Basic and Clinical Endocrinology 7th International student edition Edition
Dennis Styne MD
Puberty is best considered as one stage in the continuing process of growth and development that begins during gestation and continues until the end of reproductive life. After an interval of childhood quiescence—the juvenile pause—the hypothalamic pulse generator increases activity in the peripubertal period, just before the physical changes of puberty commence. This leads to increased secretion of pituitary gonadotropins and, subsequently, gonadal sex steroids that bring about secondary sexual development, the pubertal growth spurt, and fertility. Historical records show that the age at onset of particular stages of puberty in boys and girls in Western countries has steadily declined over the last several hundred years; this is probably due to improvements in socioeconomic conditions, nutrition, and, therefore, the general state of health during that period. However, this trend ceased during the last 5 decades in developed societies, suggesting the attainment of optimal conditions to allow puberty to begin at a genetically determined age.
Many endogenous and exogenous factors can alter age at onset of puberty. Moderate obesity may be associated with an earlier onset, while severe obesity may delay puberty. Indeed, there is evidence that the age at onset of puberty might once again be decreasing, apparently due to the increasing prevalence of obesity in young children. Chronic illness and malnutrition often delay puberty. There is a significant concordance of age at menarche between mother-daughter pairs and within ethnic populations, indicating the influence of genetic factors.
PHYSIOLOGY OF PUBERTY
Physical Changes Associated With Puberty
Descriptive standards proposed by Tanner for assessing pubertal development in males and females are in wide use. They focus attention on specific details of the examination and make it possible to objectively record subtle progression of secondary sexual development that may otherwise be overlooked. Self-assessment of pubertal development by subjects using reference pictures has been attempted, but reliability is poor. Thus, physical examination is necessary to reliably determine if puberty has begun or is proceeding.
- FEMALE CHANGES
The first sign of puberty in the female, as noted in longitudinal studies, is an increase in growth velocity that heralds the beginning of the pubertal growth spurt; girls are not usually examined frequently enough to
demonstrate this change in clinical practice, so breast development is the first sign of puberty noted by most examiners. Breast development (Figure 15-1) is stimulated chiefly by ovarian estrogen secretion, though other hormones also play a part. The size and shape of the breasts may be determined by genetic and nutritional factors, but the characteristics of the stages in Figure 15-1 are similar in all females. Standards are available for the change in areolar (nipple) plateau diameter during puberty: Nipple diameter changes little from stages B1 to B3 (mean of 3–4 mm) but enlarges substantially in subsequent stages (mean of 7.4 mm at stage B4 to 10 mm at stage B5), presumably as a result of increased estrogen secretion at the time of menarche. Other features reflecting estrogen action include enlargement of the labia minora and majora, dulling of the vaginal mucosa from its prepubertal reddish hue (due to cornification of the vaginal epithelium), and production of a clear or slightly whitish vaginal secretion prior to menarche. Pubic hair development (Figure 15-2) is determined chiefly by adrenal and ovarian androgen secretion. Breast development and growth of pubic hair usually proceed at similar rates, but because discrepancies in rates of advancement are possible, it is best to stage breast development separately from pubic hair progression.
Figure 15-1. Stages of breast development, according to Marshall and Tanner. (Photographs from van Wieringen JC et al, 1971; with permission.) Stage B1: Preadolescent; elevation of papilla only. Stage B2: Breast bud stage; elevation of breast and papilla as a small mound, and enlargement of areolar diameter. Stage B3: Further enlargement of breast and areola, with no separation of their contours.Stage B4: Projection of areola and papilla to form a secondary mound above the level of the breast (not shown). Stage B5: Mature stage; projection of papilla only, owing to recession of the areola to the general contour of the breast.
Uterine size and shape change with pubertal development as reflected by ultrasonographic studies; with prolonged estrogen stimulation, the fundus:cervix ratio increases, leading to a bulbous form, and the uterus elongates from less than 3 cm to 5 cm or more. Ovaries enlarge with puberty from a volume of less than 1 mL to 2–10 mL. Small cysts are normally present in prepubertal girls and a “multicystic” appearance develops with puberty, but on pathologic examination there is not the polycystic appearance seen in abnormalities of puberty or during reproduction. Ultrasonographers can determine the developmental stage of the uterus and ovaries by comparing the results with established standards.
- MALE CHANGES
The first sign of normal puberty in boys is usually an increase in the size of the testes to over 2.5 cm in the longest diameter, excluding the epididymis: this is equivalent to a testicular volume of 4 mL or more.
Most of the increase in testicular size is due to seminiferous tubular development secondary to stimulation by FSH, with a smaller component due to Leydig cell stimulation by LH Thus, if only Leydig cells are stimulated, as in an hCG-secreting tumor, the testis does not grow as large as in normal puberty. Pubic hair development is caused by adrenal and testicular androgen secretion and is classified separately from genital development, as noted in Figure 15-3. A longitudinal study of over 500 boys suggests adding a stage 2a to the classic five stages of pubertal development. Stage 2a indicates the absence of pubic hair in the presence of a testicular volume of 3 mL or more. Further pubertal development occurred in 82% of the subjects in stage 2a after the passage of 6 months: thus, reaching stage 2a would allow the examiner to reassure a patient that further spontaneous development is likely soon. The appearance of spermatozoa in early morning urinary specimens (spermarche) occurs at a mean chronologic age of 13.4 years or a similar bone age; this usually occurs at gonadal stage 3–4 and pubic hair stage 2–4. If puberty starts at an earlier or later chronologic age, the age of spermarche changes accordingly with reference to chronologic age although spermarche occurs in such patients at the same range of gonadal or pubic hair stages. Remarkably, spermaturia is more common earlier in puberty than later, suggesting that sperm are directly released into the urine early in puberty while ejaculation may be responsible for the presence of sperm in the urines of older children.
Figure 15-2. Stages of female pubic hair development, according to Marshall and Tanner. (Photographs from van Wieringen JC et al, 1971; with permission.) Stage P1: Preadolescent; the vellus over the area is no further developed than that over the anterior abdominal wall, ie, no pubic hair. Stage P2: Sparse growth of long, slightly pigmented, downy hair, straight or only slightly curled, appearing chiefly along the labia. This stage is difficult to see on photographs and is subtle. Stage P3: Hair is considerably darker, coarser, and curlier. The hair spreads sparsely over the superior junction of the labia majora. Stage P4: Hair is now adult in type, but the area covered by it is still considerably smaller than in most adults. There is no spread to the medial surface of the thighs. Stage P5: Hair is adult in quantity and type, distributed as an inverse triangle of the classic feminine pattern. Spread is to the medial surface of the thighs but not up the linea alba or elsewhere above the base of the inverse triangle.
Boys are reported with spermaturia and no secondary sexual development.
Thus, boys are reproductively mature prior to physical maturity and certainly prior to psychologic maturity.
Figure 15-3. Stages of male genital development and pubic hair development, according to Marshall and Tanner. (Photographs fromvan Wieringen JC et al, 1971; with permission.) Genital: Stage G1: Preadolescent. Testes, scrotum, and penis are about the same size and proportion as in early childhood. Stage G2: The scrotum and testes have enlarged, and there is a change in the texture and some reddening of the scrotal skin. There is no enlargement of the penis. Stage G3: Growth of the penis has occurred, at first mainly in length but with some increase in breadth; further growth of testes and scrotum. Stage G4: Penis further enlarged in length and girth with development of glans. Testes and scrotum further enlarged. The scrotal skin has further darkened. Stage G5: Genitalia adult in size and shape. No further enlargement takes place after stage G5 is reached. Pubic hair: Stage P1: Preadolescent. The vellus is no further developed than that over the abdominal wall, ie, no pubic hair. Stage P2: Sparse growth of long, slightly pigmented, downy hair, straight or only slightly curled, appearing chiefly at the base of the penis. This is subtle. Stage P3: Hair is considerably darker, coarser, and curlier and spreads sparsely. Stage P4: Hair is now adult in type, but the area it covers is still considerably smaller than in most adults. There is no spread to the medial surface of the thighs. Stage P5: Hair is adult in quantity and type, distributed as an inverse triangle. Spread is to the medial surface of the thighs but not up the linea alba or elsewhere above the base of the inverse triangle. Most men will have further spread of pubic hair.
- AGE AT ONSET
Ideally, the upper and lower boundaries encompassing the age at onset of puberty should be set at 2.5 SD above and below the mean. Previously, there was no comprehensive study of the start of secondary sexual development adequate to determine the lower limits of normal in United States children, so European standards, primarily those of Tanner, were modified for the USA. However, a study conducted in medical offices by specially trained pediatricians studying 17,070 girls brought in for routine visits has helped establish norms for United States girls. The study revealed that 3% of white girls reach stage 2 breast development by 6 years of age and 5% by 7 years, while 6.4% of black girls had stage 2 breast development by 6 years and 15.4% by 7
years. While this was not a randomly chosen population sampled by longitudinal study, it is the largest study available. These data indicate that the diagnosis of precocious puberty is best defined as secondary sexual development starting prior to 6 years in black girls and prior to 7 years in white girls who are otherwise healthy. It is essential to use such guidelines only in healthy girls with absolutely no signs of neurologic or other disease that might pathologically advance puberty. However, recent data indicate that boys with elevated BMIs have earlier onset of puberty. There has otherwise been no change in the age at onset of puberty in boys, so 9 years is taken as the lower limit of normal pubertal development in males. The mean age at menarche in the United States is 12.8 years and has not varied since the last government study was published in 1974. White girls have menarche later (12.9 years) than black girls (12.3 years), but this 6-month difference is less than the 1-year difference in the age at onset of puberty between the two groups.
Late onset of pubertal development may indicate hypothalamic, pituitary, or gonadal failure. The time from onset of puberty to complete adult development is also of importance; delays in reaching subsequent stages may indicate any type of hypogonadism.
- GROWTH SPURT
The striking increase in growth velocity in puberty (pubertal growth spurt) is under complex endocrine control. Hypothyroidism decreases or eliminates the pubertal growth spurt. The amplitude of growth hormone secretion increases in puberty, as does production of IGF-I; peak serum IGF-I concentrations are reached about 1 year after peak growth velocity, and serum IGF-I levels remain above normal adult levels for up to 4 years thereafter. GH and sex steroids are important in the pubertal growth spurt; when either or both are deficient, the growth spurt is decreased or absent. Sex steroids indirectly stimulate IGF-I production by increasing the secretion of GH and also directly stimulate IGF-I production in cartilage. Estrogen has recently been shown to be the most important factor in stimulating maturation of the chondrocytes and osteoblasts, ultimately leading to epiphysial fusion. A patient reported with estrogen receptor deficiency was tall, with continued growth past the age of 20 years in spite of a remarkable retardation of skeletal maturation (and decreased bone density). Patients with aromatase deficiency and therefore impaired conversion of testosterone to estrogen also demonstrate diminished advancement of bone age and decreased bone density as well as continued growth extending into the third decade. With exogenous estrogen administration, the bone age advanced and a growth spurt occurred. One affected 46,XX individual had virilized genitalia at birth and further virilization at a pubertal age with the additional feature of multicystic ovaries. The patient, in spite of high serum testosterone concentrations, had elevated FSH and LH in the absence of estrogen production. These patients demonstrate the key role played by estrogen in advancing bone age and bringing about the cessation of growth by epiphysial fusion as well as the importance of estrogen in increasing bone density.
It is essential to realize that a pubertal growth spurt occurring in a young patient with precocious puberty may increase the growth rate sufficiently to mask the presence of coexisting GH deficiency. This situation may occur, for example, in a child with a brain tumor causing precocious puberty treated with radiation that subsequently decreases GH secretion.
