Precocious puberty

In medicine, precocious puberty is puberty occurring at an unusually early age. In most of these children, the process is normal in every respect except the unusually early age, and simply represents a variation of normal development. In a minority of children, the early development is triggered by a disease such as a tumor or injury of the brain. Even in instances where 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 term is used with several slightly different meanings that are usually apparent from the context. In its broadest sense, and often simplified as early puberty, "precocious puberty" sometimes refers to any physical sex hormone effect, due to any cause, occurring earlier than the usual age, especially when it is being considered as a medical problem. Stricter definitions of "precocity" may refer only to central puberty starting before a statistically specified age based on percentile in the population (e.g., 2.5 standard deviations below the population mean), on expert recommendations of ages at which there is more than a negligible chance of discovering an abnormal cause, or based on opinion as to the age at which early puberty may have adverse effects. A common definition for medical purposes is onset before 8 years in girls or 9 years in boys.

Types and causes
Pubertas praecox is the Latin term used by physicians in the 19th century. Early pubic hair, breast, or genital development may result from natural early maturation or from several other conditions.

Central
If the cause can be traced to the hypothalamus or pituitary, the cause is considered central.

Causes can include:
 * damage to the inhibitory system of the brain (due to infection, trauma, or irradiation)
 * hypothalamic hamartoma produces pulsatile gonadotropin-releasing hormone (GnRH)
 * Langerhans cell histiocytosis
 * McCune-Albright syndrome

Central precocious puberty can be caused by intracranial neoplasm, infection, trauma, hydrocephalus, and Angelman syndrome. Bones can be considered older in individuals with early puberty. Early puberty is marked by growth hormone problems resulting from various brain disorders. Precocious puberty can make a child able to conceive when very young; the youngest mother on record is Lina Medina, who gave birth at the age of 5 years, 7 months and 21 days.

"Central precocious puberty (CPP) was reported in some patients with suprasellar arachnoid cysts (SAC), and SCFE (slipped capital femoral epiphysis) occurs in patients with CPP because of rapid growth and changes of growth hormone secretion."

If no cause can be identified, it is considered idiopathic or constitutional.

Peripheral
Secondary sexual development induced by sex steroids from other abnormal sources is referred to as peripheral precocious puberty or precocious pseudopuberty. It typically presents as a severe form of disease with children. Symptoms are usually as a sequelae from adrenal insufficiency (because of 21-hydroxylase deficiency or 17 hydroxylase deficiency, the former being more common), which includes but is not limited to: hypertension, hypotension, electrolyte abnormalities, ambiguous genitalia in females, signs of virilization in females. Blood tests will typically reveal high level of androgens with low levels of cortisol.

Causes can include:
 * Endogenous sources
 * gonadal tumors (such as arrhenoblastoma)
 * adrenal tumors
 * germ cell tumor
 * congenital adrenal hyperplasia
 * McCune–Albright syndrome
 * Exogenous hormones
 * Environmental exogenous hormones
 * As treatment for another condition

Isosexual and heterosexual
Generally, patients with precocious puberty develop phenotypically appropriate secondary sexual characteristics. This is called isosexual precocity.

Sometimes a patient may develop in the opposite direction. For example, a male may develop breasts and other feminine characteristics, while a female may develop a deepened voice and facial hair. This is called heterosexual precocity. It is very rare in comparison to isosexual precocity and is usually the result of only unusual circumstances. As an example, children with a very rare genetic condition called familial hyperestrogenism in which exceptionally high circulating levels of estrogen are present usually develop precocious puberty. Males and females are hyperfeminized by the syndrome and, hence, the precocity is classified as heterosexual in the case of males.

Research
Many causes of early puberty are somewhat unclear, though girls who have a high-fat diet and are not physically active or are obese are more likely to physically mature earlier. "Obese girls, defined as at least 10 kilograms (22 pounds) overweight, had an 80% chance of developing breasts before their ninth birthday and starting menstruation before age 12 – the western average for menstruation is about 12.7 years." Exposure to chemicals that mimic estrogen (known as xenoestrogens) is a possible cause of early puberty in girls. Bisphenol A, a xenoestrogen found in hard plastics, has been shown to affect sexual development. "Factors other than obesity, however, perhaps genetic and/or environmental ones, are needed to explain the higher prevalence of early puberty in black versus white girls." While more girls are increasingly entering puberty at younger ages, new research indicates that some boys are actually starting later (delayed puberty). "Increasing rates of obese and overweight children in the United States may be contributing to a later onset of puberty in boys, say researchers at the University of Michigan Health System."

