Prenatal testicular development

A brief summary of prenatal testicular differentiation and development follows; a more detailed description of testicular differentiation and sex development can be found in Chapter 4. Beginning at approximately 4 to 6 weeks of gestation, the primordial bipotential gonad arises from a condensation of the mesoderm of the urogenital ridge. Genes involved in the development of this bipotential gonad include the Wilms tumor (WT1) gene, GATA4, chromobox homologue 2 (CBX2), and steroidogenic factor-1 (NR5A1). During this time, the primordial germ cells proliferate and migrate from the hindgut to colonize the developing gonad. The bipotential gonad is composed of supporting cells, endothelial cells, steroid-secreting cells, and germ cells.

In the usual circumstance, the presence of a Y chromosome bearing the sex-determining region on the Y (SRY) gene promotes testicular differentiation. However, novel data emphasize the complexity of gonadal differentiation with involvement of signaling molecules—for example, SRY-box 9 (SOX9) and Forkhead transcription factor 2 (FOXL2)—that activate or repress gonadal determination factors involved in testicular and ovarian development. Sertoli cell differentiation is the earliest manifestation of testicular differentiation. At approximately 7 to 9 weeks of gestation in the human XY gonad, the Sertoli cells envelope the germ cells to form the seminiferous cords. Curiously, germ cells are not required for initial phases of testicular differentiation. Rather, the local environment directs the developmental fate of the primordial germ cells. During the migration though the hindgut, the primordial germ cells proliferate. The stem cell factor (Steel factor) and c-KIT receptor guide the primordial germ cells to the developing genital ridges. This signaling system ensures that viable primordial germ cells travel to their proper environmental niche and that misdirected primordial germ cells undergo apoptosis. Primordial germ cells that escape apoptosis and migrate to other physical locations, such as the mediastinum or central nervous system, can develop into extragonadal germ cell tumors. Primordial germ cells that occupy the genital ridge become pluripotent gonocytes that express specific stem cell markers including placental/germ cell alkaline phosphatase (PLAP) and octamer binding transcription factor 3/4 (OCT3/4).

Internal genital structures are also bipotential. Sertoli cells secrete anti-Mullerian hormone (AMH), which induces regression of the Mullerian ducts through its actions on the type II AMH receptor. The fetal Leydig cells, initially stimulated by placental hCG, secrete testosterone which stabilizes the Wolffian ducts. In the human male fetus, the testicular compartments, tubular and interstitial components, and specific cell types, Leydig, Sertoli, and germ cells can be visualized by 11 weeks of gestation. The most rapid growth in Sertoli cell number appears to occur during the latter half of the first trimester and the second trimester.⁵

During early gestation, placental hCG governs Leydig cell proliferation and testosterone and insulin-like factor 3 (INSL3) secretion until endogenous LH regulates these activities in midgestation. Due to this role of placental hCG during early gestation, gonadotropin deficiency does not influence male sexual differentiation. LH secretion influences the number of fetal Leydig cells because the number is decreased in anencephalic fetuses and is increased in 46,XY fetuses, with elevated gonadotropin concentrations secondary to complete androgen insensitivity.⁶ Follicle-stimulating hormone (FSH) secretion influences Sertoli cell differentiation and AMH and inhibin B secretion.⁷

Androgens induce the genital tubercle, urethral folds, and labioscrotal swellings to develop into the male external genital structures. In target tissues such as genital skin and prostate, testosterone is converted to dihydrotestosterone, which induces the urethral folds to fuse and form the corpus spongiosum and penile urethra. The genital tubercle develops into the corpora cavernosa of the penis and the labioscrotal folds fuse to form the scrotum. By 9 weeks of gestation, a cylindrical 2-mm phallus with genital swellings has developed. By 12 to 14 weeks of gestation, the urethral folds have fused to form the cavernous urethra and corpus spongiosum. By 14 weeks, the external genitalia are clearly masculine apart from testicular location. In the absence of sufficient androgen concentrations, the urethral folds and labioscrotal swellings do not fuse and develop into the labia minora and labia majora, respectively.

