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Harrison's Internal Medicine > Chapter 341. The Female Reproductive System: Infertility and Contraceptin >

The Female Reproductive System: Infertility and Contraception: Introduction

The female reproductive system regulates the hormonal changes responsible for puberty and adult reproductive function. Normal reproductive function in women requires the dynamic integration of hormonal signals 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.

For further discussion of related topics, see the following chapters: menstrual cycle disorders (Chap. 51), hyperandrogenic disorders (Chap. 50), sexually transmitted diseases (Chap. 124), sexual differentiation (Chap. 343), menopause (Chap. 342), gynecologic malignancies (Chap. 93), and male hormonal contraception (Chap. 340).

Development of the Ovary and Early Follicular Growth

The ovary orchestrates the development and release of a mature oocyte and also elaborates hormones (e.g., estrogen, progesterone, inhibin) 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' gestation. Germ cells can only persist within the genital ridge and are then referred to as oogonia. In contrast to testis development, germ cells are essential for induction of normal ovarian development, reflecting a key role of oogonia in the formation of primordial follicles. 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 streak ovary containing only stromal cells is found in patients with 45, X Turner syndrome (Chap. 343).

Starting at ~8 weeks' 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. Granulosa cells are derived from mesonephric cells that invade the ovary early in its development, pushing the germ cells to the periphery or ovarian cortex. Although recent studies have reopened the debate, the weight of evidence supports the concept that 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' gestation after which there is inexorable 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 (Fig. 341-1).

The oocyte persists in prophase of the first meiotic division until just before ovulation, when meiosis resumes. 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 is characterized by growth of the oocyte and the transition from squamous to cuboidal granulosa cells (Fig. 341-2). 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.

In murine models, genes that regulate ovarian development and follicle formation have been identified (Fig. 341-3). Bidirectional signals between the oocyte and its surrounding somatic cells are essential for normal follicular development. For example, the oocyte-derived factor in the germline (FIG) is required for initial follicle formation. Anti-müllerian hormone (AMH) and activins derived from somatic cells induce the development of primary follicles from primordial follicles. Oocyte-derived growth differentiation factor 9 (GDF-9) is required for migration of pre-theca cells to the outer surface of the developing follicle (Fig. 341-2). 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 already been shown to cause the syndrome of blepharophimosis/ptosis/epicanthus inversus, which is associated with ovarian failure.

Development of a Mature Follicle

The early stages of follicle growth are primarily driven by intraovarian factors, whereas maturation to the state required for ovulation, including the resumption of meiosis in the oocyte, requires the combined stimulus of FSH and luteinizing hormone (LH). Recruitment of secondary follicles from the resting follicle pool requires the direct action 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. 341-4). 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 bone morphogenic protein 6 (BMP-6), derived from the granulosa cells, and paracrine actions of GDF-9, BMP-15, and BMP-6, derived from the oocyte, are involved in granulosa cell proliferation and modulation of FSH responsiveness. Differential exposure to these factors may explain why one 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.

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 Graffian, 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, and the progesterone receptor, each of which are required for ovulation, which involves cumulus expansion and the controlled expulsion of the egg and follicular fluid. The process of luteinization is induced by LH in conjunction with the loss of oocyte-derived luteinization inhibitors including GDF-9, BMP-15, and BMP-6.

Regulation of Ovarian Function

Hypothalamic and Pituitary Secretion

Gonadotropin-releasing hormone (GnRH) neurons develop from epithelial cells outside the central nervous system and migrate, initially alongside the olfactory neurons, to the medial basal 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. 333). 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 hormonal secretion in the fetus.

After birth, and the removal of placental steroids, gonadotropin levels rise. FSH levels are much higher in girls than in boys. This rise in FSH is associated with ovarian activation (evident on ultrasound) and increased inhibin B and estradiol levels. By 12–20 months of age, the reproductive axis is again suppressed, and a period of relative quiescence persists until puberty (Fig. 341-5). 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.

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. Metabolic signals, such as adipocyte-derived leptin, also play a permissive role in reproductive function (Chap. 74). Studies of patients with isolated GnRH deficiency reveal that mutations in the G protein–coupled receptor 54 (GPR54) gene 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 metastin in the onset of puberty has been suggested by upregulation of KISS1 and GPR54 transcripts in the hypothalamus at the time of puberty. The KISS/GPR54 system may also be involved in estrogen feedback regulation of GnRH secretion.

