Delayed puberty pathophysiology: Difference between revisions

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__NOTOC__
__NOTOC__
{{Delayed puberty}}
{{Delayed puberty}}
{{CMG}}; {{AE}}
{{CMG}}; {{AE}}{{EG}}


==Overview==
==Overview==
Delayed puberty is the result of disturbances in [[HPGD|hypothalamus-pituitary-gonadal]] (HPG) axis. Genetics plays an important role in the development of delayed puberty. In case of [[Constitutional delay of puberty|constitutional delay of growth and puberty (CDGP)]],  50-75% of patients have a positive family history of delayed [[puberty]]. About 25 various [[genes]], in 3 different group of [[Kallman syndrome|Kallmann syndrome]]-related genes, [[hypothalamus]]-[[pituitary]]-[[gonadal]] (HPG) axis related genes, and [[obesity|obesity-]]<nowiki/>related [[genes]] play roles in delayed [[puberty]]. On gross pathology, lack of [[testicular]] enlargement in boys or [[breast]] development in girls is the characteristic finding of delayed [[puberty]]. Microscopic evaluation of [[ovaries]] in a patient with delayed [[puberty]] may reveal the presence of normal [[Cuboidal epithelium|cuboidal epithelium]]; the [[ovary]] has some dense [[fibrous tissue]], about 0.4 mm thick band, in the [[cortex]]. The band is extended under the [[tunica albuginea]], devoid of [[Follicle|follicles]]. Under the fibrous band, there will be numerous small [[Follicle|follicles]]. These [[Follicle|follicles]] consist of primordial (51%), intermediary (42%), and primary (7%) [[Follicle|follicles]].


==Pathophysiology==
==Pathophysiology==
===Pathogenesis===
===Pathogenesis===
*It is absolute that delayed puberty is the result of any disturbances in [[hypothalamus]]-[[pituitary]]-[[gonadal]] (HPG) axis.  
*Delayed puberty is the result of disturbances in [[hypothalamus]]-[[pituitary]]-[[gonadal]] (HPG) axis.  
*The components of HPG axis is already well identified and oriented, but the main signal of starting the [[puberty]] is not cleared completely, yet. It is not obvious that why some children start puberty at 11 and some others start at 14.
*The components of HPG axis are already well identified and oriented, but the main signal of starting [[puberty]] is not completely understood. It is not understood why some children start puberty at 11 and some others later.
*Intact HPG axis is the main factor that a child need to become maturated. The beginning of the pathway is with [[Gonadotropin releasing hormone|gonadotropin releasing hormone (GnRH)]] production from [[hypothalamus]]. Then, [[GnRH]] stimulates the gonadotropic cells in [[anterior pituitary]] gland, producing [[Luteinizing hormone|luteinizing hormone (LH)]] and [[Follicle stimulating hormone|follicle stimulating hormone (FSH)]]. Finally, [[LH]] and [[FSH]] stimulate the [[gonads]] maturation to produce the [[Sex steroids|sex-steroids]], firing the [[puberty]] process.  
*Intact HPG axis is the main factor required for the development of maturation in a child. The beginning of the pathway is with [[Gonadotropin releasing hormone|gonadotropin releasing hormone (GnRH)]] production from the [[hypothalamus]]. Then, [[GnRH]] stimulates the gonadotropic cells in the [[anterior pituitary]] gland, producing [[Luteinizing hormone|luteinizing hormone (LH)]] and [[Follicle stimulating hormone|follicle stimulating hormone (FSH)]]. Finally, [[LH]] and [[FSH]] stimulate the [[gonads]] maturation to produce the [[Sex steroids|sex-steroids]], firing the [[puberty]] process.  
*Every single failure in the mentioned pathway could lead to postpone the [[puberty]], delayed [[puberty]]. The failure may be congenital or acquired during the life.<ref name="PalmertDunkel2012">{{cite journal|last1=Palmert|first1=Mark R.|last2=Dunkel|first2=Leo|title=Delayed Puberty|journal=New England Journal of Medicine|volume=366|issue=5|year=2012|pages=443–453|issn=0028-4793|doi=10.1056/NEJMcp1109290}}</ref>  
*Every single failure in the mentioned pathway could lead to delayed [[puberty]]. The failure may be congenital or acquired during the life.<ref name="PalmertDunkel2012">{{cite journal|last1=Palmert|first1=Mark R.|last2=Dunkel|first2=Leo|title=Delayed Puberty|journal=New England Journal of Medicine|volume=366|issue=5|year=2012|pages=443–453|issn=0028-4793|doi=10.1056/NEJMcp1109290}}</ref>  
{| class="wikitable"
{| class="wikitable"
!Group
!Group
Line 20: Line 21:
| rowspan="2" |Congenital
| rowspan="2" |Congenital
|[[Chromosomal abnormality]]  
|[[Chromosomal abnormality]]  
|Lack or disorder of an specific [[cell line]] or [[enzyme]] that are responsible to produce one of [[Sex steroids|sex-steroids]] in [[gonads]]
|Lack or disorder of a specific [[cell line]] or [[enzyme]] that is responsible for producing one of the [[Sex steroids|sex-steroids]] in [[gonads]]
|-
|-
|[[Gonadal agenesis]]
|[[Gonadal agenesis]]
|Lack of [[gonads]], as main source of [[Sex steroids|sex-steroids]]
|Lack of [[gonads]], as a main source of [[Sex steroids|sex-steroids]]
|-
|-
|Acquired  
|Acquired  
Line 32: Line 33:
| rowspan="2" |Congenital
| rowspan="2" |Congenital
|[[GnRH]] deficiency
|[[GnRH]] deficiency
|Lack or disorder of an specific [[cell line]] or [[enzyme]] that are responsible to produce [[GnRH]] in [[hypothalamus]]
|Lack or disorder of a specific [[cell line]] or [[enzyme]] that is responsible for producing [[GnRH]] in [[hypothalamus]]
|-
|-
|[[LH]] and [[FSH]] deficiency
|[[LH]] and [[FSH]] deficiency
|Lack or disorder of an specific [[cell line]] or [[enzyme]] that are responsible to produce [[LH]] or [[FSH]] in [[pituitary]] gonadotropic cells
|Lack or disorder of a specific [[cell line]] or [[enzyme]] that is responsible for producing [[LH]] or [[FSH]] in [[pituitary]] gonadotropic cells
|-
|-
|Acquired  
|Acquired  
|Any external stress to the [[hypothalamus]] or [[anterior pituitary]]
|Any external stress to the [[hypothalamus]] or [[anterior pituitary]]
|Destruction of [[hypothalamus]] or [[anterior pituitary]] cell line, responsible for producing and secreting [[GnRH]], [[LH]], or [[FSH]]
|Destruction of [[hypothalamus]] or [[anterior pituitary]] cell line, responsible for producing and secreting [[GnRH]], [[LH]], or [[FSH]]
|}
==== Antimullerian hormone and inhibin B ====
* [[Antimullerian hormone]] and [[Inhibin|inhibin B]] are two [[glycoproteins]] that are secreted from [[gonads]] and can reflect their activity level. Their plasma level changes reflect the [[puberty]] status in children, as follows:<ref name="pmid26353794">{{cite journal |vauthors=Wei C, Crowne EC |title=Recent advances in the understanding and management of delayed puberty |journal=Arch. Dis. Child. |volume=101 |issue=5 |pages=481–8 |year=2016 |pmid=26353794 |doi=10.1136/archdischild-2014-307963 |url=}}</ref>
{| class="wikitable"
!Sex
!Hormone
!Source of secretion
!After birth
!Childhood
!Puberty
!Function
|-
| rowspan="2" |Boys
|[[Antimullerian hormone]]
|[[Sertoli cells]] of [[testes]]
|↑
|↓
|↓
|
* Female structures ([[Müllerian duct|mullerian]]) regression
* Inhibited by [[testosterone]] in [[puberty]]
|-
|[[Inhibin|Inhibin B]]
|[[Sertoli cells]] of [[testes]]
|↑
|↓
|↑
|
* Inhibit the [[FSH]] through negative feedback
* Marker of [[spermatogenesis]]
|-
| rowspan="2" |Girls
|[[Antimullerian hormone]]
|[[Granulosa cells]] of preantral [[follicles]] in [[ovary]]
|↑
|↑
|↓
|
* Marker for the assessment of follicular pool
|-
|[[Inhibin|Inhibin B]]
|Both preantral and small antral follicles in [[ovary]]
|↓
|↓
|↑
|
* Marker of [[gonadal]] response to [[LH]] and [[FSH]]
|}
|}


==Genetics==
==Genetics==
Delayed puberty has found to be on a genetic basis, most of the times. It is assumed that the main factor in determining the puberty timing is genetic elements.<ref name="pmid20144687">{{cite journal |vauthors=Gajdos ZK, Henderson KD, Hirschhorn JN, Palmert MR |title=Genetic determinants of pubertal timing in the general population |journal=Mol. Cell. Endocrinol. |volume=324 |issue=1-2 |pages=21–9 |year=2010 |pmid=20144687 |pmc=2891370 |doi=10.1016/j.mce.2010.01.038 |url=}}</ref>  
* Genetics plays an important role in delayed puberty. It is assumed that the main factor in determining [[puberty]] timing is [[genetic]] elements.<ref name="pmid20144687">{{cite journal |vauthors=Gajdos ZK, Henderson KD, Hirschhorn JN, Palmert MR |title=Genetic determinants of pubertal timing in the general population |journal=Mol. Cell. Endocrinol. |volume=324 |issue=1-2 |pages=21–9 |year=2010 |pmid=20144687 |pmc=2891370 |doi=10.1016/j.mce.2010.01.038 |url=}}</ref>
 
* In case of [[Constitutional delay of puberty|constitutional delay of growth and puberty (CDGP)]], 50-75% of patients have a positive family history of delayed [[puberty]].<ref name="pmid18160460">{{cite journal |vauthors=Wehkalampi K, Widén E, Laine T, Palotie A, Dunkel L |title=Patterns of inheritance of constitutional delay of growth and puberty in families of adolescent girls and boys referred to specialist pediatric care |journal=J. Clin. Endocrinol. Metab. |volume=93 |issue=3 |pages=723–8 |year=2008 |pmid=18160460 |doi=10.1210/jc.2007-1786 |url=}}</ref>
 
* It is thought that [[Constitutional delay of puberty|CDGP]] is inherited in an [[autosomal dominant]] pattern, with or without the effects of complete [[penetrance]].
* Delayed puberty is not a sex oriented [[inheritance]] and can be seen in all family members.<ref name="pmid12466356">{{cite journal |vauthors=Sedlmeyer IL, Hirschhorn JN, Palmert MR |title=Pedigree analysis of constitutional delay of growth and maturation: determination of familial aggregation and inheritance patterns |journal=J. Clin. Endocrinol. Metab. |volume=87 |issue=12 |pages=5581–6 |year=2002 |pmid=12466356 |doi=10.1210/jc.2002-020862 |url=}}</ref>
 
=== The major genes in delayed puberty ===
<span style="font-size:85%">'''Abbreviations (alphabetic):'''<br>
'''CHD7:''' Chromodomain [[helicase]] DNA-binding protein 7 gene, '''DAX1:''' DSS-AHC on the [[X-chromosome]] 1, '''EBF2:''' Early [[B-cell]] factor 2 gene, '''FGF8:''' [[Fibroblast growth factor 8]] gene, '''FGFR1:''' [[Fibroblast growth factor receptor 1]] gene, '''FSH:''' [[Follicle stimulating hormone]], '''GnRH:''' [[Gonadotropin releasing hormone]], '''GnRH1:''' [[Gonadotropin releasing hormone]] 1 gene, '''GnRHR:''' [[Gonadotropin releasing hormone]] receptor gene, '''GPR54:''' [[G protein-coupled receptor|G protein-coupled receptor-54]] gene, '''HESX-1:''' [[Homeobox]] gene 1, '''HPG axis:''' Hypothalamus-pituitary-gonadal axis, '''HS6ST1:''' [[Heparan sulfate]] 6-O-sulphotransferase 1 gene, '''KAL1:''' [[Kallman syndrome|Kallmann syndrome]] 1 gene, '''LEP:''' [[Leptin]] gene''', LEPR:''' [[Leptin receptor]] gene''', LH:''' [[Luteinizing hormone]], '''LHX3:''' LIM [[homeobox]] gene 3''', NEC1:''' [[Neuroendocrine]] convertase 1, '''NELF:''' Nasal embryonic LH-releasing hormone factor gene, '''NK3R:''' [[Neurokinin]] 3 receptor gene, '''NKB:''' [[Neurokinin B]] gene,  '''NR0B:''' [[Nuclear receptor]] 0B, '''NR5A1:''' [[Nuclear receptor]] 5A1, '''OMIM:''' [[Online Mendelian Inheritance in Man]], '''PC1:''' [[Proprotein]] convertase 1''', PROK2 :''' [[Prokineticin]] 2 gene, '''PROKR2:''' [[Prokineticin]] 2 receptor gene, '''PROP-1:''' [[PROP]] paired-like homeobox 1, '''RPX:''' [[Rathke pouch]] homeobox, '''SF-1:''' [[Steroidogenic]] factor 1, '''TAC3:''' [[Tachykinin]] 3 gene,'''TACR3:''' [[Tachykinin]] 3 receptor gene,
</span>
{| class="wikitable"
!Groups
!Gene
!Other name(s)
!OMIM number
!Chromosome
!Function
!Other related disorders
|-
| rowspan="15" |'''Kallmann syndrome'''
and
 
