Chapter 13: Disorders of the Female Reproductive System

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. 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. 15), infertility and contraception (Chap. 14), menopause (Chap. 16), disorders of sex development (Chap. 10), and disorders of the male reproductive system (Chap. 11).

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 streak ovary containing only stromal cells is found in patients with 45,X Turner’s syndrome (Chap. 10).

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. 13-1). 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. 13-2). 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 (Fig. 1 3-1) 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.

Bidirectional signaling between the germ cells and the somatic cells in the ovary is a necessary component underlying the maturation 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.

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.  13-1) 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. 13-3). 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 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 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 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.

HYPOTHALAMIC AND PITUITARY SECRETION

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. 13-4). KAL1, FGF8/FGFR1, PROK2/PROKR2, NSMF, and CDH7, among others (Chap. 11), 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. 3). 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.

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. 13-5). 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 but has not been definitively established in the human. Metabolic signals, such as adipocyte-derived leptin, play a permissive role in reproductive function (Chap. 20). 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 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 with KISS1 in KNDy neurons that project to GnRH neurons. This system is intimately involved with estrogen negative 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 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. 13-6). 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.

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.

Steroid hormone actions

Both estrogen and progesterone play critical roles in the expression of secondary sexual characteristics in women (Chap. 2). 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) α and β. Transcriptional coactivators and co-repressors modulate ER action (Chap. 2). 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.

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 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.

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 intrapituitary role in modulation of FSH production.

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.

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.

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. 13-7). 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.

THE FOLLICULAR PHASE

The follicular phase is characterized by recruitment of a cohort of secondary follicles and the ultimate selection of a dominant preovulatory follicle (Fig. 13-8). 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 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.

THE LUTEAL PHASE

The luteal phase begins with the formation of the corpus luteum from the ruptured follicle (Fig.  13-8). 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.

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 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 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 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 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 13-1). 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 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 13-1). 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.

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 PUBERTY

The differential diagnosis of precocious and delayed puberty is similar in boys (Chap. 11) 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 is present at <7 years of age for white girls or <6 years for black girls.

Precocious puberty in girls is most often centrally mediated (Table 13-2), 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 (two- to threefold stimulation) (Table 13-3). 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 epiphyseal closure and preserve adult height, as well as to manage psychosocial repercussions of precocious puberty.

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 13-2) 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 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.

Delayed puberty

Delayed puberty (Table 13-4) 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. 15). 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. 13-4, Chap. 11, Table 11-2). 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.