By definition, precocious puberty is the appearance of any sign of secondary sexual maturation before the age of nine years in boys.

Precocious puberty can be central (gonadotropin-releasing hormone-dependent) or peripheral (gonadotropin-releasing hormone-independent) (Table Precocious Puberty). In both cases, linear growth is accelerated during childhood, often with markedly advanced bone maturation. Paradoxically, a tall boy may become short in adulthood because of the very early epiphyseal closure.

Table Precocious Puberty

Central

  • Idiopathic
  • CNS tumors
  • Other CNS disorders

Peripheral

  • Congenital adrenal hyperplasia
  • Virilizing adrenal tumors
  • Leydig cell tumors
  • Familial testotoxicosis
  • McCune-Albright syndrome
  • Longstanding hypothyroidism

Central Precocious Puberty

CPP is either idiopathic or secondary to a central nervous system abnormality. The definitive diagnostic test for CPP is gonadotropin-releasing hormone stimulation of gonadotropin release. CPP is diagnosed when there is a “pubertal response,” that is, when the rise of luteinizing hormone is greater than the range of response among prepubertal children of the same sex using the same gonadotropin assay.

Idiopathic

In this condition, puberty is physiologically normal, but chronologically early.

In contrast to its occurrence in girls, CPP occurs less frequently in boys, and a larger percentage of boys with CPP have CNS lesions than the idiopathic variety. Therefore, the CNS assessment of boys with early puberty, usually including an MRI scan, should be emphasized.

In boys with idiopathic CPP, the testes usually enlarge under gonadotropin stimulation before other signs of puberty are seen. Progression of sexual maturation is often more rapid than normal. The rapid growth is associated with increased GH secretion and elevation of serum IGF-1 levels because of stimulation of this axis by gonadal steroid hormones.

The ratio of bone age to chronological age and the rise of IGF-1 above normal values for age are predictive of outcome: Children with modest clinical signs progress less rapidly and may attain their target heights.

CNS Tumors

Optic and hypothalamic glioma, astrocytoma, and, rarely, craniopharyngioma, ependymomas, and ger-minomas can cause CPP. The prevalence of CPP is increased especially in girls after cranial radiation for local tumors or leukemia. Hamartomas of the tuber cinereum are now detected in many boys previously thought to have idiopathic CPP. These hamartomas are not true neoplasms and should not be approached surgically, except in unusual circumstances. Sexual precocity may be the first manifestation of any posterior hypothalamic tumor. In addition, headaches, visual problems, diabetes insipidus, and hydrocepha-lus may develop due to an enlarging mass.

The location of these rumors usually makes surgical removal difficult. A conservative approach is recommended; the pathologic findings of a biopsy of the neoplasm should direct treatment.

Other CNS Disorders

CNS abnormalities associated with CPP include encephalitis, developmental delay, hydrocephalus, epilepsy, previous CNS radiation therapy, head trauma, arachnoid cyst, brain abscess, and sarcoid or tuberculous granuloma of the hypothalamus.

Neurofibromatosis type 1 (von Recklinghausen’s disease) and septooptic dysplasia are associated with both precocious puberty and delayed puberty.

Chronic Exposure to Sex Steroids CPP may be secondary to prolonged sex steroid exposure associated with peripheral precocious puberty (PPP). Boys may develop CPP as a consequence of prolonged hyperandrogenic state in inadequately treated congenital virilizing adrenal hyperplasia. Patients with this disorder may initially have PPP but later develop CPP after prolonged excessive androgen stimulation.

Peripheral Precocious Puberty

In this disorder, the secretion of testosterone is independent of gonadotropin-releasing hormone. Affected individuals do not have a pubertal response to gonadotropin-releasing hormone stimulation and may have suppressed gonadotropin concentrations. Usually, the testes are smaller than expected from the serum testosterone level.

The causes of PPP include congenital adrenal hyperplasia (CAH), human chorionic gonadotropin-secreting tumors, virilizing adrenal tumors, tesricular tumors, testotoxicosis, McCune-Albright syndrome, and longstanding hypothyroidism.

Congenital Adrenal Hyperplasia

Undiagnosed or undertreated CAH due to 21-hydroxylase deficiency is the most common cause of PPP in boys. Approximately 75% of patients with CAH due to 21-hydroxylase deficiency have salt loss resulting from impaired aldosterone secretion and low serum sodium and high serum potassium levels. Increased plasma concentrations of 17-hydroxyprogesterone, advanced bone age, and rapid growth are characteristic findings. One-fourth of patients with CAH are non-salt losers; these boys may escape early diagnosis and present with virilizarion during childhood.

Germ cell or mixed germ cell tumors, hepatomas, and hepatoblastomas may secrete human chorionic gonadotropin. Boys with these human chorionic gonadotropin-secreting neoplasms may have slightly enlarged testes and may be difficult to differentiate from boys with CPP on the basis of physical examination. Plasma human chorionic gonadotropin levels are elevated without an increase in the concentration of follicle-stimulating hormone or luteinizing hormone. The prevalence of mediasrinal germ cell tumors is increased 30 to 50 times in boys with Klinefelter’s syndrome.