In girls, the pubertal growth spurt begins in early puberty and is mostly completed by menarche. In boys, the pubertal growth spurt occurs toward the end of puberty, at an average age 2 years older than in girls. Total height attained during the growth spurt in girls is about 25 cm; in boys, it is about 28 cm. The mean adult height differential of 12 cm between men and women is due in part to heights already attained before onset of the pubertal growth spurt and in part to the height gained during the spurt.
- CHANGES IN BODY COMPOSITION
Changes in body composition are also prominent during pubertal development. Prepubertal boys and girls start with equal lean body mass, skeletal mass, and body fat, but at maturity men have approximately 1˝ times the lean body mass, skeletal mass, and muscle mass of women, while women have twice as much body fat as men. Attainment of peak values of percentage of body fat, lean body mass, and bone mineral density is earlier by several years in girls than in boys, as is the earlier peak of height velocity and velocity of weight gain in girls.
The most important phases of bone accretion occur during infancy and during puberty. Girls reach peak mineralization between 14 and 16 years of age, while boys reach a later peak at 17.5 years; both milestones occur after peak height velocity (Figure 15-4). The density of bone is determined by genes as decreased bone mass is found in familial patterns even if subjects are studied before puberty. Patients with delay in puberty for any reason will have a significant decrease in bone accretion. Moderate exercise will increase bone mass, but excessive exercise will itself delay puberty; the ultimate outcome of excessive exercise is the combination of exercise-induced amenorrhea, premature osteoporosis, and disordered eating known as the female athletic triad.
Figure 15-4. Sequence of secondary sexual development in British males (A) and females (B). The range of ages in Britain is indicated. American boys and girls start pubertal stages earlier than British children (see text). (Reproduced, with permission, from Marshall WA, Tanner JM: Variations in the pattern of pubertal changes in boys. Arch Dis Child 1970;45:13.)
Unfortunately in the United States, only a minority of adolescents receive the recommended daily allowance of calcium, and a future epidemic of osteopenia or even osteoporosis in normal subjects who have this deficiency is a possibility. It is especially important to ensure adequate calcium intake in delayed or absent puberty and in patients treated with GnRH agonists.
- OTHER CHANGES OF PUBERTY
Other changes that are characteristic of puberty are mediated either directly or indirectly by the change in sex steroids. Bone density increases during normal pubertal development. Seborrheic dermatitis may appear at this age. The mouth flora changes, and periodontal disease, rare in childhood, may appear at this stage. Insulin resistance intensifies in normal adolescents as well as those with type 1 diabetes mellitus; this may be related to the increased GH levels of puberty.
Endocrine Changes from Fetal Life to Puberty
Pituitary gonadotropin secretion is controlled by the hypothalamus, which releases pulses of gonadotropin-releasing hormone (GnRH) into the pituitary-portal system to reach the anterior pituitary gland. Control of GnRH secretion is exerted by a“hypothalamic pulse generator” in the arcuate nucleus. It is sensitive to feedback control from sex steroids and inhibin, a gonadal protein product that controls the frequency and amplitude of gonadotropin secretion during development in both sexes and during the progression of the menstrual cycle in females (seeChapter 13). Individual GnRH neurons have an intrinsic pulsatility that may be the basis of the pattern of GnRH secretion.
In males, luteinizing hormone (LH) stimulates the Leydig cells to secrete testosterone, while follicle-stimulating hormone (FSH) stimulates the Sertoli cells to produce inhibin. Inhibin feeds back on the hypothalamic-pituitary axis to inhibit FSH. Inhibin is also released in a pulsatile pattern, but concentrations do not change with pubertal progression. In females, FSH stimulates the granulosa cells to produce estrogen and the follicles to secrete inhibin, while LH appears to play a minor role in the endocrine milieu until menarche, when it triggers ovulation and later stimulates the theca cells to secrete androgens (see Chapters 12 and 13).
- FETAL LIFE
The concept of the continuum of development between the fetus and the adult is well illustrated by the changes that occur in the hypothalamic-pituitary-gonadal axis. Gonadotropins are demonstrable in fetal pituitary glands and serum during the first trimester. The pituitary content of gonadotropins rises to a plateau at mid gestation. Serum concentrations of LH and FSH rise to a peak at mid gestation and then gradually decrease until term. During the first half of gestation, hypothalamic GnRH content also increases, and the hypophysial-portal circulation achieves anatomic maturity. These data are compatible with a theory of early unrestrained GnRH secretion stimulating pituitary gonadotropin secretion, followed by the appearance of factors that inhibit GnRH release and decrease gonadotropin secretion after mid gestation. Since the male fetus has measurable serum testosterone concentrations but lower serum gonadotropin concentrations than the female fetus, negative feedback inhibition of gonadotropin secretion by testosterone appears operative after mid gestation.
- CHANGES AT BIRTH
At term, serum gonadotropin concentrations are suppressed, but with postnatal clearance of high circulating estrogen concentrations, negative inhibition is reduced and postnatal peaks of serum LH and FSH are measurable for several months after birth. Serum testosterone concentrations may be increased to midpubertal levels during the several months after birth in normal males. While episodic peaks of serum gonadotropins may occur until 2 years of age, serum gonadotropin concentrations are low during later years in normal childhood. These peaks of gonadotropins and sex steroids in normal infants complicate the diagnosis of central precocious puberty at these youngest ages since it is difficult to decide whether to attribute the gonadotropin and sex steroid peaks to central precocious puberty or to normal physiology.
- THE JUVENILE PAUSE OR THE MID CHILDHOOD NADIR OF GONADOTROPIN SECRETION
While serum gonadotropin concentrations are low in mid childhood, sensitive assays indicate that pulsatile secretion occurs and that the onset of puberty is heralded more by an increase in amplitude of secretory events than a change in frequency. Twenty-four-hour mean concentrations of LH, FSH, and testosterone rise measurably within 1 year after the development of physical pubertal changes. Patients with gonadal failure—such as those with the syndrome of gonadal dysgenesis (Turner's syndrome)—demonstrate an exaggeration of the normal pattern of gonadotropin secretion, with exceedingly high concentrations of serum LH and FSH during the first several years of life (seeChapter 14). Such patients show that negative feedback inhibition is active during childhood; without sex steroid or inhibin secretion to exert inhibition, serum gonadotropin values are greatly elevated. During mid childhood, normal individuals and patients with primary hypogonadism have lower serum gonadotropin levels than they do in the neonatal period, but the range of serum gonadotropin concentrations in hypogonadal patients during mid childhood is still higher than that found in healthy children of the same age. The decrease in serum gonadotropin concentrations in primary agonadal children during mid childhood is incompletely understood but has been attributed to an increase in the central nervous system inhibition of gonadotropin secretion during these years. Thus, the juvenile pause in normals and those with primary gonadal failure appear to be due to central nervous system restraint of GnRH secretion.
- PERIPUBERTAL GONADOTROPIN INCREASE
Prepubertal children demonstrate a circadian rhythm of LH and FSH secretion with the rhythm of sex steroid secretion lagging behind the gonadotropin rhythm, the delay presumably due to the time necessary for biosynthesis of sex steroids. Thus, the changes that are described below which occur at puberty do not arise de novo but are based upon preexisting patterns of endocrine secretion. In the peripubertal period, endogenous GnRH secretion increases in amplitude and frequency during the early hours of sleep and serum testosterone and estrogen concentrations rise several hours later, suggesting that biosynthesis or aromatization occurs during the period of delay—a pattern that differs from the prepubertal period mainly in the increased amplitude of the secretion encountered in puberty (Figure 15-5). As puberty progresses in both sexes, the peaks of serum LH and FSH occur more often during waking hours; and, finally, in late puberty, the peaks occur at all times, eliminating the diurnal variation.
During the peripubertal period of endocrine change prior to secondary sexual development, gonadotropin secretion becomes less sensitive to negative feedback inhibition. Before this time, a small dose of exogenous sex steroids virtually eliminates gonadotropin secretion,
while afterward a far larger dose is required to suppress serum FSH and LH. In prepuberty or early puberty, naltrexone, an opioid receptor antagonist, can completely suppress gonadotropin secretion as a consequence of its weak opioid effects, while after mid puberty the anti-opioid effects predominate and gonadotropin secretion increases, demonstrating an increase in resistance to opioids with pubertal development.
Figure 15-5. Plasma LH and testosterone measured during a 24-hour period in a 14-year-old boy in pubertal stage 2. Samples collected at night are displayed with electroencephalographic sleep stages, but there is no relationship between LH and the depth of sleep stages. (Reproduced, with permission, from Boyar RM et al: Simultaneous augmented secretion of luteinizing hormone and testosterone during sleep. J Clin Invest 1974; 54:609.)
Most studies of gonadotropin secretion measure gonadotropin concentrations by radioimmunoassay (RIA). However, highly sensitive “sandwich” assays (immunoradiometric assay [IRMA]) and immunochemiluminometric assays (ICMA) have been developed for gonadotropin determination. They can be used to indicate the state of pubertal development based on basal samples without the necessity for GnRH testing. Elevated LH values (> 0.3 IU/L) determined by third-generation assays in random blood samples are highly predictive of elevated peak GnRH-stimulated LH and therefore indicate the onset of central precocious puberty or normal puberty. These third-generation assays further reflect the remarkable logarithmic increase in spontaneous LH secretion in the latest stages of prepuberty and earliest stages of puberty as the testicular volume increases from 1 mL to 10 mL; these increases in serum LH are far greater proportionately than those found in the last stages of pubertal development. The magnitude of increase in serum testosterone is also greater in the early stages of puberty and correlates with the increase in serum LH during this same period of early pubertal development.
- SEX STEROID SECRETION
Sex steroid secretion is correlated with the development of gonadotropin secretion. During the postnatal period of increased episodic gonadotropin secretion, plasma concentrations of gonadal steroids are episodically elevated. This indicates the potential for secretory activity in the neonatal gonad. Later, when gonadotropin secretion decreases in mid childhood, gonadal activity decreases, but testes can still be stimulated by LH or hCG and ovaries by FSH with resulting secretion of gonadal steroids. An ultrasensitive estradiol assay demonstrates higher values of serum estradiol in prepubertal girls than prepubertal boys, indicating definite basal ovarian activity during the juvenile pause. With the onset of puberty, serum gonadal steroid concentrations progressively increase. While sex steroids are secreted in a diurnal rhythm in early puberty, they are bound to sex hormone-binding globulin, and the half-life of sex steroids is longer than that of gonadotropins. Thus, random daytime measurements of serum sex steroids are more helpful in determining pubertal status than random measurements of serum gonadotropins.
Most (97–99%) of the circulating estradiol and testosterone is associated with sex hormone-binding globulin (SHBG). The free hormone is the active fraction, but SHBG modulates the activity of the total testosterone and estradiol. Prepubertal boys and girls have equal concentrations of SHBG, but because testosterone decreases SHBG and estrogen increases SHBG, adult males have only half the concentration of SHBG than that of adult females. Thus, lower SHBG levels amplify androgen effect in men; while adult men have 20 times the amount of plasma testosterone that adult women have, adult men have 40 times the amount of free testosterone that adult women have (see Chapter 12).
- GNRH STIMULATION
The use of intravenous GnRH has further clarified the pattern of pubertal development. When GnRH is administered to children under 2 years of age, pituitary secretion of LH and FSH increases markedly. During the juvenile pause, the period of low basal gonadotropin secretion (after age 2 until the peripubertal period), exogenous GnRH has less effect on LH release. By the peripubertal period, 100 ľg of intravenous GnRH induces a greater rise in LH concentrations in boys and girls, and this response continues until adulthood. There is no significant change in the magnitude of FSH secretion after GnRH with the onset of puberty, though females at all ages release more FSH than males.