Testicular descent occurs in two phases. The transabdominal phase begins at approximately 12 weeks of gestation and is influenced by the Leydig cell product, insulin-like factor 3 (INSL3), and its cognate receptor, leucine-rich repeat-containing G protein–coupled receptor 8 (LGR8). The second androgen-dependent phase, descent of the testes through the inguinal canal, is usually accomplished by the end of week 35.⁸

Postnatal testicular development

Following a brief perinatal decline, the hypothalamic-pituitary-testicular axis is active during the first few months of life with testosterone concentrations peaking at 1 to 2 months of age.⁹ By approximately 6 months of age, testosterone concentrations decline to prepubertal levels. Despite the increased neonatal HPG activity, sexual hair does not develop and gametogenesis does not occur due to limited androgen receptor (AR) signaling in certain tissues (e.g., Sertoli cells). Throughout infancy, AR is expressed in Leydig cells, but not in Sertoli cells.¹⁰ During infancy and childhood, seminiferous cords are solid and generally filled with immature Sertoli cells. The germ cells are limited to spermatogonia and Leydig cells are rarely visualized.¹¹ After early infancy, which provides a window of opportunity to assess testicular function, hCG stimulation may be needed to assess Leydig cell function. Inhibin B and AMH continue to be secreted during childhood providing valuable markers of Sertoli cell function.

Reactivation of the GnRH pulse generator at the time of puberty stimulates pituitary LH and FSH secretion (Figure 17-1). The LH stimulation leads to increased testicular testosterone and INSL3 secretion. The increased testosterone acts as a paracrine factor to induce Sertoli cell maturation. Pubertal maturation of the seminiferous tubules is characterized by cytoskeletal rearrangements including development of tight junctions, Sertoli cell polarization, Sertoli cell proliferation, migration of spermatogonia toward the basement membrane, and decreased AMH secretion.¹² FSH stimulates Sertoli cells to secrete inhibin B, which from midpuberty onward serves as the major negative regulator of pituitary FSH secretion. Prior to puberty, inhibin B is germ cell independent. After puberty, inhibin B secretion becomes germ cell dependent and provides a marker of germ cell depletion in adults.¹³

The increase in Sertoli cell number contributes to the increase in testicular volume that marks the onset of gonadarche in boys. As puberty progresses, the seminiferous tubules are larger and develop a lumen; typical Leydig cells become apparent. Although much variation in chronologic age and testicular volume has been described, spermarche precedes peak pubertal linear growth velocity and generally occurs at a median testicular volume of 10 to 12 mL.¹⁴ Beginning in early puberty, testosterone and AMH show an inverse relationship reflecting the paracrine actions of testosterone to repress AMH secretion by Sertoli cells. Intratesticular testosterone and AR expression in Sertoli cells are essential for the decline in AMH concentrations, meiosis, and spermatogenesis.¹¹ Hence, AMH concentrations provide an indication of Sertoli cell function and androgen action in the testes.

Endocrinology

The onset of puberty is heralded by an increase in the secretion of gonadotropin releasing hormone (GnRH) (see Figure 17-1) from a diffusely distributed network of hypothalamic neurons. Intermittent secretion of GnRH into the hypophysial portal circulation stimulates gonadotropes in the anterior pituitary to synthesize and secrete luteinizing hormone (LH) and follicle stimulating hormone (FSH) that, in turn, bind to ligand specific receptors in the Leydig and Sertoli cells of testes, respectively. Gonadotropin stimulation initiates gonadarche, and the production of sex steroids, most notably testosterone, and at later pubertal stages estradiol as well.¹⁵ Testosterone and estradiol, together with inhibin, activin, and follistatin, provide signals that regulate the subsequent activity of the hypothalamus and pituitary gland. The transition from prepubertal quiescence to the adolescent pattern of GnRH secretion is a gradual rather than abrupt process. LH and FSH pulsatility has been detected in normal children as young as 4 years of age.16–19 Throughout childhood, GnRH secretion appears to undergo small but progressive increases until the onset of puberty, when GnRH secretion increases, first at night and eventually throughout the day.^20,21

Neuroendocrine regulation of pubertal onset

Understanding what factors contribute to the dampening of the HPG axis after infancy and what factors lead to the reemergence of GnRH secretion is critical to understanding the regulation of pubertal timing. Research into kisspeptin (Kiss1) and its receptor (Kiss1R, formerly G protein–coupled receptor 54, GPR54) in both animal and human studies has identified them as critical components of the HPG axis. The first indications of the importance of this signaling complex as a regulator of the HPG axis came in 2003 when two independent groups reported deletions and inactivating mutations of GPR54 in patients with hypogonadotropic hypogonadism (HH).^22,23 Subsequently, activating mutations in this pathway were associated with central precocious puberty in the case of a female with an autosomal dominant mutation in GPR54.²⁴ Thus, it is clear that activation of Kiss1R by kisspeptins plays a pivotal role in the onset of puberty.

