Editing Precocious puberty

{{Short description|Puberty occurring at an unusually early age}}
{{Infobox medical condition (new)
| name          = Precocious puberty
| synonyms      = Early puberty
| image         = 
| caption       = Precocious development in a child two years of age
| image_size    = 200px
| field         = [[Gynecology]], [[andrology]], [[endocrinology]]
| onset         = 
| duration      = 
| types         = 
| causes        = [[Idiopathic]], [[brain tumor]]
| risks         = 
| diagnosis     = 
| differential  = 
| prevention    = 
| treatment     = 
| medication    = 
| prognosis     = 
| frequency     = 
| deaths        = 
}}

In [[medicine]], '''precocious puberty''' is [[puberty]] 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 [[human variability|variation]] of [[Human development (biology)|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]] or [[brain injury|injury]] of the [[Human brain|brain]].<ref>{{cite web|url=http://kidshealth.org/parent/medical/sexual/precocious.html#|title=Precocious Puberty|publisher=KidsHealth|access-date=2013-09-09}}</ref>

Even when there is no underlying disease, unusually early puberty can have adverse effects on social behavior and [[psychological development]] (having more mature knowledge than one's peers, feeling inadequate, trying to attend and establish friendships with older people, [[Depression in childhood and adolescence|depression]]). Affected children also face shorter adult [[human height|height]] potential and possible lifelong health risks. Central precocious puberty can be treated by suppressing the [[pituitary]] [[hormone]]s that induce [[sex steroid]] production. The opposite condition is [[delayed puberty]].<ref name="Howard_al.2018">{{cite journal |last1=Howard |first1=S. R. |last2=Dunkel |first2=L. |title=The Genetic Basis of Delayed Puberty |language=en |journal=Neuroendocrinology |volume=106 |issue=3 |pages=283–291 |date=2018 |pmid=28926843 |doi=10.1159/000481569 |s2cid=4772278|url=https://qmro.qmul.ac.uk/xmlui/bitstream/123456789/31203/3/Howard%20Genetic%20Basis%20of%20Delayed%20Puberty%202017%20Accepted.pdf }}</ref><ref name="Klein_al.2017">{{cite journal |last1=Klein |first1=D. A. |last2=Emerick |first2=J. E. |last3=Sylvester |first3=J. E. |last4=Vogt |first4=K. S. |title=Disorders of Puberty: An Approach to Diagnosis and Management |journal=American Family Physician |volume=96 |issue=9 |pages=590–599 |date=November 2017 |pmid=29094880}}</ref>

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 steroid|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]]s below the population mean),<ref name="MeshName |precocious+puberty">{{MeshName|precocious+puberty}}</ref> 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.<ref name="ReferenceA">{{Cite web|title=default - Stanford Children's Health|url=https://www.stanfordchildrens.org/en/topic/default?id=precocious-puberty-early-puberty-90-P01973|access-date=2021-02-16|website=www.stanfordchildrens.org}}</ref>

== Causes ==
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. Other names for this type are ''complete'' or ''true precocious'' puberty.<ref>David Gardner, Dolores Shoback. Basic And Clinical Endocrinology. McGraw-Hill Medical; 2011. 9th Edition. Pg. 550</ref>

Causes of central precocious puberty can include:
* [[Tuber cinereum hamartoma|hypothalamic hamartoma]] produces pulsatile [[gonadotropin-releasing hormone]] (GnRH)
* [[Langerhans cell histiocytosis]]
* [[McCune–Albright syndrome]]

Central precocious puberty can also be caused by [[brain tumor]]s, infection (most commonly [[tuberculous meningitis]], especially in developing countries), trauma, [[hydrocephalus]], and [[Angelman syndrome]].<ref>{{Cite journal | last1 = Dickerman | first1 = R. D. | last2 = Stevens | first2 = Q. E. | last3 = Steide | first3 = J. A. | last4 = Schneider | first4 = S. J. | title = Precocious puberty associated with a pineal cyst: is it disinhibition of the hypothalamic-pituitary axis? | journal = Neuro Endocrinology Letters | volume = 25 | issue = 3 | pages = 173–175 | year = 2004 | pmid = 15349080}}</ref> 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.<ref>{{cite journal|last1=Kumar|first1=Manoj|last2=Mukhopadhyay|first2=Satinath|last3=Dutta|first3=Deep|title=Challenges and controversies in diagnosis and management of gonadotropin dependent precocious puberty: An Indian perspective|journal=Indian Journal of Endocrinology and Metabolism|date=2015-01-15|volume=19|issue=2|pages=228–235|doi=10.4103/2230-8210.149316|pmid=25729684|pmc=4319262 |doi-access=free }}</ref>

