Precocious Pseudopuberty

In gonadotropin-independent precocious puberty, the presence of testosterone in boys or estrogen in girls is not secondary to activation of the HPG axis. Luteinizing hormone (LH) and follicle-stimulating hormone (FSH) concentrations are low, and response to exogenous gonadotropin-releasing hormone (GnRH) is suppressed (prepubertal).

Circulating sex steroids (testosterone or estrogen) cause secondary sexual development. The sex steroids (estrogen or testosterone) come from either the adrenal gland or the gonad, independent of the hypothalamic-pituitary portion of the pubertal axis. In aromatase excess syndromes, an apparent increase in the extraglandular aromatization of androgens leads to an increase in the circulating estrogen levels. This is associated with isosexual precocious puberty in girls and prepubertal gynecomastia in boys. Sex steroids may also be ingested or absorbed from exogenous sources. Thus, the exact pathophysiology varies with the underlying cause of precocious puberty.[4]

The etiologies of PPP can vary between boys and girls and include production of sex steroids by the gonad in an unregulated fashion, such as in McCune-Albright syndrome (MAS) or familial male-limited precocious puberty (FMPP); sex steroid secretion by the adrenal gland as occurs in congenital adrenal hyperplasia (CAH); tumors that secrete human chorionic gonadotropin (HCG); sex steroid–excreting tumors of the adrenal gland, ovary, or testis; or exposure to exogenous sex hormones.[6]

Certain aromatic oils, such as lavender and tea tree oil, present in some skin creams, hair care products, and aromatherapy oils and sprays, have estrogenic activity. Transdermal estrogen creams or testosterone gels or ingestion of oral contraceptives are other possible exogenous sources of exposure to sex steroid hormones.[2]

Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders characterized by impaired cortisol synthesis.  21-hydroxylase is the enzyme responsible for the conversion of 17α-hydroxyprogesterone to 11-deoxycortisol, and its deficiency accounts for 95% of cases of CAH. 11β-hydroxylase deficiency is a second enzyme deficiency leading to CAH. Both 21-hydroxylase and 11β-hydroxylase enzyme deficiencies lead to a decrease in cortisol production. This decrease in cortisol production results in chronic stimulation of the adrenal cortex by adrenocorticotropic hormone (ACTH), with an increase in the cortisol precursors. These precursors then are shunted into the androgen pathway, leading to excessive androgen production and, therefore, the signs and symptoms of androgen excess.[5]

Potential HCG-secreting tumors may cause Leydig cell stimulation and some testicular enlargement in boys. The locations of HCG-secreting tumors include tumors of the liver (hepatomas, hepatoblastomas) and choriocarcinomas of the gonads, mediastinum, retroperitoneum, or pineal gland.

Adrenocortical tumors are rare in childhood and their etiology is unknown. Adrenocortical tumors may occur at any age from infancy into adolescence, and the clinical manifestations of these tumors depend on the type of the hormones they secrete. The most frequent hormonal effects are secondary to androgen secretion, resulting in virilization of girls and early puberty in boys. The primary hormonal picture is rarely that of estrogen effects, which lead to feminization in males and precocious pseudopuberty in females.

Ovarian tumors can be either feminizing or masculinizing. The most common tumor associated with isosexual precocity is the benign ovarian follicular cyst. The cells lining the cysts are luteinized, leading to estrogen production.

Granulosa cell tumor is the next most common feminizing neoplasm of the ovary. Juvenile granulosa cell tumors that develop in premenarchal females produce sexual precocity as a consequence of estrogen secretion. This may present as premature breast development or vaginal bleeding. Virilization may also be present. These tumors may also secrete HCG. Sex-cord tumors may have characteristics of both granulosa and Sertoli cells.

Masculinizing tumors (Leydig-Sertoli cell tumors or arrhenoblastomas) are unusual before adolescence. These tumors are the most common virilizing ovarian tumor. The masculinizing tumors tend to have abnormal differentiation that leads to an unusual pattern of steroid secretion with androstenedione predominating over testosterone secretion.

