Chapter 15. Puberty

• ACTH Adrenocorticotropin
• AZF Azoospermia factor
• cAMP Cyclic adenosine monophosphate
• DHEA Dehydroepiandrosterone
• DHEAS Dehydroepiandrosterone sulfate
• FSH Follicle-stimulating hormone
• GH Growth hormone
• GnRH Gonadotropin-releasing hormone
• hCG Human chorionic gonadotropin
• HESX-1 Hesx-1 homeodomain
• HDL High-density lipoprotein
• HPLC MS/MS High performance liquid chromatography tandem mass spectroscopy
• hGH Human growth hormone
• ICMA Immunochemiluminometric assay
• IGF-1 Insulin-like growth factor 1
• KAL1 Kallmann syndrome
• LDL Low-density lipoprotein
• LH Luteinizing hormone
• LHX3 LIM homeobox gene 3
• PROP-1 Prophet of PIT 1
• PROK1 Prokineticin receptor 2
• PRL Prolactin
• PSA Prostate-specific antigen
• SHBG Sex hormone–binding globulin
• SF-1 Steroidogenic factor 1
• SHOX Short stature homeobox
• SRIF Somatostatin
• TGF-α Transforming growth factor alpha

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. This trend appears to be continuing but now due more to the effects of the obesity epidemic than the improvement in general health.

Many endogenous and exogenous factors can alter age at onset of puberty. While obesity may decrease the age of onset of puberty, 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. Recent study of genetic loci associated with the age of onset of puberty suggests the existence of several genes that are likely involved in the regulation of menarche and puberty.

Physical Changes Associated with Puberty

Descriptive standards proposed by Tanner for assessing pubertal development in males and females are in wide use (denoted as Sexual Maturation stages or, often, Tanner stages). 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 is used in clinical studies but reliability is less than that achieved by physical examination.

Female Changes

The first sign of puberty in the female, as noted in longitudinal studies, is an increase in height 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, although 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. Areolae become more pigmented and erectile as development progresses. Other features reflecting estrogen action include enlargement of the labia minora and majora, dulling of the vaginal mucosa from its prepubertal reddish hue to more of a pink color (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.

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. An endometrial stripe appears with the onset of puberty that is not found in premature thelarche. Ovaries enlarge with pubertal progression. Small cysts are normally present in prepubertal girls and a multicystic appearance develops during puberty, but the polycystic appearance seen in abnormalities of puberty or during the reproductive years in normal girls is not present. Experienced ultrasonographers can determine the developmental stage of the uterus and ovaries by comparing the results with established standards.

It is important to note that girls achieve reproductive maturity prior to physical maturity and certainly prior to psychologic maturity.

Male Changes

The first sign of normal puberty in boys is usually an increase in the size of the testes to more than 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 follicle-stimulating hormone (FSH), with a smaller component due to Leydig cell stimulation by luteinizing hormone (LH). Thus, if only Leydig cells are stimulated, as with a human chorionic gonadotropin (hCG)-secreting tumor, the testis does not grow as large as in normal puberty. Pubic hair development is brought about by adrenal and testicular androgen secretion and is classified separately from genital development, as noted in Figure 15–3. A longitudinal study of more than 500 boys suggests adding a stage 2a (absence of pubic hair in the presence of a testicular volume of 3 mL or more) to the classic five stages of pubertal development. 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 mean bone age; this usually occurs at gonadal stage 3 to 4 and pubic hair stage 2 to 4. 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 required for the presence of sperm in the urines of older children. However, boys are reported with spermaturia and no secondary sexual development.

It is important to note that boys achieve reproductive maturity prior to physical maturity and certainly prior to psychologic maturity.

Age at Onset

Ideally, the upper and lower boundaries encompassing the age at onset of puberty should be set at 2.5 standard deviations (SDs) above and below the mean (encompassing 98.8% of the normal population). Previously, there was no comprehensive study of the start of secondary sexual development adequate to determine the lower limits of normal in US children, as national studies began reporting children who were already 12 years of age or older. Thus, European standards, primarily those of Tanner, were modified for use in the United States. However, a study conducted in medical offices by specially trained pediatricians studying 17,070 girls brought in for routine visits provided information on girls in the United States as young as 3 years. The study revealed that 3% of white girls reach stage 2 breast development by 6 years of age and 5% by 7 years, whereas 6.4% of black girls had stage 2 breast development by 6 years and 15.4% by 7 years. Although this was not a randomly chosen population sampled by longitudinal study (and this led to controversy), it is the largest study available. These data led to the Lawson Wilkins Pediatric Endocrine Society statement that the diagnosis of precocious puberty could be 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. Recent analysis of data from NHANES III demonstrated that children of normal BMI values rarely have breast or pubic hair development before 8 years, although increased BMI in a subset of girls or Hispanic and African American ethnicity led to earlier development. It is essential to use any such guidelines only in healthy girls with absolutely no signs of neurologic or other disease that might pathologically advance puberty or a grave diagnosis may be missed.

Recent data indicate that boys with elevated body mass indices have earlier onset of puberty. However, there has been no change in the age at onset of puberty in boys in the general population, so 9 years is taken as the lower limit of normal pubertal development in males, whereas 13½ years is the upper limit of normal development (although 14 years is often used as a simplified limit). The mean age at menarche in the United States is 12.8 years 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. A compensation occurs in pubertal development so that those girls who enter puberty at the earliest ages of the normal range take more time to reach menarche, and those who enter at older ages of the normal range progress faster to menarche.

There is frequent discussion about an earlier age of puberty in children in the United States, which is demonstrated in some longitudinal studies in the US and abroad. The Bogalusa Heart Study shows that the gap between the age of menarche in Blacks and Whites has widened in the past decades, and this may be due to differing patterns of weight (and fat) gain. However longitudinal study from the Fells Institute shows that those girls who develop early have a tendency to increase their body mass index values after more than those who start puberty later. The presence or absence of menarche however, does not affect the interpretation of a BMI value. Late onset of pubertal development above the upper age limit of normal may indicate hypothalamic, pituitary, or gonadal failure or, alternatively, normal variation (constitutional delay). The time from onset of puberty until adult development is complete is also of importance; significant 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 involving thyroid hormone, growth hormone (GH), and estrogen. Hypothyroidism decreases or eliminates the pubertal growth spurt. The amplitude of GH secretion increases in puberty, as does production of insulin-like growth factor (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 estrogen are important in the pubertal growth spurt; when either or both are deficient, the growth spurt is decreased or absent. Estrogen indirectly stimulate IGF-I production by increasing the secretion of GH. It also directly stimulates IGF-I production in cartilage. Estrogen is 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 with 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 the bone density increased. Such 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.

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.

