoryplacodePituitaryHypothalamusGnRH1 GnRHR TAC3R KISS1R KISS1 TAC3 MigrationFunction


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InternalMed_Harrison. The mechanisms responsible for the childhood quiescence and pubertal reactivation of the reproductive axis remain incompletely understood. GnRH neurons in the hypothalamus respond to both excitatory and inhibitory factors. Increased sensitivity to the inhibitory influence of gonadal steroids has long been implicated in the inhibition of GnRH secretion during childhood but has not been definitively established in the human. Metabolic signals, such as adipocyte-derived leptin, play a permissive role in reproductive function (Chap. 415e). Studies of patients with isolated GnRH deficiency reveal that mutations in the G protein–coupled receptor 54 (GPR54) gene (now known as KISS1R) preclude the onset of puberty. The ligand for this receptor, metastin, is derived from the parent peptide, kisspeptin-1 (KISS1), and is a powerful stimulant for GnRH release. A potential role for kisspeptin in the onset of puberty has been suggested by upregulation of KISS1 and KISS1R transcripts in the


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InternalMed_Harrison. kisspeptin-1 (KISS1), and is a powerful stimulant for GnRH release. A potential role for kisspeptin in the onset of puberty has been suggested by upregulation of KISS1 and KISS1R transcripts in the hypothalamus at the time of puberty. TAC3 and dynorphin (Dyn), which appear to play an inhibitory rather than stimulatory role in GnRH control, are co-expressed


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InternalMed_Harrison. FIGURE 412-5 Follicle-stimulating hormone (FSH) and luteinizing hormone (LH) are increased during the neonatal years but go through a period of childhood quiescence before increasing again during puberty. Gonadotropin levels are cyclic during the reproductive years and increase dramatically with the loss of negative feedback that accompanies menopause. Granulosa cell Androstenedione Testosterone EstroneEstradiolaromatase Cholesterol LH pregnenolone progesterone 17-OHP 3˜HSD 17 hydroxylase 17,20 lyase AndrostenedioneTestosterone17 ˜HSD FIGURE 412-6 Estrogen production in the ovary requires the cooperative function of the theca and granulosa cells under the control of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). HSD, hydroxysteroid dehydrogenase; OHP, hydroxyprogesterone. with KISS1 in KNDy neurons that project to GnRH neurons. This system is intimately involved with estrogen negative feedback regulation of GnRH secretion.


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InternalMed_Harrison. Ovarian steroid-producing cells do not store hormones but produce them in response to LH and FSH during the normal menstrual cycle. The sequence of steps and the enzymes involved in the synthesis of steroid hormones are similar in the ovary, adrenal, and testis. However, the enzymes required to catalyze specific steps are compartmentalized and may not be abundant or even present in all cell types. Within the developing ovarian follicle, estrogen synthesis from cholesterol requires close integration between theca and granulosa cells—sometimes called the two-cell model for steroidogenesis (Fig. 412-6). FSH receptors are confined to the granulosa cells, whereas LH receptors are restricted to the theca cells until the late stages of follicular development, when they are also found on granulosa cells. The theca cells surrounding the follicle are highly vascularized and use cholesterol, derived primarily from circulating lipoproteins, as the starting point for the synthesis of


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InternalMed_Harrison. on granulosa cells. The theca cells surrounding the follicle are highly vascularized and use cholesterol, derived primarily from circulating lipoproteins, as the starting point for the synthesis of androstenedione and testosterone under the control of LH. Androstenedione and testosterone are transferred across the basal lamina to the granulosa cells, which receive no direct blood supply. The mural granulosa cells are particularly rich in aromatase and, under the control of FSH, produce estradiol, the primary steroid secreted from the follicular phase ovary and the most potent estrogen. Theca cell–produced androstenedione and, to a lesser extent, testosterone are also secreted into peripheral blood, where they can be converted to dihydrotestosterone in skin and to estrogens in adipose tissue. The hilar interstitial cells of the ovary are functionally similar to Leydig cells and are also capable of secreting androgens. Although stromal cells proliferate in response to androgens (as in


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InternalMed_Harrison. The hilar interstitial cells of the ovary are functionally similar to Leydig cells and are also capable of secreting androgens. Although stromal cells proliferate in response to androgens (as in polycystic ovarian syndrome [PCOS]), they do not secrete androgens.


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InternalMed_Harrison. Development of the rich capillary network following rupture of the follicle at the time of ovulation makes it possible for large molecules such as low-density lipoprotein (LDL) to reach the luteinized granulosa and theca lutein cells. As in the follicle, both cell types are required for steroidogenesis in the corpus luteum. The large luteinized granulosa cells are the main source of progesterone production, whereas the smaller theca lutein cells produce 17-hydroxyprogesterone, a substrate for aromatization to estradiol by the luteinized granulosa cells. LH is critical for normal structure and function of the corpus luteum. Because LH and human chorionic gonadotropin (hCG) bind to a common receptor, the role of LH in support of the corpus luteum can be replaced by hCG in the first 10 weeks after conception, and hCG is commonly used for luteal phase support in the treatment of infertility.


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InternalMed_Harrison. Disorders of the Female Reproductive System 2378 Steroid Hormone Actions Both estrogen and progesterone play critical roles in the expression of secondary sexual characteristics in women (Chap. 400e). Estrogen promotes development of the ductule system in the breast, whereas progesterone is responsible for glandular development. In the reproductive tract, estrogens create a receptive environment for fertilization and support pregnancy and parturition through carefully coordinated changes in the endometrium, thickening of the vaginal mucosa, thinning of the cervical mucus, and uterine growth and contractions. Progesterone induces secretory activity in the estrogen-primed endometrium, increases the viscosity of cervical mucus, and inhibits uterine contractions. Both gonadal steroids play critical roles in the negative and positive feedback controls of gonadotropin secretion. Progesterone also increases basal body temperature and has therefore been used clinically as a marker of


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InternalMed_Harrison. play critical roles in the negative and positive feedback controls of gonadotropin secretion. Progesterone also increases basal body temperature and has therefore been used clinically as a marker of ovulation. The vast majority of circulating estrogens and androgens are carried in the blood bound to carrier proteins, which restrain their free diffusion into cells and prolong their clearance, serving as a reservoir. High-affinity binding proteins include sex hormone–binding globulin (SHBG), which binds androgens with somewhat greater affinity than estrogens, and corticosteroid-binding globulin (CBG), which also binds progesterone. Modulations in binding protein levels by insulin, androgens, and estrogens contribute to high bioavailable testosterone levels in PCOS and to high circulating estrogen and progesterone levels during pregnancy. Estrogens act primarily through binding to the nuclear receptors, estrogen receptor (ER) α and β. Transcriptional coactivators and corepressors


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InternalMed_Harrison. estrogen and progesterone levels during pregnancy. Estrogens act primarily through binding to the nuclear receptors, estrogen receptor (ER) α and β. Transcriptional coactivators and corepressors modulate ER action (Chap. 400e). Both ER subtypes are present in the hypothalamus, pituitary, ovary, and reproductive tract. Although ERα and -β exhibit some functional redundancy, there is also a high degree of specificity, particularly in expression within cell types. For example, ERα functions in the ovarian theca cells, whereas ERβ is critical for granulosa cell function. There is also evidence for membrane-initiated signaling by estrogen. Similar signaling mechanisms pertain for progesterone with evidence of transcriptional regulation through progesterone receptor (PR) A and B protein isoforms, as well as rapid membrane signaling.


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InternalMed_Harrison. Inhibin was initially isolated from gonadal fluids based on its ability to selectively inhibit FSH secretion from pituitary cells. Inhibin is a heterodimer composed of an α subunit and a βA or βB subunit to form inhibin A or inhibin B, both of which are secreted from the ovary. Activin is a homodimer of inhibin β subunits with the capacity to stimulate the synthesis and secretion of FSH. Inhibins and activins are members of the transforming growth factor β (TGF-β) superfamily of growth and differentiation factors. During the purification of inhibin, follistatin, an unrelated monomeric protein that inhibits FSH secretion, was discovered. Within the pituitary, follistatin inhibits FSH secretion indirectly through binding and neutralizing activin.


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InternalMed_Harrison. Inhibin B is secreted from the granulosa cells of small antral follicles, whereas inhibin A is present in both granulosa and theca cells and is secreted by dominant follicles. Inhibin A is also present in luteinized granulosa cells and is a major secretory product of the corpus luteum. Inhibin B is constitutively secreted by granulosa cells and increases in serum in conjunction with recruitment of secondary follicles to the pool of actively growing follicles under the control of FSH. Inhibin B has been used clinically as a marker of ovarian reserve. Inhibin B is an important inhibitor of FSH, independent of estradiol, during the menstrual cycle. Although activin is also secreted from the ovary, the excess of follistatin in serum, combined with its nearly irreversible binding of activin, make it unlikely that ovarian activin plays an endocrine role in FSH regulation. However, there is evidence that activin plays an autocrine/paracrine role in the ovary, in addition to its


InternalMed_Harrison

InternalMed_Harrison. of activin, make it unlikely that ovarian activin plays an endocrine role in FSH regulation. However, there is evidence that activin plays an autocrine/paracrine role in the ovary, in addition to its intrapituitary role in modulation of FSH production.


