1. Preface
Precocious puberty is defined as the onset of secondary sex characteristics in boys before the age of 9, 2 to 2.5 standard deviations earlier than the mean age at the onset of puberty in Caucasians. According to the pathological process, precocious puberty can be divided into the following categories: (1) central precocious puberty (also known as gonadotropin-dependent precocious puberty) due to the premature maturation of the hypothalamic-pituitary-gonadal axis; (2) Peripheral precocious puberty (also known as non-gonadotropin-dependent precocious puberty), caused by excessive secretion of sex hormones by the gonads or adrenal glands, exogenous sources of sex steroids, or ectopic production of gonadotropins by germ cell tumors; (3) Benign pubertal variation, including nonprogressive or intermittent progressive central precocious puberty or isolated androgen-mediated sexual characteristics (such as pubic and/or axillary hair, acne, and sweat gland odor) in boys caused by early activation of the hypothalamic-pituitary-adrenal axis (adrenal precocious puberty). Both disorders may be a variant of normal puberty.
Adolescence is a complex physical and psychological process that ends with full sexual maturity, including reproductive capacity. Activation of hypothalamic neurons begins at the beginning of puberty to increase pulsed GnRH secretion, and the gene networks involved in their activation are gradually revealed. GnRH synthesis begins early in fetal life, and the system is active during the first 6-9 months of a boy's life (called "mini-puberty"), after which the gonadotropin axis becomes quiescent. The timing of puberty is highly heritable, and the reactivation of hypothalamic GnRH secretion is determined by genetic, ethnic, nutritional, and environmental influences.
The transition from childhood to puberty depends on the reactivation of the hypothalamic-pituitary-gonadal axis and is controlled by neuroendocrine and metabolic factors]. The secretion of GnRH is controlled by kisspeptin and its receptor KISS1R, and is regulated by enhanced stimulation of neurokinin B and its receptors and decreased inhibition of dynorphin and its receptor, resulting in increased GnRH secretion in a pulsatile pattern (Figure 6.1).
Figure 6.1
Activation of the hypothalamic-pituitary-gonadal axis during puberty. GnRH pulses are induced by kisspeptin and its receptor KISS1R, and regulated by neurokinin B (NKB) on KNDy neurons and its receptor NK3R, possibly by increasing kisspeptin levels. NPTX levels increase during puberty and are negatively correlated with MKRN3, which is responsible for inhibiting puberty initiation, but the exact role is unclear. Gain-of-function mutations in the kisspeptin and KISS1R genes and loss-of-function mutations in MKRN3 are associated with CPP (modified by Aguirre RS et al.)
In addition, GnRH pulsations are controlled by excitatory and inhibitory signals, so at the onset of puberty, excitatory signals increase while inhibitory signals decrease [5]. The main neurotransmitter responsible for inhibiting childhood GnRH secretion is γ-aminobutyric acid (GABA), while glutamate, neuropeptide Y, endorphins, opioids, and melatonin are responsible for activating the GnRH pulse generator, which sets the time for puberty.
In summary, an increase in the frequency and range of GnRH secretion, as well as an increase in kisspeptin excitatory input through KNDy neurons and glutamate and a decrease in inhibitory signals from GABA neurons, marks the onset of puberty.
Metabolic control is another important factor influencing the onset of puberty, especially in girls; In fact, important information about nutritional status and energy reserves is sent indirectly to GnRH neurons via mostly unidentified intermediate inputs via insulin and leptin signaling pathways (Figure 6.1) [7, 8]. During peripuberty, body composition and sensitivity to insulin change, in fact, higher body fat content leads to early puberty, which in turn is associated with a higher risk of obesity later in life [ 9 ] .
Over the past two decades, different studies have shown that the onset of puberty is advanced by 12-18 months [10], with some hypothetical reasons including the role of nutritional status and growth, as well as the influence of extrinsic factors such as exposure to endocrine-disrupting chemicals (EDCs). EDCs cause hypomethylation and may be able to alter the course of puberty. These chemicals are capable of interfering with the activity of steroid hormones, particularly estrogens and antiandrogens demonstrated in animal models [15], and also appear to be associated with transitions in puberty [16].