Ovarian Steroids

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 testes. However, the specific 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. 341-6). 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 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 polycystic ovarian syndrome (PCOS)], they do not secrete androgens.

Rupture of the follicle at the time of ovulation is accompanied by the development of a rich capillary network induced by angiogenic factors such as granulosa-cell derived vascular endothelial growth factor (VEGF), making it possible for large molecules such as low-density lipoprotein (LDL) to reach the luteinized granulosa and theca lutein cells. Luteinized granulosa cells express genes involved in progestin synthesis. Theca lutein cells produce 17-hydroxyprogesterone, a substrate for aromatization by the luteinized granulosa cells. While the major secretory product of the corpus luteum is progesterone, estradiol and 17-hydroxyprogesterone are also produced. 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.

Steroid Hormone Actions

(See Chap. 332) Both estrogen and progesterone play critical roles in the expression of secondary sexual characteristics in women. 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 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) and . Transcriptional coactivators and co-repressors modulate ER action (Chap. 332). Both ER subtypes are present in the hypothalamus, pituitary, ovary, and reproductive tract. Although ER and - exhibit some functional redundancy, there is also a high degree of specificity, particularly in cell type expression. For example, ER functions in the ovarian theca cells, whereas ER 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) and protein isoforms, as well as rapid membrane signaling.

Ovarian Peptides

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 -subunit and a A- or B-subunit to form inhibin A or inhibin B, both of which are secreted from the ovary. Activin is a homodimer of inhibin subunits with the capacity to stimulate the synthesis and secretion of FSH. Inhibins and activins are members of the transforming growth factor (TGF-) superfamily of growth and differentiation factors. During the purification of inhibin, follistatin, an unrelated monomeric protein that inhibits FSH secretion, was discovered. Follistatin inhibits FSH secretion indirectly through binding and neutralizing activin.

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 increases in serum in response to FSH and is used clinically as a marker of ovarian reserve. Inhibin B also plays an important negative feedback role on 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, as indicated above, there is evidence that activin plays an autocrine/paracrine role in the ovary, and it may also act locally in the pituitary to modulate FSH production.

Müllerian-inhibiting substance (MIS) (also known as anti-müllerian hormone, AMH) plays an important role in ovarian biology in addition to its traditional role in the degeneration of the müllerian ducts in the male. MIS is produced by granulosa cells and, like inhibin B, is a marker of ovarian reserve. MIS may also inhibit the recruitment of primordial follicles into the follicle pool by inhibiting aromatase expression.

Hormonal Integration of the Normal Menstrual Cycle

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 influence the differential 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.

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. 341-7). This negative feedback control of FSH is critical to 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. The neural signaling pathways that distinguish estrogen negative versus positive feedback are incompletely understood.

The Follicular Phase

This phase is characterized by recruitment of a cohort of secondary follicles and the ultimate selection of a dominant preovulatory follicle (Fig. 341-8). The follicular phase begins, by convention, on the first day of menses. However, follicular recruitment is initiated by the rise in FSH that begins in the late luteal phase 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 stimulating early follicular phase levels of inhibin B. Inhibin B in conjunction with rising levels of estradiol, and 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, attest to the importance of the 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.

The Luteal Phase

This phase begins with the formation of the corpus luteum from the ruptured follicle in response to ovulation signals. 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.

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.

Clinical Assessment of Ovarian Function

Menstrual bleeding should become regular within 2 to 4 years of menarche, although anovulatory and irregular cycles are common before that. For the remainder of adult reproductive life, the cycle 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 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 follicular phase. The duration of menstrual bleeding in ovulatory cycles varies between 4 and 6 days. There is a gradual shortening of cycle length with age such that women over the age of 35 have cycles that are shorter than during their younger reproductive years. Anovulatory cycles increase as women approach the menopause, and bleeding patterns may be erratic.

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 mid-cycle 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 >0.5°F (0.24°C) 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.

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.


