Amenorrhea pathophysiology

Revision as of 20:22, 29 July 2020 by WikiBot (talk | contribs) (Bot: Removing from Primary care)
(diff) ← Older revision | Latest revision (diff) | Newer revision → (diff)
Jump to navigation Jump to search

Amenorrhea Microchapters

Home

Patient Information

Primary amenorrhea
Secondary amenorrhea

Overview

Historical Perspective

Classification

Pathophysiology

Causes

Differentiating Amenorrhea from other Diseases

Epidemiology and Demographics

Risk Factors

Screening

Natural History, Complications and Prognosis

Diagnosis

Diagnostic Criteria

History and Symptoms

Physical Examination

Laboratory Findings

Electrocardiogram

X-ray

Echocardiography and Ultrasound

CT scan

MRI

Other Imaging Findings

Other Diagnostic Studies

Treatment

Medical Therapy

Surgery

Primary Prevention

Secondary Prevention

Cost-Effectiveness of Therapy

Future or Investigational Therapies

Case Studies

Case #1

Amenorrhea pathophysiology On the Web

Most recent articles

Most cited articles

Review articles

CME Programs

Powerpoint slides

Images

American Roentgen Ray Society Images of Amenorrhea pathophysiology

All Images
X-rays
Echo & Ultrasound
CT Images
MRI

Ongoing Trials at Clinical Trials.gov

US National Guidelines Clearinghouse

NICE Guidance

FDA on Amenorrhea pathophysiology

CDC on Amenorrhea pathophysiology

Amenorrhea pathophysiology in the news

Blogs on Amenorrhea pathophysiology

Directions to Hospitals Treating Amenorrhea

Risk calculators and risk factors for Amenorrhea pathophysiology

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

Overview

Amenorrhea is defined as absence of menstrual cycle. The causes of amenorrhea include hypothalamic, pituitary, thyroid, adrenal, ovarian, uterine, and vaginal. About 25 different genes are involved in the pathogenesis of amenorrhea including 3 different groups of Kallmann syndrome related genes, hypothalamus-pituitary-gonadal (HPG) axis related genes, and obesity related genes. On gross pathology, normal endometrium is the characteristic findings of amenorrhea. Patients of amenorrhea from Craniopharyngioma as have cystic mass filled with motor oil-like fluid on gross pathology. On microscopic histopathological analysis, craniopharyngioma presents as trabecular squamous epithelium surrounded by palisaded columnar epithelium, small-to-medium sized cells with moderate amount of basophilic cytoplasm, bland nuclei, and calcifications. On microscopic histopathological analysis, pituitary adenoma as a cause of amenorrhea presents as loss of fibrous stroma and nested cells of normal anterior pituitary (based on the type of adenoma).

Pathophysiology

Physiology of normal puberty

Menarche and Menstruation

Hypothalamic-pituitary-ovarian (HPO) axis maturation

Pathogenesis

Hypothalamic pathogenesis

Pituitary pathogenesis

Thyroid pathogenesis

Adrenal pathogenesis

Ovarian pathogenesis

Uterine pathogenesis

Genetics

The major genes in amenorrhea

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

and

Isolated hypogonadotropic hypogonadism[29]

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

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,

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 convertase 1 (PC1)

Makorin RING-finger protein 3 (MKRN3)

Estrogen receptor α (ESR1)

Associated Conditions

The associated conditions that are related to amenorrhea, are as following:[75]

 
 
 
 
 
 
 
 
Associated conditions
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Primary amenorrhea
 
 
 
Secondary amenorrhea
 
 
 
Functional amenorrhea
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Kallmann syndrome
Turner syndrome
Noonan syndrome
Gonadal dysgenesis
Chemotherapy/Radiation therapy
Coxsackie
Galactosemia
Autoimmune oophiritis
Lyase deficiency
Congenital lipoid adrenal hyperplasia
Androgen insensitivity
Congenital hypopituitarism
Bardet-Biedl syndrome
CHARGE syndrome
Gaucher disease
Septo-optic dysplasia
Cystic Fibrosis
Thalassemia
 
 
 
Astrocytoma
Germinoma
Glioma
Craniopharyngioma
Prolactinoma
Langerhans cell histiocytosis
Rathke pouch cyst
• Isolated hypogonadotropic hypogonadism
HPO axis development disturbance
• Post central nervous system Infection
Chemotherapy/Radiation therapy
Trauma
Asthma
Inflammatory bowel disease
Celiac disease
Juvenile rheumatoid arthritis
Sickle cell disease
Hemosiderosis
Chronic renal disease
AIDS
Diabetes mellitus
Hypothyroidism
Hyperprolactinemia
Growth hormone deficiency
Cushing syndrome
 
 
 