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InternalMed_Harrison. AMH (also known as müllerian-inhibiting substance) is important in ovarian biology in addition to the function from which it derived its name (i.e., promotion of the degeneration of the müllerian system during embryogenesis in the male). AMH is produced by granulosa cells from small follicles and, like inhibin B, is a marker of ovarian reserve. AMH inhibits the recruitment of primordial follicles into the follicle pool and counters FSH stimulation of aromatase expression. Relaxin, which is produced by the theca lutein cells of the corpus luteum, is thought to play a role in decidualization of the endometrium and suppression of myometrial contractile activity, both of which are essential for the early establishment of pregnancy.


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InternalMed_Harrison. The sequence of changes responsible for mature reproductive function is coordinated through a series of negative and positive feedback loops that alter pulsatile GnRH secretion, the pituitary response to GnRH, and the relative secretion of LH and FSH from the gonadotrope. The frequency and amplitude of pulsatile GnRH secretion differentially modulate the synthesis and secretion of LH and FSH, with slow frequencies favoring FSH synthesis and increased amplitudes favoring LH synthesis. Activin is produced in both pituitary gonadotropes and folliculostellate cells and stimulates the synthesis and secretion of FSH. Inhibins function as potent antagonists of activins through sequestration of the activin receptors. Although inhibin is expressed in the pituitary, gonadal inhibin is the principal source of feedback inhibition of FSH.


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InternalMed_Harrison. For the majority of the cycle, the reproductive system functions in a classic endocrine negative feedback mode. Estradiol and progesterone inhibit GnRH secretion, and the inhibins act at the pituitary to selectively inhibit FSH synthesis and secretion (Fig. 412-7). This negative feedback control of FSH is critical for development of the single mature oocyte that characterizes normal reproductive function in women. In addition to these negative feedback controls, the menstrual cycle is uniquely dependent on estrogen-induced positive feedback to produce an LH surge that is essential for ovulation of a mature follicle. Estrogen negative feedback in women occurs primarily at the hypothalamus with a small pituitary contribution, whereas estrogen positive feedback occurs at the pituitary with hypothalamic GnRH secretion playing a permissive role.


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InternalMed_Harrison. The follicular phase is characterized by recruitment of a cohort of secondary follicles and the ultimate selection of a dominant preovulatory follicle (Fig. 412-8). The follicular phase begins, by convention, on the first day of menses. However, follicle recruitment is initiated by the rise in FSH that begins in the late luteal phase of the previous cycle in conjunction with the loss of negative feedback of gonadal steroids and likely inhibin A. The fact that a 20–30% increase in FSH is adequate for follicular recruitment speaks to the marked sensitivity of the resting follicle pool to FSH. The resultant granulosa cell proliferation is responsible for increasing early follicular phase levels of inhibin B. Inhibin B in conjunction with rising levels of estradiol, and


InternalMed_Harrison

InternalMed_Harrison. FIGURE 412-7 The reproductive system in women is critically dependent on both negative feedback of gonadal steroids and inhibin to modulate follicle-stimulating hormone (FSH) secretion and on estrogen positive feedback to generate the preovulatory luteinizing hormone (LH) surge. GnRH, gonadotropin-releasing hormone. FIGURE 412-8 Relationship between gonadotropins, follicle development, gonadal secretion, and endometrial changes during the normal menstrual cycle. E2, estradiol; Endo, endometrium; FSH, follicle-stimulating hormone; LH, luteinizing hormone; Prog, progesterone.


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InternalMed_Harrison. probably inhibin A, restrain FSH secretion during this critical period such that only a single follicle matures in the vast majority of cycles. The increased risk of multiple gestation associated with the increased levels of FSH characteristic of advanced maternal age, or with exogenous gonadotropin administration in the treatment of infertility, attests to the importance of negative feedback regulation of FSH. With further growth of the dominant follicle, estradiol and inhibin A increase exponentially and the follicle acquires LH receptors. Increasing levels of estradiol are responsible for proliferative changes in the endometrium. The exponential rise in estradiol results in positive feedback on the pituitary, leading to the generation of an LH surge (and a smaller FSH surge), thereby triggering ovulation and luteinization of the granulosa cells.


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InternalMed_Harrison. The luteal phase begins with the formation of the corpus luteum from the ruptured follicle (Fig. 412-8). Progesterone and inhibin A are produced from the luteinized granulosa cells, which continue to aromatize theca-derived androgen precursors, producing estradiol. The combined actions of estrogen and progesterone are responsible for the secretory changes in the endometrium that are necessary for implantation. The corpus luteum is supported by LH but has a finite life span because of diminished sensitivity to LH. The demise of the corpus luteum results in a progressive decline in hormonal support of the endometrium. Inflammation or local hypoxia and ischemia result in vascular changes in the endometrium, leading to the release of cytokines, cell death, and shedding of the endometrium.


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InternalMed_Harrison. If conception occurs, hCG produced by the trophoblast binds to LH receptors on the corpus luteum, maintaining steroid hormone production and preventing involution of the corpus luteum. The corpus luteum is essential for the hormonal maintenance of the endometrium during the first 6–10 weeks of pregnancy until this function is taken over by the placenta. Menstrual bleeding should become regular within 2–4 years of menarche, although anovulatory and irregular cycles are common before that. For the remainder of adult reproductive life, the cycle shortening of cycle length with age such that women over the age of 2379 35 have cycles that are shorter than during their younger reproductive years. Anovulatory cycles increase as women approach menopause, and bleeding patterns may be erratic.


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InternalMed_Harrison. Women who report regular monthly bleeding with cycles that do not vary by >4 days generally have ovulatory cycles, but several other clinical signs can be used to assess the likelihood of ovulation. Some women experience mittelschmerz, described as midcycle pelvic discomfort that is thought to be caused by the rapid expansion of the dominant follicle at the time of ovulation. A constellation of premenstrual moliminal symptoms such as bloating, breast tenderness, and food cravings often occur several days before menses in ovulatory cycles, but their absence cannot be used as evidence of anovulation. Methods that can be used to determine whether ovulation is likely include a serum progesterone level >5 ng/mL ~7 days before expected menses, an increase in basal body temperature of 0.24°C (>0.5°F) in the second half of the cycle due to the thermoregulatory effect of progesterone, or the detection of the urinary LH surge using ovulation predictor kits. Because ovulation occurs ~36 h after


InternalMed_Harrison

InternalMed_Harrison. in the second half of the cycle due to the thermoregulatory effect of progesterone, or the detection of the urinary LH surge using ovulation predictor kits. Because ovulation occurs ~36 h after the LH surge, urinary LH can be helpful in timing intercourse to coincide with ovulation.


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InternalMed_Harrison. Ultrasound can be used to detect the growth of the fluid-filled antrum of the developing follicle and to assess endometrial proliferation in response to increasing estradiol levels in the follicular phase, as well as the characteristic echogenicity of the secretory endometrium of the luteal phase.


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InternalMed_Harrison. The first menstrual period (menarche) occurs relatively late in the series of developmental milestones that characterize normal pubertal development (Table 412-1). Menarche is preceded by the appearance of pubic and then axillary hair (adrenarche) as a result of maturation of the zona reticularis in the adrenal gland and increased adrenal androgen secretion, particularly dehydroepiandrosterone (DHEA). The triggers for adrenarche remain unknown but may involve increases in body mass index, as well as in utero and neonatal factors. Menarche is also preceded by breast development (thelarche). The breast is exquisitely sensitive to the very low levels of estrogen that result from peripheral conversion of adrenal androgens and the low levels of estrogen secreted from the ovary early in pubertal maturation. Breast development precedes the appearance of pubic and axillary hair in ~60% of girls. The interval between the onset of breast development and menarche is ~2 years. There has been a


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InternalMed_Harrison. maturation. Breast development precedes the appearance of pubic and axillary hair in ~60% of girls. The interval between the onset of breast development and menarche is ~2 years. There has been a gradual decline in the age of menarche over the past century, attributed in large part to improvement in nutrition, and there is a relationship between adiposity and earlier sexual maturation in girls. In the United States, menarche occurs at an average age of 12.5 years (Table 412-1). Much of the variation in the timing of puberty is due to genetic factors, with heritability estimates of 50–80%. Both adrenarche and thelarche occur ~1 year earlier in black compared with white girls, although the timing of menarche differs by only 6 months between these ethnic groups.


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InternalMed_Harrison. Other important hormonal changes also occur in conjunction with puberty. Growth hormone (GH) levels increase early in puberty, stimulated in part by the pubertal increases in estrogen secretion. GH increases insulin-like growth factor-I (IGF-I), which enhances linear growth. The growth spurt is generally less pronounced in girls than in boys, with a peak growth velocity of ~7 cm/year. Linear growth is ultimately limited by closure of epiphyses in the long bones as a result of prolonged exposure to estrogen. Puberty is also associated with mild insulin resistance. Disorders of the Female Reproductive System length counted from the first day of menses to the first day of subsequent menses is ~28 days, with a range of 25–35 days. However, cycle-to-cycle variability for an individual


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InternalMed_Harrison. Onset of Breast/ Age of Peak woman is ±2 days. Luteal phase length is relatively constant between 12 and 14 days in normal cycles; thus, the major variability in cycle length is due to variations in the fol-White 10.2 11.9 12.6 14.3 17.1 licular phase. The duration of menstrual bleeding in ovula-Black 9.6 11.5 12 13.6 16.5 tory cycles varies between 4 and 6 days. There is a gradual Source: From FM Biro et al: J Pediatr 148:234, 2006. Abbreviations: CNS, central nervous system; GnRH, gonadotropin-releasing hormone; hCG, human chorionic gonadotropin. The differential diagnosis of precocious and delayed puberty is similar in boys (Chap. 411) and girls. However, there are differences in the timing of normal puberty and differences in the relative frequency of specific disorders in girls compared with boys.


