Difference between revisions of "Anti-Müllerian hormone"

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{{protein
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{{Infobox protein
 
|Name=anti-Müllerian hormone
 
|Name=anti-Müllerian hormone
 
|caption=
 
|caption=
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|Symbol=AMH
 
|Symbol=AMH
 
|AltSymbols=
 
|AltSymbols=
|EntrezGene=268
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|EntrzGene=268
 
|OMIM=600957
 
|OMIM=600957
 
|RefSeq=NM_000479
 
|RefSeq=NM_000479
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|ECnumber=
 
|ECnumber=
 
|Chromosome=19
 
|Chromosome=19
 
 
|Arm=p
 
|Arm=p
 
|Band=13.3
 
|Band=13.3
 
|LocusSupplementaryData=
 
|LocusSupplementaryData=
 
}}
 
}}
'''Anti-Müllerian hormone''' (AMH) is a [[dimeric]] [[glycoprotein]] that inhibits the development of the [[Müllerian duct]]s in a male [[embryo]]. It is named after [[Johannes Peter Müller]]. It has also been called Müllerian inhibiting factor (MIF), Mullerian inhibiting hormone (MIH), and Mullerian inhibiting substance (MIS).  
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{{Infobox protein
 +
| Name = anti-Müllerian hormone receptor, type II
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| caption =
 +
| image =
 +
| width =
 +
| HGNCid = 465
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| Symbol = AMHR2
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| AltSymbols =
 +
| EntrezGene = 269
 +
| OMIM = 600956
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| RefSeq = NM_020547
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| UniProt = Q16671
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| PDB =
 +
| ECnumber =
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| Chromosome = 12
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| Arm = q
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| Band = 13
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| LocusSupplementaryData =
 +
}}
 +
'''Anti-Müllerian hormone''' ('''AMH'''), also known as Müllerian-inhibiting hormone (MIH), is a [[glycoprotein]] [[hormone]] structurally related to [[Activin and inhibin|inhibin and activin]] from the [[transforming growth factor beta]] superfamily, whose key roles are in growth differentiation and [[folliculogenesis]].<ref name="Rzeszowska_2016" /> In humans, the [[gene]] for AMH is ''AMH'', on [[chromosome 19]]p13.3,<ref name="pmid3754790">{{cite journal | vauthors = Cate RL, Mattaliano RJ, Hession C, Tizard R, Farber NM, Cheung A, Ninfa EG, Frey AZ, Gash DJ, Chow EP | title = Isolation of the bovine and human genes for Müllerian inhibiting substance and expression of the human gene in animal cells | journal = Cell | volume = 45 | issue = 5 | pages = 685–98 | date = June 1986 | pmid = 3754790 | doi = 10.1016/0092-8674(86)90783-X }}</ref> while the gene {{Gene|AMHR2}} codes for its [[Receptor (biochemistry)|receptor]] on [[chromosome 12]].<ref name="pmid7493017">{{cite journal | vauthors = Imbeaud S, Faure E, Lamarre I, Mattéi MG, di Clemente N, Tizard R, Carré-Eusèbe D, Belville C, Tragethon L, Tonkin C, Nelson J, McAuliffe M, Bidart JM, Lababidi A, Josso N, Cate RL, Picard JY | title = Insensitivity to anti-müllerian hormone due to a mutation in the human anti-müllerian hormone receptor | journal = Nature Genetics | volume = 11 | issue = 4 | pages = 382–8 | date = December 1995 | pmid = 7493017 | doi = 10.1038/ng1295-382 }}</ref>
 +
 
 +
AMH is activated by [[SOX9]] in the [[Sertoli cell]]s of the male fetus.<ref>{{cite journal | vauthors = Taguchi O, Cunha GR, Lawrence WD, Robboy SJ | title = Timing and irreversibility of Müllerian duct inhibition in the embryonic reproductive tract of the human male | journal = Developmental Biology | volume = 106 | issue = 2 | pages = 394–8 | date = December 1984 | pmid = 6548718 | doi = 10.1016/0012-1606(84)90238-0  }}</ref> Its expression inhibits the development of the female reproductive tract, or [[Müllerian duct]]s ([[paramesonephric ducts]]), in the male [[embryo]], thereby arresting the development of fallopian tubes, uterus, and upper vagina.<ref name="pmid7828438">{{cite journal | vauthors = Behringer RR | title = The in vivo roles of müllerian-inhibiting substance | journal = Current Topics in Developmental Biology | volume = 29 | issue =  | pages = 171–87 | year = 1994 | pmid = 7828438 | doi = 10.1016/S0070-2153(08)60550-5 | series = Current Topics in Developmental Biology }}</ref><ref>{{cite journal | vauthors = Rey R, Lukas-Croisier C, Lasala C, Bedecarrás P | title = AMH/MIS: what we know already about the gene, the protein and its regulation | journal = Molecular and Cellular Endocrinology | volume = 211 | issue = 1-2 | pages = 21–31 | date = December 2003 | pmid = 14656472 | doi = 10.1016/j.mce.2003.09.007 }}</ref><ref>{{cite journal | vauthors = Taguchi O, Cunha GR, Lawrence WD, Robboy SJ | title = Timing and irreversibility of Müllerian duct inhibition in the embryonic reproductive tract of the human male | journal = Developmental Biology | volume = 106 | issue = 2 | pages = 394–8 | date = December 1984 | pmid = 6548718 | doi = 10.1016/0012-1606(84)90238-0 }}</ref><ref name="pmid21807466">{{cite journal | vauthors = Panidis D, Katsikis I, Karkanaki A, Piouka A, Armeni AK, Georgopoulos NA | title = Serum anti-Müllerian hormone (AMH) levels are differentially modulated by both serum gonadotropins and not only by serum follicle stimulating hormone (FSH) levels | journal = Medical Hypotheses | volume = 77 | issue = 4 | pages = 649–53 | date = October 2011 | pmid = 21807466 | doi = 10.1016/j.mehy.2011.07.005 }}</ref> AMH expression is critical to sex differentiation at a specific time during fetal development, and appears to be tightly regulated by [[nuclear receptor]] [[Steroidogenic factor 1|SF-1]], [[GATA transcription factor|transcription GATA factors]], sex-reversal gene [[DAX1]], and [[follicle-stimulating hormone]] (FSH).<ref>{{cite journal | vauthors = Shen WH, Moore CC, Ikeda Y, Parker KL, Ingraham HA | title = Nuclear receptor steroidogenic factor 1 regulates the müllerian inhibiting substance gene: a link to the sex determination cascade | journal = Cell | volume = 77 | issue = 5 | pages = 651–61 | date = June 1994 | pmid = 8205615 | doi = 10.1016/0092-8674(94)90050-7 }}</ref><ref>{{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 | date = May 1998 | pmid = 9590178 | doi = 10.1016/s0092-8674(00)81172-1 }}</ref><ref>{{cite journal | vauthors = Viger RS, Mertineit C, Trasler JM, Nemer M | title = Transcription factor GATA-4 is expressed in a sexually dimorphic pattern during mouse gonadal development and is a potent activator of the Müllerian inhibiting substance promoter | journal = Development | volume = 125 | issue = 14 | pages = 2665–75 | date = July 1998 | pmid = 9636081 }}</ref> Mutations in both the AMH gene and the type II AMH receptor have been shown to cause the persistence of Müllerian derivatives in males that are otherwise normally masculinized.<ref>{{cite journal | vauthors = Belville C, Josso N, Picard JY | title = Persistence of Müllerian derivatives in males | journal = American Journal of Medical Genetics | volume = 89 | issue = 4 | pages = 218–23 | date = December 1999 | pmid = 10727997 | doi = 10.1002/(sici)1096-8628(19991229)89:4<218::aid-ajmg6>3.0.co;2-e }}</ref>
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AMH is also a product of [[granulosa cell]]s of the preantral and small antral follicles in women. As such, AMH is only present in the ovary until menopause.<ref name="Pellatt_2010">{{cite journal | vauthors = Pellatt L, Rice S, Mason HD | title = Anti-Müllerian hormone and polycystic ovary syndrome: a mountain too high? | journal = Reproduction | volume = 139 | issue = 5 | pages = 825–33 | date = May 2010 | pmid = 20207725 | doi = 10.1530/REP-09-0415 }}</ref> Production of AMH regulates folliculogenesis by inhibiting recruitment of follicles from the resting pool in order to select for the dominant follicle, after which the production of AMH diminishes.<ref name="Pellatt_2010" /><ref>{{cite journal | vauthors = Kollmann Z, Bersinger NA, McKinnon BD, Schneider S, Mueller MD, von Wolff M | title = Anti-Müllerian hormone and progesterone levels produced by granulosa cells are higher when derived from natural cycle IVF than from conventional gonadotropin-stimulated IVF | journal = Reproductive Biology and Endocrinology | volume = 13 | pages = 21 | date = March 2015 | pmid = 25889012 | pmc = 4379743 | doi = 10.1186/s12958-015-0017-0 }}</ref> As a product of the granulosa cells, which envelop each egg and provide them energy, AMH can also serve as a molecular biomarker for relative size of the [[ovarian reserve]].<ref name="pmid14742691">{{cite journal | vauthors = Weenen C, Laven JS, Von Bergh AR, Cranfield M, Groome NP, Visser JA, Kramer P, Fauser BC, Themmen AP | title = Anti-Müllerian hormone expression pattern in the human ovary: potential implications for initial and cyclic follicle recruitment | journal = Molecular Human Reproduction | volume = 10 | issue = 2 | pages = 77–83 | date = February 2004 | pmid = 14742691 | doi = 10.1093/molehr/gah015 }}</ref> In humans, this is helpful because the number of cells in the follicular reserve can be used to predict timing of menopause.<ref>{{cite journal | vauthors = van Disseldorp J, Faddy MJ, Themmen AP, de Jong FH, Peeters PH, van der Schouw YT, Broekmans FJ | title = Relationship of serum antimüllerian hormone concentration to age at menopause | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 93 | issue = 6 | pages = 2129–34 | date = June 2008 | pmid = 18334591 | doi = 10.1210/jc.2007-2093 }}</ref> In bovine, AMH can be used for selection of females in multi-ovulatory embryo transfer programs by predicting the number of antral follicles developed to ovulation.<ref>{{cite journal | vauthors = Rico C, Médigue C, Fabre S, Jarrier P, Bontoux M, Clément F, Monniaux D | title = Regulation of anti-Müllerian hormone production in the cow: a multiscale study at endocrine, ovarian, follicular, and granulosa cell levels | journal = Biology of Reproduction | volume = 84 | issue = 3 | pages = 560–71 | date = March 2011 | pmid = 21076084 | doi = 10.1095/biolreprod.110.088187 }}</ref> AMH can also be used as a marker for ovarian dysfunction, such as in women with [[polycystic ovary syndrome]] (PCOS).
  