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.<ref>{{Cite journal|last1=Subbiah|first1=Sridhar|last2=Nahar|first2=Uma|last3=Samujh|first3=Ram|last4=Bhansali|first4=Anil|date=May 2013|title=Heterosexual precocity: rare manifestation of virilizing adrenocortical oncocytoma|journal=Annals of Saudi Medicine|volume=33|issue=3|pages=294–297|doi=10.5144/0256-4947.2013.294|pmid=23793435|pmc=6078526|issn=0256-4947|quote = So far, in the pediatric age group, only three cases of functioning adrenocortical oncocytoma have been reported. We report a case of functioning adrenocortical oncocytoma in a 3 1/2-year-old female child who presented with premature pubarche, clitoromegaly, and increased serum dehydroepiandrosterone sulfate and testosterone. She was managed successfully with right adrenalectomy, and the tumor histology was consistent with adrenal oncocytoma.}}</ref><ref>{{Cite journal|last1=Santos-Silva|first1=Rita|last2=Bonito-Vítor|first2=Artur|last3=Campos|first3=Miguel|last4=Fontoura|first4=Manuel|s2cid=9961260|date=2014|title=Gonadotropin-Dependent Precocious Puberty in an 8-Year-Old Boy with Leydig Cell Testicular Tumor|journal=Hormone Research in Paediatrics|volume=82|issue=2|pages=133–137|doi=10.1159/000358084|pmid=24862970|issn=1663-2818}}</ref>

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<ref name="Telegraph">{{cite news|title=Six decades later, world's youngest mother awaits aid|url=http://www.telegraphindia.com/1020827/asp/foreign/story_1140311.asp|work=[[The Telegraph (Kolkata)|The Telegraph]]|date=August 27, 2002|access-date=April 13, 2016|archive-url=https://web.archive.org/web/20090722030008/http://www.telegraphindia.com/1020827/asp/foreign/story_1140311.asp|archive-date=July 22, 2009|url-status=dead}}</ref> or 6 years 5 months as mentioned in another report.<ref>{{cite magazine | url=http://www.time.com/time/magazine/article/0,9171,893791,00.html | magazine=[[Time (magazine)|Time]] | title=Little Mother | date=December 16, 1957 | access-date=January 9, 2008 | archive-url=https://web.archive.org/web/20090422210901/http://www.time.com/time/magazine/article/0,9171,893791,00.html | archive-date=April 22, 2009 | url-status=dead }}</ref>

"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."<ref>{{cite journal|last=Yamato|first=Fumiko|author2=Takaya, Junji |author3=Higashino, Hirohiko |author4=Yamanouchi, Yasuo |author5=Suehara, Hiroshi |author6= Kobayashi, Yohnosuke |s2cid=27162486|title=Slipped capital femoral epiphysis during the treatment of precocious puberty with a gonadotropin-releasing hormone-agonist: aetiological considerations|journal=European Journal of Pediatrics|date=March 2005|volume=164|issue=3|pages=173–174|doi=10.1007/s00431-004-1578-7|pmid=15592875}}</ref>

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

=== Peripheral ===
Secondary sexual development induced by [[sex steroid]]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 [[Congenital adrenal hyperplasia due to 21-hydroxylase deficiency|21-hydroxylase deficiency]] or [[Congenital adrenal hyperplasia due to 11β-hydroxylase deficiency|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]]s with low levels of cortisol.

