Chapter 3: Puberty

Puberty is the transitional process leading to reproductive maturity. Proper diagnosis and management of pubertal disorders requires understanding of (1) basic endocrinology of the hypothalamic-pituitary-gonadal axis; (2) developmental changes that occur at different points throughout childhood; and (3) the wide variability in timing of physical changes of puberty seen in normal children.

The three anatomic sites most pertinent to pubertal development are the hypothalamus, the anterior pituitary gland, and the gonads (ovaries or testes), known collectively as the hypothalamic-pituitary-gonadal (HPG) axis (Figure 3-1). Also shown in this figure are the critical hormones and feedback loops of the HPG axis.

Kisspeptins are peptides secreted by neurons in the arcuate and anteroventral periventricular nucleus of the hypothalamus.¹ These peptides bind to a G-protein–coupled receptor called GPR54 on hypothalamic neurons that secrete gonadotropin-releasing hormone (GnRH). The resulting pulses of GnRH in turn induce pulsatile secretion of the gonadotropins, luteinizing hormone (LH), and follicle-stimulating hormone (FSH). LH and FSH working in concert lead to germ cell (spermatozoa or ova) maturation and also stimulation of sex steroid (androgen or estrogen) secretion by the gonads, along with gonadal peptides such as inhibins. The sex steroids exert a negative feedback effect at both hypothalamic and pituitary levels, reducing the secretion of kisspeptin, GnRH, and LH, whereas inhibins control FSH secretion via a separate negative feedback loop at the pituitary level. Later in life, once menstrual cycles begin, women also develop a positive feedback cycle whereby estrogens stimulate gonadotropin release during phases of the cycle critical for ovulation.

Inhibins are dimeric gonadal peptides that inhibit FSH secretion by the pituitary gland. The two major forms of inhibin are inhibin A and inhibin B. Inhibin A is a product of ovarian follicles and is only measurable in females. Inhibin B is the product of granulosa cells in girls and of Sertoli cells in boys, and may be useful, along with anti-müllerian hormone (AMH), for evaluation of testicular abnormalities, including cryptorchidism.

Activins are dimeric gonadal proteins that stimulate FSH secretion, although there appears to be less clinically relevant information gleaned from measuring activins than there is from measuring inhibins.

These basic hormonal pathways are modulated by many different central nervous system (CNS) inputs, including stimulatory effects of glutaminergic neural systems, inhibitory effects of γ-aminobutyric acid (GABA)-ergic systems, and direct interactions between glial cells and hypothalamic neurons. The CNS in turn integrates the effects of many external factors such as nutrient availability, exercise, stress, social/psychological factors, and indirect effects of chronic disease.

Fetal Period

Four critical developmental steps during fetal life establish the required anatomy for the HPG axis and normal pubertal development. First, GnRH-producing neurons must migrate from the olfactory region to proper positions in the hypothalamus, with dependence on products of the KAL-1 (Kallmann syndrome 1) and FGFR1 (fibroblast growth factor receptor-1) genes for normal anatomical development. Second, the mechanism for pulsatile GnRH secretion and responsiveness must be established, with dependence on genes such as KISS-1 (producing kisspeptin) and GnRHR (GnRH receptor). Third, normal development of the hypothalamus and gonadotropin-secreting cells of the pituitary depends on genes such as NR5A1 (SF-1), NROB1 (DAX-1), PROP1, HESX1, LHX, LH-β, LHR (LH receptor), FSH-β, and FSHR (FSH receptor) among others.² Fourth, the gonads must form properly, with differentiation of Leydig and Sertoli cells in the testis, and granulosa and theca cells in the ovary.

Neonatal Period, Infancy, and Childhood

Provided that these developmental steps occur properly, the pubertal mechanism is already active for brief periods during fetal, neonatal, and early infant life (“mini-puberty of infancy”). Understanding when infants normally have elevated LH, FSH, and sex steroids (Figure 3-2) allows efficient laboratory assessment whenever the integrity of the HPG axis is in question, as with congenital or acquired CNS, pituitary, or gonadal abnormalities. After the first year of life, the pubertal mechanisms are quiescent, reflecting an active suppression of pulsatile GnRH secretion that remains in place until the child approaches the time of adolescence. During this period of pubertal latency, it is difficult to distinguish the child who has hypogonadotropic hypogonadism (pathologic inability to produce sex steroids owing to hypothalamic-pituitary abnormalities) from the normal child whose GnRH secretion is still under active restraint. In addition, the knowledge that the underlying pubertal mechanism is dormant only because of active CNS restraint helps explain why CNS abnormalities are often associated with precocious puberty.

Preadolescence and Adolescence

The harbinger of puberty is the increase in pulsatile release of GnRH, which occurs first at night, well over a year before any physical signs of puberty appear. Specific proteins that repress KISS-1 have recently been identified in rats, and it appears that silencing of the genes for these repressor proteins is the trigger for initiation of puberty. Though measurement of GnRH in peripheral blood in humans is of little clinical value for assessment of puberty, LH serves as a good proxy for the return of GnRH pulsatility, provided that an ultrasensitive LH assay (with analytical sensitivity down to 0.1 IU/L) is used. For most of these ultrasensitive assays, an LH level above 0.3 to 0.55 IU/L is suggestive of early central activation of puberty.

In boys, the rise in testosterone matches the increase in LH levels. The binding protein for both testosterone and estradiol, sex hormone–binding globulin (SHBG) declines as testosterone increases, leading to a rapid rise in the free (active) fraction of testosterone. Estrogen levels also increase somewhat in boys during puberty mostly from peripheral conversion (aromatization) of testosterone to estradiol. The peak of this estradiol rise is typically seen around the age of 13, corresponding to mid-puberty (Tanner stage 3—see as follows), the period during which adolescent male breast enlargement (gynecomastia) is most often seen.

In girls, estradiol secretion (in response to both FSH and LH) during early puberty is episodic, making random measurement of estradiol an insensitive marker for pubertal onset, especially compared to ultrasensitive assays for LH. Although rising levels of estradiol should theoretically increase SHBG levels in girls as they progress through puberty, what is actually observed is a mild downward trend in SHBG, likely caused by other factors known to decrease SHBG, such as rising insulin-like growth factor-1 (IGF-1), increase in average insulin levels during adolescence, and increased secretion of androgens by the adrenals and the ovaries.

Adrenarche

Although often used as a synonym for pubarche, the first appearance of pubic hair, the term adrenarche is better defined biochemically as a detectable increase in the secretion of adrenal androgens, including androstenedione and dehydroepiandrosterone (DHEA) associated with a significant increase in CYP17A1 expression (resulting in activation of 17α-hydroxylase/17,20-lyase in the zona reticularis in the adrenal cortex) starting at age 5 years, or its longer-lived sulfated metabolite, DHEAS. These biochemical changes represent a gradual process that may start well before the age of 6, several years before pubic hair appears or puberty actually begins.

Pubertal changes of the growthhormone—IGF-1 axis

Growth hormone (GH) pulses increase in amplitude during puberty, with a resulting increase in circulating IGF-1 concentrations. These changes may explain the transient insulin resistance seen during early and mid-puberty, a phenomenon that is independent of any insulin resistance arising from increased body mass index (BMI) or total adipose tissue.

The end result of the developmental and endocrinologic changes described previously is the appearance of the physical changes that characterize the final phase of puberty. In girls, the most obvious changes involve breast development (thelarche), the presence of pubic hair (pubarche), and the onset of menstrual periods (menarche). For boys, the focus is on genital and pubic hair development as well as increase in muscle strength, deepening of the voice, and appearance of facial hair. Any delay in pubertal onset also delays the expected acceleration of growth, so that the very common referrals of adolescents for short stature and delayed growth also requires assessment of pubertal status.

All guidelines for pubertal norms should be viewed with circumspection, as studies of puberty in children are fraught with major methodological (issues with design or measurement) and statistical difficulties.^3,4 Therefore, though a study may demonstrate convincingly that breast development in a 7-year-old girl can be normal, such a study cannot be used to predict that breast development in a specific 7-year-old patient is normal. More information from medical history and physical examination, and perhaps biochemical evaluation is required, as well as monitoring the rate of progression of the breast development.

Factors Affecting the Timingof Puberty

Genetic factors

Family studies, particularly twin studies, suggest that genetic factors contribute to at least one-half to three-quarters of the variability in timing of puberty.^2,5 Ethnicity is a known factor, with black girls showing earlier onset of breast development and especially adrenarche compared to white girls. Table 3-1 lists many of the genes associated with normal puberty or with pubertal disorders.

BMI and fat mass

A girl’s nutritional status, as assessed by BMI and/or measurement of body fat mass, is strongly associated with alterations in pubertal timing.⁶ Girls who are significantly underweight or who have extremely low body fat are more likely to have delayed menarche and/or secondary amenorrhea. Higher BMI/obesity in girls is associated with earlier appearance of breasts, pubic hair, and onset of menstrual periods, with evidence pointing to leptin, a product of adipose tissue, as a signal that must reach a minimum threshold for the initiation of puberty.⁷ Based on these findings and arguments from evolutionary biology, the current hypothesis is that increased body fat is a cause of earlier puberty in girls, although alternate hypotheses (eg, increased fat is the result, rather than the cause of, an accelerated pubertal process) may still be possible.

The link between higher body fat and altered timing of puberty is less obvious in boys, which may either reflect different evolutionary pressures or simply the greater methodological difficulty of scoring male genital development (as opposed to noting onset of menarche in girls) for studies of puberty in boys. The trend appears to be that higher BMI in boys is associated with later, rather than earlier, onset of puberty.

Environmental chemicals

The effect of environmental chemical exposures on the timing of puberty is a topic under great debate and active research.⁸ A wide variety of endocrine-disrupting chemicals have been identified that have the ability to mimic (agonists) or block (antagonists) the effects of sex steroids, or have toxic effects on critical components of the reproductive axis. Examples include pollutants such as polychlorinated or polybrominated biphenyls, dioxins, pesticide or fungicide residues, phthalates and other compounds from plastics, toxins such as lead, or even naturally occurring food components such as soy isoflavones. Further complicating the story is that endocrine-disrupting chemicals may exert their effects during the prenatal or prepubertal years as well as in the immediate peripubertal period, making epidemiological study of these compounds an extremely ambitious task. While awaiting results of further studies, the clinician can provide some reassurance to anxious parents that these compounds are generally two or more orders of magnitude weaker than primary sex steroids like estradiol. Accordingly, avoidance of obvious sources of known endocrine disruptors would becommon sense.

Chronic illness

Typically, significant chronic disease in childhood is associated with a later onset of puberty. Exceptions include diseases involving the CNS, where there may be disturbances of the normal mechanisms that restrain puberty during the childhood years. In some cases, the effects are mixed, as with cerebral palsy, where onset of breast development may occur earlier, despite later onset of menstrual periods.

Physical Changes in Girls: Thelarche

Thelarche is the onset of breast enlargement in girls. Asymmetrical breast development, with one breast developing before the other, or a mild difference in sizebetween the two breasts, is not uncommon. Criteria for Tanner staging of breast development are shown inFigure 3-3. A common difficulty in staging of breast development is encountered with overweight girls, where even a physician may not be able to distinguish by observation alone between fatty tissue in the breast area versus actual glandular tissue. Palpation of breast tissue is a more accurate method for determining if Tanner stage B2 has truly been attained. Other issues include the lack of an absolute objective boundary between stage B2 and B3, as well as determining the difference between a large breast at stage B3 and a small breast at stage B5. In the latter case, a more developed papilla (the pigmented projection of the nipple) close to 1 cm in diameter suggests stage B5.

A number of recent studies suggest that the mean age at thelarche is somewhere between 9 and 10 years in white or Asian girls, several months earlier in black girls, and somewhere in between for Hispanic girls.^{9, 10, and 11} Mean age, however, is not particularly helpful when faced with patients referred for evaluation of precocious or delayed puberty. The lower age threshold for breast development in healthy girls appears to be earlier than in previous decades, with some pediatric endocrinologists in the United States subscribing to an age threshold of 7 years in white girls and 6 years in black girls.¹² Additional support for this threshold comes from a study of over 1200 girls in three US cities, where 10% of white girls, 14.9% of Hispanic girls, and 23.4% of black girls had reached breast Tanner stage II before 8 years of age.¹³ In clinical practice, however, many pediatric endocrinologists continue to be cautious about white girls who start puberty before 8 years (or black girls before age7 years), preferring to evaluate such girls carefully before labeling their puberty as normal.³ At the upper end, the +2 standard deviation (SD) age threshold for breast development is just under 13 years of age. Regardless of which cutoffs are used, statistically derived age thresholds should never be used as absolute indicators of health or disease without additional clinical and biochemical information.

Physical Changes in Girls: Pubarche

Pubarche is the first appearance of pubic or axillary hair, although typically axillary hair appears 1 to 2 years after pubic hair in white girls (this time gap may be shorter in black girls). Because pubarche is so dependent on adrenal androgen secretion, the terms pubarche and adrenarche are frequently used interchangeably, although, as noted previously, the onset of increased adrenal androgen secretion may actually precede pubarche by a few years. Although pubarche typically occurs around the same time as gonadarche (activation of the HPG axis), each is actually the result of different regulatory pathways (adrenal vs gonadal) and may, on occasion, follow significantly different timing patterns. Therefore, the appearance of pubic hair should not be considered a sign of true pubertal onset.

Criteria for Tanner staging of pubic hair development are shown in Figure 3-4. In some ethnic groups, the amount of pubic hair is less for any given Tanner stage. There is no Tanner staging scale for axillary hair, which is rated on a simple three-point scale, where stage 1 signifies no hair, stage 3 signifies axillary hair adult in quantity and quality, and stage 2 is somewhere in between.

From available studies, the median age of pubarche is 10.5 to 10.9 years in white girls, 8.8 to 9.4 years in black girls, and around 10.4 years in Hispanic girls. Estimates of the lower age limit for pubarche vary widely among different studies, ranging from 8 to 9 years in white girls. Black girls have a significantly earlier pubarche, with at least one study noting that 5.2% of 4-year-old healthy black girls already had some pubic hair.

Timing of menarche

Menarche is the onset of menstruation in girls. The mean age of menarche is about 12.6 years in white girls, 12.1 years in black girls, and 12.2 years in Hispanic girls. The lower (~ −2 SD) age threshold is about 10.5 years in white girls and 10 years in black girls. The upper (+2 SD) cutoff is between 14.5 and 15 years for white girls and about 14 and 14.5 years in black girls.

Of note, girls who have earlier thelarche may have a slightly longer period of time before menarche. Thus, a girl with thelarche at the age of 9 years may have 2.8 years before menarche, while another girl with thelarche at the age of 11 years may only have 1.8 years until menarche. There are also girls who have early thelarche, but whose tempo of pubertal progression is slow, with a normal final outcome; thus, the tempo of puberty should be part of the assessment of pubertal development.

Physical Changes in Boys: Testicular Enlargement

Although there exists a system for Tanner staging of male genital development during puberty (Figure 3-5), in practice, the differences among the intermediate stages are too subjective for consistency from observer to observer. Much more accurate is the measurement of testicular size using a model such as the Prader orchidometer, shown in Figure 3-6. A volume of 3 to 4 mL is considered to be an indicator of pubertal onset, as the seminiferous tubular volume increases under gonadotropin stimulation. If an orchidometer is not available, a testis length of 2.5 cm along the longest axis corresponds to approximately 4 mL volume. The median age at testicular enlargement to 3 mL volume, based on a recent study of over 4000 subjects, is 10.14 years in white boys and 9.14 years in black boys.¹⁴ While these data suggest that testicular enlargement to 3 mL can be normal in boys as young as 7 years, many pediatric endocrinologists continue to evaluate closely any boys who start puberty before age 8 years. Lack of testicular enlargement by the age of 14 years is generally considered to be delayed.

