Precocious puberty is defined as the appearance of secondary sexual characteristics before the age of eight years in girls and nine years in boys. Precocious puberty is classified as either central or peripheral precocious puberty. Central precocious puberty is gonadotropin-dependent and occurs due to early activation of the hypothalamic pituitary gonadal axis. Peripheral precocious puberty, also known as precocious pseudo puberty, is gonadotropin-independent and occurs due to excess production of sex hormones either from the gonads, the adrenal glands, ectopic or exogenous sources.
Precocious puberty is isosexual if the signs of sexual development are consistent with the phenotypic gender of the child before the earliest accepted age of sexual maturation. If the signs of sexual development are inappropriate for the patient’s gender, then it is considered contrasexual. If left untreated, precocious pseudopuberty can lead to short stature in adulthood and have psychological consequences on the individual. Therefore, early recognition and treatment of this condition are essential to reduce morbidity.
Functioning follicular cysts are the most common cause of precocious pseudo puberty in girls. Functional follicular cysts secrete estrogen and can present as premature breast development. Vaginal bleeding may also occur after cysts degenerate.
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.
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 six and ten years in boys.
Excess 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.
Familial male-limited precocious puberty is a rare condition that can cause isosexual precocious pseudopuberty in boys. It presents in boys as young as two years of age with precocious puberty, symmetric testicular enlargement, and positive family history of precocious puberty in male relatives.
III. Boys & Girls:
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.
McCune Albright Syndrome is a rare condition that can present with irregular café au lait spots, polyostotic fibrous dysplasia, and precocious pseudopuberty 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's syndrome, gigantism, or acromegaly.
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.
Inadvertent exposure to androgen, estrogen, or endocrine-disrupting chemicals from exogenous sources can lead to precocious puberty in both genders and gynecomastia in males. Accidental exposure to estrogens may occur in the form of creams, ointment, 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. Endocrine-disrupting chemicals that interfere with the natural synthesis and function or hormones are found in pesticides, plasticizers, lavender, fennel, and tea tree oils and can also lead to precocious puberty.
The incidence of precocious puberty is estimated to be between 1:5000 to 1:10,000. Precocious pseudopuberty 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. The prevalence of precocious pseudopuberty 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. 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. Familial male precocious puberty is also rare, with a prevalence of <1/1,000,000.
Overall, precocious puberty is ten times more common in females than in males. Specific causes of precocious pseudopuberty may show a sex preference. For example, McCune Albright syndrome is more common in females, while familial male precocious puberty (FMPP) only affects males.
Although the traditional age cut off for precocious puberty is eight years for girls and nine years for boys, data from European studies indicate an overall decline in the age of onset of puberty in the past few decades. 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 than 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 % in African Americans, 15% in Hispanics, and 10% of White race girls between the ages of 7 to 8 years. 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. 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 ages of seven in Caucasian girls and six years in African American girls.
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.
In girls, breast budding (Thelarche) is the first detectable secondary sexual characteristic. However, pubarche is the initial manifestation in 15% of girls. On average, menarche occurs two years after thelarche. 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 of >2.5 cm or testicular volume of >4 mL. Penile growth and pubarche occur approximately six months after testicular enlargement. Growth spurt in boys occurs later compared to girls at an average age of 14 years.
In precocious pseudopuberty, the excess secretion of sex hormones occurs from the gonads, adrenal glands, 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:
The histopathology differs depending on the underlying cause:
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 eight years in girls and nine years in boys.
I. Lab Investigations
Baseline measurement of testosterone in boys and estradiol in girls should be obtained. The elevation of baseline sex hormones with suppressed gonadotropins indicates precocious pseudopuberty. 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 >20 pg/mL indicate puberty. Significantly elevated serum estradiol levels (>100 pg/mL) in a girl indicates either an estrogen secreting ovarian cyst or ovarian tumor. On the other hand, low baseline estradiol level <10 pg/ml indicates central precocious puberty.
In precocious pseudopuberty, the baseline LH and FSH levels are in the prepubertal range. Basal LH levels should be measured early in the morning. Basal LH levels < 0.2 mIU/mL indicate either precocious pseudopuberty 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.
Measurement of serum adrenal steroid levels is useful in differentiating premature adrenarche from precocious pseudopuberty. 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 indicate 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.
Serum thyroid-stimulating hormone (TSH) concentration and free T4 levels should be checked in patients with signs and symptoms of primary hypothyroidism.
Radiographs of hand and wrist should be done in cases of suspected precocious puberty to assess epiphyseal maturation. A normal or slightly delayed bone age (< 2y over 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.
In girls with suspected precocious pseudopuberty, 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. In boys, testicular ultrasound is helpful in identifying malignancies, such as Leydig cell tumor. In patients with clinical signs or lab evidence of excess adrenal androgens, an abdominal ultrasound or computer tomography of the abdomen is recommended.
III. Other Tests
Cases of precocious pseudopuberty should be promptly referred to an endocrinologist to prevent complications. The goals of managing precocious pseudopuberty are to treat the underlying cause and block the production or response of excess sex hormones. Specific treatments depend on the cause:
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:
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 > 0.3 IU/L or an elevation of LH in response to GnRH stimulation test.
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. 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. Cases of precocious pseudopuberty caused by exogenous hormones or endocrine-disrupting chemicals resolve spontaneously upon discontinuing exposure.
Patients with precocious puberty may encounter different complications, depending on the primary diagnosis:
Patients with precocious pseudopuberty should be offered psychological and emotional support as the physical changes of puberty may lead to emotional distress. Affected patients are often subjected to higher societal expectations based on their physical maturity rather than their age. Parents and teachers, therefore, need to be counseled and reminded to maintain age-appropriate expectations. Patients who experience early puberty may start engaging in risk-taking behavior (drugs, alcohol use, ad sexual activity) at an earlier age and require age-appropriate sex education.
Patients with precocious pseudopuberty are usually seen initially by a primary care physician or pediatrician. All physicians should be aware of the physiological pubertal changes, their normal sequence, and the age cutoff for considering pubertal changes as precocious. The onset of puberty before the age of six years in African American girls, seven years in caucasian girls, and nine years in boys should be evaluated thoroughly for precocious puberty. [Level 5] Cases of precocious pseudopuberty should be promptly identified and referred to a pediatric endocrinologist for further management to prevent the development of short stature in adulthood.
Although primarily managed by an endocrinologist, patients often require interprofessional care. Consultations with oncology are required in cases of precocious puberty due to malignancy. Referral to surgery may be required for surgical excision of an underlying adrenal, ovarian, or testicular tumor. A referral to urology may be required due to the proximity of the gonads to the genitourinary system. Patients with McCune Albright syndrome may require referral to orthopedics to correct bone deformities due to fibrous dysplasia. Patients with precocious pseudopuberty can develop depression or behavioral disorders, which may require consultation with a psychiatrist and a child psychologist. Interdisciplinary collaboration is important for optimal patient outcomes in precocious pseudopuberty.
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