Peripheral Precocious Puberty

Etiology

Girls

Ovarian cysts

Functioning follicular cysts are the most common cause of peripheral precocious puberty in girls. Functional follicular cysts secrete estrogen and can present as premature breast development. Vaginal bleeding may also occur after cysts degenerate.[2]

Ovarian tumors

Ovarian tumors such as granulosa cell tumors, Sertoli/Leydig cell tumors, Leydig cell tumors, and gonadoblastoma can all result in precocious puberty. Granulosa cell tumor is the most common sex cord tumor in girls and is associated with excess estrogen production, which can lead to isosexual precocious puberty. On the other hand, gonadoblastoma, Leydig cell tumors, and Sertoli/Leydig tumors lead to excess androgen production and can present with contrasexual precocious puberty.[3][2]

Boys

Leydig cell tumors

Leydig cell tumor is the most common testicular sex cord-stromal tumor and is associated with excess testosterone production. This condition commonly presents with asymmetric testicular enlargement and precocious puberty between the ages of 6 and 10 years in boys.[4]

Human chorionic gonadotropin-secreting tumors

Excess human chorionic gonadotropin-secreting tumors (hCG) production from testicular tumors (embryonal cell carcinoma, choriocarcinoma) and ectopic sites (pineal gland, mediastinum, liver, retroperitoneum) can lead to isosexual precocious puberty in boys.[5]

Familial male-limited precocious puberty

Familial male-limited precocious puberty is a rare condition that can cause isosexual peripheral precocious puberty in boys. It presents in boys as young as 2 years with precocious puberty, symmetric testicular enlargement, and a positive family history of precocious puberty in male relatives.

Boys and Girls

Primary hypothyroidism

Long-standing untreated primary hypothyroidism can present as precocious puberty in boys and girls. Girls affected by this condition present with early breast development and galactorrhea, followed by vaginal bleeding. Van Wyk and Grumbach syndrome refers to the combination of primary hypothyroidism, precocious puberty, delayed bone age, and ovarian cysts in girls. In boys, primary hypothyroidism may cause premature testicular enlargement.[6][7]

McCune-Albright syndrome

McCune Albright Syndrome is a rare condition that can present with irregular café au lait spots, polyostotic fibrous dysplasia, and peripheral precocious puberty in girls. Estrogen overproduction in this condition leads to early breast development, vaginal bleeding, recurrent follicular cysts, and accelerated bone growth. At times, vaginal bleeding may precede the onset of breast development. McCune-Albright syndrome can also present with endocrinopathies such as thyrotoxicosis, Cushing syndrome, gigantism, or acromegaly.[8]

Adrenal pathology

Excess adrenal production of androgens can occur secondary to congenital adrenal hyperplasia or adrenal tumors and present with isosexual precocious puberty in males and contrasexual precocious puberty in females. Excess androgen production in congenital adrenal hyperplasia can occur due to a deficiency in either 21-hydroxylase or 11-beta-hydroxylase deficiency. At times, adrenal tumors may secrete estrogen only or both estrogen and androgens.[8]

Exogenous sex steroids/endocrine-disrupting chemicals

Inadvertent exposure to androgen, estrogen, or endocrine-disrupting chemicals from exogenous sources can lead to precocious puberty in both genders and gynecomastia in males.[9] Accidental exposure to estrogens may occur in the form of creams, ointments, or oral contraceptive pills prescribed for adults. Estrogen is also present in food sources such as soy products and some folk remedies. Exposure to androgen-containing topical creams can lead to virilization and precocious puberty in girls.[10] Endocrine-disrupting chemicals that interfere with the natural synthesis and function of hormones are found in pesticides, plasticizers, lavender, fennel, and tea tree oils and can lead to precocious puberty.[11]

Epidemiology

The incidence of precocious puberty is estimated to be between 1:5000 to 1:10,000.[12] Peripheral precocious puberty is less common than central precocious puberty. An Iranian case series estimated that 23.3% of cases of precocious puberty are due to peripheral causes.[13] The prevalence of peripheral precocious puberty varies depending on the underlying cause. For example, non-classic congenital adrenal hyperplasia affects 0.1% of the worldwide population and is more common in Hispanics, Mediterranean, Eastern European Jews, and Yugoslavs.[14] McCune Albright syndrome is a rare condition with a prevalence of 1/100,000 to 1/1,000,000 and is more common in females.[15] Familial male precocious puberty is also rare, with a prevalence of <1/1,000,000.[16]

Overall, precocious puberty is 10 times more common in females than in males.[17] Specific causes of peripheral precocious puberty may show a sex preference. For example, McCune Albright syndrome is more common in females, while familial male precocious puberty only affects males.

