Robert W. Rebar
Arasen A. V. Paupoo
• Normal pubertal development occurs in a predictable orderly sequence over a definite time frame.
• The major causes of delayed puberty include anatomic genital tract abnormalities and hypo- and hypergonadotropic amenorrhea.
• When pubertal development occurs asynchronously with development of breasts in the absence of significant pubic and axillary hair, the diagnosis is usually androgen insensitivity.
• The most common cause of precocious puberty is constitutional (idiopathic), but more serious causes must be ruled out and therapy geared toward optimizing adult height.
• The most common cause of heterosexual development at the expected age of puberty is polycystic ovary syndrome.
Puberty is the period during which secondary sexual characteristics develop and the capability of sexual reproduction is attained. The physical changes accompanying pubertal development result directly or indirectly from maturation of the hypothalamus, stimulation of the sex organs, and secretion of sex steroids. Hormonally, puberty in humans is characterized by the resetting of the classic negative gonadal steroid feedback loop, alterations in circadian and ultradian (frequent) gonadotropin rhythms, and the acquisition in the woman of a positive estrogen feedback loop, which controls the monthly rhythm as an interdependent expression of gonadotropins and ovarian steroids.
The ability to evaluate and treat aberrations of pubertal development requires an understanding of the normal hormonal and physical changes that occur at puberty. An understanding of these changes is important in evaluating young women with amenorrhea.
Normal Pubertal Development
Factors Affecting Time of Onset
The major determinant of the timing of the onset of puberty is no doubt genetic, but a number of other factors appear to influence both the age at onset and the progression of pubertal development. Among these influences are nutritional state, general health, geographic location, exposure to light, and psychological state (1). The concordance of the age of menarche in mother–daughter pairs and between sisters and in ethnic populations illustrates the importance of genetic factors (1). Typically, the age of menarche is earlier than average in children with moderate obesity (up to 30% above normal weight for age), whereas delayed menarche is common in those with severe malnutrition. Children who live in urban settings, closer to the equator, and at lower altitudes typically begin puberty earlier than those who live in rural areas, farther from the equator, and at higher elevations. The risk of earlier onset of puberty is 10 to 20 times greater after international adoption for unclear reasons (2). Other risk factors implicated for precocious puberty include exposure to estrogenic endocrine-disrupting chemicals and the absence of a father in the home (3,4). Blind girls apparently undergo menarche earlier than sighted girls, suggesting some influence of light (5).
In Western Europe, the age of menarche declined 4 months each decade between 1850 and 1960 (1). Data suggest that the trend toward earlier pubertal development may be continuing among girls (but not boys) who live in the United States (6). It is presumed that these changes represent improved nutritional status and healthier living conditions.
One of the more controversial hypotheses centers on the role of total body weight and body composition on the age of menarche. It is argued that a girl must reach a critical body weight (47.8 kg) before menarche can occur (7). Body fat must increase to 23.5% from the typical 16% of the prepubertal state, which presumably is influenced by nutritional status (8). This hypothesis is supported by observations that menarche occurs earliest in obese girls, followed by normal-weight girls, then underweight girls, and lastly anorectic girls (Fig. 29.1). The importance of other factors is indicated by observations that menarche is often delayed in morbidly obese girls, those with diabetes, and those who exercise intensely but are of normal body weight and body fat percentage. Girls with precocious puberty may undergo menarche even if they have a low body fat percentage, and other girls show no pubertal development with a body fat percentage of 27% (9). The hypothesis linking menarche to body weight and composition does not always seem valid because menarche is a late event in pubertal development.
Figure 29.1 Normal twins at 12 years of age. The heavier twin (weighing 143 lb) is clearly more advanced in puberty than the lighter twin (weighing 87 lb). Anecdotal photographs and data such as these served to provide the basis for the theory that body fat, body mass, and menarche are linked. (From Wilkins L. The diagnosis and treatment of endocrine disorders in childhood and adolescence. 3rd ed. Springfield, IL: Charles C Thomas, 1965, with permission.)
Physical Changes during Puberty
The changes associated with puberty occur in an orderly sequence over a definite time frame. Any deviation from this sequence or time frame should be regarded as abnormal. The pubertal changes, their relationship to one another, and the ages at which they occur are distinctly different in girls than in boys. Although this chapter focuses on girls, changes in boys are considered briefly.
Tanner Stage
In girls, pubertal development typically takes place over 4.5 years (Fig. 29.2). The first sign of puberty is accelerated growth, and breast budding is usually the first recognized pubertal change, followed by the appearance of pubic hair, peak growth velocity, and menarche. The stages initially described by Marshall and Tanner are often used to describe breast and pubic hair development (10).
Figure 29.2 Schematic sequence of events at puberty. An idealized average girl and an idealized average boy are represented. (From Rebar RW. Practical evaluation of hormonal status. In: Yen SSC, Jaffe RB, eds. Reproductive endocrinology: physiology, pathophysiology and clinical management. 3rd ed. Philadelphia, PA: WB Saunders, 1991:830, with permission; based on data from Marshall WA, Tanner JM. Variations in patterns of pubertal changes in girls. Arch Dis Child 1969;44:291–303, and Marshall WA, Tanner JM. Variation in the pattern of pubertal changes in boys. Arch Dis Child 1970;45:13–23, with permission.)
With regard to breast development (Fig. 29.3), Tanner stage 1 refers to the prepubertal state and includes no palpable breast tissue, with the areolae generally less than 2 cm in diameter. The nipples may be inverted, flat, or raised. In Tanner stage 2, breast budding occurs, with a visible and palpable mound of breast tissue. The areolae begin to enlarge, the skin of the areolae thins, and the nipple develops to varying degrees. Tanner stage 3 is reflected by further growth and elevation of the entire breast. When the individual is seated and viewed from the side, the nipple is generally at or above the midplane of breast tissue. In most girls, Tanner stage 4 is defined by projection of the areola and papilla above the general breast contour in a secondary mound. Breast development is incomplete until Tanner stage 5, in which the breast is mature in contour and proportion. In most women, the nipple is more pigmented at this stage than earlier in development, and Montgomery’s glands are visible around the circumference of the areola. The nipple is generally below the midplane of breast tissue when the woman is seated and viewed from the side. Full breast development usually occurs over 3 to 3.5 years, but it may occur in as little as 2 years or not progress beyond stage 4 until the first pregnancy. Breast size is no indication of breast maturity.
Figure 29.3 Diagrammatic depiction of Tanner breast stages in adolescent women. (From Ross GT, Van de Wiele RL, Frantz AG. The ovaries and the breasts. In: Williams RH, ed. Textbook of endocrinology. 6th edition. Philadelphia, PA: WB Saunders, 1981:355, with permission; adapted from Marshall WA, Tanner JM. Variations in patterns of pubertal changes in girls. Arch Dis Child 1969;44:291–303).
Pubic hair staging is related both to quantity and distribution (Fig. 29.4). In Tanner stage 1, there is no sexually stimulated pubic hair present, but some nonsexual hair may be present in the genital area. Tanner stage 2 is characterized by the first appearance of coarse, long, crinkly pubic hair along the labia majora. In Tanner stage 3, coarse, curly hair extends onto the mons pubis. Tanner stage 4 is characterized by adult hair in thickness and texture, but the hair is not distributed as widely as in adults and typically does not extend onto the inner aspects of the thighs. Except in certain ethnic groups, including Asians and American Indians, pubic hair extends onto the thighs in Tanner stage 5.
Figure 29.4 Diagrammatic depiction of Tanner pubic hair staging in adolescent women. (From Ross GT, VandeWiele RL, Frantz AG. The ovaries and the breasts. In: Williams RH, ed. Textbook of endocrinology. 6th ed. Philadelphia, PA: WB Saunders, 1981:355, with permission; adapted from Marshall WA, Tanner JM. Variations in patterns of pubertal changes in girls. Arch Dis Child 1969;44:291–303.)
The staging of male pubertal sexual maturation is based on genital size and pubic hair development. Tanner stage 1 is prepubertal. Tanner stage 2 of genital growth begins when testicular enlargement is first evident. Testis length along the longitudinal axis ranges from 2.5 to 3.2 cm. The size of the penis increases. Pigmented, curly pubic hair is first visible around the base of the penis. In Tanner stage 3, there is further growth of the penis in both length and diameter, the scrotum develops further, and testis length increases to 3.3 to 4 cm. Thicker, curly hair extends above the penis. Tanner stage 4 involves further growth of the genitalia, with testis length ranging from 4 to 4.5 cm. Extension of pubic hair over the genital area continues, but the volume is less than in the adult. At this stage, the prostate gland is palpable by rectal examination. In Tanner stage 5, the genitalia are within the adult range in size. Average flaccid penile length in adult men ranges between 8.6 and 10.5 cm from tip to base. Pubic hair spreads laterally onto the medial thighs. Hair may or may not extend from the pubic area toward the umbilicus and anus.
Figure 29.5 Patterns of circulating luteinizing hormone (LH), follicle-stimulating hormone (FSH), and estradiol in a stage 3 pubertal girl over a 24-hour period with the encephalographic stage of sleep indicated. (From Boyar RM, Wu RHK, Roffwarg H, et al.Human puberty: 24-hour estradiol patterns in pubertal girls. J Clin Endocrinol Metab 1976;43:1418–1421, with permission.)
Pigmented pubic hair is often the first recognized sign of male puberty even though it typically occurs 6 months after genital growth begins. Tanner stage 3 puberty often is accompanied by symmetric or asymmetric gynecomastia, and mature sperm first can be identified with microscopic urinalysis.
Height and Growth Rate
Plotting height increments (i.e., growth velocity) against the phases of puberty allows one to see relationships during puberty (Fig. 29.2). Girls reach peak height velocity early in puberty before menarche. As a consequence, they have limited growth potential after menarche. In contrast, boys reach peak height velocity about 2 years later than girls. Boys grow an average of 28 cm during the growth spurt, in comparison to a mean of 25 cm for girls. Adult men eventually are an average of 13 cm taller than adult women because they are taller at the onset of the growth spurt. Hormonal control of the pubertal growth spurt is complex. Growth hormone (GH), insulinlike growth factor 1 (IGF-1), and gonadal steroids play major roles. Adrenal androgens appear to be less important. Mutations limiting conversion of androgens to estrogens in males confirmed that estrogen is the major stimulus to the pubertal growth spurt in both boys and girls (11).
During the growth spurt associated with puberty, the long bones in the body lengthen and the epiphyses ultimately close. The bone or skeletal age of any individual can be estimated closely by comparing x-rays documenting the development of bones in the nondominant hand (most commonly), knee, or elbow to standards of maturation for the normal population. The Greulich and Pyle atlas is used most often for this purpose (12). Skeletal age is more closely correlated with pubertal stage than with chronologic age during puberty. With height and chronologic age, an individual’s bone age can be used to predict final adult height using the Bayley-Pinneau tables (13). Bone age determinations can be used to assess the degree of delay, monitor subsequent development, and estimate final adult height.