 
== Structure ==
 
== Structure ==
AMH is a [[protein]] [[hormone]] structurally related to [[inhibin]] and [[activin]], and a member of the [[transforming growth factor-β]] (TGF-β) family. It is present in [[fish]], [[reptile]]s, [[bird]]s, [[marsupial]]s, and placental [[mammal]]s.
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AMH is a [[protein dimer|dimeric]] [[glycoprotein]] with a [[molar mass]] of 140 [[kilodalton|kDa]].<ref>[http://www.biomed.cas.cz/physiolres/pdf/prepress/932076.pdf] {{cite journal | vauthors = Hampl R, Šnajderová M, Mardešić T | title = Antimüllerian hormone (AMH) not only a marker for prediction of ovarian reserve | journal = Physiological Research | volume = 60 | issue = 2 | pages = 217–23 | year = 2011 | pmid = 21114374 }}</ref> The molecule consists of two identical subunits linked by sulfide bridges, and characterized by the N-terminal dimer (pro-region) and C-terminal dimer.<ref name="Rzeszowska_2016">{{cite journal | vauthors = Rzeszowska M, Leszcz A, Putowski L, Hałabiś M, Tkaczuk-Włach J, Kotarski J, Polak G | title = Anti-Müllerian hormone: structure, properties and appliance | journal = Ginekologia Polska | volume = 87 | issue = 9 | pages = 669–674 | date = 2016 | pmid = 27723076 | doi = 10.5603/gp.2016.0064 }}</ref> AMH acts with receptors, AMH-RI and AMH-RII, upon which, after a series of conformational changes and phosphorylation steps, gene expression is regulated in the cell.<ref name="Rzeszowska_2016" />
 
 
== Gene ==
 
In humans the [[gene]] for AMH is ''AMH'', on [[chromosome]] 19p13.3, while the gene ''AMH-RII'' codes for its [[Receptor (biochemistry)|receptor]] on [[chromosome]] 12.  
 
  
==Functions==
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== Function ==
 
=== Embryogenesis ===
 
=== Embryogenesis ===
In mammals AMH is secreted by [[Sertoli cell]]s of the [[testis|testes]] during [[embryogenesis]] of the fetal male and prevents the development of the [[mullerian duct]]s into the [[uterus]] and other mullerian structures. The effect is ipsilateral, that is each testis suppresses Müllerian development only on its own side. In humans this action takes place by 8 weeks gestation. In female [[embryogenesis]] the absence of AMH allows for the development of upper [[vagina]], [[uterus]] and [[cervix]], and [[oviducts]].  
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In mammals, AMH prevents the development of the [[Müllerian duct]]s into the [[uterus]] and other Müllerian structures.<ref name="pmid7828438"/> The effect is ipsilateral, that is each testis suppresses Müllerian development only on its own side.<ref name=boron>{{cite book | first = Walter F. | last = Boron | name-list-format = vanc |title=Medical Physiology: A Cellular and Molecular Approaoch |publisher=Elsevier/Saunders |location= |year=2003 |isbn=978-1-4160-2328-9 | page = 1114 }}</ref> In humans, this action takes place during the first 8 weeks of gestation. If no hormone is produced from the gonads, the Müllerian ducts automatically develop, while the [[Wolffian ducts]], which are responsible for male reproductive parts, automatically die.<ref>An Introduction to Behavioral Endocrinology, Randy J Nelson, 3rd edition, Sinauer</ref> Amounts of AMH that are measurable in the blood vary by age and sex. AMH works by interacting with specific [[Receptor (biochemistry)|receptors]] on the surfaces of the cells of target tissues ([[anti-Müllerian hormone receptor]]s). The best-known and most specific effect, mediated through the AMH type II receptors, includes programmed cell death ([[apoptosis]]) of the target tissue (the fetal Müllerian ducts).
Amounts of AMH that are measurable in the blood vary by age and sex. AMH works by interacting with specific [[Receptor (biochemistry)|receptor]]s on the surfaces of the cells of target tissues. The best known and most specific effect, mediated through the AMH type II receptors, includes programmed cell death ([[apoptosis]]) of the target tissue (the fetal mullerian ducts).
 