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InternalMed_Harrison. Precocious Puberty Traditionally, precocious puberty has been defined as the development of secondary sexual characteristics before the age of 8 in girls based on data from Marshall and Tanner in British girls studied in the 1960s. More recent studies led to recommendations that girls be evaluated for precocious puberty if breast development or pubic hair is present at <7 years of age for white girls or <6 years for black girls.


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InternalMed_Harrison. Precocious puberty in girls is most often centrally mediated (Table 412-2), resulting from early activation of the hypothalamic-pituitary-ovarian axis. It is characterized by pulsatile LH secretion (which is initially associated with deep sleep) and an enhanced LH and FSH response to exogenous GnRH (twoto threefold stimulation) (Table 412-3). True precocity is marked by advancement in bone age of >2 standard deviations, a recent history of growth acceleration, and progression of secondary sexual characteristics. In girls, centrally mediated precocious puberty is idiopathic in ~85% of cases; however, neurogenic causes must be considered. Mutations in genes associated with GnRH deficiency have been reported in small numbers of patients with idiopathic precocious puberty (KISS, KISS1R, TAC3, TAC3R, and DAX-1), but their frequency is insufficient to warrant their use in clinical testing. GnRH agonists that induce pituitary desensitization are the mainstay of treatment to prevent premature


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InternalMed_Harrison. TAC3R, and DAX-1), but their frequency is insufficient to warrant their use in clinical testing. GnRH agonists that induce pituitary desensitization are the mainstay of treatment to prevent premature epiphyseal closure and preserve adult height, as well as to manage psychosocial repercussions of precocious puberty.


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InternalMed_Harrison. Peripherally mediated precocious puberty does not involve activation of the hypothalamic-pituitary-ovarian axis and is characterized by suppressed gonadotropins in the presence of elevated estradiol. Management of peripheral precocious puberty involves treating the underlying disorder (Table 412-2) and limiting the effects of gonadal steroids using aromatase inhibitors, inhibitors of steroidogenesis, and ER blockers. It is important to be aware that central precocious puberty can also develop in girls whose precocity was initially peripherally mediated, as in McCune-Albright syndrome and congenital adrenal hyperplasia. Incomplete and intermittent forms of precocious puberty may also occur. For example, premature breast development may occur in girls before the age of 2 years, with no further progression and without significant advancement in bone age, estrogen production, or compromised


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InternalMed_Harrison. History and physical × × Assessment of growth velocity × × Bone age × × LH, FSH × × Estradiol, testosterone × × DHEAS × × 17-Hydroxyprogesterone × TSH, T4 × × Complete blood count × Sedimentation rate, C-reactive protein Electrolytes, renal function × IGF-I, IGFBP-3 Abbreviations: ACTH, adrenocorticotropic hormone; DHEAS, dehydroepiandrosterone sulfate; FSH, follicle-stimulating hormone; hCG, human chorionic gonadotropin; IGF-I, insulin-like growth factor-I; IGFBP-3, IGF-binding protein 3; LH, luteinizing hormone; MRI, magnetic resonance imaging; TSH, thyroid-stimulating hormone; T4, thyroxine. height. Premature adrenarche can also occur in the absence of progressive pubertal development, but it must be distinguished from late-onset congenital adrenal hyperplasia and androgen-secreting tumors, in which case it may be termed heterosexual precocity. Premature adrenarche may be associated with obesity, hyperinsulinemia, and the subsequent predisposition to PCOS.


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InternalMed_Harrison. Delayed Puberty Delayed puberty (Table 412-4) is defined as the absence of secondary sexual characteristics by age 13 in girls. The diagnostic considerations are very similar to those for primary amenorrhea (Chap. 69). Between 25 and 40% of delayed puberty in girls is of ovarian origin, with Turner’s syndrome accounting for the majority of such patients. Functional hypogonadotropic hypogonadism encompasses diverse etiologies such as systemic illnesses, including celiac disease and chronic renal disease, and endocrinopathies such as diabetes and hypothyroidism. In addition, girls appear to be particularly susceptible to the adverse effects of decreased energy balance resulting from exercise, dieting, and/or eating disorders. Together these reversible conditions account for ~25% of delayed puberty in girls. Congenital hypogonadotropic hypogonadism in girls or boys can be caused by mutations in several different genes or combinations of genes (Fig. 412-4, Chap. 411, Table 411-2).


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InternalMed_Harrison. puberty in girls. Congenital hypogonadotropic hypogonadism in girls or boys can be caused by mutations in several different genes or combinations of genes (Fig. 412-4, Chap. 411, Table 411-2). Approximately 50% of girls with congenital hypogonadotropic hypogonadism, with or without anosmia, have a history of some degree of breast development, and 10% report one to two episodes of vaginal bleeding. Family studies suggest that genes identified in association with absent puberty may also cause delayed puberty, and recent reports have further suggested that a genetic susceptibility to environmental stresses such as diet and exercise may account for at least some cases of functional hypothalamic amenorrhea. Although neuroanatomic causes of delayed puberty are considerably less common in girls than in boys, it is always important to rule these out in the setting of hypogonadotropic hypogonadism.


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InternalMed_Harrison. menopause and Postmenopausal Hormone Therapy JoAnn E. Manson, Shari S. Bassuk Menopause is the permanent cessation of menstruation due to loss of ovarian follicular function. It is diagnosed retrospectively after 12 413 LH or FSH, IU/L perimenopause precedes the final menses by 2–8 years, with a mean 2381 duration of 4 years. Smoking accelerates the menopausal transition by 2 years. Although the periand postmenopausal transitions share many symptoms, the physiology and clinical management of the two differ. Estradiol or estrone, pg/mL


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InternalMed_Harrison. Although the periand postmenopausal transitions share many symptoms, the physiology and clinical management of the two differ. Estradiol or estrone, pg/mL FIGURE 413-1 Mean serum levels of ovarian and pituitary hormones during the menopausal transition. FSH, follicle-stimulating hormone; LH, luteinizing hormone. (From JL Shifren, I Schiff: J Womens Health Gend Based Med 9 Suppl 1:S3, 2000.) months of amenorrhea. The average age at menopause is 51 years among U.S. women. Perimenopause refers to the time period preceding menopause, when fertility wanes and menstrual cycle irregularity increases, until the first year after cessation of menses. The onset of FSHβ, LHR, FSHR KAL1, FGF8, FGFR1, NSMF, PROK2, PROKR2, KISS1, KISS1R, TAC3, TAC3R, GnRH1, GnRHR, SEM3A, HS6ST1, WDR11, CHD7 Abnormalities of pituitary development/function CNS tumors/infiltrative disorders Craniopharyngioma Astrocytoma, germinoma, glioma Prolactinomas, other pituitary tumors Histiocytosis X


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InternalMed_Harrison. Abnormalities of pituitary development/function CNS tumors/infiltrative disorders Craniopharyngioma Astrocytoma, germinoma, glioma Prolactinomas, other pituitary tumors Histiocytosis X Abbreviations: CHD7, chromodomain-helicase-DNA-binding protein 7; CNS, central nervous system; FGF8, fibroblast growth factor 8; FGFR1, fibroblast growth factor 1 receptor; FSHβ, follicle-stimulating hormone β chain; FSHR, FSH receptor; GNRHR, gonadotropinreleasing hormone receptor; HESX1, homeobox, embryonic stem cell expressed 1; HS6ST1, heparin sulfate 6-O sulfotransferase 1; IHH, idiopathic hypogonadotropic hypogonadism; KAL, Kallmann; KISS1, kisspeptin 1; KISSR1, KISS1 receptor; LHR, luteinizing hormone receptor; NSMF, NMDA receptor synaptonuclear signaling and neuronal migration factor; PROK2, prokineticin 2; PROKR2 prokineticin receptor 2; PROP1, prophet of Pit1, paired-like homeodomain transcription factor SEMA3A, semaphorin-3A; WDR11, WD repeat-containing protein 11.


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InternalMed_Harrison. Low-dose oral contraceptives have become a therapeutic mainstay in perimenopause, whereas postmenopausal hormone therapy (HT) has been a common method of symptom alleviation after menstruation ceases.


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InternalMed_Harrison. Ovarian mass and fertility decline sharply after age 35 and even more precipitously during perimenopause; depletion of primary follicles, a process that begins before birth, occurs steadily until menopause (Chap. 412). In perimenopause, intermenstrual intervals shorten significantly (typically by 3 days) as a result of an accelerated follicular phase. Follicle-stimulating hormone (FSH) levels rise because of altered folliculogenesis and reduced inhibin secretion. In contrast to the consistently high FSH and low estradiol levels seen in menopause, perimenopause is characterized by “irregularly irregular” hormone levels. The propensity for anovulatory cycles can produce a hyperestrogenic, hypoprogestagenic environment that may account for the increased incidence of endometrial hyperplasia or carcinoma, uterine polyps, and leiomyoma observed among women of perimenopausal age. Mean serum levels of selected ovarian and pituitary hormones during the menopausal transition are shown in Fig.