Another practical clinical approach to predicting adult height uses midparental height. The adjusted midparental height is calculated by adding 13 cm to the mother’s height (for boys) or subtracting 13 cm from the father’s height (for girls) and then determining the mean of the heights of the parents, including the adjusted height of the opposite-sex parent. Adding and subtracting 8.5 cm to the calculated predicted height approximates the target range of the 3rd to the 97th percentile for the anticipated adult height of the child. This quick calculation can be of assistance in evaluating individuals with delayed or precocious pubertal development and those with short stature.
Several changes in body composition occur during pubertal development. Although lean body mass, skeletal mass, and body fat are equal in prepubertal boys and girls, by maturity, men have 1.5 times the lean body mass and almost 1.5 times the skeletal mass of women, whereas women have twice as much body fat as men (1). The changes in body contour in girls, with accumulation of fat at the thighs, hips, and buttocks, occur during the pubertal growth spurt. In this regard, testosterone is a potent anabolic steroid and is responsible for the major changes in boys, whereas estrogen increases total body fat in a characteristic distribution at the thighs, buttocks, and abdomen in girls.
Other physical changes show sexual dimorphism at puberty. In boys both the membranous and cartilaginous portions of the vocal cords lengthen much more than they do in girls, accounting for deepening of the voice. Comedones, acne, and seborrhea of the scalp begin because of increased secretion of adrenal and gonadal steroids at puberty. In general, early-onset acne correlates with the development of severe acne later in puberty. The appearance of comedones in the nasal creases and behind the pinna may be the first indications of impending pubertal development.
Hormonal Changes
By 10 weeks of gestation, gonadotropin-releasing hormone (GnRH) is present in the hypothalamus, and luteinizing hormone (LH) and follicle-stimulating hormone (FSH) are present in the pituitary gland (14). Gonadotropin levels are elevated in both female and male fetuses before birth; the levels of FSH are higher in females. At birth, gonadotropin and sex steroid concentrations are still high, but the levels decline during the first several weeks of life and remain low during the prepubertal years. The hypothalamic–pituitary unit appears to be suppressed by the extremely low levels of gonadal steroids present in childhood. Gonadal suppression of gonadotropin secretion is demonstrated by higher gonadotropin levels in children with gonadal dysgenesis and those who undergo gonadectomy before puberty (15).
Several of the hormonal changes associated with pubertal development begin before any of the physical changes are obvious. Early in puberty, there is increased sensitivity of LH to GnRH. Sleep-entrained increases in both LH and FSH can be documented early in puberty (16). In boys, the nocturnal increases in gonadotropin levels are accompanied by simultaneous increases in circulating testosterone levels (17). In contrast, in girls, the nighttime increases in circulating gonadotropin levels are followed by increased secretion of estradiol the next day (18) (Fig. 29.5). This delay in estradiol secretion is believed to result from the additional synthetic steps required in the aromatization of estrogens from androgens. Basal levels of both FSH and LH increase through puberty. The patterns differ in boys and girls, with LH levels (measured in mIU/mL) eventually becoming greater than FSH levels (19) (Fig. 29.6). Although it now appears that gonadotropins are always secreted in an episodic or pulsatile fashion, even before puberty, the pulsatile secretion of gonadotropins is more easily documented as puberty progresses and basal levels increase (20).
Increased adrenal androgen secretion is important in stimulating adrenarche, the appearance of pubic and axillary hair, in both boys and girls. Pubarche specifically refers to the appearance of pubic hair. Progressive increases in circulating levels of the major adrenal androgens, dehydroepiandrosterone (DHEA) and its sulfate (DHEAS), begin as early as 2 years of age, accelerate at 7 to 8 years of age, and continue until 13 to 15 years of age (21–23). The accelerated increases in adrenal androgens begin about 2 years before the increases in gonadotropin and gonadal sex steroid secretion when the hypothalamic–pituitary–gonadal unit is still functioning at a low prepubertal level.
In girls, mean levels of estradiol, secreted predominantly by the ovaries, increases steadily during puberty (19). Although, as noted, increases in estradiol first appear during the daytime hours, basal levels eventually increase during both the day and night. Estrone, which is secreted in part by the ovaries and arises in part from extraglandular conversion of estradiol and androstenedione, increases early in puberty but plateaus by midpuberty. Thus, the ratio of estrone to estradiol decreases throughout puberty, indicating that ovarian production of estradiol becomes increasingly important and peripheral conversion of androgens to estrone becomes less important during maturation.
In boys, most of the testosterone in the circulation arises from direct secretion by the Leydig cells of the testis. Testosterone induces development of a male body habitus and voice change, whereas dihydrotestosterone (DHT), produced following 5α reduction within target cells, induces enlargement of the penis and prostate gland, beard growth, and temporal hair recession during puberty. Mean plasma testosterone levels rise progressively during puberty, with the greatest increase occurring during Tanner stage 2 (24).
Growth hormone secretion increases along with increased gonadotropin secretion at the onset of puberty. It is believed that the increase in GH is mediated by estrogen, which in boys is dependent on aromatization of testosterone to estradiol and reflects increasing sex steroid production at puberty. Nonetheless, there are profound sex differences in GH secretion during puberty. Girls have higher basal levels of GH throughout puberty, reaching maximal levels around the time of menarche and decreasing thereafter. In contrast, basal concentrations of GH remain constant throughout puberty in boys. Growth hormone secretion is highly pulsatile, with most pulses occurring during sleep and with sex steroids increasing pulse amplitude rather than altering pulse frequency.
Growth hormone stimulates production of IGF-1 in all tissues, with concentrations found in the circulation spilling over from the liver. During puberty the negative feedback effect of IGF-1 on GH secretion must be reduced because both IGF-1 and GH levels are high. GH and IGF-1 play significant roles in the changes in body composition that occur at puberty because both hormones are potent anabolic agents.
In the final stages of puberty in both boys and girls, GH secretion begins to diminish, returning to prepubertal levels in adult life, despite continued exposure to high levels of gonadal steroids.
Mechanisms Underlying Puberty
The mechanisms responsible for the numerous hormonal changes that occur during puberty are poorly understood, although it is recognized that a “central nervous system program” must be responsible for initiating puberty. It appears that the hypothalamic–pituitary–gonadal axis in girls develops in two distinct stages during puberty. First, sensitivity to the negative or inhibitory effects of the low levels of circulating sex steroids present in childhood decreases early in puberty. Second, late in puberty, there is maturation of the positive or stimulatory feedback response to estrogen, which is responsible for the ovulatory midcycle surge of LH.
Current evidence suggests that the central nervous system inhibits the onset of puberty until the appropriate time (25). Based on this theory, the neuroendocrine control of puberty is mediated by GnRH-secreting neurons in the medial basal hypothalamus, which together act as an endogenous pulse generator. At puberty, the GnRH pulse generator is reactivated (i.e., disinhibited), leading to increased amplitude and frequency of GnRH pulses. In turn, the increased GnRH secretion results in increased gonadotropin and then gonadal steroid secretion. What causes this “disinhibition” of GnRH release is unknown.
Figure 29.6 Increases (± standard error) in circulating levels of gonadotropins and adrenal and gonadal steroids through puberty in girls. DHEA, dehydroepiandrosterone; DHEAS, dehydroepiandrosterone sulfate. (From Emans SJH, Goldstein DP. The physiology of puberty. In: Emans SJH, Goldstein DP, eds. Pediatric and adolescent gynecology. 3rd ed. Boston, MA: Little, Brown, 1990:95, with permission.)
The relationship between body mass and the onset of puberty focused attention on leptin, produced by adipocytes, as a candidate for the factor initiating puberty. In the infertile leptin-deficient mouse, leptin therapy can induce sexual maturation and maintain fertility. Observations of two patients with leptin receptor mutations who failed to enter puberty suggest that leptin may have a similar role in humans (25).
Longitudinal studies of leptin secretion noted that there is increased leptin secretion around the time of pubertal onset. Leptin levels are increased throughout puberty in girls but not in boys. There is speculation that leptin is a trigger for pubertal onset, but a more widely held view is that leptin plays a more permissive role in regulating pubertal onset (25).
Aberrations of Pubertal Development
Classification
Several aberrations of pubertal development, as detailed in Table 29.1, can occur in girls. Pubertal aberrations can be classified in four broad categories:
Table 29.1 Aberrations of Pubertal Development
1. Delayed or interrupted puberty exists in girls who fail to develop any secondary sex characteristics by age 13, have not had menarche by age 15 (95th percentile is 14.5 yr), or have not attained menarche 5 or more years since the onset of pubertal development.
2. Asynchronous pubertal development is characterized by pubertal development that deviates from the normal pattern of puberty.
3. Precocious puberty is defined as pubertal development beginning before the age of 7 years in white girls and before the age of 6 years in African American girls (6). This new definition is controversial and is challenged because some feel that evaluation for breast or pubic hair development before 9 or 8 years of age in white or African American girls, respectively, may be warranted (26). It is clear that, in most cases, development nearer to the mean age of puberty is less likely to have a pathologic basis. Precocious pubertal development is characterized in several ways. In isosexual precocious puberty, the early changes are common to the phenotypic sex of the individual. In heterosexual precocious puberty, the development is characteristic of the opposite sex. Precocious puberty is sometimes termed “true” when it is of central origin with activation of the hypothalamic–pituitary unit. In precocious pseudopuberty, also known as precocious puberty of peripheral origin, secretion of hormones in the periphery (commonly by neoplasms) stimulates pubertal development.
4. Heterosexual puberty is characterized by a pattern of development that is typical of the opposite sex occurring at the expected age of normal puberty.
Disorders of sexual development and amenorrhea may be considered in relation to this classification of the aberrations of puberty. It is very helpful to document the growth of the individual and to plot the individual’s height and weight on one of several commonly available growth charts (Fig. 29.7).
Figure 29.7 Growth chart showing stature by age percentiles for girls aged 2 to 18 years. Weight can be plotted in a similar fashion. Several excellent growth charts are available to clinicians, including those from Ross Laboratories (Columbus, OH), Serono Laboratories (Randolph, MA), and Genentech, Inc. (South San Francisco, CA). (From Hamill PVV, Drizd TA, Johnson CL, et al. Physical growth: National Center for Health Statistics percentiles. Am J Clin Nutr 1979;32:607–629, with permission; based on data from the National Center for Health Statistics.)
Delayed or Interrupted Puberty
The history and physical examination, with particular attention to growth, are most important in the evaluation of individuals with delayed puberty. Pubertal delay is much more common in boys than in girls. It is important to remember that puberty may be delayed in any child suffering from any severe chronic disease, including celiac disease, Crohn disease, sickle cell anemia, and cystic fibrosis. Chronic illness should be reviewed during the history and physical examination. One possible approach to evaluation is depicted in Figure 29.8.