Normal Pubertal Development in Girls

The first menstrual period (menarche) occurs relatively late in the series of developmental milestones that characterize normal pubertal development (Table 341-1). Menarche is preceded by the appearance of pubic and then axillary hair 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), which is exquisitely sensitive to the very low levels of estrogens 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 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 341-1). Much of the variation in the timing of puberty is due to genetic factors, with heritability estimates of 50–80%. Both adrenarche and breast development occur ~1 year earlier in African-American compared with Caucasian girls, although the timing of menarche differs by only 6 months between these ethnic groups.

Table 341-1 Mean Age (Years) of Pubertal Milestones in Girls, with 95% Confidence Intervals

  Onset of Breast/Pubic Hair Development Age of Peak Height Velocity Menarche Final Breast/Pubic Hair Development Adult Height
Caucasian 10.2 11.9 12.6 14.3 17.1
African Amercan 9.6 11.5 12 13.6 16.5

Source: From FM Biro et al: J Pediatr 148:234, 2006.

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 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 Puberty

The differential diagnosis of precocious and delayed puberty is similar in boys 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.

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 were present at <7 years of age for Caucasian girls or <6 years for African-American girls.

Precocious puberty is most often centrally mediated (Table 341-2), resulting from early activation of the hypothalamic-pituitary-ovarian axis. It is characterized by pulsatile LH secretion and an enhanced LH and FSH response to exogenous GnRH (two- to threefold stimulation) (Table 341-3). True precocity is marked by advancement in bone age of >2 SD, 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 also be considered. GnRH agonists that induce pituitary desensitization are the mainstay of treatment to prevent premature epiphyseal closure and preserve adult height, as well to manage psychosocial repercussions of precocious puberty.

Table 341-2 Differential Diagnosis of Precocious Puberty

Central (GnRH dependent)  Peripheral (GnRH independent) 
  Idiopathic   Congenital adrenal hyperplasia
  CNS tumors   Estrogen-producing tumors
    Hamartomas     Adrenal tumors
    Astrocytomas     Ovarian tumors
    Adenomyomas   Gonadotropin/hCG-producing tumors
    Gliomas   Exogenous exposure to estrogen or androgen
    Germinomas   McCune-Albright syndrome
  CNS infection   Aromatase excess syndrome
  Head trauma  
  CNS malformation  
    Arachnoid or suprasellar cysts  
    Septo-optic dysplasia  

Note: GnRH, gonadotropin-releasing hormone; CNS, central nervous system; hCG, human chorionic gonadotropin.

Table 341-3 Evaluation of Precocious and Delayed Puberty

  Precocious Delayed
Initial screening tests     
  History and physical x x
  Assessment of growth velocity x x
  Bone age x x
  LH, FSH x x
  Estradiol, testosterone x x
  DHEAS x x
  17-Hydroxyprogesterone x  
  TSH, T4
x x
  Complete blood count   x
  Sedimentation rate, C-reactive protein   x
  Electrolytes, renal function   x
  Liver enzymes   x
  IGF-I, IGFBP-3   x
  Urinalysis   x
Secondary tests     
  Pelvic ultrasound x x
  Cranial MRI x x
  -hCG x  
  GnRH/agonist stimulation test x x
  ACTH stimulation test x  
  Inflammatory bowel disease panel x x
  Celiac disease panel   x
  Prolactin   x
  Karyotype   x

Note: LH, luteinizing hormone; FSH, follicle-stimulating hormone; DHEAS, dehydroepiandrosterone sulfate; TSH, thyroid-stimulating hormone; T4, thyroxine; IGF, insulin-like growth factor; IGFBP-3, IGF-binding protein 3; hCG, human chorionic gonadotropin; ACTH, adrenocorticotropic hormone.

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 341-2) and limiting the effects of gonadal steroids using aromatase inhibitors, inhibitors of steroidogenesis, and estrogen receptor 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, androgen production, or compromised 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 subsequent predisposition to PCOS.

Delayed Puberty

Delayed puberty (Table 341-4) 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. 51). Between 25 and 40% of delayed puberty in girls is of ovarian origin, with Turner syndrome constituting a 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 abnormalities in energy balance that result 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 (Chap. 340, Table 340-2). Family studies suggest that genes identified in association with absent puberty may cause delayed puberty and that there may be a genetic susceptibility to environmental stresses such as diet and exercise. 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.