Physical Changes in Boys: Pubarche

Tanner staging criteria for pubic hair in boys are shown in Figure 3-7. As with girls, androgen secretion from the adrenals is an important determinant of pubarche. However, androgen secretion from the testes is also a major factor in pubarche, increasing the chances that precocious pubic hair development in boys may signify true precocious puberty.

The average age of pubarche in boys is around 12 to 12.5 years in white and Hispanic boys, with black boys starting about 1 year earlier. Pubarche before the age of 10 years is commonly considered worthy of further observation and clinical workup, while lack of pubic hair development after the age of 14.5 years in white and Hispanic males (after 14 years in blacks) can be considered delayed. Axillary hair typically appears about 1 to 2 years after pubic hair.

Physical Changes in Boys: Other

Spermarche, the ability to produce and ejaculate sperm, typically occurs around the age of 13.5 years (at least Tanner stage 3). Voice break, the transition to the deeper adult voice, occurs at a mean age of about 13.9 years. Peak height velocity, increased muscular strength, and worsening of acne typically occur around this same time.

Facial hair, usually starting with the upper lip, typically appears around the age of 15 years, but may not be of full adult quality until well past the teenage years.

Growth during puberty

Girls have their peak growth velocity early in puberty, typically beginning right before thelarche. Boys, in contrast, have their peak growth spurt during mid-puberty (between Tanner stages 3 and 4), at a mean age of 13.5 years, often corresponding to a testicular volume of 10 to 12 mL.

A common misconception is that the amount of growth remaining for a girl after menarche is only a couple of inches, which often leads to predictions of severe short stature in girls who have early normal menstruation.¹⁵ In fact, the amount of growth remaining varies greatly depending on when menarche occurs. Thus, a girl who has menarche at the age of 10 years grows, on average, an additional 4 in, whereas another girl who has menarche at the average of 12.7 years will grow on average another 3 in. The girl who has menarche at the age of 15 years may only grow 2 in more, but because she is already at a taller height by the time that she has her first menstrual period, her final height is likely to be within her expected genetic potential.

Introduction

The first sign of clinically detectable puberty in girls is breast development in 85% of cases with pubic hair preceding thelarche in the other 15%. In actuality, ovarian enlargement is the first true sign of female puberty, but it requires ultrasonography for detection. Analogously, testicular enlargement is the first sign in boys. Whether puberty is truly occurring earlier than was previously thought, especially in girls, is controversial as some of the suggestive large-scale epidemiological data (ie, the Pediatric Research in Office Settings [PROS] network⁹) may be flawed because of ascertainment bias in subject selection, use of visual (as opposed to manual) determination of breast staging, and failure to perform diagnostic testing in children in the younger age ranges to definitively rule out pathological causes of precocity. A new report on the timing of male pubertal onset also from the PROS network suggests that genital and pubic hair growth and testicular enlargement are occurring 6 months to 2 years earlier than in past studies, especially in blacks.¹⁴ That said, Danish Registry data suggest that 0.2% of all Danish girls and fewer than 0.05% of all Danish boys have some sort of precocious puberty.

Thus, the clinician must first determine in a child with “borderline” early puberty whether observed changes may represent normal variants or have a more serious organic basis. The next dilemma is when and if diagnostic testing is required as often nothing more than a bone age is required in clear examples of normal or slowly progressive variants. This decision may often be best left to the pediatric endocrinology consultant who can, in the most cost-effective manner, determine whether, how (basally or after stimulation), where (noting tremendous variability in assays and clinical laboratories), and how often testing is required. Finally, decisions regarding the necessity for and type of treatment will usually require the specialist’s input, noting that not all organic etiologies and certainly not the normal variants require treatment.

Presumed Normal Variants

Idiopathic isolated premature thelarche

Definition.

Most commonly, premature thelarche begins around 2 years of age, but it may be present from birth onward (Figure 3-8A). The observed tissue may be asymmetrical, unilateral, or bilateral. Although asymmetrical and/or unilateral breast tissue often causes parents to be concerned about the possibility of malignancy, this is rarely the case. In 30% to 60% of affected girls, the early breast tissue spontaneously regresses within an average of 18 months from its development. When it persists, the degree of breast development typically does not exceed Tanner stage 3.

Etiology.

The etiology of typical isolated premature thelarche is unknown. Most studies have failed to show differences between basal and GnRH-stimulated gonadotropin levels in girls with simple premature thelarche versus age-matched normal girls (both of whom has an FSH-predominant response); in contrast, girls with true precocious puberty have an LH-predominant response. Conventional assays usually cannot detect elevated serum estradiol levels in girls with isolated premature thelarche, although higher mean levels compared to those in age-matched normal girls have been reported using an ultrasensitive recombinant cell bioassay, but with significant overlap between the two groups. By default, heightened sensitivity of breast tissue to estrogen has been invoked as a potential etiology. A causative role for environmental endocrine disruptors has also been suggested. A strong association between the prevalence of premature thelarche and BMI has recently been reported in 4- to 8-year-old girls. In cases of either exaggerated isolated thelarche with advanced bone age and/or increased height velocity or self-limited recurrent episodes of isolated breast-budding that may be associated with advanced bone age and/or stepped-up height velocity, activating mutations of the G_sα gene have been reported in up to 25% of affected girls, akin to the mutation reported in full-blown McCune-Albright syndrome (see section Idiopathic Isolated Precocious Menarche).

Diagnosis, evaluation, and natural history.

For girls with “classic” precocious isolated thelarche, that is, starting at or prior to the age of 2 years, who, by definition, have no associated growth spurt and a bone age that is within 2 SD of their chronological age, no other diagnostic studies typically need to be performed. Such girls usually will go on to have menarche at a normal age and attain normal adult stature. Because a small subset of girls who present with precocious thelarche may progress to either a variant characterized by isolated progressive breast development in conjunction with accelerated linear growth and advancing bone age or to true precocious puberty, ongoing follow-up either by a pediatrician or a pediatric endocrinologist is mandatory with judicious use of additional/ongoing laboratory and radiologic testing as dictated by the clinical course. The presence of a mild degree of thelarche, without androgenic manifestations of puberty, may also occur in the very earliest stages of peripheral precocious puberty caused by a granulosa cell tumor.

Treatment.

Unless the condition progresses as noted earlier, no treatment is indicated.

Idiopathic isolated precocious adrenarche

Definition.

This is another common pubertal variant that is characterized by the early development of pubic hair, axillary hair and odor, and/or a small amount of acne using the same age criteria defined previously, along with elevation of adrenal-specific steroids, such as DHEA and/or DHEAS; without this biochemical confirmation, the entity should just be called precocious pubarche (Figure 3-8A).

Etiology.

Premature adrenarche appears to result from increased production of adrenal androgens in both sexes at an earlier than normal age resulting from premature maturation of the zona reticularis of the adrenal cortex.¹⁶ More specifically, it has been proposed that there is a reduction in 3β-hydroxysteroid dehydrogenase activity and induction of the 17,20-lyase component of the P450c17 enzyme complex in the zona reticularis through preferential hyperphosphorylation secondary to an autosomal dominant mutation of the kinase responsible for serine/threonine phosphorylation, leading to increased serum concentrations of DHEA and DHEAS. Some children with precocious adrenarche have been reported to have heightened androgen receptor gene activity whereas others have been found to be more likely to harbor a specific polymorphism in the adrenocorticotropic hormone (ACTH) (melanocortin 2 receptor = MC2R) receptor promoter. Finally, etiologic or permissive roles for corticotropin-releasing hormone, insulin, IGF-1, and leptin have also been proposed. Precocious adrenarche occurs much more commonly in girls than in boys (perhaps as much as 10-fold) and appears to develop more often in obese and/or African American girls. It also appears to occur more often in children with low birth weight.

Diagnosis, evaluation, and natural history.

In both girls and boys, by definition, there is no clinical evidence of virilization, that is, no growth spurt, increase in muscle bulk, voice-deepening, or temporal hair recession (male pattern baldness). In addition, affected girls will not manifest clitoromegaly and boys will not have penile enlargement. Furthermore, there is no evidence of ovarian estrogen-mediated components of puberty in girls and no testicular enlargement or function in boys. If a child presents at a very young age, it is generally presumed that an organic cause is more likely to be found. However, in infant boys with isolated scrotal hair, typically no cause is found and the hair subsequently falls out within 12 months. In most cases of idiopathic precocious adrenarche, serum levels of DHEA and/or DHEAS are in the respective pubertal ranges for girls and boys, and the bone age is mildly, but not significantly, advanced. In girls with precocious adrenarche, serum levels of other adrenal steroids are usually normal or only slightly elevated for age, especially if measured after stimulation with ACTH, but normal after leuprolide administration. These observations suggest that precocious adrenarche in girls is associated with functional adrenal hyperandrogenism, but no biochemical evidence of ovarian hyperandrogenism. Thus, if a child presents with the classical phenotype, no other laboratory or radiological studies are usually warranted, unless there is significant rapidity of progression of symptoms. On rare occasion, children with more serious organic pathologies associated with hyperandrogenism (eg, nonclassic adrenal hyperplasia [NCAH], adrenal tumors, and gonadal tumors) or true precocious puberty may initially present similarly to those with apparent idiopathic isolated premature adrenarche. Thus, in unclear situations, serum measurements (at 8 am) of 17-hydroxyprogesterone (basally or after ACTH stimulation) and testosterone, along with ultrasounds of the adrenals and/or gonads, may need to be done. With the presence of isolated adrenarche in girls, measurement of LH, FSH, and estradiol is not indicated (as these should only be determined when there are isolated female changes of puberty or both female and male changes). Historically, this pubertalvariant has been considered to be benign and self-limited, but recent epidemiological and biochemical data suggest that, at least in girls with associated low birth weight and rapid postnatal catch-up growth, precocious adrenarche may be followed by early onset and rapid progression of true puberty as well as by future development of functional ovarian hyperandrogenism/polycystic ovarian syndrome (PCOS). Additional features of this syndrome include early-onset insulin resistance with a disturbance of the insulin-IGF-1 system, atherogenic lipid profiles, and hypertension (collectively known as the metabolic syndrome or syndrome X), and a positive family history of type 2 diabetes mellitus (T2DM), hypertension, PCOS, and anovulation beginning in late adolescence. Recently, it has been shown that boys with precocious adrenarche are also insulin-resistant. Thus, the adjective “benign” or term “normal variant” should not necessarily be applied to cases of premature adrenarche.

Treatment.

Currently, there remains no proven treatment for idiopathic precocious adrenarche and no specific means by which to forestall future functional ovarian hyperandrogenism, although basic practices to limit weight gain, regulate cholesterol intake, and avoid smoking seem advisable. Investigative use of metformin in children with precocious adrenarche has been shown, in small cohorts, to improve body composition and delay the onset of true puberty, and, in so doing, perhaps improve adult height.

Idiopathic isolated precocious menarche

Definition.

This is defined as menstruation without any other manifestations of puberty in a young girl prior to the age of 9 years.

Etiology.

The cause is unknown, with the ultimate assignment of an idiopathic basis for its basis being a diagnosis of exclusion, so that one must also consider a foreign body, local masses, severe primary hypothyroidism, and McCune-Albright syndrome.

Diagnosis, evaluation, and natural history.

In the setting of isolated early menarche, the situation is usually self-limited, albeit disturbing to parents and patients. In most cases, there is only one period, but there may be two or more. Adult height and subsequent menstrual patterns and fertility are usually normal.

Treatment.

None is required.

Rapid tempo puberty

Definition.

No formal definition exists.¹⁷ By the use of a statistical approach, pubertal progression may be considered unduly fast if the start of puberty is within the normal range for gender and race, but subsequent milestones are achieved more than 2 SD ahead of their expected mean age of occurrence. As guidelines, in girls, the typical interval from breast budding (Tanner stage 2)to menarche (usually associated with at least Tanner stage 4 breasts) is 2.4 ± 1.1 years (mean ± 1 SD). In boys, the usual time from pubertal onset (Tanner stage 2 testes, ie, ≥ 3 mL in volume) to adult testicular volume (mean 20 mL) is 3.2 ± 1.8 years.

Etiology.

The exact etiology is unknown. Factors that may modify the rate of pubertal maturation include family genetics, a history of low birth weight (small for gestational age [SGA]), rapid and/or excessive growth in early childhood (especially if having been born SGA), diet, diminished physical activity, and an array of other factors (eg, treatment of hypothyroidism, adoption, and endocrine disruptors).

Diagnosis, evaluation, and natural history.

Unfortunately, from a practical standpoint, the typically affected adolescent usually presents to medical attention nearly or even fully developed and having had marked height acceleration unduly early. In fact, such adolescents may already be in their postspurt height deceleration phase as a result of markedly advanced bone age that appears as a by-product of the phenomenon without yielding the requisite number of inches that would have occurred with a normal pubertal tempo. This process is often missed in a first affected child in a family because of the natural infrequency of visits to the primary care provider for well-child physical examinations in this age group.

Treatment.

There are also no proven treatment strategies for rapid tempo puberty. In fact, when identified late as is often the situation in the index case in a family, there is often no viable treatment option. When there is reasonable remaining growth potential, transient interruption of the HPG axis, as is done in children with bona fide central precocious puberty, is usually considered using GnRH analogs without or with added GH. However, in the United States, use of either drug class to treat rapid tempo puberty is not FDA-sanctioned, so that their use may be moot because of an inability to obtain insurance company authorization. More importantly, there are no data demonstrating treatment efficacy in this situation, although, from a theoretical standpoint, combination therapy might be helpful. Use of other off-label agents, such as aromatase inhibitors in boys, may be considered, but once again this approach is based solely on a theoretical basis and anecdotal experience.¹⁸

Pathological Causes of Precocious Puberty

Isosexual central precocious puberty

Definition.

Central precocious precocity (CPP) results from activation of the HPG axis at an earlier-than-normal age (Figure 3-8A).¹⁹ Although as noted previously that the start of normal puberty may be occurring earlier than previously thought, most pediatric endocrinologists still consider 8 years in girls and 9 years in boys as general cut-points between early normal and early puberty, recognizing that an individualized approach needs to be taken for African American girls between 6 and 8 years, Caucasian girls between 7 and 8 years, and all boys between 8 and 9 years (as pathological causes of precocity have occasionally been reported in this age range), and especially in those children who present with a significant degree and/or rapid progression of puberty during these intervals. Isosexual development refers to pubertal changes appropriate for the sex of the child, such as breast budding in girls and testicular enlargement in boys. This contrasts with contrasexual development in which the pubertal features in females are male-hormone–directed, for example, clitoromegaly, or in males are female-hormone–directed, for example, breast development. In general, the presence of both female- and male-hormone–mediated features of puberty in females is a valuable clue to a central source for the precocity, although isolated estrogenic manifestations can occur as the initial presentation of precocious puberty, at least early on, in girls with a central etiology for their precocity. Additionally, on rare occasions, tumorous production of androgen by an adrenal tumor can provide sufficient substrate for either peripheral or intratumoralaromatization to estrogen, thereby confusing the clinical picture.

Etiology.

