Delayed puberty pathophysiology

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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.
  31. 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 (2008). "Mutations in CHD7, encoding a chromatin-remodeling protein, cause idiopathic hypogonadotropic hypogonadism and Kallmann syndrome". Am. J. Hum. Genet. 83 (4): 511–9. doi:10.1016/j.ajhg.2008.09.005. PMC 2561938. PMID 18834967.
  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.
  36. Guo W, Burris TP, McCabe ER (1995). "Expression of DAX-1, the gene responsible for X-linked adrenal hypoplasia congenita and hypogonadotropic hypogonadism, in the hypothalamic-pituitary-adrenal/gonadal axis". Biochem. Mol. Med. 56 (1): 8–13. PMID 8593542.
  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.
  38. Zanaria E, Muscatelli F, Bardoni B, Strom TM, Guioli S, Guo W, Lalli E, Moser C, Walker AP, McCabe ER (1994). "An unusual member of the nuclear hormone receptor superfamily responsible for X-linked adrenal hypoplasia congenita". Nature. 372 (6507): 635–41. doi:10.1038/372635a0. PMID 7990953.
  39. Nachtigal MW, Hirokawa Y, Enyeart-VanHouten DL, Flanagan JN, Hammer GD, Ingraham HA (1998). "Wilms' tumor 1 and Dax-1 modulate the orphan nuclear receptor SF-1 in sex-specific gene expression". Cell. 93 (3): 445–54. PMID 9590178.
  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.
  41. 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 (2001). "Heterozygous HESX1 mutations associated with isolated congenital pituitary hypoplasia and septo-optic dysplasia". Hum. Mol. Genet. 10 (1): 39–45. PMID 11136712.
  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.
  45. 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 (1998). "Mutations in PROP1 cause familial combined pituitary hormone deficiency". Nat. Genet. 18 (2): 147–9. doi:10.1038/ng0298-147. PMID 9462743.
  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.
  47. Mantzoros CS, Flier JS, Rogol AD (1997). "A longitudinal assessment of hormonal and physical alterations during normal puberty in boys. V. Rising leptin levels may signal the onset of puberty". J. Clin. Endocrinol. Metab. 82 (4): 1066–70. doi:10.1210/jcem.82.4.3878. PMID 9100574.
  48. Jansen E, Ayoubi TA, Meulemans SM, Van de Ven WJ (1995). "Neuroendocrine-specific expression of the human prohormone convertase 1 gene. Hormonal regulation of transcription through distinct cAMP response elements". J. Biol. Chem. 270 (25): 15391–7. PMID 7797529.
  49. Jackson RS, Creemers JW, Ohagi S, Raffin-Sanson ML, Sanders L, Montague CT, Hutton JC, O'Rahilly S (1997). "Obesity and impaired prohormone processing associated with mutations in the human prohormone convertase 1 gene". Nat. Genet. 16 (3): 303–6. doi:10.1038/ng0797-303. PMID 9207799.
  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.