Editing Delayed puberty

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| name = Delayed puberty
| synonyms = Late Puberty
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| causes = Genetic; Malnutrition
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'''Delayed puberty''' is when a person lacks or has incomplete development of specific [[sexual characteristics]] past the usual age of onset of [[puberty]].<ref name=":3" /> The person may have no physical or [[hormone|hormonal]] signs that puberty has begun. In the United States, girls are considered to have delayed puberty if they lack breast development by age 13 or have not started menstruating by age 15.<ref name=":3" /><ref name=":1" /> Boys are considered to have delayed puberty if they lack enlargement of the testicles by age 14.<ref name=":1">{{Cite book | first = Fred F | last = Ferri | name-list-style = vanc |title=Ferri's clinical advisor 2019 : 5 books in 1 |isbn=9780323550765 |oclc=1040695302| date = 2018-05-26 | publisher = Elsevier Health Sciences }}</ref> Delayed puberty affects about 2% of adolescents.<ref>{{cite journal | vauthors = Howard SR, Dunkel 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 | doi-access = free }}</ref><ref name=":11">{{cite journal | vauthors = Klein DA, Emerick JE, Sylvester JE, Vogt KS | 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>

Most commonly, puberty may be delayed for several years and still occur normally, in which case it is considered constitutional delay of growth and puberty, a common variation of healthy physical development.<ref name=":1" /> Delay of puberty may also occur due to various causes such as [[malnutrition]], various [[systemic disease]]s, or defects of the [[reproductive system]] ([[hypogonadism]]) or the body's responsiveness to [[sex hormone]]s.<ref name=":1" />

Initial workup for delayed puberty not due to a chronic condition involves measuring serum [[Follicle-stimulating hormone|FSH]], [[Luteinizing hormone|LH]], [[testosterone]]/[[estradiol]], as well as bone age radiography.<ref name=":11" /> If it becomes clear that there is a permanent defect of the reproductive system, treatment usually involves replacement of the appropriate hormones ([[testosterone]]/[[dihydrotestosterone]] for boys,<ref name="pmid11600557">{{cite journal | vauthors = Saad RJ, Keenan BS, Danadian K, Lewy VD, Arslanian SA | title = Dihydrotestosterone treatment in adolescents with delayed puberty: does it explain insulin resistance of puberty? | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 86 | issue = 10 | pages = 4881–6 | date = October 2001 | pmid = 11600557 | doi = 10.1210/jcem.86.10.7913 | s2cid = 24606172 | doi-access = free }}</ref> [[estradiol]] and [[progesterone]] for girls).<ref name=":6" />

==Timing and definitions==

Puberty is considered delayed when the child has not begun puberty when two [[standard deviation]]s or about 95% of children from similar backgrounds have.<ref name=":0" /><ref name=":4" /><ref>{{cite journal | vauthors = Traggiai C, Stanhope R | title = Disorders of pubertal development | journal = Best Practice & Research. Clinical Obstetrics & Gynaecology | volume = 17 | issue = 1 | pages = 41–56 | date = February 2003 | pmid = 12758225 | doi = 10.1053/ybeog.2003.0360 }}</ref>

In North American girls, puberty is considered delayed when breast development has not begun by age 13, when they have not started menstruating by age 15,<ref name=":1" /> and when there is no increased growth rate.<ref name=":4" />  Furthermore, slowed progression through the [[Tanner scale]] or lack of [[menarche]] within 3 years of breast development may also be considered delayed puberty.<ref name=":4" />

In the United States, the age of onset of puberty in girls depends heavily on their racial background. Delayed puberty means the lack of breast development by age 12.8 years for White girls, and by age 12.4 years for Black girls.<ref name=":0" /><ref name=":4" /> The lack of menstruation by age 15 in any ethnic background is considered delayed.<ref name=":4" />