McCune-Albright syndrome (MAS) involves the overactivity of the cyclic adenosine monophosphate (cAMP) signaling pathway. The G-proteins involved in signal transduction are heterotrimers that consist of alpha, beta, and gamma subunits, each of which is encoded by separate genes. Inactive stimulatory G-protein (Gs) is normally activated by the interaction with a hormone-bound receptor that results in an exchange of guanosine triphosphate (GTP) for guanosine 5'-diphosphate (GDP) and dissociation of the active alpha subunit. In the case of Gs, the GTP-bound alpha subunit interacts with and stimulates adenylate cyclase and specific ion channels. Intrinsic GTPase activity of the alpha subunit inactivates the G-protein. Mutations in the Gs (alpha) gene may result in inhibition of the GTPase activity of Gs, leading to prolonged activation in the absence of a stimulatory hormone.

Familial male precocious puberty (FMPP), also called testotoxicosis, is a dominant mutation in the LH receptor gene that results in the production of a receptor that is capable of spontaneous activation in the absence of either LH or HCG. 

Van Wyk-Grumbach syndrome is a rare syndrome characterized by hypothyroidism, precocious puberty with multicystic ovaries, and features of polycystic ovarian disease (PCOD). The exact mechanism for the development of sexual precocity secondary to hypothyroidism is unknown. It is believed to be secondary to the structural similarity between thyroid-stimulating hormone (TSH) and LH. This is the only form of sexual precocity in which growth may be arrested rather than stimulated.[2]

The incidence of precocious puberty is estimated to be 1 per 5000-10,000 individuals. Gonadotropin-independent precocious puberty is about one fifth as common as gonadotropin-dependent precocious puberty.[1, 8]

The overall ethnic predilections depend on the etiology of the precocious puberty.

• Nonclassic CAH due to 21-hydroxylase deficiency: In a heterogeneous US population, the carrier frequency is approximately 1 in 6 individuals, and the disease frequency is 1 in 100 individuals. However, in Ashkenazi Jews, the carrier frequency is 1 in 3 individuals, and the disease frequency is as high as 1 in 27 individuals. Importantly, note that not all individuals affected with this mild inborn error of steroid hormone metabolism are symptomatic. Nonclassical CAH may present with premature development of pubic hair, advanced bone age, and accelerated linear growth velocity. In females, it may be clinically indistinguishable from PCOS because of the development of cystic acne, hirsutism, and secondary amenorrhea.

• Classic CAH due to 21-hydroxylase deficiency: Worldwide, the incidence is about 1 in 10,000-15,000 live births. Approximately 75% of cases are of the salt-wasting type, which usually is diagnosed in infancy because girls have ambiguous genitalia and both sexes have potentially life-threatening salt-wasting adrenal crises. The other 25% of cases, known as simple virilizers, may be missed in infancy and may present in early childhood with signs of inappropriate somatic growth, epiphyseal maturation, pubic hair, acne, and progressive clitoromegaly in girls. If bone age advances sufficiently, true central precocious puberty may be triggered.

• McCune-Albright syndrome (MAS): This disorder is sporadic, usually attributable to somatic cell mutations, and has been reported in white, black, and Asian populations.

• Familial male precocious puberty: This disorder is inherited in an autosomal dominant pattern expressed only in males and has been reported in individuals who are white, black, and Asian. De novo mutations may arise; therefore, consider diagnosis even in cases without a clear family history of precocious puberty.

If precocious puberty is defined on the basis of mean age of pubertal development plus or minus 2 standard deviations from the mean, the frequency of precocious puberty should be the same for both genders. However, girls present more often for evaluation of precocity than boys. Most cases of precocious puberty in girls are secondary to idiopathic central precocious puberty.

Some causes of gonadotropin-independent precocious puberty are more common in one gender than the other.

• McCune-Albright syndrome (MAS): Ninety-five percent of patients are female.

• Familial male precocious puberty (FMPP): The pattern of inheritance is autosomal dominant with greater than 90% penetrance. Female carriers are unaffected by early sexual development or endocrine abnormalities.

• Ectopic HCG-secreting tumors: These tumors are rare and are associated with sexual precocity in males. This precocity is thought to be secondary to the stimulatory effect of HCG on the Leydig cells leading to increased testosterone secretion.