Although the traditional age cut-off for precocious puberty is 8 years for girls and 9 years for boys, data from European studies indicate an overall decline in the age of onset of puberty in the past few decades.[18] A trend towards an earlier onset of puberty has been attributed to genetic factors, obesity, and exposure to endocrine-disrupting chemicals. For example, menarche has been observed to occur earlier in girls with high body mass index, low birth weight, and whose mothers had early menarche. A significant racial variation in the age of onset of pubertal changes has also been observed in multiple studies. For example, cross-sectional studies conducted in the US indicate that African American girls tend to experience puberty earliest, followed by Hispanic and then Caucasian girls.

A multicenter study involving subjects in San Fransisco, New York, and Cincinnati also confirmed this finding. They also found that breast development is present in 23% of African Americans, 15% of Hispanics, and 10% of White girls between the ages of 7 to 8 years.[19] Similarly, testicular enlargement occurs approximately one year earlier in African American boys (mean age 9.14 years) compared to White race (10.14 years) and Hispanic (10.04) boys.[1] Due to observed racial differences in the mean age of puberty, the Lawson Wilkins Pediatric Endocrine Society (LWEPS) recommends evaluation if breast development or pubic hair appears before the age of 7 in Caucasian girls and 6 years in African American girls.

Pathophysiology

Normal Puberty

Puberty is the transition of a child to sexual maturity and is marked by activation of the hypothalamic-pituitary-gonadal axis. A surge in the secretion of gonadotropin-releasing hormone (GnRH) from the hypothalamus stimulates the pituitary to increase its secretion of follicular stimulating hormone (FSH) and luteinizing hormone (LH). An increase in the basal levels of FSH and LH leads to activation of gonads, and an event referred to as "gonadarche," which is the main event in puberty. Activation of the gonads leads to an increase in the secretion of sex hormones, estrogen in girls, and testosterone in boys. In girls, an increase in estradiol leads to breast development (thelarche), an increase in bone mineral density, linear skeletal growth (growth spurt), and eventually epiphyseal fusion, which leads to the cessation of linear growth. The peripubertal rise of FSH also causes an increase in uterine volume and growth of ovarian follicles, which leads to cyclical ovulation and menstruation (menarche). "Adrenarche" occurs due to a pubertal increase in the secretion of adrenal androgens-dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS). Adrenarche manifests as an increase in pubic and axillary hair growth ("pubarche"), acne, and adult-type body odor. Other pubertal changes include an increase in the secretion of growth hormone and weight and body composition changes.[20]

In girls, breast budding (Thelarche) is the first detectable secondary sexual characteristic. However, pubarche is the initial manifestation in 15% of girls.[21] On average, menarche occurs 2 years after thelarche.[22] A peak in height velocity leads to a growth spurt, which occurs before menarche at approximately 12 years of age in girls. In boys, the first detectable sign of puberty is testicular enlargement, defined as a testicular diameter greater than 2.5 cm or testicular volume greater than 4 mL. Penile growth and pubarche occur approximately 6 months after testicular enlargement. Growth spurt in boys occurs later compared to girls at an average age of 14 years.