  
===Ovarian function===
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=== Ovarian ===
While AMH is measurable in males during childhood and adulthood, AMH cannot be detected in women until [[puberty]]. AMH is expressed by [[granulosa cells]] of the [[ovary]] in the reproductive age and controls the formation of primary follicles by inhibiting excessive follicular recruitment by FSH. It therefore has a role in folliculogenesis,<ref>{{cite journal |author=Weenen C, Laven J, Von Bergh A, Cranfield M, Groome N, Visser J, Kramer P, Fauser B, Themmen A |title=Anti-Müllerian hormone expression pattern in the human ovary: potential implications for initial and cyclic follicle recruitment |journal=Mol Hum Reprod |volume=10 |issue=2 |pages=77-83 |year=2004 |id=PMID 14742691 | url=http://molehr.oxfordjournals.org/cgi/content/abstract/10/2/77}}</ref>
+
AMH is expressed by [[granulosa cells]] of the [[ovary]] during the reproductive years, and limits the formation of primary follicles by inhibiting excessive follicular recruitment by FSH.<ref name = "pmid14742691" /><ref name="DewaillyAndersen2014">{{cite journal | vauthors = Dewailly D, Andersen CY, Balen A, Broekmans F, Dilaver N, Fanchin R, Griesinger G, Kelsey TW, La Marca A, Lambalk C, Mason H, Nelson SM, Visser JA, Wallace WH, Anderson RA | title = The physiology and clinical utility of anti-Mullerian hormone in women | journal = Human Reproduction Update | volume = 20 | issue = 3 | pages = 370–85 | year = 2014 | pmid = 24430863 | doi = 10.1093/humupd/dmt062 }}</ref> AMH expression is greatest in the recruitment stage of folliculogenesis, in the preantral and small antral follicles. This expression diminishes as follicles develop and enter selection stage, upon which FSH expression increases.<ref name="Dumont 2015 137">{{cite journal | vauthors = Dumont A, Robin G, Catteau-Jonard S, Dewailly D | title = Role of Anti-Müllerian Hormone in pathophysiology, diagnosis and treatment of Polycystic Ovary Syndrome: a review | journal = Reproductive Biology and Endocrinology | volume = 13 | pages = 137 | date = December 2015 | pmid = 26691645 | pmc = 4687350 | doi = 10.1186/s12958-015-0134-9 }}</ref> Some authorities suggest it is a measure of certain aspects of ovarian function,<ref>{{cite journal | vauthors = Broer SL, Eijkemans MJ, Scheffer GJ, van Rooij IA, de Vet A, Themmen AP, Laven JS, de Jong FH, Te Velde ER, Fauser BC, Broekmans FJ | title = Anti-mullerian hormone predicts menopause: a long-term follow-up study in normoovulatory women | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 96 | issue = 8 | pages = 2532–9 | date = August 2011 | pmid = 21613357 | doi = 10.1210/jc.2010-2776 }}</ref> useful in assessing conditions such as [[polycystic ovary syndrome]] and [[premature ovarian failure]].<ref>{{cite journal | vauthors = Visser JA, de Jong FH, Laven JS, Themmen AP | title = Anti-Müllerian hormone: a new marker for ovarian function | journal = Reproduction | volume = 131 | issue = 1 | pages = 1–9 | date = January 2006 | pmid = 16388003 | doi = 10.1530/rep.1.00529 }}</ref>
and some authorities suggest it is a measure of some aspects of ovarian function useful in assessing conditions such as [[polycystic ovary syndrome]] and [[premature ovarian failure]].<ref>{{cite journal |author=Visser J, de Jong F, Laven J, Themmen A |title=Anti-Müllerian hormone: a new marker for ovarian function |journal=Reproduction |volume=131 |issue=1 |pages=1-9 |year=2006 |id=PMID 16388003 | url=http://www.reproduction-online.org/cgi/content/full/131/1/1}}</ref>
 
  
=== Other functions ===
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=== Other ===
AMH production by the [[Sertoli cell]]s of the testes remains high throughout childhood but declines to low levels during puberty and adult life. AMH measurements have become widely used in the last few years in the evaluation of testicular presence and function in infants with [[intersex]] conditions, [[ambiguous genitalia]], and [[cryptorchidism]].
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AMH production by the [[Sertoli cell]]s of the testes remains high throughout childhood in males but declines to low levels during puberty and adult life. AMH has been shown to regulate production of [[sex hormone]]s,<ref name="pmid15555913">{{cite journal | vauthors = Trbovich AM, Martinelle N, O'Neill FH, Pearson EJ, Donahoe PK, Sluss PM, Teixeira J | title = Steroidogenic activities in MA-10 Leydig cells are differentially altered by cAMP and Müllerian inhibiting substance | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 92 | issue = 3 | pages = 199–208 | date = October 2004 | pmid = 15555913 | doi = 10.1016/j.jsbmb.2004.07.002 }}</ref> and changing AMH levels (rising in females, falling in males) may be involved in the onset of puberty in both sexes. Functional AMH receptors have also been found to be expressed in neurons in the brains of embryonic mice, and are thought to play a role in sexually [[Sexual dimorphism|dimorphic]] brain development and consequent development of gender-specific behaviours.<ref name="pmid19359476">{{cite journal | vauthors = Wang PY, Protheroe A, Clarkson AN, Imhoff F, Koishi K, McLennan IS | title = Müllerian inhibiting substance contributes to sex-linked biases in the brain and behavior | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 106 | issue = 17 | pages = 7203–8 | date = April 2009 | pmid = 19359476 | pmc = 2678437 | doi = 10.1073/pnas.0902253106 }}</ref>
  
 
== Pathology ==
 
== Pathology ==
In men, inadequate embryonal AMH activity can lead to the ''[[Persistent mullerian duct syndrome]]'' (PMDS), in which a rudimentary uterus is present and testes are usually [[cryptorchidism|undescended]]. The AMH gene (''AMH'') or the gene (''AMH-RII'') for its receptor are usually abnormal.
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In men, inadequate embryonal AMH activity can lead to the ''[[Persistent Müllerian duct syndrome]]'' (PMDS), in which a rudimentary uterus is present and testes are usually [[cryptorchidism|undescended]]. The AMH gene (''AMH'') or the gene for its receptor (''AMH-RII'') are usually abnormal. AMH measurements have also become widely used in the evaluation of testicular presence and function in infants with [[intersex]] conditions, [[ambiguous genitalia]], and [[cryptorchidism]].
 +
 