Twin studies from Finland demonstrate that the heritability estimate (proportion of variance of age of onset of puberty attributable to genetic variance) for age at onset of pubertal growth spurt was 0.91, 0.93 for age at peak height velocity, and 0.97 for adult height. In addition, the age at onset of the pubertal growth spurt was negatively associated with BMI in childhood.

Precocious puberty may coexist with GH deficiency: this situation may occur, for example, in a child with a brain tumor causing central precocious puberty, who is treated with central nervous system radiation that subsequently causes GH deficiency. The precocious puberty may raise the growth rate to the normal range, cloaking the GH deficiency but the child does not grow at the excessive rate characteristic of precocious puberty with GH sufficiency.

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 1½ times the lean body mass, skeletal mass, and muscle mass of women, whereas 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, whereas 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 genetic factors; decreased bone mass is found in familial patterns even if subjects are studied before puberty. Patients with delay in puberty for any reason have a significant decrease in bone accretion and a delay in reaching peak bone mineral density, although bone density may later reach normal values in those with constitutional delay in puberty. Moderate exercise increases bone mass, but excessive exercise itself delays puberty; the ultimate outcome of excessive exercise in girls is the combination of exercise-induced amenorrhea, premature osteoporosis, and disordered eating, which is known as the female athletic triad.

Unfortunately, in the United States, only a minority of adolescents receive the recommended daily allowance of calcium (>1000 mg/d depending on age) and vitamin D, and a future epidemic of osteopenia or even osteoporosis in normal subjects who have this deficiency is a possibility although genetic influences are prominent in later adult bone density. It is especially important to ensure adequate calcium intake and vitamin D in patients with delayed or absent puberty and in patients treated with gonadotropin-releasing hormone (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. For example, seborrheic dermatitis may appear, the mouth flora changes, and periodontal disease, rare in childhood, may occur. Insulin resistance intensifies in normal adolescents as well as those with type 1 diabetes mellitus.

Endocrine Changes from Fetal Life to Puberty

Pituitary gonadotropin secretion is controlled by the hypothalamus, which releases pulses of GnRH into the pituitary-portal system to reach the anterior pituitary gland by 20 weeks of gestation. 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 (see Chapter 13).

In males, LH stimulates the Leydig cells to secrete testosterone, and 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, and LH appears to play a minor role in the endocrine milieu until menarche. Then LH triggers ovulation and later stimulates the theca cells to secrete androgens (see Chapter 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 midgestation. Fetal serum concentrations of LH and FSH rise to a peak at midgestation and then gradually decrease until term. During the first half of gestation, hypothalamic GnRH content also increases, and the hypophyseal-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 central nervous system factors that inhibit GnRH release and decrease gonadotropin secretion after midgestation. Because 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 to operate after midgestation.

Changes at Birth

At term, serum gonadotropin concentrations are suppressed in the neonate, 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 to up to a few years after birth. Serum testosterone concentrations may be increased to midpubertal levels during the several months after birth in normal males, and serum estradiol rises in pulses for the first 2 years in infant girls. These peaks of gonadotropins and sex steroids in normal infants complicate the diagnosis of central precocious puberty at these youngest ages, because it is difficult to decide whether to attribute the gonadotropin and sex steroid peaks to central precocious puberty or to normal physiology (the mini-puberty of infancy). While episodic peaks of serum gonadotropins may occur until 2 years of age, serum gonadotropin concentrations are low during later years in normal childhood.

The Juvenile Pause or the Midchildhood Nadir of Gonadotropin Secretion

While serum gonadotropin concentrations are low in midchildhood, 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 before the development of physical pubertal changes. Patients with gonadal failure—such as those with the syndrome of gonadal dysgenesis (Turner 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. 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 midchildhood, 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 midchildhood is still higher than that found in healthy children of the same age. The decrease in serum gonadotropin concentrations in primary agonadal children during midchildhood 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 normal children and those with primary gonadal failure appears 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 of low amplitude with a pattern of low levels of sex steroid secretion lagging behind the gonadotropin rhythm. The delay is presumably due to the time necessary for biosynthesis and secretion of sex steroids. Thus, the changes that are described later and that occur at puberty do not arise de novo but are based on 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. 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, whereas afterward a far larger dose is required to suppress serum FSH and LH. Thus, an equilibrium of pubertal concentrations of gonadotropins and sex steroids is reached.

The switch that triggers the onset of puberty is unknown, but several neurotransmitters are invoked in the process, including gamma-aminobutyric acid and N-methyl-d-aspartate. Most recently, KISS1, a human metastasis suppressor gene at locus 19p13.3, which codes for metastin (or kisspeptin), a 145 amino acid peptide, has been implicated. Metastin is the endogenous agonist for GPR54, a Gq/11-coupled receptor of the rhodopsin family (metastin receptor), which is found in the brain, mainly in the hypothalamus and basal ganglia, as well as in the placenta. KISS1 mRNA levels increase with puberty in intact male and female monkeys from the juvenile to midpubertal stages. Furthermore, administration of KISS1 via intracerebral catheters to GnRH-primed juvenile female rhesus monkeys stimulates GnRH release, release that is abolished by infusion of GnRH antagonist. Thus, it is postulated that KISS1 signaling through the GPR54 receptor of primate hypothalamus may be activated at the end of the juvenile pause and contribute to the pubertal resurgence of pulsatile GnRH release of puberty, serving as a trigger for the onset of puberty.

Highly sensitive sandwich assays (immunoradiometric [IRMA]) and immunochemiluminometric assays (ICMA) are available for gonadotropin determination. They can be used to indicate the onset of pubertal development solely with basal samples usually without the necessity for GnRH testing (see GnRH and GnRH agonist testing in the Central Precocious Puberty section). Elevated basal 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. Note that standard LH and FSH assays are not sensitive enough to detect the changes seen with the ultrasensitive assays. Furthermore, the laboratory must have pubertal standard values available to permit accurate interpretation of the measurements. Since both types of assays are available commercially, care in ordering is needed.

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 midchildhood, gonadal activity decreases, but the testes can still be stimulated by LH or hCG and the 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, as are gonadotropins, sex steroids are bound to sex hormone–binding globulin (SHBG), so that 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 but still are not infallible.

Most (97%-99%) of the circulating estradiol and testosterone is associated with 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 compared with adult females. Thus, lower SHBG levels amplify androgen effects 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.

GnRH Stimulation

The use of intravenous, exogenous GnRH has further clarified the pattern of pubertal development. When GnRH is administered to children less than 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, intravenous GnRH or GnRH agonist 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 to 120 minutes in response to a central nervous system pulse generator. 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 demonstrates the normal pubertal pattern of episodic secretion of gonadotropins after only a few days of 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.