Stress
• Excessive exercise
Malnutrition
Obesity
Anorexia nervosa
Bulimia
 

Gross Pathology

Gross pathology of craniopharyngioma in third ventricle brain, biphasic mixture - Source: Librepathology

Microscopic Pathology

References

  1. Chumlea WC, Schubert CM, Roche AF, Kulin HE, Lee PA, Himes JH, Sun SS (2003). "Age at menarche and racial comparisons in US girls". Pediatrics. 111 (1): 110–3. PMID 12509562.
  2. "Menstruation in Girls and Adolescents: Using the Menstrual Cycle as a Vital Sign - ACOG".
  3. 3.0 3.1 Golden NH, Carlson JL (2008). "The pathophysiology of amenorrhea in the adolescent". Ann. N. Y. Acad. Sci. 1135: 163–78. doi:10.1196/annals.1429.014. PMID 18574222.
  4. Apter D (1997). "Development of the hypothalamic-pituitary-ovarian axis". Ann. N. Y. Acad. Sci. 816: 9–21. PMID 9238251.
  5. Boyar RM, Rosenfeld RS, Kapen S, Finkelstein JW, Roffwarg HP, Weitzman ED, Hellman L (1974). "Human puberty. Simultaneous augmented secretion of luteinizing hormone and testosterone during sleep". J. Clin. Invest. 54 (3): 609–18. doi:10.1172/JCI107798. PMC 301594. PMID 4852310.
  6. Wiksten-Almströmer M, Hirschberg AL, Hagenfeldt K (2007). "Menstrual disorders and associated factors among adolescent girls visiting a youth clinic". Acta Obstet Gynecol Scand. 86 (1): 65–72. doi:10.1080/00016340601034970. PMID 17230292.
  7. Perkins RB, Hall JE, Martin KA (2001). "Aetiology, previous menstrual function and patterns of neuro-endocrine disturbance as prognostic indicators in hypothalamic amenorrhoea". Hum. Reprod. 16 (10): 2198–205. PMID 11574516.
  8. Hebebrand J, Muller TD, Holtkamp K, Herpertz-Dahlmann B (2007). "The role of leptin in anorexia nervosa: clinical implications". Mol. Psychiatry. 12 (1): 23–35. doi:10.1038/sj.mp.4001909. PMID 17060920.
  9. Grinspoon S, Gulick T, Askari H, Landt M, Lee K, Anderson E, Ma Z, Vignati L, Bowsher R, Herzog D, Klibanski A (1996). "Serum leptin levels in women with anorexia nervosa". J. Clin. Endocrinol. Metab. 81 (11): 3861–3. doi:10.1210/jcem.81.11.8923829. PMID 8923829.
  10. Haas V, Onur S, Paul T, Nutzinger DO, Bosy-Westphal A, Hauer M, Brabant G, Klein H, Müller MJ (2005). "Leptin and body weight regulation in patients with anorexia nervosa before and during weight recovery". Am. J. Clin. Nutr. 81 (4): 889–96. PMID 15817868.
  11. Misra M, Miller KK, Almazan C, Ramaswamy K, Aggarwal A, Herzog DB, Neubauer G, Breu J, Klibanski A (2004). "Hormonal and body composition predictors of soluble leptin receptor, leptin, and free leptin index in adolescent girls with anorexia nervosa and controls and relation to insulin sensitivity". J. Clin. Endocrinol. Metab. 89 (7): 3486–95. doi:10.1210/jc.2003-032251. PMID 15240636.
  12. Katzman DK, Golden NH, Neumark-Sztainer D, Yager J, Strober M (2000). "From prevention to prognosis: clinical research update on adolescent eating disorders". Pediatr. Res. 47 (6): 709–12. PMID 10832726.
  13. Thong FS, McLean C, Graham TE (2000). "Plasma leptin in female athletes: relationship with body fat, reproductive, nutritional, and endocrine factors". J. Appl. Physiol. 88 (6): 2037–44. PMID 10846016.
  14. Weimann E, Blum WF, Witzel C, Schwidergall S, Böhles HJ (1999). "Hypoleptinemia in female and male elite gymnasts". Eur. J. Clin. Invest. 29 (10): 853–60. PMID 10583427.
  15. Welt, Corrine K.; Chan, Jean L.; Bullen, John; Murphy, Robyn; Smith, Patricia; DePaoli, Alex M.; Karalis, Aspasia; Mantzoros, Christos S. (2004). "Recombinant Human Leptin in Women with Hypothalamic Amenorrhea". New England Journal of Medicine. 351 (10): 987–997. doi:10.1056/NEJMoa040388. ISSN 0028-4793.
  16. Wieck A, Haddad PM (2003). "Antipsychotic-induced hyperprolactinaemia in women: pathophysiology, severity and consequences. Selective literature review". Br J Psychiatry. 182: 199–204. PMID 12611781.
  17. Magiakou MA, Mastorakos G, Webster E, Chrousos GP (1997). "The hypothalamic-pituitary-adrenal axis and the female reproductive system". Ann. N. Y. Acad. Sci. 816: 42–56. PMID 9238254.
  18. Seminara SB, Hayes FJ, Crowley WF (1998). "Gonadotropin-releasing hormone deficiency in the human (idiopathic hypogonadotropic hypogonadism and Kallmann's syndrome): pathophysiological and genetic considerations". Endocr. Rev. 19 (5): 521–39. doi:10.1210/edrv.19.5.0344. PMID 9793755.
  19. Karavitaki N, Cudlip S, Adams CB, Wass JA (2006). "Craniopharyngiomas". Endocr. Rev. 27 (4): 371–97. doi:10.1210/er.2006-0002. PMID 16543382.
  20. Koutras DA (1997). "Disturbances of menstruation in thyroid disease". Ann. N. Y. Acad. Sci. 816: 280–4. PMID 9238278.
  21. Poppe K, Velkeniers B, Glinoer D (2007). "Thyroid disease and female reproduction". Clin. Endocrinol. (Oxf). 66 (3): 309–21. doi:10.1111/j.1365-2265.2007.02752.x. PMID 17302862.