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InternalMed_Harrison. or carcinoma, uterine polyps, and leiomyoma observed among women of perimenopausal age. Mean serum levels of selected ovarian and pituitary hormones during the menopausal transition are shown in Fig. 413-1. With transition into menopause, estradiol levels fall markedly, whereas estrone levels are relatively preserved, a pattern reflecting peripheral aromatization of adrenal and ovarian androgens. Levels of FSH increase more than those of luteinizing hormone, presumably because of the loss of inhibin as well as estrogen feedback.


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InternalMed_Harrison. The Stages of Reproductive Aging Workshop +10 (STRAW+10) classification provides a comprehensive framework for the clinical assessment of ovarian aging. As shown in Fig. 413-2, menstrual cycle characteristics are the principal criteria for characterizing the menopausal transition, with biomarker measures as supportive criteria. Because of their extreme intraindividual variability, FSH and estradiol levels are imperfect diagnostic indicators of perimenopause in menstruating women. However, a consistently low FSH level in the early follicular phase (days 2–5) of the menstrual cycle does not support a diagnosis of perimenopause, while levels >25 IU/L in a random blood sample are characteristic of the late menopause transition. FSH measurement can also aid in assessing fertility; levels of <20 IU/L, 20 to <30 IU/L, and ≥30 IU/L measured on day 3 of the cycle indicate a good, fair, and poor likelihood of achieving pregnancy, respectively. Antimüllerian hormone and inhibin B may also be


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InternalMed_Harrison. <20 IU/L, 20 to <30 IU/L, and ≥30 IU/L measured on day 3 of the cycle indicate a good, fair, and poor likelihood of achieving pregnancy, respectively. Antimüllerian hormone and inhibin B may also be useful for assessing reproductive aging.


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InternalMed_Harrison. Menopause, years = elevated. **Approximate expected level based on assays using current international pituitary standard. FIGURE 413-2 The Stages of Reproductive Aging Workshop +10 (STRAW +10) staging system for reproductive aging in women. AMH, antimüllerian hormone; FSH, follicle-stimulating hormone. (From SD Harlow et al: Menopause 14:387, 2012. Reproduced with permission.)


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InternalMed_Harrison. Determining whether symptoms that develop in midlife are due to ovarian senescence or to other age-related changes is difficult. There is strong evidence that the menopausal transition can cause hot flashes, night sweats, irregular bleeding, and vaginal dryness, and there is moderate evidence that it can cause sleep disturbances in some women. There is inconclusive or insufficient evidence that ovarian aging is a major cause of mood swings, depression, impaired memory or concentration, somatic symptoms, urinary incontinence, or sexual dysfunction. In one U.S. study, nearly 60% of women reported hot flashes in the 2 years before their final menses. Symptom intensity, duration, frequency, and effects on quality of life are highly variable.


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InternalMed_Harrison. For women with irregular or heavy menses or hormone-related symptoms that impair quality of life, low-dose combined oral contraceptives are a staple of therapy. Static doses of estrogen and progestin (e.g., 20 μg of ethinyl estradiol and 1 mg of norethindrone acetate daily for 21 days each month) can eliminate vasomotor symptoms and restore regular cyclicity. Oral contraceptives provide other benefits, including protection against ovarian and endometrial cancers and increased bone density, although it is not clear whether use during perimenopause decreases fracture risk later in life. Moreover, the contraceptive benefit is important, given that the unintentional pregnancy rate among women in their forties rivals that of adolescents. Contraindications to oral contraceptive use include cigarette smoking, liver disease, a history of thromboembolism or cardiovascular disease, breast cancer, or unexplained vaginal bleeding. Progestin-only formulations (e.g., 0.35 mg of norethindrone daily)


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InternalMed_Harrison. smoking, liver disease, a history of thromboembolism or cardiovascular disease, breast cancer, or unexplained vaginal bleeding. Progestin-only formulations (e.g., 0.35 mg of norethindrone daily) or medroxyprogesterone (Depo-Provera) injections (e.g., 150 mg IM every 3 months) may provide an alternative for the treatment of perimenopausal menorrhagia in women who smoke or have cardiovascular risk factors. Although progestins neither regularize cycles nor reduce the number of bleeding days, they reduce the volume of menstrual flow.


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InternalMed_Harrison. Nonhormonal strategies to reduce menstrual flow include the use of nonsteroidal anti-inflammatory agents such as mefenamic acid (an initial dose of 500 mg at the start of menses, then 250 mg qid for 2–3 days) or, when medical approaches fail, endometrial ablation. It should be noted that menorrhagia requires an evaluation to rule out uterine disorders. Transvaginal ultrasound with saline enhancement is useful for detecting leiomyomata or polyps, and endometrial aspiration can identify hyperplastic changes.


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InternalMed_Harrison. For sexually active women using contraceptive hormones to alleviate perimenopausal symptoms, the question of when and if to switch to HT must be individualized. Doses of estrogen and progestogen (either synthetic progestins or natural forms of progesterone) in HT are lower than those in oral contraceptives and have not been documented to prevent pregnancy. Although a 1-year absence of spontaneous menses reliably indicates ovulation cessation, it is not possible to assess the natural menstrual pattern while a woman is taking an oral contraceptive. Women willing to switch to a barrier method of contraception should do so; if menses occur spontaneously, oral contraceptive use can be resumed. The average age of final menses among relatives can serve as a guide for when to initiate this process, which can be repeated yearly until menopause has occurred.


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InternalMed_Harrison. One of the most complex health care decisions facing women is whether to use postmenopausal HT. Once prescribed primarily to relieve vasomotor symptoms, HT has been promoted as a strategy to forestall various disorders that accelerate after menopause, including osteoporosis and cardiovascular disease. In 2000, nearly 40% of post-menopausal women age 50–74 in the United States had used HT. This widespread use occurred despite the paucity of conclusive data, until recently, on the health consequences of such therapy. Although many women rely on their health care providers for a definitive answer to the question of whether to use postmenopausal hormones, balancing the benefits and risks for an individual patient is challenging.


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InternalMed_Harrison. Although observational studies suggest that HT prevents cardiovascular and other chronic diseases, the apparent benefits may result at least in part from differences between women who opt to take postmenopausal hormones and women who do not. Those choosing HT tend to be healthier, have greater access to medical care, are more compliant with prescribed treatments, and maintain a more health-promoting lifestyle. Randomized trials, which eliminate these confounding factors, have not consistently confirmed the benefits found in observational studies. Indeed, the largest HT trial to date, the Women’s Health Initiative (WHI), which examined more than 27, 000 postmenopausal women age 50–79 (mean age, 63) for an average of 5–7 years, was stopped early because of an overall unfavorable benefit-risk ratio in the estrogen-progestin arm and an excess risk of stroke that was not offset by a reduced risk of coronary heart disease (CHD) in the estrogen-only arm.


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InternalMed_Harrison. The following summary offers a decision-making guide based on a synthesis of currently available evidence. Prevention of cardiovascular disease is eliminated from the equation due to lack of evidence for such benefits in recent randomized clinical trials. See Table 413-1.


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InternalMed_Harrison. Definite Benefits • SymptomS of menopauSe Compelling evidence, including data from randomized clinical trials, indicates that estrogen therapy is highly effective for controlling vasomotor and genitourinary symptoms. Alternative approaches, including the use of antidepressants (such as paroxetine, 7.5 mg/d; or venlafaxine, 75–150 mg/d), gabapentin (300–900 mg/d), clonidine (0.1–0.2 mg/d), or vitamin E (400–800 IU/d), or the consumption of soy-based products or other phytoestrogens, may also alleviate vasomotor symptoms, although they are less effective than HT. Paroxetine is the only nonhormonal drug approved by the U.S. Food and Drug Administration for treatment of vasomotor symptoms. Bazedoxifene, an estrogen agonist/antagonist, in combination with conjugated estrogens has also received approval for vasomotor symptom management. For genitourinary symptoms, the efficacy of vaginal estrogen is similar to that of oral or transdermal estrogen; oral ospemifene is an additional option.


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InternalMed_Harrison. oSteoporoSiS (See also Chap. 425) Bone density By reducing bone turnover and resorption rates, estrogen slows the aging-related bone loss experienced by most postmenopausal women. More than 50 randomized trials have demonstrated that postmenopausal estrogen therapy, with or without a progestogen, rapidly increases bone mineral density at the spine by 4–6% and at the hip by 2–3% and that those increases are maintained during treatment.