Causes can include:
* Endogenous sources
** [[Gonad]]al tumors (such as [[arrhenoblastoma]])
** [[Adrenal]] tumors
** [[Germ cell tumor]]<ref>{{Cite journal | last1 = Masse | first1 = R. J. | last2 = Shaw | first2 = P. J. | last3 = Burgess | first3 = M. | doi = 10.1111/j.1440-1754.1993.tb03022.x | title = Intracranial choriocarcinoma causing precocious puberty and cured with combined modality therapy | journal = Journal of Paediatrics and Child Health | volume = 29 | issue = 6 | pages = 464–467 | year = 2008 | pmid =  8286166| s2cid = 21886832 }}</ref><ref>{{Cite journal | doi = 10.2165/00148581-200406040-00002 | last1 = Antoniazzi | first1 = F. | last2 = Zamboni | first2 = G. | s2cid = 21330464 | title = Central precocious puberty: current treatment options | journal = Paediatric Drugs | volume = 6 | issue = 4 | pages = 211–231 | year = 2004 | pmid = 15339200}}</ref>
** [[Congenital adrenal hyperplasia]]
** [[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 [[phenotype|phenotypically]] appropriate [[secondary sexual characteristic]]s. This is called ''[[isosexual]]'' precocity.<ref name=":0">{{cite journal|last1=Jarzabek-Bielecka|first1=G|last2=Warchoł-Biedermann|first2=K|last3=Sowińska|first3=E|last4=Wachowiak-Ochmańska|first4=K|title=[Precocious puberty].|journal=Ginekologia Polska|date=April 2011|volume=82|issue=4|pages=281–6|pmid=21735696}}</ref>

In some cases, a patient may develop characteristics of the opposite sex. For example, a male may [[gynecomastia|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.<ref name=":0" /> The "opposite" case would be the hyper-masculinisation of both male and female patients with [[congenital adrenal hyperplasia due to 21-hydroxylase deficiency|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.{{citation needed|date=August 2020}}

=== 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 [[Obesity|obese]] are more likely to physically mature earlier.<ref name="Tanner">(Tanner, 1990).</ref><ref name="ncbi">{{Cite journal | last1 = Kaplowitz | first1 = P. B. | last2 = Slora | first2 = E. J. | last3 = Wasserman | first3 = R. C. | last4 = Pedlow | first4 = S. E. | last5 = Herman-Giddens | first5 = M. E. | title = Earlier onset of puberty in girls: relation to increased body mass index and race | journal = Pediatrics | volume = 108 | issue = 2 | pages = 347–353 | year = 2001 | pmid = 11483799| doi=10.1542/peds.108.2.347}}</ref><ref name="newscientist.com">{{cite magazine|first=Phil|last=McKenna|title=Childhood obesity brings early puberty for girls|magazine=[[New Scientist]]|date=2007-03-05|access-date=2010-05-22|url=https://www.newscientist.com/article/dn11307-childhood-obesity-brings-early-puberty-for-girls.html |archive-url = https://web.archive.org/web/20080419072722/http://www.newscientist.com/article/dn11307-childhood-obesity-brings-early-puberty-for-girls.html |archive-date = 2008-04-19}}</ref> "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."<ref name=newscientist.com/> In addition to diet and exercise habits, exposure to chemicals that mimic [[estrogen]] (known as [[xenoestrogen]]s) is another possible cause of early puberty in girls. [[Bisphenol A]], a [[xenoestrogen]] found in hard [[plastic]]s, has been shown to affect sexual development.<ref>{{Cite journal | last1 = Libertun | first1 = C. | last2 = Lux-Lantos | first2 = V. | last3 = Bianchi | first3 = M. | last4 = Fernández | first4 = M. | title = Neonatal Exposure to Bisphenol a Alters Reproductive Parameters and Gonadotropin Releasing Hormone Signaling in Female Rats | doi = 10.1289/ehp.0800267 | journal = Environmental Health Perspectives | year = 2009 | pmid =  19479018| pmc = 2685838| volume=117 | issue = 5 | pages=757–762| bibcode = 2009EnvHP.117..757F }}</ref> "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."<ref name=ncbi/> While more girls are increasingly entering puberty at younger ages, new research indicates that some boys are actually starting later ([[delayed puberty]]).<ref name="www.msnbc.msn.com">{{cite web |first=Elizabeth|last=Cooney|title=Puberty gap: Obesity splits boys, girls. Adolescent males at top of the BMI chart may be delayed|publisher=[[NBC News]]|date=2010-02-11|access-date=2010-05-22|url=http://www.nbcnews.com/id/35332881|archive-url=https://web.archive.org/web/20160111055843/http://www.nbcnews.com/id/35332881|url-status=dead|archive-date=January 11, 2016}}</ref><ref name="www.sciencedaily.com">{{cite web|title=Childhood Obesity May Contribute to Later Onset of Puberty for Boys|website=[[Science Daily]]|date=February 2010|access-date=2010-05-22|url=https://www.sciencedaily.com/releases/2010/02/100201171651.htm}}</ref> "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."<ref name=www.sciencedaily.com/>