  22. Speiser, Phyllis W.; White, Perrin C. (2003). "Congenital Adrenal Hyperplasia". New England Journal of Medicine. 349 (8): 776–788. doi:10.1056/NEJMra021561. ISSN 0028-4793.
  23. Gilling-Smith C, Story H, Rogers V, Franks S (1997). "Evidence for a primary abnormality of thecal cell steroidogenesis in the polycystic ovary syndrome". Clin. Endocrinol. (Oxf). 47 (1): 93–9. PMID 9302378.
  24. Ehrmann DA, Barnes RB, Rosenfield RL (1995). "Polycystic ovary syndrome as a form of functional ovarian hyperandrogenism due to dysregulation of androgen secretion". Endocr. Rev. 16 (3): 322–53. doi:10.1210/edrv-16-3-322. PMID 7671850.
  25. Pastor CL, Griffin-Korf ML, Aloi JA, Evans WS, Marshall JC (1998). "Polycystic ovary syndrome: evidence for reduced sensitivity of the gonadotropin-releasing hormone pulse generator to inhibition by estradiol and progesterone". J. Clin. Endocrinol. Metab. 83 (2): 582–90. doi:10.1210/jcem.83.2.4604. PMID 9467578.
  26. Kaufman FR, Kogut MD, Donnell GN, Goebelsmann U, March C, Koch R (1981). "Hypergonadotropic hypogonadism in female patients with galactosemia". N. Engl. J. Med. 304 (17): 994–8. doi:10.1056/NEJM198104233041702. PMID 6782485.
  27. Varner RE, Younger JB, Blackwell RE (1985). "Müllerian dysgenesis". J Reprod Med. 30 (6): 443–50. PMID 4020785.
  28. Edmonds DK (2003). "Congenital malformations of the genital tract and their management". Best Pract Res Clin Obstet Gynaecol. 17 (1): 19–40. PMID 12758224.
  29. 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.
  30. 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.
  31. 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.
  32. 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.
  33. 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.
  34. 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.
  35. 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.
  36. 36.0 36.1 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.
  37. 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.
  38. 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.
  39. 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.
  40. 40.0 40.1 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.
  41. 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.
  42. 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.
  43. 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.
  44. 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.
  45. 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.
  46. 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.
  47. 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.
  48. 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.
  49. 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.
  50. 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.
  51. Silveira LF, MacColl GS, Bouloux PM (2002). "Hypogonadotropic hypogonadism". Semin. Reprod. Med. 20 (4): 327–38. doi:10.1055/s-2002-36707. PMID 12536356.
  52. 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.
  53. 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.
  54. 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.
  55. 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.
  56. 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.
  57. 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.
  58. 58.0 58.1 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.
  59. 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.
  60. 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.
  61. 61.0 61.1 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.
  62. 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.
  63. 63.0 63.1 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.
  64. 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)
  65. 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.
  66. 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.
  67. 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.
  68. 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.
  69. 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.
  70. 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.
  71. 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.
  72. 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.
  73. 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.
  74. 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.
  75. Fernandez-Miranda JC, Gardner PA, Snyderman CH, Devaney KO, Strojan P, Suárez C, Genden EM, Rinaldo A, Ferlito A (2012). "Craniopharyngioma: a pathologic, clinical, and surgical review". Head Neck. 34 (7): 1036–44. doi:10.1002/hed.21771. PMID 21584897.

Template:WH Template:WS