Table 341-4 Differential Diagnosis of Delayed Puberty


    Turner syndrome
    Gonadal dysgenesis
    Chemotherapy/radiation therapy
    Autoimmune oophoritis
    Congenital lipoid hyperplasia
  Steroidogenic enzyme abnormalities
    17-hydroxylase deficiency
    Aromatase deficiency
  Gonadotropin/receptor mutations
  Androgen resistance syndrome


    Hypothalamic syndromes
       Letpin/leptin receptor
       HESX1 (septooptic dysplasia)
       PC1 (prohormone convertase)
    IHH and Kallmann syndrome
       KAL, FGFR1
       GnRHR, GPR54
    Abnormalities of pituitary development/function
  CNS tumors/infiltrative disorders
    Astrocytoma, germinoma, glioma
    Prolactinomas, other pituitary tumors
    Histiocytosis X
    Chronic diseases
    Excessive exercise
    Eating disorders

Note: FSH, follicle-stimulating hormone chain; FSHR, FSH receptor; LHR, luteinizing hormone receptor; HESX1, homeobox, embryonic stem cell expressed 1; IHH, idiopathic hypogonadotropic hypogonadism; KAL, Kallmann; FGFR1, fibroblast growth factor 1; GnRHR, gonadotropin-releasing hormone receptor; GPR54, G protein-coupled receptor 54; PROP1, prophet of Pit1, paired-like homeodomain transcription factor; CNS, central nervous system.


Definition and Prevalence

Infertility is defined as the inability to conceive after 12 months of unprotected sexual intercourse. In a study of 5574 English and American women who ultimately conceived, pregnancy occurred in 50% within 3 months, 72% within 6 months, and 85% within 12 months. These findings are consistent with predictions based on fecundability, the probability of achieving pregnancy in one menstrual cycle (approximately 20–25% in healthy young couples). Assuming a fecundability of 0.25, 98% of couples should conceive within 13 months. Based on this definition, the National Survey of Family Growth reports a 14% rate of infertility in the United States in married women aged 15–44. The infertility rate has remained relatively stable over the past 30 years, although the proportion of couples without children has risen, reflecting a trend to delay childbearing. This trend has important implications because of an age-related decrease in fecundability, which begins at age 35 and decreases markedly after age 40.

Causes of Infertility

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%, female factors in 58%, and is unexplained in about 17% of couples (Fig. 341-9). Not uncommonly, both male and female factors contribute to infertility.

Approach to the Patient: Infertility

Initial Evaluation

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. A description of the range of investigations that may be required and a brief description of infertility treatment options, including adoption, should be reviewed. 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.

Psychological Aspects of Infertility

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. Infertility and its treatment do not appear to be associated with long-term psychological sequelae.

Female Causes

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 FSH, LH, and estradiol with or without an increase in prolactin), (2) PCOS (irregular cycles and hyperandrogenism in the absence of other causes of androgen excess), (3) ovarian (low estradiol with increased FSH), or (4) 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. 51-2). The approach to further evaluation of these disorders is described in detail in Chap. 51.

Ovulatory Dysfunction

In women with a history of regular menstrual cycles, evidence of ovulation should be sought as described above. An endometrial biopsy to exclude luteal phase insufficiency is no longer considered an essential part of the infertility workup for most patients. Even in the presence of ovulatory cycles, evaluation of ovarian reserve is recommended for women over 35 by measurement of FSH on day 3 of the cycle or in response to clomiphene, an estrogen antagonist (see below). An FSH level < 10 IU/mL on cycle day 3 predicts adequate ovarian oocyte reserve. Antral follicle count, inhibin B, and MIS are also being investigated as indicators of ovarian reserve.

Tubal Disease

This may result from pelvic inflammatory disease (PID), appendicitis, endometriosis, pelvic adhesions, tubal surgery, and previous use of an intrauterine device (IUD). 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.