Changes in the timing of puberty are heritable. This is evidenced by studies comparing homologous twins to fraternal twins. Understanding of the underlying mechanisms, including genes that explain the variation, remains unclear. Recently, a number of rare genetic causes of precocious puberty have been reported, and three genes have been identified in the pathogenesis of central precocious puberty: KISS1 [19], which encodes kisspeptin, its KISS1R receptor [20], and MKRN3, a hypothalamic inhibitor thought to act on the gonadal axis (Figure 6.1).
Secondary sexual development should be classified according to Tanner stage, and pubic hair (P) and genital (G) development should be assessed in boys (Figure 6.2). The first outward signs of puberty in boys are from G1 to G2, including testicular enlargement with testicular volume greater than 4 mL or testicle length greater than 25 mm[21], and normal puberty development by age 9. 14 years, an average of 11.5 years.
Figure 2
The Tanner stage of pubertal development
Pubic hair development (P):
• Stage 1: Before puberty, no pubic hair
• Stage 2: Thin, straight pubic hair along the base of the penis
• Stage 3: Darker, thicker, curlier hair that extends to the middle of the pubic bone
• Stage 4: The hair looks like an adult but does not extend to the thighs
• Stage 5: Hair stretches from thighs to thighs and looks mature
External genitalia development (G):
• Stage 1: Prepuberty
• Stage 2: The testicles and scrotum enlarge, the skin of the scrotum becomes red and the texture changes
• Stage 3: The penis enlarges and the testicles grow further
• Stage 4: The penis becomes enlarged, its width increases, the glans penis, testicles and scrotum become enlarged, and the skin of the scrotum darkens
• Stage 5: Adult genitalia
Precocious puberty is defined as the onset of sexual characteristics in boys before the age of 9 years, 2 to 2.5 standard deviations earlier than the mean age at the onset of puberty in Caucasian people [21].
By definition of precocious puberty, the prevalence is expected to be around 2%, or 2 per 100 children. However, population studies show that different rates depend on the population studied. The nine-year Danish national registry shows a very low incidence in boys (< 1 in 10,000) and five times lower than in girls (< 5/10,000 vs 20-23/10,000 girls) [22].
Depending on the underlying pathological process, precocious puberty can be divided into:
- Central precocious puberty (CPP, also known as gonadotropin-dependent precocious puberty) results from premature maturation of the hypothalamic-pituitary-gonadal axis. CPP is characterized by an enlarged testicle and penis in boys and maturation of pubic hair.
- Peripheral precocious puberty (PPP, also known as nongonadotropin-dependent precocious puberty) is caused by excessive secretion of sex hormones by the gonads or adrenal glands, exogenous sources of sex steroids, or ectopic production of gonadotropins by germ cell tumors.
- Benign or non-progressive pubertal variations, including isolated androgen-mediated sexual characteristics (e.g., pubic and/or axillary hair, acne, and sweat gland odor) in boys caused by early activation of the hypothalamic-pituitary-adrenal axis (precocious adrenal puberty). Both disorders may be a variant of normal puberty.
In at least 50 percent of cases of precocious puberty, pubertal manifestations resolve or stop progressing without treatment [23]. Although the underlying mechanism in these cases of nonprogressive precocious puberty is unknown, the gonadotropin axis is not activated.
2. Central precocious puberty
Central precocious puberty (CPP, also known as gonadotropin-dependent precocious puberty) is the most common mechanism of precocious puberty due to premature maturation of the hypothalamic-pituitary-gonadal axis. Although onset is early, the pattern and timing of pubertal events is usually normal.
2.1 Causes
Some brain malformations and acquired injuries are associated with CPP (Table 6.1), although some authors report that 25-60% of boys have idiopathic disease [24]. The most commonly detected brain abnormalities associated with CPP include hypothalamic hamartoma, encephalitis, hydrocephalus, neurofibromatosis type 1, meningomyomyelocele, and neonatal encephalopathy [25]. Hypothalamic hamartomas, called gray matter nodular hamartomas, are the most common cause of organic causes of CPP and usually occur in children younger than 4 years of age. It is a benign congenital tumor consisting of GnRH neurons or astrocytes that produce transforming growth factor (TGF)α, which can lead to premature activation of pulsatile GnRH release [26]. The disease phenotype caused by hamartomas may be associated with neurologic abnormalities such as smiling (laughing or crying), focal or generalized tonic-clonic seizures, and cognitive impairment [27].
