Precocious Puberty

Introduction

Precocious puberty refers to the appearance of physical and hormonal signs of pubertal development at an earlier age than is considered normal. For many years, puberty was considered precocious in girls younger than 8 years; however, recent studies indicate that signs of early puberty (breasts and pubic hair) are often present in girls (particularly black girls) aged 6-8 years. For boys, onset of puberty before age 9 years is considered precocious.

In most cases, the process is normal in every aspect except the unusually early age and simply represents a variation of normal development. In a minority of children with precocious puberty, the early development is triggered by a disease such as a tumor or injury of the brain. Even when there is no disease, unusually early puberty can have adverse effects on social behavior and psychological development, can reduce adult height potential, and may shift some lifelong health risks. Central precocious puberty can be treated by suppressing the pituitary hormones that induce sex steroid production. The opposite condition is delayed puberty.

 

Associated Anatomy

Puberty results from the activation and maturation of the hypothalamic-pituitary-gonadal (HPG) axis. At birth, there is a brief activation of the HPG axis that results in the increased production of steroidal hormones. This activation may result in breast development in females and pubic hair in males. This phenomenon is known as the “mini-puberty of the infancy” usually regresses over the first two years of life. Although it is considered to be benign, there is very little information on its etiology as well as clinical significance.

The HPG axis then becomes dormant until its subsequent activation in adolescence. The pulsatile release of gonadotropin-releasing hormone (GnRH) from the hypothalamus stimulates the secretion of follicle stimulating hormone (FSH) and luteinizing hormone (LH) from the anterior pituitary gland. FSH and LH initiate spermatogenesis and the release of testosterone in males, and oogenesis and the release of estradiol in the females, respectively. Activation of the gonads is known as gonadarche.

It is important for a clinician to be familiar with the terminology of pubertal progression. Thelarche is the development of breasts, which is a response to estrogen. Pubarche is the development of pubic hair, which is a response to androgens. Adrenarche is the onset of adrenal androgen production, which contributes to pubarche.

 

Causes

To understand what causes precocious puberty in some children, it’s helpful to know what causes puberty to begin. The brain starts the process with the production of a hormone called gonadotropin-releasing hormone (GnRH).

When this hormone reaches the pituitary gland — a small bean-shaped gland at the base of your brain — it leads to the production of more hormones in the ovaries for females (estrogen) and the testicles for males (testosterone).

Estrogen is involved in the growth and development of female sexual characteristics. Testosterone is responsible for the growth and development of male sexual characteristics.

Why this process begins early in some children depends on whether they have central precocious puberty or peripheral precocious puberty.

Central precocious puberty

The cause for this type of precocious puberty often can’t be identified.

In central precocious puberty, the puberty process starts too soon. The pattern and timing of the steps in the process are otherwise normal. For the majority of children with this condition, there’s no underlying medical problem and no identifiable reason for the early puberty.

In rare cases, central precocious puberty may be caused by:

• A tumor in the brain or spinal cord (central nervous system)
• A defect in the brain present at birth, such as excess fluid buildup (hydrocephalus) or a noncancerous tumor (hamartoma)
• Radiation to the brain or spinal cord
• Injury to the brain or spinal cord
• McCune-Albright syndrome — a rare genetic disease that affects bones and skin color and causes hormonal problems
• Congenital adrenal hyperplasia — a group of genetic disorders involving abnormal hormone production by the adrenal glands
• Hypothyroidism — a condition in which the thyroid gland doesn’t produce enough hormones

Peripheral precocious puberty

Estrogen or testosterone in your child’s body causes this type of precocious puberty.

The less common peripheral precocious puberty occurs without the involvement of the hormone in your brain (GnRH) that normally triggers the start of puberty. Instead, the cause is release of estrogen or testosterone into the body because of problems with the ovaries, testicles, adrenal glands or pituitary gland.

In both girls and boys, the following may lead to peripheral precocious puberty:

• A tumor in the adrenal glands or in the pituitary gland that releases estrogen or testosterone
• McCune-Albright syndrome, a rare genetic disorder that affects the skin color and bones and causes hormonal problems
• Exposure to external sources of estrogen or testosterone, such as creams or ointments

In girls, peripheral precocious puberty may also be associated with:

• Ovarian cysts
• Ovarian tumors

In boys, peripheral precocious puberty may also be caused by:

• A tumor in the cells that make sperm (germ cells) or in the cells that make testosterone (Leydig cells).
• A rare disorder called gonadotropin-independent familial sexual precocity, which is caused by a defect in a gene, can result in the early production of testosterone in boys, usually between ages 1 and 4.