In females, most cases (~80%) of CPP have been considered to be idiopathic. With the application of magnetic resonance imaging (MRI), a somewhat higher percentage of organic causes has been detected in girls (Table 3-2). In contrast, only about 10% of central cases are idiopathic in males, with the remainder being associated with an underlying lesion of the CNS. The most concerning causes of CPP are tumors that arise in the suprasellar region, which may also be present with other, usually anterior, pituitary hormone deficiencies. Tumor-associated isolated CPP can occur with histologically benign hypothalamic hamartomas, the most common cause of CPP in very young children (Figure 3-9A and 3-9B). They may trigger puberty through secretion of GnRH (“ectopic GnRH pulse generator”) or transforming growth factor-β, another puberty-inducing growth factor. Hamartomas may, on occasion, be associated with gelastic (laughing) or other seizures. Other brain tumors that may cause CPP (with or without other pituitary hormone abnormalities) are glial cell tumors, germ cell tumors, and, occasionally, craniopharyngiomas, and pinealomas. The occurrence of combined “idiopathic” isolated GH deficiency or multiple anterior pituitary hormone deficiencies, an ectopic neurohypophysis, and CPP has been described.

Other CNS causes include congenital brain defects that arise in the suprasellar region (eg, subarachnoid cysts, arachnoidoceles, and Rathke cleft cysts); other congenital midline anomalies (eg, hydrocephalus, meningomyelocele, and optic nerve hypoplasia [ONH]); cranial irradiation; previous meningoencephalitis; moderate-to-severe head trauma; and perinatal insult. The well-known association of CPP with neurofibromatosis-1 (Figure 3-10), characterized by associated smooth-bordered café-au-lait spots (resembling the coast-of-California), axillary and inguinal freckles, Lisch nodules, and neurofibromas, may result from the presence of a hypothalamic optic glioma, but may also have no detectable tumor on MRI. CPP may also occur in the setting of untreated or undertreated peripheral causes of puberty (see section Precocious Pseudopuberty), such as CAH, or after transdermal testosterone exposure, in which premature activation of the GnRH pulse generator occurs, presumably as a result of prior or ongoing CNS exposure to high levels of androgens (or androgens aromatized to estrogens). Another cause of sexual precocity that begins outside the HPG axis is referred to as the “overlap” or Van Wyk-Grumbach syndrome, in which CPP develops in the setting of long-standing untreated primary hypothyroidism. The mechanism of this phenomenon is not well understood, although, in the past, it had been ascribed to both elevated thyrotropin-releasing hormone (TRH) levels that stimulate pituitary FSH/LH secretion and, more recently, to the hypothyroid state itself in which the elevated TSH promiscuously interacts with gonadotropin receptors in the gonads. Rarely, males with hyperprolactinemia may develop CPP (although hypogonadism is much more likely). A heightened risk of CPP has been reported in children adopted from abroad, although this association may be clouded by inaccurate birthdates.

Rare cases of CPP have been described in association with activating mutations of KISS-1, the gene encoding kisspeptin, as well as GPR54, the G-protein–coupled receptor mediating the effects of kisspeptin, the downstream effects of which, in either case, result in premature stimulation of GnRH neurons.²⁰ The frequency of such mutations is unknown, but it should be pointed out that there is a 27.5% prevalence of familial CPP. At the current time, there is not enough phenotypic information to make specific recommendations as to who should be considered for genetic testing that is currently only available in research laboratories. In addition, serum kisspeptin levels have been reported to be useful marker of CPP. More recently, in some but not all populations, precocious puberty (and adult height) has been associated with certain haplotypes of the gene, LIN28B. This gene is related to both cell pluripotency and cancer, but how it might regulate pubertal timing is unknown.

Diagnosis, evaluation, and natural history.

The initial evaluation of the child with precocious puberty is aimed at determining whether the process is normal or abnormal, has an idiopathic or pathological basis, what the rate of progression of the pubertal changes has been or will be, and whether the process originates centrally or peripherally (Figures 3-11 and 3-12). The initial test to perform is a bone age x-ray that provides an index of the potency of the process, although it is not useful in delineating the source of the hormonal process. More specifically, if not significantly advanced (ie, within 20% of the chronological age in months) and not associated with acceleration in height velocity, this suggests either a normal variant, slow progression pattern, or a process of relatively short duration. If a girl with precocious puberty has a significantly advanced bone age, a laboratory workup must be initiated that is dictated by the findings on the physical examination. Measurement of free T₄ and TSH in both sexes is useful to rule out long-standing primary hypothyroidism that is usually apparent on clinical grounds.

If breast development is evident with or without androgen effects, measurement of random serum gonadotropins, using ultrasensitive assays for FSH and LH, and estradiol (using liquid chromatography tandem mass spectrometry or other methods to remove cross-reacting steroids) should be undertaken. Ultrasensitive bioassays for serum estrogenic bioactivity are under development. A pelvic ultrasound in this setting is a useful adjunctive diagnostic tool.²¹ Noting that mean prepubertal ovarian volumes (calculated for an oblate ovoid by multiplying the measurements in millimeters of the three dimensions by 0.523) increase gradually with age (3 years: 0.51 mm³;5.0 years: 0.78 mm³; 7 years: 1.14 mm³; and 9 years:1.31 mm³), the presence of bilaterally enlarged ovaries for age suggests hypothalamic-pituitary activation (or, less likely, McCune-Albright syndrome). In addition, the maturation of the uterus can be determined simultaneously and is useful as another indicator of the potency of estrogenic action. Measurement of serum androgen levels in girls with breast development with or without concomitant androgen effects rarely adds any useful diagnostic information. Because of the pulsatile and initially preferential sleep-entrained secretion of serum gonadotropins, random daytime measurements of LH and FSH may be low in the setting of central activation. However, use of immunofluorometric (IFMA), electrochemiluminescent (ECL), and high-sensitivity immunochemiluminescent (ICMA) assays for LH correlates much better with true CPP. However, if random gonadotropin levels are low, yet clinical suspicion suggests CPP, a GnRH stimulation test would next be performed.²² The most common protocol currently used for this test involves the subcutaneous administration of leuprolide acetate (not the depot form) at a dose of 20 μg/kg with measurement of gonadotropins every 30 minutes for 2 hours (usual maximum occurs at 30 minutes) and the sex steroid of interest 2 and 24 hours later. The results of these tests correlate remarkably well with those from multiple-sample, longer GnRH stimulation tests. The rationale for this interpretation is that, with central precocity, as with normal puberty, endogenous hypothalamic GnRH is being produced in a pubertal pattern that “primes” the pituitary gonadotrophs, so that, after administration of a single pharmacological dose of GnRH, there is abundant release of LH as typically occurs in teenagers. Measuring FSH levels during the test serves only to ensure biological activity of the leuprolide, and the peak concentration attained tends to be overlap between the prepubertal and pubertal state. Regardless, if CPP is confirmed biochemically and is progressive, a head MRI—in a closed unit—with contrast (required for detailed assessment of hypothalamic-pituitary region anatomy) must be performed to look for potential lesions in the hypothalamic-pituitary region, which are typically found in approximately 10% of girls with CPP. In cases of idiopathic CPP in girls, the MRI will frequently demonstrate exaggerated pituitary height (mean 6.2 ± 0.2 mm) as is typically seen in the adolescent female pubertal range.

The workup for a boy with isosexual precocity and a significantly advanced bone age is directed by the size of the testes. In cases of CPP, both testes are symmetrically enlarged for age, the degree to which will be governed by the potency and duration of the underlying etiology. Laboratory testing and the use of the leuprolide GnRH test are similar to that outlined above for girls, except for the substitution of testosterone for estradiol measurements. As with girls, if central precocity is confirmed biochemically, a contrast-enhanced head MRI must be performed as up to 50% of affected males will have demonstrable lesions of the CNS.

Treatment.

As to general issues related to treatment of precocious puberty, not all cases, including not all cases of CPP, require treatment (Table 3-3).^23,24 Children with CPP or early normal puberty with a strong familial basis may profit from a period of observation without treatment, especially if outcomes of affected family members have been unremarkable. In addition, not all children with de novo CPP require treatment as a significant number have either a slowly progressive and/or transient process. Unless clinical findings suggest a rapid progression and/or significant resultant psychosocial difficulties, most children with CPP should be observed for a 3- to 6-month period before a decision to initiate GnRH agonist therapy is made.

The specific reasons that favor treatment include preservation of acceptable final stature based on family height genetics; prevention of psychological trauma (eg, from menstruation at a young age); reversal of mature physical appearance and risk of pregnancy in girls (as others assume that affected children are older than they appear); and reduction of anxiety, aggressiveness, and preoccupation with sexuality. Of note, serious psychological effects of early puberty are not typically encountered and GnRH agonist treatment typically only halts, but not actually reverses, existing physical changes of puberty induced by gonadal steroids. Thus, the goal of therapy is to inhibit secretion of gonadotropins and thereby reduce production of sex-specific sex steroids. This is accomplished by the administration of GnRH agonists that behave antagonistically because of biochemical modifications that result in a prolonged reversible duration of action causing downregulation of pituitary GnRH receptors (after initial stimulation for the first 1-2 months of use), ultimately eliminating responsiveness to endogenous GnRH and, thus, decreasing LH and FSH secretion. Verification of adequate suppression can be confirmed by demonstration of prepubertal LH levels as measured in one of the aforementioned ultrasensitive assays measured just before a dose of therapeutic GnRH agonist or 1 hour after its administration in which the therapeutic agent is simultaneously used as an acute gonadotropin stimulator. Efficacy of treatment should be based on assessment of progression of Tanner stage and growth every3 to 6 months, and by periodic bone age and biochemical documentation of axis suppression. In the United States, the most commonly used GnRH agonists are monthly or 3-monthy intramuscular depot injections of leuprolide acetate and the histrelin implant.^25,26 Histrelin is a 12-month subdermal implant requiring surgical insertion and removal on an annual basis either under local or short-term general anesthesia. Three-year efficacy studies with the implant have been performed showing sustained suppression of the HPG axis. Other available, but rarely used, FDA-approved GnRH agonist formulations are nafarelin acetate that is given twice daily by the intranasal route and leuprolide acetate that is given by daily subcutaneous injection. In children treated with depot leuprolide acetate, verification of adequate suppression of the hypothalamic-pituitary gonadal axis can be confirmed by demonstration of prepubertal LH levels using one of the aforementioned ultrasensitive assays measured 1 to 3 hour(s) after its administration in which the therapeutic agent is simultaneously used as an acute gonadotropin stimulator. Suppression in patients treated with histrelin may require acute GnRH agonist stimulation as random LH levels are not suppressed in approximately 60% of cases, with other criteria suggesting suppression. Regardless of treatment choice, ongoing documentation of axis suppression should be performed every 3 to 6 months. In girls, compared to serum levels of LH, FSH, and estradiol, those of free α-subunit (the shared component of heterodimeric glycoprotein hormones such as LH and FSH) respond more rapidly to implant removal and may represent the most sensitive indicator of gonadotropin recovery after cessation of histrelin treatment.

The clearest criteria for initiation of GnRH agonist treatment of children with sexual precocity include chronological age less than 6 years, a random LH level of more than 0.3 mIU/mL by ICMA in girls or boys, an LH response to leuprolide injection of more than 4.2 mIU/mL by IFMA and more than 3.3 mIU/mL by ICMA in girls or more than 3.3 by IFMA or more than 4.1 mIU/mL by ICMA in boys, a pubertal serum concentration of estradiol (in girls) or testosterone (in boys), advancement of bone age by more than 2 years over chronological age, the presence of an organic lesion or a pituitary height more than 6.0 mm on MRI, an abnormally low adult height prediction (eg, < 152.5 cm in girls, < 165 cm in boys, or < 5 cm below predicted adult target height), and existing or anticipated psychological sequelae of precocious puberty. However, the ultimate decision to treat immediately, observe, and possibly treat later, or merely to observe must involve a careful analysis of all of the above criteria on a case-by-case basis. The implementation of treatment in cases of early normal, but rapid tempo puberty in girls between 8 and 9 years and in boys between 9 and 10.5 years is often considered, but available data show that the GnRH agonists merely slow the pace of puberty without any significant effect on final adult height on average. Whether there may be a benefit in selected cases remains uncertain.

The optimal duration of GnRH agonist treatment also remains unclear, but, as a general guideline, most pediatric endocrinologists release or taper therapy beginning at about 11 years in girls and 12 years in boys. From a clinical perspective, successful GnRH agonist treatment is associated with a stabilization of estrogen effects in girls (with no effect on androgen-mediated events) and androgen effects in boys. It is unusual that treatment results in complete reversal of physical changes to the prepubertal state. Height velocity and the rate of bone age maturation will slow down and, on some occasions, the linear growth rate actually becomes subnormal. This is not necessarily problematic as long as bone age maturation slows commensurately, but, on occasion, GH therapy must be added. Outcome data insofar as final height is concerned suggest that the best results occur in taller children at start of GnRH agonist therapy and when GnRH agonist therapy is initiated prior to the age of 6 years. Based on data from Japan and Italy, once GnRH analog therapy is discontinued, reactivation of the HPG axis usually occurs within 12 months, with menarche or resumption of menses occurring between 12 and 12.5 years on average and ovulation documented in 90% of girls at least 2 years after menarche, followed by subsequent fertility.^27,28 Unfortunately, there are limited long-term fertility data in individuals treated with GnRH agonists as children, with only a few reports of successful childbearing in this population. Additionally, children treated with GnRH agonists for CPP may be at increased risk for PCOS. Other problems noted with leuprolide injections include sterile abscesses at the site of administration, as well as a tendency toward obesity; ultimate bone density appears unaffected. No specific side effects have been identified for the histrelin implant other than transient local discomfort and occasional breakage of the implant on removal. For large tumors in the hypothalamic-pituitary region, developmental anomalies, and hydrocephalus that are associated with CPP, surgical interventions are justified, although these are not for the purpose of treatment of precocious puberty. Finally, hypothalamic hamartomas are benign and tend to be very slow growing, and therefore surgical therapy is not usually recommended, unless the lesion is pedunculated.

Precocious pseudopuberty

Definition.

The term, precocious pseudopuberty, refers to gonadal or adrenal sex steroid secretion not resulting from activation of HPG axis (ie, pituitary-independentor peripheral in origin).¹⁹ This can involve isolated androgen, isolated estrogen, or combined androgen and estrogen production.

Etiology.