High levels of beta-hCG in serum and cerebrospinal fluid observed in a 9-year-old boy suggest a pineal gland tumor. The tumor is called a chorionic gonadotropin secreting pineal tumor. Radiotherapy and chemotherapy reduced tumor and beta-hCG levels normalized.

In a study using neonatal melatonin on rats, results suggest that elevated melatonin could be responsible for some cases of early puberty.

Familial cases of idiopathic central precocious puberty (ICPP) have been reported, leading researchers to believe there are specific genetic modulators of ICPP. Mutations in genes such as LIN28, and LEP and LEPR, which encode leptin and the leptin receptor, have been associated with precocious puberty. The association between LIN28 and puberty timing was validated experimentally in vivo, when it was found that mice with ectopic overexpression of LIN28 show an extended period of pre-pubertal growth and a significant delay in puberty onset.

Mutations in the kisspeptin (KISS1) and its receptor, KISS1R (also known as GPR54), involved in GnRH secretion and puberty onset, are also thought to be the cause for ICPP However, this is still a controversial area of research, and some investigators found no association of mutations in the LIN28 and KISS1/KISS1R genes to be the common cause underlying ICPP.

Clinical and social significance
Medical evaluation is sometimes necessary to recognize the few children with serious conditions from the majority who have entered puberty early but are still medically normal. Early sexual development warrants evaluation because it may:
 * 1) induce early bone maturation and reduce eventual adult height;
 * 2) indicate the presence of a tumor or other serious problem;
 * 3) cause the child, particularly a girl, to become an object of adult sexual interest.

Early puberty is believed to put girls at higher risk of sexual abuse, unrelated to pedophilia because the child has developed secondary sex characteristics. Early puberty also puts girls at a higher risk for teasing or bullying, mental health disorders and short stature as adults. Helping children control their weight is suggested to help delay puberty. Early puberty additionally puts girls at a "far greater" risk for breast cancer later in life. Girls as young as 8 are increasingly starting to menstruate, develop breasts and grow pubic and underarm hair; these "biological milestones" typically occurred only at 13 or older in decades past. Females of African ancestry are especially prone to early puberty. There are theories debating the trend of early puberty, but the exact causes are not known.

Though boys face fewer problems upon early puberty than girls, early puberty is not always positive for boys; early sexual maturation in boys can be accompanied by increased aggressiveness due to the surge of hormones that affect them. Because they appear older than their peers, pubescent boys may face increased social pressure to conform to adult norms; society may view them as more emotionally advanced, despite the fact that their cognitive and social development may lag behind their appearance. Studies have shown that early maturing boys are more likely to be sexually active and are more likely to participate in risky behaviors.

Diagnostic criteria
Studies indicate that breast development in girls and the appearance of pubic hair in girls and boys are starting earlier than in previous generations. As a result, "early puberty" in children, particularly girls, as young as 9 and 10 is no longer considered abnormal, although it may be upsetting to parents and can be harmful to children who mature physically at a time when they are immature mentally.

No age reliably separates normal from abnormal processes in children, but the following age thresholds for evaluation are thought to minimize the risk of missing a significant medical problem:
 * Breast development in boys before appearance of pubic hair or testicular enlargement.;
 * Pubic hair or genital enlargement (gonadarche) in boys with onset before 9.5 years;
 * Pubic hair (pubarche) before 8 or breast development (thelarche) in girls with onset before 7 years;
 * Menstruation (menarche) in girls before 10 years.

Treatment
One possible treatment is with anastrozole. Histrelin acetate (Supprelin LA), triptorelin or leuprolide, any GnRH agonists, may be used. Non-continuous usage of GnRH agonists stimulates the pituitary gland to release follicle stimulating hormone (FSH) and luteinizing hormone (LH). However, when used regularly, GnRH agonists cause a decreased release of FSH and LH. Prolonged use has a risk of causing osteoporosis. After stopping GnRH agonists, pubertal changes resume within 3 to 12 months.