Peripheral Precocious Puberty

In peripheral precocious puberty, the excess secretion of sex hormones occurs from the gonads, adrenal glands, or ectopic or exogenous sources. This process does not depend on the activation of the hypothalamic-pituitary-gonadal axis and is associated with suppressed levels of GnRH, FSH, and LH. The exact pathophysiology varies depending on the underlying disorders:

• HCG-producing tumors: excess testosterone production occurs due to stimulation of the LH receptors on the Leydig cells, which leads to testicular enlargement and isosexual precocious puberty in boys.
• Congenital adrenal hyperplasia: excess androgen production occurs most commonly due to 21 hydroxylase deficiency or less commonly due to 11β-hydroxylase deficiency. Both these disorders lead to a decrease in cortisol production, which stimulates adrenocorticotropic hormone (ACTH) secretion and accumulation of cortisol precursors. The cortisol precursors are then redirected to the androgen pathway leading to excess androgen production. This manifests as virilization in girls (hirsutism, clitoromegaly), isosexual precocious puberty in boys, and signs of adrenarche (axillary, pubic hair, body odor, and acne) in both sexes.[23]
• Primary hypothyroidism: peripheral precocious puberty occurs due to stimulation of the FSH receptors as thyroid-stimulating hormone (TSH) and follicular stimulating hormone (FSH) are structurally similar. Stimulation of the ovaries causes estrogen production, which leads to premature breast development and galactorrhea, followed by vaginal bleeding. It also leads to the development of ovarian cysts. "Van Wyk and Grumbach syndrome" refers to the combination of primary hypothyroidism, precocious puberty, delayed bone age, and ovarian cysts in girls. In boys, this condition presents with premature testicular enlargement.
• McCune Albright syndrome: This condition occurs due to a post-zygotic activating mutation of the GNAS gene coding for the alpha subunit of the Gs protein, which leads to overactivity of the cyclic adenosine monophosphate (cAMP) pathway. Stimulation of the cAMP pathway leads to the formation of functional follicular ovarian cysts, which lead to signs of estrogen excess and precocious puberty in girls.[8]
• Familial male-limited precocious puberty: FMPP is an autosomal dominant condition caused by an activating mutation of the luteinizing hormone (LH) receptor. This causes premature stimulation of the Leydig cells in the absence of Luteinizing hormone-releasing hormone (LHRH) and increased testosterone production in boys.[24]

Histopathology

The histopathology differs depending on the underlying cause:

• Ovarian cysts: Follicular cysts appear histologically as thin-walled cysts containing follicular fluid and are lined by granulosa and theca interna cells.[25]
• Ovarian tumors:  the appearance of granulosa cell tumors varies depending on the type of cells (adult vs juvenile). Adult-type granulosa cells appear as elongated pale cells with scant cytoplasm and grooved nuclei. These cells often appear as rosettes around collections of eosinophilic fluid referred to as "Call-Exner bodies" and resemble primordial follicles. Juvenile-type granulosa cells appear as immature cells with frequent mitotic activity.[26]
• Leydig cell tumors: Leydig cell tumors histologically appear as groups of large cells with regular round nuclei and eosinophilic cytoplasm. Eosinophilic cytoplasmic inclusions referred to as Reinke crystals, characteristic of Leydig cell tumors, may also be seen.
• Congenital adrenal hyperplasia: histological features include diffuse cortical hyperplasia.

History and Physical

History

The first step of approaching precocious puberty is to elicit a detailed history and conduct a comprehensive physical exam. History taking should begin by inquiring about the age of onset of signs of sexual development. Generally, the threshold for evaluating pubertal signs is 8 years in girls and 9 years in boys.

• Patients should be asked explicitly about the type of pubertal changes and progression rate as it can help guide evaluation. Signs of androgen excess such as pubic and axillary hair growth, acne, adult-type body odor,  and hirsutism indicate adrenal pathology. On the other hand, breast development and menstrual bleeding indicate estrogen excess.
• Rapid progression of pubertal signs may indicate an underlying testicular, ovarian, or adrenal tumor. Establishing the sequence of pubertal changes is essential as peripheral precocious puberty often presents with an abnormal sequence. For example, in McCune-Albright syndrome, menstrual bleeding may precede the onset of breast development.[27]
• Patients should also be inquired about a recent increase in height.  Usually, patients with peripheral precocious puberty have a rapid increase in height velocity, causing them to move up to higher centiles on the growth chart, at least initially.
• A history of neurological symptoms (headache, visual changes, seizures) should be elicited to exclude a central cause for precocious puberty. A history of chronic disease and insults to the central nervous system (head trauma, perinatal asphyxia, neoplasms, radiation) should also be noted.
• Patients should be inquired about the ingestion of sex hormones or exposure to topical agents with estrogenic/androgenic/endocrine-disrupting activity.
• Family history should focus on the timing of pubertal onset in parents, history of ambiguous genitalia in siblings (possible congenital adrenal hyperplasia), and history of precocity in male relatives (familial male limited precocious puberty).