Figure 29.8 Flow diagram for the evaluation of delayed or interrupted pubertal development, including primary amenorrhea, in phenotypic girls. Girls with asynchronous development often present because of failure to menstruate. FSH, follicle-stimulating hormone; PRL, prolactin; T4, thyroxine; TSH, thyroid-stimulating hormone; CNS, central nervous system; MRI, magnetic resonance imaging; CT, computed tomography. (From Rebar RW. Normal and abnormal sexual differentiation and pubertal development. In: Moore TR, Reiter RC, Rebar RW, et al., eds. Gynecology and obstetrics: a longitudinal approach. New York: Churchill Livingstone, 1993:97–133, with permission.)
Figure 29.9 Hysterosalpingograms of normal and abnormal female genital tracts. The radiographic photographs have been reversed to accentuate the uterine cavities. A: Normal study with bilateral spill. B: Bicornuate uterus. C: Uterus didelphis. D: Uterus didelphis with double vagina. (Courtesy of Dr. A. Gerbie; from Spitzer IB, Rebar RW. Counselling for women with medical problems: ovary and reproductive organs. In: Hollingsworth D, Resnik R, eds. Medical counselling before pregnancy. New York: Churchill Livingstone, 1988:213–248, with permission.)
Anatomic Abnormalities of the Genital Outflow Tract
Those girls who have mature secondary sex characteristics and any of a number of disorders of the outflow tract and uterus, often termed müllerian agenesis and dysgenesis, are most often identified on examination(Fig. 29.9). One of the most logical classification schemes that was proposed is shown in Table 29.2 (27). The incidence of these anomalies was estimated to be 0.02% of the female population several, but the incidence may have increased as a result of the maternal ingestion of diethylstilbestrol (DES) and the resultant increase in anomalies of the lumen of the uterus (class VI) (28,29). Of the disorders unrelated to drug use, the septate uterus (class V) is most common.
Table 29.2 Classification of Müllerian Anomalies
Disorders of the outflow tract and uterus often occur as a part of a syndrome of malformations that include abnormalities of the skeletal and renal systems (Mayer-Rokitansky-Küster-Hauser syndrome). Familial aggregates of the most common disorders of müllerian differentiation in girls—müllerian aplasia and incomplete müllerian fusion—are best explained on the basis of polygenic and multifactorial inheritance (30). It is clear that the HOX genes, a family of regulatory genes that encode for transcription factors, are essential for proper development of the müllerian tract in the embryonic period, and HOXA 13 is altered in hand–foot–genital syndrome (31). WNT4 may be involved in uterine development, as a WNT4 mutation was described in cases involving a Mayer-Rokitansky-Küster-Hauser-like syndrome with hyperandrogenism (32).
The most common single anatomic disorder of puberty is the imperforate hymen, which prevents the passage of endometrial tissue and blood. These products can accumulate in the vagina (hydrocolpos) or uterus (hydrometrocolpos) and result in a bulging hymen that is often bluish in color. The affected individual often has a history of vague abdominal pain with approximately monthly exacerbations. It is sometimes difficult to distinguish an imperforate hymen from a transverse vaginal septum, and in most situations, examination under anesthesia is required.
Regardless of the cause, uterine anomalies not involving segmental müllerian agenesis or hypoplasia (class I) are compatible with normal pregnancy. However, increased fetal wastage is reported in the presence of these anomalies (33). Uterine malformations are associated with spontaneous abortion, preterm labor, abnormal presentations, and complications of labor (i.e., retained placenta). Many of these uterine anomalies can be identified with hysterosalpingography (Fig. 29.9). Hysterosalpingography, laparoscopy, and hysteroscopy are used to differentiate a septate uterus (class V) from a bicornuate uterus (class IV). Magnetic resonance imaging (MRI) and endovaginal ultrasonography (sometimes with sonohysterography) are as accurate as these invasive techniques in identifying the abnormality (34).
Obstruction or malformation of the distal genital tract must be distinguished from androgen insensitivity. Individuals with androgen insensitivity have breast development in the absence of significant pubic and axillary hair development; the vagina may be absent or foreshortened in these women.
Hypergonadotropic and Hypogonadotropic Hypogonadism
Basal levels of FSH and prolactin should be determined in individuals in whom secondary sex characteristics have not developed to maturity (Fig. 29.8). Bone age should be estimated from x-rays of the nondominant hand. If prolactin levels are elevated, thyroid function should be assessed to determine whether the individual has primary hypothyroidism. Paradoxically, primary hypothyroidism can result in precocious puberty. If thyroid function is normal, a hypothalamic or pituitary neoplasm is possible, and careful evaluation of the hypothalamic and pituitary area by MRI or computed tomography (CT) is indicated.
The karyotype should be determined in any individual with delayed puberty and increased basal FSH concentrations. Regardless of the karyotype, the individual with hypergonadotropic hypogonadism has some form of ovarian “failure” (i.e., primary hypogonadism).
Forms of Gonadal Failure
Turner Syndrome
The diagnosis of Turner syndrome requires the presence of characteristic features in phenotypic females coupled with complete or partial absence of the second sex chromosome, with or without cell line mosaicism. Most affected individuals have a 45,X karyotype, while others have mosaic karyotypes (i.e., 45,X/46,XX; 45,X/46,XY). Intrauterine growth restriction is common in infants with a 45,X karyotype. After birth, these patients generally grow slowly, beginning in the second or third year of life. They typically have many of the associated stigmata, including lymphedema and sometimes large cystic hygromas of the neck at birth; a webbed neck; multiple pigmented nevi; disorders of the heart, kidneys (most commonly horseshoe), and great vessels (most commonly coarctation of the aorta); and small hyperconvex fingernails (35) (Fig. 29.10). Diabetes mellitus, thyroid disorders, essential hypertension, and other autoimmune disorders are often present in individuals with 45,X karyotypes.
Figure 29.10 Typical appearance of two individuals with 45,X gonadal dysgenesis. A: This 16-year-old individual has obvious short stature, a webbed neck, shortened fourth metatarsals, and a thoracotomy scar from the repair of the coarctation of the aorta that was performed at 13 years of age. B: This 11-year-old individual also has obvious short stature and stigmata of Turner syndrome. Note that these two individuals look more like each other than they might look like any genetic siblings.
Most 45,X patients have normal intelligence, but many affected individuals have an unusual cognitive defect characterized by an inability to appreciate the shapes and relations of objects with respect to one another (i.e., space-form blindness). Patients with a small ring X chromosome have an increased risk of mental retardation (36). As they grow older, affected children typically are shorter than normal. Although they do not develop breasts at puberty, some pubic or axillary hair may develop because appropriate adrenarche can occur with failure of thelarche (i.e., breast development).
Although less severe short stature and some adolescent development may occur with chromosomal mosaicism, it is reasonable to assume that any short, slowly growing, sexually infantile girl has Turner syndrome until proved otherwise because this disorder is so prevalent (about 1 in 2,500 newborn phenotypic females). In fact, the 45,X karyotype is the single most frequent chromosomal disorder in humans, but most affected fetuses are aborted spontaneously early in pregnancy. However, trisomy is the most common chromosomal type or category of abnormality in first-trimester losses.
The short stature commonly associated with the Turner phenotype appears to result from the loss of a homeobox-containing gene (which encodes for an osteogenic gene) located on the pseudoautosomal region (PAR 1) of the short arms of the X (Xp22) and Y (Yp11.3) chromosomes (37). This gene, which is called either SHOX (short stature homeobox-containing gene) or PHOG (pseudoautosomal homeobox osteogenic gene), escapes X inactivation because of its pseudoautosomal location. The gene appears to account for about two-thirds of the height deficit commonly associated with Turner syndrome.
Even in the presence of typical Turner stigmata, a karyotype is indicated to eliminate the possibility of the presence of any portion of a Y chromosome. Analysis of pooled data suggests that the presence of Y chromosome material is associated with a 12% risk of a gonadoblastoma (38). If a Y chromosome is identified, laparoscopic prophylactic gonadectomy is recommended at the time of diagnosis to eliminate the risk of malignancy. Although gonadoblastomas are benign tumors with no metastatic potential that can arise spontaneously in gonads containing a portion of a Y chromosome, they can be precursors to germ cell malignancies, such as dysgerminomas (most commonly), teratomas, embryonal carcinomas, or endodermal sinus tumors (39). In individuals in whom there is no evidence of neoplastic dissemination, the uterus may be left in situ for donor in vitrofertilization and embryo transfer.
Individuals with Turner syndrome are at increased risk of sudden death from aortic rupture or dissection resulting from cystic medial necrosis during pregnancy, and the risk may be as great as 2% or more (40). In addition, this may occur even if the aortic root diameter is normal. Because of their small stature, ascending aortic diameters of less than 5 cm may represent significant dilatation. Thus, the use of the aortic size index (ascending aortic diameters measured by MRI at the level of the right pulmonary artery normalized to body surface area) is preferred (41). Patients with an aortic size index greater than 2.0 cm/m2 require close cardiovascular surveillance and those with an aortic size index of 2.5 cm/m2 or more are at highest risk for aortic dissection. In fact, the risk of acute aortic dissection is increased by more than 100-fold in young and middle-aged women with Turner syndrome. If pregnancy is being considered, preconception assessment must include cardiologic evaluation with MRI of the aorta.
The evaluation of other commonly involved organ systems should include a careful physical examination, with special attention to the cardiovascular system, and thyroid function tests (including antibody assessment), fasting blood glucose, renal function tests, and intravenous pyelography or a renal ultrasonography.
Treatment of Turner Syndrome
To increase final adult height, commonly accepted treatment strategies include use of exogenous GH (42–44). With recombinant human GH use, the average height gain varied from 4 to 16 cm. It appears that early initiation of therapy (between 2–8 years of age), gradually increasing the dose, and continuing treatment for a mean of 7 years can lead to achievement of a final height greater than 150 cm in most patients (43). Weekly doses of GH of 0.375 mg/kg divided into seven daily doses are typical. Therapy may be continued until a satisfactory height is attained or until little growth potential remains (bone age ≥14 years and growth velocity <2 cm per year). It is not clear if a nonaromatizable anabolic steroid such as oxandrolone will provide additional growth. In girls older than 8 years of age or those with extreme short stature, consideration can be given to using higher doses of GH and adding oxandrolone (45). The dose of oxandrolone should be 0.05 mg/kg per day or less, as higher doses will result in virilization and more rapid skeletal maturation. In addition, liver enzymes should be monitored.
The gonadal steroid treatment of patients with Turner syndrome is as follows:
1. To promote sexual maturation, therapy with exogenous estrogen should be initiated when the patient is psychologically ready, at about 12 to 13 years of age, and after GH therapy was administered for several years. Low-dose estrogen can be introduced at this time without compromising final adult height (46).
2. Because the intent is to mimic normal pubertal development, therapy with low-dose estrogen alone (such as 0.025 mg per day transdermal estradiol or 0.3–0.625 mg conjugated estrogens orally each day) should be initiated.