Gonadotropins are released in secretory spurts in response to endogenous GnRH, which itself is secreted episodically about every 90–120 minutes in response to a central nervous system “pulse generator.” Individual GnRH-containing neurons in culture secrete GnRH in a pulsatile manner with an intrinsic rhythm. GnRH can be administered to patients in episodic boluses by a programmable pump that mimics the natural secretory episodes. A prepubertal subject without significant gonadotropin peaks will demonstrate the normal pubertal pattern of episodic secretion of gonadotropins after only a few days of such exogenously administered GnRH boluses. Hypogonadotropic patients, who in the basal state do not have normal secretory episodes of gonadotropin release, may be converted to a pattern of normal adult episodic gonadotropin secretion by this method of pulsatile GnRH administration. Varying the timing of pulsatile GnRH administration can regulate the ratio of FSH to LH just as the frequency of endogenous hypothalamic GnRH release shifts during the menstrual cycle and puberty to naturally alter this ratio. Increasing the frequency of GnRH pulses increases the LH:FSH ratio; an increased ratio is characteristic of midcycle and peripubertal dynamics. Alternatively, if GnRH is administered continuously rather than in pulses or if long-acting superactive analogs of GnRH
are given, a brief period of increased gonadotropin secretion is followed by LH and FSH suppression (see below). This phenomenon is responsible for the therapeutic effects of GnRH analogs in conditions such as central precocious puberty.
- LEPTIN AND PUBERTY
Leptin is a hormone produced in adipose cells that suppresses appetite through interaction with its receptor in the hypothalamus. Leptin plays a major role in pubertal development in mice and rats. Genetically leptin-deficient mice (ob/ob) will not initiate puberty. Leptin replacement promotes pubertal development in this mouse, and leptin administration will cause an immature normal mouse to progress through puberty. A leptin-deficient human at 9 years of age had a bone age of 13 years but no significant gonadotropin pulses and no physical evidence of pubertal development. With leptin treatment, gonadotropin peaks appeared, implying that puberty would follow. This and other data suggested that leptin might be the elusive factor which triggers the onset of puberty. Puberty and menarche occur at a younger age in obese children, and leptin seemed likely candidate to account for this phenomenon.
However, leptin does not appear to trigger the onset of puberty in normal adolescents; leptin may accompany pubertal changes rather than cause them. Leptin increases in girls during puberty in synchrony with the increase in fat mass, while leptin decreases in boys, with increased lean body mass and decreased fat mass. Thus, leptin levels vary with body composition and not with sex. Leptin appears to be a necessary component of pubertal development in human beings but not a major stimulant to this development.
Ovulation & Menarche
The last stage in hypothalamic-pituitary development is the onset of positive feedback, leading to ovulation and menarche. The ovary contains a paracrine system that regulates follicular atresia or development; it is only in the last stages of puberty that gonadotropins come into play in the maturation of the follicle. After mid puberty, estrogen in the right amount at the right time can stimulate gonadotropin release just as it can suppress gonadotropin secretion in other situations. The frequency of pulsatile GnRH release increases during the late follicular phase of the normal menstrual cycle and raises the ratio of LH to FSH secretion. This stimulates the ovary to produce estrogen and leads to the midcycle LH surge that causes ovulation. Administration of pulsatile GnRH by programmable pump can be used to bring about fertility in patients with hypothalamic GnRH deficiency by mimicking this natural pattern. However, even if the midcycle surge of gonadotropins is present, ovulation may not occur during the first menstrual cycles; 90% of menstrual cycles are anovulatory in the first year after menarche, and it is not until 4–5 years after menarche that the percentage of anovulatory cycles decreases to less than 20%. However, some of the first cycles after menarche may be ovulatory.
Thus, just as boys are reproductively mature prior to physical maturity, girls may become fertile and even pregnant prior to physical or emotional maturity.
While the hypothalamic-pituitary axis has been well characterized in recent years, our understanding of the mechanism of control of adrenal androgen secretion is still somewhat rudimentary. The adrenal cortex normally secretes the weak androgens dehydroepiandrosterone (DHEA), its sulfate, dehydroepiandrosterone sulfate (DHEAS), and androstenedione in increasing amounts beginning at about 6–7 years of age in girls and 7–8 years of age in boys (Table 15-1). A continued rise in adrenal androgen secretion persists until late puberty. Thus, adrenarche (the secretion of adrenal androgens) occurs years before gonadarche (the secretion of
gonadal sex steroids). The observation that patients with Addison's disease, who do not secrete adrenal androgens, and patients with premature adrenarche, who secrete increased amounts of adrenal androgens at an early age, usually enter gonadarche at a normal age suggests that age at adrenarche does not significantly influence age at gonadarche. Furthermore, patients treated with a GnRH agonist to suppress gonadotropin secretion progress through adrenarche despite their suppressed gonadarche. Measurements of urinary 17-ketosteroids reflect principally adrenal androgen secretion and not secretion of testosterone or its metabolites. Thus, urinary 17-ketosteroid levels rise considerably at adrenarche but need not do so at gonadarche.
Table 15-1. Serum third-generation gonadotropins and sex steroids in puberty.1
Miscellaneous Metabolic Changes
The onset of puberty is associated with many changes in laboratory values that are either directly or indirectly caused by the rise of sex steroid concentrations. Thus, in boys, hematocrit rises and HDL concentrations fall as a consequence of increasing testosterone. In both boys and girls, alkaline phosphatase rises during the pubertal growth spurt. Serum IGF-I concentrations rise with the growth spurt, but IGF-I is more closely correlated with sex steroid concentration than with growth rate. IGF-I levels peak 1 year after peak growth velocity is reached and remain elevated for 4 years thereafter even though growth rate is decreasing. Prostate-specific antigen (PSA) is measurable after the onset of puberty in boys and provides another biochemical indication of pubertal onset.
DELAYED PUBERTY OR ABSENT PUBERTY (SEXUAL INFANTILISM)
Any girl of 13 or boy of 14 years of age without signs of pubertal development falls more than 2.5 SD above the mean and is considered to have delayed puberty (Table 15-2). By this definition, 0.6% of the healthy population are classified as having constitutional delay in growth and adolescence. These normal patients need reassurance rather than treatment and will ultimately progress through the normal stages of puberty, albeit later than their peers. The examining physician must make the sometimes difficult decision about which patients older than these guidelines are constitutionally delayed and which have organic disease.
Constitutional Delay in Growth & Adolescence
A patient with delayed onset of secondary sexual development whose stature is shorter than that of age-matched peers but who consistently maintains a normal growth velocity for bone age and whose skeletal development is delayed more than 2 SD from the mean is likely to have constitutional delay in puberty (Figure 15-6). These patients are at the older end of the distribution curve of age at onset of puberty. A family history of a similar pattern of development in a parent or sibling supports the diagnosis. The subject is usually thin as well. Studies suggest that disproportionately poor growth of the spine in constitutional delay in growth and adolescence relative to increased growth of the legs leads to a noticeable disproportion (lowering) of the upper to lower segment ratio; the disproportion is said to be an indicator of greater final height attainment in this group. In many cases, even if they show no physical signs of puberty at the time of examination, the initial elevation of gonadal sex steroids has already begun, and their basal LH concentrations measured by ultrasensitive third-generation assays or their plasma LH response to intravenous GnRH is pubertal. These results suggest that secondary sexual development will commence within a period of months. However, in
some cases, observation for endocrine or physical signs of puberty must continue for a period of months or years before the diagnosis is made. Generally, signs of puberty will appear after the patient reaches a skeletal age of 11 years (girls) or 12 years (boys), but there is great variation. Patients with constitutional delay in adolescence will almost always manifest secondary sexual development by 18 years of chronologic age, though there is one reported case of spontaneous puberty occurring at 25 years of age. This patient may have had Kallmann's syndrome. Reports of patients with Kallman's syndrome and others with constitutional delay in puberty within one family suggest a possible relationship between the two conditions. See below and Chapter 5. Adrenarche is characteristically delayed—along with gonadarche—in constitutional delay in puberty.
Table 15-2. Classification of delayed puberty.
Figure 15-6. 134/12-year-old girl with constitutional delay in growth and puberty. History revealed a normal growth rate but short stature at all ages. Physical examination revealed a height of 138 cm (-4.5 SD) and a weight of 28.6 kg (-3 SD). The patient had recently developed early stage 2 breast development, with 1 cm of glandular tissue on the right breast and 2 cm on the left breast. The vaginal mucosa was dulled, and there was no pubic hair. Karyotype was 46,XX. Bone age was 10 years. After administration of GnRH, LH and FSH rose in a pubertal pattern. Estradiol was 40 pg/mL. She has since spontaneously progressed through further pubertal development. (Reproduced, with permission, from Styne DM, Kaplan SL: Pediatr Clin North Am 1979;26:123.)
The absent or decreased ability of the hypothalamus to secrete GnRH or of the pituitary gland to secrete LH and FSH leads to hypogonadotropic hypogonadism. This classification denotes an irreversible condition requiring replacement therapy. If the pituitary deficiency is limited to gonadotropins, patients are usually close to normal height for age until the age of the pubertal growth spurt, in contrast to the shorter patients with constitutional delay. Bone age is usually not delayed in childhood but does not progress normally after the patient reaches the age at which sex steroid secretion ordinarily stimulates maturation of the skeleton. However, if GH deficiency accompanies gonadotropin deficiency, severe short stature will result.
- CENTRAL NERVOUS SYSTEM DISORDERS
- Tumors—A tumor involving the hypothalamus or pituitary gland can interfere with hypothalamic-pituitary-gonadal function as well as the control of GH, ACTH, TSH, PRL, and vasopressin secretion. Thus, delayed puberty may be a manifestation of a central nervous system tumor accompanied by any or all of the following: GH deficiency, secondary hypothyroidism, secondary adrenal insufficiency, hyperprolactinemia, and diabetes insipidus. The combination of anterior and posterior pituitary deficiencies acquired after birth makes it imperative that a hypothalamic-pituitary tumor be considered as the cause.
Craniopharyngioma is the most common type of hypothalamic-pituitary tumor leading to delay or absence of pubertal development. This neoplasm originates in Rathke's pouch but may develop into a suprasellar tumor. The peak age incidence of craniopharyngioma is between 6 and 14 years. Presenting symptoms may include headache, visual deficiency, growth failure, polyuria, and polydipsia; presenting signs may include visual defects, optic atrophy, or papilledema. Clinical manifestations may reflect gonadotropin, thyroid, and GH deficiency. Laboratory evaluation may reveal any type of anterior or posterior pituitary deficiencies. Bone age is often retarded at the time of presentation.
Calcification in the suprasellar region is the hallmark of craniopharyngiomas; 80% of cases will have calcifications on lateral skull x-ray, and a higher percentage will show this on CT scan (but calcifications will not be seen on MRI). The tumor often presents a cystic appearance on CT or MRI scan and at the time of surgery may contain dark, cholesterol-laden fluid. The rate of growth of craniopharyngiomas is quite variable—some are indolent and some are quite aggressive. Small intrasellar tumors may be resected by transsphenoidal surgery; larger ones require partial resection and radiation therapy (see Chapter 5).
Extrasellar tumors that involve the hypothalamus and produce sexual infantilism include germinomas, gliomas (sometimes with neurofibromatosis), and astrocytomas (see Chapter 5). Intrasellar tumors such as chromophobe adenomas are quite rare in children compared to adults. Hyperprolactinemia—with or without a diagnosed microadenoma or galactorrhea—may delay the onset or progression of puberty; with therapy to decrease prolactin concentrations, puberty progresses.