Endometriosis is defined as the presence of endometrial glands or stroma outside the endometrial cavity and uterine musculature. Its presence is suggested by a history of dyspareunia (painful intercourse), worsening dysmenorrhea that often begins before menses, or by a thickened rectovaginal septum or deviation of the cervix on pelvic examination. The pathogenesis of the infertility associated with endometriosis is unclear but may involve effects on the normal endometrium as well as adhesions. Endometriosis is often clinically silent, however, and can only be excluded definitively by laparoscopy.

Male Causes

(See also Chap. 340) Known causes of male infertility include primary testicular disease, disorders of sperm transport, and hypothalamic-pituitary disease resulting in secondary hypogonadism. However, the etiology is not ascertained in up to 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.

Infertility: Treatment

The treatment of infertility should be tailored to the problems unique to each couple. In many situations, including unexplained infertility, mild to moderate endometriosis, and/or borderline semen parameters, a stepwise approach to infertility is optimal, beginning with low-risk interventions and moving to more invasive, higher risk interventions only if necessary. After determination of all infertility factors and their correction, if possible, this approach might include, in increasing order of complexity: (1) expectant management, (2) clomiphene citrate (see below) with or without intrauterine insemination (IUI), (3) gonadotropins with or without IUI, and (4) in vitro fertilization (IVF). The time used to complete the evaluation, correction, and expectant management can be longer in women <30 years of age, but this process should be advanced rapidly in women >35. In some situations expectant management will not be appropriate.

Ovulatory Dysfunction

Treatment of ovulatory dysfunction should first be directed at identification of the etiology of the disorder to allow specific management when possible. Dopamine agonists, for example, may be indicated in patients with hyperprolactinemia (Chap. 333); lifestyle modification may be successful in women with low body weight or a history of intensive exercise (Chap. 76).

Medications used for ovulation induction include clomiphene citrate, gonadotropins, and pulsatile GnRH. Clomiphene citrate is a nonsteroidal estrogen antagonist that increases FSH and LH levels by blocking estrogen negative feedback at the hypothalamus. The efficacy of clomiphene for ovulation induction is highly dependent on patient selection. It induces ovulation in ~60% of women with PCOS and is the initial treatment of choice. It may be combined with agents that modify insulin levels, such as metformin. Clomiphene citrate is less successful in patients with hypogonadotropic hypogonadism. Aromatase inhibitors have also been investigated for the treatment of infertility. Initial studies are promising, but these medications have not been approved for this indication.

Gonadotropins are highly effective for ovulation induction in women with hypogonadotropic hypogonadism and PCOS and are used to induce multiple follicular recruitment in unexplained infertility and in older reproductive-aged women. Disadvantages include a significant risk of multiple gestation and the risk of ovarian hyperstimulation, but careful monitoring and a conservative approach to ovarian stimulation reduce these risks. Currently available gonadotropins include urinary preparations of LH and FSH, highly purified FSH, and recombinant FSH. Though FSH is the key component, there is growing data that the addition of some LH (or hCG) may improve results, particularly in hypogonadotropic patients.

Pulsatile GnRH is highly effective for restoring ovulation in patients with hypothalamic amenorrhea. Pregnancy rates are similar to those following the use of gonadotropins, but rates of multiple gestation are lower and there is virtually no risk of ovarian hyperstimulation. Unfortunately, pulsatile GnRH is not widely available in the United States.

None of these methods are effective in women with premature ovarian failure in whom donor oocyte or adoption are the methods of choice.

Tubal Disease

If hysterosalpingography suggests a tubal or uterine cavity abnormality, or if a patient is 35 at the time of initial evaluation, laparoscopy with tubal lavage is recommended, often with a hysteroscopy. Although tubal reconstruction may be attempted if tubal disease is identified, it is generally being replaced by the use of IVF. These patients are at increased risk of developing an ectopic pregnancy.


Though 60% of women with minimal or mild endometriosis may conceive within 1 year without treatment, laparoscopic resection or ablation appears to improve conception rates. Medical management of advanced stages of endometriosis is widely used for symptom control but has not been shown to enhance fertility. In moderate to severe endometriosis, conservative surgery is associated with pregnancy rates of 50 and 39%, respectively, compared with rates of 25 and 5% with expectant management alone. In some patients, IVF may be the treatment of choice.