3. Progestins (5–10 mg medroxyprogesterone acetate or 200 mg micronized progesterone orally for 12 to 14 days every 1 to 2 months) can be added to prevent endometrial hyperplasia after the patient first experiences vaginal bleeding or after 6 to 12 months of unopposed estrogen use if the patient has not yet had any bleeding.
4. The dose of estrogen is increased slowly over 1 to 2 years until the patient is taking about twice as much estrogen as the amount administered to postmenopausal women.
5. Girls with gonadal dysgenesis must be monitored carefully for the development of hypertension with estrogen therapy.
6. The patients and their parents should be counseled regarding the emotional and physical changes that will occur with therapy.
7. It is important to educate the patient that hormone replacement therapy is usually required until the time of normal menopause to maintain feminization and prevent osteoporosis (47).
Mosaic Forms of Gonadal Dysgenesis
Individuals with rare mosaic forms of gonadal dysgenesis may develop normally at puberty. The decision to initiate therapy with exogenous estrogen should be based mainly on circulating FSH levels. Levels in the normal range for the patient’s age imply the presence of functional gonads.
These individuals can become pregnant, with success rates of more than 50% using donor oocytes (48). The increased risk of sudden death during pregnancy resulting from aortic rupture should be assumed to be similar to that of other women with the Turner phenotype (40).
Pure Gonadal Dysgenesis
The term pure gonadal dysgenesis refers to 46,XX or 46,XY phenotypic females who have streak gonads. This condition may occur sporadically or may be inherited as an autosomal recessive trait or as an X-linked trait in XY gonadal dysgenesis (Fig. 29.11). Affected girls typically are of average height and have none of the stigmata of Turner syndrome, but they have elevated levels of FSH because the streak gonads produce neither steroid hormones nor inhibin. When gonadal dysgenesis occurs in 46,XY individuals, it is sometimes termed Swyer syndrome. Surgical extirpation is warranted in individuals with a 46,XY karyotype to prevent development of germ cell neoplasms. Both 46,XX and 46,XY forms of gonadal dysgenesis benefit from exogenous estrogen and are potential candidates for donor oocytes.
Figure 29.11 A: A 16-year-old individual with 46,XX gonadal dysgenesis and primary amenorrhea. Circulating follicle-stimulating hormone (FSH) levels were markedly elevated. The small amount of breast development (Tanner stage 2) is unusual, but some pubertal development may occur in such patients. B: A 16-year-old individual with 46,XY gonadal dysgenesis who presented with primary amenorrhea and markedly elevated FSH levels. Most affected individuals do not present with as much pubic and axillary hair development. The right gonad contained a dysgerminoma, but there was no evidence of metastases. (From Rebar RW. Normal and abnormal sexual differentiation and pubertal development. In: Moore TR, Reiter RC, Rebar RW, et al., eds. Gynecology and obstetrics: a longitudinal approach.New York: Churchill Livingstone, 1993:97–133, with permission.) C: Clitoromegaly noted in the girl with 46,XY gonadal dysgenesis depicted in Figure 29.11B. D: The same individual as depicted in Figure 29.11B and D with 46,XY gonadal dysgenesis 1 year after gonadectomy and replacement with exogenous estrogen.
In early gonadal failure, the ovaries apparently develop normally but contain no oocytes by the expected age of puberty. These disorders are considered further in the discussion delineating the evaluation of amenorrhea (see Chapter 30).
Hypogonadotropic Hypogonadism
Hypothalamic–pituitary disturbances are usually associated with low levels of circulating gonadotropins (with both LH and FSH levels less than or equal to 10 mIU/mL) (49). There are both sporadic and familial causes of hypogonadotropic hypogonadism, and the differential diagnosis is extensive. Mutations in several genes cause hypogonadotropic hypogonadism in humans (50). This condition can arise from abnormalities in hypothalamic GnRH secretion, impaired release of gonadotropins from the pituitary gland, or both.
At least 17 different single-gene mutations are identified as being associated with delayed or absent puberty in humans (51). They are estimated to account for about 30% of individuals with disorders of puberty. These genes include KAL1 (X-linked Kallmann syndrome), FGFR1 (autosomal Kallmann syndrome), DAX1 (the gene for X-linked congenital adrenal hypoplasia), GNRHR (the gene for the GnRH receptor), PC1 (the gene for prohormone convertase 1), and GPR54 (encoding a G-protein coupled receptor). Delayed puberty may result from mutations in genes affecting gonadotrophs specifically (GnRHR, LHβ, FSHβ) or in genes involved more generally in the development and functioning of the pituitary gland (LHX3, PROP1, HESX1).
Constitutional Delay
It is important to remember that low levels of LH and FSH are normally present in the prepubertal years; thus, girls with constitutionally delayed puberty may mistakenly be presumed to have hypogonadotropic hypogonadism. Constitutional delay is the most common cause of delayed puberty. In a normal population, 2% to 3% of normal children will be classified as having pubertal delay, and this finding may be considered a normal variant. Constitutional delayed growth and adolescence can be diagnosed only after careful evaluation excludes other causes of delayed puberty and normal sexual development is documented by longitudinal follow-up. The farther below the third percentile for height that the young girl is, the less likely it is that the cause is constitutional. Because some children are severely handicapped socially by constitutional pubertal delay, some physicians occasionally provide exogenous estrogen in low doses for 3 to 4 months to stimulate some pubertal development. However, the benefits of treatment are not well documented, and there is little evidence to support the idea that treatment improves psychosocial function.
Kallmann Syndrome
As originally described in 1944, Kallmann syndrome consisted of the triad of anosmia, hypogonadism, and color blindness in men (52). Women may be affected, and other associated defects may include cleft lip and palate, cerebellar ataxia, nerve deafness, and abnormalities of thirst and vasopressin release. The frequency approximates 1 in 10,000 men and 1 in 50,000 women. Sporadic cases are more common than inherited forms. Inheritance is described as being X-linked recessive, autosomal dominant, and autosomal recessive. Because autopsy studies show partial or complete agenesis of the olfactory bulb, the term olfactogenital dysplasia is used to describe the disorder. These anatomic findings coincide with embryologic studies documenting that GnRH neurons originally develop in the epithelium of the olfactory placode and normally migrate into the hypothalamus (53). In some affected individuals, gene defects were found in one protein, anosmin-1, that facilitates this neuronal migration, thus leading to an absence of GnRH neurons in the hypothalamus and olfactory bulbs and consequent hypogonadotropic hypogonadism and anosmia (Kallmann syndrome) (54). The gene defect resulting in loss of this adhesion protein is localized to the Xp22.3 locus in an X-linked form of the syndrome, and this locus is designated KAL1. Other features of X-linked Kallmann syndrome include unilateral renal agenesis, bimanual synkinesia, and sensorineural hearing loss. In some cases of autosomal dominant Kallmann syndrome, inactivating mutations of the gene encoding the fibroblast growth factor receptor-1 (FGFR1 or KAL2) were reported. The disorder is so heterogeneous that it appears likely that it forms a structural continuum with other midline defects. Septo-optic dysplasia represents the most severe form of the disorder.
Clinically, affected individuals typically present with sexual infantilism and an eunuchoid habitus, but some degree of breast development may occur (Fig. 29.12). Primary amenorrhea is the rule. The ovaries are usually small, with follicles seldom developing beyond the primordial stage. Circulating gonadotropin levels are usually very low but almost invariably measurable. Affected individuals respond readily to pulsatile administration of exogenous GnRH, and this is the most physiologic approach to ovulation induction (48). For women not seeking pregnancy, therapy with exogenous estrogen and progestin is indicated.
Isolated gonadotropin deficiency can occur in association with the Prader-Labhart-Willi syndrome, which is characterized by obesity, short stature, hypogonadism, small hands and feet (acromicria), mental retardation, and infantile hypotonia. When the syndrome occurs in association with the Laurence-Moon-Bardet-Biedl syndrome, retinitis pigmentosa, postaxial polydactyly, obesity, and hypogonadism may be present. Prader-Labhart-Willi syndrome apparently results from rearrangements of chromosome 15q11 to q13, an imprinted region of the human genome (55). Laurence-Moon-Bardet-Biedl syndrome, inherited in an autosomal recessive manner, is apparently heterogeneous, with at least four involved gene loci having been mapped to date (56).
Multiple pituitary hormone deficiencies, which are usually hypothalamic in origin, may be congenital and either part of an inherited constellation of findings or sporadic. If GH or thyroid-stimulating hormone (TSH) concentrations are subnormal, growth and pubertal development will be affected. Thus, the condition should be diagnosed before the age of puberty. Because individuals with hypopituitarism have a high mortality rate, predominantly caused by vascular and respiratory disease, it is important to identify affected individuals. Later age at diagnosis, female sex, and above all craniopharyngioma are identified as significant independent risk factors (57). Untreated gonadotropin deficiency is an important risk factor for early mortality.
Tumors of the Hypothalamus and Pituitary
Several different tumors of the hypothalamic and pituitary regions may lead to hypogonadotropic hypogonadism (58) (Fig. 29.13A). Except for craniopharyngiomas, these tumors are relatively uncommon in children. A craniopharyngioma is a tumor of the Rathke’s pouch. It is the most common neoplasm associated with delayed puberty, and it accounts for 10% of all childhood central nervous system tumors. Craniopharyngiomas are usually suprasellar in location and may be asymptomatic well into the second decade of life. Such tumors may present as headache, visual disturbances, short stature or growth failure, delayed puberty, or diabetes insipidus. Visual field defects (including bilateral temporal hemianopsia), optic atrophy, or papilledema may be seen on physical examination. Laboratory evaluation should document hypogonadotropism and may reveal hyperprolactinemia as a result of interruption of hypothalamic dopamine inhibition of prolactin release. Radiographically, the tumor may be either cystic or solid and may show areas of calcification. Appropriate therapy for hypothalamic–pituitary tumors may involve surgical excision or radiotherapy (with adequate pituitary hormone replacement therapy) and are best managed by a team of physicians that includes an endocrinologist, a neurosurgeon, and a radiotherapist.
Figure 29.12 Left A 21.½-year-old woman with Kallmann syndrome. Note that the patient has some pubic and axillary hair. Bone age was 16 years. It is rare to see affected individuals today who were not given oral contraceptive agents to induce menses (with some consequent breast development). (From Wilkins L. The diagnosis and treatment of endocrine disorders in childhood and adolescence. 3rd ed. Springfield, IL: Charles C Thomas, 1965, with permission.)