'''Isolated hypogonadotropic hypogonadism'''<ref name="BonomiLibri2011">{{cite journal|last1=Bonomi|first1=Marco|last2=Libri|first2=Domenico Vladimiro|last3=Guizzardi|first3=Fabiana|last4=Guarducci|first4=Elena|last5=Maiolo|first5=Elisabetta|last6=Pignatti|first6=Elisa|last7=Asci|first7=Roberta|last8=Persani|first8=Luca|title=New understandings of the genetic basis of isolated idiopathic central hypogonadism|journal=Asian Journal of Andrology|volume=14|issue=1|year=2011|pages=49–56|issn=1008-682X|doi=10.1038/aja.2011.68}}</ref>
|'''KAL1'''
|[[KAL1 gene|KAL1]], [[anosmin-1]]
|308700
|Xp22.3
|
* Migration of [[GnRH]] [[neurons]]
* [[Olfactory bulb]] development
|
* Midline facial defects ([[cleft lip]] and/or [[cleft palate]])
* Short [[metacarpals]]
* [[Renal agenesis]]
* [[Sensorineural hearing loss]]
* Bimanual [[synkinesis]]
* [[Oculomotor]] abnormalities
* [[Cerebellar ataxia]]
|-
|'''FGFR1'''
|KAL2
|136350
|8q12
|
* [[Embryogenesis]]
* [[Homeostasis]]
* [[Wound healing]]
* [[Olfactory bulb]] differentiation and development
* [[GnRH]] [[neurons]] migration and function
|
* [[Cleft palate]] or [[Cleft lip|lip]]
* Dental [[agenesis]]
* Bimanual [[synkinesis]]
|-
|'''PROKR2'''
|KAL3
|607123
|20p13
| rowspan="2" |
* [[Neuroendocrine system]] ([[arcuate nucleus]], [[olfactory tract]], and [[suprachiasmatic nucleus]])
* [[Olfactory bulb]] development
* [[Gonadal]] development
* [[GnRH]] increase
| rowspan="2" |
* [[Fibrous dysplasia]]
* [[Sleep disorder]]
* Severe [[obesity]]
* [[Synkinesis]]
* [[Epilepsy]]
|-
|'''PROK2'''
|KAL4
|607002
|3p21.1
|-
|'''CHD7'''
|KAL5
|608892
|8q12.1
|
* [[Olfactory bulb]] development
|
* [[CHARGE syndrome]]:
** [[Coloboma|'''C'''olobomata]]
** [[Heart|'''H'''eart]] anomalies
** [[Choanal atresia|Choanal '''A'''tresia]]
** [[Retardation|'''R'''etardation]]
** [[Genital|'''G'''enital]] anomalies
** [[Ear|'''E'''ar]] anomalies
|-
|'''FGF8'''
|KAL6
|600483
|10q24
|
* Primary generation of [[neural tissue]]
* [[Olfactory bulb]] differentiation and development
* [[GnRH]] neurons migration and function
|
* [[Cardiac]] developmental abnormalities
* [[Craniofacial]] developmental abnormalities
* [[Forebrain]] developmental abnormalities
* [[Midbrain]] developmental abnormalities
* [[Cerebellar]] developmental abnormalities
|-
|'''GPR54'''
|KISS1R
|604161
|19p13.3
|
* Regulation of [[GnRH]] secretion
| -
|-
|'''KISS1'''
|KISS1, kisspeptin1
|603286
|1q32
|
* Sexual [[maturation]] and HPG activation with pulsatile [[GnRH]]
| -
|-
|'''HS6ST1'''
| -
|604846
|2q21
|
* Extracellular sugar modifications
* [[FGFR]]-[[FGF1|FGF]] interactions modulator
* [[Anosmin-1]] interaction with [[cell membrane]]
| -
|-
|'''TAC3'''
|NKB
|162330
|12q13–q21
| rowspan="2" |
* HPG axis function
* Stabilize development during [[puberty]]
* Fetal [[gonadotropins]] secretion
* [[GnRH]] secretion regulation
| rowspan="2" |
* [[Micropenis]]
* [[Cryptorchidism]]
|-
|'''TACR3'''
|NK3R
|152332
|4q25
|-
|'''GnRH1'''
| -
|152760
|8p21–8p11.2
|
* One of the most important elements in HPG axis
|
* [[Teeth]] abnormal [[maturation]] and biomineralization
|-
|'''GnRHR'''
| -
|138850
|4q21.2
|
* [[Gonadal]] normal functions
|
* Atrophic [[gonads]] along with low [[LH]]/[[FSH]] and [[sex hormones]]
* Sexual [[puberty]] disturbance
* Inability to [[Conceive a child|conceive]]
* Failure to impact from exogenous [[GnRH]]
|-
|'''NELF'''
| -
|608137
|''9q34.3''
|
* ''Modulating [[neuron]] migration in developmental process''
* ''[[Olfactory]] axons and also [[GnRH]] [[neurons]] functions''
| -
|-
|'''EBF2'''
| -
|609934
|''8p21.2''
|
* Effective role in HPG axis
| -
|-
| rowspan="5" |'''HPG axis development'''
|'''DAX1'''
|NR0B
|300473
|''Xp21.2''
|
* Increased expression during the [[spermatogenesis]] and [[steroidogenesis]]
* Both [[Sertoli cell|sertoli]] and [[leydig cells]]
* Peak expression during [[puberty]]
|
* Congenital [[Adrenal cortex insufficiency|adrenal cortex hypoplasia]]
|-
|'''SF-1'''
|NR5A1
|184757
|''9q33.3''
|
* Mainly expressed in [[Sertoli cell|sertoli]] and [[leydig cells]]
* Plays an important role in [[steroidogenesis]] and [[spermatogenesis]]
* Dominantly expressed by [[leydig cells]] in [[puberty]]
|
* Male [[pseudohermaphroditism]]
* [[Denys-Drash syndrome]]
* [[Hypospadias]]
|-
|'''HESX-1'''
|RPX
|601802
|''3p14.3''
|
* ''[[Pituitary]] development''
* ''Midfacial differentiation''
* ''[[Mutation]] may lead to [[pituitary]] [[hypoplasia]]''
|
* Septooptic dysplasia
* Reduced [[prosencephalon]]
* [[Anophthalmia]]
* [[Microphthalmia]]
* Defective [[olfactory]] development
* [[Rathke pouch]] bifurcations
* Abnormalities in the [[corpus callosum]], [[hippocampus]], and [[septum pellucidum]]
|-
|'''LHX3'''
|LIM3
|600577
|''9q34.3''
|
* Development of [[pituitary gland]] and its [[hormone]] secretion
|
* Neonatal [[hypoglycemia]]
* Short neck with limited rotation
* Mild [[Sensorineural hearing loss|sensorineural hearing loss]]
* Skin laxity
* Skeletal abnormalities
|-
|'''PROP-1'''
| -
|601538
|''5q35.3''
|
* ''Developing anterior [[pituitary gland]]''
* ''[[Gonadotrophs]]''
* ''[[Thyrotrophs|Tthyrotrophs]]''
* ''[[Somatotrophs]]''
* ''[[Lactotrophs|Lactotrophs]]''
* Low [[LH]] and [[FSH]] delay the [[puberty]]
|
* [[Thyroid]] dysfunctions
* [[Growth retardation]]
* [[Libido]]/[[Lactation]] problems
|-
| rowspan="3" |'''Obesity related'''
'''hypogonadotropic hypogonadism'''
|'''LEP'''
|OB
|164160
|''7q32.1''
| rowspan="2" |
* ''Modulation of [[body weight]]''
* Beginning the [[puberty]]
* [[Recombinant]] [[leptin]] injection in female mice result in [[puberty]]
* Increased about 50% just before [[puberty]] and also during the [[puberty]]
| rowspan="2" |
* [[Hematopoiesis]] disorders
* [[Angiogenesis]] disorders
* [[Wound healing]] disorders
* [[Immune]] or [[inflammatory response]] disorders
|-
|'''LEPR'''
|OBR
|601007
|''1p31.3''
|-
|'''PC1'''
|NEC1
|162150
|''5q15''
|
* ''Regulates [[neuroendocrine]] pathway''
* [[Proopiomelanocortin]] (POMC) cleavage
* Processing [[proinsulin]] and [[proglucagon]] in [[pancreas]].
|
* Extreme childhood [[obesity]]
* Abnormal glucose [[homeostasis]]
* [[Hypocortisolism]]
* Elevated plasma [[proinsulin]], and also [[POMC]]
|}
 
=== Kisspeptin system (KISS1R and KISS1) ===
* The GPR54 [[gene]], also called KISS1R, with [[Online Mendelian Inheritance in Man|Online Mendelian Inheritance in Man (OMIM)]] number of 604161 is on chromosome 19p13.3. The KISS1 gene, also called [[Kisspeptin|kisspeptin1]], with [[OMIM]] number of 603286 is on [[chromosome]] 1q32.
* The [[GnRH]] secretion has to be pulsatile to stimulate [[gonadotropins]]. In regulation of [[GnRH]] secretion, [[kisspeptin]] and the related [[G-protein coupled receptor]] (KISS1R or GPR54) have key roles. [[Kisspeptin|Kisspeptins]] are encoded by KISS1 gene, [[neuropeptides]] secreted from [[hypothalamus]] nuclei. It is found that patients with idiopathic [[hypogonadotropic hypogonadism]] have KISS1 receptor (GPR54) inactivating [[gene]] [[mutations]].<ref name="pmid12944565">{{cite journal |vauthors=de Roux N, Genin E, Carel JC, Matsuda F, Chaussain JL, Milgrom E |title=Hypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54 |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=100 |issue=19 |pages=10972–6 |year=2003 |pmid=12944565 |pmc=196911 |doi=10.1073/pnas.1834399100 |url=}}</ref><ref name="SeminaraMessager2003">{{cite journal|last1=Seminara|first1=Stephanie B.|last2=Messager|first2=Sophie|last3=Chatzidaki|first3=Emmanouella E.|last4=Thresher|first4=Rosemary R.|last5=Acierno|first5=James S.|last6=Shagoury|first6=Jenna K.|last7=Bo-Abbas|first7=Yousef|last8=Kuohung|first8=Wendy|last9=Schwinof|first9=Kristine M.|last10=Hendrick|first10=Alan G.|last11=Zahn|first11=Dirk|last12=Dixon|first12=John|last13=Kaiser|first13=Ursula B.|last14=Slaugenhaupt|first14=Susan A.|last15=Gusella|first15=James F.|last16=O'Rahilly|first16=Stephen|last17=Carlton|first17=Mark B.L.|last18=Crowley|first18=William F.|last19=Aparicio|first19=Samuel A.J.R.|last20=Colledge|first20=William H.|title=TheGPR54Gene as a Regulator of Puberty|journal=New England Journal of Medicine|volume=349|issue=17|year=2003|pages=1614–1627|issn=0028-4793|doi=10.1056/NEJMoa035322}}</ref>
* By the time of [[puberty]], the KISS1 genes become activated through [[neuroanatomical]] and functional changes from environmental triggers, critical for [[brain]] sexual [[maturation]] and HPG activation with pulsatile [[GnRH]].<ref name="pmid23015158">{{cite journal| author=Kaur KK, Allahbadia G, Singh M| title=Kisspeptins in human reproduction-future therapeutic potential. | journal=J Assist Reprod Genet | year= 2012 | volume= 29 | issue= 10 | pages= 999-1011 | pmid=23015158 | doi=10.1007/s10815-012-9856-1 | pmc=3492584 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23015158  }}</ref>
* Along HPG axis [[neurons]], [[gamma-aminobutyric acid]] is [[inhibitory]] and [[glutamate]] is [[Excitatory neurotransmitter|excitatory neurotransmitters]]. In related KNDy [[neurons]] in [[arcuate nucleus]], the materials secreted include [[kisspeptin]], [[neurokinin B]], and [[dynorphin A]]. Before [[puberty]] begins, inhibitory [[dynorphin A]] is the dominant element; decreased by stimulatory effect of [[neurokinin B]], when [[puberty]] started. Conclusively, [[kisspeptin]] and [[GnRH]]/[[LH]] are increased.<ref name="UenoyamaTsukamura2014">{{cite journal|last1=Uenoyama|first1=Yoshihisa|last2=Tsukamura|first2=Hiroko|last3=Maeda|first3=Kei-ichiro|title=KNDy neuron as a gatekeeper of puberty onset|journal=Journal of Obstetrics and Gynaecology Research|volume=40|issue=6|year=2014|pages=1518–1526|issn=13418076|doi=10.1111/jog.12398}}</ref>
 