Male Factor Infertility

The treatment options for male factor infertility have expanded greatly in recent years (Chap. 340). Secondary hypogonadism is highly amenable to treatment with pulsatile GnRH or gonadotropins. In vitro techniques have provided new opportunities for patients with primary testicular failure and disorders of sperm transport. Choice of initial treatment options depends on sperm concentration and motility. Expectant management should be attempted initially in men with mild male factor infertility (sperm count of 15 to 20 x 106/mL and normal motility). Moderate male factor infertility (10 to 15 x 106/mL and 20–40% motility) should begin with IUI alone or in combination with treatment of the female partner with clomiphene or gonadotropins, but it may require IVF with or without intracytoplasmic sperm injection (ICSI). For men with a severe defect (sperm count of <10 x 106/mL, 10% motility), IVF with ICSI or donor sperm should be used. If ICSI is performed because of azoospermia due to congenital bilateral absence of the vas deferens, genetic testing and counseling should be provided because of the risk of cystic fibrosis.

Assisted Reproductive Technologies

The development of assisted reproductive technologies (ART) has dramatically altered the treatment of male and female infertility. IVF is indicated for patients with many causes of infertility that have not been successfully managed with more conservative approaches. IVF or ICSI is often the treatment of choice in couples with a significant male factor or tubal disease, whereas IVF using donor oocytes is used in patients with premature ovarian failure and in women of advanced reproductive age. Success rates depend on the age of the woman and the cause of the infertility and are generally 18–24% per cycle when initiated in women <40. In women >40, there is a marked decrease in both the number of oocytes retrieved and their ability to be fertilized. Though often effective, IVF is expensive and requires careful monitoring of ovulation induction and invasive techniques including the aspiration of multiple follicles. IVF is associated with a significant risk of multiple gestation (31% twins, 6% triplets, and 0.2% higher order multiples).


Though various forms of contraception are widely available, ~30% of births in the United States are the result of unintended pregnancy. Teenage pregnancies continue to represent a serious public health problem in the United States, with >1 million unintended pregnancies each year—a significantly greater incidence than in other industrialized nations.

Contraceptive methods are widely used (Table 341-5). Only 15% of couples report having unprotected sexual intercourse in the past 3 months. A reversible form of contraception is used by >50% of couples, while sterilization (in either the male or female) has been employed as a permanent form of contraception by over a third of couples. Pregnancy termination is relatively safe when directed by health care professionals but is rarely the option of choice.

Table 341-5 Effectiveness of Different Forms of Contraception

Method of Contraception Theoreticala Effectiveness, %
Actuala Effectiveness, %
Percent Continuing Use at 1 Yearb
Contraceptive Methods Used by U.S. Womenc
Barrier methods        
  Condoms 98 88 63 20
  Diaphragm 94 82 58 2
  Cervical cap 94 82 50 <1
Spermicides 97 79 43 1
  Male 99.9 99.9 100 11
  Female 99.8 99.6 100 28
Intrauterine device       1
  Copper T380 99 97 78  
  Progestasert 98 97 81  
  Mirena 99.9 99.8    
Oral contraceptive pill     72 27
  Combination 99.9 97    
  Progestin only 99.5 97    
Long-acting progestins        
  Depo-Provera 99.7 99.7 70 <1

aAdapted from J Trussel et al: Obstet Gynecol 76:558, 1990.

bAdapted from Contraceptive Technology Update. Contraceptive Technology, Feb. 1996, Vol 17, No 1, pp 13–24.

cAdapted from LJ Piccinino and WD Mosher: Fam Plan Perspective 30:4, 1998.

No single contraceptive method is ideal, although all are safer than carrying a pregnancy to term. The effectiveness of a given method of contraception depends not only on the efficacy of the method itself. Discrepancies between theoretical and actual effectiveness emphasize the importance of patient education and compliance when considering various forms of contraception (Table 341-5). Knowledge of the advantages and disadvantages of each contraceptive is essential for counseling an individual about the methods that are safest and most consistent with his or her lifestyle. The World Health Organization (WHO) has extensive family planning resources for the physician and patient that can be accessed on line.