In North American boys, puberty is considered delayed when the testes remain less than 2.5&nbsp;cm in diameter<ref name=":1" /> or less than 4 mL in volume by the age of 14.<ref name=":11" /> Delayed puberty is more common in males.<ref name=":1" />

Although the absence of pubic and/or axillary hair is common in children with delayed puberty, the presence of sexual hair is due to adrenal sex hormone secretion unrelated to the sex hormones produced by the ovaries or testes.<ref name=":7">{{cite journal|vauthors=Dunkel L, Quinton R|date=June 2014|title=Transition in endocrinology: induction of puberty|journal=European Journal of Endocrinology|language=en-US|volume=170|issue=6|pages=R229–39|doi=10.1530/EJE-13-0894|pmid=24836550|doi-access=free}}</ref><ref name=":4" />

The age of onset of puberty is dependent on genetics, general health, socioeconomic status, and environmental exposures. Children residing closer to the equator, at lower altitudes, in cities and other urban areas generally begin the process of puberty earlier than their counterparts.<ref name=":0" /> Mildly obese to morbidly obese children are also more likely to begin puberty earlier than children of normal weight.<ref name=":13" /> Variations in genes related to obesity, such as FTO or NEGRI, have been associated with earlier onset of puberty.<ref name=":0" /> Children whose parents started puberty at an earlier age were also more likely to experience it themselves, especially in women where onset of menstruation correlated well between mothers and daughters and between sisters.<ref name=":0" />

==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" />

==Diagnosis==
[[Pediatric endocrinology|Pediatric endocrinologists]] are the physicians with the most training and experience in evaluating delayed puberty. A complete medical history, review of systems, growth pattern, and physical examination, as well as laboratory testing and imaging, will reveal most of the systemic diseases and conditions capable of arresting development or delaying puberty, as well as providing clues to some of the recognizable [[syndrome]]s affecting the reproductive system.<ref name=":0" />

Timely medical assessment is a necessity since as many as half of girls with delayed puberty have an underlying pathology.<ref name=":4">{{Cite book|title=Practical pediatric and adolescent gynecology|last=Adams |first= Paula J. Hillard | name-list-style = vanc |date=2013|publisher=Wiley-Blackwell|isbn=9781118538586|oclc=929718561}}</ref>

=== History and physical ===

==== Constitutional and physiologic delay ====
Children with constitutional delay are reported to be shorter than their peers, lacking a [[growth spurt]], and having an overall smaller build.<ref name=":8" /> Their growth has begun to slow down years before the expected growth spurt secondary to puberty, which helps differentiate a constitutional delay from an HPG-axis related disorder.<ref name=":7" /> A complete family history with the ages at which parents hit the pubertal milestones can also provide a reference point for the expected age of puberty.<ref name=":11" /><ref name=":0" /> Growth measurement parameters in children with suspected constitutional delay include a height, a weight, the rate of growth, and the calculated mid-parental height which represents the expected adult height for the child.<ref name=":1" /><ref name=":11" />

==== Malnutrition or chronic disease ====
Diet and physical activity habits, as well as history of previous serious illnesses and medication history can provide clues as to the cause of delayed puberty.<ref name=":0" /> Delayed growth and puberty can be the first signs of severe chronic illnesses such as metabolic disorders including [[inflammatory bowel disease]] and [[hypothyroidism]].<ref name=":0" /> Symptoms such as fatigue, pain, and abnormal stooling pattern are suggestive of an underlying chronic condition.<ref name=":11" /> Low [[Body mass index|BMI]] can lead a physician to diagnose an eating disorder, [[undernutrition]], child abuse, or chronic gastrointestinal disorders.<ref name=":11" />

==== Primary failure of the ovaries or testes ====
A [[eunuchoid]] body shape where the arm span exceeds the height by more than 5&nbsp;cm suggests a delay in growth plate closure secondary to [[hypogonadism]].<ref name=":0" /> [[Turner syndrome]] has unique diagnostic features including a webbed neck, short stature, shield chest, and low hairline.<ref name=":11" /> [[Klinefelter syndrome]] presents with tall stature as well as small, firm testes.<ref name=":11" />