Table 6.1 Causes of CPP
| Central nervous system lesions – congenital malformations |
|---|
| • Hypothalamic hamartoma |
| • Suprasellar arachnoid cyst |
| •hydrocephalus |
| • Glioma type 1 or neurofibromatosis |
| • Tuberous sclerosis |
| • Optic nerve dysplasia |
| • Chiari II malformation and meningocele |
| CNS lesions – acquired injury |
| • Tumors: astrocytoma, ependymoma, pineal tumor, hypothalamic or optic glioma, craniopharyngioma, germinoblastoma (which does not secrete hCG), meningiomas |
| • Post-injury (perinatal, infectious, traumatic, radiation therapy) |
| • Granulomatosis |
| • Cerebral palsy |
| No central nervous system lesions |
| • Idiopathic |
| • Endocrine disruptors |
| • No central nervous system pathology – congenital causes |
| • Genetic changes: Gain-of-function mutations in the genes encoding kisspeptin (KISS1) and kisspeptin receptors (KISS1R [formerly GPR54]), loss-of-function mutations in ring finger 3 (MKRN3). |
| • Chromosomal abnormalities |
| No central nervous system lesions – acquired conditions |
| • International adoption |
| • Early exposure to steroids (secondary central precocious puberty) |
Other CNS tumors associated with CPP include astrocytoma, ependymoma, pineal tumor, hypothalamic or optic glioma, craniopharyngioma, germinoblastoma (which does not secrete hCG), and meningiomas. In patients with neurofibromatosis, CPP is usually, but not always, associated with optic glioma [28].
Cranial irradiation, particularly at high doses for CNS malignancies, may lead to CPP in boys, leading to rapid progression of bone age maturation and the risk of short stature [29, 30].
CPP is also associated with congenital or acquired pathologies such as hydrocephalus, cysts, trauma, inflammatory diseases, tuberous sclerosis, or septal dysplasia.
Specific gene mutations are associated with CPP, although they represent only a small number of cases. The study describes the activation of the gene KISS1, which encodes kisspeptin and KISS1R (formerly GPR54), which encodes the kisspeptin receptor, and the inactivation of the MKRN3 gene in premature reactivation of GnRH secretion, previously thought to be idiopathic (Figure 6.1) [32].
MKRN3, an imprinted gene located in a key region of Prader-Willi syndrome (15q11-q13), encodes makorin ring finger protein 3, which represents one of the main factors involved in inhibiting the initiation of puberty. Therefore, loss-of-function mutations in this gene will lead to weakened inhibition and early onset of puberty. Due to maternal imprinting, the MKRN3 protein is derived only from RNA transcribed by paternally inherited gene copies [31]. Isolated analysis of central precocious puberty families caused by MKRN3 mutations clearly shows autosomal dominant inheritance with full penetrance. MKRN3 mutations have been shown to be associated with up to 46% of familial cases of CPP [33] and found in children with overt sporadic disease [34]. Due to the imprinting pattern of MKRN3 (maternal silencing), the disease phenotype can inherit from an asymptomatic father who carries the MKRN3 mutation. In fact, genotype analysis of patients with MKRN3 mutations and no family history of precocious sexual development showed that paternal inheritance existed in all study cases [34 ]]. The results of these preliminary studies suggest that familial nature of the disease may not be well understood, as accurate family history is difficult to obtain from fathers and early testicular enlargement may be missed. An increasing number of MKRN3 loss-of-function mutations have been identified in several affected families from different ethnicities]. Of note, patients with MKRN3 mutations have typical clinical and hormonal features of premature activation of the reproductive axis, including early pubertal signs such as testicular and pubic hair development, accelerated linear growth, advanced bone age, and elevated LH concentrations stimulated by basal or GnRH.