It is not yet known, however, whether this system is the initial trigger of puberty or whether it acts either as a downstream effector or in concert with other regulatory factors.^25,26 For example, the discovery that mutations in TAC3 (encoding neurokinin B) or its receptor TACR3 (encoding NK3R)²⁷ can cause HH has focused much attention on how hypothalamic neurons that coexpress kisspeptin, neurokinin B, and dynorphin (abbreviated as KNDy neurons) regulate the HPG axis in males and females.^28–30 Another excitatory factor in the hypothalamus is glutamate, an important stimulator of GnRH secretion through its actions at n-methyl, D-aspartate (NMDA) and kainate receptors. GnRH secretion is stimulated also by factors such as norepinephrine, dopamine, TGFα, neuregulin signaling via erbB4 receptors, leptin, and galanin-like peptide.^31–35 Many of these factors likely act via a complex, intricate communication network that exists between glial cells and neurons within the hypothalamus.³⁶ The potential roles that these and other compounds play in regulating the onset of puberty remains an area of active investigation.

Gamma-amino butyric acid (GABA) neurons appear to play a prominent role in inhibiting prepubertal GnRH release.³⁷ There is evidence that GABA can also stimulate GnRH secretion, but this variable action may be dependent on developmental stage, composition of GABA receptors, and expression of KCC2 (a protein that can alter the inhibitory and excitatory properties of chloride channels).³⁸ The finding that neuropeptide Y (NPY) mRNA expression in the hypothalamus of juvenile monkeys is higher than neonatal animals suggests that NPY may play a role in the juvenile pause.⁴ Other factors that likely inhibit GnRH release include endogenous opioids (i.e., β-endorphin) and melatonin, but neither of these compounds likely plays a major role in regulating the timing of puberty.³⁵

Somatic changes

In boys, the first marker for the onset of puberty is most often the change from Tanner genital stage G1 to stage G2, including enlargement of the testes (i.e., achievement of volume greater than 3 mL or testicular length greater than or equal to 25 mm). Originally Marshall and Tanner reported the mean (SD) onset of puberty in boys to be 11.64 (1.07) years.^39,40 These pubertal stages (Figure 17-2) were based on photographic observation of genital development of a longitudinal but still relatively small sample of 228 boys living in a children’s home. Despite the probably poor representative nature of this sample, comparable studies in Switzerland,⁴¹ the United States,⁴² and Denmark⁴³ reported roughly similar mean ages of puberty onset. Although the mean age of onset may be fairly uniform, the onset of puberty occurs across a wide range of ages in normal, healthy adolescents. Several pathologic states influence the timing of puberty either directly or indirectly and contribute to this splay, but the great majority of the variation in pubertal timing cannot be attributed to any clinical disorder. Ninety-five percent of boys experience the onset of genital development between 9.5 and 13.5 years,^44,45 data that have led to the traditional definition of sexual precocity in boys as development of secondary sexual characteristics before age 9 years and delayed puberty as lack of testicular enlargement by age 14 years.

Development of secondary sexual characteristics results from both gonadarche and adrenarche. Adrenarche refers to the maturation of the zona reticularis of the adrenal gland, resulting in increased production of adrenal androgens associated with secondary sexual characteristics, such as the development of pubic hair (pubarche), axillary hair, body odor, and acne. Like gonadarche, the onset of adrenarche appears to be a gradual, progressive maturational process that begins in early childhood and is marked by the further increases of production of adrenal androgens (DHEA, DHEA-S, and androstenedione) around the time of puberty.⁴⁶ Adrenarche sometimes precedes gonadarche by 1 to 2 years in boys and girls, but the timing of clinical signs can vary. Although adrenarche and gonadarche often overlap, they are separate processes that are independently regulated.^47,48 The triggers for adrenarche remain unknown; however, alterations in body weight and body mass index as well as in utero and neonatal physiology likely modulate this developmental process, perhaps along with intra-adrenal cortisol production.^49–51

Genetics

The timing of puberty is influenced by both genetic and environmental factors.^52,53 Evidence for the genetic contribution is provided by correlations in timing within families and between monozygotic twins. These data derive mostly from studies of females and suggest that more than half of the variation in the most commonly used marker for the timing of puberty, age at menarche, is attributable to additive genetic effects and the rest appears to be attributable to nonshared environmental effects.^{34,52,54–61} It is important to note that this genetic component does not preclude a significant role for environmental influences that may have changed over time. However, despite changing environmental and secular influences, genetic background still plays a significant role in regulating the variation of pubertal timing within a population at any particular point in time.