By definition, males who have precocious puberty must develop secondary sexual characteristics when younger than 9 years. In black girls, puberty when younger than 6 years is considered precocious, whereas in white girls, puberty when younger than 7 years is considered precocious.

The classic definition of sexual precocity for girls is the onset of secondary sexual characteristics prior to age 8 years.[9] The current guidelines recommend the evaluation of any girl younger than 8 years who has an advanced bone age or a rapid progression through puberty.

• McCune-Albright syndrome (MAS): Girls with MAS may present at any age. The average age of pubertal onset is 3 years; however, vaginal bleeding has been reported in females as young as 4 months.

• Familial male precocious puberty: Male patients develop progressive secondary sexual characteristics with rapid physical growth and skeletal maturation often accompanied by sexually aggressive behavior within the first 2-3 years of life.

• CAH: Clinical symptoms of nonclassic 21-hydroxylase deficiency vary and may present at any age. After the newborn period, nonclassic 21-hydroxylase deficiency may present as various hyperandrogenic symptoms, including precocious pubarche, advanced bone age, and accelerated growth in childhood. In women, irregular periods, polycystic ovarian disease, acne, hirsutism, and infertility are common manifestations. As noted above, classic CAH is usually detected in infancy with ambiguous genitalia in girls and salt-wasting adrenal crisis in boys. In addition, some clinics and hospitals include testing for increased blood concentration of 17α-hydroxyprogesterone to diagnose CAH in the routine newborn screen performed on all babies.[5]

The prognosis of PP varies with etiology.

• MAS: Prognosis varies with the number of endocrinopathies and the extent of the bone disease. Most girls have an excellent prognosis.

• Testotoxicosis: Prognosis is excellent with proper treatment.

• CAH: Prognosis is excellent with proper treatment.

• Ovarian granulosa cell tumors: Early recognition and diagnosis of ovarian granulosa cell tumors leads to improved cure rates and disease-free survival rates.

• Exogenous exposures: The most common etiology in young children has been inadvertent exposure to sex hormones through contact with adult males who use topical androgens such as Androgel or ingestion of oral contraceptives. Signs of precocious publerty (eg, pubic hair, phallic enlargement) may resolve when such exposure ceases.

The morbidity and mortality of PPP also varies with the underlying etiology.

• Short stature: Both CPP and PPP are characterized by an accelerated rate of growth and bone maturation. This early growth manifests as early tall stature; however, as the puberty progresses and the bones are continually exposed to the sex steroids, the growth plates mature and fuse at an early age. This can lead to an overall decrease in adult height.

• Multiple endocrinopathies: Children with MAS are at risk for various endocrinopathies. These individuals have an increased incidence of thyrotoxicosis, Cushing syndrome, acromegaly, hyperprolactinemia, ovarian cysts, and hyperparathyroidism as part of their primary disease process. Although the exact incidence of other nonendocrine manifestations of the disease is unclear, other potential problems include bone cysts (polyostotic fibrous dysplasia), hepatobiliary dysfunction, pancreatitis, gastrointestinal polyps, abnormal cardiac muscle cells, and even sudden or premature death.

• Contrasexual physical development: In some cases, secondary sexual characteristics of the opposite sex can develop (eg, girls with CAH or girls with an androgen-secreting adrenal or ovarian tumor may have clitoral enlargement, secondary amenorrhea, and infertility).

Inappropriate societal expectations are often placed on these children based on the appearance of advanced maturity. Reminders of the chronologic age of the child are often necessary for school personnel, caregivers, and parents.

Guidelines for sexuality education for children and adolescents have been established by the American Academy of Pediatrics.[10]

The age of onset and the time velocity of physical changes, development of secondary sexual characteristics, sex steroid exposure, and evidence of possible CNS dysfunction are important information to obtain in the patient history.[11] The following may be reported:

• CNS risk factors, including infections, perinatal asphyxia, head trauma, neoplasms, or prior radiation therapy.
• Personality changes, increased appetite, headaches, and/or visual changes.
• Exposures to skin or hair products, vitamins, or dietary supplements that may contain estrogenic or androgenic substances, including placental extracts.
• Excess consumption of soy or other phytoestrogens may also contribute to pseudopuberty.
• Ingestion of medications containing estrogens, such as oral contraceptives.
• Inadvertent transdermal transmission of topical androgen gels used by adults in the household.