- Other acquired central nervous system disorders—Other acquired central nervous system disorders may lead to hypothalamic-pituitary dysfunction. Granulomatous diseases such as Hand-Schüller-Christian disease or histiocytosis X, when involving the hypothalamus, most frequently lead to diabetes insipidus, but any other hypothalamic defect may also occur including gonadotropin deficiency. Tuberculous or sarcoid granulomas, other postinfectious inflammatory lesions, vascular lesions, and trauma more rarely cause hypogonadotropic hypogonadism.
- Developmental defects—Developmental defects of the central nervous system may cause hypogonadotropic hypogonadism or other types of hypothalamic dysfunction. Cleft palate or other midline anomalies may also be associated with hypothalamic dysfunction. Optic dysplasia is associated with small, hypoplastic optic disks and, in some patients, absence of the septum pellucidum on pneumoencephalography, CT scanning, or MRI; associated hypothalamic deficiencies are often present. (See Chapter 5.) Optic hypoplasia or dysplasia must be differentiated from optic atrophy; optic atrophy implies an acquired condition and may indicate a hypothalamic-pituitary tumor. Both anterior and posterior pituitary deficiencies may occur with congenital midline defects or acquired defects. Early onset of such a combination suggests a congenital defect, while late onset more strongly indicates a neoplasm.
- Radiation therapy—Central nervous system radiation therapy involving the hypothalamic-pituitary area can lead to hypogonadotropic hypogonadism with onset at 6–18 months (or longer) after treatment. Growth hormone is more frequently affected than gonadotropin secretion, and growth hormone deficiency occurs with exposure to as little as an 18-Gy dose. Other hypothalamic deficiencies such as gonadotropin deficiency, hypothyroidism, and hyperprolactinemia occur more often with higher doses of radiation.
- ISOLATED HORMONAL DEFICIENCY
Patients who have isolated deficiency of gonadotropins but normal GH secretion tend to be of normal height for age until the teenage years but will lack a pubertal growth spurt. They have eunuchoid proportions of increased span for height and decreased upper to lower segment ratios. Their skeletal development will be delayed for chronologic age during the teenage years, and they will continue to grow after an age when normal adolescents stop growing.
Kallmann's syndrome 1 is the most common form of isolated gonadotropin deficiency (Figure 15-7). Gonadotropin deficiency in these patients is associated with hypoplasia or aplasia of the olfactory lobes and hyposmia or anosmia; remarkably, they may not notice that they have no sense of smell, though olfactory testing will reveal it. GnRH-containing neurons fail to migrate from the olfactory placode (where they originate) to the medial basal hypothalamus in Kallmann's syndrome. This is a familial syndrome of variable manifestations in which anosmia may occur with or without hypogonadism in a given member of a kindred. X-linked Kallmann's syndrome is due to gene deletions in the region of Xp22.3, causing the absence of the KAL gene, which appears to code for an adhesion molecule. There is an association of Kallmann's syndrome with X-linked ichthyosis due to steroid sulfatase deficiency, mental retardation, and chondrodysplasia punctata. Associated abnormalities in Kallmann's syndrome may affect the kidneys and bones, and patients may have undescended testes, gynecomastia, and obesity. Mirror hand movements
(bimanual synkinesia) is reported, with MRI evidence of abnormal development of the corticospinal tract. Ultimate height is normal, though patients are delayed in reaching adult height. Kallman's syndrome 2 is inherited in an autosomal dominant pattern. Kallman's syndrome 3 exhibits an autosomal recessive pattern.
Figure 15-7. Boy, 1510/12 years old, with Kallmann's syndrome. His testes were originally undescended, but they descended into the scrotum after human chorionic gonadotropin treatment was given. His height was 163.9 cm (-1.5 SD), and the US:LS ratio was 0.86 (eunuchoid). The penis was 6.3 × 1.8 cm. Each testis was 1 × 2 cm. Plasma LH was not detectable and rose little after administration of 100 ľg of GnRH; FSH rose minimally. Testosterone did not change from 17 ng/dL. He had no ability to smell standard odors. (Reproduced, with permission, from Styne DM, Grumbach MM: Reproductive Endocrinology. Yen SSC, Jaffe RB [editors]. Saunders, 1978.)
Other cases of hypogonadotropic hypogonadism may occur sporadically or via an autosomal recessive pattern without anosmia. X-linked congenital adrenal hypoplasia is associated with hypogonadotropic hypogonadism; glycerol kinase deficiency and muscular dystrophy have been linked to this syndrome. The gene locus is at Xp21.3-p21.2 and involves a mutation in the DAX1 gene in many but not all patients. An autosomal recessive form of congenital adrenal hypoplasia is reported. Some hypogonadal patients lack only LH secretion and have spermatogenesis without testosterone production (fertile eunuch syndrome); others lack only FSH. (See Chapters 12 and 13.)
- IDIOPATHIC HYPOPITUITARY DWARFISM
Patients with congenital GH deficiency have early onset of growth failure (Figure 15-8); this feature distinguishes them from patients with GH deficiency due to hypothalamic tumors, who usually have late onset of growth failure. Even without associated gonadotropin deficiency, untreated GH-deficient patients often have delayed onset of puberty associated with their delayed bone ages. With appropriate hGH therapy, however, onset of puberty occurs at a normal age. Patients who have combined GH and gonadotropin deficiency do not undergo puberty even when bone age reaches the pubertal stage. Idiopathic hypopituitarism is usually sporadic but may follow an autosomal recessive or X-linked inheritance pattern. Birth injury or breech delivery is a common feature of the neonatal history of patients with idiopathic hypopituitarism (breech delivery being more common in the history of affected males).
The syndrome of microphallus (due to congenital gonadotropin or GH deficiency) and neonatal hypoglycemic seizures (due to congenital ACTH deficiency or GH deficiency) must be diagnosed and treated early to avoid central nervous system damage. Patients with this syndrome will not undergo spontaneous pubertal development. Testosterone in low doses (testosterone enanthate, 25 mg intramuscularly every month for three doses) can increase the size of the penis in infants diagnosed with congenital hypopituitarism without significantly advancing the bone age. Males with isolated GH deficiency can also have microphallus; the penis will enlarge to some degree with hGH therapy in these patients. It is important to note that microphallus due to hypopituitarism may be treated with testosterone, and sex reversal need not be considered (see Chapter 14).
Figure 15-8. Twenty-year-old male with congenital deficiency of GRF, GnRH, TRF, and CRF. Height was 8 SD below the mean, and the phallus was 2 × 1 cm. Bone age was 10 years, and the sella turcica was small on lateral skull x-ray. LH rose minimally from a low basal value after administration of 100 ľg of GnRH. Testosterone was virtually undetectable and did not rise after administration of GnRH. (Reproduced, with permission, from Styne DM, Grumbach MM: Reproductive Endocrinology. Yen SSC, Jaffe RB [editors]. Saunders, 1978.)
- MISCELLANEOUS DISORDERS
- Prader-Willi syndrome—Prader-Willi syndrome occurs sporadically and is associated with fetal and infantile hypotonia, short stature; poor feeding in infancy but insatiable hunger later, leading to massive obesity; characteristic facies with almond-shaped eyes, small hands and feet after infancy, mental retardation, and emotional instability in patients of either sex; delayed menarche in females; and micropenis and cryptorchism in males. Osteoporosis is common in these patients during the teenage years, but sex steroid replacement, when indicated, may help. Behavioral modification may improve the usual pattern of rampant weight gain. Patients have deletion or translocation of chromosome 15q11–13 derived from the father; if an abnormality in this area derives from the mother, Angelman syndrome results. Fluorescent in situ hybridization for this area of the chromosome is available from laboratories for diagnosis. (See Chapter 6.)
- Laurence-Moon and Bardet-Biedl syndromes—These autosomal recessive conditions are characterized by obesity, short stature, mental retardation, and retinitis pigmentosa. Hypogonadotropic hypogonadism and primary hypogonadism have variously been reported in affected patients. A distinction between Bardet-Biedl (gene locus 16q21) and Laurence-Moon syndromes may be made, with the latter demonstrating polydactyly and obesity and the former being characterized by paraplegia. (See Chapter 6.)
- Chronic disease and malnutrition—A delay in sexual maturation may be due to chronic disease or malnutrition. For example, children with intractable asthma have delayed pubertal development leading to short stature during the teenage years, though they ultimately reach an appropriate height. Children with other chronic diseases may not fare so well in long-term follow-up; eg, HIV infection in adolescence causes poor growth and pubertal progression. Weight loss to less than 80% of ideal weight caused by disease or voluntary dieting may result in gonadotropin deficiency; weight gain toward the ideal usually restores gonadotropin function.
Chronic disease may have effects on sexual maturation separate from nutritional state. For example, there is a high incidence of hypothalamic hypogonadism in thalassemia major even with regular transfusion and chelation therapy.
- Anorexia nervosa—Anorexia nervosa involves weight loss associated with significant psychologic disorder. This condition usually affects girls who develop a disturbed body image and exhibit typical behavior such as avoidance of food and induction of regurgitation after ingestion. Weight loss may be so severe as to cause fatal complications such as immune dysfunction, fluid and electrolyte imbalance, or circulatory collapse. Primary or secondary amenorrhea is a classic finding in these patients and has been correlated with the degree of weight loss, though there is evidence that patients with anorexia nervosa may cease to menstruate before their substantial weight loss is exhibited. Other endocrine abnormalities in anorexia nervosa include elevated serum growth hormone and decreased IGF-I (these are characteristic of any type of starvation), decreased serum triiodothyronine, decreased serum 1,25-dihydroxyvitamin D3and elevated 24,25-hydroxyvitamin D3levels. Weight gain to the normal range for height, however, does not ensure immediate resumption of menses. There is an increased incidence of anorexia nervosa in ballet dancers or ballet students; the incidence of scoliosis and mitral valve insufficiency is also increased in these patients. Functional amenorrhea may also occur in women of normal weight, some of whom demonstrate evidence of psychologic stress. Decreased LH response to GnRH administration, impaired monthly cycles of gonadotropin secretion, and retention of a diurnal rhythm of gonadotropin secretion are found in anorexia nervosa patients, patterns which indicate a reversion to an earlier stage of endocrine puberty.
- Increased physical activity—Girls who regularly participate in strenuous athletics, ballet dancing, etc, may have delayed thelarche, delayed menarche, and irregular or absent menstrual periods. This effect is not always related to less than ideal weight, since such amenorrheic patients may resume menses while temporarily bedridden. Increased physical activity and not decreased weight appears to be the cause of the amenorrhea. Statistical analysis of mothers' ages at menarche and the type of sport pursued by their daughters indicates that late maturation of some gymnasts may be referable to a familial tendency to late menarche, suggesting that gymnastic activity may not be the primary cause of late menarche. On the other hand there are disturbing studies indicating that intensive gymnastics training at an early age leads to a decrease in ultimate stature.
- Hypothyroidism—Hypothyroidism can delay all aspects of growth and maturation, including puberty and menarche. Galactorrhea may occur in severe primary hypothyroidism due to concomitant elevation of serum prolactin. With thyroxine therapy, catch-up growth and resumed pubertal development and menses will occur. Conversely, severe primary hypothyroidism may be associated with precocious puberty and galactorrhea (due to elevated serum prolactin) in some patients (Van Wyk-Grumbach syndrome). There is evidence that excessive TSH can stimulate FSH receptors, leading to estrogen secretion and breast development.