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.<ref>{{Cite journal | last1 = Kuo | first1 = H. C. | last2 = Sheen | first2 = J. M. | last3 = Wu | first3 = K. S. | last4 = Wei | first4 = H. H. | last5 = Hsiao | first5 = C. C. | title = Precocious puberty due to human chorionic gonadotropin-secreting pineal tumor | journal = Chang Gung Medical Journal | volume = 29 | issue = 2 | pages = 198–202 | year = 2006 | pmid = 16767969}}</ref>

In a study using neonatal melatonin on rats, results suggest that elevated melatonin could be responsible for some cases of early puberty.<ref>{{Cite journal | last1 = Esouifino | first1 = A. I. | last2 = Villanúa | first2 = M. A. | last3 = Agrasal | first3 = C. | doi = 10.1016/0022-4731(87)90194-4 | title = Effect of neonatal melatonin administration on sexual development in the rat | journal = Journal of Steroid Biochemistry | volume = 27 | issue = 4–6 | pages = 1089–1093 | year = 1987 | pmid =  3121932}}</ref>

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]],<ref name="pmid23133486">{{cite journal|last=Park|first=Sung Won |author2=Lee, Seung-Tae |author3=Sohn, Young Bae |author4=Cho, Sung Yoon |author5=Kim, Se-Hwa |author6=Kim, Su Jin |author7=Kim, Chi Hwa |author8=Ko, Ah-Ra |author9=Paik, Kyung-Hoon |author10=Kim, Jong-Won |author11=Jin, Dong-Kyu |title=polymorphisms are associated with central precocious puberty and early puberty in girls|journal=Korean Journal of Pediatrics|date=1 January 2012|volume=55|issue=10|pages=388–92|doi=10.3345/kjp.2012.55.10.388|pmid=23133486|pmc=3488615}}</ref><ref name="pmid19448623">{{cite journal|last=Ong|first=Ken K |author2=Elks, Cathy E |author3=Li, Shengxu |author4=Zhao, Jing Hua |author5=Luan, Jian'an |author6=Andersen, Lars B |author7=Bingham, Sheila A |author8=Brage, Soren |author9=Smith, George Davey |author10=Ekelund, Ulf |author11=Gillson, Christopher J |author12=Glaser, Beate |author13=Golding, Jean |author14=Hardy, Rebecca |author15=Khaw, Kay-Tee |author16=Kuh, Diana |author17=Luben, Robert |author18=Marcus, Michele |author19=McGeehin, Michael A |author20=Ness, Andrew R |author21=Northstone, Kate |author22=Ring, Susan M |author23=Rubin, Carol |author24=Sims, Matthew A |author25=Song, Kijoung |author26=Strachan, David P |author27=Vollenweider, Peter |author28=Waeber, Gerard |author29=Waterworth, Dawn M |author30=Wong, Andrew |author31=Deloukas, Panagiotis |author32=Barroso, Inês |author33=Mooser, Vincent |author34=Loos, Ruth J |author35=Wareham, Nicholas J |title=Genetic variation in LIN28B is associated with the timing of puberty|journal=Nature Genetics|date=16 May 2009|volume=41|issue=6|pages=729–733|doi=10.1038/ng.382|pmid=19448623|pmc=3000552}}</ref> and LEP and LEPR, which encode [[leptin]] and the leptin receptor,<ref name="pmid22391636">{{cite journal|last=Su|first=Pen-Hua|author2=Yang, Shun-Fa |author3=Yu, Ju-Shan |author4=Chen, Suh-Jen |author5= Chen, Jia-Yuh |title=Study of leptin levels and gene polymorphisms in patients with central precocious puberty|journal=Pediatric Research|date=15 February 2012|volume=71|issue=4–1|pages=361–367|doi=10.1038/pr.2011.69|pmid=22391636|doi-access=free}}</ref> 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.<ref name="pmid20512147">{{cite journal |vauthors=Zhu H, Shah S, Shyh-Chang N, Shinoda G, Einhorn WS, Viswanathan SR, Takeuchi A, Grasemann C, Rinn JL, Lopez MF, Hirschhorn JN, Palmert MR, Daley GQ | title = Lin28a transgenic mice manifest size and puberty phenotypes identified in human genetic association studies | journal = Nat Genet | volume = 42 | issue = 7 | pages = 626–30 |date=July 2010 | pmid = 20512147 | doi = 10.1038/ng.593 | pmc = 3069638 }}</ref>