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A study published in Nature Medicine found a link between hormonal imbalance in the womb and [[Polycystic ovary syndrome]] (PCOS), specifically prenatal exposure to anti-Müllerian hormone.<ref>{{cite journal|url=https://www.nature.com/articles/s41591-018-0035-5|title=Elevated prenatal anti-Müllerian hormone reprograms the fetus and induces polycystic ovary syndrome in adulthood|first1=Brooke|last1=Tata|first2=Nour El Houda|last2=Mimouni|first3=Anne-Laure|last3=Barbotin|first4=Samuel A.|last4=Malone|first5=Anne|last5=Loyens|first6=Pascal|last6=Pigny|first7=Didier|last7=Dewailly|first8=Sophie|last8=Catteau-Jonard|first9=Inger|last9=Sundström-Poromaa|first10=Terhi T.|last10=Piltonen|first11=Federica|last11=Dal Bello|first12=Claudio|last12=Medana|first13=Vincent|last13=Prevot|first14=Jerome|last14=Clasadonte|first15=Paolo|last15=Giacobini|date=14 May 2018|journal=Nature Medicine|volume=24|issue=6|pages=834–846|doi=10.1038/s41591-018-0035-5}}</ref> For the study, the researchers injected pregnant mice with AMH so that they had a higher than normal concentration of the hormone. Indeed, they gave birth to daughters who later developed PCOS-like tendencies. These included problems with fertility, delayed puberty, and erratic ovulation. To reverse it, the researchers dosed the polycystic mice with an IVF drug called [[cetrorelix]], which made the symptoms to go away .These experiments should be confirmed in humans, but it could be the first step in understanding the relationship between the polycystic ovary and the anti-Müllerian hormone.
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== Blood levels ==
 +
In healthy females AMH is either just detectable or undetectable in cord blood at birth and demonstrates a marked rise by three months of age; while still detectable it falls until four years of age before rising linearly until eight years of age remaining fairly constant from mid-childhood to early adulthood&nbsp;– it does not change significantly during [[puberty]].<ref name="plosone"/> The rise during childhood and adolescence is likely reflective of different stages of follicle development.<ref name="DewaillyAndersen2014"/> From 25 years of age AMH declines to undetectable levels at menopause.<ref name="plosone">{{cite journal | vauthors = Kelsey TW, Wright P, Nelson SM, Anderson RA, Wallace WH | title = A validated model of serum anti-müllerian hormone from conception to menopause | journal = PLOS One | volume = 6 | issue = 7 | pages = e22024 | year = 2011 | pmid = 21789206 | pmc = 3137624 | doi = 10.1371/journal.pone.0022024 }}</ref>
 +
 
 +
The standard measurement of AMH follows the ''Generation II assay''. This should give the same values as the previously used IBC assay, but AMH values from the previously used DSL assay should be multiplied with 1.39 to conform to current standards because it used different antibodies.<ref name=LaMarca2013>{{cite journal | vauthors = La Marca A, Sunkara SK | title = Individualization of controlled ovarian stimulation in IVF using ovarian reserve markers: from theory to practice | journal = Human Reproduction Update | volume = 20 | issue = 1 | pages = 124–40 | year = 2013 | pmid = 24077980 | pmc =  | doi = 10.1093/humupd/dmt037 }}</ref>
 +
 
 +
Weak evidence suggests that AMH should be measured only in the early [[follicular phase]] because of variation over the [[menstrual cycle]]. Also, AMH levels decrease under current use of oral contraceptives and current [[tobacco smoking]].<ref name="BroerBroekmans2014">{{cite journal | vauthors = Broer SL, Broekmans FJ, Laven JS, Fauser BC | title = Anti-Müllerian hormone: ovarian reserve testing and its potential clinical implications | journal = Human Reproduction Update | volume = 20 | issue = 5 | pages = 688–701 | year = 2014 | pmid = 24821925 | doi = 10.1093/humupd/dmu020 }}</ref>
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=== Reference ranges ===
 +
[[Reference range]]s for Anti-Müllerian hormone, as estimated from [[reference group]]s in the [[United states]], are as follows:<ref>For mass values:
 +
* [http://www.mayomedicallaboratories.com/test-catalog/print/89711 Anti-Müllerian Hormone (AMH), Serum] from Mayo Medical Laboratories. Retrieved April 2012.
 +
For molar values: Derived from mass values using 140,000 g/mol, as given in:
 +
* [http://www.biomed.cas.cz/physiolres/pdf/prepress/932076.pdf] {{cite journal | vauthors = Hampl R, Šnajderová M, Mardešić T | title = Antimüllerian hormone (AMH) not only a marker for prediction of ovarian reserve | journal = Physiological Research | volume = 60 | issue = 2 | pages = 217–23 | year = 2011 | pmid = 21114374 }}</ref>
 +
 
 +
'''Females:'''
 +
{|class="wikitable"
 +
! Age !! Unit !! Value
 +
|-
 +
|rowspan=2| Younger than 24 months || ng/mL || Less than 5
 +
|-
 +
| pmol/l || Less than 35
 +
|-
 +
|rowspan=2| 24 months to 12 years || ng/mL || Less than 10
 +
|-
 +
| pmol/l || Less than 70
 +
|-
 +
|rowspan=2| 13–45 years || ng/mL || 1 to 10
 +
|-
 +
| pmol/l || 7 to 70
 +
|-
 +
|rowspan=2| More than 45 years || ng/mL || Less than 1
 +
|-
 +
| pmol/l || Less than 7
 +
|}
 +
 
 +
'''Males:'''
 +
{|class="wikitable"
 +
! Age !! Unit !! Value
 +
|-
 +
|rowspan=2| Younger than 24 months || ng/mL || 15 to 500
 +
|-
 +
| pmol/l || 100 to 3500
 +
|-
 +
|rowspan=2| 24 months to 12 years || ng/mL ||7 to 240
 +
|-
 +
| pmol/l || 50 to 1700
 +
|-
 +
|rowspan=2| More than 12 years || ng/mL || 0.7 to 20
 +
|-
 +
| pmol/l || 5 to 140
 +
|}
 +
 
 +
AMH measurements may be less accurate if the person being measured is vitamin D deficient.<ref name="Dennis2012">{{cite journal | vauthors = Dennis NA, Houghton LA, Jones GT, van Rij AM, Morgan K, McLennan IS | title = The level of serum anti-Müllerian hormone correlates with vitamin D status in men and women but not in boys | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 97 | issue = 7 | pages = 2450–5 | date = July 2012 | pmid = 22508713 | doi = 10.1210/jc.2012-1213 }}</ref> Note that males are born with higher AMH levels than females in order to initiate sexual differentiation, and in women, AMH levels decrease over time as fertility decreases as well.<ref name="Dennis2012" />
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 +
==Clinical usage==
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=== General fertility assessment ===
 +
Comparison of an individual's AMH level with respect to average levels<ref name="plosone" /> is useful in fertility assessment, as it provides a guide to [[ovarian reserve]] and identifies women that may need to consider either egg freezing or trying for a pregnancy sooner rather than later if their long-term future fertility is poor.<ref name="pmid18024272">{{cite journal | vauthors = Cupisti S, Dittrich R, Mueller A, Strick R, Stiegler E, Binder H, Beckmann MW, Strissel P | title = Correlations between anti-müllerian hormone, inhibin B, and activin A in follicular fluid in IVF/ICSI patients for assessing the maturation and developmental potential of oocytes | journal = European Journal of Medical Research | volume = 12 | issue = 12 | pages = 604–8 | date = December 2007 | pmid = 18024272 | doi =  }}</ref> A higher level of anti-Müllerian hormone when tested in women in the general population has been found to have a positive correlation with natural fertility in women aged 30–44 aiming to conceive spontaneously, even after adjusting for age.<ref name="BroerBroekmans2014" /> However, this correlation was not found in a comparable study of younger women (aged 20 to 35 years).<ref name="BroerBroekmans2014" />
 +
 
 +
=== In vitro fertilization ===
 +
AMH is a predictor for ovarian response in [[in vitro fertilisation|''in vitro'' fertilization]] (IVF). Measurement of AMH supports clinical decisions, but alone it is not a suitable predictor of IVF success.<ref>{{cite journal | vauthors = Gnoth C, Schuring AN, Friol K, Tigges J, Mallmann P, Godehardt E | title = Relevance of anti-Mullerian hormone measurement in a routine IVF program | journal = Human Reproduction | volume = 23 | issue = 6 | pages = 1359–65 | date = June 2008 | pmid = 18387961 | doi = 10.1093/humrep/den108 }}</ref> Additionally, AMH levels are used to estimate a woman's remaining egg supply.<ref>{{cite web|url=http://www.fertileheart.com/does-a-low-amh-level-indicate-infertility/|title=Does a Low AMH Level (Anti-Mullerian Hormone) Indicate Infertility?|website=fertileheart.com|last1=Indichova|first1=Julia | name-list-format = vanc |access-date=6 February 2015 }}</ref>
 +
 