Precocious and inappropriate androgen production in girls, including features of virilization, can be caused by ovarian arrhenoblastomas and hyperthecosis (Table 3-4). In boys, premature androgen productionmay result from Leydig cell tumors (some of which harbor activating mutations of the LH receptor); human chorionogonadotropin (hCG)-secreting tumors, such as hepatoblastomas (most common) or germ-cell tumors (sometimes seen in adolescent males with Klinefelter syndrome, with the anterior mediastinum the primary location); McCune-Albright syndrome (although more often in girls); and familial testotoxicosis (also known as male LH-independent sexual precocity) (Figure 3-13). This rare condition involves gonadotropin-independent testicular maturation usually inherited in an autosomal dominant, male-limited pattern with signs of puberty generally exhibited by 4 years of age. In boys with familial testotoxicosis, testosterone production and Leydig cell hyperplasia occur in the setting of prepubertal serum LH levels as a result of a mutation in the LH receptor gene, resulting in its constitutive activation and gain of function. Affected males are fertile. Females who carry this mutation do not develop precocious puberty (because both FSH and LH action are needed for estradiol production) and apparently have normal reproductive function. Two unrelated boys with familial testotoxicosis have been described who also have pseudohypoparathyroidism type 1A owing to a tissue-specific temperature-sensitive mutation of the G_sα gene with activation in the testes because of cooler temperature and loss of function at core temperature. Last, premature and inappropriate androgen production in both sexes may occur as a result of NCAH, androgen-secreting adrenal adenomas (Figure 3-14) or carcinomas, generalized glucocorticoid resistance, and some cases of Cushing syndrome (Figure 3-15A and 3-15B). Two other novel and rare monogenic causes of premature adrenarche in both sexes are apparent cortisone reductase deficiency (resulting from loss of hexose-6-phosphate dehydrogenase activity leading to increased 11β-HSD1 dehydrogenase function, increased conversion of cortisol to cortisone, and a compensatory increase in hypothalamic-pituitary-adrenal axis activity and excess androgen production) and apparent DHEA sulphotransferase (SULT2A1) deficiency, resulting in an inability to convert DHEA to its inactive sulfate ester, DHEAS, favoring conversion to active androgen.¹⁶ A similar presentation can occur as a result of presumed unintentional exogenous transdermal testosterone exposure (Figure 3-16).²⁹ On rare occasion, an adrenal tumor may produce both androgens and estrogens, thus mimicking the presentation of central sexual precocity.

Premature production of estrogen in girls may result from large (> 2 cm) ovarian cysts, granulosa cell tumors, (30% of which contain activating mutations of the G_sα gene), and Sertoli-Leydig cell tumors. The latter are usually isolated occurrences but may, on occasion, occur as part of Peutz-Jeghers syndrome (PJS) (oral melanosisand intestinal polyps). Another rare, but important, cause is McCune-Albright syndrome (Figure 3-17A and 3-17B). This disorder occurs much more commonly in girls than in boys and is characterized by the clinical triad of polyostotic fibrous dysplasia, irregularly bordered (“coast-of Maine”) café-au-lait (brown pigmented) skin lesions, and multiple autonomous endocrinopathies (most commonly gonadotropin-independent precocious puberty, but also hyperthyroidism, acromegaly, and hypercortisolemia). Girls with McCune-Albright syndrome typically present with early occurrence of vaginal bleeding before or within a few months of breast development (secondary to the development of recurrent autonomous ovarian cysts) and then the existing skin findings are given due attention; bony lesions tend to present later. Affected boys have Leydig cell hyperplasia. As occurs in a subset of granulosa cell tumors, McCune-Albright syndrome is due to a mutation in the G_sα gene that occurs early in embryogenesis (somatic or postzygotic, rather than germ cell in origin), resulting in constitutive activation of adenylyl cyclase in multiple affected tissues; such mutations may also occur in the skin, bones, liver (cholestasis), heart (arrhythmias), and gastrointestinal tract, with affected tissues varying from patient to patient and presumed to be dependent on the exact timing of the mutation. This activation leads to autonomous function of affected tissues which, in the case of involved endocrine glands, results in unregulated production of hormone independent of the normal stimulatory factors from the hypothalamus and/or pituitary gland. Affected patients appear to be at increased risk for cancer, including bone, breast, and thyroid. Precocious and inappropriate estrogen production in boys may occur in the setting of certain adrenal tumors that either overproduce both androgen and estrogen or provide androgen substrate for subsequent aromatization by peripheral tissues or the tumor itself. Rarely, boys develop feminizing Sertoli cell tumors (usually occurring in the setting of PJS). Premature breast development caused by presumed unintentional exogenous transdermal (or oral) estrogen exposure has been reported in both boys and girls.²⁹

Diagnosis, evaluation, and natural history.

Skeletal maturation in this group of disorders is usually moderately to markedly advanced at the time of diagnosis because of the presumed potency of the process (see Figures 3-11 and 3-12). Laboratory testing should be targeted to explain the observed physical findings. Thus, if a girl with advanced bone age presents only with contrasexual androgen-mediated development, that is, evidence of virilization, evaluation consists of measurement of serum total testosterone and 17-hydroxyprogesterone levels; the former provides an index of severity of the process (without localizing the source of the androgen) and the latter is the diagnostic test for 21-hydroxylase deficiency, the most common enzyme deficiency associated with NCAH. On occasion, an ACTH stimulation test may be required to determine the specific enzymatic deficiency. Screening for Cushing syndrome with measurement of a 24-hour urine-free cortisol (and creatinine to document completeness of collection) or a midnight salivary cortisol may also be indicated if the appropriate body habitus and other features are present. If biochemical testing suggests an adrenal or ovarian tumor (arrhenoblastoma), performance of an abdominal/pelvic MRI is mandatory. Neither measurement of gonadotropins and estradiol nor a head MRI is indicated in the evaluation of virilization in girls.

The workup for a boy with peripheral pseudopuberty and a significantly advanced bone age is directed by thesize of the testes. If the testes are both prepubertal in size, the adrenal glands or exogenous administration is the source of the androgen. The same adrenal etiologies of androgen overproduction described earlier for girls also occur in boys and further testing would be performed as indicated earlier for girls. If, however, only one testis is enlarged, a radiologic search (usually starting with an ultrasound) for an androgen-producing tumor within the larger testis is mandatory. If both testes are mildly enlarged for age, the etiology is most often central, although familial testotoxicosis must also be considered. These two entities can usually be distinguished by a combination of family history and the results of a GnRH stimulation test, as outlinedearlier.

Finally, measurements of serum hCG (in males), prolactin, and free T₄ and TSH are important considerations in the child with unexplained sexual precocity. Tumors producing clinically relevant hCG only occur in males and should be suspected in the setting of disproportionately small testes for the degree of puberty that is present and in clinical situations predisposed to germ cell tumors such as Klinefelter syndrome. Measurement of prolactin would be crucial in the setting of galactorrhea along with manifestations of early puberty. Lastly, thyroid function tests should be considered in the setting of associated signs and symptoms of hypothyroidism, although these may be very subtle in childhood, and thus their measurement should probably be included in the basic workup of sexual precocity in all affected children.

Treatment.

In cases of precocious pseudopuberty, treatment should, wherever possible, be targeted to the underlying etiology (Table 3-5). For example, androgen-producing ovarian arrhenoblastomas, estrogen-producing ovarian granulosa cell tumors, adrenal sex steroid–producing tumors, hCG-producing tumors, and tumors causing Cushing syndrome should be surgically extirpated. Additional treatment with chemotherapy and/or radiation therapy for specific tumors should be directed by an experienced pediatric oncologist. Large ovarian cysts can be drained under ultrasonographic guidance. Illicit or unintentional administration of exogenous estrogens or androgens should be exposed and eliminated. Familial testotoxicosis can be treated with the antifungal drug, ketoconazole, which, atmoderately high doses, has the desirable and reversible side effect of interfering with sex steroid synthesis. This drug may also inhibit cortisol synthesis and has been associated with a reversible form of primary glucocorticoid insufficiency. Screening for hepatotoxicity is also required. Another approach to treat such boys is with a combination of a nonsteroidal antiandrogen and an aromatase inhibitor. NCAH is treated with exogenous glucocorticoids to prevent overproduction of androgens and hypothyroidism is corrected by administration of l-thyroxine. Girls with precocious puberty secondary to McCune-Albright syndrome are most commonly treated with tamoxifen, an estrogen receptor blocker, to limit the effects of excess estrogen production on estrogen-sensitive tissues. The use of later-generation aromatase inhibitors in these girls has not been shown to be of consistent benefit despite the theoretical attraction of diminished estrogen synthesis. Most recently, use of fulvestrant, a pure estrogen receptor antagonist, has been shown to reduce vaginal bleeding and rates of skeletal maturation in girls with McCune-Albright syndrome. In cases of precocious pseudopuberty, GnRH agonist therapy is ineffective unless central puberty is concomitantly triggered.

When to refer.

The criteria for referral of a child with precocious puberty to an endocrinologist are summarized in Box 3-1.

Introduction

Delayed puberty is defined as the lack of pubertal development at two standard deviations above the mean age for the general population. In practical terms, this is a chronological age of 14 years for boys and 13 years for girls.³⁰ In addition, an abnormality may be present if there is lack of the appropriate progression of puberty, more than 4 years between the first signs of puberty and menarche in girls or the onset and the completion of genital growth in boys. The goal of the assessment is to determine whether the delay or lack of development is due to a lag in normal pubertal maturation or represents an abnormality that must be investigated. Etiologies include (1) constitutional delay of growth and development; (2) secondary or functional hypogonadotropic hypogonadism caused by chronic illness or malnutrition; (3) primary hypogonadotropic hypogonadism; and (4) hypergonadotropic hypogonadism.

Constitutional Delay of Growthand Development

Definition.

Constitutional delay of growth and development (CDGD) represents an exaggerated delay of puberty in an otherwise healthy boy or girl. It is often referred to as “late-blooming” and is usually diagnosed in boys, reflecting an ascertainment bias in referral patterns. In these children, puberty occurs spontaneously and progresses normally beginning at an age later than the average.

Etiology.

CDGD is considered a variant of normal. The exact etiology of CDGD is not currently known, but familial factors are paramount. There is often a family history in up to 50% of cases, with one or both parents having had a similar pattern of development. Recently, genetic analyses have been applied to children with CDGD. A series of patients with CDGD have been reported with heterozygous point variations in the GH secretagogue receptor; the exact significance of this finding requires validation. In addition, a sequence variant within the leptin gene has been reported in a mother and her son with reduced BMI and CDGD. Last, an association with CDGD has been shown with a locus on chromosome 2.

Diagnosis, evaluation, and natural history.

Typically children with CDGD have a normal length and weight at birth, and after a period of normal growth, there is a decline in growth velocity and weight gain beginning as early as 6 months and lasting up to 2 to 3 years of age. Growth then returns to a normal rate and continues along a lower percentile than would be expected for the family height genetics for the remainder of the prepubertal years. At the expected time of puberty, the height of children with CDGD begins to drift further from the normal growth curve because of delay in the onset of the pubertal growth spurt. Confounding the issue, the natural slowing of linear growth just before the onset of puberty (often accompanied by an apparent decline in GH secretion) may be exaggerated, magnifying the difference in size from peers who are beginning to show acceleration in their growth.

At the expected age of pubertal onset, children with CDGD demonstrate delayed bone ages and prepubertal levels of gonadotropins, initially making it difficult to distinguish this condition from primary or secondary gonadotropin deficiency. GnRH agonist and/or hCG stimulation may have better discriminatory value, but suggestive studies have had small numbers of subjects, lack of replication of diagnostic thresholds, and involve prolonged testing protocols that limit clinical application.³¹ In recent studies, a single inhibin B level has demonstrated good discrimination between groups (for more detail, see section Hypogonadotropic Hypogonadism, later).³² Periodic evaluation of height, weight, and stage of sexual maturation helps differentiate this normal variant from a pathologic entity, eliminating the need for laboratory testing. Because timing and tempo of sexual development appear to be delayed in accordance with the biological state of maturity (bone age), the height of a child with CDGD should be more or less appropriate for his or her genetic target height range when the height is plotted against bone age rather than chronological age (Figure 3-18). There is a poorly understood subset of children with CDGD who have a blunted pubertal growth spurt relative to their peers and may not reach their genetic target height.³³ Unfortunately, it is not possible to anticipate which children with CDGD will fall into this category. As a result, it is important to monitor children with CDGD closely during puberty as they may require expedient intervention to attain a normal adult height.

Treatment.

Some would argue that, if delayed puberty were a physiologic variation, there is no proven medical necessity for initiating sex steroid replacement. However, there are adolescent boys with CDGD who are very short, significantly underdeveloped, and who are psychologically compromised. These boys frequently request and will profit from a short course of testosterone therapy. The administration of testosterone to adolescent boys with CDGD has been recommended for years, but it remains controversial because of the possibility of premature epiphyseal closure and reduced final height. However, if administered in low doses for a short duration, testosterone therapy is effective and does not appear to compromise final adult height. Intramuscular testosterone enanthate or cypionate ester is typically provided at 50 to 100 mg every 3 to 4 weeks, for a course of 3 to 18 months, depending on the needs of the patient. Transdermal preparations have been used off-label for this indication, but their safety and efficacy have yet to be demonstrated. A pediatric endocrinologist comfortable with prescribing testosterone is essential, as short-term doses higher than appropriate may result in an accelerated advancement in skeletal maturity and significantly short adult stature. Patients require close follow-up, at 3- to 6-month intervals, regarding height, weight, growth velocity, and pubertal and epiphysial maturation to ensure normal growth and development.

Other therapeutic approaches that have been tried in patients with CDGD include oxandrolone, aromatase inhibitors, GnRH agonists, and growth hormone. None of the medications has achieved evidence-based or FDA-approved status.

Functional HypogonadotropicHypogonadism

Definition.

More than 30% of adolescents at one time suffer from a chronic illness. Medical illnesses have a tremendous impact on normal sexual development. In the face of poorly controlled or undiagnosed illness, children may not develop secondary sexual characteristics until the condition is identified and/or treated appropriately. These children are classified as having functional (or reversible) hypogonadotropic hypogonadism.

Etiology.

Any underlying chronic illness, prolonged medical treatment requiring glucocorticoids, excessive emotional stress, intense physical activity, or inadequate nutritional state can result in reversible hypogonadism (Table 3-6). If the underlying problem can adequately be treated, normal gonadotropin secretion is expected to follow.

Virtually every adolescent child with a serious chronic disease can have or sometimes present with delayed puberty (due to recurrent infections, immunodeficiency, gastrointestinal disease, cardiac disease, renal disturbances, respiratory illnesses, chronic anemia, endocrine disease, eating disorders, and/or excessive energy expenditure). Pubertal delay associated with chronic illness is accompanied by a delay in growth and by an absent or blunted pubertal growth spurt. The degree to which growth and pubertal development are affected in chronic illness depends on the type of disease and individual factors, as well as on the age at illness onset and its duration and severity. The earlier the onset and the longer and more severe the illness, the greater the repercussions for growth and pubertal development. The basis of abnormal puberty in children with chronic illness is multifactorial. Nutritional deficiency may contribute through insufficient food supply and/or malabsorption of nutrients. Moreover, increased energy supplies are often needed in patients with lung disease, infection, or inflammation. More specific factors due to the disease itself may be involved in growth and pubertal disorders. Abnormalities of the GH-IGF-1 axis and gonadotropin secretion have been described in patients with chronic renal failure, cystic fibrosis, and Crohn disease (see Chapter 2). More recently, it has been shown that cytokines produced during chronic diseases such as juvenile idiopathic arthritis may inhibit the normal function of the GH-IGF-1 axis. Finally, concomitant medications, such as glucocorticoids, which are often given to these patients, may contribute to delayed puberty and poor pubertal growth. Therefore, early diagnosis is essential and appropriate and disease-specific therapy fundamental.

Malnutrition (as may occur in malabsorption, anorexia nervosa, bulimia, and intense exercise), chronic pain, and psychosocial factors can all disrupt the HPG axis. The pituitary gland’s affinity for iron deposition explains the high incidence of hypogonadism, pubertal delay, and growth retardation in hemochromatosis and patients hypertransfused for chronic anemias. Hypogonadism in males with HIV infection is an ongoing concern, even among patients whose viral replication is under control and who have normalized CD4⁺ cell counts. Elevated serum lead levels have been shown to be associated with pubertal delay.

