{"paper_id":"be83305f-b7a1-42dc-b0b7-f670257e2f61","body_text":"Editorial\nAbout the Anti-Müllerian Hormone (AMH) Uses in the\nClinical Practice\nS o b r eo su s o sd oH o r m ô n i oa n t i - M ü l l e r i a n on ap r á t i c ac l í n i c a .\nGustavo Arantes Rosa Maciel 1 Edmund Chada Baracat 1 Marcos Felipe Silva de Sá 2\n1 Faculty of Medicine, Hospital das Clinicas HCFMUSP, Universidade de\nSao Paulo, Sao Paulo, SP, Brazil\n2 Faculty of Medicine, Universidade de Sao Paulo, Ribeirão Preto, SP,\nBrazil\nRev Bras Ginecol Obstet 2018;40:661 –663.\nThe anti-Müllerian hormone (AMH) is a glycoprotein that\nbelongs to the transforming growth factorβ (TGF-β)s u p e r f a m -\nily, and which has a key role in the male sexual development.1 It\nis produced by the Sertoli cells in the testis and induces the\nregression of Müllerian structures. In females, the roles of the\nAMH have been the focus of recent attention. In the present\narticle, some aspects of the physiology, laboratory assessment,\nclinical uses and pitfalls, as well as current applications from\nthe health perspective of women will be discussed briefly.\nIn humans, the AMH is encoded by the AMH gene, located\non the chromosome 19p13.3, whereas the gene AMHR2,\nwhich codes for its receptor, is located on the chromosome\n12.\n1 Although the physiology of the AMH in females is not\ncompletely established, a huge amount of data produced in\nthe last few years have expanded the knowledge in this\nfield.1,2 This hormone is secreted by the ovarian granulosa\ncells of the preantral and small follicles. It has been demon-\nstrated that the AMH plays an important role in the inhibi-\ntion of the initiation of the primordial follicles. 2 Data from\nin vivo and in vitro studies in animals and humans demon-\nstrated that the AMH has a key role in the maintenance of the\nquiescent status of those follicles.\n2 Recently, it has also been\nshown that this inhibition might be induced by the adminis-\ntration of recombinant AMH or by an overexpression of the\ngene that encodes the ligand,\n3 opening a broad spectrum of\npossibilities for the clinical use of the AMH. Another impor-\ntant action in the ovary is that the AMH reduces the follicle\nsensitivity to follicle-stimulating hormone (FSH), depending\non the stage of the follicular development.\n4 According to\nsome authors, the AMH may be one factor that dictates in\nwhich stage the follicle will begin to respond to the FSH.\n5 In\nterms of antral follicles, it has been suggested that the AMH\nhas a role in the selection process together with estradiol\n(E2) and inhibin. 6 Furthermore, the AMH seems to down-\nregulate the aromatase activity in the granulosa cells of\nfollicles before selection. 7 All of these functions in the antral\nfollicles suggest that the AMH may act as a follicular gate-\nkeeper and may ensure that each small antral follicle pro-\nduces the adequate amount of E2 prior to the selection.\n1,8 In\n2016, an interesting study suggested that the AMH has a role\nin the gonadotropin-releasing hormone (GnRH) pulse gen-\neration control in the hypothalamus.\n9\nThe reference values of the AMH were established through\nseveral studies within the female lifespan. 10 The interindi-\nvidual variability of the AMH is high, mainly due to the\nhighly variable number of follicles within groups of subjects\nof similar age.\n11,12 Some features raise the attention for its\nclinical use: first, that AMH levels, after a peak around the\nsecond decade of life, decrease with age and are strongly\ncorrelated with the ovarian reserve. Second, the variability\nwithin the menstrual cycles, although present, is not signi fi-\ncant from the clinical point of view.\n12 These features turned\nthe assessment an appealing diagnostic tool.\nTo date, there are several possible uses for the AMH\nassessment: evaluation of the ovarian reserve (OR), predic -\ntion of controlled ovarian stimulation (COS), prediction of\nthe natural age of menopause, assessment of the ovarian\nfunction, differentiation of some disorders of sex develop-\nment (DSDs), and tumor marker, among others.\n1,12 However,\nthe approved uses in many countries (including Brazil) are an\nevaluation of the OR and the prediction of response to\nCOS.