Figure 29.13 Right A: A 16-year-old girl with delayed puberty. Breast budding began at 11 years of age, but there was no further development. During the year before presentation, her scholastic performance in school deteriorated, she gained 25 lb, she became increasingly lethargic, and nocturia and polydypsia were noted. Initial evaluation documented low follicle-stimulating hormone, elevated prolactin, and a bone age of 10.5 years. Computed tomography scanning documented a large hypothalamic neoplasm that proved to be an ectopic germinoma. The patient was also documented to be hypothyroid and hypoadrenal and to have diabetes insipidus. Despite the elevated prolactin, she had no galactorrhea because of the minimal breast development. (From Rebar RW. Normal and abnormal sexual differentiation and pubertal development. In: Moore TR, Reiter RC, Rebar RW, et al., eds. Gynecology and obstetrics: a longitudinal approach. New York: Churchill Livingstone, 1993:97–133, with permission.) B: A 16-year-old girl (frontal view) with primary amenorrhea who progressed in puberty until about 12 years of age. Breast budding occurred at about 10 years of age. The patient’s short stature is obvious. She proved to have hypopituitarism. Classic radiographic findings established the diagnosis of Langerhans cell–type histiocytosis (Hand-Schüller-Christian disease). C: Side view of girl shown in Figure 29.13B.
Other Central Nervous System Disorders
Other central nervous system disorders that may lead to delayed puberty include infiltrative diseases, such as Langerhans cell-type histiocytosis, particularly the form known previously as Hand-Schüller-Christian disease (Fig. 29.13B and 29.13C). Diabetes insipidus is the most common endocrinopathy (because of infiltration of the supraoptic nucleus in the hypothalamus), but short stature resulting from GH deficiency and delayed puberty caused by gonadotropin deficiency are not uncommon in this disorder (59).
Irradiation of the central nervous system for treatment of any neoplasm or leukemia may result in hypothalamic dysfunction. Although GH deficiency is the most frequent finding, partial or complete gonadotropin deficiency may develop in some patients.
Severe chronic illnesses, often accompanied by malnutrition, may lead to slowed growth in childhood and delayed adolescence. Regardless of the cause, weight loss to less than 80% to 85% of ideal body weight often results in hypothalamic GnRH deficiency. If adequate body weight and nutrition are maintained in chronic illnesses such as Crohn disease or chronic pulmonary or renal disease, sufficient gonadotropin secretion usually is present to initiate and maintain pubertal development.
Figure 29.14 A: A 20-year-old college woman with anorexia nervosa. B: A 16-year-old student with anorexia nervosa. In both cases, as is true of most such patients, pubertal development had been completed and menses initiated before anorexia led to marked weight loss.
Anorexia Nervosa and Bulimia
Significant weight loss and psychological dysfunction occur simultaneously with anorexia nervosa (60,61). Although many anorectic girls experience amenorrhea after pubertal development begins, if the disorder begins sufficiently early, pubertal development may be delayed or interrupted (Fig. 29.14). The following constellation of associated findings confirms anorexia nervosa in most individuals:
1. Relentless pursuit of thinness
2. Amenorrhea, sometimes preceding the weight loss
3. Extreme inanition
4. Obsessive-compulsive personality often characterized by overachievement
5. Distorted and bizarre attitude toward eating, food, or weight
6. Distorted body image
Because normal body weight is commonly maintained in bulimia, it is unusual for bulimic patients to experience either delayed development or amenorrhea. Girls with anorexia nervosa may have, in addition to hypogonadotropic hypogonadism, partial diabetes insipidus, abnormal temperature regulation, hypotension, chemical hypothyroidism with low serum triiodothyronine (T3) and high reverse T3 levels, and elevated circulating cortisol levels in the absence of evidence of hypercortisolism (62). Other common features include hypokalemia, anemia, hypoalbuminemia, high β-carotene levels, and high cholesterol levels. All features of anorexia nervosa are reversible with weight gain, except for amenorrhea (which persists in 30% to 47%) and osteopenia (i.e., it now seems that any bone lost cannot be fully recovered). Management of patients with anorexia nervosa is notoriously difficult. A team approach involving the primary clinician, psychiatrist, and nutritionist is most effective. In fact, anorexia nervosa has the highest mortality of any psychiatric disorder. Deaths are often sudden and unexpected. Cause of death (often unknown) can include hypoglycemia and electrolyte imbalance.
Fear of obesity, a syndrome of self-induced malnutrition common among teenage gymnasts and ballet dancers, may slow growth and delay pubertal development (63). These children voluntarily reduce their caloric intake as much as 40%, leading to nutritional growth retardation. An additive role for endurance training in the delayed development is possible, but the mechanisms are unclear at this point. These conditions are essentially severe forms of hypothalamic amenorrhea. Inevitably delayed puberty will occur unless adequate caloric intake is provided.
Hyperprolactinemia
Low levels of LH and FSH may be associated with hyperprolactinemia. As noted, galactorrhea cannot occur in the absence of complete breast development. Pituitary prolactinomas are rare during adolescence but must be considered when certain signs and symptoms are present. Many individuals with prolactinomas have a history of delayed menarche. The association between the ingestion of certain drugs (most often psychotropic agents and opiates in this age group) is well established. Primary hypothyroidism is associated with hyperprolactinemia because increased levels of thyrotropin-releasing hormone (TRH) stimulate secretion of prolactin. The empty sella syndrome, in which the sella turcica is enlarged but is replaced by cerebrospinal fluid, may be associated with hyperprolactinemia.
Use of Chemotherapeutic Agents
As survival rates following treatment for childhood malignancy improve, the effects of cancer therapy become more important. Both radiation therapy to the abdomen and systemic chemotherapeutic agents, particularly alkylating agents, have toxic effects on germ cells. Although prepubertal gonads appear less vulnerable than those of adults, ovarian failure is common. An argument can be made for endocrine assessment as early as 1 year following completion of therapy to identify children who will suffer from hypogonadism. Spontaneous ovarian activity can resume even years after therapy.
Asynchronous Puberty
Asynchronous pubertal development is characteristic of androgen insensitivity (i.e., testicular feminization). Affected individuals typically present with breast development (usually only to Tanner stage 3) out of proportion with the amount of pubic and axillary hair present (Fig. 29.15). In this disorder, 46,XY individuals have bilateral testes, female external genitalia, a blindly ending vagina (often foreshortened and sometimes absent), and no müllerian derivatives (i.e., uterus and fallopian tubes) (64). Infrequently, patients may have clitoral enlargement and labioscrotal fusion at puberty, which is referred to as incomplete androgen insensitivity.
Asynchronous puberty is heterogeneous but is always related to some abnormality of the androgen receptor or of androgen action (65). In perhaps 60% to 70% of cases, androgen receptors cannot be detected (i.e., the patient is receptor negative). In the remaining cases, androgen receptors are present (i.e., receptor positive), but mutations in the androgen receptor are detected or there is a defect at a more distal step in androgen action (i.e., a postreceptor defect). Receptor-positive individuals are indistinguishable clinically from receptor-negative individuals. Several different mutations in the androgen receptor gene, most of which occur within the androgen-binding domain of the receptor, are identified in affected individuals who are receptor positive. Severe X-linked androgen receptor gene mutations cause complete androgen insensitivity, whereas mild mutations impair virilization with or without infertility, and moderate mutations result in a wide phenotypic spectrum of expression among siblings (66).
Because the Sertoli cells of the testes make antimüllerian hormone (AMH), müllerian derivatives are absent in this disorder; thus, müllerian regression occurs normally. The testes are often normal in size and may be located anywhere along the path of embryonic testicular descent—in the abdomen, inguinal canal, or labia. Half of all individuals with androgen insensitivity develop inguinal hernias. Recognizing that most such girls will be 46,XX, it is important to determine the karyotype in prepubertal girls with inguinal hernias, especially if a uterus cannot be detected with certainty by ultrasound.
The risk of germ cell malignancy is 2% in complete androgen insensitivity syndrome (67). Most clinicians believe the risk for gonadal neoplasia is low before 25 years of age; thus, the testes should be left in place until after pubertal feminization, especially because the risk of neoplasia appears to increase with age. Exogenous estrogen should be provided after gonadectomy.
The diagnosis is often suspected by the typical physical findings and strongly suggested by normal (or even somewhat elevated) male levels of testosterone, normal or somewhat elevated levels of LH, and normal levels of FSH. The diagnosis is confirmed by a 46,XY karyotype.
Interacting with the patient and family requires sensitivity and care. It may be inadvisable to begin by informing the patient of the karyotype; the psychological implications may be devastating because the patient was reared as a girl. Family members should be informed initially that müllerian aplasia occurred and that the risk for neoplasia mandates gonadectomy after puberty. Because the disorder can be inherited in an X-linked recessive fashion, families should undergo appropriate genetic counseling and screening to identify the possible existence of other affected family members.
Figure 29.15 A: This 17-year-old individual presented with primary amenorrhea and was found to have a blind-ending vagina and bilateral inguinal masses. Circulating levels of testosterone were at the upper limits of the normal range for men and the karyotype was 46,XY, confirming androgen insensitivity. B: Two inguinal testes were found at surgery. (From Simpson JL, Rebar RW. Normal and abnormal sexual differentiation and development. In: Becker KL, ed. Principles and practice of endocrinology and metabolism. 2nd ed. Philadelphia, PA: JB Lippincott, 1995:788–822, with permission.)
Precocious Puberty
Although precocious pubertal development may be classified in several ways, it is perhaps simplest to think of the development as gonadotropin dependent (in which case it is almost invariably of central origin) or gonadotropin independent (of peripheral origin). Precocious puberty is 20 times more common in girls than in boys. In fully 90% of girls, the precocious development is idiopathic, whereas this appears to be true for only 10% of boys. Family history, the rapidity with which secondary sexual characteristics are developing, the rate of growth, and the presence or absence of central nervous system disease should all be considered in deciding whether to pursue evaluation of a girl for precocious puberty. The evaluation of precocious puberty is as follows:
1. Measurement of basal gonadotropin levels is the first step in the evaluation of a child with sexual precocity (Fig. 29.16).
Figure 29.16 Flow diagram for the evaluation of precocious puberty in phenotypic females. LH, luteinizing hormone; FSH, follicle-stimulating hormone; TSH, thyroid-stimulating hormone; T4, thyroxine; T, testosterone; DHEAS, dehydroepiandrosterone sulfate; 17OHP, 17-hydroxyprogesterone; CNS, central nervous system. (From Rebar RW. Normal and abnormal sexual differentiation and pubertal development. In: Moore TR, Reiter RC, Rebar RW, et al., eds. Gynecology and obstetrics: a longitudinal approach. New York: Churchill Livingstone, 1993:97–133, with permission.)
2. Thyroid function should be evaluated to rule out primary hypothyroidism as the cause of precocious development.
3. High levels of LH (which really may be human chorionic gonadotropin detected because of cross-reactivity with LH in immunoassays) suggest a gonadotropin-producing neoplasm, most often a pinealoma (ectopic germinoma) or choriocarcinoma or, less often, a hepatoblastoma. (Gonadotropin-producing neoplasms are the only causes of precocious puberty in which the gonadotropin dependence does not equate with central precocious puberty.)