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InternalMed_Harrison. Fractures Data from observational studies indicate a 50–80% lower risk of vertebral fracture and a 25–30% lower risk of hip, wrist, and other peripheral fractures among current estrogen users; addition of a progestogen does not appear to modify this benefit. In the WHI, 5–7 years of either combined estrogen-progestin or estrogen-only therapy was associated with a 33% reduction in hip fractures and 25–30% fewer total fractures among a population unselected for osteoporosis. Bisphosphonates (such as alendronate, 10 mg/d or 70 mg once per week; risedronate, 5 mg/d or 35 mg once per week; or ibandronate, 2.5 mg/d or 150 mg once per month or 3 mg every 3 months IV) and raloxifene (60 mg/d), a selective estrogen receptor modulator (SERM), have been shown in randomized trials to increase bone mass density and decrease fracture rates. Other options for treatment of osteoporosis are bazedoxifene in combination with conjugated estrogens and parathyroid hormone (teriparatide, 20 μg/d SC). These


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InternalMed_Harrison. density and decrease fracture rates. Other options for treatment of osteoporosis are bazedoxifene in combination with conjugated estrogens and parathyroid hormone (teriparatide, 20 μg/d SC). These agents, unlike 2383 estrogen, do not appear to have adverse effects on the endometrium or breast. Increased physical activity, adequate calcium intake (1000–1200 mg/d through diet or supplements in two or three divided doses), and adequate vitamin D intake (600–1000 IU/d) may also reduce the risk of osteoporosis-related fractures. According to the Institute of Medicine’s 2011 report, 25-hydroxyvitamin D blood levels of ≥50 nmol/L are sufficient for bone-density maintenance and fracture prevention. The Fracture Risk Assessment (FRAX®) score, an algorithm that combines an individual’s bone-density score with age and other risk factors to predict her 10-year risk of hip and major osteoporotic fracture, may be of use in guiding decisions about pharmacologic treatment (see www .shef.ac.uk/FRAX/).


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InternalMed_Harrison. Definite Risks • endometrial cancer (WitH eStroGen alone) A combined analysis of 30 observational studies found a tripling of endometrial cancer risk among short-term users (1–5 years) of unopposed estrogen and a nearly tenfold increased risk among long-term users (≥10 years). These findings are supported by results from the randomized Postmenopausal Estrogen/Progestin Interventions (PEPI) trial, in which 24% of women assigned to unopposed estrogen for 3 years developed atypical endometrial hyperplasia—a premalignant lesion— as opposed to only 1% of women assigned to placebo. Use of a progestogen, which opposes the effects of estrogen on the endometrium, eliminates these risks and may even reduce risk (see later).


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InternalMed_Harrison. venouS tHromBoemBoliSm A meta-analysis of observational studies found that current oral estrogen use was associated with a 2.5-fold increase in risk of venous thromboembolism in postmenopausal women. A meta-analysis of randomized trials, including the WHI, found a 2.1-fold increase in risk. Results from the WHI indicate a nearly twofold increase in risk of pulmonary embolism and deep vein thrombosis with estrogen-progestin and a 35–50% increase in these risks with estrogen-only therapy. Transdermal estrogen, taken alone or with certain progestogens (micronized progesterone or pregnane derivatives), appears to be a safer alternative with respect to throm botic risk.


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InternalMed_Harrison. BreaSt cancer (WitH eStroGen-proGeStin) An increased risk of breast cancer has been found among current or recent estrogen users in observational studies; this risk is directly related to duration of use. In a meta-analysis of 51 case-control and cohort studies, short-term use (<5 years) of postmenopausal HT did not appreciably elevate breast cancer incidence, whereas long-term use (≥5 years) was associated with a 35% increase in risk. In contrast to findings for endometrial cancer, combined estrogen-progestin regimens appear to increase breast cancer risk more than estrogen alone. Data from randomized trials also indicate that estrogen-progestin raises breast cancer risk. In the WHI, women assigned to receive combination hormones for an average of 5.6 years were 24% more likely to develop breast cancer than women assigned to placebo, but 7.1 years of estrogen-only therapy did not increase risk. Indeed, the WHI showed a trend toward a reduction in breast cancer risk with estrogen


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InternalMed_Harrison. breast cancer than women assigned to placebo, but 7.1 years of estrogen-only therapy did not increase risk. Indeed, the WHI showed a trend toward a reduction in breast cancer risk with estrogen alone, although it is unclear whether this finding would pertain to formulations of estrogen other than conjugated equine estrogens or to treatment durations of >7 years. In the Heart and Estrogen/Progestin Replacement Study (HERS), 4 years of combination therapy was associated with a 27% increase in breast cancer risk. Although the latter finding was not statistically significant, the totality of evidence strongly implicates estrogen-progestin therapy in breast carcinogenesis.


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InternalMed_Harrison. Some observational data suggest that the length of the interval between menopause onset and HT initiation may influence the association between such therapy and breast cancer risk, with a “gap time” of <3–5 years conferring a higher HT-associated breast cancer risk. (This pattern of findings contrasts with that for CHD, as discussed later in this Chapter.) However, this association remains inconclusive and may be a spurious finding attributable to higher rates of screening mammography and thus earlier cancer detection in HT users than in nonusers, especially in early menopause. Indeed, in the WHI trial, hazard ratios for HT and breast cancer risk did not differ among women bEnEfiTS AnD RiSkS of PoSTmEnoPAuSAl HoRmonE THERAPy in THE ovERAll STuDy PoPulATion of womEn 50–79 yEARS of AgE in THE inTERvEnTion PHASE of THE womEn’S HEAlTH iniTiATivE (wHi) ESTRogEn-PRogESTin AnD ESTRogEn-AlonE TRiAlSa diseased women and women many years past (n.s.) (41 vs. 35) infarction for estrogen alone,


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InternalMed_Harrison. THE inTERvEnTion PHASE of THE womEn’S HEAlTH iniTiATivE (wHi) ESTRogEn-PRogESTin AnD ESTRogEn-AlonE TRiAlSa diseased women and women many years past (n.s.) (41 vs. 35) infarction for estrogen alone, with reduced risk in (n.s.) (35 vs. 29) trend by age = .02)


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InternalMed_Harrison. Stroke Probable increase in risk ↑37% increased risk 9 excess cases ↑35% increased risk 11 excess cases (33 vs. 24) (45 vs. 34) Ovarian cancer Probable increase in risk with long-term ↑41% increased risk 1 excess cases Not available Not available use (≥5 years) (n.s.) (5 vs. 4) Endometrial cancer Probable decrease in risk with estrogen-↓33% decreased riskf 3 fewer cases See above See above progestin during long-term follow-up (7 vs. 10) (see above for estrogen alone) (1661 vs. 1112) (2255 vs. 1403) Colorectal cancer Probable decrease in risk with estrogen-↓38% decreased risk 6.5 fewer cases No increase or No difference in riske progestin; possible increase in risk in (10 vs. 17) decrease in riske older women with estrogen alone (p for trend by age = .02 for estrogen alone)


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InternalMed_Harrison. Type 2 diabetes Probable decrease in risk ↓19% decreased risk 16 fewer cases ↓14% decreased risk 21 fewer cases (72 vs. 88) (134 vs. 155) (46 vs. 23) (n.s.) (44 vs. 29) studies and randomized trials) pausal women (p for trend by age <.05


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InternalMed_Harrison. Global indexg Probable increase in risk or no effect ↑12% increased risk 20.5 excess cases No increase in riske No difference in riske among older women and women many (189 vs. 168) years past menopause; possible decrease in risk or no effect in younger or recently menopausal women (p for trend by age = 0.02 for estrogen alone) aThe estrogen-progestin arm of the WHI assessed 5.6 years of conjugated equine estrogen (0.625 mg/d) plus medroxyprogesterone acetate (2.5 mg/d) versus placebo. The estrogen-alone arm of the WHI assessed 7.1 years of conjugated equine estrogen (0.625 mg/d) versus placebo. bNumber of cases per 10, 000 women per year. cThe WHI was not designed to assess the effect of HT on menopausal symptoms. Data from other randomized trials suggest that HT reduces risk for menopausal symptoms by 65–90%. dCoronary heart disease is defined as nonfatal myocardial infarction or coronary death. eThere was a significant interaction by age; that is, the association between HT and the


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InternalMed_Harrison. symptoms by 65–90%. dCoronary heart disease is defined as nonfatal myocardial infarction or coronary death. eThere was a significant interaction by age; that is, the association between HT and the specified outcome was different in younger women and older women. f This is the risk reduction that was observed during a cumulative 12-year follow-up period (5.6 years of treatment plus 6.8 years of postintervention observation). gThe global index is a composite outcome representing the first event for each participant from among the following: coronary heart disease, stroke, pulmonary embolism, breast cancer, colorectal cancer, endometrial cancer (estrogen-progestin arm only), hip fracture, and death. Because participants can experience more than one type of event, the global index cannot be derived by a simple summing of the component events. hIncludes some outcomes where results were divergent between the estrogen-progestin arm and the estrogen-alone arm.


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InternalMed_Harrison. Abbreviation: n.s., not statistically significant. Source: Data from JE Manson et al: JAMA 310:1353, 2013. 50–59, those 60–69, and those 70–79 years of age at trial entry. (There was insufficient power to examine finer age categories.) Additional research is needed to clarify the issue. GallBladder diSeaSe Large observational studies report a twoto threefold increased risk of gallstones or cholecystectomy among postmenopausal women taking oral estrogen. In the WHI, women randomized to estrogen-progestin or estrogen alone were ∼55% more likely to develop gallbladder disease than those assigned to placebo. Risks were also increased in HERS. Transdermal HT might be a safer alternative, but further research is needed.