Endocrinopathies such as hypothyroidism, hyperprolactinemia, and hypercortisolemia may also result in functional hypogonadotropic hypogonadism. Thyroid hormone deficiency impairs growth and development, perhaps through induction of transient reversible GH deficiency. Adolescents with poorly treated or undiagnosed hypothyroidism may also have significantly delayed sexual maturation. Prolactin is naturally synthesized and secreted by lactotrophs in the anterior pituitary gland. Its primary function is during pregnancy to enhance breast development and induce lactation, but there is evidence that it also decreases gonadotropin secretion. Therefore, hyperprolactinemia should be considered in any teenager, male or female, with delayed sexual development and galactorrhea. Adolescents with hypercortisolemia demonstrate arrested pubertal development. Glucocorticoid excess suppresses gonadotropin release and also directly inhibits sex steroid secretion from the gonads.

Diagnosis, evaluation, and natural history

(Table 3-7).

The initial approach in the diagnosis of delayed puberty requires a careful medical history, detailed growth history, complete family history, and physical examination. The medical history should include a detailed search for a reversible etiology for delayed sexual development. A history of competitive athletics or dance should be a red flag for excessive energy expenditure and the likelihood of hypothalamic dysfunction. Children with cardiac, gastrointestinal, rheumatologic, renal, or pulmonary disease need no further examination. If significant medical history is absent, a simple laboratory search for occult chronicillness is appropriate. Initial testing should include comprehensive chemistry panel, complete blood count and erythrocyte sedimentation rate, urinalysis, tissue transglutaminase antibody, TSH, and free T₄ (preferably by direct dialysis). The chemistry panel and complete urinalysis help assess hepatic and renal function, respectively, in addition to glucose status. The complete blood count evaluates bone marrow function. The erythrocyte sedimentation rate is helpful to identify inflammatory disorders, such as systemic lupus erythematosus, juvenile rheumatoid arthritis, and inflammatory bowel disease. The tissue transglutaminase antibody assay is specific for the identification of celiac disease. Free T₄ and TSH identify thyroid dysfunction.

Treatment.

Treatment of the underlying condition is the only therapy necessary.

Hypogonadotropic Hypogonadism

Definition.

The lack of any clinical manifestation of puberty by age 13 years in girls and 14 years in boys, along with persistence of low LH and FSH levels, is indicative of hypogonadotropic hypogonadism.

Etiology.

Etiologies of hypogonadotropic hypogonadism are divided by congenital and acquired forms (see Table 3-8). Congenital deficiency states include kisspeptin 1 gene mutations, KISS1 receptor mutations, isolated gonadotropin deficiency, adrenal hypoplasia congenita, and certain genetic syndromes. Acquired deficiency may result from an array of disorders affecting the brain, including tumors, malformations, trauma, surgery, radiation, infections, and infiltrative disease.

Congenital

Kisspeptin gene and receptor mutations

KISS1 and its receptor are required for normal function of the HPG axis and play an important role in the physiologic regulation of puberty. Evidence supports a role for kisspeptin in stimulating GnRH secretion. Loss-of-function mutations in the KISS1R gene³⁴ and a homozygous inactivating mutation in the KISS1 gene³⁵ have been described in consanguineous families with isolated HH without olfactory abnormalities.

To date, there are too few patients described in the literature to provide an adequate understanding of the clinical presentation. However, the patients who have been reported with KISS1 and KISS1R mutations have presented with lack of onset of pubertal development or stalled pubertal development. Biochemically, patients present with low gonadotropin levels without other pituitary hormonal deficiencies.

GnRH deficiency

GnRH-producing and olfactory neurons migrate together in embryologic development so that disruption of this process can cause either isolated hypogonadotropic hypogonadism or Kallmann syndrome. GnRH is released from neurons in the arcuate nucleus in a pulsatile fashion into the hypophysial-portal circulation, the capillaries perfusing the anterior pituitary gland. GnRH binds to GnRH receptors on the surface of gonadotrophs in the anterior pituitary gland, which, in turn, synthesize and secrete LH and FSH. The gonadotropins are released into the circulation where they stimulate gonadal steroidogenesis and gametogenesis. Gonadal steroids, principally testosterone in boys and estradiol in girls, exert negative feedback upon the hypothalamus and pituitary early in life and during puberty.

Isolated idiopathic HH has clinical and genetic heterogeneity, multiple modes of inheritance, and variable associates with other anomalies. Idiopathic hypogonadotropic hypogonadism and Kallmann syndrome are both characterized by defects in pituitary GnRH secretion.³⁶ Impairment of both GnRH and olfactory neuron migration results in Kallmann syndrome, the key components of which are hypogonadotropic hypogonadism and disordered sense of smell. Normosmic patients are not diagnosed with Kallmann syndrome, but rather idiopathic hypogonadotropic hypogonadism. Both Kallmann syndrome and idiopathic hypogonadotropic hypogonadism can occur in partial or complete forms. Kallmann syndrome and idiopathic hypogonadotropic hypogonadism can occur in multiple generations and can present at any time from the early neonatal period to adulthood, and with varying degrees of gonadotropin deficiency. Male infants may present with cryptorchidism and/or micropenis. Both male and female patients may fail to enter puberty during adolescence. In recent years, adult-onset hypogonadotropic hypogonadism has been reported with loss of libido and decreased fertility after completion of normal pubertal development.³⁷ In addition, there have been reports of spontaneous hypogonadotropic hypogonadism reversal.

Recent large-scale molecular genetic studies have highlighted multiple genes responsible for both conditions. Mutations in the following genes have all been implicated in Kallmann syndrome: Kallmann syndrome 1 sequence (anosmin-1 or KAL1), fibroblast growth factor receptor 1 (FGFR1), fibroblast growth factor 8 (FGF8 or KAL2), prokineticin receptor 2 (PROKR2) and prokineticin 2 (PROK2), nasal embryonic luteinizing releasing hormone factor (NELF), chromodomain-helicase DNA-binding protein 7 (CHD7), heparan sulphate 6-O-sulphotransferase 1 (HS6ST1), and a WD-repeat protein 11 (WDR11).³⁸ Mutations in the genes encoding the GnRH receptor (GnRHR), kisspeptin receptor (KISS1R), LH β-subunit gene (LHβ), FSH β-subunit gene (FSHβ), tachykinin 3 receptor (TAC3R), and TAC3 underlie uncomplicated normosmic hypogonadotropic hypogonadism.³⁶ Genes associated with idiopathic hypogonadotropic hypogonadism in the backdrop of obesity include those encoding leptin (LEP), the leptin receptor (LEPR), and prohormone convertase 1 (PC1). It should be pointed out that Kallmann syndrome and idiopathic hypogonadotropic hypogonadism may not be distinct disorders as these two entities may exist in different relatives within the same family suggesting that they are subtypes of a complex genetic disease that is characterized by variable expression, penetrance, and modes of inheritance. As occurs in other multifactorial complex diseases, the pathogenesis of hypogonadotropic hypogonadism may be linked to environmental factors that may exert epigenetic effects on gene expression and the concurrent involvement of single nucleotide polymorphisms or other genetic defects in two (digenic) or multiple interacting genes.

All patients with Kallmann syndrome have either anosmia or severe hyposmia (reduced sense of smell) and may exhibit symptoms of associated conditions including unilateral renal agenesis, atrial septal defect, colorblindness, metacarpal shortening, and synkinesia (alternating mirror movements) most often seen in patients with KAL1 mutations. The sense of smell can easily be confirmed by testing the recognition for common substances such as alcohol, peppermint, or coffee, or with the use of commercially available smell test kits. Patients with FGFR1 mutations have cleft lip/palate and may have dental agenesis. Those with FGF8 mutations may have involuntary mirror movements, scoliosis, short stature, joint hyperextension, and osteoporosis. Patients with either PROKR2 or PROK2 mutations may often have a sleep disorder, epilepsy, fibrous dysplasia, and/or synkinesia. The CHD7 gene is responsible for CHARGE syndrome, explaining why Kallmann syndrome and CHARGE syndrome have been reported to have overlapping phenotypes. These patients may also have hearing deficits with hypoplasia of their semicircular canals. Kisspeptin regulates GnRH secretion in the hypothalamus via the KISS1R located on the surface of GnRH neurons and its secretion increases just before the start of puberty to promote the pulsatile secretion of GnRH. There are no nonreproductive effects of mutations of either KISS1 or the KISSR known at this time. Patients with mutations of leptin or the leptin receptor have associated obesity.

Transcription factors involved in pituitary development

Mutations of pituitary transcription factors may also result in hypogonadotropic hypogonadism. Gland development is governed by activation of a cascade of transcription factors that orchestrate both pituitary morphogenesis and differentiation of all five cell lineages of the anterior pituitary: corticotrophs, gonadotrophs, thyrotrophs, somatotrophs, and lactotrophs. Of those pituitary transcription factors identified so far, defects of HESX1, LHX3, LHX4, PROP1, and POU1F1 (Pit-1) have been found to lead to the phenotype of multiple pituitary hormone deficiency in humans.³⁹ The specific phenotype of mutations of POU1F1 is characterized by a combined deficiency of GH, TSH, and prolactin. In contrast, endocrine phenotypes of mutations of HESX1, LHX3, LHX4, and PROP1 tend to overlap and have been reported to include failure of up to all five cell lineages. To make the understanding of phenotypes even more complex, the influences of these transcription factors on pituitary function seem to be dynamic with the potential to develop hormone deficiencies throughout the human lifespan.

To date, mutations of PROP1 represent the most frequently reported etiology of combined pituitary hormone deficiencies that include early loss of GH, TSH, and gonadotropins, with occasional late ACTH deficiency. The phenotypes of affected children vary widely. The pituitary gland may be hypoplastic, normal, or hyperplastic in size, with subsequent involution over time. The typical child with a PROP1 mutation may present with small genitals and hypoglycemia during the newborn period. Growth velocity, despite congenital GH deficiency, may be normal during the first 6 months of life, but then tapers off considerably. If mild hypoglycemia is not identified during infancy, CNS alterations may develop (delayed development, mental retardation, seizures, and, even neurologic devastation).

Mutations of the HESX1 gene may result in pituitary hormone insufficiency associated with ONH, historically known as septo-optic dysplasia (SOD). This syndrome is characterized by abnormalities of midline brain structures (absence of the septum pellucidum in 50% and, less frequently, agenesis of the corpus callosum), ONH, and pituitary hypoplasia. Newer findings reveal that patients with isolated ONH seem to be equally at risk as those with associated SOD to develop hypopituitarism.⁴⁰ The spectrum of endocrinopathy associated with ONH ranges from isolated GH deficiency to panhypopituitarism. Evolving endocrinopathies are common with loss of endocrine function over time. Children with ONH/SOD usually come to attention with ophthalmological issues, that is, wandering nystagmus and poor vision. Retinal examination (often requiring fundal photography) reveals unilateral or bilateral hypoplastic optic nerve(s), leading to a further workup for possible ONH/SOD and referral to a pediatric endocrinologist.

Another cause of hypogonadotropic hypogonadism is adrenal hypoplasia congenita, caused by mutations of the NROB1 gene (formally called DAX1). The NROB1 gene encodes for DAX-1 protein, which is a transcription factor necessary for the development of the hypothalamus, pituitary gonadotrophs, and the adrenal cortex. DAX1 also appears to regulate gonadotropin secretion at both the hypothalamic and pituitary levels.⁴¹ Children with NROB1 mutations usually present with primary adrenocortical failure in infancy or childhood. Those adequately treated with gluco- and mineralocorticoids later present with delayed sexual development due to hypogonadotropic hypogonadism.

Syndromes associated with hypogonadotropic hypogonadism

Prader-Willi syndrome (PWS) is a contiguous gene syndrome caused by the sporadic loss of function of genes situated within the 15q11-q13 region, with a prevalence rate of one in 16,000. PWS was the first human disorder attributed to genomic imprinting. In such disorders, genes are expressed differentially based on the parent of origin. An imprinting center has been identified within 15q11-13; gene expression may be regulated by DNA methylation at cytosine bases. PWS results from the loss of imprinted genomic material within the paternal 15q11.2-13 locus. The loss of maternal genomic material at the 15q11.2-13 locus results in Angelman syndrome. The molecular events underlying the disorder include interstitial deletions (70%), uniparental disomy (25%), imprinting center defects (< 5%), and rarely chromosomal translocations (< 1%). PWS is commonly associated with hypogonadotropic hypogonadism and small genitalia, although there are also reports of patients with hypergonadotropic hypogonadism.⁴² Characteristic facial features include narrow bifrontal diameter, almond-shaped palpebral fissures, narrow nasal bridge, and a downturned mouth. Infants typically have poor tone, delayed development, and failure-to-thrive. By age 2 years, these children develop polyphagia and progressive obesity.

Noonan syndrome is an autosomal dominant, genetically heterogeneous disease. Approximately 50% of cases are caused by gain-of-function mutations in the PTPN11 gene. The incidence of Noonan syndrome is estimated to be 1 per 1000 to 2500 live births and occurs equally in males and females (and, thus, should not be referred to as male Turner syndrome). The cardinal facial features are shown in Figure 3-19; affected individuals also manifest right-sided congenital heart disease (pulmonic stenosis) or atrial septal defect, and short stature. Testes are often small or cryptorchid. Typical patients demonstrate hypogonadotropic hypogonadism, but there are reports of patients with elevated gonadotropins.⁴³ A bleeding diathesis is present in as many as half of all patients with Noonan syndrome, with factor XI deficiency the most frequent abnormality.

CHARGE syndrome is another autosomal dominant condition with genotypic heterogeneity. Most cases are due to mutation or deletion of the chromodomain helicase DNA-binding protein-7 (CHD7) gene.⁴⁴ The estimated incidence of CHARGE syndrome is 1 in 8500 to 12,000 live births. It is associated with hypogonadotropic hypogonadism and olfactory bulb abnormalities similar to the abnormalities found in individuals with Kallmann syndrome. Boys with CHARGE syndrome may have micropenis, cryptorchidism, and/or small testes. Girls may have small labia. The cardinal features of coloboma (Figure 3-20), heart anomalies, choanal atresia, pre- and postnatal retardation of growth, genital hypoplasia, and ear anomalies clinically define CHARGE syndrome.

Bardet-Biedl syndrome (BBS) is an autosomal recessive condition with a wide spectrum of clinical features.⁴⁵ Prevalence rates in North America and Europe range from 1:140,000 to 1:160,000 live births. However, in Kuwait and Newfoundland, the rate is much higher, with an estimated incidence of 1:13,500 and 1:17,500, respectively, suggesting a founder effect. BBS is genetically heterogeneous, with 12 BBS genes identified to date. Although the cellular mechanisms that underlie BBS remain unclear, it is now evident that all of the known BBS proteins are important for ciliary transport. BBS is characterized by early-onset retinal dystrophy, obesity, postaxial polydactyly (Figure 3-21), brachydactyly of the hands and feet, mental retardation, hypogonadism, and renal disease. Hypogenitalism (cryptorchidism and/or microphallus) is reportedly more frequently in BBS boys. Genital abnormalities encompass a wide range in girls, including hypoplastic fallopian tubes, uterus, and ovaries, partial and complete vaginal atresia, absent vaginal orifice, and absent urethral orifice. Hypogonadotropic hypogonadism has only been reported in BBS girls. Primary gonadal failure has been seen in both sexes.

Acquired

CNS lesions such as neoplasms, head trauma, surgery, radiation, infections, and infiltrative disease can disrupt hypothalamic-pituitary function resulting in hypogonadotropic hypogonadism.