Frequently, a strong family history for this disorder is observed: in males, FMPP is inherited as an autosomal dominant disorder; congenital adrenal hyperplasia (CAH) is usually detected at birth.

Findings that suggest precocious puberty include advanced development with progression, rapid linear growth,  advanced skeletal maturation; and in girls, the presence of both breasts and pubic hair.[6] The age of onset of pubertal development is determined by the degree of sexual maturation present upon physical examination using the Tanner growth charts (shown below).

• Height: measure the individual's height with a stadiometer (the individual should not be wearing shoes); calculate growth velocity from previous height measurements.

• Weight: A recent study concluded that increasing body mass index (BMI) and excessive weight at age 5 years predicts the advanced stages of puberty.[12] Also, an advanced stage of puberty predicts young adults' BMI and overweight status at age 21 years.

• Abnormal vital signs: bradycardia and low normal temperature may suggest severe hypothyroidism; elevated blood pressures may be observed in response to an adrenal tumor or in congenital adrenal hyperplasia (CAH) due to 11β-hydroxylase deficiency.

• Secondary sexual characteristics: these are staged using the Tanner growth charts (shown below) for breasts and pubic hair in girls and pubic hair in boys.

Graph represents the prevalence of breast development at Tanner stage 2 or greater by age and race.

Graph represents the prevalence of pubic hair at Tanner stage 2 or greater by age and race.

See the list below:

• Accurate measurements of testicular volume and stretched penile length should also be performed and compared with normal measurements for age.

• FMPP: The age of onset is usually 2-4 years. The penis increases in size, but testicular volume is increased to a size that is less than expected for the degree of sexual maturation. Nodular Leydig cell hyperplasia can be observed, and seminiferous tubular development is usually sufficient to allow spermatogenesis.[13]

• Androgenic effects: Perform a careful evaluation, looking for the presence of acne, hirsutism, increased muscle mass, and clitoromegaly in females. Looking for these signs helps focus the differential diagnosis toward androgenic causes of precocious puberty. 

• Estrogenic effects: Breast development and changes in the vaginal mucosa are signs of estrogen exposure. The vaginal mucosa in prepubertal girls is reddish in hue. Estrogen causes the mucosa to thicken and take on a more pinkish hue. Vaginal maturation index may be helpful. Superficial cells are detected with high estrogen effect, whereas only parabasal cells are observed in the absence of recent estrogen exposure. Increased growth rate and weight gain may also be early signs of sex hormone exposure.

• Skin: Perform a thorough examination of the skin looking for the presence of large irregular café-au-lait pigmentation or multiple smaller café-au-lait spots. Large café-au-lait spots with irregular borders may be a marker of McCune-Albright syndrome (MAS). Multiple café-au-lait spots with smooth borders are characteristic of neurofibromatosis type 1, a syndrome in which precocious puberty is common but usually is gonadotropin-dependent.

• Abdominal: A thorough abdominal examination is critical because adrenal or ovarian tumors may be palpable.[14]  In girls, ultrasonography is a more sensitive technique for examination of the ovaries for mass lesions. Consider the use of pelvic MRI if the clinical presentation is suggestive of a functional ovarian tumor. In boys, physical examination of the testes should reveal a testicular mass, but ultrasonography may be a more sensitive technique.

In patients with MAS, long-term complications stem from the multiple endocrinopathies that these patients may develop. Patients may also develop extremely deforming and disabling polyostotic bone changes.

Testotoxicosis: Complications of testotoxicosis are related to early sexual and physical maturation. Other complications are psychological and related to the early sexual and physical maturation.

In CAH, complications from overtreatment with hydrocortisone (eg, poor growth, adrenal suppression, features of Cushing syndrome) may be observed. Undertreatment of females may result in irreversible virilization and polycystic ovarian syndrome. Young men with untreated or poorly treated classic CAH may develop testicular adrenal rests, responsive to glucocorticoid suppression. Subfertility may be associated with CAH in both men and women. Adrenal tumors are more common in patients with CAH than in the general population.