Significant chromosomal abnormalities are associated with complex syndromic phenotypes that may include precocious puberty caused by activation of the hypothalamic-pituitary-gonadal axis. These syndromes include 1p36 deletion, 7q11.23 microdeletion (Williams-Beuren syndrome), 9p deletion [42], maternal monoparental disomy on chromosomes 7 (Silver-Russell syndrome) and chromosome 14 (Temple syndrome) [43], inverted duplication of chromosome 15 [44], de novostromal deletion of chromosome 15, and maternal monoparental disomy (Prader-Willi syndrome) [45] , as well as the cyclin-dependent kinase-like 5 gene (CDKL5, located in the Xp22 region) [46], with a phenotype reminiscent of Rett syndrome.
According to the Danish National Registry, children who are internationally adopted have a 10-20-fold increased risk of CPP, especially when adopted after the age of 2, while children who migrate with their families have only a slightly increased risk of CPP [ 47]. The reason for this finding is unknown, but it has been hypothesized that nutritional deprivation in early life, increased obesity after adoption, and stressful psychosocial factors trigger pubertal maturity. In addition, environmental influences, including early exposure to endocrine-disrupting factors such as estrogen and anti-androgen chemicals, can affect the onset of puberty. In fact, most adopted children from malaria-endemic countries have been exposed to the pesticide dichlorodiphenyltrichloroethane (DDT) both antenatally and during infancy [48]. DDT has significant estrogenic properties and its derivative dichlorodiphenyl dichloroethylene (DDE) is believed to have antiandrogenic effects [ 49]. These findings initially suggest that DDT may be involved in exposing the early pathogenesis of precocious puberty in children, although more animal and human studies are needed to determine the role of these chemicals in puberty disorders.
Long-term exposure to high serum levels of sex steroids, such as those occurring in steroid-producing tumors, ortotoxicosis, McCune-Albright syndrome, and poorly controlled congenital adrenal hyperplasia, leads to increased growth, accelerated bone age, and effects as triggers for the maturation of the hypothalamic center important for the onset of puberty. Sexual steroid reduction following treatment of the primary underlying disease activates precocious hypothalamic GnRH pulse generators through a feedback mechanism, resulting in secondary CPP [50].
2.2 Evaluation
Evaluation is necessary in boys who show signs of developing secondary sexual characteristics before age 9, beginning with history and physical examination. In most cases, radiographic measurements of bone age are taken to determine whether epiphyseal maturity has increased accordingly.
2.3 History and physical examination
The first step in evaluating children with suspected CPP is to obtain a complete family history (the age at which parents and siblings began to enter puberty) and personal history, including when changes in puberty were first noticed and progress in pubertal performance. Children with CPP usually show a normal pubertal sequence, but at an earlier age, linear growth and bone maturation are rapid due to high concentrations of sex steroids. In addition, other questions address any evidence of possible CNS dysfunction, such as headache, behavioral or visual changes, seizures, or a history of previous CNS disease or trauma. Physical examination includes height, weight, and rate of height gain (HV, measured in centimeters per year). Children with CPP exhibit early growth acceleration, with HV exceeding 95% of their age. 6.2）。 Genital evaluation is performed by measuring testicular volume rather than penis size, as penis growth is not an early adolescent event and accurate measurements are difficult and inconvenient for adolescent boys. CPP should be suspected when Tanner's genital stage changes from G1 to G2, including testicular volume greater than 4 mL or testicle length greater than 25 mm, which is generally associated with Tanner's initial pubic hair development [21]. Conversely, CPP was excluded when Tanner's pubic hair stage changed from P1 to P2 without testicular volume enlargement. For all these reasons, the measurement of testicular volume is essential for physical evaluation and is usually carried out using the Prader testis measuring instrument (Figure 6.3).
Figure 6.3
Prad Orchid Meter
2.4 bone age
Imaging assessment of bone age (Greulich and Pyle or TW2/TW3 20 bone profile) in patients with CPP to assess epiphyseal maturity is helpful in differentiating diagnostic precocious puberty. In fact, bone age in patients with CPP is typically at least 1 year earlier or more than 2 standard deviations (SD) from chronological age [51]. However, the absence of advanced bone age is not a reason to stop follow-up assessment when growth rates and other progressive clinical signs of puberty are present. Bone age is also used to predict adult height, although this prediction tends to overestimate adult height and is not very reliable.