\n13,14 Thus, in the present review, due to space concerns,\nonly the of ficial approved indications will be discussed.\nThe most important use of AMH assessment is the evalu-\nation of the OR. It is known that women are born with a given\nnumber of follicles (that harbor the female germ cells), and\nAddress for correspondence\nGustavo Arantes Rosa Maciel,\nFaculty of Medicine, Hospital das\nClinicas HCFMUSP , Universidade de\nSao Paulo, Av.Dr.Arnaldo, 455, room\n4025, 01246-903, Cerqueira Cezar,\nSao Paulo, SP , Brazil\n(e-mail: gustavo.maciel@fm.usp.br).\nDOI https://doi.org/\n10.1055/s-0038-1676059.\nISSN 0100-7203.\nCopyright © 2018 by Thieme Revinter\nPublicações Ltda, Rio de Janeiro, Brazil\nTHIEME\nEditorial 661\n\n\nthat most of these follicles will undergo atresia and will be\ndepleted throughout their lifespan. A small portion will be\novulated. The loss of follicles is directly related with female\nfertility and, after 37 years of age, the rate of follicle death\nbecomes more evident. The OR can be determined by the age\nof the woman, by the assessment of FSH and estradiol (E2),\nand by antral follicle counting (AFC) in the early follicular\nphase.\n14,15 The AMH was included in 2002 as a tool of\nevaluation of the OR. 14,15 None of the OR markers should\nbe used alone, because all of them present limitations. 15 Due\nto the fact that the AMH reflects the number of preantral and\nsmall antral follicles, there is a relationship between the\nserum levels of AMH and the remaining follicles. The AMH\nalso displays a strong correlation with the gold standard\nmethod of evaluation of the OR, which is AFC performed by\nsonography. A possibility of a more objective way to access\nthe OR is an important tool for the clinical practice. To date,\nthe AMH is considered the earliest and most sensitive marker\nof OR, especially in assisted reproductive technology (ART)\nscenarios.\n15 The main strength of AMH testing is to predict\ninadequate ovarian response, either poor ovarian response\n(POR) or excessive ovarian response. For instance, sensitivities\nrange between 44 and 97%, and specificities range between 41\nand 100%14 for a POR, if AMH levels are low (0.1–1.66 ng/mL).16\nAnti-Müllerian hormone levels > 1.0 ng/mL but < 3.5 ng/mL,\nif the patient is in the appropriate age, are consistent with\nnormal ovarian response to ovarian stimulation.\n15 However,\nin cases of natural fertility, the AMH seems to have a more\nlimited predictability. 16,17 Assessing OR in the general\npopulation might add extra costs to the health system. 17\nHowever, showing an information about one ’s OR might\nlead individuals to modify life choices in terms of fertility\ndecisions.\n18–20 The assessment of AMH levels is useful and\nreliable, but more studies shall further endorse the dissem-\nination of its use.\nCurrently, the main indications for OR testing are applied\nin women undergoing infertility evaluation/treatment (in-\ncluding history of premature ovarian insuf ficiency, oocyte\ndonation, fertility preservation due to social or personal\nissues or due to gonadotoxic treatments), prior to ovarian\nsurgery in women in reproductive age, in polycystic ovary\nsyndrome (PCOS), in perimenopause, and in women with\nmutation of BRCA-1o r FMR1 premutation (Fragile X syn-\ndrome). In addition, OR assessment is useful in the individu-\nalization of ART ovarian stimulation.\n15\nThe second approved use of AMH assessment is the predic -\ntion of ovarian response in ART treatment.14 To date, it is well\nestablished that both AMH and AFC are strong predictors of\novarian response in in vitro fertilization (IVF).21 The measure-\nment of AMH is useful in the prediction of poor response and\ncycle cancellation due to inadequate ovarian response, as well\nas in hyper-response and ovarian hyperstimulation syndrome,\nin COS.\n14 The AMH was shown to be a better marker in\npredicting ovarian response to COS than the age FSH, estradiol,\nand inhibin B.14 Recently, a study with a new human recombi-\nnant FSH (follitropin delta, rFSH), found that the AMH might be\na tool in predicting an adequate ovarian response in COS, with\nlower doses of rFSH with similar number of blastocysts. 22\nHowever, another study, using a different AMH more studies\nare necessary to assess thosefindings in different platforms. It\nseems that AFC and AMH may have complementary roles in\nthe preassessment of infertile women.