4. Low or pubertal levels of gonadotropins indicate the need to determine circulating estradiol concentrations in girls with isosexual development and to assess androgen levels, specifically testosterone, DHEAS, and 17α-hydroxyprogesterone in girls with heterosexual development.
5. Increased estradiol levels suggest an estrogen-secreting neoplasm, probably of ovarian origin.
6. Increased testosterone levels suggest an androgen-producing neoplasm of the ovary or the adrenal gland. Such neoplasms may be palpable on abdominal or rectal examination. Increased 17α-hydroxyprogesterone levels are diagnostic of 21-hydroxylase deficiency (i.e., congenital adrenal hyperplasia [CAH]). Levels of DHEAS are elevated in various forms of CAH.
7. If the estradiol levels are compatible with the degree of pubertal development observed, evaluation of the central nervous system by MRI or CT scanning is warranted.
8. Bone age should always be assessed in evaluating an individual with sexual precocity.
9. A GnRH stimulation test can be used to confirm central precocious puberty. After 100 μ g GnRH, an LH peak of greater than 15 mIU/mL is suggestive of gonadotropin-dependent precocious puberty (68).
Perhaps the most difficult decision for the gynecologist is determining how much evaluation is warranted for the young girl brought in by her mother for precocious breast budding only (precocious thelarche) or the appearance of pubic or axillary hair alone (precocious pubarche or adrenarche) (Fig. 29.17). In such cases, it is acceptable to many clinicians to follow the patient at frequent intervals and to proceed with evaluation if there is evidence of pubertal progression. The feasibility of this approach may depend on the concerns of the parents.
Figure 29.17 Five-year-old girl with development of pubic hair (A) as shown more closely in (B) (precocious adrenarche). Gonadotropin levels were prepubertal, and bone age was appropriate for age. No further development occurred until breast budding at approximately age 9.
Premature Thelarche
Premature thelarche is unilateral or bilateral breast enlargement without other signs of sexual maturation. There is no significant nipple or areola development. It usually occurs by 2 years of age and rarely after age 4. It may be caused by increased sensitivity of the breasts to low levels of estrogen or to increased estradiol secretion by follicular cysts. It is a benign self-limited disorder and thus only reassurance and follow-up are required. In most cases, onset of puberty, adult height, and adult reproductive function are normal (69). Rarely, premature thelarche can be a harbinger of progressive gonadarche. It is suggested that measurement of uterine volume (anteroposterior diameter × longitudinal diameter × transverse diameter × 0.523) may be the most sensitive and specific discriminator between premature thelarche and early true precocious puberty (70). If needed, breast ultrasound can help distinguish unilateral premature thelarche from fibroadenomas, cysts, neurofibromas, or other lesions.
Premature Adrenarche
Premature adrenarche or pubarche may be caused by increased sensitivity to low levels of androgens and must be distinguished from late-onset (nonclassic) CAH. If there is no evidence of breast development or of progression, these conditions are virtually always benign.
Girls with premature adrenarche are at increased risk of developing polycystic ovary syndrome (PCOS), hyperinsulinemia, acanthosis nigricans, and dyslipidemia in adolescence and adult life, especially if fetal growth was reduced and birth weight was low (71). Although mean androgen levels are within the normal range, a significant minority have an exaggerated response to corticotropin stimulation. The magnitude of this response is inversely related to insulin sensitivity. Thus, premature adrenarche may be the first sign of insulin resistance or PCOS in some individuals. Treatment of coexisting obesity and long-term follow-up are indicated to address potential complications of PCOS and insulin resistance.
Isolated Premature Menarche
Isolated premature menarche is vaginal bleeding at age 1 to 9 years in the absence of other signs of puberty. The bleeding is usually limited to a few days. It can recur for 1 to 6 years and then cease. The etiology is uncertain. Most cases are associated with subsequent normal pubertal development and fertility. The differential diagnosis includes vaginal foreign bodies, trauma, sexual abuse, vaginal infection, or neoplasms such as rhabdomyosarcoma, McCune-Albright syndrome (in which menarche may occur before other manifestations of sexual precocity), and primary hypothyroidism.
Figure 29.18 Left: A 7½ -year-old girl with Tanner stage 4 pubertal development who began menstruating 1 month earlier. She was 57 inches tall (above the 95th percentile). Luteinizing hormone and follicle-stimulating hormone levels were consistent with her development. A large neoplasm that proved to be a hypothalamic hamartoma was present on computed tomography scan. Pubertal development began at about 5 years of age. Right: A: A 10½ -year-old girl with 21-hydroxylase deficiency before treatment. 17-Ketosteroid (KS) excretion was 34 mg per day. B: The same patient after 9 months of therapy with cortisone (17-KS excretion: 4.6 mg per day). (From Wilkins L. The diagnosis and treatment of endocrine disorders in childhood and adolescence. 3rd ed. Springfield, IL: Charles C Thomas, 1965:439, with permission.)
Central (True) Precocious Puberty
In central precocious puberty, GnRH prematurely stimulates increased gonadotropin secretion. Central precocious puberty may occur in children in whom there is no structural abnormality, in which case it is termed constitutional or idiopathic. Constitutional (idiopathic) sexual precocity is the most common cause of precocious puberty. It is often familial and represents the so-called tail of the Gaussian curve (i.e., the early 2.5% for the age distribution for the onset of puberty). In many of these girls, puberty is slowly progressive, but in a few, development progresses rapidly. The major complication of sexual precocity is limitation of height. Thus, therapy may be warranted to prevent this consequence.
Alternatively, central precocious puberty may result from a tumor, infection, congenital abnormality, or traumatic injury affecting the hypothalamus. A number of congenital malformations, including hydrocephalus, craniostenosis, arachnoid cysts, and septo-optic dysplasia, can be associated with precocious puberty (and with sexual infantilism).
A common etiology (2% to 28%) of central precocious puberty is a hypothalamic hamartoma. It is a congenital malformation composed of a heterotopic mass of nerve tissue containing GnRH neurosecretory neurons, fiber bundles, and glial cells. It is not a true neoplasm and it generally does not change over time based on long-term follow-up studies with periodic CT or MRI scans. Hamartomas appear as isodense, abnormal fullnesses that do not enhance with contrast material. Extreme precocity (usually before 3 years of age) and the absence of tumor markers, such as β-human chorionic gonadotropin and α-fetoprotein, suggest a hamartoma (72). Hamartomas can be associated with laughing (gelastic) seizures, behavioral disturbances, mental retardation, and dysmorphic syndromes. It appears that hamartomas produce GnRH in a pulsatile manner and thus stimulate gonadotropin secretion (Fig. 29.18) (73). Precocious pubertal development can be controlled with GnRH-agonist therapy (74). Because deaths were reported after neurosurgical extirpation, the latter should be reserved for management of hamartomas associated with intractable seizures or hydrocephalus (75).
The efficacy of gonadotropin-releasing hormone analogues (GnRHa) in increasing adult height is undisputed only in early-onset (girls less than 6 years old) central precocious puberty (76). Concerns of weight gain and long-term decrease in bone mineral density with the use of GnRHa do not seem to be warranted. The most important clinical criterion for initiating GnRHa treatment is documented progression of pubertal development over a 3- to 6-month period. This observational period may not be necessary if the child is at or past Tanner stage 3, particularly with advanced skeletal maturation. It appears that discontinuation of GnRHa at a chronological age of about 11 years and a bone age of about 12 years is associated with maximum adult height (77–79). There are a variety of GnRHa formulations, and the choice of a particular agent depends on patient and physician preference.
Precocious Puberty of Peripheral Origin
In gonadotropin-independent precocious puberty, production of estrogens or androgens from the ovaries, adrenals, or rare steroid-secreting neoplasms leads to early pubertal development. Small functional ovarian cysts, typically asymptomatic, are common in children and may cause transient sexual precocity (80). Simple cysts (with a benign ultrasonographic appearance) can be observed and usually resolve over time. Of the various ovarian neoplasms that can secrete estrogens, granulosa-theca cell tumors occur most frequently but are still rare (81). Although such tumors may grow rapidly, more than two-thirds are benign.
Exposure to exogenous estrogens can mimic gonadotropin-independent precocious puberty. Ingestion of oral contraceptives, other estrogen-containing pharmaceutical agents, and estrogen-contaminated foods, and the topical use of estrogens, are implicated in cases of precocious development in infants and children. Ingestion of exogenous steroids over a considerable length of time is required to induce changes typical of complete precocious development.
McCune-Albright Syndrome
The McCune-Albright syndrome is characterized by the classic triad of polyostotic fibrous dysplasia of bone, irregular café-au-lait spots on the skin, and GnRH-independent sexual precocity. The café-au-lait spots are usually large, do not cross the midline, and have irregular “coast of Maine” margins. They are often located on the same side as the bony lesions. Sexual precocity often begins in the first 2 years and usually presents with menstrual bleeding. Girls develop sexual precocity as a result of functioning ovarian cysts. Serum estradiol is elevated. Other endocrinopathies may include hyperthyroidism, hypercortisolism, hyperprolactinemia, acromegaly, and hyperparathyroidism. Osteomalacia, hepatic abnormalities, and cardiac arrhythmia may occur. Mutations of the Gsα subunit of the G protein, which couples extracellular hormonal signals to the activation of adenylate cyclase, are responsible for the autonomous hyperfunction of the endocrine glands and, presumably, for the other defects present in this disorder (82). Treatment with a GnRH agonist is not effective because the precocious pubertal development is GnRH independent. Treatment with aromatase inhibitors, such as testolactone and fadrozole, has mixed results. A multicenter trial showed that tamoxifen decreases vaginal bleeding, growth rate, and the rate of bone age advancement (83).
Primary Hypothyroidism
Longstanding primary hypothyroidism is associated with sexual precocity. It can present with premature breast development or isolated vaginal bleeding. If serum prolactin is elevated, galactorrhea may be present. On pelvic ultrasound, solitary or multiple ovarian cysts may be found. Primary hypothyroidism is the only cause of precocious puberty that is associated with a delayed bone age. These features return to normal within a few months of initiation of levothyroxine therapy.
Congenital Adrenal Hyperplasia
Heterosexual precocious puberty is always of peripheral origin and is most often caused by CAH. In most untreated or poorly treated adolescent girls and in some adolescent boys, spontaneous true isosexual pubertal development does not occur until proper treatment is instituted. In most patients treated satisfactorily from early life, the onset of puberty occurs at the expected chronological age. Three adrenal enzyme defects—21-hydroxylase deficiency, 11β-hydroxylase deficiency, and 3β-hydroxysteroid dehydrogenase deficiency—can lead to heterosexual precocity and to virilization of the external genitalia because of increased androgen production beginning in utero(84). The clinical presentation of the various forms of CAH depends on the following factors: (i) the affected enzyme, (ii) the extent of residual enzymatic activity, and (iii) the physiologic consequences of deficiencies in the end products and excesses of precursor steroids.