This phenomenon is used in clinical practice to bring about ovulation or spermatogenesis to foster fertility. 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 alter this ratio naturally. 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 later). 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) do not initiate puberty. Leptin replacement promotes pubertal development in this mouse, and leptin administration causes an immature normal mouse to progress through puberty. A leptin-deficient girl at 9 years of age was remarkably obese and had a bone age of 13 years (usually appropriate for the onset of normal puberty) but no significant gonadotropin pulses and no physical evidence of pubertal development. With leptin treatment, gonadotropin peaks appeared, and pubertal development followed. Individuals with leptin receptor deficiency also have disordered puberty. While these and other data suggested that leptin might be the elusive factor that triggers the onset of puberty, clinical data proved otherwise. Longitudinal studies demonstrate that 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 in relation to testosterone production. While leptin does not appear to trigger the onset of puberty in normal adolescents, leptin may accompany pubertal changes rather than cause them. Leptin is a necessary component of pubertal development in human beings but not a major stimulant to this development.

Ovulation and 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 midpuberty, estrogen in the appropriate amount at the appropriate time can stimulate gonadotropin release, whereas higher doses of estrogen can suppress gonadotropin secretion. 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 more 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 as noted earlier.

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 to 5 years after menarche that the percentage of anovulatory cycles decreases to less than 20%. This high prevalence of anovulatory periods may be due to unrecognized PCOS in the young rather than a normal developmental phenomenon in some individuals. However, some of the first cycles after menarche may be ovulatory, and fertility is possible in the first cycle.

Just as boys are reproductively mature prior to physical maturity, girls may become fertile and even pregnant prior to physical or emotional maturity.

Adrenarche

Although 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 to 7 years of age in girls and 7 to 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 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. This 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.

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 high-density lipoprotein (HDL) concentrations fall as a consequence of increasing testosterone. In both boys and girls, alkaline phosphatase rises normally during the pubertal growth spurt (often this rise is incorrectly interpreted as evidence for a tumor or liver abnormality). 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.

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 is classified as having delay in growth and adolescence. These normal patients need reassurance rather than treatment and 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 and 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 15–5). These patients are at the older end of the normal distribution curve describing the 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. 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 or GnRH agonist is pubertal. In boys, an 8 am serum testosterone value above 20 ng/dL (0.7 mmol/L) also indicates that secondary sexual development will commence within a period of months.

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 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 almost always manifest secondary sexual development by 18 years of chronologic age, although there is one reported case of spontaneous puberty occurring at 25 years of age. Reports of patients with Kallmann syndrome and others with constitutional delay in puberty within one family suggest a possible relationship between the two conditions (see later and Chapter 4). Adrenarche is characteristically delayed—along with gonadarche—in constitutional delay in puberty.

Hypogonadotropic Hypogonadism

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 suggests 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. Patients may reach taller stature than expected. However, if GH deficiency accompanies gonadotropin deficiency, severe short stature will result.

Central Nervous System Disorders

1. Tumors—A tumor involving the hypothalamus or pituitary gland can interfere with hypothalamic-pituitary-gonadal function as well as control of GH, adrenocorticotropic hormone (ACTH), thyrotropin (TSH), prolactin (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 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 (bitemporal hemianopsia is classic), optic atrophy, or papilledema. Clinical manifestations and laboratory evaluation may reflect endocrinopathies (found in 70%-75% including GH, axis abnormalities in 75%, hyperprolactinemia 48%, hypothyroidism in 25%, adrenal insufficiency in 25%, diabetes insipidus (DI) in 4.%, as well as gonadotropin deficiency in 40% in one series. Bone age is often retarded at the time of presentation.

   Calcification in the suprasellar region is the hallmark of craniopharyngiomas; 80% of cases have calcifications on lateral skull x-ray, and a higher percentage show this on computed tomography (CT); however, calcifications cannot be seen on magnetic resonance imaging (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 4). Recurrence of this tumor after apparent complete removal is noted and lends support to the use of radiation therapy in addition to surgery.

   Extrasellar tumors that involve the hypothalamus and produce sexual infantilism include germinomas, gliomas (sometimes with neurofibromatosis), and astrocytomas (see Chapter 4). However, depending on endocrine secretory activity or location, these tumors may alternatively produce central precocious puberty. Intrasellar tumors such as chromophobe adenomas are quite rare in children compared with adults. Hyperprolactinemia—with or without a diagnosed microadenoma or galactorrhea—may delay the onset or progression of puberty; with therapy to decrease PRL concentrations, puberty progresses.

2. Other acquired central nervous system disorders—These 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.

3. 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 CT or MRI (septo-optic dysplasia); associated hypothalamic deficiencies are often present (see Chapters 4 and 6) (Hesx-1 homeodomain, HESX-1 *601802. Homeobox gene expressed in ES cells; HESX-1 #182230, septooptic dysplasia).

   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/or posterior pituitary deficiencies may occur with either congenital midline defects or acquired hypothalamic-pituitary defects. Early-onset GH deficiency or early onset of a combination of anterior and posterior pituitary deficiencies suggests a congenital defect. Patients who have isolated deficiency of gonadotropins tend to be of normal height until the teenage years but lack a pubertal spurt. They have eunuchoid proportions of increased span for height and decreased upper to lower segment ratios. Their skeletal development is delayed for chronologic age during the teenage years, they continue to grow after an age when normal adolescents stop growing. Adult height is often increased in hypogonadotropic hypogonadal individuals.

4. Radiation therapy—Central nervous system radiation therapy involving the hypothalamic-pituitary area can lead to hypogonadotropic hypogonadism with onset at 6 to 18 months (or longer) after treatment. GH is more frequently affected than gonadotropin secretion, and GH 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 Gonadotropin Deficiency

Kallmann syndrome 1 is the most common genetic form of isolated gonadotropin deficiency (Figure 15–6). Gonadotropin deficiency in these patients is associated with hypoplasia or aplasia of the olfactory lobes and olfactory bulb causing hyposmia or anosmia. Remarkably, patients may not notice that they have no sense of smell, although olfactory testing reveals the finding. GnRH-containing neurons fail to migrate from the olfactory placode (where they originate) to the medial basal hypothalamus in Kallmann 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 syndrome is due to gene deletions in the region of Xp22.3 (+308700.KAL1), causing the absence of the KAL1 gene which codes for anosmin, which appears to code for an adhesion molecule that plays a key role in the migration of GnRH neurons and olfactory nerves to the hypothalamus. There is an association of Kallmann syndrome 1 with X-linked ichthyosis due to steroid sulfatase deficiency, developmental delay, and chondrodysplasia punctata, probably due to a microdeletion. Associated abnormalities in Kallmann syndrome 1 may affect the kidneys and bones, and patients may have undescended testes, gynecomastia, and obesity. Mirror hand movements (bimanual synkinesia) are reported, with MRI evidence of abnormal development of the corticospinal tract. Adult height is normal, although patients are delayed in reaching adult height. Kallmann syndrome 2 is inherited in an autosomal dominant pattern and is due to a mutation in the FGFR1 (fibroblast growth factor receptor 1 [*136350]) gene. Kallmann syndrome 3 (*607002) exhibits an autosomal recessive pattern and appears to be related to mutations in PROKR2 (*607123) and PROK2 (PROK2 *607002), encoding pokineticin receptor-2 and prokineticin-2. FGF8 may also be involved.