2.5 Laboratory evaluation
In boys, testosterone is an excellent sign of precocious puberty because most patients have early morning plasma testosterone values in the pubertal range. Tandem mass spectrometry is better than immunoassay at distinguishing testosterone concentrations between prepubertal and early adolescence. The gold standard biochemical diagnosis of CPP is based on the evaluation of gonadotropins, primarily LH, 30 or 45 minutes after stimulation of exogenous GnRH or GnRH-releasing hormone agonists [51]. Cut-off concentrations above 5 IU/L peak LH as assessed by ultrasensitive immunoassays typically indicate activated gonadotropin axes [51, 53]]. Children with CPP tend to have a more significant increase in LH after stimulation, with a peak LH-to-FSH ratio of 0.6 to 1.0, suggesting the diagnosis. However, its sensitivity and specificity are no higher than peak LH stimulated with GnRH alone [54]. With the development of laboratory methods utilizing monoclonal antibodies, such as immunofluorescence, immunochemiluminescence, and electrochemiluminescence, which have higher sensitivity and specificity than radioimmunoassays, with a lower limit of detection ≤ 0.1 mUI/mL, it has been suggested that morning baseline LH is used to assess gonadotropin axis activation without the need for GnRH agonist testing [ 54]. However, unless LH levels are significantly elevated, stimulation testing is recommended to confirm the diagnosis of progressive CPP.
Gonadotropin assessment is unreliable in boys aged 6 months or younger than 12 months, as baseline gonadotropin concentrations are usually high due to "puberty."
2.6 Imaging
Brain magnetic resonance imaging (MRI) should be performed in boys with confirmed CPP to exclude any hypothalamic or CNS lesions (Table 6.1). The prevalence of these lesions is higher in boys (40–90%) than in girls, and are more common in younger patients with rapidly progressive puberty.
2.7 Treatment
Long-acting GnRH agonists are the gold standard for the treatment of CPP. They provide sustained stimulation of pituitary gonadotropins rather than the secretion of physiological impulses of hypothalamic GnRH, leading to gonadotropin cell desensitization and reduced release of LH and FSH [55]. This treatment can be used in patients with idiopathic or neurogenic CPP, such as secondary CPP. However, not all patients require treatment, and the decision depends on the rate of puberty progression, the rate of height growth, and estimated adult height. In fact, boys with CPP who present before age 9 and develop rapidly benefit the most from treatment because if they do not receive treatment, they develop epiphyseal fusion early and lower adult height [ 56]. In contrast, boys with the very slow-progressing CPP variant generally do not require any treatment because their untreated adult height coincides with the median range of their parents' height [57]. According to the above data, the primary goal of CPP treatment is to allow the child to grow to normal adult height, followed by relief of psychosocial pressure.
GnRH agonist administration results in initial transient stimulation of pituitary gonadotropin secretion, followed by complete but reversible suppression of the pituitary-gonadal axis. Several GnRH agonists are available in various long-acting long-acting reservoir formats, such as monthly, 3- or 6-month dosing, or intramuscular injection with subcutaneous implantation once every 12 months. Their approved and recommended doses for use of precocious puberty vary from country to country (Table 6.2). The most widely used drugs are triptorelin and leuprolide, which are injected intramuscularly 3 times a month or month [ 56]. A recent meta-analysis confirmed that quarterly formulations have similar effects to monthly formulations in inhibiting the pituitary-gonadal axis, with the advantage of fewer injections, although data in the male population are scarce [58].