Barrier Methods

Barrier contraceptives (such as condoms, diaphragms, and cervical caps) and spermicides are easily available, reversible, and have fewer side effects than hormonal methods. However, their effectiveness is highly dependent on adherence and proper use (Table 341-5). A major advantage of barrier contraceptives is the protection provided against sexually transmitted diseases (STIs) (Chap. 124). Consistent use is associated with a decreased risk of HIV, gonorrhea, nongonococcal urethritis, and genital herpes, probably due in part to the concomitant use of spermicides. Natural membrane condoms may be less effective than latex condoms, and petroleum-based lubricants can degrade condoms and decrease their efficacy for preventing HIV infection. A highly effective female condom, which also provides protection against STIs, was approved in 1994 but has not achieved widespread use.


Sterilization is the method of birth control most frequently chosen by fertile men and multiparous women >30 (Table 341-5). Sterilization refers to a procedure that prevents fertilization by surgical interruption of the fallopian tubes in women or the vas deferens in men. Although tubal ligation and vasectomy are potentially reversible, these procedures should be considered permanent and should not be undertaken without patient counseling.

Several methods of tubal ligation have been developed, all of which are highly effective with a 10-year cumulative pregnancy rate of 1.85 per 100 women. However, when pregnancy does occur, the risk of ectopic pregnancy may be as high as 30%. The success rate of tubal reanastomosis depends on the method used, but even after successful reversal, the risk of ectopic pregnancy remains high. In addition to prevention of pregnancy, tubal ligation reduces the risk of ovarian cancer, possibly by limiting the upward migration of potential carcinogens.

Vasectomy is a highly effective outpatient surgical procedure that has little risk. The development of azoospermia may be delayed for 2–6 months, and other forms of contraception must be used until two sperm-free ejaculations provide proof of sterility. Reanastomosis may restore fertility in 30–50% of men, but the success rate declines with time after vasectomy and may be influenced by factors such as the development of anti-sperm antibodies.

Intrauterine Devices

IUDs inhibit pregnancy primarily through a spermicidal effect caused by a sterile inflammatory reaction produced by the presence of a foreign body in the uterine cavity (copper IUDs) or by the release of progestins (Progestasert, Mirena). IUDs provide a high level of efficacy in the absence of systemic metabolic effects, and ongoing motivation is not required to ensure efficacy once the device has been placed. However, only 1% of women in the United States use this method compared to a utilization rate of 15–30% in much of Europe and Canada, despite evidence that the newer devices are not associated with increased rates of pelvic infection and infertility, as occurred with earlier devices. An IUD should not be used in women at high risk for development of STI or in women at high risk for bacterial endocarditis. The IUD may not be effective in women with uterine leiomyomas because they alter the size or shape of the uterine cavity. IUD use is associated with increased menstrual blood flow, although this is less pronounced with the progesterone-releasing IUD than the copper-containing device.

Hormonal Methods

Oral Contraceptive Pills

Because of their ease of use and efficacy, oral contraceptive pills are the most widely used form of hormonal contraception. They act by suppressing ovulation, changing cervical mucus, and altering the endometrium. The current formulations are made from synthetic estrogens and progestins. The estrogen component of the pill consists of ethinyl estradiol or mestranol, which is metabolized to ethinyl estradiol. Multiple synthetic progestins are used. Norethindrone and its derivatives are used in many formulations. Low-dose norgestimate and the more recently developed progestins (desogestrel, gestodene, drospirenone) have a less androgenic profile; levonorgestrel appears to be the most androgenic of the progestins and should be avoided in patients with hyperandrogenic symptoms. The three major formulations of oral contraceptives are (1) fixed-dose estrogen-progestin combination, (2) phasic estrogen-progestin combination, and (3) progestin only. Each of these formulations is administered daily for 3 weeks followed by a week of no medication during which menstrual bleeding generally occurs. Two extended oral contraceptives have recently been approved for use in the United States; Seasonalle is a 3-month preparation with 84 days of active drug and 7 day of placebo, Lybrel is a continuous preparation containing 90 g of levonorgestrel and 20 g of ethinyl estradiol. Current doses of ethinyl estradiol range from 20–50 g. However, indications for the 50-g dose are rare, and the majority of formulations contain 35 g of ethinyl estradiol. The reduced estrogen and progesterone content in the second- and third-generation pills has decreased both side effects and risks associated with oral contraceptive use (Table 341-6). At the currently used doses, patients must be cautioned not to miss pills due to the potential for ovulation. Side effects, including break-through bleeding, amenorrhea, breast tenderness, and weight gain, are often responsive to a change in formulation.