While kisspeptin and GRP54 (G protein–coupled receptor 54) play roles of importance in the onset of puberty, only rare patients have been reported with defects in the kisspeptin-GPR54 axis due to a mutation in the gene for the GRP54 receptor. The first human beings with defects in these molecules were reported in several kindreds, some consanguineous, presenting with hypogonadotropic hypogonadism. Other cases of hypogonadotropic hypogonadism may occur sporadically or in an autosomal recessive pattern without anosmia. The GnRH gene would seem a likely candidate for the cause of the condition, but while mutations of the GnRHreceptor gene, GnRHR, were noted years ago, not until 2009 were mutations in the GnRH1 gene demonstrated. Other mutations causing hypogonadotropic hypogonadism without anosmia include the GPR56, SF-1 (steroidogenic factor 1), HESX-1 (Hesx-1 homeodomain), 3 LHX3 (*600577) (LIM homeobox gene 3) PROP-1 (prophet of PIT1) (*601538) genes. X-linked congenital adrenal hypoplasia is associated with hypogonadotropic hypogonadism (DAX1 #300200). Adrenal hypoplasia, congenital AHC, glycerol kinase deficiency, and muscular dystrophy have also 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). While a specific genetic diagnosis for hypogonadotropic hypogonadism suggests a permanent defect, long-term studies do not bear this out. Men with a variety of mutations followed for years are reported to revert to normal or near-normal gonadotropin function in some cases. Thus, long-term follow-up is indicated.

Idiopathic Hypopituitary Dwarfism (Growth Hormone Deficiency in the Absence of Defined Anatomic or Organic Defects)

Patients with congenital GH deficiency have early onset of growth failure (Figure 15–7); 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 human growth hormone (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 due to one of the gene defects listed earlier.

The syndrome of microphallus (penile length <2 cm at birth 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 due to hypoglycemia (these findings may occur in septo-optic dysplasia). Patients with this syndrome do 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 enlarges with hGH therapy in these patients. It is important to note that microphallus due to hypopituitarism may be successfully treated with testosterone leading to adult male sexual function, and sex reversal should not be considered (see Chapter 14).

Birth injury, asphyxia, or breech delivery is more common in the neonatal history of patients with idiopathic hypopituitarism, especially affected males. While some subjects with breech delivery have central nervous system MRI abnormalities including interrupted pituitary stalk and ectopic posterior pituitary gland, cause and effect is not established as some individuals with breech delivery and hypopituitarism have no such MRI findings.

Miscellaneous Disorders

1. Prader-Willi syndrome—Prader-Willi syndrome (#176270) occurs sporadically and is associated with fetal and infantile hypotonia, short stature, poor feeding in infancy but insatiable hunger later, leading to remarkable 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 is common; while there is hypothalamic hypogonadism, there is also testicular dysfunction in males. Osteoporosis is common in these patients during the teenage years, but sex steroid replacement, when indicated, may increase bone density, although the effects are not proven to be long lasting if sex steroids administration cease. Behavioral modification may improve the usual pattern of rampant weight gain, but the constant vigilance of caregivers is necessary. Patients have deletion or translocation of chromosome 15q11-13 derived from their fathers. 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 commercially for diagnosis.

2. 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 syndrome (#209900) a disorder thought to be linked to a defect in the basal body of ciliated cells) and Laurence-Moon syndrome has been made, with the latter demonstrating polydactyly and obesity and the former being characterized by paraplegia. Recently it has been suggested that these two syndromes really represent a single entity, as was the case in the past.

3. 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, although they ultimately reach an appropriate adult height for family. Children with other chronic diseases may not fare so well in long-term follow-up; for example, HIV infection in adolescence causes poor growth and pubertal progression. Weight loss to less than 80% of ideal body 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.

4. Anorexia nervosa—Anorexia nervosa involves weight loss associated with a 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, although 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 GH and decreased IGF-I (these are characteristic of other types of starvation), decreased serum triiodothyronine, decreased serum 1,25-dihydroxyvitamin D and elevated 24,25-hydroxyvitamin D levels. 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 that indicate a reversion to an earlier stage of the endocrine changes of puberty.

5. Increased physical activity—Girls who regularly participate in activities such as strenuous athletics and ballet dancing may have delayed thelarche, delayed menarche, and irregular or absent menstrual periods. Increased physical activity and not decreased weight appears to be the cause of the amenorrhea in some girls; such amenorrheic patients may resume menses while temporarily bedridden even though weight does not yet change. 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 studies indicating that intensive gymnastics training at an early age leads to a decrease in ultimate stature.

6. 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 PRL due to TSH stimulation. With thyroxine therapy, catch-up growth and resumed pubertal development and menses occur. Conversely, severe primary hypothyroidism may be associated with precocious puberty and galactorrhea (due to elevated serum PRL) in some patients (Van Wyk-Grumbach syndrome). There is evidence that excessive TSH can stimulate FSH receptors, leading to estrogen secretion and breast development.

Hypergonadotropic Hypogonadism

Primary gonadal failure is heralded by elevated gonadotropin concentrations due to the absence of negative feedback effects of gonadal sex steroids and inhibin. The most common causes of hypergonadotropic hypogonadism are associated with chromosomal and somatic abnormalities (see Chapter 14), 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 later), 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; eg, the incidence in Scandinavia is rising but still 0.5 per 100,000 in childhood).

Syndrome of Seminiferous Tubule Dysgenesis (Klinefelter Syndrome)

A common form of primary testicular failure is Klinefelter syndrome (47,XXY karyotype), with an incidence of 1:1000 males. Before puberty, patients with Klinefelter 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. Surviving sperm have been found by microdissection of some seminiferous tubules in a few patients leading to successful fertilization of a partner's ovum. 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 syndrome; they may have the SRY gene translocated to an X chromosome (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 with chemotherapy before puberty, although they demonstrate 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 mutation in a gene at Yq11.23, the azoospermia factor (AZF) (#415000 spermatogenic failure, nonobstructive, Y-linked) appears to play a role in the lack of production of spermatocytes.

Patients with Down 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 greater than 2 ng/mL 72 hours after intramuscular administration of hCG (3000 U/m2) in the newborn period, although repeated doses are required after the first postnatal months. Testes may also descend during 2 weeks of treatment with hCG given three times a week.

