Precocious Puberty
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medicine Medicine is the science and Praxis (process), practice of caring for patients, managing the Medical diagnosis, diagnosis, prognosis, Preventive medicine, prevention, therapy, treatment, Palliative care, palliation of their injury or disease, ...
, precocious puberty is
puberty Puberty is the process of physical changes through which a child's body matures into an adult body capable of sexual reproduction. It is initiated by hormonal signals from the brain to the gonads: the ovaries in a female, the testicles i ...
occurring at an unusually early age. In most cases, the process is normal in every aspect except the unusually early age and simply represents a variation of normal development. There is early development of secondary sex characters and gametogenesis also starts earlier. Precocious puberty is of two types: true precocious puberty and pseudoprecocious puberty. In a minority of children with precocious puberty, the early development is triggered by a disease such as a
tumor A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...
or
injury Injury is physiological damage to the living tissue of any organism, whether in humans, in other animals, or in plants. Injuries can be caused in many ways, including mechanically with penetration by sharp objects such as teeth or with ...
of the
brain The brain is an organ (biology), organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It consists of nervous tissue and is typically located in the head (cephalization), usually near organs for ...
. Even when there is no underlying disease, unusually early puberty can have adverse effects on social behavior and
psychological development Developmental psychology is the science, scientific study of how and why humans grow, change, and adapt across the course of their lives. Originally concerned with infants and children, the field has expanded to include adolescence, adult deve ...
(having more mature knowledge than one's peers, feeling inadequate, trying to attend and establish friendships with older people, depression). Affected children also face shorter adult
height Height is measure of vertical distance, either vertical extent (how "tall" something or someone is) or vertical position (how "high" a point is). For an example of vertical extent, "This basketball player is 7 foot 1 inches in height." For an e ...
potential and possible lifelong health risks. Central precocious puberty can be treated by suppressing the pituitary
hormone A hormone (from the Ancient Greek, Greek participle , "setting in motion") is a class of cell signaling, signaling molecules in multicellular organisms that are sent to distant organs or tissues by complex biological processes to regulate physio ...
s that induce
sex steroid Sex hormones, also known as sex steroids, gonadocorticoids and gonadal steroids, are steroid hormones that interact with vertebrate steroid hormone receptors. The sex hormones include the androgens, estrogens, and progestogens. Their effects a ...
production. The opposite condition is
delayed puberty Delayed puberty is when a person lacks or has incomplete development of specific sexual characteristics past the usual age of onset of puberty. The person may have no physical or hormone, hormonal signs that puberty has begun. In the United States ...
. 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 deviation In statistics, the standard deviation is a measure of the amount of variation of the values of a variable about its Expected value, mean. A low standard Deviation (statistics), deviation indicates that the values tend to be close to the mean ( ...
s 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.


Causes

Early
pubic hair Pubic hair (or pubes , ) is terminal hair, terminal body hair that is found in the sex organ, genital area and pubic region of adolescent and adult humans. The hair is located on and around the sex organs, and sometimes at the top of the inside ...
,
breast The breasts are two prominences located on the upper ventral region of the torso among humans and other primates. Both sexes develop breasts from the same embryology, embryological tissues. The relative size and development of the breasts is ...
, or genital development may result from natural early maturation or from several other conditions.


Central

If the cause can be traced to the
hypothalamus The hypothalamus (: hypothalami; ) is a small part of the vertebrate brain that contains a number of nucleus (neuroanatomy), nuclei with a variety of functions. One of the most important functions is to link the nervous system to the endocrin ...
or pituitary, the cause is considered central. Other names for this type are ''complete'' or ''true precocious'' puberty. Causes of central precocious puberty can include: * hypothalamic hamartoma produces pulsatile
gonadotropin-releasing hormone Gonadotropin-releasing hormone (GnRH) is a releasing hormone responsible for the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the anterior pituitary. GnRH is a tropic peptide hormone synthesized and rele ...
(GnRH) * Langerhans cell histiocytosis * McCune–Albright syndrome Central precocious puberty can also be caused by
brain tumor A brain tumor (sometimes referred to as brain cancer) occurs when a group of cells within the Human brain, brain turn cancerous and grow out of control, creating a mass. There are two main types of tumors: malignant (cancerous) tumors and benign ...
s, infection (most commonly tuberculous meningitis, especially in developing countries), trauma,
hydrocephalus Hydrocephalus is a condition in which cerebrospinal fluid (CSF) builds up within the brain, which can cause pressure to increase in the skull. Symptoms may vary according to age. Headaches and double vision are common. Elderly adults with n ...
, and
Angelman syndrome Angelman syndrome (AS) is a genetic disorder that affects approximately 1 in 15,000 individuals. AS impairs the function of the nervous system, producing symptoms, such as severe intellectual disability, developmental disability, limited to no ...
. Precocious puberty is associated with advancement in bone age, which leads to early fusion of epiphyses, thus resulting in reduced final height and short stature. Adrenocortical oncocytomas are rare with mostly benign and nonfunctioning tumors. There have been only three cases of functioning adrenocortical oncocytoma that have been reported up until 2013. Children with adrenocortical oncocytomas will present with "premature pubarche, clitoromegaly, and increased serum dehydroepiandrosterone sulfate and testosterone" which are some of the presentations associated with precocious puberty. Precocious puberty in girls begins before the age of 8. The youngest mother on record is Lina Medina, who gave birth at the age of either 5 years, 7 months and 17 days or 6 years 5 months as mentioned in another report. "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 An idiopathic disease is any disease with an unknown cause or mechanism of apparent spontaneous origin. For some medical conditions, one or more causes are somewhat understood, but in a certain percentage of people with the condition, the cause ...
or constitutional.