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<ref name="pmid21664234">{{cite journal|last=Teles|first=Milena Gurgel|author2=Silveira, Leticia Ferreira Gontijo |author3=Tusset, Cintia |author4= Latronico, Ana Claudia |s2cid=27207961|title=New genetic factors implicated in human GnRH-dependent precocious puberty: The role of kisspeptin system|journal=Molecular and Cellular Endocrinology|date=1 October 2011|volume=346|issue=1–2|pages=84–90|doi=10.1016/j.mce.2011.05.019|pmid=21664234}}</ref><ref name="pmid20237166">{{cite journal|last=Silveira|first=LG |author2=Noel, SD |author3=Silveira-Neto, AP |author4=Abreu, AP |author5=Brito, VN |author6=Santos, MG |author7=Bianco, SD |author8=Kuohung, W |author9=Xu, S |author10=Gryngarten, M |author11=Escobar, ME |author12=Arnhold, IJ |author13=Mendonca, BB |author14=Kaiser, UB |author15=Latronico, AC|title=Mutations of the KISS1 gene in disorders of puberty|journal=The Journal of Clinical Endocrinology and Metabolism|date=May 2010|volume=95|issue=5|pages=2276–80|doi=10.1210/jc.2009-2421|pmid=20237166|pmc=2869552}}</ref> 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.<ref name="pmid21939553">{{cite journal|last=Tommiska|first=Johanna|author2=Sørensen, Kaspar |author3=Aksglaede, Lise |author4=Koivu, Rosanna |author5=Puhakka, Lea |author6=Juul, Anders |author7= Raivio, Taneli |title=LIN28B, LIN28A, KISS1, and KISS1R in idiopathic central precocious puberty|journal=BMC Research Notes|date=1 January 2011|volume=4|issue=1|pages=363|doi=10.1186/1756-0500-4-363|pmid=21939553|pmc=3184284 |doi-access=free }}</ref>

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.<ref>{{cite journal |vauthors=Abreu AP, Dauber A, Macedo DB, Noel SD, Brito VN, Gill JC, Cukier P, Thompson IR, Navarro VM, Gagliardi PC, etal | year = 2013 | title = Central precocious puberty caused by mutations in the imprinted gene MKRN3 | doi = 10.1056/nejmoa1302160| pmid = 23738509 | journal = N Engl J Med | volume = 368 | issue = 26| pages = 2467–2475 | pmc = 3808195 }}</ref> The identification of mutations in MKRN3 leading to sporadic cases of CPP has been a significant contribution to better understanding the mechanism of puberty.<ref>{{cite journal |vauthors=Macedo DB, Abreu AP, Reis AC, Montenegro LR, Dauber A, Beneduzzi D, Cukier P, Silveira LF, Teles MG, Carroll RS, etal | year = 2014 | title = Central precocious puberty that appears to be sporadic caused by paternally inherited mutations in the imprinted gene makorin ring finger 3 | journal = J Clin Endocrinol Metab | volume = 99 | issue = 6| pages = E1097–1103 | doi=10.1210/jc.2013-3126| pmid = 24628548 | pmc = 4037732}}</ref> 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.<ref>{{cite journal |vauthors=Abreu AP, Macedo DB, Brito VN, etal | year = 2015 | title = A new pathway in the control of the initiation of puberty: the MKRN3 gene | journal = Journal of Molecular Endocrinology | volume = 54 | issue = 3| pages = R131–R139 | doi=10.1530/jme-14-0315| pmid = 25957321 | pmc = 4573396}}</ref>

== 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.<ref name=ncbi/><ref name="adc.bmj.com">{{Cite journal | last1 = Zukauskaite | first1 = S. | last2 = Lasiene | first2 = D. | last3 = Lasas | first3 = L. | last4 = Urbonaite | first4 = B. | last5 = Hindmarsh | first5 = P. | title = Onset of breast and pubic hair development in 1231 preadolescent Lithuanian schoolgirls | doi = 10.1136/adc.2004.057612 | journal = Archives of Disease in Childhood | volume = 90 | issue = 9 | pages = 932–936 | year = 2005 | pmid =  15855182| pmc =1720558 }}</ref><ref name="news.bbc.co.uk">{{cite news |first=Michelle |last=Roberts |title=Why puberty now begins at seven|work=BBC News|date=2005-05-15|access-date=2010-05-22|url=http://news.bbc.co.uk/2/hi/health/4530743.stm}}</ref> 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<ref name=www.msnbc.msn.com/><ref name="www.suntimes.com">{{cite news|first=Jim|last=Ritter|title=Parents worried by girls' earlier start of puberty|newspaper=[[Chicago Sun-Times]]|date=2000-08-02}}</ref> and can be harmful to children who mature physically at a time when they are immature mentally.<ref name="www.center4research.org">{{cite web |url=http://www.center4research.org/early-puberty-girls/|title=Early Puberty in Girls|author=Diana Zuckerman |publisher=Cornell University Program on Breast Cancer and Environmental Risk Factors |year=2001 |work=The Ribbon |access-date=18 February 2018 }}</ref>