Primary gonadal failure is heralded by elevated gonadotropin concentration due to the absence of negative feedback effects of gonadal sex steroids. The most common causes of hypergonadotropic hypogonadism are associated with chromosomal and somatic abnormalities, but isolated gonadal failure can also present with delayed puberty without other physical findings. When hypergonadotropic hypogonadism is present in patients with a Y chromosome or a fragment of a Y chromosome (genetic males or conditions noted below), testicular dysgenesis must be considered in the differential diagnosis. The risk of testicular cancer rises in testicular dysgenesis. (Testicular cancer in normal boys is rare; for example, the incidence in Scandinavia is 0.5 per 100,000 in childhood.)
- SYNDROME OF SEMINIFEROUS TUBULE DYSGENESIS (KLINEFELTER'S SYNDROME)
(See Chapters 12 and 14.) The most common form of primary testicular failure is Klinefelter's syndrome (47,XXY karyotype), with an incidence of 1:1000 males. Before puberty, patients with Klinefelter's syndrome have decreased upper segment:lower segment ratios, small testes, and an increased incidence of developmental delay and personality disorders. Onset of puberty is not usually delayed, because Leydig cell function is characteristically less affected than seminiferous tubule function in this condition and testosterone is adequate to stimulate pubertal development. Serum gonadotropin levels rise to castrate concentrations after the onset of puberty; the testes become firm and are rarely larger than 3.5 cm in diameter. After the onset of puberty, there are histologic changes of seminiferous tubule hyalinization and fibrosis, adenomatous changes of the Leydig cells, and impaired spermatogenesis. Gynecomastia is common, and variable degrees of male secondary sexual development are found.
Other forms of male hypergonadotropic hypogonadism are found with 46,XX/47,XXY, 48,XXYY, 48,XXXY, and 49,XXXXY karyotypes. Phenotypic males are described with 46,XX karyotypes and some physical features of Klinefelter's syndrome (see Chapter 14).
- OTHER FORMS OF PRIMARY TESTICULAR FAILURE
Patients surviving treatment for malignant diseases form a growing category of testicular failure. Chemotherapy—primarily with alkylating agents—or radiation therapy directed to the gonads may lead to gonadal failure; injury is more likely if treatment is given during puberty than if it occurs in the prepubertal period, but even prepubertal therapy leads to risk. Normal pubertal development may occur in boys treated prepubertally with polychemotherapy, though they demonstrated elevated peak serum LH and elevated basal and peak serum FSH after GnRH as well as a high incidence of decreased or absent sperm counts; this indicates that prepubertal status does not protect a child against testicular damage from chemotherapy and that normal physical development may hide significant endocrine and reproductive damage.
The “Sertoli cell only” syndrome (germinal cell aplasia) is a congenital form of testicular failure manifested by azoospermia and elevated FSH concentrations but generally normal secondary sexual characteristics, normal testosterone concentrations, and no other anomalies. A gene at Yq11.23, the azoospermia factor (AZF), appears to play a role in the production of spermatocytes. Patients with Down's syndrome may have elevated LH and FSH levels even in the presence of normal testosterone levels, suggesting some element of primary gonadal failure.
- CRYPTORCHISM OR ANORCHIA
Phenotypic males with a 46,XY karyotype but no palpable testes have either cryptorchism or anorchia. Cryptorchid males should produce a rise in testosterone levels > 2 ng/mL 72 hours after intramuscular administration of 3000 units/m2 of chorionic gonadotropin, and the testes may descend during 2 weeks of treatment with chorionic gonadotropin given three times a week. Patients with increased plasma testosterone levels in response to chorionic gonadotropin administration but without testicular descent have cryptorchism; their testes should be brought into the scrotum by surgery to decrease the likelihood of further testicular damage due to the elevated intra-abdominal temperature and to guard against the possibility of undetected tumor formation. Cryptorchid testes may demonstrate congenital abnormalities and may not function normally even if brought into the scrotum early in life. Furthermore, the descended testis in a unilaterally cryptorchid boy may itself show abnormal histologic features; such patients have a 69% incidence of decreased sperm counts. Thus, unilateral cryptorchid patients can be infertile even if they received early treatment of their unilateral cryptorchism. In addition, patients undergoing orchiopexy may sustain subtle damage to the vas deferens, leading to the later production of antibodies to sperm that may result in infertility.
It is important to determine if any testicular tissue is present in a boy with no palpable testes, since unnoticed malignant degeneration of the tissue is a possibility. The diagnosis of anorchia due to the testicular regression syndrome may be pursued by ultrasound or MRI, laparotomy or laparoscopic examination, or by the endocrine evaluation noted above. Except for the absence of testes, patients with anorchia have normal infantile male genital development, including wolffian
duct formation and müllerian duct regression. The testes were presumably present in these patients early in fetal life during sexual differentiation but degenerated after the 13th week of gestation for unknown reasons (also called the “vanishing testes syndrome”) (seeChapter 12). The presence of antimüllerian factor in a young child indicates the presence of testicular tissue, although during puberty antimüllerian factor becomes nondetectable and this test cannot be employed at that stage. The presence of normal basal gonadotropin levels in a prepubertal boy without palpable testes suggests the presence of testicular tissue even if the testosterone response to hCG is low, while the presence of elevated gonadotropin levels without any testosterone response to hCG suggests anorchia.
- SYNDROME OF GONADAL DYSGENESIS (TURNER'S SYNDROME)
(See Chapters 13 and 14.) 45,X gonadal dysgenesis is associated with short stature, female phenotype with sexual infantilism, and a chromatin-negative buccal smear. (We do not recommend routinely ordering a buccal smear since it is difficult for some laboratories to perform the test reliably.) Patients have “streak” gonads consisting of fibrous tissue without germ cells. Other classic but variable phenotypic features include micrognathia, “fish” mouth (downturned corners of the mouth), ptosis, low-set or deformed ears, a broad shield-like chest with the appearance of widely spaced nipples, hypoplastic areolae, a short neck with low hairline and webbing of the neck (pterygium colli), short fourth metacarpals, cubitus valgus, structural anomalies of the kidney, extensive nevi, hypoplastic nails, and vascular anomalies of the left side of the heart (most commonly coarctation of the aorta associated with hypertension). The medical history of patients with the syndrome of gonadal dysgenesis will often reveal small size at birth, lymphedema of the extremities most prominent in the newborn period, and loose posterior cervical skin folds. (The terms “Bonnevie-Ullrich syndrome” and “infant Turner's syndrome” are applied to this neonatal appearance.) Affected patients often have a history of frequent otitis media with conductive hearing loss. Intelligence is normal, but there is often impaired spatial orientation. Patients have no pubertal growth spurt and reach a mean final height of 143 cm. Short stature is a classic feature of Turner's syndrome but not of other forms of hypergonadotropic hypogonadism that occur without karyotype abnormalities. The short stature is linked to the absence of the SHOX homeobox gene of the pseudoautosomal region of the X chromosome (Xpter–p22.32). GH function is usually normal in Turner's syndrome. However, exogenous hGH treatment improves growth rate and increases adult stature in affected girls (see Chapter 14). Pubic hair may appear late and is usually sparse in distribution owing to the absence of any ovarian secretions; thus, adrenarche progresses in Turner's syndrome even in the absence of gonadarche. Autoimmune thyroid disease (usually hypothyroidism) is common in Turner's syndrome, and determination of thyroid function and thyroid antibody levels is important in evaluation of these patients.
Serum gonadotropin concentrations in Turner's syndrome are extremely high between birth and age 4 years. They decrease toward the normal range in prepubertal patients in the juvenile pause and then rise again to castrate levels after age 10 years. (See Chapter 14.)
Sex chromatin-positive variants of gonadal dysgenesis include 45,X/46,XX, 45,X/47,XXX, and 45,X/46, XX/47,XXX mosaicism with chromatin-positive buccal smears. Patients with these karyotypes may resemble patients with the classic syndrome of gonadal dysgenesis, or they may have fewer manifestations and normal or nearly normal female phenotypes. Streak gonad formation is not invariable; some patients have had secondary sexual development, and menarche and rare pregnancies have been reported.
Sex chromatin-negative variants of the syndrome of gonadal dysgenesis have karyotypes with 45,X/46,XY mosaicism. Physical features vary; some patients have the features of classic Turner's syndrome, while others may have ambiguous genitalia or even the features of phenotypic males. Gonads are dysgenetic but vary from streak gonads to functioning testes. These patients are at risk for gonadoblastoma formation. Since gonadoblastomas may secrete androgens or estrogens, patients with gonadoblastoma may virilize or feminize as though they had functioning gonads, confusing the clinical picture. Gonadoblastomas may demonstrate calcification on abdominal x-ray. Malignant germ cell tumors may arise in dysgenetic testes, and orchiectomy is generally indicated. In some mosaic patients with one intact X chromosome and one chromosomal fragment, it is difficult to determine whether the fragment is derived from an X chromosome or a Y chromosome. PCR techniques to search for specific sequences may be helpful if a karyotype reveals no Y chromosomal material.
Patients with Turner's syndrome have benefited from in vitro fertilization techniques. After exogenous hormonal preparation, a fertilized ovum (possibly a sister's ovum fertilized by the patient's male partner, or an extra fertilized ovum from another couple undergoing in vitro fertilization) can be introduced into the patient's uterus, and the pregnancy is then brought to term by exogenous hormone administration.
- OTHER FORMS OF PRIMARY OVARIAN FAILURE
Ovaries appear to be more resistant to damage from the chemotherapy used in the treatment of malignant disease
than are testes. Nonetheless, ovarian failure can occur with medical therapy. Damage is common if the ovaries are not surgically “tacked” out of the path of the beam or shielded by lead in abdominal radiation therapy. Normal gonadal function after chemotherapy does not guarantee normal function later. Late-onset gonadal failure has been described after chemotherapy. Premature menopause has also been described in otherwise healthy girls owing to the presence of antiovarian antibodies; patients with Addison's disease may have autoimmune oophoritis as well as adrenal failure. A sex steroid biosynthetic defect due to 17α-hydroxylase deficiency (P450c17) will be manifested as sexual infantilism and primary amenorrhea in a phenotypic female (regardless of genotype) with hypokalemia and hypertension. The patient with 17α-hydroxylase deficiency may have ovaries or testes and still present as a phenotypic female.
- PSEUDO-TURNER SYNDROME (NOONAN'S SYNDROME, ULLRICH'S SYNDROME, MALE TURNER'S SYNDROME)
Pseudo-Turner syndrome is associated with manifestations of Turner's syndrome such as webbed neck, ptosis, short stature, cubitus valgus, and lymphedema, but other clinical findings such as a normal karyotype, triangular facies, pectus excavatum, right-sided heart disease, and an increased incidence of mental retardation differentiate these patients from those with Turner's syndrome. Males may have undescended testes and variable degrees of germinal cell and Leydig cell dysfunction. Pseudo-Turner syndrome follows an autosomal dominant pattern of inheritance with incomplete penetrance (gene locus 12q24).
- FAMILIAL AND SPORADIC FORMS OF 46,XX OR 46,XY GONADAL DYSGENESIS
These forms of gonadal dysgenesis are characterized by structurally normal chromosomes and streak gonads or partially functioning gonads. They do not have the physical features of Turner's syndrome. If there is some gonadal function, 46,XY gonadal dysgenesis may present with ambiguous genitalia or virilization at puberty. If no gonadal function is present, patients appear as phenotypic sexually infantile females. Patients with 46,XY gonadal dysgenesis and dysgenetic testes should undergo gonadectomy to eliminate the possibility of malignant germ cell tumor formation.