==== Genetic or acquired defect of the hormonal pathway of puberty ====
Lacking the sense of smell ([[anosmia]]) along with delayed puberty are strong clinical indications for [[Kallmann syndrome]].<ref name=":7" /><ref>Oxford Endocrinology Library. Testosterone Deficiency in Men. 2008. {{ISBN|978-0199545131}} Editor: Hugh Jones. Chapter 9. Puberty & Fertility.</ref><ref name=":14">Male Hypogonadism. Friedrich Jockenhovel. Uni-Med Science. 2004. {{ISBN|3-89599-748-X}}. Chapter 3. Diagnostic work up of hypogonadism.</ref> Deficiencies in GnRH, the signalling hormone produced by the hypothalamus, can cause congenital malformations including cleft lip and scoliosis.<ref name=":0" /> The presence of neurological symptoms including headaches and visual disturbances suggest a brain disorder such as a brain tumor causing [[hypopituitarism]].<ref name=":0" /> The presence of neurological symptoms in addition to [[lactation]] are signs of high prolactin levels and could indicate either a drug side effect or a [[prolactinoma]].<ref name=":11" />

=== Imaging ===
[[File:X-ray of hand, where bone age is automatically found by BoneXpert software.jpg|thumb|Determination of bone age allows for comparison with chronological age and assessment of future growth potential.]]
Since bone maturation is a good indicator of overall physical maturation, an [[X-ray]] of the left hand and wrist to assess [[bone age]] usually reveals whether the child has reached a stage of physical maturation at which puberty should be occurring.<ref name=":1" /><ref name=":0" /> X-ray displaying a bone age <11 years in girls or <13 years in boys (despite a higher chronological age) is most often consistent with constitutional delay of puberty.<ref name=":0" /><ref name=":9" /> An MRI of the brain should be considered if neurological symptoms are present in addition to delayed puberty, two findings suspicious for pituitary or hypothalamic tumors.<ref name=":1" /><ref name=":7" /> An MRI can also confirm the diagnosis of [[Kallmann syndrome]] due to the absence or abnormal development of the olfactory tract.<ref name=":7" /> However, in the absence of clear neurological symptoms, an MRI may not be the most cost-effective option.<ref name=":7" /> A pelvic ultrasound can detect anatomical abnormalities including undescended testes and [[Müllerian agenesis]].<ref name=":1" /><ref name=":5" />

=== Laboratory evaluation ===
[[File:Delayed Puberty.png|alt=|thumb|Workup for delayed puberty]]
The first step in evaluating children with delayed puberty involves differentiating between the different causes of delayed puberty. Constitutional delay can be evaluated with a thorough history, physical, and bone age.<ref name=":11" /> Malnutrition and chronic diseases can be diagnosed through history and disease-specific testing.<ref name=":1" /> Screening studies include a complete blood count, an [[erythrocyte sedimentation rate]], and thyroid studies.<ref name=":1" /> [[Hypogonadism]] can be differentiated between hyper- and hypo-gonadotropic hypogonadism by measuring serum [[follicle-stimulating hormone]] (FSH) and [[luteinizing hormone]] (LH) ([[gonadotropin]]s to measure pituitary output), and estradiol in girls (to measure gonadal output).<ref name=":0" /><ref name=":5" /> By the age of 10–12, children with failure of the ovaries or testes will have high LH and FSH because the brain is attempting to jump-start puberty, but the gonads are not responsive to these signals.<ref name=":0" /><ref name=":1" />