Patients with increased plasma testosterone levels in response to hCG 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. Since both the descended and the undescended testes may be affected, there may be preexisting disease that is manifested by the lack of descent of one testis. Lack of normal descent of the testes is hypothesized to cause the testicular dysgenesis syndrome (TDS), which explains the late occurrence of testicular disease. 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. This finding may depend on the surgical technique used.

It is important to determine if any testicular tissue is present in a boy with no palpable testes, because unnoticed malignant degeneration of the tissue is a possibility. The diagnosis of anorchia due to the testicular regression syndrome may be pursued by ultrasound, MRI, laparotomy, or laparoscopic examination. There are other endocrine evaluations besides the hCG test that may help in diagnosis. The presence of anti-Müllerian factor in a young child indicates the presence of testicular tissue, although during puberty anti-Müllerian factor becomes undetectable, and this test cannot be employed at that stage. Inhibin may be measured as an indication of functioning testicular tissue. Except for the absence of testes, 46 XY patients who are otherwise normal and have the vanishing testes syndrome of late fetal loss of the testes 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 (see Chapter 14). When these boys reach adulthood, they are reported to establish a normal male gender identity. The presence of normal basal gonadotropin levels in a prepubertal boy without palpable testes at least suggests the presence of testicular tissue even if the testosterone response to hCG is low, whereas the presence of elevated gonadotropin levels without any testosterone response to hCG suggests anorchia.

Syndrome of Gonadal Dysgenesis (Turner Syndrome)

45,XO 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; it is now difficult for laboratories to perform the test reliably, and it has been replaced with modern karyotyping procedures. 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 proximal to the coarctation). However, some affected girls can have almost normal female phenotypes. The medical history of patients with the syndrome of gonadal dysgenesis often reveals 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 syndrome are applied to this neonatal appearance.) Affected patients often have a history of frequent otitis media with conductive hearing loss. There may be frequent urinary tract infections associated with a horseshoe-shaped kidney, duplication of ureters, or other anatomic defects. Intelligence is normal, but there is often impaired spatial orientation, which may lead to difficulty in mathematics, especially geometry. Patients have no pubertal growth spurt, and reach a mean final height of 143 cm. Short stature is a classic feature of Turner syndrome, but not of other forms of hypergonadotropic hypogonadism that occur without karyotype abnormalities. The short stature is linked to the absence of the (short stature homeobox) SHOX homeobox gene of the pseudoautosomal region of the X chromosome (Xpter-p22.32) (OMIM*312865). GH function is usually normal in Turner syndrome. However, exogenous hGH treatment improves growth rate and increases adult stature toward the normal range in affected girls. It improves lipid profiles and decreases diastolic blood pressure (see Chapter 6). Pubic hair may appear late and is usually sparse in distribution owing to the absence of any ovarian secretions; thus, adrenarche progresses in Turner syndrome even in the absence of gonadarche. Autoimmune thyroid disease (usually hypothyroidism) is common in Turner syndrome, and determination of thyroid function and thyroid antibody levels is important in evaluation of these patients.

Serum gonadotropin concentrations in Turner syndrome are extremely high between birth and about 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 syndrome, whereas others may have ambiguous genitalia or even the features of phenotypic males. Gonads are usually dysgenetic but vary from streak gonads to functioning testes. These patients are at risk for gonadoblastoma formation; this is a benign tumor that has the potential for malignant transformation and then may metastatize. Because 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. Polymerase chain reaction techniques to search for specific Y chromosome sequences may be helpful if a karyotype reveals no Y chromosomal material.

Patients with Turner syndrome who desire fertility can be treated with 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 support with exogenous hormone administration. A serious possible complication is uterine rupture.

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. Bone marrow transplantation with whole-body irradiation for acute lymphoblastic leukemia or non–Hodgkin lymphoma appear to cause the most damage to endocrine function.

Premature menopause has also been described in otherwise healthy girls owing to the presence of anti-ovarian antibodies. Patients with Addison disease may have autoimmune oophoritis as well as adrenal failure. A sex steroid biosynthetic defect due to 17α-hydroxylase deficiency (P450c17) manifests as sexual infantilism and primary amenorrhea in a phenotypic female (regardless of genotype) with hypokalemia and hypertension (see Chapter 14). A patient with 17α-hydroxylase deficiency may have ovaries or testes and still present as a phenotypic female.

Noonan Syndrome (Pseudo–Turner Syndrome, Ullrich Syndrome, Male Turner Syndrome (Omim#163950 Noonan Syndrome 1; NS1)

Noonan syndrome is associated with phenotypic manifestations of Turner syndrome such as webbed neck, ptosis, short stature, cubitus valgus, and lymphedema, but other additional clinical findings such as a normal karyotype, triangular facies, pectus excavatum, right-sided heart disease, and an increased incidence of developmental delay differentiate these patients from those with Turner syndrome. Males may have undescended testes and variable degrees of germinal cell and Leydig cell dysfunction. Noonan syndrome follows an autosomal dominant pattern of inheritance with incomplete penetrance (gene locus 12q24). hGH is approved by the FDA to increase stature in these patients.

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 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 may 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 (OMIM #277000) 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.

46,XY disorder of sexual development (DSD), previously called 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 4½ 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 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.

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 syndrome and others with constitutional delay are occasionally found in the same kindred.

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 due to primary gonadal failure or (2) decreased due to secondary or tertiary hypogonadism or constitutional delayed puberty. Gonadotropins must be measured in a third generation assay with pediatric standards as the customary gonadotropin determinations are too insensitive to reveal the small changes of puberty. A single ultrasensitive, 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 or GnRH agonist is helpful in differential diagnosis; secondary sexual development usually follows within months after conversion to a pubertal LH response to GnRH. Because it is difficult, if not impossible, to obtain GnRH presently, GnRH agonists are more frequently used for diagnosis with serum LH values measured 2 hours after administration. 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 or GnRH agonist testing but is too cumbersome for most clinical settings. 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 20 ng/dL (0.7 mmol/L) indicates the likelihood of pubertal development within 6 months. Measurement of testosterone or estradiol must be done in an ultrasenstivie assay with pediatric standards or, as with gonadotropin assays, the small changes of pubertal development will be missed. Presently highly sensitive high performance liquid chromatography tandem mass spectroscopy (HPLC MS/MS) assays are available at national laboratories for this purpose.

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 deficiencies should immediately lead to investigation for central nervous system tumor or congenital defect in a patient with delayed puberty. CT or MRI scanning is 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 that they have significant psychologic problems may require psychological evaluation and therapy 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. Although the majority of these patients do quite well, severe depression must be treated appropriately, because short patients with pubertal delay have become suicidal. In some cases, it helps to excuse the patient from physical education class, because 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.