Differential Diagnosis

Precocious puberty requires differentiation from the benign forms of puberty. These include:

• Premature Thelarche: It is the premature unilateral or bilateral development of the breast tissue in girls between the age of 12 to 24 months. There are no other associated pubertal changes. Bone age, growth velocity, and biochemical testing are normal. It is usually a diagnosis of exclusion. Frequent clinical follow up to monitor growth, and pubertal progression is required.

• Premature Adrenarche: The early production of adrenal androgens characterizes this benign condition. It presents with pubic or axillary hair, body odor, or acne before the age of 8 years.  There is no breast development in females and no testicular enlargement in males. Bone age is usually not advanced. It is essential to rule out exposure to androgen sources such as creams or gels, adrenal tumors, and late-onset CAH.

• Premature Menarche: Isolated premature menarche is the onset of vaginal bleeding in girls less than 7 years of age. They may present with either a single episode or few cycles (less than 3) of bleeding and have normal progression to puberty. Recent studies have suggested no effect on adult height. Sexual abuse, vaginal foreign body, and infections of the vulva and vagina need to be ruled out.

 

Drugs

Gonadotropin-Releasing Hormone Agonists:

Continuous administration of LHRH and GnRH agonists provides negative feedback and results in decreased levels of LH and FSH 2-4 weeks after initiating treatment.

Potent, long-acting synthetic derivatives of native GnRH, such as natrelin, suppress pituitary production of gonadotropins because they provide constant stimulus, whereas the pituitary responds only to pulsatile GnRH stimulation. In use since the late 1970s, GnRH agonists are safe and effective.

Follwing medications from this group are approved for use:

Leuprolide acetate (Lupron, Lupron Depot-Ped, Lupron Depot 3 month)

Suppresses ovarian and testicular steroidogenesis by decreasing LH and FSH levels. Available in a monthly depot formulation in 7.5-, 11.25-, and 15-mg dose. Annual cost is approximately $10,000-20,000. Individualize duration of therapy according to age and maturity of child and predicted adult height; in most cases, continuing treatment after age 10-11 y is unnecessary.

Triptorelin (Triptodur, Trelstar, Trelstar Depot)

Indicated for central precocious puberty in pediatric patients aged 2 years or older. Triptorelin suppresses gonadotropin secretion via GnRH receptor desensitization and down-regulation. This reduces gonadal steroids to prepubertal levels.

Nafarelin (Synarel)

Analogue of GnRH that is approximately 200 times more potent than natural endogenous GnRH. Upon long-term administration, suppresses gonadotrope responsiveness to endogenous GnRH, thereby reducing secretion of LH and FSH, which in turn reduces ovarian and testicular steroid production. Administered intranasally to induce gonadotropin suppression. Consider as second-line agent if leuprolide proves difficult to administer. Adherence to a bid intranasal drug regimen may be difficult to achieve. Available as nasal spray; 200 mcg/spray. One 10 mL bottle contains 7-day supply for daily dose of 1600 mcg.

Histrelin (Supprelin LA)

LHRH agonist that is a potent inhibitor of gonadotropin secretion when administered long term. Desensitizes responsiveness of pituitary gonadotropin. Circulating LH and FSH levels initially increase following administration, leading to transient increase in concentration of gonadal steroids (testosterone and dihydrotestosterone in males and estrone and estradiol in premenopausal females). However, long-term administration decreases LH and FSH levels. Implant can provide continuous SC release of histrelin at nominal rate of 50-65 mcg/d over 12 mo. Indicated for CPP (neurogenic or idiopathic).

Progestin:

Before availability of GnRH agonists, these agents were the mainstay of therapy. Progestins work by providing feedback suppression of pituitary gonadotropin secretion. They lack significant androgenic or estrogenic activity.