Genetic disorders causing GnRH deficiency

The study of genetic disorders that cause GnRH deficiency, such as isolated hypogonadotropic hypogonadism (HH) and Kallmann syndrome (KS), has significantly increased our understanding of development and function of the hypothalamic pituitary gonadal (HPG) axis.^59,62–67 These studies have led to the identification of many genes that play critical roles in the HPG axis. For example, this work has defined roles for the genes that lead to HH (GNRHR, GNRH1, GPR54, NELF, FGFR1, FGF8, PROK2, PROKR2, TAC3, TACR3, CHD7, and HS6ST1), to X-linked (KAL1) and autosomal (NELF, FGFR1, PROK2, PROKR2, FGF8, WDR11 and CHD7) forms of KS, to obesity and HH (LEP, LEPR, and PC1), and to abnormal HPG development (DAX1, SF-1, HESX-1, LHX3, and PROP-1). Moreover, research in this field permits recognition that, in some cases, HH and KS can be caused by mutations in the same genes and derive from a monogenic or oligogenic basis.⁶⁸ In contrast to this great progress, the specific genetic factors that regulate the variation in pubertal timing in the general population are just emerging. In addition to genes identified through genome wide association studies (discussed later), another factor may be the makorin RING-finger protein 3 (MKRN3). Loss-of-function mutations in MKRN3 were associated with GnRH-dependent precocious puberty.⁶⁹

Genetic variation in normal puberty

Observations regarding the greater concordance in age at pubertal development in monozygotic twins and correlation at age of menarche in mothers and daughters emphasized the role of genetic influences in the timing of normal pubertal development.¹⁰¹ Approaches utilized to identify specific genetic factors include candidate genes studies and genome-wide association (GWA) studies.

External factors and secular trends in the timing of puberty

Although these genetic advances are exciting, genetic factors cannot explain the reported secular changes in pubertal timing (discussed later) that have occurred since the late 20th century. Clearly, changes in lifestyle or environmental factors must be involved, likely as independent regulators but also as factors that mediate effects through gene by environment (G X E) interactions. Variables such as increased adiposity, insulin resistance, physical inactivity, psychological factors, and changed dietary habits have all been implicated as possible mediators of the observed change in pubertal timing.^52,110,111

The mean age of menarche in mid-19th century Europe was likely between 17 and 18 years.⁵² Starting from the late 19th century to the mid-20th century, a gradual decline in age at puberty has been reported, more convincingly in girls than in boys,^52,112 after which this trend may have slowed. The change in the timing in puberty has likely been the result of better hygiene and nutrition as well as increased stability in socioeconomic conditions.

The extent to which age at puberty has declined in males is controversial. In the mid-1990s, data from the Third National Health and Nutrition Examination Survey (NHANES III), where genital ratings were performed by visual inspection, reported earlier age at puberty in both boys and girls113–116 than what previously had been reported from the United States.^44,115,117 Using the traditional cutoff of 9 years, these data suggest that an increased number of boys would be classified as having precocious puberty. However, due to lack of data on pubertal onset in the previous population-based study (Third National Health Examination Survey [NHES III]),⁴⁴ some controversy remained as how to interpret the NHANES III findings.^113,114,116 Furthermore, questions have been raised regarding the criteria used for genital staging in NHANES III.¹¹⁸ A subsequent secular trend analysis between NHES III (which lacked data from the early pubertal stages) and NHANES III did not find clear evidence supporting earlier age at puberty, although some indications were present in non-Hispanic white boys.¹¹⁵ These data were also reviewed by an expert panel, which concluded that the available data are insufficient in quality and quantity to confirm a change in pubertal timing in U.S. boys.¹¹² Conversely, at the same time in Europe, in comparison with NHANES III studies, some data were reported suggesting older ages at pubertal onset in boys.^41,119–121 Only a few European studies contained data to assess secular trend in the timing of puberty in Europe, and those do not support a substantial enough change in the age at pubertal onset in boys from the mid-1960s to the late 1990s to warrant a change in the age definitions for precocious and delayed puberty.^43,120

Effect of BMI on pubertal timing

Among white American children aged 6 to 11 years, rates of obesity have increased from approximately 5% between 1963 and 1965 to 12% in 1999–2000.¹²² The possibility that the increasing rates of obesity contributed to the secular trend toward early puberty onset was originally highlighted in 1997.¹²³ However, despite strong evidence in support of a link between increased adiposity and early onset of pubertal markers in girls,^124,124 data in boys have remained somewhat ambiguous, with increased body mass index (BMI) being associated in general with earlier puberty but with obesity being associated with delayed puberty in some cases.^125,126

Several population studies regarding pubertal timing and BMI have been conducted in boys. A retrospective study of 1520 men with serial height and weight measurements between the ages of 9 and 18 years reported that boys with high childhood BMI tended to have an earlier puberty, whereas boys with a later puberty tended to be taller and were less obese as adults than those who had experienced an earlier puberty.¹²⁷ Similarly, high BMI gain during childhood has been related to an earlier onset of puberty and reduced height gain during adolescence.¹²⁸