\n23\nAn important issue for the clinical practice is related to\ntechnical aspects of the laboratorial assessment of the AMH\nserum levels. Several assays to detect the serum levels of the\nAMH were developed, but most of them are based on a\nsandwich type of immunometric or enzyme-linked immuno-\nsorbent assay (ELISA) tests with two monoclonal antibodies\n(ABs) that were both raised against recombinant human AMH\n(rhAMH). The ABs are able to recognize epitopes in the\nproregion (F2B/7A) and/or in the mature regions (F2B/\n12H).\n24 However, there have been studies questioning the\nstability of AMH upon storage, sample handling and sample\ndiluting, due to a complement system interference, that could\nfalsely alter the serum titles.25 This problem has motivated the\nbiggest manufacturer of AMH tests to withdraw its tests from\nthe world market in 2013, but a few assays remained available.\nIn a short period of time, the manufacturers addressed the\nproblem by adding the ABs in solution, instead of a in solid\nphase and new automated platforms were created. The com-\nplement interference issue seemed to be adequately solved.\n23\nAlthough the implementation of automated platforms must be\nconsidered an advance, an international standard developed in\naccordance with the International Federation of Clinical Chem-\nistry is still needed because, the variation amongst platforms\ncan interfere in the clinical interpretation.\n23\nAnother issue for the diagnostic use of AMH is that its\nlevels might be in fluenced by speci fic biological, reproduc -\ntive or environmental conditions. The serum levels of AMH\ntend to be decreased in several clinical situations: low levels\nof vitamin D,\n26 use of oral contraceptive pills or GnRH\nagonists, endometriosis, endometriomas, history of ovarian\nsurgery, smoking habit, mutations and permutation in the\nBRCA-1 and in the FMR1 genes, respectively. On the other\nhand, PCOS, granulosa cells tumors, and DSDs are associated\nwith remarkable increases in the level of AMH.\n23 All these\nsituations must be considered when AMH tests are used.\nIn conclusion, the assessment of AMH may be useful in\nseveral clinical situations, especially to evaluate the OR and\nto help to predict ovarian response in IVF cycles. However, an\ninternational standardization of the measuring methods is\nstill necessary. Although an exciting amount of information\nis contributing to reveal its functions, the physiology of the\nAMH is not completely understood, and the elucidation of\nkey steps of its physiological roles has the potential to\nincrease its utility in the clinical practice.\nReferences\n1 Dewailly D, Andersen CY, Balen A, et al. The physiology and\nclinical utility of anti-Mullerian hormone in women. Hum Reprod\nUpdate 2014;20(03):370 –385 Doi: 10.1093/humupd/dmt062\n2 Visser JA, de Jong FH, Laven JS, Themmen AP. Anti-Müllerian\nhormone: a new marker for ovarian function. Reproduction 2006;\n131(01):1–9 Doi: 10.1530/rep.1.00529\n3 Kano M, Sosulski AE, Zhang L, et al. AMH/MIS as a contraceptive\nthat protects the ovarian reserve during chemotherapy. Proc Natl\nRev Bras Ginecol Obstet Vol. 40 No. 11/2018\nEditorial662\n\n\nAcad Sci U S A 2017;114(09):E1688 –E1697 Doi: 10.1073/\npnas.1620729114\n4 Dewailly D, Robin G, Peigne M, Decanter C, Pigny P, Catteau-Jonard\nS. Interactions between androgens, FSH, anti-Müllerian hormone\nand estradiol during folliculogenesis in the human normal and\npolycystic ovary. Hum Reprod Update 2016;22(06):709 –724 Doi:\n10.1093/humupd/dmw027\n5 Durlinger AL, Visser JA, Themmen AP. Regulation of ovarian\nfunction: the role of anti-Müllerian hormone. Reproduction\n2002;124(05):601–609 Doi: 10.1530/rep.0.1240601\n6 Grynberg M, Pierre A, Rey R, et al. Differential regulation of\novarian anti-müllerian hormone (AMH) by estradiol through α-\nand β-estrogen receptors. J Clin Endocrinol Metab 2012;97(09):\nE1649–E1657 Doi: 10.1210/jc.2011-3133\n7 Grossman MP, Nakajima ST, Fallat ME, Siow Y. Müllerian-inhibit-\ning substance inhibits cytochrome P450 aromatase activity in\nhuman granulosa lutein cell culture. Fertil Steril 2008;89(5,\nSuppl):1364–1370 Doi: 10.1016/j.fertnstert.2007.03.066\n8 Jeppesen JV, Anderson RA, Kelsey TW, et al. Which