Editing Delayed puberty (section)

==Causes==
Pubertal delay can be separated into four categories from most to least common:<ref name=":1" />

=== Constitutional and physiologic delay ===
Children who are healthy but have a slower rate of physical development than average have a [[constitutional delay]] with a subsequent delay in puberty. It is the most common cause of delayed puberty in girls<ref name=":3">{{Cite book|title=Williams Gynecology|last=Hoffman|first=Barbara | name-list-style = vanc |publisher=McGraw-Hill Education|year=2016|isbn=978-0-07-184908-1}}</ref><ref name=":4" /> (30%)<ref name=":0" /> and even more so in boys<ref name=":1" /> (65%).<ref name=":7" /> It is commonly inherited, with as much as 80% of the variation in the age of onset of puberty due to genetic factors.<ref name=":7" /><ref>{{cite journal | vauthors = Howard SR, Dunkel L | title = Management of hypogonadism from birth to adolescence | journal = Best Practice & Research. Clinical Endocrinology & Metabolism | volume = 32 | issue = 4 | pages = 355–372 | date = August 2018 | pmid = 30086863 | doi = 10.1016/j.beem.2018.05.011 | series = Issue Update in paediatric endocrinology | s2cid = 51934183 | url = http://qmro.qmul.ac.uk/xmlui/handle/123456789/40963 }}</ref> These children have a history of shorter stature than their age-matched peers throughout childhood, but their height is appropriate for [[bone age]], meaning that they have delayed skeletal maturation with potential for future growth.<ref name=":0">{{Cite book | last1 = Fritz | first1 = Marc A | last2 = Speroff | first2 = Leon | name-list-style = vanc |title=Clinical Gynecologic Endocrinology and Infertility. |date=2015|publisher=Lippincott Williams & Wilkins|isbn=9781451189766|oclc=885230917}}</ref>

It is often difficult to establish if it is a true constitutional delay of growth and puberty or if there is an underlying pathology because lab tests are not always discriminatory.<ref name="WeiCrowne2015">{{cite journal | vauthors = Wei C, Crowne EC | title = Recent advances in the understanding and management of delayed puberty | journal = Archives of Disease in Childhood | volume = 101 | issue = 5 | pages = 481–8 | date = May 2016 | pmid = 26353794 | doi = 10.1136/archdischild-2014-307963 | s2cid = 5372175 | type = Review }}</ref> In the absence of any other symptoms, short stature, delayed growth in height and weight, and/or delayed puberty may be the only clinical manifestations of certain chronic diseases including [[coeliac disease]].<ref name="Mearin2015">{{cite journal | vauthors = Mearin ML | title = The prevention of coeliac disease | journal = Best Practice & Research. Clinical Gastroenterology | volume = 29 | issue = 3 | pages = 493–501 | date = June 2015 | pmid = 26060113 | doi = 10.1016/j.bpg.2015.04.003 | type = Review }}</ref><ref name="LefflerGreen2015">{{cite journal | vauthors = Leffler DA, Green PH, Fasano A | title = Extraintestinal manifestations of coeliac disease | journal = Nature Reviews. Gastroenterology & Hepatology | volume = 12 | issue = 10 | pages = 561–71 | date = October 2015 | pmid = 26260366 | doi = 10.1038/nrgastro.2015.131 | s2cid = 15561525 | type = Review }}</ref><ref name="GuandaliniAssiri2014">{{cite journal | vauthors = Guandalini S, Assiri A | title = Celiac disease: a review | journal = JAMA Pediatrics | volume = 168 | issue = 3 | pages = 272–8 | date = March 2014 | pmid = 24395055 | doi = 10.1001/jamapediatrics.2013.3858 }}</ref><ref name="LevyBernstein2014">{{cite journal | vauthors = Levy J, Bernstein L, Silber N | title = Celiac disease: an immune dysregulation syndrome | journal = Current Problems in Pediatric and Adolescent Health Care | volume = 44 | issue = 11 | pages = 324–7 | date = December 2014 | pmid = 25499458 | doi = 10.1016/j.cppeds.2014.10.002 | type = Review }}</ref>

