Editing Precocious puberty (section)

=== 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>