- PRIMARY AMENORRHEA ASSOCIATED WITH NORMAL SECONDARY SEXUAL DEVELOPMENT
If a structural anomaly of the uterus or vagina interferes with the onset of menses but the endocrine milieu remains normal, the patient presents with primary amenorrhea in the presence of normal breast and pubic hair development. A transverse vaginal septum will seal the uterine cavity from the vaginal orifice, leading to the retention of menstrual flow—as may an imperforate hymen. The Rokitansky-Küster-Hauser syndrome combines congenital absence of the vagina with abnormal development of the uterus, ranging from a rudimentary bicornuate uterus that may not open into the vaginal canal to a virtually normal uterus; surgical repair may be possible in patients with minimal anatomic abnormalities, and fertility has been reported. Associated abnormalities include major urinary tract anomalies and spinal or other skeletal disorders. The rarest anatomic abnormality in this group is absence of the uterine cervix in the presence of a functional uterus.
Male pseudohermaphroditism is an alternative cause of primary amenorrhea if a patient has achieved thelarche. The syndrome of complete androgen resistance leads to female external genitalia and phenotype without axillary or pubic hair development in the presence of pubertal breast development (syndrome of testicular feminization; see Chapter 14).
Differential Diagnosis of Delayed Puberty (Table 15-3)
Patients who do not begin secondary sexual development by age 13 (girls) or age 14 (boys) and patients who do not progress through development on a timely basis (girls should menstruate within 5 years after breast budding; boys should reach stage 5 pubertal development 4˝ years after onset) should be evaluated for hypogonadism. The yield of diagnosable conditions is quite low in children younger than these ages, but many patients and families will request evaluation well before these limits. Without significant signs or symptoms of disorders discussed above, it is best to resist evaluation and offer support until these ages in most cases.
If the diagnosis is not obvious on the basis of physical or historical features, the differential diagnostic process begins with determination of whether plasma gonadotropins are (1) elevated owing to primary gonadal failure or (2) decreased owing to secondary or tertiary hypogonadism or constitutional delayed puberty. A patient with constitutional delay may have a characteristic history of short stature for age with normal growth velocity for bone age and a family history of delayed but spontaneous puberty. The patient's mother may have had late onset of menses, or the father may have begun to shave late or continued growing after high school. Not all patients with constitutional delay are so classic, and gonadotropin-deficient patients may have some features similar to those of constitutional delay in adolescence. Indeed, patients with Kallmann's
syndrome and others with constitutional delay are occasionally found in the same kindred.
Table 15-3. Differential diagnosis of delayed puberty.
Laboratory evaluation is sometimes helpful but not always. A single third-generation determination of serum LH concentration in the pubertal range suggests that puberty is progressing. Determination of the rise in LH after administration of GnRH is helpful in differential diagnosis; secondary sexual development usually follows within months after conversion to a pubertal LH response to GnRH. An appropriate LH rise following administration of a superactive GnRH agonist is proposed as another useful indicator of normal pubertal progression. Frequent nighttime sampling (every 20 minutes through an indwelling catheter) to determine the amplitude of peaks of LH secretion during sleep is an alternative to GnRH testing but quite cumbersome. Unfortunately, the results of GnRH infusions or nighttime sampling are not always straightforward. Patients may have pubertal responses to exogenous GnRH but may not spontaneously secrete adequate gonadotropins to allow secondary sexual development. In females with amenorrhea, the frequency and amplitude of gonadotropin secretion may not change to allow monthly menstrual cycles. The retention of a diurnal rhythm of gonadotropin secretion (normal in early puberty) into late puberty is a pattern linked to inadequate pubertal progression. In males, a morning serum testosterone concentration over 50 ng/dL indicates the likelihood of pubertal development within 6 months. Other methods of differential diagnosis between constitutional delay and hypogonadotropic hypogonadism have been proposed but are complex or are not definitive.
Clinical observation for signs of pubertal development and laboratory evaluation for the onset of rising levels of sex steroids may have to continue until the patient is 18 years of age before the diagnosis is definite. In most cases, if spontaneous pubertal development is not noted by 18 years of age, the diagnosis is gonadotropin deficiency. Of course, the presence of neurologic impairment or other endocrine deficiency should immediately lead to investigation for central nervous system tumor or congenital defect in a patient with delayed puberty. CT or MRI scanning will be helpful in this situation.
Treatment of Delayed Puberty
- CONSTITUTIONAL DELAY IN GROWTH AND ADOLESCENCE
- Psychologic support—Teenagers who are so embarrassed about short stature and lack of secondary sexual development as to have significant psychologic problems may require special help if they have passed the ages of 13 years for girls or 14 years for boys. Patients with constitutional delay in growth and adolescence should be counseled that normal pubertal development will occur spontaneously. Peer pressure and teasing can be oppressive. While the majority of these patients will do quite well, severe depression must be treated appropriately, since short patients with pubertal delay have become suicidal. In some cases it helps to excuse the patient from physical education class, as the lack of development is most apparent in the locker room. In general, boys feel more stress than girls when puberty is delayed.
- Sex steroids—The following treatment can be given: (1) for girls, a 3-month course of conjugated estrogen (0.3 mg) or ethinyl estradiol (5–10 ľg) given orally each day; (2) for boys, a 3-month course of testosterone enanthate or cypionate (100 mg) given intramuscularly once every 28 days for three doses. This treatment will elicit noticeable secondary sexual development and a slight increase in stature. The low doses
recommended do not advance bone age and will not significantly change final height. Such low-dose sex steroid treatment has been claimed to promote spontaneous pubertal development after sex steroid therapy is discontinued, but responding individuals may include those boys who are on the brink of further pubertal development and are therefore most likely to achieve a growth response to androgen therapy. A short course of therapy may improve patients' psychologic outlook and allow them to await spontaneous pubertal development with greater confidence. Continuous gonadal steroid replacement in these patients is not indicated, as it will advance bone age and lead to epiphysial fusion and a decrease in ultimate stature; however, after a 3- to 6-month break to observe spontaneous development, another course of therapy may be offered if no pubertal progression occurs.
- PERMANENT HYPOGONADISM
Once a patient has been diagnosed as having delayed puberty due to permanent primary or secondary hypogonadism, replacement therapy must be considered.
Males with hypogonadism may be treated with testosterone enanthate or cypionate intramuscularly every month, gradually increasing the dosage from 100 mg to 300 mg every 28 days. Frequent erections or priapism may occur if the higher dose is used initially. Oral halogenated testosterone and methylated testosterone are not recommended because of the risk of hepatocellular carcinoma or cholestatic jaundice. A testosterone patch or gel provides an alternative to intramuscular testosterone enanthate.
Testosterone therapy may not cause adequate pubic hair development, but patients with secondary or tertiary hypogonadism may benefit from hCG administration with increased pubic hair growth resulting from endogenous androgen secretion in addition to the exogenous testosterone.
Therapy with oxandrolone has been suggested as a method of increasing secondary sexual development and increasing growth without advancing skeletal development; such claims have not been sufficiently well documented to justify a preference for oxandrolone therapy over low-dose depot testosterone. Furthermore, testosterone, which can be aromatized, increases the generally low endogenous growth hormone secretion in constitutional delayed puberty to normal, while oxandrolone, which cannot be aromatized, does not increase growth hormone secretion (see Chapter 12).
Females may be treated with ethinyl estradiol (increasing from 5 ľg/d to 10–20 ľg/d depending upon clinical results) or conjugated estrogens (0.3 or 0.625 mg/d) on days 1–21 of the month. Ten milligrams of medroxyprogesterone acetate are then added on days 12–21 after physical signs of estrogen effect are noted and breakthrough bleeding occurs (and always within 6 months after initiating estrogen). Neither hormone is administered from day 22 to the end of the month to allow regular withdrawal bleeding (see Chapter 13). Later, the patient may be switched to sequential oral contraceptives. Gynecologic examinations should be performed yearly.
Hypothalamic hypogonadism may be treated with GnRH pulses by programmable pump, and fertility may be achieved. Likewise, in the absence of a functional pituitary gland, hCG and menotropins (human postmenopausal gonadotropin) may be administered in pulses. These techniques are cumbersome and best reserved for the time when fertility is desired.
- COEXISTING GH DEFICIENCY
The treatment of patients with coexisting GH deficiency requires consideration of their bone age and amount of growth left before epiphysial fusion; if they have not yet received adequate treatment with growth hormone, sex steroid therapy may be kept in the lower range or even delayed to optimize final adult height. The goal is to allow appropriate pubertal changes to support psychologic development and to allow the synergistic effects of combined sex steroids and GH without fusing the epiphyses prematurely.
Constitutional delayed puberty may be associated with decreased growth hormone secretion in 24-hour profiles of spontaneous secretion or in stimulated testing. Growth hormone secretion increases when pubertal gonadal steroid secretion rises, so decreased GH secretion in this condition should be considered temporary. Growth hormone therapy is not proved to increase final height in patients with constitutional delay in puberty and normal height predictions; studies have shown an increased growth rate in the first year of such therapy, with a decreasing growth rate thereafter. Nonetheless, true growth hormone-deficient patients may have delayed puberty due to the growth hormone deficiency or to coexisting gonadotropin deficiency. Therefore, deciding whether a pubertal patient has temporary or a permanent GH deficiency can be difficult; previous observation may indicate a long history characteristic of constitutional delay in adolescence, while a recent decrease in growth rate may suggest the onset of a brain tumor or other cause of hypopituitarism.
- THE SYNDROME OF GONADAL DYSGENESIS
In the past, patients with the syndrome of gonadal dysgenesis were frequently not given estrogen replacement until after age 13 years, for fear of compromising final height. It has now been demonstrated that low-dose estrogen therapy (5–10 ľg of ethinyl estradiol orally) can be administered to allow feminization and improve psychologic status at 12–13 years of age without decreasing
final height in these patients. Low-dose estrogen will increase growth velocity, while high-dose estrogen suppresses it. Even if growth velocity is increased, however, final height is not increased with such estrogen treatment. Treatment of Turner's syndrome with GH successfully increases adult stature (see Chapter 14).
- BONE MASS
After infancy, most bone mass accrues during the second decade, and disorders of puberty may affect the process. Delayed puberty in boys causes decreased cross sectional bone density when the subjects are tested as adults. A range of defects in girls such as anorexia nervosa, athletics-induced delayed puberty, and Turner's syndrome also cause decreased bone density. The use of testosterone in boys and estrogen and progesterone in girls is helpful in increasing bone mass but has not been demonstrated to result in normal adult bone mass. Appropriate ingestion of dairy products containing calcium or calcium supplementation should be encouraged in hypogonadal or constitutionally delayed patients as well as in normal children; unfortunately, however, no long-term follow-up is yet available to prove the efficacy of this therapy.
PRECOCIOUS PUBERTY (SEXUAL PRECOCITY)
The appearance of secondary sexual development before the age of 7 years in Caucasian girls and 6 years in African-American girls and 9 years in boys of either race constitutes precocious sexual development (Table 15-4). When the cause is premature activation of the hypothalamic-pituitary axis, the diagnosis is central (complete or true) precocious puberty; if ectopic gonadotropin secretion occurs in boys or autonomous sex steroid secretion occurs in either sex, the diagnosis is incomplete precocious puberty. In all forms of sexual precocity, there is an increase in growth velocity, somatic development, and skeletal maturation. When unchecked, this rapid epiphysial development may lead to tall stature during the early phases of the disorder but to short final stature because of early epiphysial fusion. This is the paradox of the tall child growing up to become a short adult. Plasma IGF-I values may be elevated for age but more appropriate for pubertal stage in the untreated state.