In a study of 463 Danish choir boys, a significant downward trend in age at voice break was found over a 10-year period (from 14 years to 13.7 years).¹²⁹ Age at voice break was significantly different between boys in the different prepubertal BMI quartiles, and a trend toward earlier voice break was associated with increasing BMI SDS. Boys in the heaviest quartile at 8 years of age had an increased likelihood of earlier voice break compared with those in the thinnest quartile, suggesting a relationship between prepubertal BMI and the timing of puberty in boys.¹²⁹

Another Danish study included an evaluation of secular trends in pubertal onset over a 15-year period and their relationship to BMI in boys.¹²¹ In a total of 1528 boys, onset of puberty, defined as age at attainment of a testicular volume > 3 mL, occurred 3 months earlier in 2006–2008 than in 1991–1993. Significantly higher levels of luteinizing hormone but not testosterone were found in boys between 11 and 16 years of age in 2006–2008 compared with boys of the same age in 1991–1993. BMI SD scores increased significantly from 1991–1993 to 2006–2008 as well. Interestingly, pubertal onset and levels of luteinizing hormone were no longer significantly different between study periods after adjustment for BMI. In this study, the estimated mean age at onset of puberty had, therefore, declined during the 15-year interval, and this decline was associated at least partly with an increase in BMI.¹²¹

In a study from Jamaica, the effects of birth size, growth rates throughout childhood, and body composition on the timing of onset of puberty were assessed in both boys and girls.¹³⁰ Fast weight gain from age 0 to 6 months and during childhood, but not large birth size, was associated with advanced puberty in both sexes. In addition, elevated fat mass at 8 years of age was associated with advanced puberty in both sexes. These data support the hypothesis that fast growth throughout childhood, especially with fat-mass accretion, is associated with advanced pubertal development.^130,131

In a study from Germany, body weight, height, peak height velocity, and pubertal stages were evaluated in 1421 peripubertal children.¹³² In contrast to the findings from other studies, the researchers found no significant differences in mean pubic hair stage in girls and boys with obesity when compared with either lean or normal-weight children and, when analysis was restricted to children at pubic hair stage 2, age at this stage was found not to differ significantly between normal-weight and obese individuals. In boys, testicular volume at a given age was also similar across all weight groups.¹³³

In summary, research to date highlights inconsistencies in how obesity has been found to affect pubertal timing in boys and emphasizes the need for future research in this area.

Effect of endocrine disrupting chemicals

Some evidence supports associations between human pubertal timing and exposure to environmental modifiers, although much of the data relate to girls. Earlier menarche and pubarche have been associated with exposure to polybrominated biphenyls (PBB) and dichlorodiphenyl dichloroethene (DDT), whereas delayed breast and pubic hair development as well as delayed menarche have been associated with lead exposure.^134,135 In addition, elevated serum levels of a mycotoxin (zearalenone) have been reported in girls with precocious puberty,¹³⁶ and phthalate exposure has been associated with changes in pubertal timing. A study in Denmark demonstrated that delayed pubarche, but not thelarche, was associated with high phthalate excretion in urine samples from healthy school girls, which may suggest antiandrogenic actions of phthalates.¹³⁷ Greater exposure to pesticides has been reported in boys with cryptorchidism or hypospadias.¹³⁸

The extent to which these effects are associations versus cause-and-effect relationships is unknown as is full understanding of underlying mechanisms. To what extent any effects are shared versus different in girls compared to boys is also not known. Finally, what effects these exposures have in the general population as opposed to isolated examples of associated abnormalities is not clear. Certainly more research is this area is needed.^139,140

GnRH-dependent forms of precocious puberty

The most common form of precocious puberty is the activation of pulsatile GnRH secretion 2 to 2.5 SDs earlier than average, recognizing that the normal limits for the onset of puberty can vary by geographic area and by ethnicity. This form of precocious puberty is called central or gonadotropin-dependent precocious puberty, and it represents true pubertal development. Central precocious puberty (CPP) may result from hypothalamic tumors or central nervous system (CNS) lesions (neurogenic CPP) but in most cases remains unexplained (idiopathic CPP) (Table 17-1).^141,142

Hypothalamic hamartomas are an example of a cause of neurogenic CPP. The hamartomas are congenital malformations characterized by heterotropic gray matter, neurons, and glial cells, and they are generally located on the floor of the third ventricle or attached to the tuber cinereum. On MR imaging, hamartomas exhibit an isodense fullness. Histologic examination has shown immunoreactivity for GnRH and for astroglial factors such as TGFα. Postulated potential mechanisms include increased GnRH secretion from neurons emancipated from suppression or that TGFα stimulates GnRH secretion from GnRH neurons. Most hypothalamic hamartomas are sporadic, but they may occur in association with Pallister-Hall syndrome, which is due to mutations in the GLI3 gene. Optic gliomas, which can be associated with NF1, can also cause GnRH-dependent precocious puberty.¹⁴³ Other etiologies of neurogenic CPP include pineal tumors, suprasellar cysts, previous head trauma, CNS radiation, and static encephalopathy.¹⁴⁴