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 [[testicle|testicular]] enlargement
* [[Pubic hair]] or genital enlargement ([[gonadarche]]) in boys with onset before 9 years
* Pubic hair ([[pubarche]]) before 8 or breast development ([[thelarche]]) in girls with onset before 7 years
* [[Menstruation]] ([[menarche]]) 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.<ref name=newscientist.com/><ref name="Stattin & Magnussion">(Stattin & Magnussion, 1990)</ref><ref name="Mendle">{{cite journal |vauthors=Mendle J, Leve L, Van Ryzin M, Natsuaki M | title = Linking Childhood Maltreatment With Girls' Internalizing Symptoms: Early Puberty as a Tipping Point | journal = Journal of Research on Adolescence | volume = 24 | issue = 3 | pages = 626–30 |date=August 2013 |doi=10.1111/jora.12075| pmid = 25419091 |pmc=4236856 }}</ref>

== Treatment ==
One possible treatment is with [[anastrozole]]. GnRH agonists, including [[histrelin]], [[triptorelin]], or [[leuprorelin]], are other possible treatments. Non-continuous use{{clarify|date=May 2022}} of GnRH agonists stimulates the pituitary gland to release [[follicle stimulating hormone]] (FSH) and [[luteinizing hormone]] (LH).{{why|date=May 2022}}<ref name=nejm_PP>{{cite journal|last=[[Florence Comite]]|author2=Cutler, Gordon B. |author3=Rivier, Jean |author4=Vale, Wylie W. |author5=Loriaux, D. Lynn |author6= Crowley, William F. |title=Short-Term Treatment of Idiopathic Precocious Puberty with a Long-Acting Analogue of Luteinizing Hormone-Releasing Hormone|journal=New England Journal of Medicine|date=24 December 1981|volume=305|issue=26|pages=1546–1550|doi=10.1056/NEJM198112243052602|pmid=6458765}}</ref>  Triptorelin depot is widely used to treat central precocious puberty (CPP) in children.<ref>{{Cite journal |last1=Bertelloni |first1=Silvano |last2=Mucaria |first2=Cristina |last3=Baroncelli |first3=Giampiero I. |last4=Peroni |first4=Diego |date=July 2018 |title=Triptorelin depot for the treatment of children 2 years and older with central precocious puberty |url=https://pubmed.ncbi.nlm.nih.gov/29957076/ |journal=Expert Review of Clinical Pharmacology |volume=11 |issue=7 |pages=659–667 |doi=10.1080/17512433.2018.1494569 |issn=1751-2441 |pmid=29957076}}</ref>

Puberty blockers work by stabilizing puberty symptoms, decreasing growth velocity, and slowing skeletal maturation.<ref>{{cite journal | vauthors = Latronico AC, Brito VN, Carel JC | title = Causes, diagnosis, and treatment of central precocious puberty | journal = The Lancet. Diabetes & Endocrinology | volume = 4 | issue = 3 | pages = 265–274 | date = March 2016 | pmid = 26852255 | doi = 10.1016/S2213-8587(15)00380-0 }}</ref> 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.<ref>{{cite journal | vauthors = Fuqua JS | title = Treatment and outcomes of precocious puberty: an update | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 98 | issue = 6 | pages = 2198–2207 | date = June 2013 | pmid = 23515450 | doi = 10.1210/jc.2013-1024 }}</ref> 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.<ref>{{cite journal | vauthors = Magiakou MA, Manousaki D, Papadaki M, Hadjidakis D, Levidou G, Vakaki M, Papaefstathiou A, Lalioti N, Kanaka-Gantenbein C, Piaditis G, Chrousos GP, Dacou-Voutetakis C | title = The efficacy and safety of gonadotropin-releasing hormone analog treatment in childhood and adolescence: a single center, long-term follow-up study | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 95 | issue = 1 | pages = 109–117 | date = January 2010 | pmid = 19897682 | doi = 10.1210/jc.2009-0793 | doi-access = free }}</ref> Individuals with precocious puberty, early adrenarche, and early normal puberty show less stress after treatment compared to individuals without preexisting developmental conditions.<ref>{{cite journal | vauthors = Menk TA, Inácio M, Macedo DB, Bessa DS, Latronico AC, Mendonca BB, Brito VN | title = Assessment of stress levels in girls with central precocious puberty before and during long-acting gonadotropin-releasing hormone agonist treatment: a pilot study | journal = Journal of Pediatric Endocrinology & Metabolism | volume = 30 | issue = 6 | pages = 657–662 | date = May 2017 | pmid = 28599388 | doi = 10.1515/jpem-2016-0425 }}</ref>