Table 6.2 Long-acting GnRH agonists for the treatment of CPP
| GnRH agonist | usability | Dose, frequency, and method of administration |
|---|---|---|
| Histaminerelin acetate subcutaneous implant | We | A 50 mg implant is surgically implanted every 12 months |
| Leprolide acetate (leuprolide) | USA, Canada, EU, Australia, South Africa and elsewhere | Intramuscular long-acting injections, given every 28 days: • 美国:PW ≤25 kg,7.5 mg;PW >25 kg,11.25 mg • EU: 3.75 mg Intramuscular long-acting injections every 12 weeks • USA: 11.25, 22.5, or 30 mg (dose selection criteria not yet determined) • EU: 11.25 mg |
| Goserelin acetate | USA, UK, EU, Canada, South Africa and elsewhere | Anterior abdominal wall subcutaneous implants: 3.6 mg every 28 days or 10.8 mg every 12 weeks |
| Triptorelin dihydroxynaphthate | UK, EU, South Africa and elsewhere | Intramuscular long-acting injections every 28 days: HP ≤20 kg:1.875 mg HP 20-30 kg:2.5 mg HP >30 kg:3.75 mg In some countries, intramuscular long-acting injections of 11.25/22.5 mg are given every 12/24 weeks |
- US weight in the United States, CAN Canada, EU EU, AU Australia, SA South America, United Kingdom and United Kingdom, PW patients
Short-acting GnRH agonist formulations, including daily subcutaneous and multi-daily intranasal sprays, may also be used, but long-acting formulations are preferable because they are more effective at puberty suppression in addition to improving adherence.
Use of GnRH agonists resolves or stabilizes pubertal symptoms, reduces growth rates to normal prepubertal values, and reduces bone age earlier [56]. Progression in testicular development usually indicates poor adherence, treatment failure, or misdiagnosis and requires further evaluation.
The duration of GnRH agonist therapy should be long enough to optimize final adult height but still allow for progression of pubertal characteristics that occur at the same time as the individual's peers, although the optimal time to stop treatment has not been formally established due to lack of data, and information on GnRH agonist therapy in boys is not officially available. As described in girls, it is generally recommended that boys stop treatment between the bone age of 12 and 12.5 years or when significant growth deceleration occurs to avoid losing physiologic pubertal growth spurts [59]. When monthly GnRH agonist therapy is discontinued, normal puberty resumes within a few months.
Treatment may be related to headaches and menopausal symptoms such as hot flashes; These adverse effects are usually transient and resolve spontaneously or with symptomatic treatment. Local complications, including sterile abscesses at the injection site, occur in 3 to 13 percent of patients [60]. Fat mass tends to increase with treatment, while lean mass and bone density tend to decrease, although longitudinal studies suggest that the prevalence of obesity does not increase during or after treatment and bone density is normal after treatment is stopped [61, 62].
3. Peripheral precocious puberty
Peripheral precocious puberty (PPP, also known as nongonadotropin-dependent precocious puberty) is due to the secretion of sex hormones independent of the premature maturation of the hypothalamic-pituitary-gonadal axis. In fact, FSH and LH levels are usually suppressed in PPP, and they do not increase after GnRH stimulation. Further characterization is based on whether sexual characteristics are appropriate for the child's gender (heterosexuality) or not suitable for the boy's feminization (heterosexuality).
3.1 Causes
PPP is caused by excessive secretion of sex hormones originating from the gonads or adrenal glands or from exogenous sources.
Leydig cell tumor is a testosterone-secreting tumor that causes PPP in boys. In general, it should be considered in any boy with asymmetrically enlarged testicles. Even if an obvious mass cannot be palpated and there is no obvious mass on ultrasonography, a biopsy should be performed if the larger testicle enlarges during follow-up. These tumors are almost always benign and easily removed by radical orchiectomy [63].
Human chorionic gonadotropin secretes germ cell tumors secrete hCG, and in boys, hCG activates LH receptors on Leydig cells, resulting in increased testosterone production. The increase in testicular size is lower than expected for serum testosterone levels and the degree of pubertal development because most testicular enlargement is composed of tubular components dependent on mature FSH. These tumors occur in the gonads, brain (usually in the pineal region), liver, retroperitoneum, and anterior mediastinum, reflecting the location of embryonic germ cells prior to gonadal crest fusion. The histologic of hCG-secreting tumors ranges from agerminoblastomas that respond rapidly to treatment to more malignant embryonal cell carcinoma and choriocarcinoma [64]. ]. Familial male localized precocious puberty, also known as orchosis, is caused by an activating mutation in the LH receptor gene that causes premature maturation of Leydig cells and testosterone secretion. Affected boys typically appear between the ages of 1 and 4 [65]. Although this rare disorder is autosomal dominant, only boys are affected because estrogen biosynthesis in girls requires activation of both LH and FSH receptors.