Loss-of-function mutations of the makorin RING-finger protein 3 (MKRN3) located at chromosome 15q11-q13 have been associated with GnRH-dependent precocious puberty. All clinically affected individuals inherited the mutated allele from their fathers, which can be explained because this gene is imprinted and expressed only by the paternal allele. Curiously, almost half of these patients were boys; this differs from the typical female predominance of GnRH-dependent precocious puberty. The finding of MKRN3 as a cause of CPP is also interesting because it calls attention to the importance of inhibitory factors in the regulation of pubertal timing (see Figure 17-1) because loss of function of this gene (and loss of a presumed inhibitory role) leads to CPP.⁶⁹

GnRH-independent forms of precocious puberty

Precocious development of secondary sexual characteristics may also be caused by mechanisms that do not involve activation of pulsatile GnRH secretion. These forms of precocity are called gonadotropin-independent or peripheral precocity and include gonadal and adrenal tumors, tumors producing human chorionic gonadotropin, mutations activating the gonadotropic pathway, and exposure to exogenous sex steroids (see Table 17-1). Familial male-limited precocious puberty (FMPP, OMIM ID: 176410), also known as testotoxicosis, is a rare dominant form of gonadotropin independent precocity caused by constitutively activating mutations of the human LH choriogonadotropin receptor (LHCGR).¹⁴⁵ This disorder usually presents by age 1 to 4 years with physical signs of puberty, rapid virilization, growth acceleration, skeletal (bone age) advancement, and elevated testosterone levels despite prepubertal levels of LH.^146,147 McCune-Albright syndrome (MAS, OMIM ID: 174800) is another rare cause of male sexual precocity of genetic origin. It is caused by a postzygotic somatic activating mutation of the GNAS1 gene. The mosaic constitutive activation of the GSα protein signaling leads to autonomous cell proliferation and scattered hyperfunction in endocrine organs with a wide phenotypic spectrum.^148,149 The classical features include the clinical triad of bone fibrous dysplasia (BFD), café-au-lait skin spots, and precocious development of secondary sexual characteristics. In addition, excessive pituitary function (such as hyperthyroidism due to activation of thyroid-stimulating hormone [TSH] secretion and hypercortisolism due to constitutive activation of ACTH secretion), kidney phosphate wasting, cholestasis, and hypertrophic heart disease can be present.^148,150 For reasons that are not clear, MAS leads to sexual precocity more often in girls than in boys.

In 1960, Van Wyk and Grumbach first described a syndrome characterized by breast development, uterine bleeding, and multicystic ovaries in the presence of long-standing primary hypothyroidism.¹⁵¹ A unique diagnostic feature of the Van Wyk–Grumbach syndrome is the combination of delayed bone age with apparent sexual precocity. Boys with this syndrome have macroorchidism without significant virilization. Testicular histology shows enlargement of the seminiferous tubules without an increase in Leydig cell number.^152,153 Typically, GnRH stimulation shows a prepubertal response with suppressed LH confirming gonadotropin-releasing hormone (GnRH)-independent precocious puberty. Most cases appear to originate from autoimmune thyroid disease, but there are some case reports where the syndrome is secondary to unrecognized congenital hypothyroidism.¹⁵⁴ The pathophysiology of Van Wyk–Grumbach syndrome involves a complex mechanism, which is, at least in part, mediated by the direct action of TSH on FSH receptors. Recombinant human TSH (Rec-hTSH) elicits a dose-dependent cAMP response in cells expressing the human FSH-receptor in vitro; however, the concentration of rec-hTSH required for half-maximal stimulation was several logs greater than that of hFSH.¹⁵² Early recognition and initiation of thyroid hormone replacement can lead not only to resolution of symptoms and improvement in adult height but also to avoidance of further diagnostic procedures, fear of malignancy, and unnecessary surgery.

Another cause of GnRH-independent precocious puberty includes the virilizing forms of congenital adrenal hyperplasia (CAH). These are autosomal recessive disorders that present with premature pubic hair development, axillary hair development, accelerated linear growth, and phallic enlargement in the absence of testicular enlargement. The most common form is 21-hydroxylase deficiency due to loss-of-function mutations in CYP21A2. Mutations in 11β-hydroxylase (CYP11B1) and 3β-hydroxysteroid dehydrogenase type 2 (HSD3B2) account for 5% to 10% of cases. Long-term exposure to androgens in this condition can activate central precocious puberty even when the excessive androgen secretion from the adrenals is suppressed by appropriate cortisol and mineralocorticoid replacement.