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.<ref>{{cite journal | vauthors = Carel JC, Léger J | title = Clinical practice. Precocious puberty | journal = The New England Journal of Medicine | volume = 358 | issue = 22 | pages = 2366–2377 | date = May 2008 | pmid = 18509122 | doi = 10.1056/NEJMcp0800459 }}</ref>

In the USA, since 1993, the [[Food and Drug Administration|US Food and Drug Administration (FDA)]] has supported the use of puberty blockers to treat precocious puberty.<ref>{{cite web |last=Benisek |first=Alexandra |title=What Are Puberty Blockers? |url=https://www.webmd.com/children/what-are-puberty-blockers |access-date=2024-08-01 |website=WebMD |language=en}}</ref> Currently under FDA regulation the use of puberty blockers is considered on-label for the treatment of central precocious puberty.<ref name="Lopez_2018">{{cite journal | vauthors = Lopez CM, Solomon D, Boulware SD, Christison-Lagay E | title = Trends in the "Off-Label" Use of GnRH Agonists Among Pediatric Patients in the United States | journal = Clinical Pediatrics | volume = 57 | issue = 12 | pages = 1432–1435 | date = October 2018 | pmid = 30003804 | doi = 10.1177/0009922818787260 }}</ref>]<ref name="apa.org">{{cite web |title=Proposed Talking Points to Oppose Gender-Affirming Care Criminalization Bills |url=https://www.apa.org/pi/lgbt/resources/policy/issues/gender-affirmative-care |website=apa.org |publisher=American Psychological Association |access-date=11 October 2022 |archive-url=https://web.archive.org/web/20210505180900/https://www.apa.org/pi/lgbt/resources/policy/issues/gender-affirmative-care |archive-date=5 May 2021 |language=en-US |url-status=dead}}</ref>

For years, the [[Food and Drug Administration|FDA]], [[Endocrine Society]], [[American Academy of Pediatrics|American Academy of Pediatrics(AAP)]] and many other pediatric associations have supported the use of [[Gonadotropin-releasing hormone modulator|Gonadotropin-releasing hormone analogs]][[Gonadotropin-releasing hormone agonist|(GnRHas)]] in central precocious puberty (CPP).<ref>{{cite journal | vauthors = Kletter GB, Klein KO, Wong YY | title = A pediatrician's guide to central precocious puberty | journal = Clinical Pediatrics | volume = 54 | issue = 5 | pages = 414–424 | date = May 2015 | pmid = 25022947 | doi = 10.1177/0009922814541807 }}</ref> 

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 modulator|Gonadotropin-releasing hormone analogs]][[Gonadotropin-releasing hormone agonist|(GnRHas)]] in early onset central precocious puberty.<ref name="Carel_2009">{{cite journal | vauthors = Carel JC, Eugster EA, Rogol A, Ghizzoni L, Palmert MR, Antoniazzi F, Berenbaum S, Bourguignon JP, Chrousos GP, Coste J, Deal S, de Vries L, Foster C, Heger S, Holland J, Jahnukainen K, Juul A, Kaplowitz P, Lahlou N, Lee MM, Lee P, Merke DP, Neely EK, Oostdijk W, Phillip M, Rosenfield RL, Shulman D, Styne D, Tauber M, Wit JM | title = Consensus statement on the use of gonadotropin-releasing hormone analogs in children | journal = Pediatrics | volume = 123 | issue = 4 | pages = e752–e762 | date = April 2009 | pmid = 19332438 | doi = 10.1542/peds.2008-1783 | url = http://orbi.ulg.ac.be/handle/2268/109500 }}</ref> They confirmed that the use of [[Gonadotropin-releasing hormone modulator|Gonadotropin-releasing hormone analogs]][[Gonadotropin-releasing hormone agonist|(GnRHas)]] has had a positive effect on increasing adult height.<ref name="Carel_2009" /><ref>{{cite journal | vauthors = Chen M, Eugster EA | title = Central Precocious Puberty: Update on Diagnosis and Treatment | journal = Paediatric Drugs | volume = 17 | issue = 4 | pages = 273–281 | date = August 2015 | pmid = 25911294 | pmc = 5870137 | doi = 10.1007/s40272-015-0130-8 }}</ref> However these Endocrine Societies believe additional research should be conducted before routinely suggesting [[Gonadotropin-releasing hormone agonist|GnRHAs]] for other conditions.<ref name="Carel_2009" /> There is still some uncertainty surrounding the effectiveness of [[Gonadotropin-releasing hormone agonist|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.<ref>{{cite journal | vauthors = Lewis KA, Eugster EA | title = Experience with the once-yearly histrelin (GnRHa) subcutaneous implant in the treatment of central precocious puberty | language = English | journal = Drug Design, Development and Therapy | volume = 3 | pages = 1–5 | date = September 2009 | pmid = 19920916 | doi = 10.2147/DDDT.S3298 | doi-access = free | pmc = 2769233 }}</ref>