New preparations of topical sex steroids, that have different systemic effects and length of action than parenteral or oral sex steroids, have enlarged the therapeutic armamentarium for delayed puberty. The classic recommendation for girls has been a 3-month course of conjugated estrogen (0.3 mg) or ethinyl estradiol (5-10 μg) given orally each day. Topical estrogen is said to carry less risk of hypertension, gallstones, increased fat mass, decreased insulin sensitivity, and increased triglycerides (topical estrogen does not, however, increase HDL cholesterol and decrease low-density lipoprotein [LDL] cholesterol, as does oral estrogen). Estrogen-impregnated patches are available and might be used to initiate puberty, but the lowest dose available leads to serum estrogen values higher than physiologic levels found in early puberty. They might be used for only a few days each week to reduce the delivered dose. Alternatively, 17-beta estradiol patches (0.025 mg/patch; Vivelle Dot matrix patch) may be cut into fragments the size of one-eighth to one-fourth of a patch fragments to initiate pubertal development with more physiologic estrogen values. However, the use of such topical estrogen preparations is not approved by the Food and Drug Administration (FDA).

The classic recommendation for boys is a 3-month course of testosterone enanthate or cypionate (50 mg) given intramuscularly once every 28 days for three doses. The possibility that a higher dose will cause priapism limits the initial dose to 50 mg. New patch or testosterone gel preparations could be used to initiate puberty, but the dose in manufactured packets is too high to mimic the physiologic levels found in early puberty. These preparations are made for full replacement in adult males. The entire gel packet or lowest-dose patch could be used every other day over the 3-month period of treatment, although this leads to variable daily dosage. The gel is available in a pump but even one pump dose is too high for the initial therapy. The testosterone patches are not impregnated like the estrogen patches and cannot be cut down in size. Thus, to date, the low-dosage injection of testosterone or the use of an estimated one-half or less of the 5 mg testosterone gel packet are the only methods of reaching appropriate dosage. The topical use of testosterone is not approved by the FDA for such purposes. Therapy with oxandrolone has been suggested as a method of increasing secondary sexual development and increasing growth without advancing skeletal development. This method is not widely preferred. Furthermore, testosterone, which can be aromatized, increases the generally low endogenous GH secretion in constitutional delayed puberty to normal, whereas oxandrolone, which cannot be aromatized, does not increase GH secretion.

Hormonal treatment of boys or girls elicits noticeable secondary sexual development and a slight temporary increase in stature. The low doses recommended do not advance bone age substantially and do not significantly change adult height if used for 3 months. Low-dose sex steroid treatment has been reported to promote spontaneous pubertal development after sex steroid therapy is discontinued, although 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. However, 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, because it advances bone age and leads to epiphyseal fusion and a decrease in ultimate stature. After a 3- to 6-month break to observe spontaneous development, a second course of therapy may be offered if no spontaneous pubertal progression occurs during observation.

Permanent Hypogonadism

Once a patient has been diagnosed as having delayed puberty due to permanent primary or secondary hypogonadism, replacement therapy must be considered at the average age of onset of puberty, in most cases when the diagnosis is made in childhood.

Males with hypogonadism may be treated with testosterone gel, testosterone patches, or testosterone enanthate or cypionate given intramuscularly every month, as described earlier for temporary conditions. Treatment as for constitutional delay should be started and gradually increased to the adult range over months to years to mimic the normal progression of puberty and to avoid abrupt exposure to high-dose androgen and the possibility of frequent erections or priapism. Oral halogenated testosterone and methylated testosterone are never recommended because of the risk of hepatocellular carcinoma or cholestatic jaundice. 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 testicular androgen secretion in addition to the exogenous testosterone.

Testosterone gel or patches, as described earlier, are used for permanent replacement but are not FDA-approved for individuals less than 16 years. Girls may be treated with oral ethinyl estradiol (increasing from 5 μg/d to 10 to 20 μg/d depending on clinical results), or conjugated estrogens (0.3 or 0.625 mg/d). One may start with daily doses with eventual conversion to treatment on days 1 to 21 of the month after several months of daily ingestion. Five to ten milligrams of medroxyprogesterone acetate are then added on days 12 to 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 to simplify treatment. As described earlier, estrogen patch therapy may have benefits (but these are not proven) over oral estrogen and may be preferable (but these are not FDA-approved for individuals under 16 years of age). Gynecologic examinations should be performed yearly for those on replacement therapy.

Hypothalamic hypogonadism may be treated with GnRH pulses by programmable pumps to achieve fertility or to promote pubertal development. 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 epiphyseal fusion. If such a patient has not yet received adequate treatment with GH, sex steroid therapy may be kept at the lower dosage or even delayed to optimize 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 GH secretion in 24-hour profiles of spontaneous secretion or in stimulated testing. GH secretion increases when pubertal gonadal steroid secretion rises due to the effects of estrogen, so decreased GH secretion in this condition should be considered temporary. Nonetheless, true GH-deficient patients may have delayed puberty due to the GH 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, whereas 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 adult height. However, low-dose estrogen therapy (5-10 μg of ethinyl estradiol orally) can be administered to allow feminization and improve psychologic status at 12 to 13 years of age without decreasing final height, as shown in several studies. Low-dose estrogen increases growth velocity, whereas high-dose estrogen suppresses it. Even if growth velocity is increased, however, adult height is not increased with such estrogen treatment. Treatment of Turner syndrome with GH successfully increases adult stature (see Chapters 6 and 14). During childhood these girls must be regularly screened for strabismus, hearing loss, and autoimmune thyroid disease as well as learning difficulties. There are several recommendations for the preparation of these girls to transition to adult care and necessary follow-up for issues that will affect their later life, including monitoring for the development of aortic dilation at 5- to 10-year intervals since this defect may progress to aortic aneurysms. The induction of fertility was described earlier in this chapter.

Bone Mass

After infancy, most bone mass accrual takes place during the second decade of life, and disorders of puberty may affect this process. Delayed puberty in boys causes decreased cross-sectional bone density, when the subjects are tested as young adults, because they have not yet reached peak bone acquisition. Although there is some controversy, it appears likely that normalization of volumetric bone density occurs with maturity and exposure to a normal androgen milieu. A range of defects in girls such as anorexia nervosa, athletics-induced delayed puberty, and Turner syndrome also cause decreased bone density. The use of testosterone in boys and estrogen and progesterone in girls with hypogonadotropic hypogonadism 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 and vitamin D should be encouraged in hypogonadal or constitutionally delayed patients as well as in normal children at least as a common sense measure. No long-term follow-up is yet available, however, to prove the efficacy of this therapy in susceptible subjects.