Children with severe, long-term primary hypothyroidism occasionally present with PPP with premature testicular enlargement called "overlap" or Van Wyk-Grumbach syndrome. The proposed mechanism is cross-reactivity and stimulation of FSH receptors by high serum thyrotropin (TSH) concentrations, as TSH and FSH share a common α subunit [66]. After thyroxine therapy begins, signs of pubertal development subside.
Exogenous estrogen or testosterone exposure can cause PPP in heterosexual and homosexual boys, respectively. Male feminization and gynecomastia in boys are attributed to excessive estrogen exposure from creams, ointments, and sprays (eg, oral contraceptives, estrogen creams used to treat menopausal symptoms) [67]. Other possible sources of estrogen exposure include food contaminated with hormones, phytoestrogens that share the same chemical structure as estrogen (e.g., soy), and folk remedies with estrogenic activity, such as lavender oil and tea tree oil [68].
Multiple case reports of transdermal testosterone products leading to virilization in children have also been reported [69].
Causes of excess androgen production include androgen-producing tumors (i.e., Cushing syndrome, adrenal adenoma) and adrenal steroid biosynthetase deficiencies, such as atypical (or late-onset) congenital adrenal hyperplasia (NCCAAH). Boys with adrenal causes of PPP may have precocious pubic hair without testicular enlargement (testicles less than 4 mL in size or less than 2.5 cm in diameter). Rarely, adrenal tumors lead to feminization due to androgen and estrogen production, the latter due to intraadrenal or peripheral aromatization of androgens [70].
McCune-Albright syndrome (MAS) is a rare disorder defined as the triad of PPP, irregular coffee-milk skin pigmentation, and abnormal hyperplasia of bone fibers. MAS patients have somatic (post-zygotic) mutations in the Gs protein α subunit that activate adenylate cyclase [71]]. This mutation results in persistent stimulation of endocrine function (e.g., precocious puberty, thyrotoxicosis, gigantism or acromegaly, Cushing's syndrome, prolactin-secreting adenomas, and hypophosphatemic rickets), with a markedly different clinical phenotype depending on the tissue affected by the mutation. PPP is the most commonly reported manifestation of MAS, although it is less common in boys than in girls. Ultrasound-detected testicular lesions are very common and include hyperechoic and hypoechoic lesions (likely to represent areas of Leydig cell proliferation), microstones, and focal calcifications [ 72 ]. Mutations can also be found in other non-endocrine organs, such as the liver and heart, leading to cholestasis and/or hepatitis, intestinal polyps, and arrhythmias, respectively. An increased risk of malignancy has been reported [73].
4 Ratings
4.1 History and physical examination
As described in CPP, the first step in evaluating a child with suspected PPP is to obtain a complete family history to identify familiar causes and personal history, including time to first notice of initial pubertal changes, progression of pubertal manifestations, and exclusion of estrogen or androgen exogenous exposure. Children with PPP usually have a source of peripheral gonadotropins and are more likely to exhibit deviations from the normal pubertal sequence, linear growth, and rapid bone maturation. Physical examination can identify possible causes of PPP. In fact, patients with mild or asymmetric testicular enlargement may be suspected of being a testicular cause, and skin coffee spots may cause MAS, while premature pubic hair appearance without testicular enlargement suggests an adrenal source of sex hormones. Finally, children with isolated heterosexual development such as gynecomastia may have been exposed to exogenous estrogens.
4.2 Bone age
For CPP, the bone age of patients with PPP is usually at least 1 year or more than 2 standard deviations (SD) [51] earlier than the chronological age, with the exception of hypothyroidist boys who present with delayed bone age.