Stimulating the body by administering an artificial version of [[gonadotropin-releasing hormone]] (GnRH, the hypothalamic hormone) can differentiate between constitutional delay of puberty and a GnRH deficiency in boys, although no studies have been done in girls to prove this.<ref name=":0" /><ref>{{cite journal | vauthors = Jungmann E, Trautermann C | title = [The status of the gonadotropin releasing hormone test in differential diagnosis of delayed puberty in adolescents over 14 years of age] | language = de | journal = Medizinische Klinik | volume = 89 | issue = 10 | pages = 529–33 | date = October 1994 | pmid = 7808353 }}</ref> It is often sufficient to simply measure the baseline gonadotrophin levels to differentiate between the two.<ref name=":7" />

In girls with [[hypogonadotropic hypogonadism]], a serum [[prolactin]] level is measured to identify if they have the pituitary tumor [[prolactinoma]]. High levels of prolactin would warrant further testing with MRI imaging, except if drugs inducing the production of prolactin can be identified.<ref name=":0" /> If the child has any neurological symptoms, it is highly recommended that the physician obtains a head MRI to detect possible brain lesions.<ref name=":0" />

In girls with [[hypergonadotropic hypogonadism]], a [[karyotype]] can identify chromosomal abnormalities, the most common of which is [[Turner syndrome]].<ref name=":0" /> In boys, a karyotype is indicated if the child may have a congenital gonadal defect such as [[Klinefelter syndrome]].<ref name=":1" /> In children with a normal karyotype, defects in the synthesis of the [[Adrenal gland|adrenal]] steroid sex hormones can be identified by measuring [[17-hydroxylase]], an important enzyme involved in the production of sex hormones.<ref name=":0" />

==Management==
The goals of short-term hormone therapy are to induce the beginning of sexual development and induce a growth spurt, but it should be limited to children with severe distress or anxiety secondary to their delayed puberty.<ref name=":1" /><ref name=":0" /> Bone age must be monitored frequently to prevent precocious closure of the bone plates, thereby stunting growth.<ref name=":0" />

=== Constitutional and physiologic delay ===
If a child is healthy with a constitutional delay of growth and puberty, reassurance and prediction based on the bone age can be provided.<ref name=":7" /><ref name=":8" /> No other intervention is usually necessary, but repeat evaluation by measuring serum testosterone or estrogen is recommended.<ref name=":1" /><ref name=":11" /><ref name=":0" /> Furthermore, the diagnosis of [[hypogonadism]] can be excluded once the adolescent has started puberty by age 16–18.<ref name=":11" /><ref name=":9" />

Boys over 14 years of age whose growth is severely stunted or are experiencing severe distress secondary to their lack of puberty can be started on [[testosterone]] to increase their height.<ref name=":7" /> Testosterone treatment can also be used to stimulate sexual development, but it can close bone plates prematurely stopping growth altogether if not carefully administered.<ref name=":6">{{Cite book|title=Brody's human pharmacology : molecular to clinical| first=Lynn|last=Wecker | name-list-style = vanc |date=2010|publisher=Elsevier Mosby|isbn=9780323053747|oclc=804133604}}</ref><ref name=":0" /> Another therapeutic option is the use of [[aromatase inhibitor]]s to inhibit the conversion of androgens to estrogens as estrogens are responsible for stopping bone growth plate development and thus growth.<ref name=":7" /> However, due to side effects, therapy with testosterone alone is most often used.<ref name=":7" /> Overall, neither growth hormone nor aromatase inhibitors are recommended for constitutional delay to increase growth.<ref name=":8" /><ref>{{cite journal | vauthors = Wit JM, Oostdijk W | title = Novel approaches to short stature therapy | journal = Best Practice & Research. Clinical Endocrinology & Metabolism | volume = 29 | issue = 3 | pages = 353–66 | date = June 2015 | pmid = 26051296 | doi = 10.1016/j.beem.2015.01.003 | series = Hormone replacement strategies in paediatric and adolescent endocrine disorders }}</ref>

Girls can be started on [[estrogen]] with the same goals as their male counterparts.<ref name=":7" />