Physical Exam

• The initial step in the physical exam is to record the vital signs. The presence of hypertension may indicate congenital adrenal hyperplasia due to 11 beta-hydroxylase deficiency and bradycardia may indicate hypothyroidism.
• Growth parameters, including height, weight, and head circumference, should be plotted to determine the growth velocity.
• The general exam should focus on looking for signs of specific conditions such as thyroid enlargement and café au lait spots. In McCune Albright syndrome, the café-au-lait spots have a "Coast of Maine" appearance and are described as large, hyperpigmented spots with irregular borders and a segmental distribution. These should be differentiated from the café au lait spots of neurofibromatosis, which tend to have regular borders. Other findings seen in McCune Albright syndrome include polyostotic fibrous dysplasia, which presents as bony deformities, pathological fractures, gait abnormalities, and bone pain.
• Neurological exam and visual field testing should be done to detect neurological deficits secondary to a possible intracranial mass. An abdominal exam should be done to identify any palpable masses that could arise due to adrenal or ovarian tumors.
• The most important part of the exam is to grade sexual maturity using the Tanner staging. Sexual maturity rating (SMR) is determined for pubic hair, breast and genitalia development, and graded on a scale of 1 to 5, with 1 representing prepuberty and 5 representing adult development. While assessing breast development in girls, care should be taken to distinguish between irregular ductal breast tissue the subcutaneous tissue, which is smooth and soft. Similarly, palpation of the testes, measurement of stretched penile length, and testicular volume with an orchidometer should be done accurately. Penile dimensions disproportionately greater than testicular dimensions indicate peripheral precocious puberty due to adrenal pathology. Moderate symmetric enlargement of testes may indicate familial male limited precocious puberty or an HCG-secreting tumor. On the other hand, asymmetric testicular enlargement and a palpable testicular mass may indicate a Leydig cell tumor.

Evaluation

Lab Investigations

Sex hormones

Baseline measurement of testosterone in boys and estradiol in girls should be obtained. The elevation of baseline sex hormones with suppressed gonadotropins indicates peripheral precocious puberty. A significantly elevated testosterone level indicates testicular neoplasm in boys or an adrenal source in both boys and girls. In girls, estradiol levels are interpreted with reference to the tanner stage of breast development. Estradiol levels of greater than 20 pg/mL indicate puberty. Significantly elevated serum estradiol levels (>100 pg/mL) in a girl indicate either an estrogen-secreting ovarian cyst or ovarian tumor. On the other hand, a low baseline estradiol level of less than 10 pg/mL indicates central precocious puberty.

Luteinizing hormone, follicular stimulating hormone, and human chorionic gonadotropin levels

In peripheral precocious puberty, the baseline luteinizing hormone (LH) and follicular stimulating hormone (FSH) levels are in the prepubertal range. Basal LH levels should be measured early in the morning. Basal LH levels less than 0.2 mIU/mL indicate peripheral precocious puberty or benign pubertal variants. Random measurements of FSH are not very useful in diagnosis. Elevated HCG levels indicate the presence of HCG-secreting tumors such as embryonal cell carcinoma, choriocarcinoma, and dysgerminoma. 

Serum adrenal steroids

Measuring serum adrenal steroid levels is useful in differentiating premature adrenarche from peripheral precocious puberty. In patients with premature adrenarche, levels of dehydroepiandrosterone sulfate (40-135 mcg/dL), testosterone (1.1-3.7 micromol/L), and 17 hydroxyprogesterone (115-200 ng/dL) are only mildly elevated. Elevation of DHEAS and testosterone above these ranges indicates adrenal tumors or congenital adrenal hyperplasia. An elevated early morning 17 hydroxyprogesterone (>200 ng/dL) indicates non-classical congenital hyperplasia due to 21 hydroxylase deficiency. Elevated 11 deoxy cortisol and deoxy cortisone indicate 11 B hydroxylase deficiency.[28][29][30]

Thyroid function test

Serum thyroid-stimulating hormone (TSH) concentration and free T4 levels should be checked in patients with signs and symptoms of primary hypothyroidism.