Central (Complete or True) Precocious Puberty (Figure 15-9)
- CONSTITUTIONAL CENTRAL (COMPLETE OR TRUE) PRECOCIOUS PUBERTY
Children who demonstrate isosexual precocity at an age more than 2.5 SD below the mean may simply represent the lower reaches of the distribution curve of age at onset of puberty; often there is a familial tendency toward early puberty. True precocious puberty is rarely reported to be due to an autosomal dominant or (in males) X-linked autosomal dominant trait.
Table 15-4. Classification of precocious puberty.
- IDIOPATHIC CENTRAL (COMPLETE OR TRUE) ISOSEXUAL PRECOCIOUS PUBERTY
Affected children with no familial tendency toward early development and no organic disease may be considered to have idiopathic central isosexual precocious puberty. Electroencephalographic abnormalities or other evidence of neurologic dysfunction such as epilepsy or developmental delay may be found in these patients. Pubertal development may follow the normal course or may wax and wane. Serum gonadotropin and sex steroid concentrations and response to GnRH are similar to those found in normal pubertal subjects. In idiopathic central precocious puberty, as in all forms of true isosexual precocity, testicular enlargement in boys should be the first sign; in girls, breast development or, rarely, pubic hair appearance may be first. Girls present with idiopathic central precocious puberty more commonly than boys. Children with precocious puberty have a tendency toward obesity based upon elevated BMI in the untreated state.
- CENTRAL NERVOUS SYSTEM DISORDERS
- Tumors—Central nervous system tumor as a cause of central precocious puberty is more common in boys
than in girls. Optic gliomas or hypothalamic gliomas, astrocytomas, ependymomas, germinomas, and other central nervous system tumors may cause precocious puberty by interfering with neural pathways that inhibit GnRH secretion, thus releasing the central nervous system restraint of gonadotropin secretion. A survey found that 46% of patients with optic gliomas and neurofibromatosis type 1 had precocious puberty, but no patients with isolated neurofibromatosis (that did not have optic gliomas) demonstrated precocious puberty. Remarkably, craniopharyngiomas, which are known to cause delayed puberty, can also trigger precocious pubertal development. Radiation therapy is often indicated in radiosensitive tumors such as germinomas and craniopharyngiomas, where complete surgical extirpation is impossible. Hamartomas of the tuber cinereum contain GnRH and neurosecretory cells such as are found in the median eminence; they may cause precocious puberty by secreting GnRH. Some hypothalamic hamartomas associated with central precocious puberty do not elaborate GnRH but instead contain TGF-α, which stimulates GnRH secretion itself. With improved methods of imaging the central nervous system, hamartomas, with their characteristic radiographic appearance, are now more frequently diagnosed in patients who were previously thought to have idiopathic precocious puberty. These tumors do not grow and so pose no increasing threat to the patients in the absence of intractable seizures. These seizures are rare in patients with pedunculated hamartomas causing central precocious puberty. Because of the location of the hamartoma, surgery is a dangerous alternative to GnRH therapy.
Figure 15-9. Boy 25/12 years of age with idiopathic true precocious puberty. By 10 months of age, he had pubic hair and phallic and testicular enlargement. At 1 year of age, his height was 4 SD above the mean; the phallus was 10 × 3.5 cm; each testis was 2.5 × 1.5 cm. Plasma LH was pubertal and rose in an adult pattern after administration of 100 ľg of GnRH. Plasma testosterone was 416 ng/dL. At the time of the photograph, he had been treated with medroxyprogesterone acetate (to suppress LH and FSH secretion) for 1˝ years, with reduction of his rapid growth rate and decreased gonadotropin and testosterone secretion. His height was 95.2 cm (> 2 SD above mean height for his age); plasma testosterone was 7 ng/dL, and after 100 ľg of GnRH, plasma LH rose only slightly, demonstrating suppression. (Reproduced, with permission, from Styne, DM, Grumbach MM: Reproductive Endocrinology. Yen SSC, Jaffe RB [editors]. Saunders, 1978.)
Tumors or other abnormalities of the central nervous system may cause growth hormone deficiency in association with central precocious puberty. This may also occur after irradiation therapy for such tumors. Such patients will grow much faster than isolated growth hormone-deficient patients but slower than children with classic precocious puberty. Often the growth hormone deficiency will be unmasked after successful treatment of precocious puberty. This combination must be considered during the diagnostic process. (See also Chapter 6.)
- Other causes of true precocious puberty—Infectious or granulomatous conditions such as encephalitis, brain abscess, postinfectious (or postsurgical or congenital) suprasellar cysts, sarcoidosis, and tuberculous granulomas of the hypothalamus cause central precocious puberty. Suprasellar cysts and hydrocephalus cause central precocious puberty that is particularly amenable to surgical correction. Brain trauma may be followed by either precocious or delayed puberty. Radiation therapy for acute lymphoblastic leukemia of the central nervous
system, or prior to bone marrow transplantation, is characteristically associated with hormonal deficiency, but an increasing number of cases are reported of precocious puberty occurring after such therapy; higher doses of radiation may be more likely to cause gonadotropin-releasing hormone deficiency, and lower doses down to 18 Gy may lead to central precocious puberty. Epilepsy and developmental delay are associated with central precocious puberty in the absence of a central nervous system anatomic abnormality.
- VIRILIZING SYNDROMES
Patients with long-untreated virilizing adrenal hyperplasia who have advanced bone ages may manifest precocious puberty after the adrenal hyperplasia is controlled with glucocorticoid suppression. Children with virilizing tumors or those given long-term androgen therapy may follow the same pattern when the androgen source is removed. Advanced maturation of the hypothalamic-pituitary-gonadal axis appears to occur with any condition causing excessive androgen secretion and advanced skeletal age.
Incomplete Isosexual Precocious Puberty
Males may manifest premature sexual development in the absence of hypothalamic-pituitary maturation from either of two causes: (1) ectopic or autonomous endogenous secretion of hCG or LH or iatrogenic exogenous administration of chorionic gonadotropin, which can stimulate Leydig cell production of testosterone; or (2) autonomous endogenous secretion of androgens from the testes or adrenal glands or from iatrogenic exogenous administration of androgens. (In females, secretion of hCG will not by itself cause secondary sexual development.)
- Gonadotropin-secreting tumors—These include hepatomas or hepatoblastomas of the liver as well as teratomas or choriocarcinoma of the mediastinum, gonads, retroperitoneum, or pineal gland and germinomas of the central nervous system. The testes are definitely enlarged but not to the degree found in central precocious puberty.
- Autonomous androgen secretion—Secretion of androgens can occur because of inborn errors of adrenal enzyme function, as in 21-hydroxylase (P450c21) or 11β-hydroxylase (P450c11β) deficiency, virilizing adrenal carcinomas, interstitial cell tumors of the testes, or premature Leydig and germinal cell maturation. Newly recognized forms of late-onset congenital adrenal hyperplasia, generally of the 21-hydroxylase deficiency form, may occur years after birth with no congenital or neonatal manifestations of virilization. Adrenal rest tissue may be found in the testes as a vestige of the common embryonic origin of the adrenal glands and the testes; in states of ACTH excess—primarily congenital adrenal hyperplasia—adrenal rests can enlarge (sometimes to remarkable size) and secrete adrenal androgens (seeChapter 14).
In boys with familial gonadotropin-independent premature Leydig and germinal cell maturation, plasma testosterone levels are in the pubertal range but plasma gonadotropin levels and the LH response to exogenous GnRH are in the prepubertal range or lower because autonomous testosterone secretion suppresses endogenous GnRH release. The cause of this sex-limited dominant condition lies in a constitutive activation of the LH receptor causing increased cyclic adenosine monophosphate (cAMP) production in the absence of LH leaving the LH receptor “on”; several mutations have been reported in the LH receptor gene in different families (eg, Asp578 → Gly or Met571 → Ile). The differential diagnosis rests between testosterone-secreting tumor of the adrenal, testosterone-secreting Leydig cell neoplasm, and premature Leydig and germinal cell maturation.
If hCG secretion causes incomplete male isosexual precocity, FSH is not elevated; and since the seminiferous tubules are not stimulated, the testes do not enlarge as much as in complete sexual precocity. If incomplete sexual precocity is due to a testicular tumor, the testes may be large, asymmetric, and irregular in contour. Symmetric bilateral moderate enlargement of the testes suggests familial gonadotropin-independent premature maturation of Leydig and germinal cells, which is a sex-limited dominant condition. The testes are somewhat smaller in this condition than in true precocious puberty but are still over 2.5 cm in diameter.
Females with incomplete isosexual precocity have a source of excessive estrogens. In all cases of autonomous endogenous estrogen secretion or exogenous estrogen administration, serum LH and FSH levels are low.
- Follicular cysts—If follicular cysts are large enough, they can secrete sufficient estrogen to cause breast development and even vaginal withdrawal bleeding; some girls have recurrent cysts that lead to several episodes of vaginal bleeding. Patients with cysts may have levels of serum estrogen high enough to mimic a tumor. Larger follicular cysts can twist on their pedicles and become infarcted, causing symptoms of acute abdomen in addition to the precocious estrogen effects.
- Granulosa or theca cell tumors—These tumors of the ovaries secrete estrogen and are palpable in 80% of cases. Gonadoblastomas found in streak gonads, lipoid tumors, cystadenomas, and ovarian carcinomas are rare ovarian sources of estrogens or androgens.
- Adrenal rest tissue—Adrenal rest tissue has long been known to cause testicular enlargement and androgen secretion in boys, particularly with the increased ACTH secretion of congenital adrenal hyperplasia. Recently, however, a girl with an ovarian adrenal rest was reported to have hypertension, precocious puberty, Cushing's syndrome, and ovarian enlargement.
- Exogenous estrogen administration—Ingestion of estrogen-containing substances or even cutaneous absorption of estrogen can cause feminization in children. Epidemics of gynecomastia and precocious thelarche in Puerto Rico and Italy have variously been attributed to ingestion of estrogen-contaminated food, estrogens in the environment, or undetermined causes. One outbreak of gynecomastia in boys and precocious thelarche in girls in Bahrain was traced to ingestion of milk from a cow given continuous estrogen treatment by its owner to ensure uninterrupted milk production.
- Hypothyroidism—Severe untreated hypothyroidism can be associated with sexual precocity and galactorrhea (Van Wyk-Grumbach syndrome); treatment with thyroxine will correct hypothyroidism, halt precocious puberty and galactorrhea, and lower PRL levels. The cause of this syndrome was initially postulated to be increased gonadotropin secretion associated with the massive increase in TSH secretion. However, TSH can act on FSH receptors, causing gonadotropic effects due to elevated serum TSH concentrations.
- McCune-Albright syndrome—McCune-Albright syndrome is classically manifested as a triad of irregular café au lait spots, fibrous dysplasia of long bones with cysts, and precocious puberty. However, hyperthyroidism, adrenal nodules with Cushing's syndrome, acromegaly, hyperprolactinemia, hyperparathyroidism, hypophosphatemic hyperphosphaturic rickets, or autonomous endogenous functioning ovarian cysts are described in girls. Precocious puberty may be central or incomplete; longitudinal studies demonstrate that some patients start with incomplete precocious puberty and progress to central precocious puberty. Long-term follow-up of McCune-Albright patients reveals a high incidence of pathologic fractures and orthopedic deformities due to the bone cysts, as well as hearing impairment due to the thickening of the temporal area of the skull. Patients may have a mutation of the Arg201 in exon 8 of the gene encoding the G protein alpha subunit that stimulates cAMP formation; this mutation impairs GTPase activity of the alpha subunit and increases adenylyl cyclase activity leading to the endocrine abnormalities described above. This defect originates in somatic rather than germ cells, leading to genetic mosaicism wherever the defective gene product is expressed; thus, a wide variety of tissues are affected.