Peripheral

Secondary sexual development induced by
sex steroid Sex hormones, also known as sex steroids, gonadocorticoids and gonadal steroids, are steroid hormones that interact with vertebrate steroid hormone receptors. The sex hormones include the androgens, estrogens, and progestogens. Their effects a ...
s 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 hyperplasia (because of 21-hydroxylase deficiency or 11-beta 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
androgen An androgen (from Greek ''andr-'', the stem of the word meaning ) is any natural or synthetic steroid hormone that regulates the development and maintenance of male characteristics in vertebrates by binding to androgen receptors. This includes ...
s with low levels of cortisol. Causes can include: * Endogenous sources **
Gonad A gonad, sex gland, or reproductive gland is a Heterocrine gland, mixed gland and sex organ that produces the gametes and sex hormones of an organism. Female reproductive cells are egg cells, and male reproductive cells are sperm. The male gon ...
al tumors (such as arrhenoblastoma) ** Adrenal tumors **
Germ cell tumor A germ cell tumor (GCT) is a neoplasm derived from primordial germ cells. Germ-cell tumors can be cancerous or benign. Germ cell tumors typically originate from the gonads (ovary and testis), but can arise in other areas of the body. Extragon ...
**
Congenital adrenal hyperplasia Congenital adrenal hyperplasia (CAH) is a group of Genetic disorder#Autosomal recessive, autosomal recessive disorders characterized by impaired cortisol synthesis. It results from the deficiency of one of the five enzymes required for the Biosy ...
** McCune–Albright syndrome ** Silver–Russell syndrome ** Familial male-limited precocious puberty (testotoxicosis) * Exogenous hormones ** Environmental exogenous hormones ** As treatment for another condition


Isosexual and heterosexual

Generally, patients with precocious puberty develop phenotypically appropriate
secondary sexual characteristic A secondary sex characteristic is a physical characteristic of an organism that is related to or derived from its sex, but not directly part of its reproductive system. In humans, these characteristics typically start to appear during puberty ...
s. This is called '' isosexual'' precocity. In some cases, a patient may develop characteristics of the opposite sex. 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'' or ''contrasexual'' precocity. It is very rare in comparison to isosexual precocity and is usually the result of unusual circumstances. As an example, children with a very rare genetic condition called aromatase excess syndrome – in which exceptionally high circulating levels of estrogen are present – usually develop precocious puberty. Males and females are hyper-feminized by the syndrome. The "opposite" case would be the hyper-masculinisation of both male and female patients with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency, in which there is an excess of androgens. Thus, in the aromatase excess syndrome the precocious puberty is isosexual in females and heterosexual in males, whilst in the CAH it is isosexual in males and heterosexual in females.