Medroxyprogesterone (Depo-Provera)

Inhibits secretion of pituitary gonadotropin. Inhibits effect of LH. Effective at slowing breast growth and preventing or stopping menses when administered q3mo, although breakthrough bleeding may occur. Less used now due to relative ineffectiveness in reversing rapid advancement of skeletal maturation seen in CPP. Relatively inexpensive; consider when leuprolide cost is a factor and when adult height prediction is close to reference range or is not a major concern.

 

Epidemiology

There are very limited studies describing the trends and prevalence of precocious puberty. The first epidemiologic study from a Danish national registry estimated that 0.2 % of females had some form of precocious puberty (CPP, PPP or benign variants) while it was less than 0.05% in males. There was female predominance about 20 to 23 per 10000 girls compared to boys, which were less than 5 per 10000 boys. Another observational study in Spain estimated the annual incidence of central precocious puberty to be between 0.02 and 1.07 cases per 100000 persons. A study looking into the Korean population estimated the prevalence of CPP to be 55.9 per 100000 girls and 1.7 per 100000 boys. The reported overall incidence of CPP in Koreans was 15.3 per 100000 girls, and 0.6 per 100000 boys. The prevalence and incidence vary significantly among different populations making it difficult to estimate definitive numbers.

 

Natural Progression

The presentation is usually consistent with premature development of pubertal signs. The initial clinical signs are breast development in females and increased testicular volume (greater than 4 ml) in males. The other signs and symptoms include increased linear growth, acne, muscular changes, body odor, and pubic and axillary hair development.

The initial step is to verify whether pubertal development is occurring before the normal age of onset or not. Rapid progression of puberty, although started at a normal age, is also considered abnormal. The clinician should inquire about neurological symptoms such as headache, increased head circumference, seizures, visual and cognitive changes along with symptoms of anterior and posterior pituitary deficiency (polyuria, polydipsia, and decreased growth velocity). Ovarian pathology might present with abdominal pain. Any relevant history of head trauma, brain infections, or use of unusual creams, pills, or diet that might expose them to estrogen or testosterone should be explored.   It is also essential to take a complete family history about the onset of puberty in parents and siblings, which may point to the possibility of a familial condition.

Linear growth acceleration is one of the important features of early puberty. So the exact height, weight, growth velocity (cm/year) and BMI should be documented.  In females, accurate Tanner staging of the breast should take place, which is particularly challenging in obese or overweight girls to differentiate between adipose tissue and the glandular breast tissue. In males, an orchidometer should be used to determine the testicular volume. Volumes of more than 4 ml confirm pubertal development.  In males and females with pubic hair and body odor, the absence of increased testicular volume and breast development should prompt investigation of peripheral causes. Unilateral testicular enlargement is likely due to testicular tumors.

A thorough examination should be done to look for acanthosis nigricans, café au lait macules, neurofibromas which might indicate specific causes such as neurofibromatosis type 1 and McCune-Albright syndrome.

 

Pathophysiology

Most patients, particularly girls suspected of having central precocious puberty, are otherwise healthy children whose pubertal maturation begins at the early end of the normal distribution curve. CNS imaging studies of these otherwise healthy 6-year-old to 8-year-old girls usually reveal no structural abnormalities. A study of 200 girls in France identified abnormal brain imaging findings in 2% of girls whose onset of puberty was between age 6-8 years and in 20% of girls whose onset of puberty was before age 6 years. A smaller study from the United Kingdom reported abnormal findings in 15% of 67 girls. Abnormal CT scan or MRI findings are more frequent among boys with central precocious puberty than among girls with central precocious puberty.

The onset of puberty is caused by the secretion of high-amplitude pulses of gonadotropin-releasing hormone (GnRH) by the hypothalamus. The hypothesized mechanisms that suppress onset of puberty include (1) the HPG axis, which is highly sensitive to feedback inhibition by small amounts of sex steroids, and (2) central neural pathways that suppress the release of GnRH pulses.

CNS abnormalities associated with precocious puberty include the following:

• Tumors (eg, astrocytomas, gliomas, germ cell tumors secreting human chorionic gonadotropin [HCG])
• Hypothalamic hamartomas
• Acquired CNS injury caused by inflammation, surgery, trauma, radiation therapy, or abscess
• Congenital anomalies (eg, hydrocephalus, arachnoid cysts, suprasellar cysts)

High-amplitude pulses of GnRH cause pulsatile increases in the pituitary gonadotropin-luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Increased LH levels stimulate production of sex steroids by testicular Leydig cells or ovarian granulosa cells. Pubertal levels of androgens or estrogens cause the physical changes of puberty, including penile enlargement and sexual hair in boys and breast development in girls. These levels also mediate the pubertal growth spurt. Increased FSH levels cause enlargement of the gonads in both sexes and eventually promote follicular maturation in girls and spermatogenesis in boys.