Radiology

Bone age assessment

Radiographs of the hand and wrist should be performed in cases of suspected precocious puberty to assess epiphyseal maturation. An average or slightly delayed bone age  (<2 years of chronological age) suggests benign variants such as premature thelarche or premature adrenarche. On the other hand, significantly advanced bone age (>2 standard deviations above the mean for age) indicates accelerated linear growth and precocious puberty. Rapidly progressive bone age should raise concern for congenital adrenal hyperplasia or tumors originating from the ovaries, adrenal glands, or germ cells.[31]

Ultrasound/computer tomography

In girls with suspected peripheral precocious puberty, a pelvic ultrasound is essential to determine if ovarian cysts or tumors are the underlying etiology. Pelvic ultrasound is also helpful in determining the uterine length and volume, which is a good indicator of the duration of estrogen exposure.[32][33] In boys, testicular ultrasound is helpful in identifying malignancies, such as Leydig cell tumors. In patients with clinical signs or lab evidence of excess adrenal androgens, an abdominal ultrasound or computer tomography of the abdomen is recommended.

 Other Tests

• Patients with urological symptoms or visual changes require brain magnetic resonance imaging to exclude intracranial pathology. Brain imaging is also indicated to identify HCG, producing pineal gland tumors.
• Bone scans and skeletal surveys are required in cases of suspected McCune-Albright syndrome to identify fibrous dysplasia.
• Genetic testing may be required to identify mutations and confirm the diagnosis in patients with congenital adrenal hyperplasia, familial male-limited precocious puberty, and McCune-Albright syndrome.[34]

Treatment / Management

Cases of peripheral precocious puberty should be promptly referred to an endocrinologist to prevent complications. The goals of managing peripheral precocious puberty are to treat the underlying cause and block the production or response of excess sex hormones. Specific treatments depend on the cause:

• Tumors of the ovary, testis, or adrenal glands often require surgical excision. HCG-secreting tumors may require additional treatment with chemotherapy or radiotherapy.
• Functional follicular ovarian cysts rarely require surgical intervention and may be managed conservatively as they usually regress spontaneously.[35]
• Primary hypothyroidism is treated by providing thyroxine supplementation.
• McCune-Albright syndrome: Aromatase inhibitors are the most studied medications to manage precocious puberty in McCune-Albright syndrome. Theoretically, aromatase inhibitors suppress estrogen production and help in slowing growth maturation, leading to the cessation of menses and reducing ovarian volumes. However, studies have shown mixed results. Testolactone has been shown to be temporarily effective in slowing the growth rate and advancement of menses, while fadrozole and anastrozole have not been found to be efficacious.[36][37] On the other hand, letrozole, a 3rd generation aromatase inhibitor, was found to decrease growth rate and advancement in bone age significantly.  Long term safety of letrozole is yet to be established.[38] Tamoxifen, a selective estrogen receptor modulator, is effective in halting pubertal progression but is associated with long-term safety concerns due to endometrial stimulation.[39] Many patients with McCune Albright syndrome with advanced bone age develop central precocious puberty. In such patients, treatment with gonadotropin agonists may be helpful.
• Familial male-limited precocious puberty: This disorder is treated with an androgen receptor antagonist and aromatase inhibitor to delay epiphyseal maturation. A GnRH analog is added in cases where central precocious puberty occurs.  A case series of 25 subjects with familial male-limited precocious puberty showed that spironolactone with testolactone or anastrozole and a GnRH agonist was effective in increasing adult height.[40] Other drugs used to manage this condition include ketoconazole, which is a steroid synthesis inhibitor, and bicalutamide, which is an anti-androgen and letrozole.
(A1)

Differential Diagnosis

Benign or Non-Progressive Pubertal Variants

Benign pubertal variants represent cases of early secondary sexual development that are not progressive, have normal height velocity, and are not associated with an underlying pathological process. Most of these variants require no treatment apart from reassurance and close monitoring for signs of pubertal progression, bone age, and acceleration in height velocity.