 +
According to [[NICE guidelines]] of [[in vitro fertilisation|''in vitro'' fertilization]], an anti-Müllerian hormone level of less than or equal to 5.4 pmol/l (0.8&nbsp;ng/mL) predicts a low response to [[Controlled ovarian hyperstimulation|ovarian hyperstimulation]], while a level greater than or equal to 25.0 pmol/l (3.6&nbsp;ng/mL) predicts a high response.<ref name="nice2013">[http://guidance.nice.org.uk/CG156 Fertility: assessment and treatment for people with fertility problems]. [[NICE guidelines|NICE clinical guideline]] CG156 - Issued: February 2013</ref> Other cut-off values found in the literature vary between 0.7 and 20 pmol/l (0.1 and 2.97&nbsp;ng/ml) for low response to ovarian hyperstimulation.<ref name="LaMarca2013" /> Subsequently, higher AMH levels are associated with greater chance of live birth after IVF, even after adjusting for age.<ref name="BroerBroekmans2014" /><ref name="IliodromitiKelsey2014">{{cite journal | vauthors = Iliodromiti S, Kelsey TW, Wu O, Anderson RA, Nelson SM | title = The predictive accuracy of anti-Müllerian hormone for live birth after assisted conception: a systematic review and meta-analysis of the literature | journal = Human Reproduction Update | volume = 20 | issue = 4 | pages = 560–70 | year = 2014 | pmid = 24532220 | doi = 10.1093/humupd/dmu003 }}</ref> AMH can thereby be used to rationalise the programme of ovulation induction and decisions about the number of embryos to transfer in assisted reproduction techniques to maximise pregnancy success rates whilst minimising the risk of [[ovarian hyperstimulation syndrome]] (OHSS).<ref>{{cite journal | vauthors = Nelson SM, Yates RW, Fleming R | title = Serum anti-Müllerian hormone and FSH: prediction of live birth and extremes of response in stimulated cycles--implications for individualization of therapy | journal = Human Reproduction | volume = 22 | issue = 9 | pages = 2414–21 | date = September 2007 | pmid = 17636277 | doi = 10.1093/humrep/dem204 }}</ref><ref>{{cite journal | vauthors = Nelson SM, Yates RW, Lyall H, Jamieson M, Traynor I, Gaudoin M, Mitchell P, Ambrose P, Fleming R | title = Anti-Müllerian hormone-based approach to controlled ovarian stimulation for assisted conception | journal = Human Reproduction | volume = 24 | issue = 4 | pages = 867–75 | date = April 2009 | pmid = 19136673 | doi = 10.1093/humrep/den480 }}</ref> AMH can predict an excessive response in [[Controlled ovarian hyperstimulation|ovarian hyperstimulation]] with a [[sensitivity and specificity]] of 82% and 76%, respectively.<ref name="Broer2010">{{cite journal | vauthors = Broer SL, Dólleman M, Opmeer BC, Fauser BC, Mol BW, Broekmans FJ | title = AMH and AFC as predictors of excessive response in controlled ovarian hyperstimulation: a meta-analysis | journal = Human Reproduction Update | volume = 17 | issue = 1 | pages = 46–54 | year = 2011 | pmid = 20667894 | doi = 10.1093/humupd/dmq034 }}</ref>
 +
 
 +
Measuring AMH alone may be misleading as high levels occur in conditions like [[polycystic ovarian syndrome]] and therefore AMH levels should be considered in conjunction with a [[obstetric ultrasonography|transvaginal scan]] of the ovaries to assess [[antral follicle count]]<ref name="pmid17559842">{{cite journal | vauthors = Seifer DB, Maclaughlin DT | title = Mullerian Inhibiting Substance is an ovarian growth factor of emerging clinical significance | journal = Fertility and Sterility | volume = 88 | issue = 3 | pages = 539–46 | date = September 2007 | pmid = 17559842 | doi = 10.1016/j.fertnstert.2007.02.014 }}</ref> and ovarian volume.<ref>{{cite journal | vauthors = Wallace WH, Kelsey TW | title = Ovarian reserve and reproductive age may be determined from measurement of ovarian volume by transvaginal sonography | journal = Human Reproduction | volume = 19 | issue = 7 | pages = 1612–7 | date = July 2004 | pmid = 15205396 | doi = 10.1093/humrep/deh285 }}</ref>
 +
 
 +
=== Natural remedies ===
 +
Studies into treatments to improve low ovarian reserve and low AMH levels have met with some success. Current best available evidence suggests that [[DHEA]] improves ovarian function, increases pregnancy chances and, by reducing aneuploidy, lowers miscarriage rates.<ref>{{cite journal | vauthors = Gleicher N, Barad DH | title = Dehydroepiandrosterone (DHEA) supplementation in diminished ovarian reserve (DOR) | journal = Reproductive Biology and Endocrinology | volume = 9 | pages = 67 | date = May 2011 | pmid = 21586137 | doi = 10.1186/1477-7827-9-67 }}</ref> The studies into [[DHEA]] for low AMH show that a dose of 75&nbsp;mg for a period of 16 weeks should be taken. Improvement of oocyte/embryo quality with DHEA supplementation potentially suggests a new concept of ovarian aging, where ovarian environments, but not oocytes themselves, age. DHEA has positive outcomes for women with AMH levels over 0.8&nbsp;ng/ml or 5.7 pmol/l<ref>{{cite journal | vauthors = Gleicher N, Weghofer A, Barad DH | title = Improvement in diminished ovarian reserve after dehydroepiandrosterone supplementation | language = English | journal = Reproductive Biomedicine Online | volume = 21 | issue = 3 | pages = 360–5 | date = September 2010 | pmid = 20638339 | doi = 10.1016/j.rbmo.2010.04.006 }}</ref> DHEA has no apparent effect on oocytes or ovarian environments under this range.
 +
 
 +
Studies on [[CoQ10]] supplementation in an aged animal model delayed depletion of ovarian reserve, restored oocyte mitochondrial gene expression, and improved mitochondrial activity.<ref name="ReferenceA">{{cite journal | vauthors = Ben-Meir A, Burstein E, Borrego-Alvarez A, Chong J, Wong E, Yavorska T, Naranian T, Chi M, Wang Y, Bentov Y, Alexis J, Meriano J, Sung HK, Gasser DL, Moley KH, Hekimi S, Casper RF, Jurisicova A | title = Coenzyme Q10 restores oocyte mitochondrial function and fertility during reproductive aging | journal = Aging Cell | volume = 14 | issue = 5 | pages = 887–95 | date = October 2015 | pmid = 26111777 | doi = 10.1111/acel.12368 }}</ref> Authors note that to replicate the 12–16 weeks of using CoQ10 supplements on mice to achieve these results would be the equivalent to a decade in humans.<ref name="ReferenceA"/>
 +
 
 +
[[Vitamin D deficiency|Vitamin D]] is believed to play a role in AMH regulation. The AMH gene promoter contains a vitamin D response element that may cause vitamin D status to influence serum AMH levels. Women with levels of Vitamin D of 267.8 ± 66.4 nmol/L show a 4 times better success rate with IVF procedure than those with low levels of 104.3 ± 21 nmol/L. Vitamin D deficiency should be considered when serum AMH levels are obtained for diagnosis.<ref name="Dennis2012"/>
 +
 