 

Possible Complications

Possible complications of precocious puberty include:

• Short height. Children with precocious puberty may grow quickly at first and be tall, compared with their peers. But, because their bones mature more quickly than normal, they often stop growing earlier than usual. This can cause them to be shorter than average as adults. Early treatment of precocious puberty, especially when it occurs in very young children, can help them grow taller than they would without treatment.
• Social and emotional problems. Girls and boys who begin puberty long before their peers may be extremely self-conscious about the changes occurring in their bodies. This may affect self-esteem and increase the risk of depression or substance abuse.

 

Possible Treatment

Central precocious puberty

The decision to treat depends on the age of the child and the progression of puberty. If the child has rapidly progressing symptoms or if bone age is significantly advanced, consider treatment. The main goals of treatment are to preserve the adult height and to alleviate the associated psychosocial stress. GnRH agonists are the standard of care. Many different formulations (intranasal, intramuscular and subcutaneous) of long and short-acting GnRH agonists exist. The choice of the formulation depends on the patient and clinician preference.  In the United States, leuprolide acetate is the most common. It is a depot injection administered every 3 months.

GnRH agonist therapy is generally considered safe, with no reported significant adverse events. The most common adverse events include local skin reactions (intramuscular pain, sterile abscesses) and post-menopausal symptoms (hot flushes).

While on treatment, periodic monitoring of pubertal progression, growth velocity, and skeletal maturation are necessary.

Peripheral Precocious puberty

Treatment is directed towards eliminating the source of sex steroids. Surgery is indicated in gonadal and adrenal tumors.  If exogenous sources of sex steroids are identified, they should be eliminated. Classic congenital CAH is treated with glucocorticoids. In McCune-Albright syndrome, some benefit occurs with blocking the estrogen synthesis using aromatase inhibitors (anastrozole, letrozole) and selective estrogen selective receptor modulator (tamoxifen).  The optimal treatment for familial male-limited precocious puberty is not well established, but the preferred treatment is a combination of an androgen antagonist (spironolactone) and an aromatase inhibitor (anastrozole, testolactone).

 

Primary Prevention

Some of the risk factors for precocious puberty, such as sex and race, can’t be avoided. But, there are things that can be done in order to reduce a child’s chances of developing precocious puberty, including:

• Keeping a child away from external sources of estrogen and testosterone — such as prescription medications for adults in the house or dietary supplements containing estrogen or testosterone
• Encouraging a child to maintain a healthy weight.

 

Prognosis

Early onset of treatment is usually associated with greater success in preserving final adult height.  The outcomes depend on factors; such as advancement of bone change, age at which precocious puberty initiated, the timing of initiation, and duration of treatment. The HPG axis returns to normal after the cessation of the therapy, and these children usually have a normal progression of puberty after stopping treatment. There is very little information on the long term endocrine, metabolic, reproductive, and psychological consequences. The prognosis of peripheral precocious puberty varies depending on the cause.

 

Risk factors

Factors that increase a child’s risk of precocious puberty include:

• Being a girl. Girls are much more likely to develop precocious puberty.
• Being African-American. Precocious puberty appears to affect African-Americans more often than children of other races.
• Being obese. Children who are significantly overweight have a higher risk of developing precocious puberty.
• Being exposed to sex hormones. Coming in contact with an estrogen or testosterone cream or ointment, or other substances that contain these hormones (such as an adult’s medication or dietary supplements), can increase your child’s risk of developing precocious puberty.
• Having other medical conditions. Precocious puberty may be a complication of McCune-Albright syndrome or congenital adrenal hyperplasia — conditions that involve abnormal production of the male hormones (androgens). In rare cases, precocious puberty may also be associated with hypothyroidism.
• Having received radiation therapy of the central nervous system. Radiation treatment for tumors, leukemia or other conditions can increase the risk of precocious puberty.