=== Kallmann syndrome 1 (KAL1) ===
* The [[KAL1 gene|KAL1]] [[gene]], also called [[anosmin-1]], with [[OMIM]] number of 308700 is on [[chromosome]] Xp22.3, encode an [[Extracellular matrix protein|extracellular matrix glycoprotein]].
* [[Anosmin-1]] expressed at five weeks of [[gestation]] in [[forebrain]] area near [[olfactory bulbs]], stimulate the [[afferent fibers]] projections.<ref name="pmid10340754">{{cite journal |vauthors=Hardelin JP, Julliard AK, Moniot B, Soussi-Yanicostas N, Verney C, Schwanzel-Fukuda M, Ayer-Le Lievre C, Petit C |title=Anosmin-1 is a regionally restricted component of basement membranes and interstitial matrices during organogenesis: implications for the developmental anomalies of X chromosome-linked Kallmann syndrome |journal=Dev. Dyn. |volume=215 |issue=1 |pages=26–44 |year=1999 |pmid=10340754 |doi=10.1002/(SICI)1097-0177(199905)215:1<26::AID-DVDY4>3.0.CO;2-D |url=}}</ref>
* [[X-linked]] [[Kallman syndrome|Kallmann syndrome]] is directly associated with [[KAL1 gene|KAL1]] deletion which results in an absence of [[Olfactory system|olfactory fibers]] along with disturbed migration of [[GnRH]] [[neurons]].<ref name="pmid2687610">{{cite journal |vauthors=Schwanzel-Fukuda M, Bick D, Pfaff DW |title=Luteinizing hormone-releasing hormone (LHRH)-expressing cells do not migrate normally in an inherited hypogonadal (Kallmann) syndrome |journal=Brain Res. Mol. Brain Res. |volume=6 |issue=4 |pages=311–26 |year=1989 |pmid=2687610 |doi= |url=}}</ref>
* Male patients with [[KAL1 gene|KAL1]] [[mutation]] would have central [[hypogonadism]] and [[anosmia]]/[[hyposmia]]. Additionally, more [[diseases]] are assumed to be related to [[KAL1 gene]], such as midline [[facial]] defects ([[cleft lip]] and/or [[cleft palate]]), short [[metacarpals]], [[renal agenesis]], [[sensorineural hearing loss]], bimanual [[synkinesis]], [[oculomotor]] abnormalities, and [[cerebellar ataxia]].<ref name="pmid17624596">{{cite journal |vauthors=Trarbach EB, Silveira LG, Latronico AC |title=Genetic insights into human isolated gonadotropin deficiency |journal=Pituitary |volume=10 |issue=4 |pages=381–91 |year=2007 |pmid=17624596 |doi=10.1007/s11102-007-0061-7 |url=}}</ref>
 
=== Fibroblast growth factor receptor 1 and fibroblast growth factor 8 (FGFR1 and FGF8) ===
* The [[FGFR1]] [[gene]], also called KAL2, with [[OMIM]] number of 136350 found on [[chromosome]] 8q12, encodes receptor [[Tyrosine kinase|tyrosine kinase protein]]. The [[FGF8]] gene, also called KAL6, is found on [[chromosome]] 10q24.
* [[FGFR1]] pathway is assumed to play the main role in [[embryogenesis]], [[homeostasis]], and [[wound healing]]. [[FGF8]] critical role in primary generation of [[neural tissue]] has been established by so many researchers.<ref name="pmid15548653">{{cite journal |vauthors=González-Martínez D, Kim SH, Hu Y, Guimond S, Schofield J, Winyard P, Vannelli GB, Turnbull J, Bouloux PM |title=Anosmin-1 modulates fibroblast growth factor receptor 1 signaling in human gonadotropin-releasing hormone olfactory neuroblasts through a heparan sulfate-dependent mechanism |journal=J. Neurosci. |volume=24 |issue=46 |pages=10384–92 |year=2004 |pmid=15548653 |doi=10.1523/JNEUROSCI.3400-04.2004 |url=}}</ref>
* On the other hand, interaction between [[FGFR1]], [[FGF8]], and [[heparan sulfate]] helps [[olfactory bulb]] to become differentiated and developed, also facilitates [[GnRH]] [[neurons]] migration and function.<ref name="pmid12571102">{{cite journal |vauthors=Hébert JM, Lin M, Partanen J, Rossant J, McConnell SK |title=FGF signaling through FGFR1 is required for olfactory bulb morphogenesis |journal=Development |volume=130 |issue=6 |pages=1101–11 |year=2003 |pmid=12571102 |doi= |url=}}</ref>
* Dominant [[deletion mutation]] of [[FGFR1]] gene is found to cause a 30% decrease in [[hypothalamic]] [[GnRH]] [[neurons]].<ref name="pmid15459253">{{cite journal |vauthors=Tsai PS, Moenter SM, Postigo HR, El Majdoubi M, Pak TR, Gill JC, Paruthiyil S, Werner S, Weiner RI |title=Targeted expression of a dominant-negative fibroblast growth factor (FGF) receptor in gonadotropin-releasing hormone (GnRH) neurons reduces FGF responsiveness and the size of GnRH neuronal population |journal=Mol. Endocrinol. |volume=19 |issue=1 |pages=225–36 |year=2005 |pmid=15459253 |doi=10.1210/me.2004-0330 |url=}}</ref> Other defects related to [[FGFR1]] include [[cleft palate]] or [[Cleft lip|lip]], dental [[agenesis]] and bimanual [[synkinesis]].<ref name="pmid17624596" /> Other disorders related to [[FGF8]] include [[cardiac]], [[craniofacial]], [[forebrain]], [[midbrain]], and [[cerebellar]] developmental abnormalities.
 
=== Heparan sulfate 6-O-sulphotransferase 1 (HS6ST1) ===
* The HS6ST1 [[gene]] with [[OMIM]] number 604846 on [[chromosome]] 2q21, has some functions in [[extracellular]] sugar modifications; but has been found mutated in [[hypogonadism]].<ref name="pmid21700882">{{cite journal |vauthors=Tornberg J, Sykiotis GP, Keefe K, Plummer L, Hoang X, Hall JE, Quinton R, Seminara SB, Hughes V, Van Vliet G, Van Uum S, Crowley WF, Habuchi H, Kimata K, Pitteloud N, Bülow HE |title=Heparan sulfate 6-O-sulfotransferase 1, a gene involved in extracellular sugar modifications, is mutated in patients with idiopathic hypogonadotrophic hypogonadism |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=108 |issue=28 |pages=11524–9 |year=2011 |pmid=21700882 |pmc=3136273 |doi=10.1073/pnas.1102284108 |url=}}</ref>
 
* The modifications of [[heparan sulfate]] [[polysaccharides]] in [[extracellular matrix]] have some roles in [[FGFR]]-[[FGF1|FGF]] and also [[Anosmin-1|anosmin1]]-[[cell membrane]] interactions.<ref name="pmid15096041">{{cite journal |vauthors=Ibrahimi OA, Zhang F, Hrstka SC, Mohammadi M, Linhardt RJ |title=Kinetic model for FGF, FGFR, and proteoglycan signal transduction complex assembly |journal=Biochemistry |volume=43 |issue=16 |pages=4724–30 |year=2004 |pmid=15096041 |doi=10.1021/bi0352320 |url=}}</ref><ref name="pmid16677626">{{cite journal |vauthors=Hudson ML, Kinnunen T, Cinar HN, Chisholm AD |title=C. elegans Kallmann syndrome protein KAL-1 interacts with syndecan and glypican to regulate neuronal cell migrations |journal=Dev. Biol. |volume=294 |issue=2 |pages=352–65 |year=2006 |pmid=16677626 |doi=10.1016/j.ydbio.2006.02.036 |url=}}</ref>
* This [[gene]] has been found mutated in both [[Kallman syndrome|Kallmann syndrome]] and idiopathic [[hypogonadism]], with various course and timing or [[GnRH]] deficiencies.<ref name="pmid21700882" />
 
=== Prokineticin 2 and prokineticin 2 receptor (PROK2 and PROKR2) ===
* The [[Prokineticin|PROK2]] and [[Prokineticin receptor 2|PROKR2]] [[genes]], also called KAL4 and KAL3, with [[OMIM]] numbers of 607002 and 607123 on [[chromosomes]] 3p21.1 and 20p13, respectively. They are believed to be cause of [[Kallman syndrome|Kallmann syndrome]].
* [[Prokineticin|PROKR2,]] a [[G protein coupled receptor|G protein coupled receptor (GPCR)]], has a major role in [[olfactory bulb]] development; the [[mutation]] may lead to severe [[gonadal]] [[atrophy]].<ref name="pmid16537498">{{cite journal |vauthors=Matsumoto S, Yamazaki C, Masumoto KH, Nagano M, Naito M, Soga T, Hiyama H, Matsumoto M, Takasaki J, Kamohara M, Matsuo A, Ishii H, Kobori M, Katoh M, Matsushime H, Furuichi K, Shigeyoshi Y |title=Abnormal development of the olfactory bulb and reproductive system in mice lacking prokineticin receptor PKR2 |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=103 |issue=11 |pages=4140–5 |year=2006 |pmid=16537498 |pmc=1449660 |doi=10.1073/pnas.0508881103 |url=}}</ref>
* In [[prokineticin]] system, there are two receptors ([[Prokineticin receptor 1|PROKR1]] and [[Prokineticin receptor 2|PROKR2]]) and two [[ligands]] ([[Prokineticin|PROK1]] and [[Prokineticin|PROK2]]). [[Prokineticin|PROK1]] and its receptor ([[Prokineticin receptor 1|PROKR1]]) have some roles in [[gastrointestinal]] system [[motility]]. However, [[Prokineticin|PROK2]] and [[Prokineticin receptor 2|PROKR2]] are parts of [[neuroendocrine system]], located in [[arcuate nucleus]], [[olfactory tract]], and [[suprachiasmatic nucleus]].<ref name="pmid11259612">{{cite journal |vauthors=Li M, Bullock CM, Knauer DJ, Ehlert FJ, Zhou QY |title=Identification of two prokineticin cDNAs: recombinant proteins potently contract gastrointestinal smooth muscle |journal=Mol. Pharmacol. |volume=59 |issue=4 |pages=692–8 |year=2001 |pmid=11259612 |doi= |url=}}</ref>
* It seems that mutated versions of [[Prokineticin|PROK2]] and [[Prokineticin receptor 2|PROKR2]] could lead to decrease [[GnRH]] production and [[hypogonadism]]. Other disorders caused by their [[mutations]] include [[fibrous dysplasia]], [[sleep disorder]], severe [[obesity]], [[synkinesis]], and [[epilepsy]].<ref name="pmid18559922">{{cite journal |vauthors=Cole LW, Sidis Y, Zhang C, Quinton R, Plummer L, Pignatelli D, Hughes VA, Dwyer AA, Raivio T, Hayes FJ, Seminara SB, Huot C, Alos N, Speiser P, Takeshita A, Van Vliet G, Pearce S, Crowley WF, Zhou QY, Pitteloud N |title=Mutations in prokineticin 2 and prokineticin receptor 2 genes in human gonadotrophin-releasing hormone deficiency: molecular genetics and clinical spectrum |journal=J. Clin. Endocrinol. Metab. |volume=93 |issue=9 |pages=3551–9 |year=2008 |pmid=18559922 |pmc=2567850 |doi=10.1210/jc.2007-2654 |url=}}</ref>
 
=== Tachykinin 3 and tachykinin 3 receptor (TAC3 and TACR3) ===
* The [[Tachykinin|TAC3]] and [[Tachykinin receptor 3|TACR3]] [[genes]], also called [[Neurokinin B|neurokinin B (NKB)]] and [[neurokinin]] 3 receptor (NK3R), with [[OMIM]] numbers of 162330 and 152332, are on [[chromosomes]] 12q13–q21 and 4q25, respectively.<ref name="pmid19079066">{{cite journal |vauthors=Topaloglu AK, Reimann F, Guclu M, Yalin AS, Kotan LD, Porter KM, Serin A, Mungan NO, Cook JR, Imamoglu S, Akalin NS, Yuksel B, O'Rahilly S, Semple RK |title=TAC3 and TACR3 mutations in familial hypogonadotropic hypogonadism reveal a key role for Neurokinin B in the central control of reproduction |journal=Nat. Genet. |volume=41 |issue=3 |pages=354–358 |year=2009 |pmid=19079066 |pmc=4312696 |doi=10.1038/ng.306 |url=}}</ref>
* Normal function of [[Tachykinin|TAC3]]/[[Tachykinin receptor 3|TACR3]] system is necessary for an intact HPG axis and also its development during [[puberty]]. [[Tachykinin|TAC3]]/[[Tachykinin receptor 3|TACR3]] system disturbance is known to cause [[micropenis]] and also [[cryptorchidism]] in males, showing the major role in fetal [[gonadotropins]] secretion.<ref name="pmid15212980">{{cite journal |vauthors=Pinto FM, Almeida TA, Hernandez M, Devillier P, Advenier C, Candenas ML |title=mRNA expression of tachykinins and tachykinin receptors in different human tissues |journal=Eur. J. Pharmacol. |volume=494 |issue=2-3 |pages=233–9 |year=2004 |pmid=15212980 |doi=10.1016/j.ejphar.2004.05.016 |url=}}</ref>
* [[Tachykinin receptor 3|TACR3]] encoded protein (NK3R) is [[G protein-coupled receptor|GPCR]], initially produced in [[central nervous system]]. The major mechanism, through which the mutated [[gene]] may lead to [[neuroendocrine]] disturbance and delayed [[puberty]], is not completely discovered.<ref name="pmid19719764">{{cite journal |vauthors=Semple RK, Topaloglu AK |title=The recent genetics of hypogonadotrophic hypogonadism - novel insights and new questions |journal=Clin. Endocrinol. (Oxf) |volume=72 |issue=4 |pages=427–35 |year=2010 |pmid=19719764 |doi=10.1111/j.1365-2265.2009.03687.x |url=}}</ref>
* [[Tachykinin|TAC3]] encoded protein (NKB) is produced in [[arcuate nucleus]] of [[hypothalamus]] and play an important role in [[GnRH]] secretion. Parallel to that, [[kisspeptin]] is also produced and secreted in [[arcuate nucleus]], where both of them are inhibited by [[estrogen]]. It may be considered that [[kisspeptin]] and [[Neurokinin B|NKB]] have same roles in diverting [[negative feedback]] from [[sex hormones]] to [[GnRH]]. Their mutation is related with [[hypogonadism]].
 