All sources agree that the appearance of secondary sexual development before the age of 9 years in boys is precocious puberty. However, there remains controversy over the lower limits of normal in girls. There is acceptance by the Pediatric Endocrine Society that the appearance of secondary sexual development before the age of 7 years in Caucasian girls and 6 years in African-American girls constitutes precocious sexual development but others remain concerned that pubertal development between 7 and 8 years for Caucasian and 6 and 8 for African American girls indicate a pathological state (Table 15–4). However, if a girl has the onset of puberty before 8 years, one must have a high index of suspicion for pathology. The child must have absolutely no sign of central nervous system disorder or other possible cause that might trigger pathologic precocious puberty. A careful search for historical or physical features of organic disease must occur before a girl with precocious puberty between 6 or 7 and 8 is considered normal. When the cause of precocious puberty is premature activation of the hypothalamic-pituitary axis and the condition is gonadotropin dependent, 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 condition is not gonadotropin-dependent, and the diagnosis is incomplete precocious puberty. If feminization occurs in girls and virilization occurs in boys, the condition is isosexual precocity, but if the feminization occurs in boys and virilization in girls, the condition is contrasexual precocity. In all forms of sexual precocity, there is an increase in growth velocity, somatic development, and skeletal maturation. When unchecked, this rapid skeletal 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 are appropriate for pubertal stage in untreated precocious puberty.

Central (Complete or True) Precocious Puberty

(Figure 15–8)

Constitutional or Familial Central (Complete or True) Precocious Puberty

Otherwise normal children who demonstrate isosexual precocity at an age slightly more than 2.5 SD below the mean may simply represent the lower reaches of the distribution curve describing the age of onset of puberty; often there is a familial tendency toward early puberty. True precocious puberty is reported, rarely, to be due to an autosomal dominant or (in males) X-linked dominant trait.

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. Epilepsy and developmental delay are associated with central precocious puberty in the absence of a central nervous system anatomic abnormality, indicating a central nervous system process is responsible for the condition.

Pubertal development may follow the normal course or may wax and wane. Serum gonadotropin and sex steroid concentrations and response to GnRH or GnRH agonists 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 on elevated body mass index in the untreated state. While families with inactivating mutations of the GRP54 gene experience absent or delayed puberty, a patient presented with isosexual precocious puberty and demonstrated a mutation of GRP54 that led to prolonged activation of intracellular signaling pathways in response to kisspeptin. This further emphasizes the importance of the GRP54 Kisspepetin axis in the control of puberty.

Central Nervous System Disorders

1. Tumors—Central nervous system tumors are more common causes of central precocious puberty in boys than in girls but may occur in either, so a high index of suspicion is essential. 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. Patients with optic gliomas and neurofibromatosis type 1 may have precocious puberty, but no patients with isolated neurofibromatosis (that did not have optic gliomas) are reported with 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. Reportedly, complete removal of craniopharyngiomas is associated with unexpected recurrence; radiation therapy appears to be a key therapy for this tumor in addition to surgery.

   Hamartomas of the tuber cinereum contain GnRH and neurosecretory cells similar to those 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 transforming growth factor (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 enlarge and so pose no additional threat to the patients in the absence of intractable seizures. These seizures are rare in patients with the pedunculated hamartomas causing central precocious puberty. Because of the location of the hamartoma, surgery is a dangerous alternative to GnRH analog therapy.

   Tumors or other abnormalities of the central nervous system may cause GH deficiency in association with central precocious puberty. GH deficiency may also occur after irradiation therapy for such tumors, even if precocious puberty was the sole endocrine finding before irradiation. Such patients grow much faster than isolated GH-deficient patients but slower than children with classic precocious puberty and adequate GH secretion. Often, the GH deficiency is unmasked after successful treatment of precocious puberty. This combination must be considered during the diagnostic process (see also Chapter 6).

2. 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 there are increasing reports of precocious puberty occurring after such therapy. Higher doses of radiation may be more likely to cause GnRH deficiency, and lower doses down to 18 Gy may lead to central precocious puberty.

Virilizing Syndromes

Patients with long-untreated virilizing adrenal hyperplasia who have advanced bone ages may manifest precocious puberty after treatment 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 in Boys

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 administration of hCG, 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 does 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 since only Leydig cells are stimulated by hCG.

Autonomous Androgen Secretion

Secretion of androgens can occur because of inborn errors of adrenal enzyme function, as in 21-hydroxylase deficiency (P450c21 OMIM#201910 adrenal hyperplasia, congenital, caused by 21-hydroxylase) or 11β;-hydroxylase deficiency (P450c11β; OMIM#202010). Adrenal hyperplasia, congenital, caused by steroid 11-beta-hydroxylase deficiency), virilizing adrenal carcinomas, interstitial cell tumors of the testes, or premature Leydig and germinal cell maturation. 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 (see Chapter 14).

In boys with familial gonadotropin-independent premature Leydig and germinal cell maturation (#176410. precocious puberty, male-limited), 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 (leaving the LH receptor on), causing increased cyclic adenosine monophosphate (cAMP) production in the absence of LH. Several mutations have been reported in the LH receptor gene in different families (eg, Asp578 to Gly or Met571 to 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. As only the Leydig cells are stimulated and because 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.

Incomplete Contrasexual Precocity in Boys

Estrogen may be secreted by rare adrenal tumors leading to feminization in boys. Sertoli cell tumors associated with Peutz-Jeghers syndrome is another possible etiology.

Incomplete Isosexual Precocious Puberty in Girls

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.

Other Ovarian Tumors

Granulosa or theca cell tumors of the ovaries secrete estrogen and are palpable in 80% of cases. Gonadoblastomas are found in streak gonads, lipoid tumors, and cystadenomas. 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 untreated or incompletely congenital adrenal hyperplasia. While the hyperplastic tissue is not a neoplasm by itself, neoplastic transformation may follow.

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, soy formula, 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 which was given continuous estrogen treatment by its owner to ensure uninterrupted milk production. Tea tree and lavender oils have estrogenic effects in children and exposure can cause thelarche.

Hypothyroidism

Severe untreated hypothyroidism can be associated with sexual precocity and galactorrhea (Van Wyk-Grumbach syndrome); treatment with thyroxine corrects hypothyroidism, halts precocious puberty and galactorrhea, and lowers PRL levels. The cause of this syndrome was initially postulated to be increased gonadotropin secretion associated with the massive increase in TSH secretion. However, it appears that TSH, at high concentrations, can activate FSH receptors.