 

Signs or Symptoms

Precocious puberty signs and symptoms include development of the following before age 8 in girls and before age 9 in boys.

• Breast growth and first period in girls
• Enlarged testicles and penis, facial hair and deepening voice in boys
• Pubic or underarm hair
• Rapid growth
• Acne
• Adult body odor

 

Studies

Active Not Recruiting

Number of studies: 1

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Completed

Number of studies: 25

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Enrolling by Invitation

Number of studies: 1

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Not Yet Recruiting

Number of studies: 2

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Recruiting

Number of studies: 4

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Results Available

Number of studies: 9

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Results Not available

Number of studies: 34

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Suspended

Number of studies: 0

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Terminated

Number of studies: 1

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Withdrawn

Number of studies: 0

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Types

Precocious puberty classifies into two major categories based on the etiology

• Central precocious puberty (GnRH dependent)
• Peripheral precocious puberty (GnRH independent)

Central Precocious puberty (CPP)

This type of precocious puberty represents true pubertal development due to the earlier maturation and activation of the HPG axis. Most of the time, the common cause in females is idiopathic, and in males, there is usually an underlying pathology. It is attributable to a multitude of conditions.

The most relevant categories include

• CNS tumors – Hypothalamic hamartoma, optic glioma, arachnoid cysts, astrocytoma, ependymoma, hydrocephalus, septo optic dysplasia, pineal tumors
• CNS injury- head trauma,  cranial irradiation, cerebral palsy, infections( Tuberculous meningitis)
• Genetics – Loss of function mutation encoding the MRF3 (Makorin ring finger 3) gene, a gain of function mutation encoding the kisspeptin (KISS1) and its receptor (KISSR) genes
• Syndromes – Neurofibromatosis type 1, Sturge Weber syndrome, Tuberous sclerosis
• Environmental – internationally adopted children, withdrawal from sex steroid therapy.
• Familial precocious puberty

The most common brain lesion causing CPP is hypothalamic hamartoma. The ectopic neural cells in the lesion serve as an accessory GnRH pulse generator.  It presents with precocious puberty in infancy as early as 12 months of age. The most characteristic association is gelastic seizures, which are usually refractory to medications. The other associated features include cognitive, behavioral, and psychiatric symptoms. Increased prevalence is a noted feature in internationally adopted children. The exact mechanism is not known, but suggestions are that better nutrition and exposure to endocrine disrupting chemicals can play a role. There have been some reports of familial forms, but the genetic basis is not well understood. Recent years have seen some interesting associations with mutations of kisspeptin (KISS1) and makorin ring finger (MRF3) genes and their receptors. These genes are responsible for the stimulatory and inhibitory signals to the GnRH release. Loss or gain of function mutations in these genes results in CPP.

Peripheral Precocious Puberty (PPP)

Precocious development of secondary sexual characteristics independent of the GnRH pulsatile secretion constitutes PPP; this is due to the production of sex steroids from endogenous or exogenous sources. It is less frequent compared to the CPP. Some important causes include

• Congenital adrenal hyperplasia
• McCune-Albright syndrome (CAH)
• Gonadal tumors – Sex cord-stromal tumors such as Leydig cell tumors and Sertoli cell tumors, Germ cell tumors such as dysgerminoma, teratoma, and embryonal tumors.
• Adrenal tumors
• Familial male-limited precocious puberty (testitoxicosis)
• Exogenous exposure to sex steroids
• Van Wyk and Grumbach syndrome

Tumors are rare causes of PPP. There is an increased androgen production in CAH, adrenal tumors, and Leydig cell tumors. There is an increased production of human chorionic gonadotropin (hCG) with germ cell tumors, hepatoblastoma, pineal, and mediastinal tumors.

Testitoxicosis is a rare autosomal dominant disorder with the clinical phenotype limited to males. It is caused by a germline activating mutation of the LH receptor gene, resulting in the activation of the Leydig cells and high testosterone levels. Van Wyk and Grumbach syndrome are characterized by primary hypothyroidism, ovarian cysts, and precocious puberty. Researchers speculate that untreated primary hypothyroidism results in pituitary hyperstimulation and the production of multiple pituitary hormones resulting in precocious puberty. McCune-Albright syndrome is a sporadic condition caused by activating mutation of the GNAS 1 gene, which encodes the alpha subunit of the G protein. This gene activation increases the cAMP formation, and all its dependent receptors become hyper-functional.  It usually presents as a triad of precocious puberty, fibrous dysplasia of the skeletal system and café au lait pigmentation.  The other likely endocrine manifestations are hyperthyroidism, Cushing syndrome, and growth hormone excess.