Virilizing Adrenal Tumors

Virilizing adrenal carcinomas and adenomas secrete large amounts of DHEA, DHEAS, and, occasionally, testosterone. Rare adrenal adenomas produce both testosterone and aldosterone, leading to precocious puberty and hypertension with hypokalemia.

Adrenal rests, or heterotopic adrenal tissue in the testes, may enlarge with endogenous corricorropin stimulation in boys with undiagnosed or undertreated CAH and may mimic interstitial cell tumors, occasionally leading to massive enlargement of the testes.

Leydig Cell Tumor

This testicular tumor may cause sexual precocity. It causes a unilateral enlargement of the testes. These tumors must be differentiated from testicular adrenal rest cell hyperplasia, which usually occurs bilaterally, and may be seen in patients with poorly controlled CAH. Most of these tumors are benign and present in boys less than six years of age.

Familial Testotoxicosis

Affected boys have penile enlargement, which may be present at birth, and bilateral enlargement of the testes to the early or mid-puberty range. Basal and gonadotropin-releasing hormone-srimulated gonadotropins are prepubertal. Plasma testosterone levels are in the normal pubertal or adult range. If untreated, affected individuals may have superimposed CPP. This condition is caused by heterozygous activating mutations of the Gs protein-coupled luteinizing hormone / human chorionic gonadorropin receptor. It is commonly inherited as a male-limited autosomal dominant trait.

McCune-Albright Syndrome

This syndrome, which occurs far more frequently in females than in males, includes a unique form of PPP in which there is an activating missense mutation in the gene for the α-subunit of the Gs protein — the G protein that stimulates cAMP formation. Abnormalities consist of localized osseous lesions (polyostoric fibrous dysplasia), melanotic cutaneous macules (cafe au lait spots), and endocrinopathy Endocrinopathies may include sexual precocity, hyperthyroidism, hyperadrenocorricism, pituitary gigantism, and hypophosphatemia.

Longstanding Hypothyroidism

This is an uncommon cause of PPP in boys, in which precocious puberty may occur in association with impaired growth and delayed bone age. The signs of sexual maturation are not accompanied by a pubertal growth spurt; rather, growth is impaired. In some cases, there is an enlargement of the sella rurcica and pituitary gland, which has led to misdiagnosis of a pituitary neoplasm.

Treatment

Treatment of CPP is indicated to prevent progression of puberty, untimely statural growth, the development of associated psychosocial problems, and foreshortened adult height.

Three principal agents have been used in the treatment of CPP, whether idiopathic or neurologic: medroxyprogesterone acetate, cyproterone acetate, and gonadotropin-releasing hormone agonists. The first two drugs have been replaced by gonadotropin-releasing hormone agonists; at present, they are useful as backup agents for occasional patients who develop untoward effects from gonadotropin-releasing hormone agonist therapy.

Chronic administration of gonadotropin-releasing hormone agonists suppresses luteinizing hormone and follicle-stimulating hormone release, gonadal steroid output, and gametogenesis after an initial, brief stimulation of gonadorropin release. Suppression is due to binding of the agonist to the gonadotropin-releasing hormone receptors on gonadotropes and desensirizarion of the gonadorropes to gonadotropin-releasing hormone. Various agonists are available, but the intramuscular depot formulation of leuprorelin (leuprolide acetate) is the most commonly prescribed; it is safe and effective. Careful monitoring of serum gonadotropins and gonadal steroids is necessary for the evaluation of effectiveness of the treatment. Untoward reactions to gonadotropin-releasing hormone agonists include local and systemic allergic reactions, sterile abscess, and weight gain. Changes in secondary sexual characteristics occur within the first six months of therapy: the pubic hair thins, the testes decrease in size, acne and seborrhea regress, penile erections and masturbation become much less frequent, high energy levels and aggressive behavior diminish, and self-esteem improves. From the second year on, height velocity for bone age is usually appropriate.

Treatment of PPP depends on the diagnosis: if there is an underlying cause resulting in early puberty, medical therapy involves treatment of this cause, if possible. Examples of treatment for underlying conditions include surgery and radiation or chemotherapy for tumors of CNS, ectopic gonadorropin-producing, testicular, or adrenal origin.

Treatment with glucocorricoids and mineralocorticoids (when appropriate) suppresses the abnormal androgen secretion and arrests virilization and corrects electrolyte imbalance.

In testotoxicosis and McCune-Albright syndrome, ketoconazole and, recently, the more potent aromatase inhibitors have been used to suppress gonadal and adrenal biosynthesis. Secondary CPP often occurs when the bone age advances to or has already reached the pubertal range, at which time addition of a gonadotropin-releasing hormone agonist is appropriate. Another approach involves the use of the antiandrogen, spironolactone, combined with testolactone, an inhibitor of the conversion of androgens to estrogens. Recently, tamoxifen, a potent antiestrogen agent, has been proposed as an alternative treatment in patients with McCune-Albright syndrome.

Treatment with levothyroxine in patients with longstanding hypothyroidism not only corrects the hypothyroid state, but may reverse the incomplete sexual maturation and pituitary enlargement (when associated).

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