Table 341-6 Oral Contraceptives: Contraindications and Disease Risk

    Previous thromboembolic event or stroke
    History of an estrogen-dependent tumor
    Active liver disease
    Undiagnosed abnormal uterine bleeding
    Women over age 35 who smoke heavily (>15 cigarettes per day)
    Women receiving anticonvulsant drug therapy
Disease Risks 
    Coronary heart disease—increased only in smokers > 35; no relation to progestin type
    Hypertension—relative risk 1.8 (current users) and 1.2 (previous users)
    Venous thrombosis—relative risk ~4; markedly increased with factor V Leiden or prothrombin-gene mutations (see Chap. 110)
    Stroke—increased only in combination with hypertension; unclear relation to migraine headache
    Cerebral vein thrombosis—relative risk ~13–15; synergistic with prothrombin-gene mutation
    Cervical cancer—relative risk 2–4
    Ovarian cancer—50% reduction in risk
    Endometrial cancer—40% reduction in risk

The microdose progestin-only minipill is less effective as a contraceptive, having a pregnancy rate of 2–7 per 100 women-years. However, it may be appropriate for women with cardiovascular disease or for women who cannot tolerate synthetic estrogens.

New Methods

A weekly contraceptive patch (Ortho Evra) is available and has similar efficacy to oral contraceptives but may be associated with less breakthrough bleeding. Approximately 2% of patches fail to adhere, and a similar percentage of women have skin reactions. Efficacy is lower in women >90 kg. The amount of estrogen delivered may be comparable to that of a 40-g ethinyl estradiol oral contraceptive, raising the possibility of increased risk of venous thromboembolism, which must be balanced against potential benefits for women not able to successfully use other methods. A monthly contraceptive estrogen/progestin injection (Lunelle) is highly effective, with a first-year failure rate of <0.2%, but it may be less effective in obese women. Its use is associated with bleeding irregularities that diminish over time. Fertility returns rapidly after discontinuation. A monthly vaginal ring (NuvaRing) that is intended to be left in place during intercourse is also available for contraceptive use. It is highly effective, with a 12-month failure rate of 0.7%. Ovulation returns within the first recovery cycle after discontinuation.

Long-Term Contraceptives

Long-term progestin administration in the form of Depo-Provera acts primarily by inhibiting ovulation and causing changes in the endometrium and cervical mucus that result in decreased implantation and sperm transport. Depo-Provera requires an IM injection and is effective for 3 months, but return of fertility after discontinuation may be delayed for up to 12–18 months. Although highly effective, Norplant is no longer being manufactured. Amenorrhea, irregular bleeding, and weight gain are the most common adverse effects associated with both injectable forms of contraception. A major advantage of the injectable progestin-based contraceptives is the apparent lack of increased arterial and venous thromboembolic events, but increased gallbladder disease and decreased bone density may result.

Postcoital Contraception

Postcoital contraceptive methods prevent implantation or cause regression of the corpus luteum and are highly efficacious if used appropriately. Unprotected intercourse without regard to the time of the month carries an 8% incidence of pregnancy, an incidence that can be reduced to 2% by the use of emergency contraceptives within 72 h of unprotected intercourse. A notice published in 1997 by the U.S. Food and Drug Administration indicated that certain oral contraceptive pills could be used within 72 h of unprotected intercourse [Ovral (2 tablets, 12 h apart) and Lo/Ovral (4 tablets, 12 h apart)]. Preven (50 mg ethinyl estradiol and 0.25 mg levonorgestrel) and Plan B (0.75 mg Levonorgestrel) are now approved for postcoital contraception. Side effects are common with these high doses of hormones and include nausea, vomiting, and breast soreness. Recent studies suggest that 600 mg mifepristone (RU486), a progesterone receptor antagonist, may be equally as effective as or more effective than hormonal regimens, with fewer side effects. Mifepristone is now available in the United States as Mifeprex, to be used with or with

out misoprostol (synthetic prostaglandin E1, an off-label indication for this use of misoprostol).

Further Readings