Mccune-Albright Syndrome

McCune-Albright syndrome (#174800. McCune-Albright syndrome; MAS) 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 syndrome, acromegaly, hyperprolactinemia, hyperparathyroidism, hypophosphatemic hyperphosphaturic rickets, or autonomous endogenous-functioning ovarian cysts (in girls) also occur. 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 patients with McCune-Albright syndrome 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. Thickening of the skull base can impinge on local brain structures with fatal consequences. Bone growth may be partly mediated by elevated GH secretion and may cease with somatostatin analogue therapy. Patients may have a mutation of Arg201 in exon 8 of the gene encoding the Gs alpha subunit that stimulates cAMP formation; this mutation impairs GTPase activity of the alpha subunit and increases adenylate cyclase activity leading to the endocrine abnormalities described earlier. 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 can be 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 on the defect under investigation) (see Chapter 14). Both adrenal and ovarian tumors are associated with elevation of serum testosterone; 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. The rare families reported with aromatase deficiency had contrasexual development although not precocious puberty per se. One affected 46,XX individual had virilized genitalia at birth and further virilization at a pubertal age with the additional feature of polycystic ovaries. The patient, in spite of high serum testosterone concentrations, had elevated FSH and LH in the absence of estrogen production.

Variations in Pubertal Development

Premature Thelarche

The term premature thelarche denotes unilateral or bilateral breast enlargement without other signs of androgen or estrogen secretion. Patients are usually younger than 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 or minimal. 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 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. Other abnormalities in ovulation and menstruation have been reported following premature thelarche. Recently, girls with fluctuating thelarche were reported as having mutations in the GNAS1 gene, though without other signs of McCune-Albright syndrome.

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 to 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 then the occurrence of other signs of puberty at the normal age for puberty. Prematue adrenarche is more common in girls than in boys, and premature adrenarche is usually found in children over 6 years of age. Sometimes premature adrenarche can overlap with the new age limits of puberty in girls. Plasma and urinary DHEAS levels are elevated to stage 2 pubertal levels, higher than normally found in this age group but well below those seen with. 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 14). This condition may also present in a manner similar to polycystic ovarian syndrome (see Chapter 13). Infants born small for gestational age (SGA) have a predilection to develop premature adrenarche. These girls may also progress to polycystic ovarian syndrome. Daughters of women with PCOS demonstrate elevated androgen concentrations before the age of puberty, and these daughters may progress themselves to develop PCOS.

Adolescent Gynecomastia

Up to 75% 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 require reduction mammoplasty if psychologic distress is extreme. After 2 years of gynecomastia, the likelihood of spontaneous regression decreases due to the formation of scar tissue. Early studies of aromatase inhibitors in the medical treatment of gynecomastia were disappointing, but more recent evaluation of anastrazole demonstrate promise.

Some pathologic conditions such as Klinefelter and the syndromes 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 earlier. Serum gonadotropin and sex steroid concentrations are determined in order to distinguish gonadotropin-mediated secondary sexual development (serum gonadotropin and sex steroid levels elevated to pubertal levels) from autonomous endogenous secretion or exogenous administration of gonadal steroids (serum gonadotropin levels suppressed and sex steroid levels elevated). Gonadotropins must be measured in a third generation assay with pediatric standards as the customary gonadotropin determinations are too insensitive to reveal the small changes of puberty.

Measurement of testosterone or estradiol must be done in an ultrasensitive assay with pediatric standards or, as with gonadotropin assays, the small changes of pubertal development will be missed. Presently highly sensitive high performance liquid chromatography tandem mass spectroscopy (HPLC MS/MS) assays are available at national laboratories for this purpose. Third-generation ultrasensitive 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 someday eliminate the need for GnRH agonist testing or 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 (β;-hCG) is positive, the likely diagnosis is an extra-pituitary, hCG-secreting tumor. β;-LH values are suppressed, so no confusion with hCG levels is possible. If no abdominal or thoracic source of hCG is found, MRI of the brain 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 in third-generation assays, 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 (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, because premature thelarche causes no increase in uterine volume while central precocious puberty does and also is associated with an "endometrial stripe." Ovarian size determination is a less useful method of distinguishing between the two possibilities but may reveal pubertal ovarian cysts. As noted earlier, some girls initially thought to have precocious thelarche progress to complete precocious puberty, but there is no way presently 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 because of better resolution; the use of contrast may help 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.

However, current treatment for precocious puberty due to a central nervous system lesion involves the use of GnRH agonists that 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 downregulate GnRH receptors and reduce pituitary gland response to GnRH, thereby causing decreased secretion of gonadotropin and sex steroids and rapidly stopping the progression 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 and puberty progresses. 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. Injection of these agents every 4 weeks 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 of these agonists have generally been limited to allergic skin reactions and elevation of immunoglobulins directed against GnRH. Significant anaphylactic reactions to an injection have rarely been reported. Decrease in bone mineral density is a potential side effect of GnRH agonists; increased dietary calcium and recommended vitamin D intake supplementation is wise especially in the era of frequent deficiencies of these in all children. 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 approved for precocious puberty but a 3-month preparation is presently only approved for adults. Individual monitoring is essential to ascertain gonadotropin suppression. A new implantable depot preparation of GnRH agonist may be left in for 1 year without the requirement for frequent monitoring.

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, height in patients with central precocious puberty approaches 152 cm in girls and 155 to 164 cm in boys. The first patients treated with GnRH agonists have now reached adult 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 found 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 and even pregnancy are 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 will likely achieve an appropriate adult height without therapy. Psychologic support is important for patients with sexual precocity. The somatic changes or menses frighten some children and may make them the object of ridicule. These patients do not experience social maturation to match their physical development, although their peers, teachers, and relatives 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. Children with precocious puberty are more often sexually abused, so appropriate precautions are necessary.

Incomplete Precocious Puberty

Treatment of the disorders discussed earlier 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 are halted in progression or may even regress.

Males with familial Leydig and germ cell maturation do 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. Ketoconazole also suppresses adrenal function as a significant side effect. After initial control with ketoconazole, the boys developed central precocious puberty, because prolonged exposure to androgens led to maturation of their hypothalamic-pituitary axis; treatment with a GnRH agonist then effectively halted this pubertal progression.

Newer therapy for McCune-Albright syndrome in girls is a combination of testolactone (an aromatase inhibitor) and spironolactone (which acts as an antiandrogen). Long-term follow-up demonstrated some decrease in menses, improvement in growth patterns and bone age advancement. Some escaped from control, necessitating the addition of a GnRH agonist, which then suppressed pubertal development. Tamoxifen, an estrogen agonist and antagonist, combined with aromatase inhibitors (such as anastrazole or newer agents such as letrazole) has been successfully used to decrease uterine bleeding and advancement in bone age in clinical trials. Girls with recurrent estrogen-secreting ovarian cyst formation may have a decreased incidence of cysts with medroxyprogesterone acetate therapy. 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. Severe, persistent cases of adolescent gynecomastia have been reportedly treated successfully by testolactone and dihydrotestosterone heptanoate, although surgical removal of breast tissue is often necessary, as noted earlier.

General

Physical Changes Associated with Puberty

Delayed Puberty and Sexual Infantilism

Sexual Precocity