6.4.3 Laboratory evaluation
Peripheral causes of PP typically have the same early morning elevated plasma testosterone levels as in the adolescent range, as well as suppressed gonadotropins (FSH and LH) [51]. In boys with precocious pubic hair without testicular enlargement, measurement of adrenal steroids may help distinguish PPP from benign adrenal precocious puberty. In fact, an early morning increase in 17-hydroxyprogesterone (17-OHP) levels above 1000 ng/dL is diagnosed as non-classic congenital adrenal hyperplasia (NCCAH), while moderately elevated levels between 200 and 1000 ng/dL suggest NCCAH, and a high-dose (250 mcg) ACTH stimulation test is recommended to confirm the diagnosis [ 74]. When 24-hour urine free cortisol (UFC), late-night salivary cortisol, and early morning ACTH serum values are elevated, elevated DHEAS levels may be due to rare adrenal tumors or rare ACTH-dependent Cushing disease.
In addition, hCG doses are recommended to assess the likelihood of hCG-secreting tumors and TSH concentrations for thyroid assessment to exclude suspected chronic primary hypothyroidism.
4.4 Imaging
Testicular ultrasonography may be performed in boys with PPP and mild or asymmetric testicular enlargement to assess for the possibility of Leydig cell tumor, orchemia, or MAS. Finally, if an adrenal tumor is suspected, abdominal ultrasound and/or computed tomography (CT) should be performed.
4.4.1 Treatment
Treatment of PPP aims to remove or block the production of excess sex hormones depending on the cause. Testicular and adrenal tumors are treated surgically, while identification and removal of exogenous steroids allows for the resolution of pubertal changes.
Glucocorticoid replacement therapy is only recommended for boys with NCCAH who have an advanced bone age and a height predictive value below the family target height.
The combination of an antiandrogen (androgen receptor antagonist such as spironolactone or biscalutamide) and an aromatase inhibitor such as anastrozole or letrozole in boys with ortotoxicity and MAS may inhibit the conversion of testosterone to estradiol, further delaying bone maturation. Although the data provided by this combination therapy look promising, long-term studies are needed to further determine the safety and efficacy of these drugs. In the past, ketoconazole was included in treatment regimens as inhibitors of steroid synthesis, but its use was limited due to its potential hepatotoxicity and side effects of adrenal insufficiency [76 , 77]. Testicular Leydig cell hyperplasia is common in MAS, but surgical treatment is avoided to preserve fertility.
Decreased levels of sex steroids can lead to CPP, often associated with advanced bone age; Therefore, GnRH agonist therapy is required.
5. Benign or non-progressive pubertal variation
Precocious adrenal puberty is a very mild hyperandrogen disorder characterized by pubic and/or axillary hair in boys before the age of 9 years with mildly elevated serum dehydroepiandrosterone sulfate (DHEAS) (typically 40–115 mcg/dL or 1.1–3.1 mcmol/L) [ 78]. Children with precocious adrenal puberty tend to be above average height, bone age and linear growth rate above average, but remain within the normal range, and adults with a family target height predict normal height. The process is generally thought to be caused by premature development of the adrenal reticular band as a variant of normal development, although some studies have described premature adrenal onset as possibly associated with obesity and low birth weight, possibly due to insulin resistance [78, 79], 80].
Some cases of premature pubic hair onset, known as "idiopathic premature pubic hair onset," occur in children with normal androgen levels and may reflect the increased sensitivity of the sebaceous units of hair follicles to age-appropriate androgen levels [81].
Nonprogressive or intermittent progressive precocious puberty represents a form of CPP in which pubertal symptoms are clinically stable or progress very slowly. Bone age is usually less large compared to true CPP boys, and serum LH concentrations are in the prepubertal or early adolescent range, indicating incomplete activation of the hypothalamic-pituitary-gonadal axis. In these cases, treatment with GnRH agonists is not required because their adult height is not affected ].
None of these forms require specific endocrine therapy, but only evidence of clinical monitoring of puberty progression to distinguish them from genuine cases of CPP or PPP.
Cite this chapter
Cappa, M., Chioma, L. (2021). Disorders of Pubertal Development: Precocious Puberty. In: Foresta, C., Gianfrilli, D. (eds) Pediatric and Adolescent Andrology. Trends in Andrology and Sexual Medicine. Springer, Cham. https://doi.org/10.1007/978-3-030-80015-4_6