Overall, studies have shown no significant difference in final adult height between adolescents treated with sex steroids and those who were only observed with no treatment.<ref name=":02">{{cite journal | vauthors = Zhu J, Chan YM | title = Adult Consequences of Self-Limited Delayed Puberty | journal = Pediatrics | volume = 139 | issue = 6 | pages = e20163177 | date = June 2017 | pmid = 28562264 | doi = 10.1542/peds.2016-3177 | pmc = 8579478 | s2cid = 41944095 }}</ref>

=== Malnutrition or chronic disease ===
If the delay is due to systemic disease or [[malnutrition]], the therapeutic intervention is likely to focus direction on those conditions. In patients with [[coeliac disease]], an early diagnosis and the establishment of a [[gluten-free diet]] prevents long-term complications and allows restoration of normal maturation.<ref name="Mearin2015" /><ref name="LevyBernstein2014" /> Thyroid hormone therapy will be necessary in the case of hypothyroidism.<ref name=":0" />

=== Primary failure of the ovaries or testes (hypergonadotropic hypogonadism) ===
Whereas children with constitutional delay will have normal levels of sex hormones post-puberty, gonadotropin deficiency or hypogonadism may require lifelong sex steroid replacement.<ref name=":1" />

In girls with [[primary ovarian failure]], [[estrogen]] should be started when puberty is supposed to start.<ref name=":0" /> [[Progestin]]s are usually added after there is acceptable breast development, about 12 to 24 months after starting estrogen, as starting treatment with progestin too early can negatively affect breast growth.<ref name=":0" /> After acceptable breast growth, administering [[estrogen]] and [[progestin]] in a cyclical manner can help establish regular menses once puberty is started.<ref name=":6" /><ref name=":9" /> The goal is to complete sexual maturation over 2 to 3 years.<ref name=":0" /> Once sexual maturation has been achieved, a trial period with no hormonal therapy can determine whether or not the child will require life-long treatment.<ref name=":1" /> Girls with congenital GnRH deficiency require enough sex hormone supplementation to maintain body levels in the expected pubertal levels necessary to induce ovulation, especially when fertility is a concern.<ref name=":0" />

Males with primary failure of the testes will be on lifelong [[testosterone]].<ref name=":14" />

Pulsatile GnRH, weekly multi-LH, or hCG and FSH can be used to induce fertility in adulthood for both males and females.<ref name=":7" /><ref name=":9" />

=== Genetic or acquired defect of the hormonal pathway of puberty (hypogonadotropic hypogonadism) ===
Boys aged >12 years old with [[hypogonadotropic hypogonadism]] are most often treated with short-term testosterone while males with testicular failure will be on life-long [[testosterone]].<ref name=":7" /><ref name=":10">{{cite journal | vauthors = Watson S, Fuqua JS, Lee PA | title = Treatment of hypogonadism in males | journal = Pediatric Endocrinology Reviews | volume = 11 | pages = 230–9 | date = February 2014 | issue = Suppl 2 | pmid = 24683947 }}</ref><ref name="legato">{{cite book | veditors = Legato MJ | editor-link = Marianne Legato | date = 2004 | title = Principles of Gender-Specific Medicine | volume = 1–2 | isbn = 978-0-12-440905-7 | page = 22 | last1 = Legato | first1 = Marianne J. | last2 = Bilezikian | first2 = John P. | publisher = Elsevier Science }}</ref> Choice of formulation (topical vs injection) is dependent on the child's and family's preference as well as on how well they tolerate side effects.<ref name=":10" /> Although testosterone therapy alone will result in the start of puberty, to increase fertility potential, they may need pulsatile GnRH or hCG with rFSH.<ref name=":7" /><ref name=":10" /> hCG can be used by itself in boys with spontaneous onset of puberty from non-permanent forms of [[hypogonadotropic hypogonadism]] and rFSH can be added in cases of low sperm count after 6 to 12 months of treatment.<ref name=":7" />