Sellar and suprasellar tumors may alter pituitary function directly and/or disrupt the hypothalamic-pituitary stalk, leading to pituitary hormone deficiencies. Craniopharyngiomas are the most common suprasellar tumors identified in children. These tumors have a benign histology with a malignant behavior, having the tendency to invade surrounding structures and to recur after what was thought to be complete resection. They frequently present as cystic structures (single or lobulated) filled with a turbid, proteinaceous material of brownish-yellow color that glitters and sparkles because of a high content of floating cholesterol crystals that has been compared to machinery oil. The tumor frequently arises in the pituitary stalk and projects into the hypothalamus. It extends voraciously along the path of least resistance (anteriorly into the prechiasmatic cistern and subfrontal spaces; posteriorly into the prepontine and interpeduncular cisterns, cerebellopontine angle, third ventricle, posterior fossa, and foramen magnum; and laterally toward the subtemporal spaces). Craniopharyngiomas account for 5% to 10% of intracranial tumors and 56% of suprasellar tumors in children and usually are diagnosed between the ages of 5 and 10 years. Affected patients present with characteristic symptoms of increased intracranial pressure (headache, nausea, and vomiting), pituitary dysfunction, and/or visual disturbance. Most children present with growth failure secondary to GH deficiency. Adolescents present with growth failure and delayed or absent sexual development, which can be overlooked until after symptoms of increased intracranial pressure develop. Some patients also have central hypothyroidism and adrenal insufficiency. The neurologic examination is suggestive of increased intracranial pressure, in the form of papilledema and visual field deficits. The radiologic hallmark of craniopharyngiomas is the appearance of suprasellar calcification on neuroimaging. If hypopituitarism were not present prior to therapy, resection of the tumor will likely disrupt the hypothalamic-pituitary communication fairly acutely. For this reason, children with a history of craniopharyngioma should be followed regularly by a pediatric endocrinologist.

Traumatic brain injury is, unfortunately, common in the adolescent population, especially in males. Necrotic, hypoxic, ischemic, and shearing lesions involving the hypothalamus and/or the pituitary are now being reported more frequently in adolescents with traumatic brain injury. Children at highest risk appear to be those who have suffered moderate or severe trauma. Clinical signs of anterior hypopituitarism are often subtle and may be masked by the sequelae of traumatic brain injury. Therefore, posttraumatic anterior pituitary dysfunction may remain undiagnosed and, possibly, aggravate symptoms of brain injury. Moreover, it may, if undiagnosed, lead to a potentially fatal adrenal crisis.

Leukemia and brain tumors account for 53% of all cancers diagnosed among children younger than 15 years. Although there are obvious differences between leukemia and brain tumors, these two childhood cancers share some important features that influence the long-term health and quality of life of survivors. Both cancers require CNS-targeted therapy. Because the peak incidence for both cancers is during a vulnerable neurocognitive developmental period, CNS-directed therapy, in particular moderate- or high-dose cranial radiotherapy, often has significant long-term consequences. This is especially true for brain tumor survivors. This knowledge has led to efforts to reduce radiation exposure in the treatment of brain tumors and to use other measures of CNS prophylaxis in the treatment of acute lymphoblastic leukemia. Radiation-induced damage to the hypothalamic-pituitary axis is associated with a wide spectrum of subtle and frank abnormalities in anterior pituitary hormone secretion.⁴⁶ The frequency, rapidity of onset, and the severity of these abnormalities correlate with the total radiation dose delivered to the axis, as well as to the fraction size, younger age, prior pituitary compromise by tumor and/or surgery, and the length of follow-up. Although the hypothalamus is the primary site of radiation-induced damage, secondary pituitary atrophy evolves with time due to impaired secretion of hypothalamic tropic factors and/or time-dependent direct radiation-induced damage. Abnormalities in gonadotropin secretion are dose-dependent. Precocious puberty can occur after radiation doses less than 30 Gy in girls and in both sexes equally with a radiation dose of 30 to 50 Gy. Gonadotropin deficiency is usually a long-term complication following a minimum radiation dose of 30 Gy. Radiation-induced anterior pituitary hormone deficiencies are irreversible and progressive. Regular testing is mandatory to ensure timely diagnosis and early hormone-replacement therapy.

Inflammatory and infectious diseases of the pituitary gland are rare, and diagnosis via imaging may be difficult. They encompass a wide spectrum of pathology, including autoimmune hypophysitis, granulomatous hypophysitis, local manifestations of systemic disease, and a multitude of infectious processes (HIV, herpes simplex virus, and Mycoplasma are just a few reported). Granulomatous hypophysitis is rare, with an estimated incidence of one case per 10 million per year. It is characterized by granulomas with epithelioid histiocytes and multinucleated giant cells. Lymphocyte collections also occur, but they are not the dominant feature. It was initially thought to be a distinct entity occurring in isolation, but newer cases have been described in association with systemic conditions such as Takayasu disease, ruptured intrasellar Rathke cleft cyst, Crohn disease, thyroiditis and adrenalitis, and granulomatosis with polyangiitis (Wegener granulomatosis). Because of their ultrastructural similarity and autoimmune origin, it has been suggested that granulomatous and lymphocytic hypophysitis may have similar pathogenetic backgrounds or even may represent different stages of the same disease. Lymphocytic hypophysitis is a rare disorder predominantly affecting women usually during the ante- or postpartum period. It is characterized by destruction and lymphocytic infiltration of the pituitary gland, probably by an autoimmune process, leading to a pituitary mass lesion and/or various degrees of hypopituitarism. The lesion is usually confined to the adenohypophysis. Posterior pituitary gland or stalk involvement is rare, although patients presenting with diabetes insipidus have been reported. The clinical presentation and radiologic findings may mimic those of a pituitary adenoma, with a firm diagnosis established only after biopsy with histologic examination.

Diagnosis, evaluation, andnatural history

Random measurement of various puberty-related hormones has been attempted to distinguish idiopathic normosmic hypogonadotropic hypogonadism from CDGP, including FSH, LH, and testosterone.³¹ However, this approach may not be effective because of significant overlap between patients with an immature hypothalamic-pituitary axis and those with permanent gonadotropin deficiencies. A peak serum LH less than 10 mIU/mL after GnRH stimulation (100 μg IV) differentiated patients with hypogonadotropic hypogonadism from those with CDGP with a sensitivity of 82% and a specificity of 98% in adolescents older than 14 years. Recently, however, a baseline serum inhibin Bconcentration of less than 35 pg/mL in males ages 14 to18 years with testicular volumes less than 3 mL was shown to provide 100% sensitivity and specificity in the diagnosis of hypogonadotropic hypogonadism. However, the sensitivity and specificity was lower when evaluating boys with testicular volumes of 3 to 6 mL.

If the patient is found to have permanent hypogonadotropic hypogonadism, the history and physician examination should narrow the differential. A family or patient history of hypogonadism and/or absent or reduced sense of smell might indicate isolated gonadotropin deficiency. An abnormal perinatal history, with any of the following, should alert one to the possibility of a pituitary transcription factor abnormality: micropenis, hypoglycemia, cleft lip/palate, bifid uvula, prolonged jaundice, giant cell hepatitis, hypotension, and/or electrolyte disturbance. History and physical examination identify any of the syndromic etiologies for hypogonadotropic hypogonadism. Low tone with poor feeding during infancy and delayed development, along with rapid weight gain and polyphagia after 2 years, may indicate PWS. Pulmonic stenosis and short stature suggest Noonan syndrome. A perinatal history of choanal atresia or childhood history of coloboma could be indicative of CHARGE syndrome. Progressive vision loss in a child with postaxial polydactyly or renal disease is indicative of BBS. Signs or symptoms of increased intracranial pressure point toward the possibility of an intracranial tumor. A history of traumatic brain injury may result in pituitary insufficiency many years after the event and should alert the physician to the possibility of hypopituitarism. Last, a history of prior brain (especially hypothalamic) cancer and/or radiation to that area of the brain should alert to the possibility of gonadotropin deficiency.

Commercial genetic analyses may be applied to confirm some of the syndromes associated with hypogonadotropic hypogonadism. For example, DNA methylation analysis is the test of choice for PWS. Additionally, evaluation of the PTPN11 gene, mutations of which are present in approximately 50% of patients with Noonan syndrome, should also be considered at least for uncertain cases.

An MRI of the brain with contrast dye enhancement in a closed-tube system should be obtained in all patients with hypogonadotropic hypogonadism. Abnormalities of the olfactory placode indicate Kallmann syndrome (Figure 3-22). Congenital malformations of the anterior or posterior pituitary, congenital lesions of septum pellucidum and corpus callosum, as well as acquired tumors or infiltrative lesions may also be identified with MRI.

Treatment

The basic principles of hormonal treatment of permanent hypogonadism, either hypo- or hypergonadotropic varieties, are the same.

Therapy for boys is aimed at replacement of testosterone in a stepwise fashion, targeted at mimicking normal physiology. Therefore, in boys with hypogonadism, as well as for those with CDGD, intramuscular testosterone is begun in a similar manner, but for those with permanent hypogonadism, there will need to be continued administration with increases of 50 mg made over a 2- to 3-year period. Using this approach, most adult men receive 200 to 300 mg every 2 to 4 weeks. This dosing is based on the daily adult male testosterone production rate of 6 mg. Once reaching final adult height, older adolescent boys can take testosterone transdermally by patch or gel.

Therapy for girls with permanent hypogonadism is typically initiated with daily low-dose estrogen therapy alone for 1 to 2 years. This can be in the form of any number of equivalent estrogen preparations. Conjugated equine estrogens (eg, Premarin) have traditionally been used at 0.3 mg daily for the first 6 months, 0.625 mg daily for the second 6 months, followed by 0.6 to 1.2 mg starting in the second year. Ethinyl estradiol (eg, Estrace) has also been used with replacement at 0.02 mg for the first 6 months, followed by 0.1 mg daily for the second 6 months, and 0.2 mg thereafter. Transdermal estradiol preparations (eg, Vivelle dot) are also available and are advanced slowly throughout the following 2 years to a total daily dose of 0.025 to 0.1 mg/day. Although it is not clear that cutting patches reliably allow the necessary dose escalation, serum estradiol levels can be measured to guide the clinician with ongoing dosing decisions. The initial duration of unopposed estrogen, if not exceeded, for 1 to 2 years does not appear to expose the uterus to any undue risk for endometrial hyperplasia and/or malignancy. At the end of the first few years, cyclical progesterone must be added. The two options include oral medroxyprogesterone (eg, Provera) and micronized progesterone (eg, Prometrium). Medroxyprogesterone at10 mg or micronized progesterone at 200 mg is provided on days 20 to 30 of the cycle. With this approach, withdrawal bleeding generally occurs in the following 3 to 10 days, although there can be some variability between patients. Another option is to provide progesterone on days 100 to 120 of the cycle to minimize menstruation. Alternatively, at adult dosing, the aforementioned estrogendelivery methods are often abandoned in favor of a more conventional oral contraceptive or substituted with a weekly estrogen patch used in conjunction with oral progesterone. There are also oral contraceptive agents (eg, Seasonale) that decrease the frequency of menstruation to quarterly intervals.

Patients of either sex with hypogonadotropic hypogonadism are potentially fertile, but sex steroid therapy alone will not ordinarily be sufficient to initiate gametogenesis, although there are rare cases in men in which testosterone replacement alone has stimulated spermatogenesis, presumably by local intratesticular action on the seminiferous tubules. Thus, the typical approach to fertility induction is pump-administered GnRH therapy (assuming an intact pituitary gland) or parenteral combination gonadotropin treatment (synthetic LH/hCG and recombinant FSH) if the pituitary is nonfunctioning, supervised by an experienced reproductive endocrinologist.

Definition

Elevated serum LH and FSH levels in an adolescent being seen for delayed sexual development (see age criteria earlier) are indicative of a primary defect in gonadal (testicular or ovarian) function. The hypergonadotropic state implies that the hypothalamic-pituitary component of pubertal signaling has been activated through lack of negative feedback that is normally exerted by the actions of sex steroids. Etiologies are classified as congenital versus acquired and may be further segregated by the sex of the patient (see Table 3-8).

Etiology

Boys

Congenital testicular failure.

Congenital causes of primary testicular failure include congenital anorchia (also known as the “vanishing testis” syndrome) and Klinefelter syndrome.

• Congenital anorchia— Bilateral congenital anorchia is defined as the complete absence of testicular tissue with a normal male karyotype, phallus, and scrotum. The true prevalence of this condition is unknown because prospective studies have not been performed. However, it is estimated to occur in approximately 0.5 to 1.0 cases per 20,000 boys. The pathogenesis of congenital anorchia has not been completely elucidated. The fetal testis and systemic testosterone must be present during the first 12 weeks of gestation for normal external male genitalia to develop. It follows that an anorchic boy with otherwise normal male external genitalia must have had, early in fetal life, functional testes that subsequently may have undergone torsion or atrophy. Clinical findings are not enough to make the diagnosis, which must be confirmed through endocrinologic evaluation and/or provocative testing. Classically, an hCG stimulation test was done to identify any occult testicular tissue by assessing testosterone response. Other hormones (inhibin B and AMH) released only by the gonads can now be measured in serum to search for the presence of occult testicular tissue. The typical hormonal characteristics of congenital bilateral anorchia can be identified between 6 weeks and6 months of life secondary to the mini-puberty of infancy during which time there will be elevated concentrations of gonadotropins, a low concentration of testosterone, and a lack of increase in serum testosterone after hCG. Regarding imaging, ultrasonography would appear attractive because it is noninvasive and nonionizing. However, it is actually difficult to differentiate between testes and enlarged inguinal lymph nodes, and thus it is not definitive in the inguinal area where the cryptorchid testes are often situated. MRI may be the most innocuous and precise method, but it has the disadvantage of the long scanning time and the need for sedation. Surgical exploration may be the only definitive option to identify any testicular tissue but must be carried out with great care considering the small dimensions of the organs.

• Klinefelter syndrome— The most common cause of hypergonadotropic hypogonadism in boys is Klinefelter syndrome, occurring in about 1 in 500 to 1000 live male births. The term Klinefelter syndrome describes a group of chromosomal disorders in which there is at least one extra X chromosome added to a normal male karyotype of 46,XY. The extra X chromosome in patients with Klinefelter syndrome is usually acquired through an error in meiosis (nondisjunction during parental gametogenesis) where a sperm or an egg carries an extra X chromosome in addition to the normal single sex chromosome. It also may result from an error in division during mitosis of the zygote.

  Klinefelter syndrome may be diagnosed serendipitously in fetal life on amniocenteses or by chorionic villous sampling. During infancy, affected boys may be identified through chromosomal evaluations done for hypospadias, small phallus, or cryptorchidism. The prepubertal boy may have issues with development, academic performance, or social interactions. The adolescent-aged boy may be discovered during an evaluation for disproportionately small testes despite fairly robust development of pubic and axillary hair, along with a eunuchoidal body habitus and gynecomastia. In early and mid-puberty, serum testosterone levels may actually be quite normal, with a reduction in circulating concentrations with age in association with rising gonadotropin levels, typically FSH more so than LH. Older adolescent boys and adult men withKlinefelter syndrome have more clear-cut testosterone deficiency (with elevated gonadotropins), along with more obvious clinical findings, including a eunuchoidal body habitus with sparse body and facial hair, gynecomastia, increased fat mass, small testes (generally < 5 mL)and small penis, azoospermia, and often decreased verbal intelligence (Figure 3-23). If not previously diagnosed, adult men typically come to medical attention because of infertility or, rarely, breast malignancy.