Once precocious puberty is established clinically, the next step is determining whether the process is GnRH-dependent (CPP) or GnRH-independent (PPP). The gold-standard biochemical diagnosis is based on the assessment of gonadotropins, mainly LH, after stimulation with exogenous GnRH or GnRH agonists. Biochemical diagnostic criteria for CPP include a serum LH concentration greater than 5 U/L after GnRH or leuprolide administration.[6]

The following laboratory studies may be peformed:

• Sex steroids: The common laboratory finding for all causes of precocious pseudopuberty consists of pubertal levels of sex steroids (ie, substances with either androgenic or estrogenic effects in the presence of low-basal luteinizing hormone [LH] and follicle-stimulating hormone [FSH] with the lack of a pubertal increase in LH and FSH concentrations in response to exogenous gonadotropin-releasing hormone [GnRH] stimulation).

• LH and FSH levels: LH and FSH levels are in the prepubertal range. LH and FSH levels are not increased in response to exogenous gonadotropin-releasing hormone.

• Adrenal steroid precursors: Enzyme deficiencies in the pathway for cortisol synthesis lead to elevated cortisol precursors. The exact elevated precursor depends on the enzymatic deficiency. 17α-Hydroxyprogesterone is elevated in 21-hydroxylase deficiency and also in 11β-hydroxylase deficiency (see 17-Hydroxyprogesterone, Serum and 17-Hydroxyprogesterone, Urine). 11-Deoxycortisol and deoxycorticosterone are elevated in 11β-hydroxylase deficiency but should be either low or low-normal in patients with 21-hydroxylase deficiency. Androstenedione is more stable and is not an acute phase reactant. Therefore, androstenedione may provide a more reliable marker of 21-hydroxylase deficiency than does the 17α-hydroxyprogesterone. An elevated androstenedione is not a specific cause of precocious puberty because androstenedione may be elevated in individuals with tumors and CAH.

• Human chorionic gonadotropin (HCG): This is elevated in patients with HCG-secreting tumors.

• Urinary 17-ketosteroids: The level of 17-ketosteroids in a 24-hour urine collection provides a means of quantifying the amount of adrenal androgens being produced. 17-Ketosteroids tend to be markedly elevated in patients with tumors of the adrenal glands. Dehydroepiandrosterone (DHEA) and DHEA-sulfate and metabolites (eg, androstenedione) are the major constituents of this assay. Testosterone and dihydrotestosterone contribute less than 1% of total urinary 17-ketosteroids.

• Estradiol: A random measurement of estradiol may not be elevated because secretion may be cyclic in individuals with McCune-Albright syndrome (MAS).

• Testosterone: In FMPP, the levels of testosterone are pubertal with low-basal LH and FSH.

• Thyroid function test: Serum thyroid-stimulating hormone (TSH) should be elevated markedly, and the serum free thyroxine (T4) should be markedly decreased if the patient's sexual precocity is secondary to severe primary hypothyroidism.

The number of imaging studies that a clinician should obtain depends on the suspected diagnosis.

Ultrasonography is a sensitive test that aids in the evaluation of the ovaries, testes, and adrenal glands.

• Ultrasonography of the ovaries and uterus can aid in determining the etiology of PPP. The uterus is sensitive to estrogen and is a good bioassay to determine the length of time and magnitude of estrogen exposure. In girls with MAS, the ovaries are frequently asymmetric secondary to the presence of large unilateral cysts. Ovarian tumors are also visible using ovarian ultrasonography.  

• Testicular ultrasonography may detect Leydig cell tumors that are not palpable on testicular examination.

• Ultrasonography of the adrenal glands may help establish the diagnosis of an adrenal tumor; however, abdominal CT scanning and MRI are more sensitive techniques for imaging the adrenal gland.

Many clinicians perform bone scanning in young girls suspected of having MAS. Areas of fibrous dysplasia are positive on bone scan. A skeletal survey may identify the presence of polyostotic fibrous dysplasia, which is observed in patients with MAS.