=== Malnutrition or chronic disease ===
When underweight or sickly children are present with pubertal delay, it is warranted to search for illnesses that cause a temporary and reversible delay in puberty.<ref name=":1" /> Chronic conditions such as [[sickle cell disease]]<ref>{{Citation|last1=Aeddula|first1=Narothama Reddy |last2=Baradhi|first2=Krishna M.| name-list-style = vanc |title=Sickle Cell Nephropathy|date=2018|url=https://www.ncbi.nlm.nih.gov/books/NBK526017/|work=StatPearls|publisher=StatPearls Publishing|pmid=30252273|access-date=2019-01-26}}</ref><ref>{{cite journal | vauthors = Stimpson SJ, Rebele EC, DeBaun MR | title = Common gynecological challenges in adolescents with sickle cell disease | journal = Expert Review of Hematology | volume = 9 | issue = 2 | pages = 187–96 | date = 2016 | pmid = 26613137 | doi = 10.1586/17474086.2016.1126177 | s2cid = 23987807 }}</ref><ref>{{cite journal | vauthors = Huang AW, Muneyyirci-Delale O | title = Reproductive endocrine issues in men with sickle cell anemia | journal = Andrology | volume = 5 | issue = 4 | pages = 679–690 | date = July 2017 | pmid = 28662541 | doi = 10.1111/andr.12370 | s2cid = 207012502 | doi-access = free }}</ref> and [[thalassemia]],<ref>{{cite journal | vauthors = Castaldi MA, Cobellis L | title = Thalassemia and infertility | journal = Human Fertility | volume = 19 | issue = 2 | pages = 90–6 | date = June 2016 | pmid = 27335221 | doi = 10.1080/14647273.2016.1190869 | s2cid = 27130445 }}</ref> [[cystic fibrosis]],<ref>{{cite journal | vauthors = Johannesson M, Gottlieb C, Hjelte L | title = Delayed puberty in girls with cystic fibrosis despite good clinical status | journal = Pediatrics | volume = 99 | issue = 1 | pages = 29–34 | date = January 1997 | pmid = 8989333 | doi = 10.1542/peds.99.1.29 }}</ref> [[HIV/AIDS]], [[hypothyroidism]],<ref>{{cite journal | vauthors = Tsutsui K, Son YL, Kiyohara M, Miyata I | title = Discovery of GnIH and Its Role in Hypothyroidism-Induced Delayed Puberty | journal = Endocrinology | volume = 159 | issue = 1 | pages = 62–68 | date = January 2018 | pmid = 28938445 | doi = 10.1210/en.2017-00300 | s2cid = 3498163 | doi-access = free }}</ref> [[chronic kidney disease]],<ref name="ThebautAmouyal2013">{{cite journal | vauthors = Thébaut A, Amouyal M, Besançon A, Collet M, Selbonne E, Valentin C, Vonthron M, Zakariya M, Linglart A | title = [Puberty, fertility and chronic diseases] | journal = Archives de Pédiatrie | volume = 20 | issue = 6 | pages = 673–84 | date = June 2013 | pmid = 23619213 | doi = 10.1016/j.arcped.2013.03.015 | type = Review }}</ref><ref>{{cite journal | vauthors = Haffner D, Zivicnjak M | title = Pubertal development in children with chronic kidney disease | journal = Pediatric Nephrology | volume = 32 | issue = 6 | pages = 949–964 | date = June 2017 | pmid = 27464647 | doi = 10.1007/s00467-016-3432-3 | s2cid = 19894051 }}</ref> and chronic gastroenteric disorders (such as [[coeliac disease]]<ref name="LefflerGreen2015" /><ref name="TersigniCastellani">{{cite journal | vauthors = Tersigni C, Castellani R, de Waure C, Fattorossi A, De Spirito M, Gasbarrini A, Scambia G, Di Simone N | title = Celiac disease and reproductive disorders: meta-analysis of epidemiologic associations and potential pathogenic mechanisms | journal = Human Reproduction Update | volume = 20 | issue = 4 | pages = 582–93 | date = 2014 | pmid = 24619876 | doi = 10.1093/humupd/dmu007 | type = Review | doi-access = free | hdl = 10807/56796 | hdl-access = free }}</ref> and [[inflammatory bowel disease]]<ref name="Sanderson2014">{{cite journal | vauthors = Sanderson IR | title = Growth problems in children with IBD | journal = Nature Reviews. Gastroenterology & Hepatology | volume = 11 | issue = 10 | pages = 601–10 | date = October 2014 | pmid = 24957008 | doi = 10.1038/nrgastro.2014.102 | s2cid = 28365424 | type = Review }}</ref><ref name="WongCattoSmith2014">{{cite journal | vauthors = Wong SC, Catto-Smith AG, Zacharin M | title = Pathological fractures in paediatric patients with inflammatory bowel disease | journal = European Journal of Pediatrics | volume = 173 | issue = 2 | pages = 141–51 | date = February 2014 | pmid = 24132387 | doi = 10.1007/s00431-013-2174-5 | hdl = 11343/282814 | s2cid = 26007421 | type = Review | hdl-access = free }}</ref><ref>{{cite journal | vauthors = Corica D, Romano C | title = Biological Therapy in Pediatric Inflammatory Bowel Disease: A Systematic Review | journal = Journal of Clinical Gastroenterology | volume = 51 | issue = 2 | pages = 100–110 | date = February 2017 | pmid = 27636407 | doi = 10.1097/MCG.0000000000000696 | s2cid = 24102740 }}</ref>) cause a delayed activation of the [[Hypothalamus|hypothalamic]] region of the brain to send signals to start puberty.<ref name=":2">{{Cite book|title=Williams textbook of endocrinology.|last=Schlomo |first=Melmed | name-list-style = vanc |date=2015 |publisher=Elsevier|isbn=978-0323341578|oclc=995483654}}</ref>