Androgen secreting tumors are rare causes of GnRH-independent precocious puberty in boys. Leydig cell tumors secrete testosterone. Because these tumors are usually unilateral, testicular volume may be asymmetric. The majority of Leydig cell tumors are benign. Ultrasound may be useful because the tumor may be too small to palpate. Mutations in the LHCGR gene have been identified in some adenomas.¹⁵⁵ In boys, tumors secreting hCG stimulate testicular testosterone secretion. These tumors are generally hepatic in origin. Virilization is a common presentation for adrenal tumors in children.

The classification of precocious puberty is not always clear. As noted earlier, treatment of peripheral forms of sexual precocity, such as CAH or testicular or adrenal tumors, can lead to true central precocious puberty through subsequent activation of pulsatile GnRH secretion. In addition, in some cases of precocious pubertal development among girls, pubertal manifestations will regress or stop progressing, making treatment unnecessary; such cases are not as commonly seen in boys.^156,157 The mechanisms responsible for these nonprogressive forms of precocious puberty are not known. There is evidence that in some cases the HPG axis is intermittently but not fully activated.^157,158 Another form of early development of secondary sexual characteristics occurs when the hypothalamic-pituitary-adrenal (HPA) axis matures 1 to 2 years before the HPG axis, causing premature adrenarche. Premature adrenarche, more common among girls, is not associated with progressive pubertal development and is manifested by pubic and axillary hair with modest elevation of DHEA-S, but without substantial advancement in bone age and hence does not require treatment.

In cases of progressive central or peripheral precocity, the concerns include short adult stature due to early epiphyseal fusion and adverse psychosocial outcomes.^141,159 Several studies have assessed adult height in subjects with a history of precocious puberty. Mean heights range from 151 to 156 cm in boys and from 150 to 154 cm in girls in older patient series, which corresponds to a loss of more than 20 cm in boys and 12 cm in girls from predicted adult height.¹⁶⁰ Height loss due to precocious puberty is inversely correlated with the age at the onset of puberty, and treated patients today tend to have a later onset of puberty than did patients in historical series.¹⁶⁰ It is important to assess carefully the growth rate and skeletal maturation of individuals with central precocious puberty due to CNS lesions (e.g., tumors, cerebral malformations or injury from trauma or radiation) because these lesions may be associated with concomitant growth hormone (GH) deficiency, which can be masked by sex steroid–driven adequate growth rates. In such cases, undiagnosed and untreated GH deficiency may result in severely compromised adult height.

Although available data derive mostly from study of girls with early puberty, it has been suggested that a higher proportion of early-maturing adolescents engage in exploratory risky behaviors (sexual intercourse and legal and illegal substance use) at an earlier age than adolescents maturing within the normal age range or later.^161,162 However, available data regarding potential adverse psychosocial outcomes specific to patients with precocious puberty are limited, as it is not clear that data obtained from individuals with maturation at the early end of the normal spectrum are fully applicable to precocious puberty.

Pathologic entities leading to sexual precocity warrant treatment, but whether and at what ages one should initiate treatment for idiopathic central precocious puberty is less certain. Currently, robust data regarding the short-term and long-term psychosocial sequelae of CPP and data regarding whether treating CPP with gonadotropin releasing hormone analogues (GnRHa) alter these outcomes are lacking.¹⁶³ Thus, one needs to be cautious when using psychosocial outcomes as a rationale for pharmacologic intervention to halt pubertal progression, especially among boys with the onset of puberty close to the normal range.

Evaluation of the boy with precocious development of secondary sexual characteristics

Boys with sexual precocity require careful evaluation because many have underlying disorders.¹⁴¹ Those with premature pubarche (early development of pubic hair or body odor) need to be assessed for peripheral causes of precocity before determining that the premature pubarche stems simply from premature adrenarche. Premature adrenarche may be distinguished from true precocity over time by lack of progression. Conversely, progressive precocity is marked by significant bone age advancement (> 2 SD for age), a history of growth acceleration, and a progression of secondary sexual characteristics on physical examination.