Brain MRI to detect small lesions in the pineal or hypothalamic-optic regionis is indicated in children younger than 6 years with sexual precocity or in any child with neurologic signs or symptoms.[3] Routine screening of girls with precocious puberty older than 6 years is controversial and may not be necessary.[15]

Pelvic MRI can be useful in the diagnosis and evaluation of females with precocious puberty. Uterine volume and evaluation of the different uterine layers can be well visualized on MRI. In premenarchal girls, the uterine corpus is small, and the cervical length is greater than that of the uterine body until about 13 years of age. The ovarian tumors have characteristic MRI findings and may assist in the diagnosis of ovarian neoplasms.

 Other tests that may be useful in the assessment of PPP include the following:

• Bone age: Perform a bone age assessment for any patient who presents with clinical signs of early puberty. Bone age is advanced (>2 standard deviations above the mean for age) in children who have had significant sex steroid exposure over an extended time, regardless of etiology. However, the absence of advanced bone age is not a reason to discontinue follow-up assessment when increased growth velocity and other clinical symptoms of progressive puberty are present.[11]

• Genetic testing: Genetic testing can be used to confirm the diagnosis and provide genetic counseling for different types of CAH (including the most common form, 21-hydroxylase deficiency), gain-of-function mutations in the GNAS gene for MAS, and gain-of-function mutations of the LHCGR gene encoding the luteinizing hormone/choriogonadotropin receptor (LH/CGR) for FMPP.

Medical and surgical therapies are directed at treatment of the underlying cause of precocious puberty. The therapies are designed to minimize both the short-term and the long-term morbidity and mortality of precocious puberty. The initial evaluation can usually be performed on an outpatient basis. However, inpatient studies and surgical treatment may be required. 

Therapy is primarily carried out by a pediatric endocrinologist. Treatment options based on etiology include: the following:

• MAS may be mild and slowly progressive; thus, no outpatient medical management is required. If the puberty is rapidly progressive or adult height is severely compromised, treatment may be indicated. Drugs used to treat PPP have included cyproterone acetate (CPA) and medroxyprogesterone acetate (MPA), which, despite  short-term reports of efficacy in controlling breast development and vaginal bleeding, do not appear to influence growth rate or final adult height. ^[16]  Letrozole was effective in a small cohort of 9 girls. Growth rate and vaginal bleeding decreases were reported, but long-term safety and efficacy have not been established. ^[16]  A gonadotropin agonist may have an additional benefit but only if the bone age is so advanced that central precocious puberty has begun.

• The management of testotoxicosis is difficult and controversial. Treatment options include CPA, MPA, ketoconazole, spironolactone, testolactone, anastrozole, letrozole, and bicalutamide.[16] Ketoconazole is associated with decreased glucocorticoid production and hepatotoxicity. An alternative regimen of spironolactone and testolactone has been shown to be an effective treatment, although both drugs require multiple daily dosing. Bicalutamide along with anastrozole have been effective in slowing growth velocity and bone age advancement with once-daily dosing. Progression to CPP is common, and the addition of GnRHa is often required.[6]  

• Treatment of CAH with near-physiologic replacement doses of hydrocortisone is used to suppress adrenal androgen production.

If the patient has a tumor that is causing the precocious puberty, surgical consultation is indicated.

In girls with MAS, surgical options such as cystectomy or oophorectomy are considered suboptimal, as there is a high likelihood of cyst recurrence. These surgeries may also impact fertility in girls with the potential for otherwise normal reproductive function and thus are not recommended.[16]

The following specialists may be consulted in the diagnosis and treatment of PPP:

• Pediatric endocrinologist: Pediatric endocrinologists may be invaluable in the diagnosis of precocious puberty, as well as in the treatment and follow-up care for the patient.

• Pediatric hematologist and oncologist (if supported by the diagnosis): In the case of malignancy leading to the sexual precocity, the oncologist needs to be involved for possible chemotherapy.

• Surgeon: In the case of malignancy, surgical subspecialists need to be consulted. Recommendation for clitoral reduction in virilized females is controversial.

• Pediatric urologist: A urologist may be needed for patients with testicular tumors.