If puberty has not started after 1 year of treatment, then permanent [[hypogonadotropic hypogonadism]] should be considered.<ref name=":7" />

Girls with hypogonadotropic hypogonadism are started on the same sex steroid therapy as their counterparts with a constitutional delay, however doses are gradually increased to reach full adult replacement levels.<ref name=":7" /> Dosage of estrogen is titrated based on the woman's ability to have withdrawal bleeds and to maintain appropriate bone density.<ref name=":7" /> Induction of fertility must also be done through pulsatile GnRH.<ref name=":7" />

=== Others ===
[[Growth hormone]] is another option that has been described, however it should only be used in proven growth hormone deficiency<ref>{{cite journal | vauthors = Heinrichs C, Bourguignon JP | title = Treatment of delayed puberty and hypogonadism in girls | journal = Hormone Research | volume = 36 | issue = 3–4 | pages = 147–52 | year = 1991 | pmid = 1818011 | doi = 10.1159/000182149 | hdl = 2268/260267 | hdl-access = free }}</ref><ref name="pmid12970282">{{cite journal | vauthors = Massa G, Heinrichs C, Verlinde S, Thomas M, Bourguignon JP, Craen M, François I, Du Caju M, Maes M, De Schepper J | title = Late or delayed induced or spontaneous puberty in girls with Turner syndrome treated with growth hormone does not affect final height | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 88 | issue = 9 | pages = 4168–74 | date = September 2003 | pmid = 12970282 | doi = 10.1210/jc.2002-022040 | hdl = 2268/257143 | hdl-access = free }}</ref> such as [[idiopathic short stature]].<ref name=":7" /> Children with a constitutional delay have not been shown to benefit from growth hormone therapy.<ref name=":7" /> Although serum growth hormone levels are low in constitutional delay of puberty, they increase after treatment with sex hormones and in those cases, growth hormone is not suggested to accelerate growth.<ref name=":0" />

Subnormal [[vitamin A]] intake is one of the etiological factors in delayed pubertal maturation. Supplementation of both vitamin A and [[iron]] to normal constitutionally delayed children with subnormal vitamin A intake is as efficacious as hormonal therapy in the induction of growth and puberty.<ref>{{cite journal | vauthors = Zadik Z, Sinai T, Zung A, Reifen R | title = Vitamin A and iron supplementation is as efficient as hormonal therapy in constitutionally delayed children | journal = Clinical Endocrinology | volume = 60 | issue = 6 | pages = 682–7 | date = June 2004 | pmid = 15163330 | doi = 10.1111/j.1365-2265.2004.02034.x | s2cid = 27016335 }}</ref>

More therapies are being developed to target the more discreet modulators of the [[HPG axis]] including [[kisspeptin]] and [[neurokinin B]].<ref>{{cite book | vauthors = Newton CL, Anderson RC, Millar RP | title = Advanced Therapies in Pediatric Endocrinology and Diabetology | chapter = Therapeutic Neuroendocrine Agonist and Antagonist Analogs of Hypothalamic Neuropeptides as Modulators of the Hypothalamic-Pituitary-Gonadal Axis | language = en | journal = Endocrine Development | volume = 30 | pages = 106–29 | date = 2016 | pmid = 26684214 | doi = 10.1159/000439337 | isbn = 978-3-318-05636-5 }}</ref><ref>{{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 }}</ref>

In cases of severe delayed puberty secondary to [[hypogonadism]], evaluation by a psychologist or psychiatrist, as well as counseling and a supportive environment are an important supplemental therapy for the child.<ref name=":1" /><ref name="pmid25735941">{{cite book | vauthors = Berenbaum SA, Beltz AM, Corley R | title = The importance of puberty for adolescent development: conceptualization and measurement | journal = Advances in Child Development and Behavior | volume = 48 | pages = 53–92 | date = 2015 | pmid = 25735941 | doi = 10.1016/bs.acdb.2014.11.002 | isbn = 9780128021781 }}</ref> Transition from pediatric to adult care is also vital as many children are lost during transition of care.<ref name=":8" />