The evaluation of a boy with sexual precocity is outlined in Box 17-1. Considerations include first verifying that the pubertal development is occurring outside the range of normal development prior to initiating an evaluation. It is also important to note that all tests are not appropriate in each case and that the diagnostic yield of each test is not known. Hence, it is important to allow history and physical examination to guide the evaluation. The child with bilateral enlarged testicles, for example, is most likely to have central precocious puberty, with FSH having led to the expansion of seminiferous tubule volume (although cases of hypothyroidism can also present with bilateral testicular enlargement). Conversely, the child with bilateral prepubertal sized testicles is more likely to have peripheral precocity, whereas the child with unilateral testicular enlargement may well have a testicular tumor. Testing should be directed accordingly.

Peripheral causes of sexual precocity are characterized by suppressed LH and FSH values in the setting of elevated sex steroid levels. Testosterone levels will be elevated in instances of isosexual precocity (secondary sexual characteristics consistent with male gender), whereas estradiol levels may be elevated in the rare instances of contrasexual precocity (secondary sexual characteristics inconsistent with gender, such as marked breast development as the presenting sign in a boy). Determining the underlying mechanism for progressive peripheral precocity is important because all instances will result from pathologic conditions or exogenous exposures.¹⁶⁴ Levels of androgens that are elevated beyond the range expected for the pubertal stage suggest an adrenal or testicular cause of the precocity. DHEA-S is often used as a screen for adrenal tumors or adrenal pathology. Determination of the 17-hydroxyprogesterone concentration is used to screen for congenital adrenal hyperplasia due to 21-OH deficiency. Congenital adrenal hyperplasia and hormone secreting tumors of the adrenal are discussed in detail in Chapter 13.

Historically, the gold standard for the diagnosis of central precocious puberty was GnRH stimulation testing and the demonstration of pubertal gonadotropin responses. However, with the advent of ultrasensitive gonadotropin assays,¹⁶⁵ the recognition that these assays can identify individuals with CPP using unstimulated random samples,¹⁶⁶ and the unavailability of GnRH for testing has led some to forego stimulation testing. GnRH agonists can be used as an alternative to GnRH for stimulation testing, but again the diagnosis can often be made through the combination of clinical features and a baseline LH value in the pubertal range. Although determining the diagnostic cutoff for the basal LH level is difficult because of a lack of normative data and variability among assays, a value of ≥ 0.3 IU/L using an ultrasensitive assay with a detection limit near 0.1 IU/L is commonly cited.¹⁶³ If stimulation testing is done, a diagnostic cutoff of 5 IU/L for peak value has been suggested. LH values are more useful than FSH values in the diagnostic evaluation of precocious puberty, but stimulated LH/FSH values can help to identify patients with slowly progressive precocious puberty because these children tend to have FSH predominant responses.^157,167 Whether due to referral bias or to differences in underlying physiology, idiopathic central precocious puberty is a more common cause of precocious puberty among girls than among boys in endocrinology clinics.^168,169 Hence, all boys with CPP should have brain magnetic resonance imaging (MRI) to exclude underlying pathology.¹⁶³

In summary, it is important for physicians evaluating patients with suspected precocious puberty to address these questions: Is pubertal development occurring outside the normal range of development? What is the underlying mechanism, and is that mechanism associated with a risk of a serious condition, such as an intracranial lesion? Is the pubertal development likely to progress, and may this impair the child’s normal physical and psychosocial development?

Treatment of the child with precocious puberty

Unless underlying pathology that requires intervention is present, whether the precocious pubertal development is likely to impair the boy’s normal physical or psychosocial development is often the feature that determines if treatment is needed.

Central precocious puberty

A prerequisite for the consideration of therapy for CPP is the presence of documented, progressive pubertal development over a 3- to 6-month period, although this period of observation may not be necessary if the child is at or beyond Tanner stage 3 genital development. Documentation of progressive development is important because nonprogressive forms of precocious puberty do not require intervention.¹⁶³ Because epiphyseal fusion is an estrogen-dependent process, early and progressive production of sex steroids can cause rapid advancement of skeletal maturation and result in compromised adult height. Thus, preservation of adult stature is one of the main reasons to consider treatment of CPP with GnRH agonists, which down-regulate the pituitary-gonadal axis and limit pubertal progression. Although the data derive primarily from studies among girls, it appears that the risk of short stature is most pronounced in those children with earlier onset of symptoms and more shortened prepubertal growth periods.¹⁷⁰ Other factors, such as advanced bone age, may also contribute to poorer height outcomes.¹⁷⁰ In girls, available data suggest that the greatest height gain (preservation) occurs with onset of puberty prior to 6 years of age, with more moderate benefit being seen with onset between 6 and 8 years.¹⁶³ However, insufficient data exist to draw similar conclusions regarding age of onset and height outcomes among boys^171,172; consequently, a consensus conference recommended considering initiation of GnRHa therapy for all boys with onset of CPP before age 9 years who have compromised height potential.¹⁶³

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