follicles make the\nmost anti-Mullerian hormone in humans? Evidence for an abrupt\ndecline in AMH production at the time of follicle selection. Mol Hum\nReprod 2013;19(08):519–527 Doi: 10.1093/molehr/gat024\n9 Cimino I, Casoni F, Liu X, et al. Novel role for anti-Müllerian hormone\nin the regulation of GnRH neuron excitability and hormone secre-\ntion. Nat Commun 2016;7:10055 Doi: 10.1038/ncomms10055\n10 Cui L, Qin Y, Gao X, et al. Antimüllerian hormone: correlation with\nage and androgenic and metabolic factors in women from birth to\npostmenopause. Fertil Steril 2016;105(02):481–5.e1 Doi: 10.1016/\nj.fertnstert.2015.10.017\n11 Gougeon A. Ovarian follicular growth in humans: ovarian ageing\nand population of growing follicles. Maturitas 1998;30(02):\n137–142 Doi:10.1016/S0378-5122(98)00069-3\n12 La Marca A, Stabile G, Artenisio AC, Volpe A. Serum anti-Mullerian\nhormone throughout the human menstrual cycle. Hum Reprod\n2006;21(12):3103–3107 Doi: 10.1093/humrep/del291\n13 Azziz R, Carmina E, Chen Z, et al. Polycystic ovary syndrome. Nat\nRev Dis Primers 2016;2:16057 Doi: 10.1038/nrdp.2016.57\n14 La Marca A, Sighinol fi G, Radi D, et al. Anti-Mullerian hormone\n(AMH) as a predictive marker in assisted reproductive technology\n(ART). Hum Reprod Update 2010;16(02):113 –130 Doi: 10.1093/\nhumupd/dmp036\n15 Tal R, Seifer DB. Ovarian reserve testing: a user’s guide. Am J Obstet\nGynecol 2017;217(02):129–140 Doi: 10.1016/j.ajog.2017.02.027\n16 Broer SL, van Disseldorp J, Broeze KA, et al; IMPORT study group.\nAdded value of ovarian reserve testing on patient characteristics\nin the prediction of ovarian response and ongoing pregnancy: an\nindividual patient data approach. Hum Reprod Update 2013;19\n(01):26–36 Doi: 10.1093/humupd/dms041\n17 Steiner AZ, Pritchard D, Stanczyk FZ, et al. Association between\nbiomarkers of ovarian reserve and infertility among older women of\nreproductive age. JAMA 2017;318(14):1367 –1376 Doi: 10.1001/\njama.2017.14588\n18 Zarek SM, Mitchell EM, Sjaarda LA, et al. Is anti-Müllerian\nhormone associated with fecundability? Findings from the EAGeR\ntrial. J Clin Endocrinol Metab 2015;100(11):4215 –4221 Doi:\n10.1210/jc.2015-2474\n19 Mac Dougall K, Beyene Y, Nachtigall RD. Age shock: mispercep-\ntions of the impact of age on fertility before and after IVF in\nwomen who conceived after age 40. Hum Reprod 2013;28(02):\n350–356 Doi: 10.1093/humrep/des409\n20 Azhar E, Seifer DB, Melzer K, Ahmed A, Weedon J, Minkoff H.\nKnowledge of ovarian reserve and reproductive choices. J Assist\nReprod Genet 2015;32(03):409 –415 Doi: 10.1007/s10815-014-\n0415-9\n21 Magnusson Å, Nilsson L, Oleröd G, Thurin-Kjellberg A, Bergh C.\nThe addition of anti-Müllerian hormone in an algorithm for\nindividualized hormone dosage did not improve the prediction\nof ovarian response-a randomized, controlled trial. Hum Reprod\n2017;32(04):811–819 Doi: 10.1093/humrep/dex012\n22 Nyboe Andersen A, Nelson SM, Fauser BC, García-Velasco JA, Klein\nBM, Arce JC; ESTHER-1 study group. Individualized versus con-\nventional ovarian stimulation for in vitro fertilization: a multi-\ncenter, randomized, controlled, assessor-blinded, phase 3\nnoninferiority trial. Fertil Steril 2017;107(02):387 –396.e4 Doi:\n10.1016/j.fertnstert.2016.10.033\n23 Iliodromiti S, Anderson RA, Nelson SM. Technical and perfor-\nmance characteristics of anti-Müllerian hormone and antral\nfollicle count as biomarkers of ovarian response. Hum Reprod\nUpdate 2015;21(06):698 –710 Doi: 10.1093/humupd/dmu062\n24 Kevenaar ME, Meerasahib MF, Kramer P, et al. Serum anti-muller-\nian hormone levels re flect the size of the primordial follicle pool\nin mice. Endocrinology 2006;147(07):3228 –3234 Doi: 10.1210/\nen.2005-1588\n25 Rustamov O, Smith A, Roberts SA, et al. Anti-Mullerian hormone:\npoor assay reproducibility in a large cohort of subjects suggests\nsample instability. Hum Reprod 2012;27(10):3085 –3091 Doi:\n10.1093/humrep/des260\n26 Dennis NA, Houghton LA, Jones GT, van Rij AM, Morgan K,\nMcLennan IS. The level of serum anti-Müllerian hormone corre-\nlates with vitamin D status in men and women but not in boys.\nJ Clin Endocrinol Metab 2012;97(07):2450 –2455 Doi: 10.1210/\njc.2012-1213\nRev Bras Ginecol Obstet Vol. 40 No. 11/2018\nEditorial 663","source_license":"CC-BY-4.0","license_restricted":false}