 +
===Women with cancer===
 +
In women with cancer, [[radiation therapy]] and [[chemotherapy]] can damage the ovarian reserve. In such cases, a pre-treatment AMH is useful in predicting the long-term post-chemotherapy loss of ovarian function, which may indicate [[fertility preservation]] strategies such as [[oocyte cryopreservation]].<ref name="BroerBroekmans2014"/> A post-treatment AMH is associated with decreased fertility.<ref name="DewaillyAndersen2014"/><ref name="BroerBroekmans2014"/>
  
== Research ==
+
[[Granulosa cell tumor]]s of the ovary secrete AMH, and AMH testing has a [[sensitivity and specificity|sensitivity]] ranging between 76 and 93% in diagnosing such tumors.<ref name="BroerBroekmans2014"/> AMH is also useful in diagnosing recurrence of granulosa cell tumors.<ref name="BroerBroekmans2014"/>
AMH has been synthesized. Its ability to inhibit growth of tissue derived from the Müllerian ducts has raised hopes of usefulness in the treatment of a variety of medical conditions including [[endometriosis]], [[adenomyosis]] and uterine [[cancer]]. Research is underway in several laboratories.
+
 
 +
=== Neutering status in animals ===
 +
In veterinary medicine, AMH measurements are used to determine neutering status in male and female dogs and cats. AMH levels can also be used to diagnose cases of ovarian remnant syndrome.<ref>{{cite journal | vauthors = Place NJ, Hansen BS, Cheraskin JL, Cudney SE, Flanders JA, Newmark AD, Barry B, Scarlett JM | title = Measurement of serum anti-Müllerian hormone concentration in female dogs and cats before and after ovariohysterectomy | journal = Journal of Veterinary Diagnostic Investigation | volume = 23 | issue = 3 | pages = 524–7 | date = May 2011 | pmid = 21908283 | doi = 10.1177/1040638711403428 }}</ref>
 +
 
 +
=== Biomarker of polycystic ovary syndrome ===
 +
[[Polycystic ovary syndrome]] (PCOS) is an endocrine disorder most commonly found in women of reproductive age that is characterized by oligo- or [[anovulation]], [[hyperandrogenism]], and [[polycystic ovaries]] (PCO).<ref>{{cite journal | vauthors = Azziz R | title = Controversy in clinical endocrinology: diagnosis of polycystic ovarian syndrome: the Rotterdam criteria are premature | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 91 | issue = 3 | pages = 781–5 | date = March 2006 | pmid = 16418211 | doi = 10.1210/jc.2005-2153 }}</ref> This endocrine disorder increases AMH levels at nearly two to three times higher in women with PCOS than in normal type women. This is often attributed to the increased follicle count number characteristic of PCOS, indicating an increase in granulosa cells since they surround each individual egg.<ref>{{cite journal | vauthors = Dewailly D | title = Diagnostic criteria for PCOS: Is there a need for a rethink? | language = English | journal = Best Practice & Research. Clinical Obstetrics & Gynaecology | volume = 37 | pages = 5–11 | date = November 2016 | pmid = 27151631 | doi = 10.1016/j.bpobgyn.2016.03.009 }}</ref> However, increased AMH levels have also been attributed not just to the increased number of follicles, but also to an increased amount of AMH produced per follicle.<ref>{{cite journal | vauthors = Verma AK, Rajbhar S, Mishra J, Gupta M, Sharma M, Deshmukh G, Ali W | title = Anti-Mullerian Hormone: A Marker of Ovarian Reserve and its Association with Polycystic Ovarian Syndrome | journal = Journal of Clinical and Diagnostic Research | volume = 10 | issue = 12 | pages = QC10-QC12 | date = December 2016 | pmid = 28208941 | pmc = 5296514 | doi = 10.7860/JCDR/2016/20370.8988 }}</ref> The high levels of androgens, characteristic of PCOS, also stimulate and provide feedback for increased production of AMH, as well.<ref name="Dumont 2015 137"/> In this way, AMH has been increasingly considered to be a tool or biomarker that can be used to diagnose or indicate PCOS.
 +
 
 +
===Potential future usage===
 +
AMH has been synthesized. Its ability to inhibit growth of tissue derived from the Müllerian ducts has raised hopes of usefulness in the treatment of a variety of medical conditions including [[endometriosis]], [[adenomyosis]], and uterine [[cancer]]. Research is underway in several laboratories.
 +
If there were more standardized AMH assays, it could potentially be used as a [[biomarker]] of [[polycystic ovary syndrome]].<ref name="DewaillyLujan2013">{{cite journal | vauthors = Dewailly D, Lujan ME, Carmina E, Cedars MI, Laven J, Norman RJ, Escobar-Morreale HF | title = Definition and significance of polycystic ovarian morphology: a task force report from the Androgen Excess and Polycystic Ovary Syndrome Society | journal = Human Reproduction Update | volume = 20 | issue = 3 | pages = 334–52 | year = 2013 | pmid = 24345633 | doi = 10.1093/humupd/dmt061 }}</ref>
 +
 
 +
In mice, an increase in AMH has been shown to reduce the number of growing follicles and thus the overall size of the ovaries. This increase in AMH production reduces primary, secondary and antral follicles without reducing the number of primordial follicles suggesting a blockade of primordial follicle activation. This may provide a viable method of contraception which protects the ovarian reserve of oocytes during chemotherapy without extracting them from the body allowing the potential for natural reproduction later in life.<ref>{{cite journal | vauthors = Kano M, Sosulski AE, Zhang L, Saatcioglu HD, Wang D, Nagykery N, Sabatini ME, Gao G, Donahoe PK, Pépin D | title = AMH/MIS as a contraceptive that protects the ovarian reserve during chemotherapy | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 114 | issue = 9 | pages = E1688-E1697 | date = February 2017 | pmid = 28137855 | pmc = 5338508 | doi = 10.1073/pnas.1620729114 }}</ref>
 +
 
 +
== Names ==
 +
The adjective "Müllerian" is written [[eponym#Orthographic conventions|either "Müllerian" or "müllerian"]], depending on the governing [[style guide]]; the derived term with the [[prefix]] of "[[wikt:anti-#Prefix|anti-]]" is then "anti-Müllerian", "anti-müllerian", or "antimüllerian". The Müllerian ducts are named after [[Johannes Peter Müller]].<ref>{{cite book|title=Biology Today: An Issues Approach|last2=Baker|first2=Pamela|date=2004|publisher=Garland Science|isbn=978-1-136-83875-0|edition=Third|location=New York|page=296|name-list-format=vanc|last1=Minkoff|first1=Eli}}</ref>
 +
 
 +
A list of the names that have been used for the antimüllerian hormone is as follows. For the sake of simplicity, this list ignores some [[orthography|orthographic]] variations; for example, it gives only one row for "Müllerian-inhibiting hormone", although there are 4 acceptable stylings thereof (cap M or lowercase m, hyphen or space).
 +
 
 +
{| class="wikitable sortable" border="1"
 +
|-
 +
! Protein name styling !! Protein symbol
 +
|-
 +
| Anti-Müllerian hormone || AMH
 +
|-
 +
| Müllerian-inhibiting factor || MIF
 +
|-
 +
| Müllerian-inhibiting hormone || MIH
 +
|-
 +
| Müllerian-inhibiting substance || MIS
 +
|-
 +
| Müllerian duct inhibitory factor || MDIF
 +
|-
 +
| Müllerian regression factor || MRF
 +
|-
 +
| Anti-paramesonephric hormone || APH
 +
|}
  