=== Gonadotropin releasing hormone and its receptor (GnRH1 and GnRHR) ===
* The [[Gonadotropin-releasing hormone|GnRH1]] and [[GnRHR]] [[genes]] with [[OMIM]] numbers 152760 and 138850 are on [[chromosomes]] 8p21–8p11.2 and 4q21.2, respectively.<ref name="pmid19535795">{{cite journal |vauthors=Bouligand J, Ghervan C, Tello JA, Brailly-Tabard S, Salenave S, Chanson P, Lombès M, Millar RP, Guiochon-Mantel A, Young J |title=Isolated familial hypogonadotropic hypogonadism and a GNRH1 mutation |journal=N. Engl. J. Med. |volume=360 |issue=26 |pages=2742–8 |year=2009 |pmid=19535795 |doi=10.1056/NEJMoa0900136 |url=}}</ref>
* In HPG axis, [[GnRH]] is one of the most effective elements; therefore, its defect could directly influence the axis and slow down its progress. Mutated [[gene]] in mice make them sexually infantile, [[infertile]], and with low [[sex hormones]] and [[gonadotropins]].<ref name="pmid198666">{{cite journal |vauthors=Cattanach BM, Iddon CA, Charlton HM, Chiappa SA, Fink G |title=Gonadotrophin-releasing hormone deficiency in a mutant mouse with hypogonadism |journal=Nature |volume=269 |issue=5626 |pages=338–40 |year=1977 |pmid=198666 |doi= |url=}}</ref>
* The GnRHR [[gene]] is also responsible for [[gonadal]] normal functions, its mutation could lead to [[hypogonadism]] and delayed [[puberty]]. It seems that the [[mutation]] has other outcomes, such as [[atrophic]] [[gonads]] along with low [[LH]]/[[FSH]] and [[sex hormones]], sexual [[puberty]] disturbance, inability to [[Conceive a child|conceive]], and resistance from exogenous [[GnRH]]. <ref name="pmid20068010">{{cite journal |vauthors=Wu S, Wilson MD, Busby ER, Isaac ER, Sherwood NM |title=Disruption of the single copy gonadotropin-releasing hormone receptor in mice by gene trap: severe reduction of reproductive organs and functions in developing and adult mice |journal=Endocrinology |volume=151 |issue=3 |pages=1142–52 |year=2010 |pmid=20068010 |doi=10.1210/en.2009-0598 |url=}}</ref>
* Variable expressivity in these genes could cause spectrum of symptoms, from fertile eunuch syndrome and partial idiopathic [[hypogonadotropic hypogonadism]] to complete [[GnRH]] resistance (i.e., characterized by [[cryptorchidism]]), [[microphallus]], very low [[LH]]/[[FSH]], and delayed [[puberty]].<ref name="pmid12536356">{{cite journal |vauthors=Silveira LF, MacColl GS, Bouloux PM |title=Hypogonadotropic hypogonadism |journal=Semin. Reprod. Med. |volume=20 |issue=4 |pages=327–38 |year=2002 |pmid=12536356 |doi=10.1055/s-2002-36707 |url=}}</ref>
* The other disorders that have been associated with [[GnRH]] mutation include [[tooth]] abnormal [[maturation]] and biomineralization.<ref name="pmid17948256">{{cite journal |vauthors=Tiong J, Locastro T, Wray S |title=Gonadotropin-releasing hormone-1 (GnRH-1) is involved in tooth maturation and biomineralization |journal=Dev. Dyn. |volume=236 |issue=11 |pages=2980–92 |year=2007 |pmid=17948256 |doi=10.1002/dvdy.21332 |url=}}</ref>
 
=== Chromodomain helicase DNA-binding protein 7 (CHD7)  ===
* The [[CHD7]] gene, also called KAL5, with [[OMIM]] number 608892 is found on [[chromosome]] 8q12.1.
* The main result of the [[CHD7]] gene [[mutation]] is [[autosomal dominant]] [[CHARGE syndrome]]; combination of [[hypogonadism]] and [[Kallman syndrome|Kallmann syndrome]], which includes:<ref name="pmid188349672">{{cite journal |vauthors=Kim HG, Kurth I, Lan F, Meliciani I, Wenzel W, Eom SH, Kang GB, Rosenberger G, Tekin M, Ozata M, Bick DP, Sherins RJ, Walker SL, Shi Y, Gusella JF, Layman LC |title=Mutations in CHD7, encoding a chromatin-remodeling protein, cause idiopathic hypogonadotropic hypogonadism and Kallmann syndrome |journal=Am. J. Hum. Genet. |volume=83 |issue=4 |pages=511–9 |year=2008 |pmid=18834967 |pmc=2561938 |doi=10.1016/j.ajhg.2008.09.005 |url=}}</ref>
** [[Coloboma|'''C'''olobomata]]
** [[Heart|'''H'''eart]] anomalies
** [[Choanal atresia|Choanal '''A'''tresia]]
** [[Retardation|'''R'''etardation]]
** [[Genital|'''G'''enital]] anomalies
** [[Ear|'''E'''ar]] anomalies
* Screening for CHD7 gene is recommended in patients with [[hypogonadism]] or [[Kallman syndrome|Kallmann syndrome]] with specific features, such as [[semicircular canals]] [[hypoplasia]] or [[aplasia]], [[dysmorphic]] ears, and [[deafness]].
 
=== Nasal embryonic LH-releasing hormone factor (NELF) ===
* The NELF [[gene]] with [[OMIM]] number 608137 on [[chromosome]] ''9q34.3'' is found mostly in [[nervous tissues]] specifically during [[fetal development]]. It has also been found in [[olfactory bulb]] and [[pituitary]] [[LH]] releasing cells.
* The most common function is in [[olfactory]] axons and also [[GnRH]] [[neurons]], before and during [[neuron]] migration in developmental process.<ref name="pmid108987962">{{cite journal |vauthors=Kramer PR, Wray S |title=Novel gene expressed in nasal region influences outgrowth of olfactory axons and migration of luteinizing hormone-releasing hormone (LHRH) neurons |journal=Genes Dev. |volume=14 |issue=14 |pages=1824–34 |year=2000 |pmid=10898796 |pmc=316793 |doi= |url=}}</ref>
* It has some relations with Kallmann syndrome. <ref name="pmid21300340">{{cite journal |vauthors=Xu N, Kim HG, Bhagavath B, Cho SG, Lee JH, Ha K, Meliciani I, Wenzel W, Podolsky RH, Chorich LP, Stackhouse KA, Grove AM, Odom LN, Ozata M, Bick DP, Sherins RJ, Kim SH, Cameron RS, Layman LC |title=Nasal embryonic LHRH factor (NELF) mutations in patients with normosmic hypogonadotropic hypogonadism and Kallmann syndrome |journal=Fertil. Steril. |volume=95 |issue=5 |pages=1613–20.e1–7 |year=2011 |pmid=21300340 |pmc=3888818 |doi=10.1016/j.fertnstert.2011.01.010 |url=}}</ref>


In case of constitutional delay of growth and puberty (CDGP), researchers suggested 50-75% of positive family history of delayed puberty.<ref name="pmid18160460">{{cite journal |vauthors=Wehkalampi K, Widén E, Laine T, Palotie A, Dunkel L |title=Patterns of inheritance of constitutional delay of growth and puberty in families of adolescent girls and boys referred to specialist pediatric care |journal=J. Clin. Endocrinol. Metab. |volume=93 |issue=3 |pages=723–8 |year=2008 |pmid=18160460 |doi=10.1210/jc.2007-1786 |url=}}</ref>  
=== Early B-cell factor 2 (EBF2) ===
* The EBF2 [[gene]] with [[OMIM]] number of 609934 is on [[chromosome]] ''8p21.2; mostly expressed in mice [[osteoblasts]] and [[osteoclast]] cells.''<ref name="pmid12466206">{{cite journal |vauthors=Corradi A, Croci L, Broccoli V, Zecchini S, Previtali S, Wurst W, Amadio S, Maggi R, Quattrini A, Consalez GG |title=Hypogonadotropic hypogonadism and peripheral neuropathy in Ebf2-null mice |journal=Development |volume=130 |issue=2 |pages=401–10 |year=2003 |pmid=12466206 |doi= |url=}}</ref>
* The gene is believed to have an effective role in HPG axis. In mutated version, it can cause defect in the axis, leading to secondary [[hypogonadism]].<ref name="pmid16423815">{{cite journal |vauthors=Trarbach EB, Baptista MT, Garmes HM, Hackel C |title=Molecular analysis of KAL-1, GnRH-R, NELF and EBF2 genes in a series of Kallmann syndrome and normosmic hypogonadotropic hypogonadism patients |journal=J. Endocrinol. |volume=187 |issue=3 |pages=361–8 |year=2005 |pmid=16423815 |doi=10.1677/joe.1.06103 |url=}}</ref>


It is thought that CDGP is inherited in an [[autosomal dominant]] pattern, with or without the effects of complete [[penetrance]]. It is not sex oriented inheritance and can be seen in all family members.<ref name="pmid12466356">{{cite journal |vauthors=Sedlmeyer IL, Hirschhorn JN, Palmert MR |title=Pedigree analysis of constitutional delay of growth and maturation: determination of familial aggregation and inheritance patterns |journal=J. Clin. Endocrinol. Metab. |volume=87 |issue=12 |pages=5581–6 |year=2002 |pmid=12466356 |doi=10.1210/jc.2002-020862 |url=}}</ref>
=== DSS-AHC on the X-chromosome 1 (DAX1) ===
* The [[DAX1]] [[gene]], also called [[nuclear receptor]] 0B (NR0B), with [[OMIM]] number of 300473 on [[chromosome]] ''Xp21.2, mostly expressed in all members of HPG axis ([[hypothalamus]], [[pituitary]], and [[gonads]]).''<ref name="pmid8593542">{{cite journal |vauthors=Guo W, Burris TP, McCabe ER |title=Expression of DAX-1, the gene responsible for X-linked adrenal hypoplasia congenita and hypogonadotropic hypogonadism, in the hypothalamic-pituitary-adrenal/gonadal axis |journal=Biochem. Mol. Med. |volume=56 |issue=1 |pages=8–13 |year=1995 |pmid=8593542 |doi= |url=}}</ref>
* During the [[spermatogenesis]] and [[steroidogenesis]], it seems that both [[Sertoli cell|sertoli]] and [[leydig cells]] have increased expression of [[DAX1]] gene. It is assumed that during [[puberty]], the peak expression of [[DAX1]] occurred.<ref name="pmid16834661">{{cite journal |vauthors=Kojima Y, Sasaki S, Hayashi Y, Umemoto Y, Morohashi K, Kohri K |title=Role of transcription factors Ad4bp/SF-1 and DAX-1 in steroidogenesis and spermatogenesis in human testicular development and idiopathic azoospermia |journal=Int. J. Urol. |volume=13 |issue=6 |pages=785–93 |year=2006 |pmid=16834661 |doi=10.1111/j.1442-2042.2006.01403.x |url=}}</ref>
* Another disease that can be caused by [[DAX1]] mutation is congenital [[Adrenal cortex insufficiency|adrenal cortex hypoplasia]].<ref name="pmid7990953">{{cite journal |vauthors=Zanaria E, Muscatelli F, Bardoni B, Strom TM, Guioli S, Guo W, Lalli E, Moser C, Walker AP, McCabe ER |title=An unusual member of the nuclear hormone receptor superfamily responsible for X-linked adrenal hypoplasia congenita |journal=Nature |volume=372 |issue=6507 |pages=635–41 |year=1994 |pmid=7990953 |doi=10.1038/372635a0 |url=}}</ref>