Incomplete Contrasexual Precocity in Girls
Excess androgen effect can be caused by premature adrenarche or more significant pathologic conditions such as congenital or nonclassic adrenal hyperplasia or adrenal or ovarian tumors. P450c21 adrenal hyperplasia can be diagnosed on the basis of elevated serum 17-hydroxyprogesterone concentrations in the basal or ACTH-stimulated state (other adrenal metabolites may be elevated depending upon the defect under investigation). (See Chapter 14.) Both adrenal and ovarian tumors generally secrete testosterone, while adrenal tumors secrete DHEA. Thus, the source of the tumor may be difficult to differentiate if it produces only testosterone; MRI or CT scanning may be inadequate to diagnose the tumor's organ of origin, and selective venous sampling may be needed.
Variations in Pubertal Development
- PREMATURE THELARCHE
The term “premature thelarche” denotes unilateral or bilateral breast enlargement without other signs of androgen or estrogen secretion of puberty. Patients are usually under 3 years of age; the breast enlargement may regress within months or remain until actual pubertal development occurs at a normal age. Areolar development and vaginal mucosal signs of estrogen effect are usually absent. Premature thelarche may be caused by brief episodes of estrogen secretion from ovarian cysts. Plasma estrogen levels are usually low in this disorder, perhaps because blood samples are characteristically drawn after the initiating secretory event. However, ultrasensitive estradiol assays do show a difference in estrogen production between control girls and those with premature thelarche. Classically, premature thelarche is self-limited and does not lead to central precocious puberty. However, there are reports of progression to central precocious puberty in a minority of cases, and follow-up for such progression is indicated.
- PREMATURE MENARCHE
In rare cases, girls may begin to menstruate at an early age without showing other signs of estrogen effect. An unproved theory suggests that they may be manifesting increased uterine sensitivity to estrogen. In most subjects, menses stop within 1–6 years, and normal pubertal progression occurs thereafter.
- PREMATURE ADRENARCHE
The term “premature adrenarche” denotes the early appearance of pubic or axillary hair without other signs of virilization or puberty. This nonprogressive disorder is compatible with a normal age at onset of other signs of puberty. It is more common in girls than in boys and
usually is found in children over 6 years of age, overlapping with the new age limits of puberty in girls. Plasma and urinary DHEAS are elevated to stage 2 pubertal levels, which are higher than normally found in this age group. Bone and height ages may be slightly advanced for chronologic age. Patients may have abnormal electroencephalographic tracings without other signs of neurologic dysfunction. The presenting symptoms of late-onset adrenal hyperplasia may be similar to those of premature adrenarche, and the differential diagnosis may require ACTH stimulation testing (see Chapter 9). Other abnormalities in ovulation and menstruation have been reported following premature thelarche. This condition may be related to ovarian hyperandrogenism (see Chapter 13). Intrauterine growth-retarded babies have a predilection to develop premature adrenarche; girls may also progress to a polycystic ovary type of condition, and boys and girls alike may develop insulin resistance.
- ADOLESCENT GYNECOMASTIA
Up to seventy-five percent of boys have transient unilateral or bilateral gynecomastia, usually beginning in stage 2 or 3 of puberty and regressing about 2 years later. Serum estrogen and testosterone concentrations are normal, but the estradiol:testosterone ratio may be elevated and SHBG concentrations may be high. Reassurance is usually all that is required, but some severely affected patients with extremely prominent breast development will require reduction mammoplasty if psychologic distress is extreme.
Aromatase inhibitors are in clinical trials as medical therapy for pronounced adolescent gynecomastia.
Some pathologic conditions such as Klinefelter's and Reifenstein's syndromes and the syndrome of incomplete androgen resistance are also associated with gynecomastia; these disorders should be clearly differentiated from the gynecomastia of normal puberty in males.
Differential Diagnosis of Precocious Puberty
The history and physical examination should be directed toward one of the diagnostic possibilities discussed above. Serum gonadotropin and sex steroid concentrations are determined in order to distinguish gonadotropin-mediated secondary sexual development (serum gonadotropin and sex steroid levels elevated) from autonomous endogenous secretion or exogenous administration of gonadal steroids (serum gonadotropin levels suppressed and sex steroid levels elevated).
Third-generation immunoassays can identify the onset of increased gonadotropin secretion with a single basal unstimulated serum sample. In the past, a GnRH test was required to confirm an increase in LH secretion at puberty because of the overlap of pubertal and prepubertal values of LH in the basal state. These third-generation gonadotropin assays can be applied to urine as well as serum samples; this may eliminate the need for GnRH testing and serial serum sampling.
If serum LH concentrations measured in an assay that cross-reacts with hCG are quite high in a boy or if a pregnancy screening test (βhCG) is positive, the likely diagnosis is an extrapituitary hCG-secreting tumor. β-LH values will be suppressed. If no abdominal or thoracic source of hCG is found, MRI of the head with particular attention to the hypothalamic-pituitary area is indicated to evaluate the possibility of a germinoma of the pineal gland.
If serum sex steroid levels are very high and gonadotropin levels are low, an autonomous source of gonadal steroid secretion must be assumed. If plasma gonadotropin and sex steroid levels are in the pubertal range, the most likely diagnosis is complete precocious puberty. In such patients, third-generation LH assays or the GnRH test will confirm the diagnosis (Table 15-5
Differentiation between premature thelarche and central precocious puberty is usually accomplished by physical examination, but determination of serum estradiol or gonadotropins may be required. The evaluation of uterine size by ultrasound may also be useful as premature thelarche causes no increase in uterine volume while central precocious puberty does; ovarian size determination is a less useful method of distinguishing between the two possibilities. As noted above, some girls initially thought to have precocious thelarche progress to complete precocious puberty, but there is no way to distinguish girls who will progress from those who will not.
The onset of true or complete precocious puberty may indicate the presence of a hypothalamic tumor. Boys more often than girls have central nervous system tumors associated with complete precocious puberty. Skull x-rays are not usually helpful, but CT or MRI scanning is indicated in children with true precocious puberty. The present generation of CT and MRI scanners can make thin cuts through the hypothalamic-pituitary area with good resolution; small hypothalamic hamartomas are now being diagnosed more frequently. Generally, MRI is preferable to CT scan because of better resolution; the use of contrast may help to evaluate possible central nervous system lesions.
Treatment of Precocious Puberty
- CENTRAL PRECOCIOUS PUBERTY
In the past, medical treatment of true precocious puberty involved medroxyprogesterone acetate or cyproterone
acetate, progestational agents that reduce gonadotropin secretion by negative feedback.
Table 15-5. Differential diagnosis of precocious puberty.
However, current treatment for precocious puberty due to a central nervous system lesion is much more effective. GnRH agonists are the preferred treatment for true precocious puberty to suppress sexual maturation and decrease growth rate and skeletal maturation. Chronic administration of highly potent and long-acting analogs of GnRH has been shown to down-regulate GnRH receptors and reduce pituitary gland response to GnRH, thereby causing decreased secretion of gonadotropin and sex steroids and rapidly stopping the progression of signs of sexual precocity. In girls, pubertal enlargement of the ovaries and uterus reverts toward the prepubertal state, and the multicystic appearance of the pubertal ovary regresses as well. This suppressive effect is reversed after therapy is discontinued. GnRH agonist treatment has been successful for idiopathic precocious puberty and precocious puberty caused by hamartomas of the tuber cinereum, neoplasms of the central nervous system, or long-term androgen exposure. The GnRH agonists were originally given by daily subcutaneous injection or intranasal insufflation; the successful use of these agents in microcapsules that are injected every 4 weeks or in depot preparations has now made treatment much easier and has improved compliance. Complete suppression of gonadotropin secretion is necessary because an incompletely suppressed patient may appear to have arrested pubertal development while actually secreting low but significant levels of sex steroids. Under these conditions, bone age advances while the growth rate is decreased, leading to even shorter adult stature. Side effects have generally been limited to allergic skin reactions and elevation of immunoglobulins directed against GnRH. Significant anaphylactic reactions to an injection have been reported. Decrease in bone mineral density is a potential side effect of GnRH agonists; increased dietary calcium supplementation is necessary. The FDA has approved histrelin, a GnRH agonist administered on a daily basis, and leuprolide acetate, a long-acting GnRH agonist, administered every 28 days for the management of precocious puberty. A daily dose form of leuprolide is also available. Individual monitoring is essential to ascertain gonadotropin suppression.
Growth velocity decreases within 5 months after the start of therapy, and rapid bone age advancement decreases to a rate below the increase in chronologic age. Without therapy, final height in patients with central precocious puberty approaches 152 cm in girls and 155–164 cm in boys. The first patients treated with GnRH agonists have now reached final height: The girls have a mean height of 157 cm and the boys a mean height of 164 cm—a definite improvement over the untreated state. The worst height prognosis is in children with an early diagnosis of precocious puberty who are not treated. The best outcomes of therapy are noted when diagnosis and therapy are achieved early, and as earlier diagnosis is now made in children with central precocious puberty and earlier therapy is offered, better results are expected in the future. Menarche is reported after the discontinuation of therapy in girls, indicating a reversion to normal pubertal endocrine function following GnRH agonist treatment. The new lower age limits of normal pubertal development in girls have led clinicians to reassess the criteria used to identify appropriate candidates for therapy. Patients without significant elevation of serum estrogen, who have a predicted height appropriate for family, and who have slowly progressing variants without early menarche may achieve an appropriate final height without therapy.
Psychologic support is important for patients with sexual precocity. The somatic changes or menses will frighten some children and may make them the object of ridicule. These patients do not experience social maturation to match their physical development, though their peers, teachers, and relatives will tend to treat them as if they were older because of their large size. Thus, supportive counseling must be offered to both patient and family. Evidence indicates that children with precocious puberty are more often sexually abused, so appropriate precautions are necessary.
- INCOMPLETE PRECOCIOUS PUBERTY
Treatment of the disorders discussed above under incomplete precocious puberty is directed toward the underlying tumor or abnormality rather than toward the signs of precocious puberty. If the primary cause is controlled, signs of sexual development will be halted in progression or may even regress.
Males with familial Leydig and germ cell maturation will not initially respond to GnRH agonist therapy, but some have improved with medroxyprogesterone acetate. Affected boys were successfully treated with ketoconazole, an antifungal agent that can block 17,20-lyase and therefore decrease testosterone production. After initial control with ketoconazole, the boys developed true precocious puberty, because prolonged exposure to androgens matured their hypothalamic-pituitary axis; treatment with a GnRH agonist then effectively halted this pubertal progression. Newer therapy involves the use of an aromatase inhibitor and an antiandrogen combination as for the treatment of McCune-Albright syndrome.
A successful therapy for McCune-Albright syndrome in girls is a combination of testolactone (an aromatase inhibitor) and spironolactone (which acts as an anti-androgen). Long-term follow-up demonstrated
some decrease in menses and improvement in growth patterns and bone age advancement. Some escaped from control, necessitating the addition of a GnRH agonist, which then suppressed pubertal development. Girls with recurrent estrogen-secreting ovarian cyst formation may have a decreased incidence of cysts with medroxyprogesterone acetate therapy, and a GnRH agonist may also be effective in such cases. Surgical removal of ovarian cysts may be unnecessary if such medical therapy is first utilized.
Precocious thelarche or adrenarche requires no treatment, as both are self-limited benign conditions. No therapy has been reported for premature menarche, and none may be indicated. Severe, persistent cases of adolescent gynecomastia have been treated successfully by testolactone and dihydrotestosterone heptanoate, though surgical removal of breast tissue is often necessary. Aromatase inhibitors may ultimately be approved for this use.
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