== Outlook ==
Constitutional delay of growth and puberty is a variation of normal development with no long-term health consequences, however it can have lasting psychological effects.<ref name=":02" /><ref>{{Cite book|title=Endocrinology adult and pediatric : reproductive endocrinology| first1 = J. Larry | last1 = Jameson | first2 = David | last2 = de Kretser | first3 = John C. | last3 = Marshall | name-list-style = vanc |isbn=9780323240604 |edition=6th |location=Philadelphia |oclc=881479176 |year = 2013}}</ref> Adolescent boys with delayed puberty have a higher level of anxiety and depression relative to their peers.<ref name=":82">{{cite journal | vauthors = Dwyer AA, Phan-Hug F, Hauschild M, Elowe-Gruau E, Pitteloud N | title = TRANSITION IN ENDOCRINOLOGY: Hypogonadism in adolescence | 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> Children with delayed puberty also display decreased academic performance in their adolescent education, but changes in academic achievement in adulthood have not been determined.<ref name=":02" />

There is conflicting evidence as to whether or not children with constitutional growth and pubertal delay reach their full height potential.<ref name=":02" /> The conventional teaching is that these children catch up on their growth during the pubertal growth spurt and just remain shorter before their delayed puberty starts.<ref>{{cite journal | vauthors = Prader A | title = Delayed adolescence | journal = Clinics in Endocrinology and Metabolism | volume = 4 | issue = 1 | pages = 143–55 | date = March 1975 | pmid = 166776 | doi = 10.1016/S0300-595X(75)80037-5 }}</ref> However, some studies show that these children fall short of their target height from about 4 to 11&nbsp;cm.<ref name=":02" /> Factors that could affect final height include familial short stature and pre-pubertal growth development.<ref name=":02" />

Pubertal delay can also affect bone mass and subsequent development of osteoporosis.<ref>{{cite journal | author = NIH Consensus Development Panel on Osteoporosis Prevention Diagnosis and Therapy | title = Osteoporosis prevention, diagnosis, and therapy | journal = JAMA | volume = 285 | issue = 6 | pages = 785–95 | date = February 2001 | pmid = 11176917 | doi = 10.1001/jama.285.6.785 }}</ref> Men with delayed puberty often have low to normal [[bone mineral density]] unaffected by [[androgen]] therapy.<ref name=":02" /> Women are more likely to have lower bone mineral density and thus an increased risk of fractures as early as even before the onset of puberty.<ref name=":02" />

Furthermore, delayed puberty is correlated with a higher risk in cardiovascular and metabolic disorders in women only, but also appears to be protective for breast and endometrial in women and testicular cancer in men.<ref name=":02" />

== See also ==
* [[Developmental milestones]]
* [[Endocrinology]]
* [[Puberty]]
* [[Constitutional growth delay]]
* [[Hypogonadism]]
* [[Kallmann syndrome]]
* [[Turner syndrome]]
* [[Klinefelter syndrome]]

== References ==
{{Reflist}}

== External links ==
{{Gonadal disorder}}
{{Medical resources
|   ICD11       = {{ICD11|5A91}}
|   ICD10       = {{ICD10|E|30|0|e|20}}
|   ICD9        = {{ICD9|259.0}}
|   DiseasesDB     = 17462
|   MeshID         = D011628
}}
{{Authority control}}

{{DEFAULTSORT:Delayed Puberty}}
[[Category:Puberty]]
[[Category:Endocrine gonad disorders]]
[[Category:Gonadotropin-releasing hormone and gonadotropins]]
[[Category:Pediatrics]]
[[Category:Sexuality and age]]
[[Category:Sexual health]]
[[Category:Human female endocrine system]]