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InternalMed_Harrison. Probable or Uncertain Risks and Benefits • coronary Heart diSeaSe/ StroKe Until recently, HT had been enthusiastically recommended as a possible cardioprotective agent. In the past three decades, multiple observational studies suggested, in the aggregate, that estrogen use leads to a 35–50% reduction in CHD incidence among postmenopausal women. The biologic plausibility of such an association is supported by data from randomized trials demonstrating that exogenous estrogen lowers plasma low-density lipoprotein (LDL) cholesterol levels and raises high-density lipoprotein (HDL) cholesterol levels by 10–15%. Administration of estrogen also favorably affects lipoprotein(a) levels, LDL oxidation, endothelial vascular function, fibrinogen, and plasminogen activator inhibitor 1. However, estrogen therapy has unfavorable effects on other biomarkers of cardiovascular risk: it boosts triglyceride levels; promotes coagulation via factor VII, prothrombin fragments 1 and 2, and fibrinopeptide A


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InternalMed_Harrison. therapy has unfavorable effects on other biomarkers of cardiovascular risk: it boosts triglyceride levels; promotes coagulation via factor VII, prothrombin fragments 1 and 2, and fibrinopeptide A elevations; and raises levels of the inflammatory marker C-reactive protein.


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InternalMed_Harrison. Randomized trials of estrogen or combined estrogen-progestin in women with preexisting cardiovascular disease have not confirmed the benefits reported in observational studies. In HERS (a secondary-prevention trial designed to test the efficacy and safety of estrogen-progestin therapy with regard to clinical cardiovascular outcomes), the 4-year incidence of coronary death and nonfatal myocardial infarction was similar in the active-treatment and placebo groups, and a 50% increase in risk of coronary events was noted during the first year among participants assigned to the active-treatment group. Although it is possible that progestin may mitigate estrogen’s benefits, the Estrogen Replacement and Atherosclerosis (ERA) trial indicated that angiographically determined progression of coronary atherosclerosis was unaffected by either opposed or unopposed estrogen treatment. Moreover, no cardiovascular benefit was found in the Papworth Hormone Replacement Therapy Atherosclerosis Study, a


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InternalMed_Harrison. atherosclerosis was unaffected by either opposed or unopposed estrogen treatment. Moreover, no cardiovascular benefit was found in the Papworth Hormone Replacement Therapy Atherosclerosis Study, a trial of transdermal estradiol with and without norethindrone; the Women’s Estrogen for Stroke Trial (WEST), a trial of oral 17β-estradiol; or the Estrogen in the Prevention of Reinfarction Trial (ESPRIT), a trial of oral estradiol valerate. Thus, in clinical trials, HT has not proved effective for the secondary prevention of cardiovascular disease in postmenopausal women.


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InternalMed_Harrison. Primary-prevention trials also suggest an early increase in cardiovascular risk and an absence of cardioprotection with postmenopausal HT. In the WHI, women assigned to 5.6 years of estrogen-progestin therapy were 18% more likely to develop CHD (defined in primary analyses as nonfatal myocardial infarction or coronary death) than those assigned to placebo, although this risk elevation was not statistically significant. However, during the trial’s first year, there was a significant 80% increase in risk, which diminished in subsequent years (p for trend by time = .03). In the estrogen-only arm of the WHI, no overall effect on CHD was observed during the 7.1 years of the trial or in any specific year of follow-up. This pattern of results was similar to that for the outcome of total myocardial infarction.


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InternalMed_Harrison. However, a closer look at available data suggests that timing of initiation of HT may critically influence the association between such therapy and CHD. Estrogen may slow early stages of atherosclerosis but have adverse effects on advanced atherosclerotic lesions. It has been hypothesized that the prothrombotic and proinflammatory effects of estrogen manifest themselves predominantly among women with subclinical lesions who initiate HT well after the menopausal transition, whereas women with less arterial damage who start HT early in menopause may derive cardiovascular benefit because they have not yet developed advanced lesions. Nonhuman primate data support this concept. Conjugated estrogens had no effect on the extent 2385 of coronary artery plaque in cynomolgus monkeys assigned to receive estrogen alone or combined with progestin starting 2 years (∼6 years in human terms) after oophorectomy and well after the establishment of atherosclerosis. However, administration of exogenous


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InternalMed_Harrison. estrogen alone or combined with progestin starting 2 years (∼6 years in human terms) after oophorectomy and well after the establishment of atherosclerosis. However, administration of exogenous hormones immediately after oophorectomy, during the early stages of atherosclerosis, reduced the extent of plaque by 70%.


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InternalMed_Harrison. Lending further credence to this hypothesis are results of subgroup analyses of observational and clinical trial data. For example, among women who entered the WHI trial with a relatively favorable cholesterol profile, estrogen with or without progestin led to a 40% lower risk of incident CHD. Among women who entered with a worse cholesterol profile, therapy resulted in a 73% higher risk (p for interaction = .02). The presence or absence of the metabolic syndrome (Chap. 422) also strongly influenced the relation between HT and incident CHD. Among women with the metabolic syndrome, HT more than doubled CHD risk, whereas no association was observed among women without the syndrome. Moreover, although there was no association between estrogen-only therapy and CHD in the WHI trial cohort as a whole, such therapy was associated with a CHD risk reduction of 40% among participants age 50–59; in contrast, a risk reduction of only 5% was observed among those age 60–69, and a risk increase of


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InternalMed_Harrison. a whole, such therapy was associated with a CHD risk reduction of 40% among participants age 50–59; in contrast, a risk reduction of only 5% was observed among those age 60–69, and a risk increase of 9% was found among those age 70–79 (p for trend by age = .08). For the outcome of total myocardial infarction, estrogen alone was associated with a borderline-significant 45% reduction and a nonsignificant 24% increase in risk among the youngest and oldest women, respectively (p for trend by age = .02). Estrogen was also associated with lower levels of coronary artery calcified plaque in the younger age group. Although age did not have a similar effect in the estrogen-progestin arm of the WHI, CHD risks increased with years since menopause (p for trend = .08), with a significantly elevated risk among women who were ≥20 years past menopause. For the outcome of total myocardial infarction, estrogen-progestin was associated with a 9% risk reduction among women <10 years past menopause as


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InternalMed_Harrison. risk among women who were ≥20 years past menopause. For the outcome of total myocardial infarction, estrogen-progestin was associated with a 9% risk reduction among women <10 years past menopause as opposed to a 16% increase in risk among women 10–19 years past menopause and a twofold increase in risk among women >20 years past menopause (p for trend = .01). In the large observational Nurses’ Health Study, women who chose to start HT within 4 years of menopause experienced a lower risk of CHD than did nonusers, whereas those who began therapy ≥10 years after menopause appeared to receive little coronary benefit. Observational studies include a high proportion of women who begin HT within 3–4 years of menopause, whereas clinical trials include a high proportion of women ≥12 years past menopause; this difference helps to reconcile some of the apparent discrepancies between the two types of studies.


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InternalMed_Harrison. For the outcome of stroke, WHI participants assigned to estrogenprogestin or estrogen alone were ∼35% more likely to suffer a stroke than those assigned to placebo. Whether or not age at initiation of HT influences stroke risk is not well understood. In the WHI and the Nurses’ Health Study, HT was associated with an excess risk of stroke in all age groups. Further research is needed on age, time since menopause, and other individual characteristics (including biomarkers) that predict increases or decreases in cardiovascular risk associated with exogenous HT. Furthermore, it remains uncertain whether different doses, formulations, or routes of administration of HT will produce different cardiovascular effects.


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InternalMed_Harrison. colorectal cancer Observational studies have suggested that HT reduces risks of colon and rectal cancer, although the estimated magnitudes of the relative benefits have ranged from 8% to 34% in various meta-analyses. In the WHI (the sole trial to examine the issue), estrogen-progestin was associated with a significant 38% reduction in colorectal cancer over a 5.6-year period, although no benefit was seen with 7 years of estrogen-only therapy. However, a modifying effect of age was observed, with a doubling of risk with HT in women age 70–79 but no risk elevation in younger women (p for trend by age = .02).


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InternalMed_Harrison. coGnitive decline and dementia A meta-analysis of 10 case-control and two cohort studies suggested that postmenopausal HT is associated with a 34% decreased risk of dementia. Subsequent randomized trials (including the WHI), however, have failed to demonstrate any benefit 2386 of estrogen or estrogen-progestin therapy on the progression of mild to moderate Alzheimer’s disease and/or have indicated a potential adverse effect of HT on the incidence of dementia, at least in women ≥65 years of age. Among women randomized to HT (as opposed to placebo) at age 50–55 in the WHI, no effect on cognition was observed during the postintervention phase. Determining whether timing of initiation of HT influences cognitive outcomes will require further study.


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InternalMed_Harrison. ovarian cancer and otHer diSorderS On the basis of limited observational and randomized data, it has been hypothesized that HT increases the risk of ovarian cancer and reduces the risk of type 2 diabetes mellitus. Results from the WHI support these hypotheses. The WHI also found that HT use was associated with an increased risk of urinary incontinence and that estrogen-progestin was associated with increased rates of lung cancer mortality. endometrial cancer (WitH eStroGen-proGeStin) In the WHI, use of estrogen-progestin was associated with a nonsignificant 17% reduction in risk of endometrial cancer. A significant reduction in risk emerged during the postintervention period (see later).