21-Hydroxylase Deficiency
Most patients with classic CAH have 21-hydroxylase deficiency (Fig. 29.19). All forms of 21-hydroxylase deficiency are caused by homozygous or compound heterozygous mutations in the human CYP21A2 gene, which encodes the 21-hydroxylase enzyme; in the carrier, heterozygote state, only one allele is mutated (85). Two CYP21A2 genes, a 3′ CYP21A2B gene encoding the functional enzyme and a pseudogene termed CYP21A2A, are situated very close to each other within the major histocompatibility locus on the short arm of chromosome 6. At least one-fourth of cases of 21-hydroxylase deficiency result from unequal crossover and genetic recombination between the two genes during meiosis. Severe mutations do not correlate with severe phenotype, and phenotypic variability likely depends on the activity of other interacting genes.
Neonatal screening suggests an incidence of about 1 in 15,000 births. Because of the location of the gene within the major histocompatibility locus, siblings with 21-hydroxylase deficiency usually have identical human leukocyte antigen (HLA) types. There are various forms of 21-hydroxylase deficiency, including simple virilizing (typically identified at birth because of genital ambiguity), salt-wasting (in which there is impairment of mineralocorticoid and glucocorticoid secretion), and late-onset or nonclassic (in which heterosexual development occurs at the expected age of puberty). The so-called classic form includes the simple virilizing and salt-wasting forms. The nonclassic form is discussed in the following section on heterosexual pubertal development.
Deficiency of 21-hydroxylase results in the impairment of the conversion of 17α-hydroxyprogesterone to 11-deoxycortisol and of progesterone to deoxycorticosterone (Fig. 29.20). As a consequence, precursors accumulate, and there is increased conversion to adrenal androgens. Because the development of the external genitalia is controlled by androgens, in the classic form of this disorder, girls are born with ambiguous genitalia, including an enlarged clitoris and fusion of the labioscrotal folds and the urogenital sinus. The internal female organs (including the uterus, fallopian tubes, and ovaries) develop normally because they are not affected by the increased androgen levels. In three-quarters of cases with classic 21-hydroxylase deficiency, salt-wasting occurs, as defined by hyponatremia, hyperkalemia, and hypotension. It is important to recognize that the extent of virilization may be the same in simple virilizing and salt-wasting CAH. Thus, even a mildly virilized newborn with 21-hydroxylase deficiency should be observed for signs of a potentially life-threatening crisis within the first weeks of life. During childhood, untreated girls with the classic form grow rapidly but have advanced bone ages, enter puberty early, experience early closure of their epiphyses, and ultimately are short in stature as adults. CAH, with appropriate therapy, is the only inherited disorder of sexual differentiation in which normal pregnancy and childbearing are possible. The classic forms of 21-hydroxylase deficiency are easily diagnosed based on the presence of genital ambiguity and markedly elevated levels of 17α-hydroxyprogesterone. Some states in the US initiated neonatal screening programs to detect 21-hydroxylase deficiency at birth.
3β-Hydroxysteroid Dehydrogenase
Deficiency of 3β-hydroxysteroid dehydrogenase (3β-HSD), caused by mutations in the HSD3B2 gene that encodes the 3β-HSDII enzyme, affects the synthesis of glucocorticoids, mineralocorticoids, and sex steroids. Typically, levels of 17-hydroxypregnenolone and DHEA are elevated (Fig. 29.20). The classic form of the disorder, detectable at birth, is quite rare, and affected girls may be masculinized only slightly. In severe cases, salt wasting may be present.
A nonclassic form of this disorder may be associated with heterosexual precocious pubertal development (as is the classic form if untreated), but postpubertal hyperandrogenism occurs more often.The androgen excess in individuals with nonclassic 3β-HSD deficiency appears to result from androgens derived from the peripheral conversion of increased serum concentrations of DHEA. This disorder is inherited in autosomal recessive fashion, with allelism at the 3β-HSD gene on chromosome 1 believed to be responsible for the varying degrees of enzyme deficiency.
11-Hydroxylase Deficiency
The classic form of 11-hydroxylase deficiency is believed to constitute 5% to 8% of all cases of CAH. Deficiency in 11-hydroxylase, caused by mutations in the CYP11B1 gene, results in the inability to convert 11-deoxycortisol to cortisol and the consequent accumulation of androgen precursors (Fig. 29.20). Markedly elevated levels of 11-deoxycortisol and deoxycorticosterone are present in the disorder. Because deoxycorticosterone acts as a mineralocorticoid, many individuals with this disorder become hypertensive. A mild
Figure 29.20 Gonadal and adrenal steroid pathways and the enzymes required for steroid conversion. DOC, deoxycorticosterone; 17α-OH Preg, 17α-hydroxypregnenolone; 17α-OH Prog, 17α-hydroxyprogesterone; DHEA, dehydroepiandrosterone sulfate. (From Rebar RW, Kenigsberg D, Hodgen GD. The normal menstrual cycle and the control of ovulation. In: Becker KL, ed. Principles and practice of endocrinology and metabolism. 2nd ed. Philadelphia, A: JB Lippincott, 1995:868–880, with permission.)
nonclassic form of 11-hydroxylase deficiency was reported but apparently is very uncommon (84).
Treatment of Congenital Adrenal Hyperplasia
The treatment of CAH involves providing replacement doses of the deficient steroid hormones. Hydrocortisone (10 to 20 mg/m2 body surface area) or its equivalent is given daily in divided doses to suppress the elevated levels of pituitary corticotropin present and thus suppress the elevated androgen levels. With such treatment, signs of androgen excess should regress. In children, growth velocity, bone age, and hormone levels should be monitored carefully because both overreplacement and underreplacement can result in premature closure of the epiphyses and short stature. Data now indicate that early diagnosis and compliance with therapy lead to adult height within 1 standard deviation of the anticipated target height in girls with 21-hydroxylase deficiency (86).
Mineralocorticoid replacement is generally required in individuals with 21-hydroxylase deficiency whether or not they are salt losing. The intent of glucocorticoid therapy should be to suppress morning 17α-hydroxyprogesterone levels to between 300 and 900 ng/dL. Sufficient fludrocortisone should be given daily to suppress plasma renin activity to less than 5 mg/mL per hour.
It is possible to diagnose 21-hydroxylase deficiency prenatally in patients known to be at risk (84). The diagnosis is established by documenting elevated levels of 17α-hydroxyprogesterone or 21-deoxycortisol in amniotic fluid. Genetic diagnosis using specific probes and cells obtained by chorionic villus sampling or amniocentesis is possible. Dexamethasone (20 μg/kg/day in three divided doses) can be administered to the pregnant women beginning before the ninth week of gestation because the urogenital sinus begins to form at nine weeks of gestation. If the fetus is determined to be a male or an unaffected female upon DNA analysis, treatment is discontinued. Otherwise, treatment is continued to term. Human studies found that this treatment regimen is effective in reducing virilization in the genetic female so that genitoplasty was not needed in the majority of cases (87,88). The majority of studies proved that this management scheme is effective for both mother and the child. Maternal complications, including hypertension, massive weight gain, and overt Cushing syndrome, were noted in about 1% of pregnancies in which the mothers are given low doses of dexamethasone. All maternal complications disappear after delivery. The long-term effects of this treatment strategy on the physical and neurodevelopmental health of the offspring remains unclear. A recent systematic review concluded that dexamethasone seems to reduce virilization without significant adverse maternal or fetal effects, though the available data allow merely weak inferences to be made (89). Despite the risks and the nonuniformity of beneficial outcome to affected female fetuses, many parents may choose prenatal medical treatment because of the psychological impact of ambiguous genitalia.
Girls with ambiguous genitalia may require reconstructive surgery, including clitoral recession and vaginoplasty. Timing of such surgery is debated, but the girl must be of appropriate size to ensure the surgery is as simple as possible.
Heterosexual Pubertal Development
The most common cause of heterosexual development at the expected age of puberty is PCOS (Fig. 29.21). Because the syndrome is heterogeneous and poorly defined, clinical difficulties result in diagnosis and management (90). For the sake of simplicity, PCOS may be defined as LH-dependent hyperandrogenism (91). The Rotterdam criteria are commonly used to identify individuals with PCOS and require the presence of at least two of the following: oligo- or anovulation, clinical and/or biochemical signs of hyperandrogenism, and polycystic ovaries, with exclusion of other etiologies (CAH, androgen-secreting tumors, Cushing syndrome) (92). Polycystic ovaries ultrasonically are defined as the presence of 12 or more follicles in each ovary measuring 2 to 9 mm in diameter and/or increased ovarian volume (>10 mL). Most clinical manifestations arise as a consequence of the hyperandrogenism and often include hirsutism beginning at or near puberty and irregular menses from the age of menarche because of oligo-ovulation or anovulation. Clinical manifestations are as follows:
Figure 29.21 Typical facial hirsutism in three women with polycystic ovarian syndrome. A: 25-year-old. B: 21-year-old C: 17-year-old.
1. Affected girls may be but are not necessarily somewhat overweight.
2. In rare instances, menarche may be delayed, and primary amenorrhea may occur.
3. Basal levels of LH tend to be elevated in most affected individuals, and androgen production is invariably increased, even though circulating levels of androgens may be near the upper limits of the normal range in many affected women.
4. In anovulatory women, estrone levels are typically greater than estradiol levels.
5. Because circulating levels of estrogens are not diminished in PCOS and androgen levels are only mildly elevated, affected girls become both feminized and masculinized at puberty. This is an important feature because girls with classic forms of CAH who do not experience precocious puberty (and even those who do) only become masculinized at puberty (i.e., they do not develop breasts).
6. Some degree of insulin resistance may be present, even in the absence of overt glucose intolerance (93).
7. Polycystic ovaries are frequently, but not always present in ultrasound examination.
Differential Diagnosis and Evaluation
Distinguishing PCOS from the nonclassic forms of CAH is problematic and controversial (94,95). The evaluation is as follows:
1. Some clinicians advocate measurement of 17α-hydroxyprogesterone in all women who develop hirsutism. Although values of 17α-hydroxyprogesterone are commonly elevated more than 100-fold in individuals with classic 21-hydroxylase deficiency, they may or may not be elevated in nonclassic late-onset forms of the disorder.
2. Measurement of 17α-hydroxyprogesterone can identify women with various forms of 11-hydroxylase deficiency.
3. Basal levels of DHEAS and 17α-hydroxyprogesterone may be moderately elevated in patients with PCOS, making the diagnosis even more difficult.
4. To screen for CAH, 17α-hydroxyprogesterone should be measured in early morning.
5. In women with regular cyclic menses, it is important to measure 17α-hydroxyprogesterone only in the follicular phase because basal levels increase at midcycle and in the luteal phase.