=== Kisspeptin system ===
=== Steroidogenic factor 1 (SF1) ===
* The GnRH secretion has to be pulsatile to stimulate gonadotropins. In regulation of GnRH secretion, kisspeptin and the related G-protein coupled receptor (KISS1R or GPR54) have key roles. Kisspeptins are encoded by KISS1 gene, neuropeptides secreted from hypothalamus nuclei. It is found that patients with idiopathic hypogonadotropic hypogonadism have KISS1 receptor (GPR54) inactivating gene mutations.<ref name="pmid12944565">{{cite journal |vauthors=de Roux N, Genin E, Carel JC, Matsuda F, Chaussain JL, Milgrom E |title=Hypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54 |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=100 |issue=19 |pages=10972–6 |year=2003 |pmid=12944565 |pmc=196911 |doi=10.1073/pnas.1834399100 |url=}}</ref>
* The [[SF1 (gene)|SF1]] [[gene]], also called [[nuclear receptor]] 5A1 (NR5A1), with [[OMIM]] number of 184757 on [[chromosome]] ''9q33.3, has some roles in [[reproduction]], [[steroidogenesis]], and [[sexual differentiation]].''
* <ref name="SeminaraMessager2003">{{cite journal|last1=Seminara|first1=Stephanie B.|last2=Messager|first2=Sophie|last3=Chatzidaki|first3=Emmanouella E.|last4=Thresher|first4=Rosemary R.|last5=Acierno|first5=James S.|last6=Shagoury|first6=Jenna K.|last7=Bo-Abbas|first7=Yousef|last8=Kuohung|first8=Wendy|last9=Schwinof|first9=Kristine M.|last10=Hendrick|first10=Alan G.|last11=Zahn|first11=Dirk|last12=Dixon|first12=John|last13=Kaiser|first13=Ursula B.|last14=Slaugenhaupt|first14=Susan A.|last15=Gusella|first15=James F.|last16=O'Rahilly|first16=Stephen|last17=Carlton|first17=Mark B.L.|last18=Crowley|first18=William F.|last19=Aparicio|first19=Samuel A.J.R.|last20=Colledge|first20=William H.|title=TheGPR54Gene as a Regulator of Puberty|journal=New England Journal of Medicine|volume=349|issue=17|year=2003|pages=1614–1627|issn=0028-4793|doi=10.1056/NEJMoa035322}}</ref>  
* It is mainly expressed in [[Sertoli cell|sertoli]] and [[leydig cells]], plays an important role in [[steroidogenesis]] and [[spermatogenesis]]. The [[SF1]] is believed to experience increase in expression during [[childhood]] into [[adolescence]], become dominantly expressed by [[leydig cells]] in [[puberty]].<ref name="pmid16834661" />
* By the time of puberty, the KISS1 genes become activated through neuroanatomical and functional changes from environmental triggers, critical for brain sexual maturation and HPG activation with pulsatile GnRH.<ref name="pmid23015158">{{cite journal| author=Kaur KK, Allahbadia G, Singh M| title=Kisspeptins in human reproduction-future therapeutic potential. | journal=J Assist Reprod Genet | year= 2012 | volume= 29 | issue= 10 | pages= 999-1011 | pmid=23015158 | doi=10.1007/s10815-012-9856-1 | pmc=3492584 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23015158  }}</ref>
* It seems that other diseases can be caused by [[SF1 (gene)|SF1]] mutation, such as male [[pseudohermaphroditism]], [[Denys-Drash syndrome]], and also [[hypospadias]].<ref name="pmid9590178">{{cite journal |vauthors=Nachtigal MW, Hirokawa Y, Enyeart-VanHouten DL, Flanagan JN, Hammer GD, Ingraham HA |title=Wilms' tumor 1 and Dax-1 modulate the orphan nuclear receptor SF-1 in sex-specific gene expression |journal=Cell |volume=93 |issue=3 |pages=445–54 |year=1998 |pmid=9590178 |doi= |url=}}</ref>
* Along HPG axis neurons, gamma-aminobutyric acid is inhibitory and glutamate is excitatory neurotransmitters. In related KNDy neurons in arcuate nucleus, the materials secreted are included kisspeptin, neurokinin B, and dynorphin A. Before the puberty begins, inhibitory dynorphine A is the dominant element; decreased by stimulatory effect of neurokinin B, when puberty started. Conclusively, kisspeptin and GnRH/LH are increased.<ref name="UenoyamaTsukamura2014">{{cite journal|last1=Uenoyama|first1=Yoshihisa|last2=Tsukamura|first2=Hiroko|last3=Maeda|first3=Kei-ichiro|title=KNDy neuron as a gatekeeper of puberty onset|journal=Journal of Obstetrics and Gynaecology Research|volume=40|issue=6|year=2014|pages=1518–1526|issn=13418076|doi=10.1111/jog.12398}}</ref>


==Associated Conditions==
=== Homeobox gene 1 (HESX1) ===
==Gross Pathology==
* The [[HESX1]] [[gene]], also called [[Rathke pouch]] [[Homeobox gene|homeobox]] (RPX), with [[OMIM]] number of 601802 is on [[chromosome]] ''3p14.3, starts to express during [[embryogenesis]] and help the formation of [[Rathke pouch]] and [[anterior pituitary]].''<ref name="pmid9620767">{{cite journal |vauthors=Dattani MT, Martinez-Barbera JP, Thomas PQ, Brickman JM, Gupta R, Mårtensson IL, Toresson H, Fox M, Wales JK, Hindmarsh PC, Krauss S, Beddington RS, Robinson IC |title=Mutations in the homeobox gene HESX1/Hesx1 associated with septo-optic dysplasia in human and mouse |journal=Nat. Genet. |volume=19 |issue=2 |pages=125–33 |year=1998 |pmid=9620767 |doi=10.1038/477 |url=}}</ref>
*On gross pathology, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].
* ''The main function of [[HESX1]] gene is [[pituitary]] development and also midfacial differentiation. [[Mutation]] may lead to [[pituitary]] [[hypoplasia]] and decreased level of all [[anterior pituitary]] [[hormones]].''<ref name="pmid11136712">{{cite journal |vauthors=Thomas PQ, Dattani MT, Brickman JM, McNay D, Warne G, Zacharin M, Cameron F, Hurst J, Woods K, Dunger D, Stanhope R, Forrest S, Robinson IC, Beddington RS |title=Heterozygous HESX1 mutations associated with isolated congenital pituitary hypoplasia and septo-optic dysplasia |journal=Hum. Mol. Genet. |volume=10 |issue=1 |pages=39–45 |year=2001 |pmid=11136712 |doi= |url=}}</ref>
==Microscopic Pathology==
* Other disorders resulting from [[HESX1]] [[mutation]] include septooptic dysplasia, reduced [[prosencephalon]], [[anophthalmia]], [[microphthalmia]], defective [[olfactory]] development, [[Rathke pouch]] bifurcations, and also abnormalities in the [[corpus callosum]], [[hippocampus]], and [[septum pellucidum]].<ref name="pmid9620767" />
*On microscopic histopathological analysis, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].
 
===Normal timing===
=== LIM homeobox gene 3 (LHX3) ===
Approximate mean ages for onset of various pubertal changes are as follows. Ages in parentheses are the approximate 3rd and 97th percentiles for attainment. For example, less than 3% of girls have not yet achieved [[thelarche]] by 13 years of age. Developmental changes during [[puberty]] in girls occur over a period of 3 – 5 years, usually between 9 and 14 years of age. They include the occurrence of secondary sex characteristics beginning with breast development, the adolescent growth spurt, the onset of [[menarche]] – which does not correspond to the end of puberty – and the acquisition of [[fertility]], as well as profound psychological modifications.
* The [[LHX3|LHX3 gene]], also called LIM3, with [[OMIM]] number of 600577 is on [[chromosome]] ''9q34.3, mainly expressed in developing anterior [[pituitary gland]].''<ref name="pmid18407919">{{cite journal |vauthors=Rajab A, Kelberman D, de Castro SC, Biebermann H, Shaikh H, Pearce K, Hall CM, Shaikh G, Gerrelli D, Grueters A, Krude H, Dattani MT |title=Novel mutations in LHX3 are associated with hypopituitarism and sensorineural hearing loss |journal=Hum. Mol. Genet. |volume=17 |issue=14 |pages=2150–9 |year=2008 |pmid=18407919 |doi=10.1093/hmg/ddn114 |url=}}</ref>
* It seems that [[LHX3|LHX3 gene]] function is very important in development of [[pituitary gland]] and its [[hormone]] secretion. Therefore, mutation in the gene is related to combined pituitary hormone deficiency (CPHD).<ref name="pmid10835633">{{cite journal |vauthors=Netchine I, Sobrier ML, Krude H, Schnabel D, Maghnie M, Marcos E, Duriez B, Cacheux V, Moers Av, Goossens M, Grüters A, Amselem S |title=Mutations in LHX3 result in a new syndrome revealed by combined pituitary hormone deficiency |journal=Nat. Genet. |volume=25 |issue=2 |pages=182–6 |year=2000 |pmid=10835633 |doi=10.1038/76041 |url=}}</ref>
* The [[LHX3|LHX3 gene]] [[mutation]] can also result in neonatal [[hypoglycemia]], short neck with limited rotation, mild [[Sensorineural hearing loss|sensorineural hearing loss,]] skin laxity, and skeletal abnormalities.<ref name="pmid18407919" />
 
=== PROP paired-like homeobox 1 (PROP1) ===
* The [[PROP1|PROP1 gene]] with [[OMIM]] number of 601538 is on [[chromosome]] ''5q35.3, with a main rule in developing anterior [[pituitary gland]] and also proper development of [[gonadotrophs]], [[thyrotrophs]], [[somatotrophs]], and [[Lactotrophs|lactotrophs.]]''<ref name="pmid9824293">{{cite journal |vauthors=Duquesnoy P, Roy A, Dastot F, Ghali I, Teinturier C, Netchine I, Cacheux V, Hafez M, Salah N, Chaussain JL, Goossens M, Bougnères P, Amselem S |title=Human Prop-1: cloning, mapping, genomic structure. Mutations in familial combined pituitary hormone deficiency |journal=FEBS Lett. |volume=437 |issue=3 |pages=216–20 |year=1998 |pmid=9824293 |doi= |url=}}</ref>
* When [[PROP1|PROP1 gene]] become inactivated through [[mutation]], patient may experience deficiency in [[LH]], [[FSH]], [[GH]], [[TSH]], and [[prolactin]] serum levels. Lack of [[LH]] and [[FSH]] would prevent the patient entering the [[puberty]].<ref name="pmid9462743">{{cite journal |vauthors=Wu W, Cogan JD, Pfäffle RW, Dasen JS, Frisch H, O'Connell SM, Flynn SE, Brown MR, Mullis PE, Parks JS, Phillips JA, Rosenfeld MG |title=Mutations in PROP1 cause familial combined pituitary hormone deficiency |journal=Nat. Genet. |volume=18 |issue=2 |pages=147–9 |year=1998 |pmid=9462743 |doi=10.1038/ng0298-147 |url=}}</ref>
* Regarding the [[gene]] function in different cell types of [[pituitary]], it can be concluded that the [[PROP1|PROP1 gene]] [[mutation]] can lead to [[thyroid]] dysfunctions, [[growth retardation]], and [[libido]]/[[lactation]] problems.
 
=== Leptin and leptin receptor (LEP and LEPR) ===
* The [[LEP]] and [[LEPR|LEPR genes]], also called OB and OBR, with [[OMIM]] numbers of 164160 and 601007 are on [[chromosome]]<nowiki/>s ''7q32.1 and 1p31.3, respectively; both of them have major roles in modulation of [[body weight]][[Lactotrophs|.]]''
* These [[genes]] are believed to carry the message of beginning the [[puberty]], [[recombinant]] [[leptin]] injection in female mice may result in [[puberty]] and also cure their [[maturation]] problems.<ref name="pmid8589726">{{cite journal |vauthors=Chehab FF, Lim ME, Lu R |title=Correction of the sterility defect in homozygous obese female mice by treatment with the human recombinant leptin |journal=Nat. Genet. |volume=12 |issue=3 |pages=318–20 |year=1996 |pmid=8589726 |doi=10.1038/ng0396-318 |url=}}</ref>
* [[leptin]] level in human beings become increased about 50% just before [[puberty]] and also during the [[puberty]].<ref name="pmid9100574">{{cite journal |vauthors=Mantzoros CS, Flier JS, Rogol AD |title=A longitudinal assessment of hormonal and physical alterations during normal puberty in boys. V. Rising leptin levels may signal the onset of puberty |journal=J. Clin. Endocrinol. Metab. |volume=82 |issue=4 |pages=1066–70 |year=1997 |pmid=9100574 |doi=10.1210/jcem.82.4.3878 |url=}}</ref>
* [[Mutation]] in these [[genes]] may also result in disorders in [[hematopoiesis]], [[angiogenesis]], [[wound healing]], and the [[immune]] or [[inflammatory response]].