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InternalMed_Harrison. all-cauSe mortality In the overall WHI cohort, estrogen with or without progestin was not associated with all-cause mortality. However, there was a trend toward reduced mortality in younger women, particularly with estrogen alone. For women 50–59, 60–69, and 70–79 years of age, relative risks (RRs) associated with estrogen-only therapy were 0.70, 1.01, and 1.21, respectively (p for trend = .04).


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InternalMed_Harrison. overall Benefit-riSK profile Estrogen-progestin was associated with an unfavorable benefit-risk profile (excluding relief from menopausal symptoms) as measured by a “global index”—a composite outcome including CHD, stroke, pulmonary embolism, breast cancer, colorectal cancer, endometrial cancer, hip fracture, and death (Table 413-1)— in the WHI cohort as a whole, and this association did not vary by 10-year age group. Estrogen-only therapy was associated with a neutral benefit-risk profile in the WHI cohort as a whole. However, there was a significant trend toward a more favorable benefit-risk profile among younger women and a less favorable profile among older women, with RRs of 0.84, 0.99, and 1.17 for women 50–59, 60–69, and 70–79 years of age, respectively (p for trend by age = .02).


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InternalMed_Harrison. cHanGeS in HealtH StatuS after diScontinuation of Hormone tHerapy In the WHI, many but not all risks and benefits associated with active use of HT dissipated within 5–7 years after discontinuation of therapy. For estrogen-progestin, an elevated risk of breast cancer persisted (RR = 1.28 [95% confidence interval, 1.11–1.48]) during a cumulative 12-year follow-up period (5.6 years of treatment plus 6.8 years of postintervention observation), but most cardiovascular disease risks became neutral. A reduction in hip fracture risk persisted (RR = 0.81 [0.68–0.97]), and a significant reduction in endometrial cancer risk emerged (RR = 0.67 [0.49–0.91]). For estrogen alone, the reduction in breast cancer risk became statistically significant (RR = 0.79 [0.65–0.97]) during a cumulative 12-year follow-up period (6.8 years of treatment plus 5.1 years of postintervention observation), and significant differences by age group persisted for total myocardial infarction and the global index, with more


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InternalMed_Harrison. period (6.8 years of treatment plus 5.1 years of postintervention observation), and significant differences by age group persisted for total myocardial infarction and the global index, with more favorable results for younger women.


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APPROACH TO THE PATIENT:

InternalMed_Harrison. APPROACH TO THE PATIENT:


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InternalMed_Harrison. The rational use of postmenopausal HT requires balancing the potential benefits and risks. Figure 413-3 provides one approach to decision making. The clinician should first determine whether the patient has moderate to severe menopausal symptoms—the primary indication for initiation of systemic HT. Systemic HT may also be used to prevent osteoporosis in women at high risk of fracture who cannot tolerate alternative osteoporosis therapies. (Vaginal estrogen or other medications may be used to treat urogenital symptoms in the absence of vasomotor symptoms.) The benefits and risks of such therapy should be reviewed with the patient, giving more emphasis to absolute than to relative measures of effect and pointing out uncertainties in clinical knowledge where relevant. Because chronic disease rates generally increase with age, absolute risks tend to be greater in older women, even when relative risks remain similar. Potential side effects—especially vaginal bleeding that may result from


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InternalMed_Harrison. rates generally increase with age, absolute risks tend to be greater in older women, even when relative risks remain similar. Potential side effects—especially vaginal bleeding that may result from use of the combined estrogen-progestogen formulations recommended for women with an intact uterus—should be noted. The patient’s own preference regarding therapy should be elicited and factored into the decision. Contraindications to HT should be assessed routinely and include unexplained vaginal bleeding, active liver disease, venous thromboembolism, history of endometrial cancer (except stage 1 without deep invasion) or breast cancer, and history of CHD, stroke, transient ischemic attack, or diabetes. Relative contraindications include hypertriglyceridemia (>400 mg/dL) and active gallbladder disease; in such cases, transdermal estrogen may be an option. Primary prevention of heart disease should not be viewed as an expected benefit of HT, and an increase in the risk of stroke as well as a


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InternalMed_Harrison. in such cases, transdermal estrogen may be an option. Primary prevention of heart disease should not be viewed as an expected benefit of HT, and an increase in the risk of stroke as well as a small early increase in the risk of coronary artery disease should be considered. Nevertheless, such therapy may be appropriate if the noncoronary benefits of treatment clearly outweigh the risks. A woman who suffers an acute coronary event or stroke while taking HT should discontinue therapy immediately.


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InternalMed_Harrison. Short-term use (<5 years for estrogen-progestogen and <7 years for estrogen alone) is appropriate for relief of menopausal symptoms among women without contraindications to such use. However, such therapy should be avoided by women with an elevated baseline risk of future cardiovascular events. Women who have contraindications for or are opposed to HT may derive benefit from the use of certain antidepressants (including venlafaxine, fluoxetine, or paroxetine), gabapentin, clonidine, soy, or black cohosh and, for genitourinary symptoms, intravaginal estrogen creams or devices, or ospemifene.


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InternalMed_Harrison. Long-term use (≥5 years for estrogen-progestogen and ≥7 years for estrogen alone) is more problematic because a heightened risk of breast cancer must be factored into the decision, especially for estrogen-progestogen. Reasonable candidates for such use include the small percentage of postmenopausal women who have persistent severe vasomotor symptoms along with an increased risk of osteoporosis (e.g., those with osteopenia, a personal or family history of nontraumatic fracture, or a weight below 125 lbs), who also have no personal or family history of breast cancer in a first-degree relative or other contraindications, and who have a strong personal preference for therapy. Poor candidates are women with elevated cardiovascular risk, those at increased risk of breast cancer (e.g., women who have a first-degree relative with breast cancer, susceptibility genes such as BRCA1 or BRCA2, or a personal history of cellular atypia detected by breast biopsy), and those at low risk of


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InternalMed_Harrison. women who have a first-degree relative with breast cancer, susceptibility genes such as BRCA1 or BRCA2, or a personal history of cellular atypia detected by breast biopsy), and those at low risk of osteoporosis. Even for reasonable candidates, strategies to minimize dose and duration of use should be employed. For example, women using HT to relieve intense vasomotor symptoms in early postmenopause should consider discontinuing therapy within 5 years, resuming it only if such symptoms persist. Because of the role of progestogens in increasing breast cancer risk, regimens that employ cyclic rather than continuous progestogen exposure as well as formulations other than medroxyprogesterone acetate should be considered if treatment is extended. For prevention of osteoporosis, alternative therapies such as bisphosphonates or SERMs should be considered. Research on alternative progestogens and androgen-containing preparations has been limited, particularly with respect to long-term safety.


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InternalMed_Harrison. such as bisphosphonates or SERMs should be considered. Research on alternative progestogens and androgen-containing preparations has been limited, particularly with respect to long-term safety. Additional research on the effects of these agents on cardiovascular disease, glucose tolerance, and breast cancer will be of particular interest.


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InternalMed_Harrison. In addition to HT, lifestyle choices such as smoking abstention, adequate physical activity, and a healthy diet can play a role in controlling symptoms and preventing chronic disease. An expanding array of pharmacologic options (e.g., bisphosphonates, SERMs, and other agents for osteoporosis; cholesterol-lowering or antihypertensive agents for cardiovascular disease) should also reduce the widespread reliance on hormone use. However, short-term HT may still benefit some women. Avoid HThYes Yes No No Free of contraindicationscto HT and no h/o CHD, stroke, or TIA? AND No increased risk of stroke (<10% by Framingham Stroke Score)?dSignificant symptoms of menopause (moderate-to-severe hot flashes, night sweats)?bAssess CHD risk and years since last menstrual period Years since last menstrual periodfAvoid HT Low (5% to <10%) Moderate (10% to 20%) 6 to 10


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InternalMed_Harrison. Decision about duration of use: continued moderate-to-severe symptoms; patient preference; weigh baseline risks of breast cancer vs osteoporosis FIGURE 413-3 Chart for identifying appropriate candidates for postmenopausal hormone therapy (HT).a aReassess each step at least once every 6–12 months (assuming the patient’s continued preference for HT). bWomen who are at high risk of osteoporotic fracture but are unable to tolerate alternative preventive medications may also be reasonable candidates for systemic HT even if they do not have moderate to severe vasomotor symptoms. Women who have vaginal dryness without moderate to severe vasomotor symp-toms may be candidates for vaginal estrogen. cTraditional contraindications are unexplained vaginal bleeding; active liver disease; history of venous thromboembolism due to pregnancy, oral contraceptive use, or an unknown etiology; blood-clotting disorder; history of breast or endo-metrial cancer; and diabetes. Oral HT should be avoided but