 

Typical Test

Physical examination

Precocious puberty in girls:

• The most reliable sign of increased estrogen production is breast enlargement. Initially, breast budding may be unilateral or asymmetric. Gradually, the breast diameter increases, the areola darkens and thickens, and the nipple becomes more prominent. Distinguishing glandular breast tissue from fat, which can mimic true breast tissue, is essential. Examining the patient while she is in the supine position usually minimizes the chance of misinterpreting fat as true breast enlargement.
• Genital examination may or may not reveal pubic hair, but enlargement of the clitoris indicates significant androgen excess that must be promptly evaluated. The vaginal mucosa, which is a deep-red color in prepubertal girls, takes on a moist pastel-pink appearance as estrogen exposure increases.
• Mild acne may be normal in early puberty, but rapid onset of severe acne, like clitoral enlargement, should increase suspicion of an androgen-excess disorder.

Precocious puberty in boys:

• The earliest sign of central precocious puberty (CPP) is enlargement of the testes, which depends on increased production of follicle-stimulating hormone (FSH); testicular length is more than 2.5 cm or testicular volume (with Prader orchidometer beads) is 4 mL or more. If progressive signs of androgen excess occur in a boy without increased testicular size, consider possible causes of precocious pseudopuberty, including congenital adrenal hyperplasia, familial male precocious puberty, and Leydig-cell tumors (a testicular nodule is usually palpable). Human chorionic gonadotropin (HCG)-secreting tumors somewhat increase testicular size by stimulating testicular Leydig-cell LH receptors.
• Other signs of puberty (eg, penis growth, reddening and thinning of the scrotum, increased pubic hair) are a consequence of increased testosterone production and occur within 1-2 years after testicular enlargement.
• Pubic hair growth that occurs without penis and testicular enlargement and other signs of increased androgen production (eg, premature adrenarche or a mild, nonclassic form of congenital adrenal hyperplasia) rather than true puberty.
• Later signs of puberty include the pubertal growth spurt, acne, voice change, and facial hair.

Laboratory workup

Initial screening tests usually include bone age, measurement of LH, FSH Testosterone, Dehydroepiandrosterone sulfate (DHEA-S), 17 OH progesterone levels, and thyroid function tests.

Bone age is an initial screening test. If the bone age is advanced (greater than two standard deviations) than the chronologic age, further testing should follow.  Hormonal testing differentiates peripheral and central causes.  A baseline prepubertal LH level of greater than 0.3 IU/L is suggestive of CPP.  Levels under 0.3 are indicative of peripheral causes or benign variants. If there is a high suspicion for central causes, a GnRH stimulation test, which is considered to be the gold standard, should be done. This test is not available in the United States so that the GnRH agonist is an alternative.  FSH levels are of limited utility.  Very high levels of estradiol in females or testosterone in males associated with suppressed LH and FSH are indicative of peripheral precocity. Measurement of adrenal androgens such as dehydroepiandrosterone sulfate (DHEA S) differentiates between testicular and adrenal sources of androgens.

Human chorionic gonadotropin (hCG) levels should be a consideration in boys. Some germ cell tumors secrete hCG, which activates the LH receptors and increases testosterone production.

In cases of PPP, pelvic ultrasonography detects ovarian tumors or cysts in females while testicular ultrasonography in males reveals nonpalpable Leydig cell tumors.

Magnetic resonance imaging is to be performed in all cases of CPP, especially in males, to rule out a hypothalamic lesion. It is also to be considered in females who present with early pubertal changes (less than 6 years of age).

References:

https://emedicine.medscape.com/article/924002-overview#a5
https://www.mayoclinic.org/diseases-conditions/precocious-puberty/diagnosis-treatment/drc-20351817
https://www.ncbi.nlm.nih.gov/books/NBK544313/
https://www.msdmanuals.com/en-sg/professional/pediatrics/endocrine-disorders-in-children/precocious-puberty