The normal variation in the age at which adolescent changes occur is so wide that puberty cannot be considered to be pathologically delayed until the menarche has failed to occur by the age of 17 or testicular development by the age of 20.
=== Proprotein convrtase 1 (PC1) ===
* The PC1 [[gene]], also called [[neuroendocrine]] convertase 1 (NEC1), with [[OMIM]] number of 162150 is on [[chromosome]] ''5q15, mainly regulates [[neuroendocrine]] pathway.''
* PC1 gene has the dramatic role of [[proopiomelanocortin]] (POMC) cleavage. On the other hand, they help processing [[proinsulin]] and [[proglucagon]] in [[pancreas]].<ref name="pmid7797529">{{cite journal |vauthors=Jansen E, Ayoubi TA, Meulemans SM, Van de Ven WJ |title=Neuroendocrine-specific expression of the human prohormone convertase 1 gene. Hormonal regulation of transcription through distinct cAMP response elements |journal=J. Biol. Chem. |volume=270 |issue=25 |pages=15391–7 |year=1995 |pmid=7797529 |doi= |url=}}</ref>
* There is assumed relationship between PC1 [[gene]] [[mutation]] and [[hypogonadotropic hypogonadism]] along with extreme childhood [[obesity]], abnormal glucose [[homeostasis]], [[hypocortisolism]], elevated plasma [[proinsulin]], and also [[POMC]] concentrations.<ref name="pmid9207799">{{cite journal |vauthors=Jackson RS, Creemers JW, Ohagi S, Raffin-Sanson ML, Sanders L, Montague CT, Hutton JC, O'Rahilly S |title=Obesity and impaired prohormone processing associated with mutations in the human prohormone convertase 1 gene |journal=Nat. Genet. |volume=16 |issue=3 |pages=303–6 |year=1997 |pmid=9207799 |doi=10.1038/ng0797-303 |url=}}</ref>


For North American, Indo-Iranian (India, Iran) and European girls
=== Makorin RING-finger protein 3 (MKRN3) ===
*[[Thelarche]]                 10y5m      (8y–13y)
* Newly discovered MKRN3 gene has a role in [[ubiquitination]] and [[cell signaling]]. The gene family [[proteins]] are majorly expressed in fetal [[brain]] during development, especially in [[arcuate nucleus]].  
*[[Pubarche]]                 11y        (8.5–13.5y)
* It seems that the gene amplification is on its peak after [[birth]], gradually declined by the time, and finally raised again when [[puberty]] begins. Therefore, it is believed to be one of the factors of starting the [[puberty]], along with [[Kisspeptin|kisspeptins]] and [[neurokinin B]].<ref name="Hughes2013">{{cite journal|last1=Hughes|first1=Ieuan A.|title=Releasing the Brake on Puberty|journal=New England Journal of Medicine|volume=368|issue=26|year=2013|pages=2513–2515|issn=0028-4793|doi=10.1056/NEJMe1306743}}</ref>
*Growth spurt            10–12.5y
*Menarche                  12.5y    (10.5–14.5)
*Adult height reached  14.5y


For North American, Indo-Iranian (India, Iran) and European boys
=== Estrogen receptor α (ESR1) ===
*Testicular enlargement    11.5y  (9.5–13.5y)
* [[Estrogen receptor]] [[mutations]] are very rare, reported as a case report with delayed [[puberty]].<ref name="QuaynorStradtman2013">{{cite journal|last1=Quaynor|first1=Samuel D.|last2=Stradtman|first2=Earl W.|last3=Kim|first3=Hyung-Goo|last4=Shen|first4=Yiping|last5=Chorich|first5=Lynn P.|last6=Schreihofer|first6=Derek A.|last7=Layman|first7=Lawrence C.|title=Delayed Puberty and Estrogen Resistance in a Woman with Estrogen Receptor α Variant|journal=New England Journal of Medicine|volume=369|issue=2|year=2013|pages=164–171|issn=0028-4793|doi=10.1056/NEJMoa1303611}}</ref>
*Pubic hair                12y    (10–14y)
* [[Estradiol]] effects on [[breast]] maturation and also presents a [[negative feedback]] to [[hypothalamus]] and [[pituitary]], by means of [[Estrogen receptor alpha|estrogen receptor α]] (encoded by ESR1 [[gene]]).<ref name="pmid18635656">{{cite journal |vauthors=Christian CA, Glidewell-Kenney C, Jameson JL, Moenter SM |title=Classical estrogen receptor alpha signaling mediates negative and positive feedback on gonadotropin-releasing hormone neuron firing |journal=Endocrinology |volume=149 |issue=11 |pages=5328–34 |year=2008 |pmid=18635656 |pmc=2584581 |doi=10.1210/en.2008-0520 |url=}}</ref>
*Growth spurt            12.5–15y
* Female mice with mutated ESR1 [[gene]] may have [[hypoplastic]] uterus plus [[hemorrhagic]], multicystic [[ovary]] without [[corpus luteum]]; which is make them [[infertile]].<ref name="pmid8248223">{{cite journal |vauthors=Lubahn DB, Moyer JS, Golding TS, Couse JF, Korach KS, Smithies O |title=Alteration of reproductive function but not prenatal sexual development after insertional disruption of the mouse estrogen receptor gene |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=90 |issue=23 |pages=11162–6 |year=1993 |pmid=8248223 |pmc=47942 |doi= |url=}}</ref>
*Completion of growth      17.5


The sources of the data, and a fuller description of normal timing and sequence of pubertal events, as well as the [[hormone|hormonal]] changes that drive them, are provided in the principal article on [[puberty]].
==Associated Conditions==
The associated conditions that are related to delayed puberty, are as following:<ref name="PalmertDunkel2012" />


=== Evaluation ===
{{Family tree/start}}
Obviously anyone who is later than average is late in the ordinary sense. There are three indications that pubertal delay may be due to an abnormal cause. The first is simply degree of lateness: although no recommended age of evaluation cleanly separates pathologic from physiologic delay, a delay of 2-3 years or more warrants evaluation.
{{Family tree | | | | | | | | | A01 | | | |A01= '''Associated conditions'''}}
*In girls, no breast development by 13 years, or no menarche by 3 years after breast development (or by 16).
{{Family tree | | | |,|-|-|-|-|-|+|-|-|-|-|-|.| | }}
*In boys, no testicular enlargement by 14 years.
{{Family tree | | | C01 | | | | C02 | | | | C03 | | C01= '''''Primary [[hypogonadism]]'''''| C02= '''''Secondary [[hypogonadism]]'''''| C03= '''''Functional [[hypogonadism]]'''''}}
{{Family tree | | | |!| | | | | |!| | | | | |!| | }}
{{Family tree |boxstyle=text-align: left; | | | C01 | | | | C02 | | | | C03 | | C01=• [[Turner syndrome]]<br> • [[Noonan syndrome]]<br> • [[Fragile X syndrome]]<br> • [[Cryptorchidism]]<br> • [[Gonadal dysgenesis]]<br> • Testicular agenesis<br> • [[Trauma]]/[[Testicular torsion]]<br> • [[Chemotherapy]]/[[Radiation therapy]]<br> • [[Mumps]], [[coxsackie]]<br> • [[Galactosemia]]<br> • Autoimmune oophiritis<br> • Autoimmune [[orchitis]]<br> • [[5-alpha reductase deficiency]]<br> • [[Adenylosuccinate lyase deficiency|Lyase deficiency]]<br> • [[Congenital lipoid adrenal hyperplasia]]<br> • [[Androgen insensitivity]]<br> • Sertoli cell only syndrome (Del Castillo syndrome)| C02= • [[Astrocytoma]]<br> • [[Germinoma]]<br> • [[Glioma]]<br> • [[Craniopharyngioma]]<br> • [[Prolactinoma]]<br> • [[Langerhans cell histiocytosis]]<br> • [[Rathke pouch]] cyst<br> • [[Kallmann syndrome]]<br> • Isolated hypogonadotropic [[hypogonadism]] <br> • HPG axis development<br> • [[Obesity]] and hypogonadotropic [[hypogonadism]]<br> • [[Prader-Willi syndrome]]<br> • [[Bardet-Biedl syndrome]]<br> • [[CHARGE syndrome]]<br> • [[Gaucher disease]]<br> • Post [[central nervous system]] [[Infection]]<br> • [[Septo-optic dysplasia]]<br> • Congenital [[hypopituitarism]]<br> • [[Chemotherapy]]/[[Radiation therapy]]<br> • [[Trauma]]|C03=• [[Cystic Fibrosis]]<br> • [[Asthma]] <br> • [[Inflammatory bowel disease]] <br> • [[Celiac disease]] <br> • [[Juvenile rheumatoid arthritis]] <br> • [[Anorexia nervosa]]/[[Bulimia]] <br> • [[Sickle cell disease]]<br> • [[Hemosiderosis]]<br> • [[Thalassemia]]<br> • [[Chronic renal disease]]<br> • [[AIDS]]<br> • [[Diabetes mellitus]] <br> • [[Hypothyroidism]]<br> • [[Hyperprolactinemia]]<br> • [[Growth hormone deficiency]] <br> • [[Cushing syndrome]]<br> • Excessive exercise<br> • [[Malnutrition]]}}


The second indicator is discordance of development. In most children, puberty proceeds as a predictable series of changes in specific order. In children with ordinary constitutional delay, all aspects of physical maturation typically remain concordant but a few years later than average. If some aspects of physical development are delayed, and others are not, there is likely something wrong. For instance, in most girls, the beginning stages of breast development precede pubic hair. If a 12 year old girl were to reach [[Tanner stage]] 3 pubic hair for a year or more without breast development, it would be unusual enough to suggest an abnormality such as defective ovaries. Similarly, if a 13 year old boy had reached stage 3 or 4 pubic hair with testes that still remained prepubertal in size, it would be unusual and suggestive of a testicular abnormality.
{{Family tree/end}}


The third indicator is the presence of clues to specific disorders of the [[reproductive system]]. For example, [[malnutrition]] or [[anorexia nervosa]] severe enough to delay puberty will give other clues as well. Poor growth would suggest the possibility of [[hypopituitarism]] or [[Turner syndrome]]. Reduced sense of smell ([[hyposmia]]) suggests [[Kallmann syndrome]].
==Gross Pathology==
*On gross pathology, lack of [[testicular]] enlargement in boys or [[breast]] development in girls is the characteristic finding of delayed [[puberty]].  
*The time to examine these developments is 2-2.5 standard deviations of age more than the standard population mean.


===Constitutional delay===
 
Children who are healthy but have a slower rate of physical development than average have constitutional delay in growth and adolescence. These children have a history of stature shorter than their age-matched peers throughout childhood, but their height is appropriate for bone age, and skeletal development is delayed more than 2.5 SD. They usually are thin and often have a family history of delayed puberty. Children with a combination of a family tendency toward short stature and constitutional delay are the most likely to seek evaluation. They quite often seek evaluation when classmates or friends undergo pubertal development and growth, thereby accentuating their delay.
==Microscopic Pathology==
*On microscopic [[histopathological]] analysis, the main finding is lack of differentiation of [[gonadal]] cells; the characteristic finding of delayed [[puberty]].
*Microscopic evaluation of [[ovaries]] in a patient with delayed [[puberty]] may reveal the presence of normal [[Cuboidal epithelium|cubical epithelium]]. The [[ovary]] has some dense [[fibrous tissue]], about 0.4 mm thick band, in the [[cortex]]. The band is extended under the [[tunica albuginea]], devoid of [[Follicle|follicles]]. Under the fibrous band there will be numerous small [[Follicle|follicles]]. These [[Follicle|follicles]] consist of:
**'''Primordial follicles:''' Consists of [[oocyte]] in first [[prophase]] covered with simple [[squamous]] layer of pregranulosa cells (51% of all [[oocytes]]).
**'''Intermediary follicles:''' Consists of [[oocyte]] covered with mixture of [[squamous]] and [[Cuboidal epithelia|cubical]] cells (42% of all [[oocytes]]).
**'''Primary follicles:''' Consists of a [[monolayer]] of [[Cuboidal epithelia|cubical]] [[granulosa cells]] (7% of all [[oocytes]]).
*There are no [[Follicle|follicles]] beyond the primary follicles in all sections.<ref name="pmid12915623">{{cite journal |vauthors=Meduri G, Touraine P, Beau I, Lahuna O, Desroches A, Vacher-Lavenu MC, Kuttenn F, Misrahi M |title=Delayed puberty and primary amenorrhea associated with a novel mutation of the human follicle-stimulating hormone receptor: clinical, histological, and molecular studies |journal=J. Clin. Endocrinol. Metab. |volume=88 |issue=8 |pages=3491–8 |year=2003 |pmid=12915623 |doi=10.1210/jc.2003-030217 |url=}}</ref>


==References==
==References==
{{reflist|2}}
{{reflist|2}}
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[[Category:Disease]]
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[[Category:Mature chapter]]
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[[Category:Developmental biology]]
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[[Category:Sexuality and age]]
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Latest revision as of 21:15, 29 July 2020

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Eiman Ghaffarpasand, M.D. [2]

Overview

Delayed puberty is the result of disturbances in hypothalamus-pituitary-gonadal (HPG) axis. Genetics plays an important role in the development of delayed puberty. In case of constitutional delay of growth and puberty (CDGP), 50-75% of patients have a positive family history of delayed puberty. About 25 various genes, in 3 different group of Kallmann syndrome-related genes, hypothalamus-pituitary-gonadal (HPG) axis related genes, and obesity-related genes play roles in delayed puberty. On gross pathology, lack of testicular enlargement in boys or breast development in girls is the characteristic finding of delayed puberty. Microscopic evaluation of ovaries in a patient with delayed puberty may reveal the presence of normal cuboidal epithelium; the ovary has some dense fibrous tissue, about 0.4 mm thick band, in the cortex. The band is extended under the tunica albuginea, devoid of follicles. Under the fibrous band, there will be numerous small follicles. These follicles consist of primordial (51%), intermediary (42%), and primary (7%) follicles.