 
== See also ==
 
== See also ==
 
* [[Sexual differentiation]]
 
* [[Sexual differentiation]]
* [[anti-Mullerian hormone receptor]]
+
* [[Anti-Müllerian hormone receptor]]
 +
* [[Alfred Jost]] discoverer.
 +
* [[PMDS]] (Persistent Müllerian Duct Syndrome)
  
==Footnotes==
+
== References ==
<references/>
+
{{Reflist|colwidth=30em}}
  
 
{{Hormones}}
 
{{Hormones}}
 
 
{{TGF beta signaling}}
 
{{TGF beta signaling}}
[[Category:Developmental biology]]
+
{{TGFβ receptor superfamily modulators}}
[[Category:hormones]]
 
  
[[de:Anti-Müller-Hormon]]
+
{{Use dmy dates|date=April 2017}}
[[fr:Hormone antimullérienne]]
 
  
{{WH}}
+
{{DEFAULTSORT:Anti-Mullerian Hormone}}
{{WS}}
+
[[Category:Animal developmental biology]]
 +
[[Category:Fish hormones]]
 +
[[Category:Hormones of the embryo]]

Latest revision as of 18:43, 27 November 2018

anti-Müllerian hormone
Identifiers
SymbolAMH
HUGO464
OMIM600957
RefSeqNM_000479
UniProtP03971
Other data
LocusChr. 19 p13.3
anti-Müllerian hormone receptor, type II
Identifiers
SymbolAMHR2
Entrez269
HUGO465
OMIM600956
RefSeqNM_020547
UniProtQ16671
Other data
LocusChr. 12 q13

Anti-Müllerian hormone (AMH), also known as Müllerian-inhibiting hormone (MIH), is a glycoprotein hormone structurally related to inhibin and activin from the transforming growth factor beta superfamily, whose key roles are in growth differentiation and folliculogenesis.[1] In humans, the gene for AMH is AMH, on chromosome 19p13.3,[2] while the gene AMHR2 codes for its receptor on chromosome 12.[3]

AMH is activated by SOX9 in the Sertoli cells of the male fetus.[4] Its expression inhibits the development of the female reproductive tract, or Müllerian ducts (paramesonephric ducts), in the male embryo, thereby arresting the development of fallopian tubes, uterus, and upper vagina.[5][6][7][8] AMH expression is critical to sex differentiation at a specific time during fetal development, and appears to be tightly regulated by nuclear receptor SF-1, transcription GATA factors, sex-reversal gene DAX1, and follicle-stimulating hormone (FSH).[9][10][11] Mutations in both the AMH gene and the type II AMH receptor have been shown to cause the persistence of Müllerian derivatives in males that are otherwise normally masculinized.[12]

AMH is also a product of granulosa cells of the preantral and small antral follicles in women. As such, AMH is only present in the ovary until menopause.[13] Production of AMH regulates folliculogenesis by inhibiting recruitment of follicles from the resting pool in order to select for the dominant follicle, after which the production of AMH diminishes.[13][14] As a product of the granulosa cells, which envelop each egg and provide them energy, AMH can also serve as a molecular biomarker for relative size of the ovarian reserve.[15] In humans, this is helpful because the number of cells in the follicular reserve can be used to predict timing of menopause.[16] In bovine, AMH can be used for selection of females in multi-ovulatory embryo transfer programs by predicting the number of antral follicles developed to ovulation.[17] AMH can also be used as a marker for ovarian dysfunction, such as in women with polycystic ovary syndrome (PCOS).

Structure

AMH is a dimeric glycoprotein with a molar mass of 140 kDa.[18] The molecule consists of two identical subunits linked by sulfide bridges, and characterized by the N-terminal dimer (pro-region) and C-terminal dimer.[1] AMH acts with receptors, AMH-RI and AMH-RII, upon which, after a series of conformational changes and phosphorylation steps, gene expression is regulated in the cell.[1]

Function

Embryogenesis

In mammals, AMH prevents the development of the Müllerian ducts into the uterus and other Müllerian structures.[5] The effect is ipsilateral, that is each testis suppresses Müllerian development only on its own side.[19] In humans, this action takes place during the first 8 weeks of gestation. If no hormone is produced from the gonads, the Müllerian ducts automatically develop, while the Wolffian ducts, which are responsible for male reproductive parts, automatically die.[20] Amounts of AMH that are measurable in the blood vary by age and sex. AMH works by interacting with specific receptors on the surfaces of the cells of target tissues (anti-Müllerian hormone receptors). The best-known and most specific effect, mediated through the AMH type II receptors, includes programmed cell death (apoptosis) of the target tissue (the fetal Müllerian ducts).

Ovarian

AMH is expressed by granulosa cells of the ovary during the reproductive years, and limits the formation of primary follicles by inhibiting excessive follicular recruitment by FSH.[15][21] AMH expression is greatest in the recruitment stage of folliculogenesis, in the preantral and small antral follicles. This expression diminishes as follicles develop and enter selection stage, upon which FSH expression increases.[22] Some authorities suggest it is a measure of certain aspects of ovarian function,[23] useful in assessing conditions such as polycystic ovary syndrome and premature ovarian failure.[24]

Other

AMH production by the Sertoli cells of the testes remains high throughout childhood in males but declines to low levels during puberty and adult life. AMH has been shown to regulate production of sex hormones,[25] and changing AMH levels (rising in females, falling in males) may be involved in the onset of puberty in both sexes. Functional AMH receptors have also been found to be expressed in neurons in the brains of embryonic mice, and are thought to play a role in sexually dimorphic brain development and consequent development of gender-specific behaviours.[26]

Pathology

In men, inadequate embryonal AMH activity can lead to the Persistent Müllerian duct syndrome (PMDS), in which a rudimentary uterus is present and testes are usually undescended. The AMH gene (AMH) or the gene for its receptor (AMH-RII) are usually abnormal. AMH measurements have also become widely used in the evaluation of testicular presence and function in infants with intersex conditions, ambiguous genitalia, and cryptorchidism.

A study published in Nature Medicine found a link between hormonal imbalance in the womb and Polycystic ovary syndrome (PCOS), specifically prenatal exposure to anti-Müllerian hormone.[27] For the study, the researchers injected pregnant mice with AMH so that they had a higher than normal concentration of the hormone. Indeed, they gave birth to daughters who later developed PCOS-like tendencies. These included problems with fertility, delayed puberty, and erratic ovulation. To reverse it, the researchers dosed the polycystic mice with an IVF drug called cetrorelix, which made the symptoms to go away .These experiments should be confirmed in humans, but it could be the first step in understanding the relationship between the polycystic ovary and the anti-Müllerian hormone.