  There is an increased incidence of autoimmune disorders, such as hypothyroidism, systemic lupus erythematous, rheumatoid arthritis, andSjögren syndrome, in patients with Klinefeltersyndrome. There is a suggestion that this may be due to their lower testosterone and relatively higher estrogen levels, as androgens may protect against and estrogens promote the development of autoimmunity. It is unclear at this time if early identification of Klinefelter syndrome and earlier initiation of androgen replacement (see as follows) will decrease the incidence of autoimmune conditions.

Acquired testicular failure.

Acquired causes of primary testicular failure include exposure to toxins, orchitis, severe trauma, and autoimmunity.

There is a large list of substances reported to have an adverse effect on testicular function. Chronic alcohol intoxication can result in testicular atrophy as seen in cirrhotic adults. Lead exposure may result in intoxication sufficient to cause systemic poisoning with testicular deposition with resultant hypogonadism. Cadmium damages testicular blood vessels, causing ischemia and tubular necrosis. Alkylating agents (cyclophosphamide, busulfan, procarbazine, and etoposide) used for chemotherapy frequently cause dose-dependent testicular damage. Direct radiation, as used to treat leukemic infiltration of the testes, is also quite toxic. Last, testicular infarction has been reported with sickle cell disease.

The most common microbial agent documented to cause orchitis and testicular damage is mumps virus. The hallmark of infection is swelling of the parotid glands. Aseptic meningitis and encephalitis are common complications of mumps together with orchitis (and oophoritis in females). Other complications include deafness and pancreatitis. Clinical diagnosis can be based on the classic parotid swelling; however, this feature is not present in all cases of mumps and can also occur in various other disorders. Laboratory diagnosis is based on isolation of the virus, detection of viral nucleic acid, or serologic confirmation (generally the presence of IgM mumps antibodies). Mumps is vaccine-preventable and one dose of mumps vaccine is about 80% successful in preventing the disease. Routine vaccination has proven highly effective in reducing the incidence of mumps and is presently available in most developed countries.

Autoimmune pathology is also linked to testicular damage but is more common in girls than boys.

Girls

Congenital ovarian failure

• X chromosome abnormalities— Turner syndrome (TS) is the prototypical etiology of primary ovarian failure identified in childhood. It is a sporadic disorder defined by the complete or partial absence of one X chromosome. X monosomy is the most commonly occurring sex chromosomal anomaly (1%-2% of all female conceptions), but 90% or more of Turner conceptions are spontaneously aborted. As a result, TS is very common prenatally, but it still occurs with an incidence of about 1 in 2000 to 2500 live female births.

  Although not mandatory for the diagnosis of TS, phenotypic stigmata of short stature and delayed sexual development are quite frequent and, in 50% of girls with TS, are the only features. Features of TS include a short and/or webbed neck, cardiac anomalies (elongated transverse aortic arch, bicuspid aortic valve, coarctation of the aorta, hypoplastic left heart), low posterior hairline, epicanthal folds, ptosis, downslanting palpebral fissures, broad shield-like chest, widely spaced and/or hypoplastic nipples, cubitus valgus, nail hypoplasia and/or hypercovexity, low-set and/or malformed ears, hearing deficits, retrognathia, dental crowding, and/or a high-arched palate. A number of these features may be secondary to lymphedema during gestation. Girls with TS may present in childhood with short stature, declining growth velocity, mildly elevated levels of FSH, and/or any grouping of TS stigmata described previously (Figure 3-24). Girls who present during adolescence with TS may come to medical attention with short stature, an absence of breast development, pubertal arrest, primary or secondary amenorrhea, hypertension, and/or scoliosis. Autoimmune conditions are found with increased prevalence in girls with TS during childhood, including hypothyroidism, inflammatory bowel disease, and rheumatoid arthritis.

  Gonadal dysgenesis is a hallmark of TS. In most patients with TS, the ovaries at birth are already gonadal streaks, consisting mainly of fibrous tissue. Ovarian deterioration appears to develop early in the second trimester with premature atresia complete before birth, although, in some patients, the atresia is not complete until adolescence or even adulthood. It is this variability that gives some girls with TS spontaneous pubertal development and an even smaller number spontaneous menarche. Therefore, the presentation of girls with TS ranges from absence of any pubertal development, to mid-pubertal failure without progression to menarche, secondary amenorrhea, or early menopause.

  Premature ovarian failure (POF) has also been identified among heterozygous carriers of the fragile X mutation.⁴⁷ Interestingly, only premutation carriers have been found to have an increased risk for POF, whereas full-mutation carriers and their noncarrier sisters appear to have the same risk seen in the general population. Approximately 16% of premutation heterozygotes have POF. An observation that potentially explains the reduced penetrance is that paternally inherited premutations were more likely to give rise to POF than were maternally inherited premutations.

  Delayed puberty in a phenotypic female can also be seen in pure gonadal dysgenesis (46,XY—Swyer syndrome) and mixed gonadal dysgenesis (45,X/46,XY).⁴⁸ Complete gonadal dysgenesis is the result of a complete lack of testicular function. Without testicular hormone production during gestation, the natural default pathway, phenotypically, is female. Girls with mixed gonadal dysgenesis may have some somatic features typical of Turner syndrome. Genital development ranges from female to ambiguous to male. Gonadectomy is clearly recommended in both conditions as dysgenetic gonads have an increased risk of developing dysgerminomas or gonadoblastomas.

  In rare cases, pure ovarian agenesis with a 46,XX karyotype also occurs. Affected girls have normal or tall stature, no dysmorphic features, and normal female external genitalia, but hypoplastic or lack of ovarian tissue.

• Autosomal abnormalities—Autosomal abnormalities have also been identified in primary ovarian failure. Galactosemia is a rare (1 in 50,000 live births) autosomal recessive disorder identified routinely by newborn screening. The condition results from impairment in galactose-1-phosphate uridyltransferase metabolism secondary to a mutation in the GALT gene. The resultant protein is a hepatic enzyme essential for the breakdown of lactose, which is most commonly found in milk products. Galactosemia usually is asymptomatic at birth, but jaundice, diarrhea, vomiting, failure-to-thrive, and sepsis soon ensue. Secondary to the lethal nature of the condition if not identified early, galactosemia is one of the diseases checked routinely in newborn screening programs. Despite adequate dietary control of the metabolic disorder with a soy-based formula, girls with galactosemia have lower intelligence, neurologic dysfunction, dyspraxia, and delayed growth, and sexual development, as well as primary ovarian failure. The prevalence of primary ovarian failure is 70% to 80% in girls with galactosemia.⁴⁹ Ovarian damage has been attributed to a toxic effect of galactose or one of its metabolites on follicular structures during fetal life.

  Blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) is a very rare autosomal dominantly inherited disorder (exact incidence unknown), mapped to the long arm of chromosome 3. Classic BPES is a complex eyelid malformation invariably characterized by four major features: blepharophimosis, ptosis, epicanthus inversus, and telecanthus. Type I BPES includes the four major features and female infertility caused by POF and type II includes only the four major features.

  Homozygous mutations in the FSH β-subunit gene have been identified resulting in both partial and complete defects in FSH function. Inactivating mutations of the FSH and LH receptor genes in conjunction with ovarian failure have also been rarely reported.

Acquired ovarian failure

• Autoimmune polyglandular syndromes (APSs)— APS can be categorized into types 1 and 2. APS 1 (autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy or APECED) is an autosomal recessive disorder caused by mutations of the autoimmune regulator (AIRE) gene, which has been mapped to chromosome 21q22.3. The three major components of APS 1 include chronic mucocutaneous candidiasis, hypoparathyroidism, and adrenal insufficiency. In most cases of APS type 1, chronic candidiasis is the first manifestation of the disease, often occurring before the age of 5 years. It is typically followed by hypoparathyroidism and then by adrenal insufficiency (Addison disease) that usually develops in adolescents. Glucocorticoid and mineralocorticoid deficiencies both occur. Antibodies to CYP21 (21-hydroxylase) and CYP17 (17-hydroxylase) seem to be the most commonly identified markers. Symptoms include weakness, fatigue, myalgias, weight loss, abdominal pain, anorexia, diarrhea, nausea, vomiting, dehydration, hypotension, and hyperpigmentation. Laboratory investigation demonstrates hyponatremia, hyperkalemia, metabolic acidosis, azotemia, and hypoglycemia in the presence of an elevated plasma ACTH level. APS 2 includes adrenal, thyroid, and/or pancreatic endocrine dysfunction. It occurs primarily in adulthood, usually in the third or fourth decades, especially in middle-aged women. It is associated with HLA-DR3 and/or HLA-DR4 haplotypes, and the pattern of inheritance is autosomal dominant with variable expressivity. All APS 2 patients have adrenal insufficiency, more than one-half have thyroid disease (Hashimoto or Graves disease), and fewer than one-half have type 1 diabetes. Antibodies to each of the component organs are usually present. Other less common autoimmune diseases may also be present in both types 1 and 2 APS, including gonadal failure, vitiligo, alopecia, chronic hepatitis, chronic atrophic gastritis with or without pernicious anemia, and hypophysitis. However, these autoimmune diseases are more common in patients with APS 1 than in those with APS 2. Specific to primary ovarian failure, the prevalence in women with APS type 2 is only 10% to 25% compared to 60% in patients with APS type 1.

• Ovarian tissue damage—With the increasing success of therapy for childhood cancers, there is a growing population of adolescent girls and women with ovarian failure. Approximately 50% of girls exposed to pelvic irradiation develop primary ovarian failure. The likelihood and severity are dependent on the dose delivered and age administered. Cytotoxic chemotherapy may cause POF in many treated patients. Implicated agents include cyclophosphamide, busulfan, procarbazine, and etoposide. The actively proliferating cells of the mature ovary appear to be especially sensitive to the effects of irradiation and cytotoxic agents.

Diagnosis, evaluation, and natural history

As stated previously, a random LH and FSH by an ultrasensitive method differentiates hypo- from hypergonadotropic hypogonadism (see Table 3-8). Elevated gonadotropins, in the presence of low gonadal sex steroids, indicate the presence of hypergonadotropic hypogonadism.

The history and physical examination are very helpful in narrowing the differential diagnosis for this category. A history of poor school performance, associated with tall stature and small testes for age, is highly suggestive of Klinefelter syndrome. A history of absent testes at birth points toward a diagnosis of congenital anorchia. An unimmunized child may have had mumps exposure and a gonadal insult. A perinatal history of lymphedema or congenital heart disease in a short girl suggests a diagnosis of TS. A family history of fragile X may indicate a premutation carrier at risk for POF. A history of galactosemia or a special formula requirement in infancy may indicate toxic exposure to the ovaries resulting in POF. Eyelid abnormalities in a girl are suggestive of BPES. The presence of other autoimmune conditions, such as thyroiditis, suggests the possibility of APS.

Measurements of serum estradiol levels in girls and testosterone levels in boys are also routinely obtained but are not necessary as serum concentrations can usually be estimated by the degree of clinical pubertal development. Similarly, a pelvic ultrasound in girls is also frequently ordered although, in most cases, the size of the ovaries and uterus can be predicted from the clinical presentation.

Hypergonadotropic hypogonadism always warrants a karyotype to look for genetic syndromes. If normal in females, additional testing should include antiovarian antibodies to detect autoimmune ovarian failure. Galactosemia is typically diagnosed on newborn screening.

Treatment

See aforementioned section Hypogonadotropic Hypogonadism for the basic tenets of treatment, with unique aspects of therapy related to genetic diseases associated with primary hypogonadism discussed as follows.

Therapy for boys with Klinefelter syndrome historically has used an escalating dosage regimen of testosterone replacement, targeted toward mimicking normal physiology. Recently, the question has arisen whether testosterone, required to treat lifelong androgen deficiency, actually may have deleterious effects on spermatogenesis, thereby reducing chances of successful testicular sperm extraction (TESE) and retrieval. An important corollary for management of adolescents with KS is that, wherever possible, semen analysis should be obtained to promote sperm cryostorage prior to development of azoospermia and, thus, to avoid the need for future TESE. Thus, with the recent advent of these newer technologies, paternity in Klinefelter syndrome must now be regarded as a feasible, if still not routine, expectation. In males with Klinefelter syndrome, microsurgical TESE and use of freshly retrieved sperm for in vitro fertilization are increasingly performed, with a 70% yield of viable sperm per procedure with up to 70% of men with Klinefelter syndrome men now able to father a child in some centers.

For girls with TS, several unique caveats exist because of their associated short stature. The trend is toward a more physiologic approach for pubertal induction than was used in the past by use of a “low and slow” approach. This starts earlier than in the past (generally ~11 years and, in some cases, even earlier vs 12-15 years a decade ago), with the aim of normalizing the timing of typical pubertal onset, minimizing the impact of hypogonadism, and initially using very low estrogen doses within the “growth-promoting” (rather than the feminizing) therapeutic range. The estrogen dose is advanced very gradually with the goal of replicating the progression of estrogen secretion from healthy pubertal ovaries. Such a dosing regimen requires transdermal 17β-estradiol to allow for low dosing and to optimize the type and route of estrogen replacement. Addition of progesterone is recommended under treatment of hypogonadotropic hypogonadism. In contrast to girls with hypogonadotropic hypogonadism, those with primary hypogonadism have intrinsic gonadal damage and, thus, traditionally have been considered infertile. That said, there is promising new technology allowing preservation/restoration of fertility via cryopreservation of oocytes and ovarian transposition in females (eg, prior to gonadotoxic therapy for cancer).

When to refer

The criteria for referral of a child with delayed puberty to an endocrinologist are summarized in Box 3-2.

Definition

Gynecomastia refers to the glandular proliferation of breast tissue in males.

Etiology

Physiologic gynecomastia occurs most commonly around the age of 13 years in conjunction with Tanner stages 3 to 4 pubic hair and testicular volumes of 10 to 12 cc bilaterally. It is thought to result from a transient imbalance in the free androgen to free estrogen ratio that allows preferential estrogen effects on breast tissue during this time. However, typically there is often no demonstrable hormonal aberration that is detectable in serum. It has been suggested that the adipose tissue-derived hormone, leptin, may influence the pathogenesis of pubertal gynecomastia. With advancing puberty, serum androgen levels rise closer to adult levels, resulting in a higher androgen-to-estrogen ratio so that, within 1 to 3 years, breast enlargement regresses in up to 90% of boys.

Pathologic gynecomastia results from absolute or relative estrogen excess due to exogenous estrogen administration, endogenous overproduction, or increased peripheral conversion of androgens to estrogens as is seen with excessive aromatase activity or androgen deficiency (Table 3-9). As isolated prepubertal gynecomastia is quite rare, it should always be considered pathological. Even in this age group, the majority has age-appropriate, undetectable sex steroid levels, and thus a specific cause is rarely identified. This suggests that the most common etiology of prepubertal gynecomastia (as with its pubertal counterpart) is idiopathic. That said, it also has been suggested that possible repeated exposures to environmental chemicals be considered as possible etiologies, including phthalates that are a group of industrial chemicals with many commercial uses, including personal-care products and plastic materials, as well as other personal-care products that contain lavender and/or tea tree oils. The list of common drugs and unintentional exposures associated with gynecomastia is shown in Table 3-10.⁵⁰ Development of gynecomastia secondary to transdermal exposure to compounded estradiol and estrone has also been reported.²⁹

Gynecomastia can rarely be the presenting sign for testicular and adrenal cancer. Leydig cell tumors secrete estradiol directly, hCG-secreting tumors stimulate the testes to secrete estradiol (through its LH-like action on Leydig cells), and Sertoli cell tumors increase androgen-to-estrogen conversion via overexpression of aromatase activity. PJS is a rare autosomal dominant disorder that is characterized by multiple gastrointestinal polyps, mucocutaneous pigmentation, and an increased risk for various neoplasms. In recent years, Sertoli cell tumors have become increasingly recognized as a cause of prepubertal gynecomastia in children with PJS. Feminizing adrenocortical tumors are typically malignant and can secrete estrogens directly, but they produce larger amounts of DHEA that are converted to estrone in peripheral tissues.