Childhood cancer survivors can also present with delayed puberty secondary to their cancer treatments, especially males.<ref name=":7" /><ref name=":8">{{cite journal | vauthors = Dwyer AA, Phan-Hug F, Hauschild M, Elowe-Gruau E, Pitteloud N | title = TRANSITION IN ENDOCRINOLOGY: Hypogonadism in adolescence | language = en-US | journal = European Journal of Endocrinology | volume = 173 | issue = 1 | pages = R15–24 | date = July 2015 | pmid = 25653257 | doi = 10.1530/EJE-14-0947 | doi-access = free }}</ref> The type of treatment, amount of exposure/dosage of drugs, and age during treatment determine the level by which the [[gonad]]s are affected, with younger patients at a lower risk of negative reproductive effects.<ref name=":8" />

Excessive physical exercise and physical stress, especially in athletes can also delay pubertal onset.<ref name="MaimounGerogopoulos2014">{{cite journal | vauthors = Maïmoun L, Georgopoulos NA, Sultan C | title = Endocrine disorders in adolescent and young female athletes: impact on growth, menstrual cycles, and bone mass acquisition | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 99 | issue = 11 | pages = 4037–50 | date = November 2014 | pmid = 24601725 | doi = 10.1210/jc.2013-3030 | s2cid = 207088675 | type = Review | doi-access = free }}</ref> Eating disorders such as [[bulimia nervosa]] and [[anorexia nervosa]] can also impair puberty due to [[undernutrition]].<ref name=":2" /><ref>{{cite journal | vauthors = Kapczuk K | title = Elite athletes and pubertal delay | journal = Minerva Pediatrica | volume = 69 | issue = 5 | pages = 415–426 | date = October 2017 | pmid = 28745464 | doi = 10.23736/S0026-4946.17.05044-7 }}</ref>

[[Carbohydrate-restricted diet]]s for weight loss have also been shown to decrease the stimulation of [[insulin]] which in turn does not stimulate [[kisspeptin]] neurons, vital in the release of puberty-starting hormones.<ref>{{cite journal | vauthors = Pankov YA | title = [Kisspeptin and leptin in the regulation of fertility] | journal = Molekuliarnaia Biologiia | volume = 49 | issue = 5 | pages = 707–15 | date = September 2015 | pmid = 26510589 | doi = 10.7868/S0026898415050134 }}</ref> This shows that carbohydrate restricted children and children with [[diabetes mellitus type 1]] can have delayed puberty.<ref name=":13">{{cite journal | vauthors = Richmond HM, Duriancik DM | title = Impact of Carbohydrate Restriction on Healthy Adolescent Development | journal = Pediatric Endocrinology Reviews | volume = 15 | issue = 1 | pages = 26–32 | date = September 2017 | pmid = 28845625 | doi = 10.17458/per.vol15.2017.rd.impactcarbohydraterestriction | doi-broken-date = 2024-11-02 }}</ref><ref>{{cite journal | vauthors = Gandhi J, Dagur G, Warren K, Smith NL, Sheynkin YR, Zumbo A, Khan SA | title = The Role of Diabetes Mellitus in Sexual and Reproductive Health: An Overview of Pathogenesis, Evaluation, and Management | journal = Current Diabetes Reviews | volume = 13 | issue = 6 | pages = 573–581 | date = 2017 | pmid = 27875946 | doi = 10.2174/1573399813666161122124017 }}</ref>