Measurements of 17α-hydroxyprogesterone appear to be of value in populations at high risk for nonclassic late-onset 21-hydroxylase deficiency. In the white population, the gene occurs in only about 1 in 1,000 individuals, but it occurs in 1 in 27 Ashkenazi Jews, 1 in 40 Hispanics, 1 in 50 Yugoslavs, and 1 in 300 Italians (84). The incidence is increased among Eskimos and French Canadians. Alternatively, screening might be restricted to hirsute teenagers presenting with the more “typical” features of nonclassic 21-hydroxylase deficiency, including severe hirsutism beginning at puberty, “flattening” of the breasts (i.e., defeminization), shorter stature than other family members, and increased DHEAS levels (between 5,000 and 7,000 ng/mL). Women with a strong family history of hirsutism or hypertension might be screened (49) (Fig. 29.22).
Figure 29.22 Left: A 19-year-old girl with secondary amenorrhea and severe acne and hirsutism beginning at the normal age of puberty. Stimulatory testing with corticotropin documented nonclassic 21-hydroxylase deficiency. Flattening of the breasts is apparent. She was shorter than her one sister and her mother. Right: Newborn girl with 46,XX karyotype and genital ambiguity. There is obvious clitoral hypertrophy, paired frenula, so-called scrotalization of the labia, and a common urogenital sinus (shown by the probe). She had 21-hydroxylase deficiency. (From Rebar RW. Normal and abnormal sexual differentiation and pubertal development. In: Moore TR, Reiter RC, Rebar RW, et al., eds. Gynecology and obstetrics: a longitudinal approach. New York: Churchill Livingstone, 1993:97–133, with permission.)
Basal Levels of 17α-Hydroxyprogesterone
Basal levels of 17α-hydroxyprogesterone higher than 800 ng/dL are virtually diagnostic of CAH. Levels between 300 and 800 ng/dL require stimulatory testing with corticotropin to distinguish between PCOS and CAH. To complicate the situation even further, nonclassic 21-hydroxylase deficiency may occur even when basal levels of 17α-hydroxyprogesterone are below 300 ng/dL, thus requiring stimulatory testing in those cases.
Cosyntropin Stimulation Test
The most commonly used stimulatory test involves measurement of 17α-hydroxyprogesterone 30 minutes after administration of a bolus of 0.25 mg of synthetic cosyntropin (Cortrosyn) (96). In normal women, this value seldom exceeds 400 ng/dL. Patients with classic 21-hydroxylase deficiency achieve peak levels of 3,000 ng/dL or higher. Patients with nonclassic 21-hydroxylase deficiency commonly achieve levels of 1,500 ng/dL or more. Heterozygous carriers achieve peak levels up to about 1,000 ng/dL. In hirsute women with hypertension, 11-deoxycortisol levels can be determined during the test. If both 11-deoxycortisol and 17α-hydroxyprogesterone levels are increased, the rare 11-hydroxylase deficiency is present. Only measurements of several steroid precursors after corticotropin stimulation can identify individuals with nonclassic forms of 3β-HSD deficiency.
The elevated levels of 17α-hydroxyprogesterone present in all forms of 21-hydroxylase deficiency are rapidly suppressed by administration of exogenous corticoids. Even a single dose of a glucocorticoid such as dexamethasone will suppress 17α-hydroxyprogesterone in CAH but not in virilizing ovarian and adrenal neoplasms.
Hirsutism
It is suggested that androgen-receptor blockade may be preferable to glucocorticoids as primary treatment of nonclassic 21-hydroxylase deficiency (97). Although menses usually (but not always) become regular shortly after beginning therapy with glucocorticoids, the hirsutism in this disorder is remarkably refractory to glucocorticoids.
Distinguishing nonclassic forms of CAH from idiopathic hirsutism may be problematic. Individuals with idiopathic hirsutism have regular ovulatory menses, thus effectively eliminating PCOS from consideration. Confusion can be created by the fact that some women with nonclassic CAH may continue to ovulate. Basal levels of 17α-hydroxyprogesterone are normal in idiopathic hirsutism, as is the response to adrenocorticotropic hormone stimulation. Idiopathic hirsutism represents enhanced androgen action at the hair follicle (98).
Mixed Gonadal Dysgenesis
The term mixed gonadal dysgenesis is used to designate those individuals with asymmetric gonadal development, with a germ cell tumor or a testis on one side and an undifferentiated streak, rudimentary gonad, or no gonad on the other side. Most individuals with this rare disorder have a mosaic karyotype of 45,X/46,XY and are raised as girls who experience virilization at puberty. Gonadectomy is indicated to remove the source of androgens and eliminate any risk for neoplasia.
Rare Forms of Male Pseudohermaphroditism
Individuals who have rare forms of male pseudohermaphroditism, especially 5α-reductase deficiency (the so-called penis at 12 syndrome) and the Reifenstein syndrome, generally have ambiguous female genitalia with variable virilization at puberty. Cushing syndrome may occur rarely during the pubertal years, as may adrenal or ovarian androgen-secreting neoplasms.
Genital Ambiguity at Birth
Ambiguous external genitalia in a newborn constitutes a major diagnostic challenge. Prompt evaluation is of critical importance to identify a possible life-threatening disorder and to assign the appropriate gender. The prime diagnosis until ruled out is CAH because it is the only condition that is life-threatening. Extreme sensitivity is required in interacting with the family, and no attempt should be made to guess the sex of the baby. The incidence of genital ambiguity is 1 in 4,500, although some degree of male undervirilization, or female virilization may be present in as many as 2% of live births (99,100).
Physical Signs
During the 3 to 4 days required for evaluation, it is important to be supportive of the parents. Many clinicians believe that it is important not to attach any unusual significance to the genital ambiguity and to treat the abnormality as just another “birth defect.” Physicians should emphasize that the child should undergo normal psychosexual development regardless of the sex-of-rearing selected. Either a name compatible with either sex should be chosen or the naming of the infant should be delayed until the studies are completed.
Although the diagnosis is not usually obvious on examination, there are some helpful distinguishing features (Fig. 29.23). In normal boys, there is only a single midline frenulum on the ventral side of the phallus; in normal girls, there are two frenula lateral to the midline. A girl with clitoral enlargement still has two frenula, and a boy with hypospadias has a single midline frenulum or several irregular fibrous bands (chordee). It is important to determine whether any müllerian derivatives are present. Studies suggest that MRI may be the most effective way of evaluating the infant for the presence of müllerian tissue (101).
The location or consistency of the gonad may be helpful in deducing its composition. A gonad located in the labial or inguinal regions almost always contains testicular tissue. A testis is generally softer than an ovary or a streak gonad and is more apt to be surrounded by blood vessels imparting a reddish cast. An ovary is more often white, fibrous, and convoluted. A gonad that varies in consistency may be an ovotestis or a testis or a streak gonad that underwent neoplastic transformation. If a well-differentiated fallopian tube is absent on only one side, the side without the tube probably contains a testis or ovotestis.
Diagnosis and Management
The fact that there is uncertainty about the sex of one’s baby is devastating and incomprehensible for most parents. Parents require reassurance that either a male or female gender will be assigned ultimately. Optimum clinical management should comprise of the following (67):
1. Gender assignment must be avoided before expert evaluation of newborns.
2. Evaluation and long-term management must be performed at a center with an experienced multidisciplinary team (pediatric endocrinologist, pediatric urologist, geneticist, clinical psychologist, and gynecologist).
3. All individuals should receive a gender assignment after appropriate assessment.
4. Open communication with patients and families is essential, and participation in decision making should be encouraged.
5. Patient and family concerns should be respected and addressed in strict confidence.
First-line testing in newborns includes:
1. Karyotyping with X- and Y-specific probe detection (even when prenatal karyotype is available)
2. Measurement of serum 17-hydroprogesterone, testosterone, gonadotropins, antimüllerian hormone, and electrolytes
3. Abdominopelvic ultrasound (to assess anatomy of the vagina, uterus, or urogenital sinus, exclude renal anomalies, and locate any inguinal gonads)
4. Urinalysis (to check for protein as a screen for any associated renal anomaly)
The results of these investigations are generally available within 48 hours and sufficient to develop a working diagnosis. If needed, additional testing may include (102):
1. Human chorionic gonadotropin- and adrenocorticotropin-stimulation tests to assess testicular and adrenal steroid biosynthesis
2. Urinary steroid analysis by gas chromatography mass spectroscopy
3. Imaging studies
4. Biopsies of gonadal material
5. Genetic testing
Although genital ambiguity is usually identified at birth, it may not be recognized for several years. Questions about changing the sex-of-rearing may arise. It was believed that sex-of-rearing may be changed before 2 years of age without psychologically damaging the child, but experience with individuals with 5α-reductase deficiency suggests that gender changes may be made after 2 years of age in certain instances (103). In any case, surgery for genital ambiguity to make the external genitalia (and development) as compatible with the sex-of-rearing of the child is warranted but was not always successful. Clitoral recession and clitorectomy are the most frequently performed surgical procedures.
Masculinized external genitalia can be classified into five “Prader” stages. Excessive androgen exposure results in virilization to varying degrees, including clitoral enlargement, labial fold fusion, and rostral migration of the urethral/vaginal perineal orifice. Prader stage V defines virilization resulting in complete labioscrotal fusion, a penile phallus with the urethra opening on the glans. Clitoroplasty is required at an early stage after it is established that a Prader stage V “male” has CAH and needs to be reassigned to the female sex (104).
Teratogens
It is important to recognize that ambiguous genitalia can result from the maternal ingestion of various teratogens, most of which are synthetic steroids (Table 29.3). Exposure to the teratogen must occur early in pregnancy, during genital organogenesis. Not all exposed fetuses manifest the same anomalies or even the presence of any anomalies. In principle, most synthetic steroids with androgenic properties, including weakly androgenic progestins, can affect female genital differentiation. The doses required to produce genital ambiguity are generally so great that the concern is only theoretical. The one agent that can lead to genital ambiguity when ingested in clinically used quantities is danazol. There is no evidence that inadvertent ingestion of oral contraceptives, which contain relatively low doses of either mestranol or ethinyl estradiol and a 19-nor-steroid, results in virilization (105,106).
Table 29.3 Androgens and Progestogens Potentially Capable of Producing Genital Ambiguitya
|
Proved |
No Effect |
Insufficient Data |
|
Testosterone enanthate |
Progesterone |
Ethynodiol diacetate |
|
Testosterone propionate |
17α-Hydroxyprogesterone |
Dimethisterone |
|
Methylandrostenediol |
Medroxyprogesterone |
Norgestrel |
|
6α-Methyltestosterone |
Norethynodrel |
Desogestrel |
|
Ethisterone |
Gestodene |
|
|
Norethindrone |
Norgestimate |
|
|
Danazol |
||
|
aThose agents proved to cause genital ambiguity do so only when administered in relatively high doses. Insufficient data exist regarding effects of dimethisterone and norgestrel. In low doses (e.g., as in oral contraceptives), progestins, even including norethindrone, seem unlikely to virilize a female fetus. |
||
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