Variants under this category include:

• Premature thelarche is isolated breast development in young girls without the development of other secondary sexual characteristics. This condition is usually seen in girls younger than 6 to 8 years. Breast development in premature thelarche often does not progress beyond tanner stage 3. The presence of normal height velocity, normal bone age, and absence of other secondary sexual characteristics differentiate this condition from peripheral precocious puberty.
• Premature pubarche is the isolated development of pubic and axillary hair before the age of 8 years in girls and 9 years in boys. This condition may be associated with a mild elevation in dehydroepiandrosterone sulfate and mild advancement in bone age. Patients with premature pubarche require close monitoring as it may be the initial sign of peripheral precocious puberty. Signs of virilization, growth acceleration, and significant advancement in bone age in these patients should prompt a workup for congenital adrenal hyperplasia or virilizing adrenal tumors.
• Benign prepubertal vaginal bleeding is the presence of isolated prepubertal vaginal bleeding that resolves spontaneously. The diagnosis of this condition requires the exclusion of other causes of vaginal bleeding, such as sexual abuse, foreign body, or local trauma. The absence of other secondary sexual characteristics, a normal pelvic ultrasound, and prepubertal gonadotropin levels differentiate this condition from precocious puberty.

Central Precocious Puberty

Central precocious puberty occurs due to premature activation of the hypothalamic-pituitary-gonadal axis and can be idiopathic, genetic, or due to central nervous system lesions. Unlike peripheral precocious puberty, patients with central precocious puberty tend to follow the normal sequence of secondary sexual development. They may also have neurological signs or visual changes. Central precocious puberty is gonadotropin-independent and is associated with elevated levels of the follicular stimulating hormone (FSH) and luteinizing hormone (LH). Central precocious puberty can be confirmed by a basal LH concentration of greater than 0.3 IU/L or an elevation of LH in response to GnRH stimulation test.[41][42]

Prognosis

Prognosis of McCune Albright syndrome varies depending on the severity of bone disease and the number of endocrinopathies. The outcome of non-classical congenital adrenal hyperplasia is generally favorable if glucocorticoids are administered early. However, despite treatment, many patients go on to develop short stature in adulthood. The prognosis of ovarian granulosa cell tumors depends on the stage of the disease and the presence of residual disease.[43] Similarly, Leydig tumors have an excellent prognosis and high disease-free survival rates if the condition is localized. However, metastatic disease is associated with poor outcome.[44] Cases of peripheral precocious puberty caused by exogenous hormones or endocrine-disrupting chemicals resolve spontaneously upon discontinuing exposure.

Complications

Patients with precocious puberty may encounter different complications, depending on the primary diagnosis:

• Short stature patients with precocious puberty initially have a growth spurt in adolescence due to rapid linear growth. However, if left untreated, this is followed by premature fusion of the epiphyseal plates, which leads to short stature in adulthood.
• Early development of breasts in girls and increased libido in boys can cause significant emotional distress.
• The changes associated with puberty may lead to long term psychosocial stress, behavioral issues, and psychiatric problems such as depression.
• Contrasexual precocious puberty in girls caused by excess androgens can lead to virilization in the form of clitoromegaly, which may require genital reconstructive surgery.
• Patients with McCune Albright syndrome can develop musculoskeletal complications (bone pain, deformities, pathological fractures, gait abnormalities) and endocrinopathies (acromegaly, hyperthyroidism, Cushing syndrome). They are also at risk of developing arrhythmias, intestinal polyps, and malignancies.
• Patients with congenital adrenal hyperplasia may suffer from suboptimal fertility. They can also develop complications due to chronic glucocorticoid therapy, e.g., cushingoid features, poor growth, osteoporosis, secondary diabetes, and adrenal suppression. Women with congenital adrenal hyperplasia have a higher risk of requiring cesarian delivery due to underlying cephalopelvic disproportion.