=== Primary failure of the ovaries or testes (hypergonadotropic hypogonadism) ===
[[File:Hypothalamus pituitary testicles axis.png|alt=|thumb|Hypothalamic-pituitary-testicular axis and the hormones produced by each part of the axis. The + signs indicate that the organ is stimulated by the hormones released from the previous organ in the chain.]]
Primary failure of the [[Ovary|ovaries]] or [[testes]] ([[gonad]]s) will cause delayed puberty due to the lack of hormonal response by the final receptors of the [[HPG axis]].<ref name=":0" /> In this scenario, the brain sends a lot of hormonal signals (high [[gonadotropin]]), but the gonads are unable to respond to said signals causing [[hypergonadotropic hypogonadism]].<ref name=":0" /> Hypergonadotropic hypogonadism can be caused by congenital defects or acquired defects.<ref name=":5">{{Cite book|title=Goldman-Cecil Medicine|last=Goldman|first=Lee | name-list-style = vanc |publisher=Elsevier|year=2015|isbn=978-1455750177}}</ref>

==== Congenital disorders ====
Congenital diseases include untreated [[cryptorchidism]] where the [[testicle]]s fail to descend from the abdomen.<ref name=":2" /> Other congenital disorders are genetic in nature. In males, there can be deformities in the [[seminiferous tubule]] as in [[Klinefelter syndrome]] (most common cause in males),<ref name=":9">{{cite journal | vauthors = Villanueva C, Argente J | title = Pathology or normal variant: what constitutes a delay in puberty? | language = en | journal = Hormone Research in Paediatrics | volume = 82 | issue = 4 | pages = 213–21 | date = 2014 | pmid = 25011467 | doi = 10.1159/000362600 | s2cid = 23869989 | doi-access = free }}</ref> defects in the production of testicular steroids, receptor mutations preventing testicular hormones from working, chromosomal abnormalities such as [[Noonan syndrome]], or problems with the cells making up the testes.<ref name=":2" /> Females can also have chromosomal abnormalities such as [[Turner syndrome]] (most common cause in girls),<ref name=":9" /> [[XX gonadal dysgenesis]], and [[XY gonadal dysgenesis]], problems in the ovarian hormone synthesis pathway such as [[aromatase deficiency]]<ref name=":2" /> or congenital anatomical deformities such as [[Müllerian agenesis]].<ref name=":5" />

==== Acquired disorders ====
Acquired diseases include [[mumps]] [[orchitis]], [[Coxsackievirus]] B infection, irradiation, [[chemotherapy]], or trauma; all problems causing the gonads to fail.<ref name=":1" /><ref name=":5" />

=== Genetic or acquired defect of the hormonal pathway of puberty (hypogonadotropic hypogonadism) ===

The [[hypothalamic–pituitary–gonadal axis]] can also be affected at the level of the brain.<ref name=":5" /> The brain does not send its hormonal signals to the gonads (low [[gonadotropin]]s), causing the gonads to never be activated in the first place, resulting in [[hypogonadotropic hypogonadism]].<ref name=":12">{{cite book | vauthors = Pariseai M |date=2008 | chapter =Gynaecological endocrinology | title = Obstetrics and gynaecology |location = St. Louis | publisher = Mosby | isbn = 9780723434726 }}</ref> The HPG axis can be altered in two places, at the hypothalamic or at the pituitary level.<ref name=":12" /> CNS disorders such as childhood brain tumors (''e.g.'' [[craniopharyngioma]], [[prolactinoma]], [[germinoma]], [[glioma]]) can disrupt the communication between the hypothalamus and the pituitary.<ref name=":2" /> Pituitary tumors, especially [[prolactinoma]]s, can increase the level of dopamine causing an inhibiting effect to the HPG axis.<ref name=":3" /> Hypothalamic disorders include [[Prader-Willi syndrome]] and [[Kallmann syndrome]],<ref name=":1" /> but the most common cause of hypogonadotropic hypogonadism is a functional deficiency in the hormone regulator produced by the hypothalamus, [[gonadotropin-releasing hormone|the gonadotropin-releasing hormone]] or GnRH.<ref name=":0" />