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InternalMed_Harrison. venous thromboembolism due to pregnancy, oral contraceptive use, or an unknown etiology; blood-clotting disorder; history of breast or endo-metrial cancer; and diabetes. Oral HT should be avoided but transdermal HT may be an option (see g below) for other contraindications, includ-ing high triglyceride levels (>400 mg/dL); active gallbladder disease; and history of venous thromboembolism due to past immobility, surgery, or bone fracture. dTen-year risk of stroke, based on Framingham Stroke Risk Score (RB D’Agostino et al: Stroke risk profile: Adjustment for antihyper-tensive medication. The Framingham Study. Stroke 25:40, 1994), as modified by JE Manson, SS Bassuk: Hot Flashes, Hormones & Your Health. New York, McGraw-Hill, 2007. eTen-year risk of CHD, based on Framingham Coronary Heart Disease Risk Score (Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults: JAMA 285:2486, 2001), as modified by JE Manson, SS Bassuk: Hot Flashes, Hormones & Your


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InternalMed_Harrison. Disease Risk Score (Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults: JAMA 285:2486, 2001), as modified by JE Manson, SS Bassuk: Hot Flashes, Hormones & Your Health. New York, McGraw-Hill, 2007. f Women >10 years past menopause are not good candidates for initiation (first use) of HT. gAvoid oral HT. Transdermal HT may be an option because it has a less adverse effect on clotting factors, triglyceride levels, and inflammation factors than oral HT. hConsider selective serotonin or serotonin–norepinephrine reuptake inhibitor, gabapentin, clonidine, soy, or another alternative. Abbreviations: CHD, coronary heart disease; h/o, history of; TIA, transient ischemic attack. (Adapted from JE Manson, SS Bassuk: Hot Flashes, Hormones & Your Health. New York, McGraw-Hill, 2007. Copyright © 2007 by the President and Fellows of Harvard College. All rights reserved.) infertility and Contraception Janet E. Hall INFERTILITY DEFINITION AND PREVALENCE Infertility


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InternalMed_Harrison. 2007. Copyright © 2007 by the President and Fellows of Harvard College. All rights reserved.) infertility and Contraception Janet E. Hall INFERTILITY DEFINITION AND PREVALENCE Infertility has traditionally been defined as the inability to conceive after 12 months of unprotected sexual intercourse. In women who ultimately conceived, pregnancy occurred in ~50% within 3 months, 75–82% within 6 months, and 85–92% within 12 months. The World Health Organization (WHO) considers infertility as a disability (an impairment of function) and thus access to health care falls under the Convention on the Rights of Persons with Disability. Thirty-four mil-lion women, predominantly from developing countries, have infertility resulting from maternal sepsis and unsafe abortion. In populations <60 years old, infertility is ranked the fifth highest serious global dis-ability. In the United States, the rate of infertility in married women age 15–44 is 6% based on the National Survey of Family Growth, 414


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InternalMed_Harrison. infertility is ranked the fifth highest serious global dis-ability. In the United States, the rate of infertility in married women age 15–44 is 6% based on the National Survey of Family Growth, 414 although prospective studies suggest that it may be as high as 12–15%. The infertility rate has remained relatively stable over the past 30 years in most countries. However, the proportion of couples without children has risen, reflecting both higher numbers of couples in childbearing years and a trend to delay childbearing. This trend has important implications because of an age-related decrease in fecundability: the incidence of primary infertility increases from ~8% between the ages of 18 and 38 to 25% and 30% between the ages of 35 and 39 and 40 and 44, respectively. It is estimated that 14% of couples in the United States have received medical assistance for infertility; of these, two-thirds received counseling, ~12% underwent infertility testing of the female and/or male partner, and


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InternalMed_Harrison. of couples in the United States have received medical assistance for infertility; of these, two-thirds received counseling, ~12% underwent infertility testing of the female and/or male partner, and 17% received drugs to induce ovulation.


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InternalMed_Harrison. The spectrum of infertility ranges from reduced conception rates or the need for medical intervention to irreversible causes of infertility. Infertility can be attributed primarily to male factors in 25% of couples and female factors in 58% of couples and is unexplained in about 17% of couples (Fig. 414-1). Not uncommonly, both male and female factors contribute to infertility. Decreases in the ability to conceive as a Infertility14% of reproductive aged women 5 million couples in the U.S. Female causes 58% Male causes 25% Unexplained 17% Primary hypogonadism ( FSH) 30–40% Secondary hypogonadism ( FSH, LH) 2% Disordered sperm transport 10–20% Unknown 40–50% FIGURE 414-1 Causes of infertility. FSH, follicle-stimulating hormone; LH, luteinizing hormone.


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InternalMed_Harrison. FIGURE 414-1 Causes of infertility. FSH, follicle-stimulating hormone; LH, luteinizing hormone. function of age in women has led to recommendations that women >34 years old who are not at increased risk of infertility seek attention after 6 months, rather than 12 months as suggested for younger women, and receive an expedited work-up and approach to treatment. APPROACH TO THE PATIENT:


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InternalMed_Harrison. APPROACH TO THE PATIENT: In all couples presenting with infertility, the initial evaluation includes discussion of the appropriate timing of intercourse and discussion of modifiable risk factors such as smoking, alcohol, caffeine, and obesity. The range of required investigations should be reviewed as well as a brief description of infertility treatment options, including adoption. Initial investigations are focused on determining whether the primary cause of the infertility is male, female, or both. These investigations include a semen analysis in the male, confirmation of ovulation in the female, and, in the majority of situations, documentation of tubal patency in the female. In some cases, after an extensive workup excluding all male and female factors, a specific cause cannot be identified, and infertility may ultimately be classified as unexplained.


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InternalMed_Harrison. Infertility is invariably associated with psychological stress related not only to the diagnostic and therapeutic procedures themselves but also to repeated cycles of hope and loss associated with each new procedure or cycle of treatment that does not result in the birth of a child. These feelings are often combined with a sense of isolation from friends and family. Counseling and stress-management techniques should be introduced early in the evaluation of infertility. Importantly, infertility and its treatment do not appear to be associated with long-term psychological sequelae.


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InternalMed_Harrison. Abnormalities in menstrual function constitute the most common cause of female infertility. These disorders, which include ovulatory dysfunction and abnormalities of the uterus or outflow tract, may present as amenorrhea or as irregular or short menstrual cycles. A careful history and physical examination and a limited number of laboratory tests will help to determine whether the abnormality is (1) hypothalamic or pituitary (low follicle-stimulating hormone [FSH], luteinizing hormone [LH], and estradiol with or without an increase in prolactin), (2) polycystic ovary syndrome (PCOS; irregular cycles and hyperandrogenism in the absence of other causes of androgen excess), (3) ovarian (low estradiol with increased FSH), or (4) a uterine or outflow tract abnormality. The frequency of these diagnoses depends on whether the amenorrhea is primary or occurs after normal puberty and menarche (see Fig. 69-2).


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InternalMed_Harrison. The approach to further evaluation of these disorders is described in detail in Chap. 69. Ovulatory Dysfunction In women with a history of regular menstrual cycles, evidence of ovulation should be sought (Chap. 412). Even in the presence of ovulatory cycles, evaluation of ovarian reserve is recommended for women age >35 years if they are interested in fertility. Measurement of FSH on day 3 of the cycle (an FSH level <10 IU/ mL on cycle day 3 predicts adequate ovarian oocyte reserve) is the most cost-effective test. Other tests include measurement of FSH in response to clomiphene citrate (blocks estrogen negative feedback on FSH), antral follicle count on ultrasound, and anti-müllerian hormone (AMH; <0.5 ng/mL predicts reduced ovarian reserve although there is variability between labs).


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InternalMed_Harrison. Tubal Disease Tubal dysfunction may result from pelvic inflammatory disease (PID), appendicitis, endometriosis, pelvic adhesions, tubal surgery, previous use of an intrauterine device (IUD), and a previous ectopic pregnancy. However, a cause is not identified in up to 50% of patients with documented tubal factor infertility. Because of the high prevalence of tubal disease, evaluation of tubal patency by hysterosalpingogram (HSG) or laparoscopy should occur early in the majority of couples with infertility. Subclinical infections with Chlamydia trachomatis may be an underdiagnosed cause of tubal infertility and requires the treatment of both partners.


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InternalMed_Harrison. Endometriosis Endometriosis is defined as the presence of endometrial glands or stroma outside the endometrial cavity and uterine musculature and accounts for 40% of infertility not due to ovulatory disorders, tubal obstruction, or male factor. Its presence is suggested by a history of dyspareunia (painful intercourse), worsening dysmenorrhea that often begins before menses, or a thickened rectovaginal septum or deviation of the cervix on pelvic examination. Mild endometriosis does not appear to impair fertility; the pathogenesis of the infertility associated with moderate and severe endometriosis may be multifactorial with impairments of folliculogenesis, fertilization, and implantation, as well as adhesions. Endometriosis is often clinically silent, however, and can only be excluded definitively by laparoscopy. MALE CAUSES (SEE ALSO CHAP. 411)


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InternalMed_Harrison. MALE CAUSES (SEE ALSO CHAP. 411) Known causes of male infertility include primary testicular disease, genetic disorders (particularly Y chromosome microdeletions), disorders of sperm transport, and hypothalamic-pituitary disease resulting in secondary hypogonadism. However, the etiology is not ascertained in up to one-half of men with suspected male factor infertility. The key initial diagnostic test is a semen analysis. Testosterone levels should be measured if the sperm count is low on repeated examination or if there is clinical evidence of hypogonadism. Gonadotropin levels will help to determine a gonadal versus a central cause of hypogonadism.