Pathophysiology

Pathogenesis

Group Form of disease Disease Pathogenesis
Primary hypogonadism Congenital Chromosomal abnormality Lack or disorder of a specific cell line or enzyme that is responsible for producing one of the sex-steroids in gonads
Gonadal agenesis Lack of gonads, as a main source of sex-steroids
Acquired Any external stress to the gonadal tissues Destruction of gonadal cell line, responsible for producing and secreting sex-steroids
Secondary hypogonadism Congenital GnRH deficiency Lack or disorder of a specific cell line or enzyme that is responsible for producing GnRH in hypothalamus
LH and FSH deficiency Lack or disorder of a specific cell line or enzyme that is responsible for producing LH or FSH in pituitary gonadotropic cells
Acquired Any external stress to the hypothalamus or anterior pituitary Destruction of hypothalamus or anterior pituitary cell line, responsible for producing and secreting GnRH, LH, or FSH

Antimullerian hormone and inhibin B

Sex Hormone Source of secretion After birth Childhood Puberty Function
Boys Antimullerian hormone Sertoli cells of testes ↑ ↓ ↓
Inhibin B Sertoli cells of testes ↑ ↓ ↑
Girls Antimullerian hormone Granulosa cells of preantral follicles in ovary ↑ ↑ ↓
  • Marker for the assessment of follicular pool
Inhibin B Both preantral and small antral follicles in ovary ↓ ↓ ↑

Genetics

  • Genetics plays an important role in delayed puberty. It is assumed that the main factor in determining puberty timing is genetic elements.[3]

The major genes in delayed puberty

Abbreviations (alphabetic):
CHD7: Chromodomain helicase DNA-binding protein 7 gene, DAX1: DSS-AHC on the X-chromosome 1, EBF2: Early B-cell factor 2 gene, FGF8: Fibroblast growth factor 8 gene, FGFR1: Fibroblast growth factor receptor 1 gene, FSH: Follicle stimulating hormone, GnRH: Gonadotropin releasing hormone, GnRH1: Gonadotropin releasing hormone 1 gene, GnRHR: Gonadotropin releasing hormone receptor gene, GPR54: G protein-coupled receptor-54 gene, HESX-1: Homeobox gene 1, HPG axis: Hypothalamus-pituitary-gonadal axis, HS6ST1: Heparan sulfate 6-O-sulphotransferase 1 gene, KAL1: Kallmann syndrome 1 gene, LEP: Leptin gene, LEPR: Leptin receptor gene, LH: Luteinizing hormone, LHX3: LIM homeobox gene 3, NEC1: Neuroendocrine convertase 1, NELF: Nasal embryonic LH-releasing hormone factor gene, NK3R: Neurokinin 3 receptor gene, NKB: Neurokinin B gene, NR0B: Nuclear receptor 0B, NR5A1: Nuclear receptor 5A1, OMIM: Online Mendelian Inheritance in Man, PC1: Proprotein convertase 1, PROK2 : Prokineticin 2 gene, PROKR2: Prokineticin 2 receptor gene, PROP-1: PROP paired-like homeobox 1, RPX: Rathke pouch homeobox, SF-1: Steroidogenic factor 1, TAC3: Tachykinin 3 gene,TACR3: Tachykinin 3 receptor gene,

Groups Gene Other name(s) OMIM number Chromosome Function Other related disorders
Kallmann syndrome

and

Isolated hypogonadotropic hypogonadism[6]

KAL1 KAL1, anosmin-1 308700 Xp22.3
FGFR1 KAL2 136350 8q12
PROKR2 KAL3 607123 20p13
PROK2 KAL4 607002 3p21.1
CHD7 KAL5 608892 8q12.1
FGF8 KAL6 600483 10q24
GPR54 KISS1R 604161 19p13.3
  • Regulation of GnRH secretion
 -
KISS1 KISS1, kisspeptin1 603286 1q32 -
HS6ST1 - 604846 2q21 -
TAC3 NKB 162330 12q13–q21
TACR3 NK3R 152332 4q25
GnRH1 - 152760 8p21–8p11.2
  • One of the most important elements in HPG axis
GnRHR - 138850 4q21.2
NELF - 608137 9q34.3 -
EBF2 - 609934 8p21.2
  • Effective role in HPG axis
 -
HPG axis development DAX1 NR0B 300473 Xp21.2
SF-1 NR5A1 184757 9q33.3
HESX-1 RPX 601802 3p14.3
LHX3 LIM3 600577 9q34.3
PROP-1 - 601538 5q35.3
Obesity related

hypogonadotropic hypogonadism

LEP OB 164160 7q32.1
LEPR OBR 601007 1p31.3
PC1 NEC1 162150 5q15

Kisspeptin system (KISS1R and KISS1)

Kallmann syndrome 1 (KAL1)

Fibroblast growth factor receptor 1 and fibroblast growth factor 8 (FGFR1 and FGF8)

Heparan sulfate 6-O-sulphotransferase 1 (HS6ST1)

Prokineticin 2 and prokineticin 2 receptor (PROK2 and PROKR2)

Tachykinin 3 and tachykinin 3 receptor (TAC3 and TACR3)

Gonadotropin releasing hormone and its receptor (GnRH1 and GnRHR)

Chromodomain helicase DNA-binding protein 7 (CHD7)

Nasal embryonic LH-releasing hormone factor (NELF)

Early B-cell factor 2 (EBF2)

DSS-AHC on the X-chromosome 1 (DAX1)

Steroidogenic factor 1 (SF1)

Homeobox gene 1 (HESX1)

LIM homeobox gene 3 (LHX3)

PROP paired-like homeobox 1 (PROP1)

Leptin and leptin receptor (LEP and LEPR)

Proprotein convrtase 1 (PC1)

Makorin RING-finger protein 3 (MKRN3)

Estrogen receptor α (ESR1)

Associated Conditions

The associated conditions that are related to delayed puberty, are as following:[1]

 
 
 
 
 
 
 
 
Associated conditions
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Primary hypogonadism
 
 
 
Secondary hypogonadism
 
 
 
Functional hypogonadism
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• Turner syndrome
• Noonan syndrome
• Fragile X syndrome
• Cryptorchidism
• Gonadal dysgenesis
• Testicular agenesis
• Trauma/Testicular torsion
• Chemotherapy/Radiation therapy
• Mumps, coxsackie
• Galactosemia
• Autoimmune oophiritis
• Autoimmune orchitis
• 5-alpha reductase deficiency
• Lyase deficiency
• Congenital lipoid adrenal hyperplasia
• Androgen insensitivity
• Sertoli cell only syndrome (Del Castillo syndrome)
 
 
 
• Astrocytoma
• Germinoma
• Glioma
• Craniopharyngioma
• Prolactinoma
• Langerhans cell histiocytosis
• Rathke pouch cyst
• Kallmann syndrome
• Isolated hypogonadotropic hypogonadism
• HPG axis development
• Obesity and hypogonadotropic hypogonadism
• Prader-Willi syndrome
• Bardet-Biedl syndrome
• CHARGE syndrome
• Gaucher disease
• Post central nervous system Infection
• Septo-optic dysplasia
• Congenital hypopituitarism
• Chemotherapy/Radiation therapy
• Trauma
 
 
 
• Cystic Fibrosis
• Asthma
• Inflammatory bowel disease
• Celiac disease
• Juvenile rheumatoid arthritis
• Anorexia nervosa/Bulimia
• Sickle cell disease
• Hemosiderosis
• Thalassemia
• Chronic renal disease
• AIDS
• Diabetes mellitus
• Hypothyroidism
• Hyperprolactinemia
• Growth hormone deficiency
• Cushing syndrome
• Excessive exercise
• Malnutrition
 

Gross Pathology

  • On gross pathology, lack of testicular enlargement in boys or breast development in girls is the characteristic finding of delayed puberty.
  • The time to examine these developments is 2-2.5 standard deviations of age more than the standard population mean.