A systematic review of studies investigating the long-term effects of treating precocious puberty with GnRH agonists found that [[Bone density|bone mineral density]] decreases during treatment but normalizes afterward, with no lasting effects on [[peak bone mass]].<ref name="Soliman">{{cite journal |last1=Soliman |first1=Ashraf T. |last2=Alaaraj |first2=Nada |last3=De Sanctis |first3=Vincenzo |last4=Hamed |first4=Noor |last5=Alyafei |first5=Fawzia |last6=Ahmed |first6=Shayma |title=Long-term health consequences of central precocious/early puberty (CPP) and treatment with Gn-RH analogue: a short update: Long term consequences of precocious puberty |journal=Acta Biomedica: Atenei Parmensis |date=5 December 2023 |volume=94 |issue=6 |pages=e2023222 |doi=10.23750/abm.v94i6.15316 |pmid=38054666|pmc=10734238 }}</ref>

== Prognosis ==
Early puberty is posited to put girls at [[Child sexual abuse|higher risk of sexual abuse]];<ref name=newscientist.com/><ref name="Mendle"/> however, a causal relationship is, as yet, inconclusive.<ref name="Mendle"/> Early puberty also puts girls at a higher risk for teasing or bullying, mental health disorders and short stature as adults.<ref name=newscientist.com/><ref name="Stattin & Magnussion"/><ref name="Caspi">(Caspi et al.1993: Lanza and Collins, 2002)</ref> Girls as young as 8 are increasingly starting to [[Menstruation|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.<ref name=ncbi/>

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.<ref name="Garn">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</ref> 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 [[Cognition|cognitive]] and [[Social emotional development|social development]] may lag behind their physical development.<ref name=Garn/> Studies have shown that early-maturing boys are more likely to be sexually active and are more likely to participate in risky behaviors.<ref name=Susman>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</ref>

== History ==
{{lang|la|Pubertas praecox}} is the [[Latin]] 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 [[Temperament#Four temperaments model|temperamental]], [[four humors|humoral]] and [[Jungian]] "complexional" causes, or general or local "plethora" (blood excess).<ref>{{cite journal|last1=Janssen|first1=Diederik|date=2021|title=Puer barbatus: Precocious Puberty in Early Modern Medicine|journal=Journal of the History of Medicine and Allied Sciences|volume=76|issue=1|pages=20–52|doi=10.1093/jhmas/jraa045|pmc=7737932|pmid=33186444|doi-access=free}}</ref>

== See also ==
* [[Acceleration (human development)]]
* [[Heterochrony#Paedomorphosis|Heterochrony: Paedomorphosis]]
* [[Secular variation#Biological anthropology|Secular trend: Biological anthropology]]
* [[Primary ovarian insufficiency]]

== References ==
{{Reflist}}

{{Medical resources
|   ICD11       = {{ICD11|5A92}}
|   ICD10       = {{ICD10|E|30|1|e|20}}, {{ICD10|E|22|8|e|20}}
|   ICD9        = {{ICD9|259.1}}
|   OMIM        = 176400
|   DiseasesDB     = 10519
|   MedlinePlus    = 001168
|   eMedicineSubj  = ped
|   eMedicineTopic = 1882
|   MeshID         = D011629
}}
{{Gonadal disorder}}
{{Authority control}}

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