After the initial diagnosis of peripheral precocious puberty and the determination of its etiology, most patients require continued monitoring.

• McCune-Albright syndrome (MAS): Closely follow the cases of patients with MAS for the occurrence of other endocrinopathies or associated pathology.

• Testotoxicosis: Treatment decisions of these patients are complex. The most extensive report followed 10 boys during 6 years of treatment, but none had reached final height.[17]  Thus, no firm recommendations for one particular form of therapy are currently available. Offer genetic counseling for families affected with this condition.

• Congenital adrenal hyperplasia (CAH): Classic simple virilizing CAH requires lifelong therapy with glucocorticoids in both males and females. Most males with late-onset nonclassic CAH do not require glucocorticoid treatment. Treat symptomatic girls with nonclassic CAH with low-dose glucocorticoids throughout their reproductive years.

• Testicular, ovarian, and adrenal tumors: These tumors are typically unilateral and should be surgically removed. Once removed, the remaining contralateral testis, ovary, or adrenal gland should recover from suppression and be adequate for normal function.

The underlying pathophysiology of gonadotropin-independent precocious puberty is autonomous function of the gonadal axis; thus, the use of gonadotropin-releasing hormone (GnRH) analogs does not appear to be effective in the management of these disorders. No medications are routinely used in young children with an FDA-approved indication for the treatment of gonadotropin-independent precocious puberty. Therefore, a physician with expertise in the area should closely monitor the use of medications.

Class Summary

Ketoconazole blocks enzymes in the steroid biosynthetic pathway. It primarily inhibits C-17,29-desmolase, the enzyme responsible for androstenedione biosynthesis.

Ketoconazole (Nizoral)

More commonly used in treating fungal infections, but may be used in treating precocious pseudopuberty. It inhibits steroid synthesis at the level of 17 α -hydroxylase/17,20-lyase, a key enzyme in sex steroid production. It also inhibits testosterone binding to its binding globulin. In some cases, especially in those children with markedly advanced bone age, a rapid decrease in sex hormone levels may trigger true central puberty. In this event, add GnRH analogs to the treatment regimen.

Class Summary

These drugs block the effect of testosterone and dihydrotestosterone at the androgen receptor.

Spironolactone (Aldactone)

Mainly used as an antimineralocorticoid diuretic. It is also a weak competitive androgen antagonist. Other properties include inhibition of 17 α -hydroyxlase/17,20-lyase and interference with testosterone binding to sex hormone binding globulin. It is typically used to treat precocious pseudopuberty in conjunction with another drug (eg, an aromatase inhibitor). Specific nonsteroidal androgen antagonists (eg, flutamide) are more effective; however, they also carry greater toxicity. Therefore, the latter class of drug is used only in children in the context of clinical trials in the United States. As noted above, adjunctive use of GnRH analogs may be required if true central puberty occurs as a complication of treatment.

Class Summary

This category of drugs is usually used in conjunction with an antiandrogen. Aromatase inhibitors prevent the conversion of androstenedione to estrone and testosterone to estrogen. Because estrogens play a major role in epiphyseal maturation (besides their obvious role in generating female secondary sexual effects), inhibiting estrogen production has salutary effects on slowing the progress of precocious pseudopuberty.

Testolactone (Teslac)

First-generation aromatase inhibitor used to prevent conversion of androstenedione to estrone and testosterone to estrogen in children. Newer preparations are now available, but no new agents have had published clinical trials. As noted above, adjunctive use of GnRH analogs may be required if true central puberty occurs as a complication of treatment.

Class Summary

Estrogen receptor blockade (eg, with tamoxifen) may be an alternative to aromatase inhibitors and progestins in the treatment of MAS in girls. The predominant problem in childhood is precocious pseudopuberty associated with excess estrogen secretion from ovarian cysts.

Tamoxifen (Nolvadex)

Competitively binds to estrogen receptor, producing a nuclear complex that decreases DNA synthesis and inhibits estrogen effects. This drug is currently being tested in clinical trials. A single case report suggested a dose of 10-30 mg PO daily is effective in controlling estrogenic affects in MAS.