Similar to hCG-secreting, Sertoli cell, and feminizing adrenocortical tumors, several other conditions are associated with increased peripheral aromatization of androgens to estrogens leading to gynecomastia. The rare entity, aromatase excess syndrome, due to an autosomal dominantly inherited gain-of-function mutation in the aromatase (CYP19) gene, is characterized by accelerated early linear growth, prepubertal gynecomastia, and testicular failure in males and premature thelarche, macromastia, enlarged uterine size, and irregular menstruation in females. In both sexes, there are elevated serum estrogen levels. Hyperthyroidism increases aromatization of androgens to estrogens and decreases free testosterone levels by increasing circulating SHBG levels. Reversible gynecomastia has been reported in 10% to 40% of hyperthyroid men.

Gynecomastia can be seen with any form of genetic or acquired hypogonadism associated with androgen deficiency. The primary defect in testicular failure is decreased serum testosterone levels, but, secondarily, because of absent central feedback, there is increased pituitary LH release and the remaining Leydig cells are stimulated to preferentially produce estradiol leading to relatively unopposed estrogenic effects on breast tissue. The most common chromosomal disorder associated with hypergonadotropic hypogonadism is Klinefelter syndrome. Affected men have about twice the usual amount of circulating estradiol resulting in elevated estradiol-to-testosterone ratios. Thus, 50% to 70% of men with Klinefelter syndrome have gynecomastia that also confers, in this population only, a significantly increased risk for breast cancer. Defects in testosterone synthesis (eg, 17β-hydroxysteroid dehydrogenase type 3 [HSD17B3]) may also cause gynecomastia in association with hypergonadotropic hypogonadism. Gynecomastia from central or secondary hypogonadism is unusual as, typically, all sex hormone levels are low, although continued peripheral aromatization of adrenal androgenic precursors to estrogen may favor a higher estrogen-to-androgen ratio that leads to breast tissue proliferation. Hyperprolactinemia may rarely cause gynecomastia by suppressing gonadotropin production and inducing hypogonadotropic hypogonadism (rather than by a direct effect on the breast).

Diagnosis, evaluation, and natural history

Appropriate examination requires the patient to be supine with hands behind the head following which the examiner brings his or her thumb and forefinger together from the periphery to the center of the breast.⁵¹ True gynecomastia is diagnosed by the presence of a palpable fibroglandular mass that measures more than or equal to 0.5 cm in diameter and is located concentrically beneath the nipple. It can develop as a unilateral, bilateral, and/or asymmetrical enlargement of the breasts, or as a painless or tender mass due to the stretching of overlying tissues. The ability to distinguish true breast tissue from fat tissue under the nipples is often difficult and some patients have both. Gynecomastia in adolescent males may be associated with anxiety, depression, and social phobia.

Gynecomastia in prepubertal boys is uncommon and of potential concern, and thus it should prompt an immediate search for an endogenous or exogenous source of estrogen and a prompt referral should be made to a pediatric endocrinologist. Conditions to consider (Box 3-3) include androgen- and estrogen-producing tumors, inherited disorders of sex steroid synthesis, aromatase excess, medications, and unintentional environmental exposures (see Table 3-10).

Conversely, gynecomastia in adolescents, especially during mid-puberty, is quite common. It is usually a physiological phenomenon typically followed by spontaneous regression within 1 to 3 years when adult testosterone levels are achieved. However, if there is evidence of underlying pathology, for example, macrogynecomastia (> 4-cm breast diameter) with rapidly progressive enlargement (indicative of the magnitude of hormonal imbalance); galactorrhea (hyperprolactinemia); small testes and lack of or reduced secondary male sexual characteristics (hypogonadism); an abdominal or testicular mass (tumor); eunuchoidal body habitus, behavioral problems, and firm small testes (Klinefelter syndrome); accelerated linear growth (excess aromatase); goiter (hyperthyroidism); and the like, diagnostic blood tests should be ordered. If the history and physical examination do not reveal a specific cause, checking an early morning blood sample for LH, testosterone, estradiol, DHEA, and hCG may be helpful. However, in a mid-adolescent–aged boy with an otherwise normal medical history and age-appropriate physical and sexual development, a diagnostic workup is usually unnecessary.

Treatment

Correction of any underlying causative endocrinopathy or elimination of any offending medication or environmental exposure is the initial step in management. As gynecomastia results from a relative estrogen excess or androgen deficiency, medical treatment to block the effects of estrogen on the breast (clomiphene, tamoxifen, and raloxifene), diminish its production (aromatase inhibitors such as testolactone, letrozole, and anastrozole), or replace androgens (danazol) has been used (mostly in adult men) in an attempt to counterbalance the effects of the estrogens. Case reports and small clinical trials in adolescents have demonstrated some degree of breast size reduction in pubertal gynecomastia with most of the above agents.⁵² The only randomized, double-blind, placebo-controlled trial in the pediatric population to date found that anastrozole was no more effective than placebo in its ability to decrease gynecomastia by at least 50% over baseline. Thus, current data are insufficient to recommend routine medical treatment for idiopathic gynecomastia at this time. If spontaneous regression does not occur after 3 years, breast reduction by an experienced surgeon is the only other option, and should be considered if there is persistent pain, embarrassment, or anxiety.

When to refer

The criteria for referral of a child with gynecomastia to an endocrinologist are summarized in Box 3-3.

Definitions

Hirsutism is defined as excessive hair growth on body parts influenced by androgen action, that is, sexual hair.⁵³ Idiopathic hirsutism is not associated with other signs of hyperandrogenism, such as external genital virilization, increased muscle bulk, temporal hair recession, or voice deepening. In contrast, hypertrichosis refers to nonandrogen-mediated, excessive growth of lanugo hair over the entire body. The latter may have an ethnic basis, occurring more often in descendants from around the Mediterranean sea or result from the chronic use of certain medications, including diphenylhydantoin, cyclosporine, minoxidil, and diazoxide.

PCOS is the most common endocrine disorder affecting females of reproductive age, occurring in 5% to 10% of women worldwide and, as defined by a 1990 NIH-sponsored consensus conference, is characterizedby irregular or loss of menstrual periods (oligo- or anovulation) and biochemical or clinical signs of hyperandrogenism, such as hirsutism, acne, or male pattern baldness. In 2003, the international Rotterdam Consensus Workshop expanded this definition to include ovarian morphology, proposing that the diagnosis include at least two of the following criteria: oligo- or anovulation, biochemical or clinical signs of hyperandrogenism, and polycystic ovaries. However, inclusion of cystic ovarian morphology is controversial, as cystic ovaries may not be found when other criteria are clearly present and may be present in women of childbearing age with no other manifestations of PCOS. Most recently, in 2006, the Androgen Excess Society (AES) suggested a definition of PCOS to include hyperandrogenism (hirsutism and/or hyperandrogenemia) and ovarian dysfunction (oligo-anovulation and/or polycystic ovaries). All definitions also require exclusion of related disorders (Table 3-11).⁵⁴ In addition, obesity, insulin resistance, and metabolic syndrome occur in at least 50% of females with PCOS.

Adolescents with PCOS manifest clinical, biochemical, endocrine, and metabolic features similar to those of affected adult women. Both the AES (two of the following three: oligo-ovulation or anovulation, hyperandrogenism, or polycystic ovaries on pelvic ultrasonography) and Rotterdam (oligo-ovulation or anovulation, hyperandrogenism and polycystic ovaries on pelvic ultrasonography) criteria have been proposed for adaptation to adolescents.^55,56 The more rigorous latter criteria may avoid overdiagnosis of PCOS in adolescents, which may occur when fewer or less stringent criteria are applied. Furthermore, because irregular menstrual patterns and decreased ovulatory rates may be normal occurrences during puberty and because a higher prevalence of polycystic ovarian morphology (without hyperandrogenism) may be observed during this time, PCOS may be particularly difficult to diagnose in young women.

Etiology

Idiopathic isolated hirsutism results from either overproduction of and/or increased hormonal action by androgens within the hair follicle and requires elimination of related diagnoses, noted as follows (see Table 3-11).

The etiology of PCOS remains unclear and is probably multifactorial, involving a combination of ovarian and adrenal hyperandrogenism. A genetic basis seems likely with autosomal dominant familial clustering and a male phenotype associated with elevated DHEA sulfate levels. Linkage studies have shown associations to genes encoding various steroidogenic enzymes, the androgen receptor, SHBG, LH, insulin, the insulin receptor, leptin, adiponectin, and various inflammatory mediators. Newer linkages have been proposed in some populations with the follistatin and DENND1A genes/regions.⁵⁷ As such, the genesis of PCOS may actually begin in utero following exposure to a hyperandrogenic and/or insulin-resistant hormonal milieu. Known childhood risk factors for future PCOS include congenital virilizing disorders; above average or low (small-for-gestational age) birth weight; precocious adrenarche; central precocious puberty; and severe obesity with acanthosis nigricans, metabolic syndrome, and glucose intolerance or T2DM. Women with PCOS manifest alterations in gonadotropin secretion characterized by increased LH pulse amplitude and, in some studies, increased pulse frequency, along with subnormal FSH induction of CYP19 aromatase activity in granulosa cells leading to a heightened androgen-to-estrogen ratio, although absolute estrogen levels tend to be above normal. Additionally, both obese and thin women with PCOS tend to be resistant to the metabolic actions of insulin, with retention of responsiveness to its growth-promoting (mitogenic) actions so that the resultant compensatory hyperinsulinemia may lead to increased ovarian androgen secretion as well as to decreased hepatic SHBG production. A unifying hypothesis that has been invoked to explain both the overproduction of ovarian and adrenal androgens and diminished insulin action is that a single mutated serine kinase activates the P450C17 enzyme (including both 17α-hydroxylase and 17,20-lyase) leading to hyperandrogenism and inhibiting signaling through the insulin receptor β-chain causing insulin resistance. Greater derangements of insulin action are seen in obese subjects with greater adrenal contributions to hyperandrogenism in thin subjects with PCOS.

Diagnosis

Evaluation begins with a detailed menstrual history and exploration of the types and duration of hyperandrogenic symptoms. PCOS is typically associated with chronic menstrual abnormalities and slowly progressive features of hyperandrogenism. Abrupt changes in menstrual pattern and/or rapid onset and/or severe manifestations of hyperandrogenism should suggest alternative etiologies, such as hypo- or hyperthyroidism, hyperprolactinemia, CAH/NCAH, androgen-secreting tumors, and Cushing syndrome. Family history may be helpful regarding other women with PCOS or thyroid disease, and for the presence of consanguinity and certain high-risk ethnicities that would increase the chances for autosomally recessively inherited adrenal hyperplasia. Important physical findings include those associated with thyroid dysfunction (eg, presence of myxedema, brady- or tachycardia, and proptosis, with or without goiter), galactorrhea, cushingoid features (eg, centralized obesity, buffalo hump, and moon facies), and generalized obesity (along with hypertension, acanthosis nigricans, and acrochordons [skin tags]).

Treatment

Girls with idiopathic hirsutism, normal menstrual cycles, and relatively normal hormonal values require only periodic examination; if obese, they should be encouraged to lose weight after which an amelioration of clinical manifestations may be noted (Table 3-12). However, if the condition worsens or menstrual cycles become irregular, further evaluation and possible medical treatment are warranted.

In teenagers and women with PCOS, treatment targets the components of the syndrome, that is, menstrual/reproductive, cutaneous, metabolic, and psychological. Because most affected females are overweight, basic therapy in this subset should target lifestyle modification involving diet and exercise, which theoretically, if successful, could restore ovulatory cycles via reduction of insulin resistance.

Historically, administration of estrogen and progesterone (oral contraceptive) has been the mainstay of treatment for those not seeking pregnancy. This approach results in regular menses, reduced risk of endometrial hyperplasia and cancer, and improves androgenic manifestations such as acne and hirsutism. Estrogen acts by increasing hepatic production of SHBG that reduces availability of free testosterone while progesterone counteracts the neoplastic potential of unopposed estrogen acting on the uterus. However, it is important that the estrogen portion not be excessive (averaging ~30 μg/day of ethinyl estradiol) and that the progesterone component has low androgenicity or even be antiandrogenic (eg, drospirenone). Of note, the suggestion has been made thatdrospirenone-containing contraceptives may be linked to an increased risk of blood clots, but the association remains uncertain. Oral contraceptives decrease LH secretion but do not appear to work by improving insulin sensitivity. Progestational agents alone are occasionally used for the purposes of inducing withdrawal bleeding, but they will not aid hyperandrogenic symptoms. GnRH agonists are occasionally used to reduce LH secretion.

Antiandrogen drugs added to nonandrogenic oral contraceptives are often used adjunctively (and occasionally alone) in females with PCOS. The most commonly used drug in the United States for this purpose, spironolactone, acts by binding to and blocking the androgen receptor and may also interfere with (adrenal) steroidogenesis. This drug must be avoided during pregnancy because of teratogenic potential. Flutamide, with similar mechanisms of action to spironolactone, has been used, but concern regarding serious hepatotoxicity (seen with high doses) has limited its use. Occasionally, adjunctive glucocorticoid therapy is used if there is a significant adrenal contribution to the prevailing hyperandrogenism. Outside the United States, cyproterone acetate is frequently used because it interferes with steroidogenesis and also possesses antigonadotropic effects. As pharmacological approaches to excess hair growth for the most part target only new hair growth, mechanical hair removal remains a key approach to the removal of preexisting hair or for progressive hirsutism that is not responsive to drug therapy. Nonpermanent hair removal methods include shaving, waxing, and use of topical depilatory creams. Permanent methods, that is, electrolysis and laser therapy, are effective but more costly and may be painful.

Improvement of insulin sensitivity is now recognized as an important component of the therapeutic armamentarium. Weight loss and exercise can, in and of themselves, increase insulin sensitivity. In addition, medication may play a role in improving insulin resistance. Metformin monotherapy of obese adolescents with PCOS appears to improve insulin sensitivity, and, in so doing, to lower serum insulin and androgen levels, attenuate adrenal steroidogenic response to ACTH, and possibly increase the rate of ovulation. It has been suggested that the use of both antiandrogen and insulin-sensitizing treatments in young, nonobese women with hyperinsulinemic hyperandrogenism has additive benefits on insulin sensitivity, hyperandrogenemia, and dyslipidemia. Insulin-sensitizing agents of the thiazolidinedione class (rosiglitazone and pioglitazone) have also proven helpful in the treatment of women with PCOS leading to an improvement of ovulatory dysfunction, hirsutism, hyperandrogenemia, and insulin resistance, with minimal adverse effects. Note, however, that rosiglitazone has a black-box warning placed by the FDA because of a possible risk of congestive heart failure or heart attack and that prescription of any insulin sensitizer therapy in females with PCOS (unless diagnosed with T2DM) constitutes an off-label use.⁵⁸

When to refer

The criteria for referral of a child with hirsutism/PCOS to an endocrinologist are summarized in Box 3-4.