Research

Although the causes of early puberty are still somewhat unclear, girls who have a high-fat diet and are not physically active or are obese are more likely to physically mature earlier.(Tanner, 1990). "Obese girls, defined as at least 10 kilograms (22 pounds) overweight, had an 80 percent chance of developing breasts before their ninth birthday and starting menstruation before age 12 – the western average for menstruation is about 12.7 years." In addition to diet and exercise habits, exposure to chemicals that mimic
estrogen Estrogen (also spelled oestrogen in British English; see spelling differences) is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three ...
(known as xenoestrogens) is another possible cause of early puberty in girls.
Bisphenol A Bisphenol A (BPA) is a chemical compound primarily used in the manufacturing of various plastics. It is a colourless solid which is Solubility, soluble in most common organic solvents, but has very poor solubility in water. BPA is produced on a ...
, a xenoestrogen found in hard
plastic Plastics are a wide range of synthetic polymers, synthetic or Semisynthesis, semisynthetic materials composed primarily of Polymer, polymers. Their defining characteristic, Plasticity (physics), plasticity, allows them to be Injection moulding ...
s, 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 Delayed puberty is when a person lacks or has incomplete development of specific sexual characteristics past the usual age of onset of puberty. The person may have no physical or hormone, hormonal signs that puberty has begun. In the United States ...
). "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 Cerebrospinal fluid (CSF) is a clear, colorless Extracellular fluid#Transcellular fluid, transcellular body fluid found within the meninges, meningeal tissue that surrounds the vertebrate brain and spinal cord, and in the ventricular system, ven ...
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 Leptin (from Ancient Greek, Greek λεπτός ''leptos'', "thin" or "light" or "small"), also known as obese protein, is a protein hormone predominantly made by adipocytes (cells of adipose tissue). Its primary role is likely to regulate long ...
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 over-expression 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. The gene MKRN3, which is a maternally imprinted gene, was first cloned by Jong et al. in 1999. MKRN3 was originally named Zinc finger protein 127. It is located on human chromosome 15 on the long arm in the Prader-Willi syndrome critical region2, and has since been identified as a cause of premature sexual development or CPP. The identification of mutations in MKRN3 leading to sporadic cases of CPP has been a significant contribution to better understanding the mechanism of puberty. MKRN3 appears to act as a "brake" on the central hypothalamic-pituitary access. Thus, loss of function mutations of the protein allow early activation of the GnRH pathway and cause phenotypic CPP. Patients with a MKRN3 mutation all display the classic signs of CCP including early breast and testes development, increased bone aging and elevated hormone levels of GnRH and LH.


Diagnosis

Studies indicate that breast development in girls and the appearance of pubic hair in both girls and boys are starting earlier than in previous generations. As a result, "early puberty" in children as young as 8 and 9 is no longer considered abnormal, particularly with girls. Although it is not considered as abnormal, 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 Pubic hair (or pubes , ) is terminal hair, terminal body hair that is found in the sex organ, genital area and pubic region of adolescent and adult humans. The hair is located on and around the sex organs, and sometimes at the top of the inside ...
or genital enlargement ( gonadarche) in boys with onset before 9 years * Pubic hair (
pubarche Pubarche () refers to the first appearance of pubic hair at puberty. It is one of the earliest physical changes of puberty and can occur independently of complete puberty. It is usually the second sign of puberty, after thelarche in females and gon ...
) before 8 or breast development (
thelarche Thelarche, also known as breast budding, is the onset of secondary breast development, often representing the beginning of pubertal development. It is the stage at which male and female breasts differentiate due to variance in hormone levels; howe ...
) in girls with onset before 7 years *
Menstruation Menstruation (also known as a period, among other colloquial terms) is the regular discharge of blood and Mucous membrane, mucosal tissue from the endometrium, inner lining of the uterus through the vagina. The menstrual cycle is characterized ...
(
menarche Menarche ( ; ) is the first menstrual cycle, or first menstruation, menstrual bleeding, in female humans. From both social and medical perspectives, it is often considered the central event of female puberty, as it signals the possibility of fe ...
) in girls before 10 years 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: * induce early bone maturation and reduce eventual adult height * indicate the presence of a tumour or other serious problem * cause the child, particularly a girl, to become an object of adult sexual interest.(Stattin & Magnussion, 1990)