Microscopic Pathology

References

  1. ↑ 1.0 1.1 Palmert, Mark R.; Dunkel, Leo (2012). "Delayed Puberty". New England Journal of Medicine. 366 (5): 443–453. doi:10.1056/NEJMcp1109290. ISSN 0028-4793.
  2. ↑ Wei C, Crowne EC (2016). "Recent advances in the understanding and management of delayed puberty". Arch. Dis. Child. 101 (5): 481–8. doi:10.1136/archdischild-2014-307963. PMID 26353794.
  3. ↑ Gajdos ZK, Henderson KD, Hirschhorn JN, Palmert MR (2010). "Genetic determinants of pubertal timing in the general population". Mol. Cell. Endocrinol. 324 (1–2): 21–9. doi:10.1016/j.mce.2010.01.038. PMC 2891370. PMID 20144687.
  4. ↑ Wehkalampi K, Widén E, Laine T, Palotie A, Dunkel L (2008). "Patterns of inheritance of constitutional delay of growth and puberty in families of adolescent girls and boys referred to specialist pediatric care". J. Clin. Endocrinol. Metab. 93 (3): 723–8. doi:10.1210/jc.2007-1786. PMID 18160460.
  5. ↑ Sedlmeyer IL, Hirschhorn JN, Palmert MR (2002). "Pedigree analysis of constitutional delay of growth and maturation: determination of familial aggregation and inheritance patterns". J. Clin. Endocrinol. Metab. 87 (12): 5581–6. doi:10.1210/jc.2002-020862. PMID 12466356.
  6. ↑ Bonomi, Marco; Libri, Domenico Vladimiro; Guizzardi, Fabiana; Guarducci, Elena; Maiolo, Elisabetta; Pignatti, Elisa; Asci, Roberta; Persani, Luca (2011). "New understandings of the genetic basis of isolated idiopathic central hypogonadism". Asian Journal of Andrology. 14 (1): 49–56. doi:10.1038/aja.2011.68. ISSN 1008-682X.
  7. ↑ de Roux N, Genin E, Carel JC, Matsuda F, Chaussain JL, Milgrom E (2003). "Hypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54". Proc. Natl. Acad. Sci. U.S.A. 100 (19): 10972–6. doi:10.1073/pnas.1834399100. PMC 196911. PMID 12944565.
  8. ↑ Seminara, Stephanie B.; Messager, Sophie; Chatzidaki, Emmanouella E.; Thresher, Rosemary R.; Acierno, James S.; Shagoury, Jenna K.; Bo-Abbas, Yousef; Kuohung, Wendy; Schwinof, Kristine M.; Hendrick, Alan G.; Zahn, Dirk; Dixon, John; Kaiser, Ursula B.; Slaugenhaupt, Susan A.; Gusella, James F.; O'Rahilly, Stephen; Carlton, Mark B.L.; Crowley, William F.; Aparicio, Samuel A.J.R.; Colledge, William H. (2003). "TheGPR54Gene as a Regulator of Puberty". New England Journal of Medicine. 349 (17): 1614–1627. doi:10.1056/NEJMoa035322. ISSN 0028-4793.
  9. ↑ Kaur KK, Allahbadia G, Singh M (2012). "Kisspeptins in human reproduction-future therapeutic potential". J Assist Reprod Genet. 29 (10): 999–1011. doi:10.1007/s10815-012-9856-1. PMC 3492584. PMID 23015158.
  10. ↑ Uenoyama, Yoshihisa; Tsukamura, Hiroko; Maeda, Kei-ichiro (2014). "KNDy neuron as a gatekeeper of puberty onset". Journal of Obstetrics and Gynaecology Research. 40 (6): 1518–1526. doi:10.1111/jog.12398. ISSN 1341-8076.
  11. ↑ Hardelin JP, Julliard AK, Moniot B, Soussi-Yanicostas N, Verney C, Schwanzel-Fukuda M, Ayer-Le Lievre C, Petit C (1999). "Anosmin-1 is a regionally restricted component of basement membranes and interstitial matrices during organogenesis: implications for the developmental anomalies of X chromosome-linked Kallmann syndrome". Dev. Dyn. 215 (1): 26–44. doi:10.1002/(SICI)1097-0177(199905)215:1<26::AID-DVDY4>3.0.CO;2-D. PMID 10340754.
  12. ↑ Schwanzel-Fukuda M, Bick D, Pfaff DW (1989). "Luteinizing hormone-releasing hormone (LHRH)-expressing cells do not migrate normally in an inherited hypogonadal (Kallmann) syndrome". Brain Res. Mol. Brain Res. 6 (4): 311–26. PMID 2687610.
  13. ↑ 13.0 13.1 Trarbach EB, Silveira LG, Latronico AC (2007). "Genetic insights into human isolated gonadotropin deficiency". Pituitary. 10 (4): 381–91. doi:10.1007/s11102-007-0061-7. PMID 17624596.
  14. ↑ González-Martínez D, Kim SH, Hu Y, Guimond S, Schofield J, Winyard P, Vannelli GB, Turnbull J, Bouloux PM (2004). "Anosmin-1 modulates fibroblast growth factor receptor 1 signaling in human gonadotropin-releasing hormone olfactory neuroblasts through a heparan sulfate-dependent mechanism". J. Neurosci. 24 (46): 10384–92. doi:10.1523/JNEUROSCI.3400-04.2004. PMID 15548653.
  15. ↑ Hébert JM, Lin M, Partanen J, Rossant J, McConnell SK (2003). "FGF signaling through FGFR1 is required for olfactory bulb morphogenesis". Development. 130 (6): 1101–11. PMID 12571102.
  16. ↑ Tsai PS, Moenter SM, Postigo HR, El Majdoubi M, Pak TR, Gill JC, Paruthiyil S, Werner S, Weiner RI (2005). "Targeted expression of a dominant-negative fibroblast growth factor (FGF) receptor in gonadotropin-releasing hormone (GnRH) neurons reduces FGF responsiveness and the size of GnRH neuronal population". Mol. Endocrinol. 19 (1): 225–36. doi:10.1210/me.2004-0330. PMID 15459253.
  17. ↑ 17.0 17.1 Tornberg J, Sykiotis GP, Keefe K, Plummer L, Hoang X, Hall JE, Quinton R, Seminara SB, Hughes V, Van Vliet G, Van Uum S, Crowley WF, Habuchi H, Kimata K, Pitteloud N, Bülow HE (2011). "Heparan sulfate 6-O-sulfotransferase 1, a gene involved in extracellular sugar modifications, is mutated in patients with idiopathic hypogonadotrophic hypogonadism". Proc. Natl. Acad. Sci. U.S.A. 108 (28): 11524–9. doi:10.1073/pnas.1102284108. PMC 3136273. PMID 21700882.
  18. ↑ Ibrahimi OA, Zhang F, Hrstka SC, Mohammadi M, Linhardt RJ (2004). "Kinetic model for FGF, FGFR, and proteoglycan signal transduction complex assembly". Biochemistry. 43 (16): 4724–30. doi:10.1021/bi0352320. PMID 15096041.
  19. ↑ Hudson ML, Kinnunen T, Cinar HN, Chisholm AD (2006). "C. elegans Kallmann syndrome protein KAL-1 interacts with syndecan and glypican to regulate neuronal cell migrations". Dev. Biol. 294 (2): 352–65. doi:10.1016/j.ydbio.2006.02.036. PMID 16677626.
  20. ↑ Matsumoto S, Yamazaki C, Masumoto KH, Nagano M, Naito M, Soga T, Hiyama H, Matsumoto M, Takasaki J, Kamohara M, Matsuo A, Ishii H, Kobori M, Katoh M, Matsushime H, Furuichi K, Shigeyoshi Y (2006). "Abnormal development of the olfactory bulb and reproductive system in mice lacking prokineticin receptor PKR2". Proc. Natl. Acad. Sci. U.S.A. 103 (11): 4140–5. doi:10.1073/pnas.0508881103. PMC 1449660. PMID 16537498.
  21. ↑ Li M, Bullock CM, Knauer DJ, Ehlert FJ, Zhou QY (2001). "Identification of two prokineticin cDNAs: recombinant proteins potently contract gastrointestinal smooth muscle". Mol. Pharmacol. 59 (4): 692–8. PMID 11259612.
  22. ↑ Cole LW, Sidis Y, Zhang C, Quinton R, Plummer L, Pignatelli D, Hughes VA, Dwyer AA, Raivio T, Hayes FJ, Seminara SB, Huot C, Alos N, Speiser P, Takeshita A, Van Vliet G, Pearce S, Crowley WF, Zhou QY, Pitteloud N (2008). "Mutations in prokineticin 2 and prokineticin receptor 2 genes in human gonadotrophin-releasing hormone deficiency: molecular genetics and clinical spectrum". J. Clin. Endocrinol. Metab. 93 (9): 3551–9. doi:10.1210/jc.2007-2654. PMC 2567850. PMID 18559922.
  23. ↑ Topaloglu AK, Reimann F, Guclu M, Yalin AS, Kotan LD, Porter KM, Serin A, Mungan NO, Cook JR, Imamoglu S, Akalin NS, Yuksel B, O'Rahilly S, Semple RK (2009). "TAC3 and TACR3 mutations in familial hypogonadotropic hypogonadism reveal a key role for Neurokinin B in the central control of reproduction". Nat. Genet. 41 (3): 354–358. doi:10.1038/ng.306. PMC 4312696. PMID 19079066.
  24. ↑ Pinto FM, Almeida TA, Hernandez M, Devillier P, Advenier C, Candenas ML (2004). "mRNA expression of tachykinins and tachykinin receptors in different human tissues". Eur. J. Pharmacol. 494 (2–3): 233–9. doi:10.1016/j.ejphar.2004.05.016. PMID 15212980.
  25. ↑ Semple RK, Topaloglu AK (2010). "The recent genetics of hypogonadotrophic hypogonadism - novel insights and new questions". Clin. Endocrinol. (Oxf). 72 (4): 427–35. doi:10.1111/j.1365-2265.2009.03687.x. PMID 19719764.
  26. ↑ Bouligand J, Ghervan C, Tello JA, Brailly-Tabard S, Salenave S, Chanson P, Lombès M, Millar RP, Guiochon-Mantel A, Young J (2009). "Isolated familial hypogonadotropic hypogonadism and a GNRH1 mutation". N. Engl. J. Med. 360 (26): 2742–8. doi:10.1056/NEJMoa0900136. PMID 19535795.
  27. ↑ Cattanach BM, Iddon CA, Charlton HM, Chiappa SA, Fink G (1977). "Gonadotrophin-releasing hormone deficiency in a mutant mouse with hypogonadism". Nature. 269 (5626): 338–40. PMID 198666.
  28. ↑ Wu S, Wilson MD, Busby ER, Isaac ER, Sherwood NM (2010). "Disruption of the single copy gonadotropin-releasing hormone receptor in mice by gene trap: severe reduction of reproductive organs and functions in developing and adult mice". Endocrinology. 151 (3): 1142–52. doi:10.1210/en.2009-0598. PMID 20068010.
  29. ↑ Silveira LF, MacColl GS, Bouloux PM (2002). "Hypogonadotropic hypogonadism". Semin. Reprod. Med. 20 (4): 327–38. doi:10.1055/s-2002-36707. PMID 12536356.
  30. ↑ Tiong J, Locastro T, Wray S (2007). "Gonadotropin-releasing hormone-1 (GnRH-1) is involved in tooth maturation and biomineralization". Dev. Dyn. 236 (11): 2980–92. doi:10.1002/dvdy.21332. PMID 17948256.
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  32. ↑ Kramer PR, Wray S (2000). "Novel gene expressed in nasal region influences outgrowth of olfactory axons and migration of luteinizing hormone-releasing hormone (LHRH) neurons". Genes Dev. 14 (14): 1824–34. PMC 316793. PMID 10898796.
  33. ↑ Xu N, Kim HG, Bhagavath B, Cho SG, Lee JH, Ha K, Meliciani I, Wenzel W, Podolsky RH, Chorich LP, Stackhouse KA, Grove AM, Odom LN, Ozata M, Bick DP, Sherins RJ, Kim SH, Cameron RS, Layman LC (2011). "Nasal embryonic LHRH factor (NELF) mutations in patients with normosmic hypogonadotropic hypogonadism and Kallmann syndrome". Fertil. Steril. 95 (5): 1613–20.e1–7. doi:10.1016/j.fertnstert.2011.01.010. PMC 3888818. PMID 21300340.
  34. ↑ Corradi A, Croci L, Broccoli V, Zecchini S, Previtali S, Wurst W, Amadio S, Maggi R, Quattrini A, Consalez GG (2003). "Hypogonadotropic hypogonadism and peripheral neuropathy in Ebf2-null mice". Development. 130 (2): 401–10. PMID 12466206.
  35. ↑ Trarbach EB, Baptista MT, Garmes HM, Hackel C (2005). "Molecular analysis of KAL-1, GnRH-R, NELF and EBF2 genes in a series of Kallmann syndrome and normosmic hypogonadotropic hypogonadism patients". J. Endocrinol. 187 (3): 361–8. doi:10.1677/joe.1.06103. PMID 16423815.
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  37. ↑ 37.0 37.1 Kojima Y, Sasaki S, Hayashi Y, Umemoto Y, Morohashi K, Kohri K (2006). "Role of transcription factors Ad4bp/SF-1 and DAX-1 in steroidogenesis and spermatogenesis in human testicular development and idiopathic azoospermia". Int. J. Urol. 13 (6): 785–93. doi:10.1111/j.1442-2042.2006.01403.x. PMID 16834661.
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  40. ↑ 40.0 40.1 Dattani MT, Martinez-Barbera JP, Thomas PQ, Brickman JM, Gupta R, Mårtensson IL, Toresson H, Fox M, Wales JK, Hindmarsh PC, Krauss S, Beddington RS, Robinson IC (1998). "Mutations in the homeobox gene HESX1/Hesx1 associated with septo-optic dysplasia in human and mouse". Nat. Genet. 19 (2): 125–33. doi:10.1038/477. PMID 9620767.
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  42. ↑ 42.0 42.1 Rajab A, Kelberman D, de Castro SC, Biebermann H, Shaikh H, Pearce K, Hall CM, Shaikh G, Gerrelli D, Grueters A, Krude H, Dattani MT (2008). "Novel mutations in LHX3 are associated with hypopituitarism and sensorineural hearing loss". Hum. Mol. Genet. 17 (14): 2150–9. doi:10.1093/hmg/ddn114. PMID 18407919.
  43. ↑ Netchine I, Sobrier ML, Krude H, Schnabel D, Maghnie M, Marcos E, Duriez B, Cacheux V, Moers A, Goossens M, Grüters A, Amselem S (2000). "Mutations in LHX3 result in a new syndrome revealed by combined pituitary hormone deficiency". Nat. Genet. 25 (2): 182–6. doi:10.1038/76041. PMID 10835633. Vancouver style error: initials (help)
  44. ↑ Duquesnoy P, Roy A, Dastot F, Ghali I, Teinturier C, Netchine I, Cacheux V, Hafez M, Salah N, Chaussain JL, Goossens M, Bougnères P, Amselem S (1998). "Human Prop-1: cloning, mapping, genomic structure. Mutations in familial combined pituitary hormone deficiency". FEBS Lett. 437 (3): 216–20. PMID 9824293.
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  46. ↑ Chehab FF, Lim ME, Lu R (1996). "Correction of the sterility defect in homozygous obese female mice by treatment with the human recombinant leptin". Nat. Genet. 12 (3): 318–20. doi:10.1038/ng0396-318. PMID 8589726.
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  50. ↑ Hughes, Ieuan A. (2013). "Releasing the Brake on Puberty". New England Journal of Medicine. 368 (26): 2513–2515. doi:10.1056/NEJMe1306743. ISSN 0028-4793.
  51. ↑ Quaynor, Samuel D.; Stradtman, Earl W.; Kim, Hyung-Goo; Shen, Yiping; Chorich, Lynn P.; Schreihofer, Derek A.; Layman, Lawrence C. (2013). "Delayed Puberty and Estrogen Resistance in a Woman with Estrogen Receptor α Variant". New England Journal of Medicine. 369 (2): 164–171. doi:10.1056/NEJMoa1303611. ISSN 0028-4793.
  52. ↑ Christian CA, Glidewell-Kenney C, Jameson JL, Moenter SM (2008). "Classical estrogen receptor alpha signaling mediates negative and positive feedback on gonadotropin-releasing hormone neuron firing". Endocrinology. 149 (11): 5328–34. doi:10.1210/en.2008-0520. PMC 2584581. PMID 18635656.
  53. ↑ Lubahn DB, Moyer JS, Golding TS, Couse JF, Korach KS, Smithies O (1993). "Alteration of reproductive function but not prenatal sexual development after insertional disruption of the mouse estrogen receptor gene". Proc. Natl. Acad. Sci. U.S.A. 90 (23): 11162–6. PMC 47942. PMID 8248223.
  54. ↑ Meduri G, Touraine P, Beau I, Lahuna O, Desroches A, Vacher-Lavenu MC, Kuttenn F, Misrahi M (2003). "Delayed puberty and primary amenorrhea associated with a novel mutation of the human follicle-stimulating hormone receptor: clinical, histological, and molecular studies". J. Clin. Endocrinol. Metab. 88 (8): 3491–8. doi:10.1210/jc.2003-030217. PMID 12915623.

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