Blood levels

In healthy females AMH is either just detectable or undetectable in cord blood at birth and demonstrates a marked rise by three months of age; while still detectable it falls until four years of age before rising linearly until eight years of age remaining fairly constant from mid-childhood to early adulthood – it does not change significantly during puberty.[28] The rise during childhood and adolescence is likely reflective of different stages of follicle development.[21] From 25 years of age AMH declines to undetectable levels at menopause.[28]

The standard measurement of AMH follows the Generation II assay. This should give the same values as the previously used IBC assay, but AMH values from the previously used DSL assay should be multiplied with 1.39 to conform to current standards because it used different antibodies.[29]

Weak evidence suggests that AMH should be measured only in the early follicular phase because of variation over the menstrual cycle. Also, AMH levels decrease under current use of oral contraceptives and current tobacco smoking.[30]

Reference ranges

Reference ranges for Anti-Müllerian hormone, as estimated from reference groups in the United states, are as follows:[31]

Females:

Age Unit Value
Younger than 24 months ng/mL Less than 5
pmol/l Less than 35
24 months to 12 years ng/mL Less than 10
pmol/l Less than 70
13–45 years ng/mL 1 to 10
pmol/l 7 to 70
More than 45 years ng/mL Less than 1
pmol/l Less than 7

Males:

Age Unit Value
Younger than 24 months ng/mL 15 to 500
pmol/l 100 to 3500
24 months to 12 years ng/mL 7 to 240
pmol/l 50 to 1700
More than 12 years ng/mL 0.7 to 20
pmol/l 5 to 140

AMH measurements may be less accurate if the person being measured is vitamin D deficient.[32] Note that males are born with higher AMH levels than females in order to initiate sexual differentiation, and in women, AMH levels decrease over time as fertility decreases as well.[32]

Clinical usage

General fertility assessment

Comparison of an individual's AMH level with respect to average levels[28] is useful in fertility assessment, as it provides a guide to ovarian reserve and identifies women that may need to consider either egg freezing or trying for a pregnancy sooner rather than later if their long-term future fertility is poor.[33] A higher level of anti-Müllerian hormone when tested in women in the general population has been found to have a positive correlation with natural fertility in women aged 30–44 aiming to conceive spontaneously, even after adjusting for age.[30] However, this correlation was not found in a comparable study of younger women (aged 20 to 35 years).[30]

In vitro fertilization

AMH is a predictor for ovarian response in in vitro fertilization (IVF). Measurement of AMH supports clinical decisions, but alone it is not a suitable predictor of IVF success.[34] Additionally, AMH levels are used to estimate a woman's remaining egg supply.[35]

According to NICE guidelines of in vitro fertilization, an anti-Müllerian hormone level of less than or equal to 5.4 pmol/l (0.8 ng/mL) predicts a low response to ovarian hyperstimulation, while a level greater than or equal to 25.0 pmol/l (3.6 ng/mL) predicts a high response.[36] Other cut-off values found in the literature vary between 0.7 and 20 pmol/l (0.1 and 2.97 ng/ml) for low response to ovarian hyperstimulation.[29] Subsequently, higher AMH levels are associated with greater chance of live birth after IVF, even after adjusting for age.[30][37] AMH can thereby be used to rationalise the programme of ovulation induction and decisions about the number of embryos to transfer in assisted reproduction techniques to maximise pregnancy success rates whilst minimising the risk of ovarian hyperstimulation syndrome (OHSS).[38][39] AMH can predict an excessive response in ovarian hyperstimulation with a sensitivity and specificity of 82% and 76%, respectively.[40]

Measuring AMH alone may be misleading as high levels occur in conditions like polycystic ovarian syndrome and therefore AMH levels should be considered in conjunction with a transvaginal scan of the ovaries to assess antral follicle count[41] and ovarian volume.[42]

Natural remedies

Studies into treatments to improve low ovarian reserve and low AMH levels have met with some success. Current best available evidence suggests that DHEA improves ovarian function, increases pregnancy chances and, by reducing aneuploidy, lowers miscarriage rates.[43] The studies into DHEA for low AMH show that a dose of 75 mg for a period of 16 weeks should be taken. Improvement of oocyte/embryo quality with DHEA supplementation potentially suggests a new concept of ovarian aging, where ovarian environments, but not oocytes themselves, age. DHEA has positive outcomes for women with AMH levels over 0.8 ng/ml or 5.7 pmol/l[44] DHEA has no apparent effect on oocytes or ovarian environments under this range.

Studies on CoQ10 supplementation in an aged animal model delayed depletion of ovarian reserve, restored oocyte mitochondrial gene expression, and improved mitochondrial activity.[45] Authors note that to replicate the 12–16 weeks of using CoQ10 supplements on mice to achieve these results would be the equivalent to a decade in humans.[45]

Vitamin D is believed to play a role in AMH regulation. The AMH gene promoter contains a vitamin D response element that may cause vitamin D status to influence serum AMH levels. Women with levels of Vitamin D of 267.8 ± 66.4 nmol/L show a 4 times better success rate with IVF procedure than those with low levels of 104.3 ± 21 nmol/L. Vitamin D deficiency should be considered when serum AMH levels are obtained for diagnosis.[32]

Women with cancer

In women with cancer, radiation therapy and chemotherapy can damage the ovarian reserve. In such cases, a pre-treatment AMH is useful in predicting the long-term post-chemotherapy loss of ovarian function, which may indicate fertility preservation strategies such as oocyte cryopreservation.[30] A post-treatment AMH is associated with decreased fertility.[21][30]

Granulosa cell tumors of the ovary secrete AMH, and AMH testing has a sensitivity ranging between 76 and 93% in diagnosing such tumors.[30] AMH is also useful in diagnosing recurrence of granulosa cell tumors.[30]

Neutering status in animals

In veterinary medicine, AMH measurements are used to determine neutering status in male and female dogs and cats. AMH levels can also be used to diagnose cases of ovarian remnant syndrome.[46]

Biomarker of polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is an endocrine disorder most commonly found in women of reproductive age that is characterized by oligo- or anovulation, hyperandrogenism, and polycystic ovaries (PCO).[47] This endocrine disorder increases AMH levels at nearly two to three times higher in women with PCOS than in normal type women. This is often attributed to the increased follicle count number characteristic of PCOS, indicating an increase in granulosa cells since they surround each individual egg.[48] However, increased AMH levels have also been attributed not just to the increased number of follicles, but also to an increased amount of AMH produced per follicle.[49] The high levels of androgens, characteristic of PCOS, also stimulate and provide feedback for increased production of AMH, as well.[22] In this way, AMH has been increasingly considered to be a tool or biomarker that can be used to diagnose or indicate PCOS.

Potential future usage

AMH has been synthesized. Its ability to inhibit growth of tissue derived from the Müllerian ducts has raised hopes of usefulness in the treatment of a variety of medical conditions including endometriosis, adenomyosis, and uterine cancer. Research is underway in several laboratories. If there were more standardized AMH assays, it could potentially be used as a biomarker of polycystic ovary syndrome.[50]

In mice, an increase in AMH has been shown to reduce the number of growing follicles and thus the overall size of the ovaries. This increase in AMH production reduces primary, secondary and antral follicles without reducing the number of primordial follicles suggesting a blockade of primordial follicle activation. This may provide a viable method of contraception which protects the ovarian reserve of oocytes during chemotherapy without extracting them from the body allowing the potential for natural reproduction later in life.[51]

Names

The adjective "Müllerian" is written either "Müllerian" or "müllerian", depending on the governing style guide; the derived term with the prefix of "anti-" is then "anti-Müllerian", "anti-müllerian", or "antimüllerian". The Müllerian ducts are named after Johannes Peter Müller.[52]

A list of the names that have been used for the antimüllerian hormone is as follows. For the sake of simplicity, this list ignores some orthographic variations; for example, it gives only one row for "Müllerian-inhibiting hormone", although there are 4 acceptable stylings thereof (cap M or lowercase m, hyphen or space).

Protein name styling Protein symbol
Anti-Müllerian hormone AMH
Müllerian-inhibiting factor MIF
Müllerian-inhibiting hormone MIH
Müllerian-inhibiting substance MIS
Müllerian duct inhibitory factor MDIF
Müllerian regression factor MRF
Anti-paramesonephric hormone APH

See also

References

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