Treatment

One possible treatment is with anastrozole. GnRH agonists, including histrelin, triptorelin, or leuprorelin, are other possible treatments. Non-continuous use of GnRH agonists stimulates the pituitary gland to release follicle stimulating hormone (FSH) and
luteinizing hormone Luteinizing hormone (LH, also known as luteinising hormone, lutropin and sometimes lutrophin) is a hormone produced by gonadotropic cells in the anterior pituitary gland. The production of LH is regulated by gonadotropin-releasing hormone (G ...
(LH). Triptorelin depot is widely used to treat central precocious puberty (CPP) in children. Puberty blockers work by stabilizing puberty symptoms, decreasing growth velocity, and slowing skeletal maturation. The outcomes of treatment are assessed in terms of height, reproduction, metabolic, and psychosocial measures. The most pronounced effects on height have been seen in children experiencing the onset of puberty before 6 years of age; however there is variability in height outcomes across studies which can be attributed to varying study designs, time of symptom presentation, and time of treatment termination. A study investigating the effects of puberty blockers on reproductive health showed no significant difference in the number of irregular menstrual cycles, pregnancies, or pregnancy outcomes between women who received treatment for precocious puberty and those who opted out of treatment. Individuals with precocious puberty, early adrenarche, and early normal puberty show less stress after treatment compared to individuals without preexisting developmental conditions. Blockers are also used in the treatment of central precocious puberty resulting from conditions like hypothalamic hamartomas or congenital adrenal hyperplasia, where early onset of puberty is a symptom. Additionally, puberty blockers can be prescribed for children with severe forms of idiopathic short stature, allowing for more time for growth before the closure of growth plates. In the USA, since 1993, the US Food and Drug Administration (FDA) has supported the use of puberty blockers to treat precocious puberty. Currently under FDA regulation the use of puberty blockers is considered on-label for the treatment of central precocious puberty.] For years, the Food and Drug Administration, FDA,
Endocrine Society The Endocrine Society is a professional, international medical organization in the field of endocrinology and metabolism, founded in 1916 as The Association for the Study of Internal Secretions. The official name of the organization was changed t ...
, American Academy of Pediatrics(AAP) and many other pediatric associations have supported the use of Gonadotropin-releasing hormone analogs (GnRHas) in central precocious puberty (CPP). In 2009, the Lawson Wilkins Pediatric Endocrine Society and European Society for Pediatric Endocrinology published a consensus statement highlighting the effectiveness of Gonadotropin-releasing hormone analogs (GnRHas) in early onset central precocious puberty. They confirmed that the use of Gonadotropin-releasing hormone analogs (GnRHas) has had a positive effect on increasing adult height. However these Endocrine Societies believe additional research should be conducted before routinely suggesting GnRHAs for other conditions. There is still some uncertainty surrounding the effectiveness of GnRHas when utilized for other conditions. Overall, puberty blockers have demonstrated an excellent safety and efficacy profile in the treatment of precocious puberty.


Side effects

The most common side effects reported include nonspecific headaches, hot flashes, and implant-related skin reactions. A systematic review of studies investigating the long-term effects of treating precocious puberty with GnRH agonists found that bone mineral density decreases during treatment but normalizes afterward, with no lasting effects on peak bone mass.


Prognosis

Early puberty is posited to put girls at higher risk of sexual abuse; however, a causal relationship is, as yet, inconclusive. Early puberty also puts girls at a higher risk for teasing or bullying, mental health disorders and short stature as adults.(Caspi et al.1993: Lanza and Collins, 2002) 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 the past. African-American girls are especially prone to early puberty. Though boys face fewer problems from early puberty than girls do, early puberty is not always positive for boys. Early sexual maturation in boys can be accompanied by increased aggressiveness due to the surge of pubertal hormones.Garn, SM. Physical growth and development. In: Friedman SB, Fisher M, Schonberg SK, editors. Comprehensive Adolescent Health Care. St Louis: Quality Medical Publishing; 1992. Retrieved on 2009-02-20 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, although their
cognitive Cognition is the "mental action or process of acquiring knowledge and understanding through thought, experience, and the senses". It encompasses all aspects of intellectual functions and processes such as: perception, attention, thought, ...
and social development may lag behind their physical development. Studies have shown that early-maturing boys are more likely to be sexually active and are more likely to participate in risky behaviors.Susman, EJ; Dorn, LD; Schiefelbein, VL. Puberty, sexuality, and health. In: Lerner MA, Easterbrooks MA, Mistry J., editors. Comprehensive Handbook of Psychology. New York: Wiley; 2003. Retrieved on 2009-02-20


History

is the
Latin Latin ( or ) is a classical language belonging to the Italic languages, Italic branch of the Indo-European languages. Latin was originally spoken by the Latins (Italic tribe), Latins in Latium (now known as Lazio), the lower Tiber area aroun ...
term used by physicians from the 1790s onward. Various hypotheses and inferences on pubertal (menstrual, procreative) timing are attested since ancient times, which, well into early modernity were explained on the basis of temperamental, humoral and Jungian "complexional" causes, or general or local "plethora" (blood excess).


See also

* Acceleration (human development) * Heterochrony: Paedomorphosis * Secular trend: Biological anthropology *
Primary ovarian insufficiency Primary ovarian insufficiency (POI), also called premature ovarian insufficiency and premature ovarian failure, is the partial or total loss of reproductive and hormonal function of the ovaries before age 40 because of follicular (egg producing ...


References

{{DEFAULTSORT:Precocious Puberty Endocrine gonad disorders Gonadotropin-releasing hormone and gonadotropins Human female endocrine system Intersex variations Pediatrics Sexual health Sexuality and age Vertebrate developmental biology