Download PDF
Semin Reprod Med
DOI: 10.1055/s-0044-1786050
Review Article

Role of Anti-Müllerian Hormone in the Central Regulation of Fertility

Ludovica Cotellessa
1   Inserm, CHU Lille, Unit 1172, Lille Neuroscience & Cognition (LilNCog), University of Lille, Lille, France.
,
Paolo Giacobini 
1   Inserm, CHU Lille, Unit 1172, Lille Neuroscience & Cognition (LilNCog), University of Lille, Lille, France.
› Author Affiliations Funding P.G. is supported by the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (ERC-2016-CoG to P.G. grant number 725149/REPRODAMH and ERC-2022-POC2 to P.G. grant number 101111874/GRASP), and by the Institut National de la Santé et de la Recherche Médicale (INSERM), France (grant number U1172).
› Further Information
    Permissions and Reprints

Abstract

In recent years, the expanding roles of anti-Müllerian hormone (AMH) in various aspects of reproductive health have attracted significant attention. Initially recognized for its classical role in male sexual differentiation, AMH is produced postnatally by the Sertoli cells in the male testes and by the granulosa cells in the female ovaries. Traditionally, it was believed to primarily influence gonadal development and function. However, research over the last decade has unveiled novel actions of AMH beyond the gonads, specifically all along the hypothalamic–pituitary–gonadal axis. This review will focus on the emerging roles of AMH within the hypothalamus and discusses its potential implications in reproductive physiology. Additionally, recent preclinical and clinical studies have suggested that elevated levels of AMH may disrupt the hypothalamic network regulating reproduction, which could contribute to the central pathophysiology of polycystic ovary syndrome. These findings underscore the intricate interplay between AMH and the neuroendocrine system, offering new avenues for understanding the mechanisms underlying fertility and reproductive disorders.

Keywords

AMH - hypothalamus - GnRH - PCOS - infertility


Publication History

Article published online:
12 April 2024

© 2024. Thieme. All rights reserved.

Thieme Medical Publishers, Inc.
333 Seventh Avenue, 18th Floor, New York, NY 10001, USA

 

  • References

  • 1 Jost A. The age factor in the castration of male rabbit fetuses. Proc Soc Exp Biol Med 1947; 66 (02) 302
    CrossrefPubMedGoogle Scholar
  • 2 Jost A. [Investigation of hormonal control of genesis of the sex organs in rabbit and notes on certain malformations of the genital apparatus in man]. Ginecol Obstet Mex 1952; 7 (07) 477-492
    PubMedGoogle Scholar
  • 3 Münsterberg A, Lovell-Badge R. Expression of the mouse anti-Müllerian hormone gene suggests a role in both male and female sexual differentiation. Development 1991; 113 (02) 613-624
    CrossrefPubMedGoogle Scholar
  • 4 Lebeurrier N, Launay S, Macrez R. et al. Anti-Mullerian-hormone-dependent regulation of the brain serine-protease inhibitor neuroserpin. J Cell Sci 2008; 121 (Pt 20): 3357-3365
    CrossrefPubMedGoogle Scholar
  • 5 Wang PY, Protheroe A, Clarkson AN, Imhoff F, Koishi K, McLennan IS. Müllerian inhibiting substance contributes to sex-linked biases in the brain and behavior. Proc Natl Acad Sci U S A 2009; 106 (17) 7203-7208
    CrossrefPubMedGoogle Scholar
  • 6 Cimino I, Casoni F, Liu X. et al. Novel role for anti-Müllerian hormone in the regulation of GnRH neuron excitability and hormone secretion. Nat Commun 2016; 7: 10055
    CrossrefPubMedGoogle Scholar
  • 7 Barbotin AL, Mimouni NEH, Kuchcinski G. et al. Hypothalamic neuroglial plasticity is regulated by anti-Müllerian hormone and disrupted in polycystic ovary syndrome. EBioMedicine 2023; 90: 104535
    CrossrefPubMedGoogle Scholar
  • 8 Silva MSB, Decoster L, Trova S. et al. Female sexual behavior is disrupted in a preclinical mouse model of PCOS via an attenuated hypothalamic nitric oxide pathway. Proc Natl Acad Sci U S A 2022; 119 (30) e2203503119
    CrossrefPubMedGoogle Scholar
  • 9 Garrel G, Racine C, L'Hôte D. et al. Anti-Müllerian hormone: a new actor of sexual dimorphism in pituitary gonadotrope activity before puberty. Sci Rep 2016; 6: 23790
    CrossrefPubMedGoogle Scholar
  • 10 Garrel G, Denoyelle C, L'Hôte D. et al. GnRH transactivates human AMH receptor gene via Egr1 and FOXO1 in gonadotrope cells. Neuroendocrinology 2019; 108 (02) 65-83
    CrossrefPubMedGoogle Scholar
  • 11 Thompson IR, Kaiser UB. GnRH pulse frequency-dependent differential regulation of LH and FSH gene expression. Mol Cell Endocrinol 2014; 385 (1-2): 28-35
    CrossrefPubMedGoogle Scholar
  • 12 Herbison AE. Control of puberty onset and fertility by gonadotropin-releasing hormone neurons. Nat Rev Endocrinol 2016; 12 (08) 452-466
    CrossrefPubMedGoogle Scholar
  • 13 Schwanzel-Fukuda M, Pfaff DW. Origin of luteinizing hormone-releasing hormone neurons. Nature 1989; 338 (6211) 161-164
    CrossrefPubMedGoogle Scholar
  • 14 Wray S, Grant P, Gainer H. Evidence that cells expressing luteinizing hormone-releasing hormone mRNA in the mouse are derived from progenitor cells in the olfactory placode. Proc Natl Acad Sci U S A 1989; 86 (20) 8132-8136
    CrossrefPubMedGoogle Scholar
  • 15 Duittoz AH, Forni PE, Giacobini P. et al. Development of the gonadotropin-releasing hormone system. J Neuroendocrinol 2022; 34 (05) e13087
    CrossrefPubMedGoogle Scholar
  • 16 Casoni F, Malone SA, Belle M. et al. Development of the neurons controlling fertility in humans: new insights from 3D imaging and transparent fetal brains. Development 2016; 143 (21) 3969-3981
    CrossrefPubMedGoogle Scholar
  • 17 Boehm U, Bouloux PM, Dattani MT. et al. Expert consensus document: European Consensus Statement on congenital hypogonadotropic hypogonadism – pathogenesis, diagnosis and treatment. Nat Rev Endocrinol 2015; 11 (09) 547-564
    CrossrefPubMedGoogle Scholar
  • 18 Malone SA, Papadakis GE, Messina A. et al. Defective AMH signaling disrupts GnRH neuron development and function and contributes to hypogonadotropic hypogonadism. eLife 2019; 8: e47198
    CrossrefPubMedGoogle Scholar
  • 19 Navarro VM, Gottsch ML, Chavkin C, Okamura H, Clifton DK, Steiner RA. Regulation of gonadotropin-releasing hormone secretion by kisspeptin/dynorphin/neurokinin B neurons in the arcuate nucleus of the mouse. J Neurosci 2009; 29 (38) 11859-11866
    CrossrefPubMedGoogle Scholar
  • 20 Clarkson J, Han SY, Piet R. et al. Definition of the hypothalamic GnRH pulse generator in mice. Proc Natl Acad Sci U S A 2017; 114 (47) E10216-E10223
    CrossrefPubMedGoogle Scholar
  • 21 Silva MSB, Desroziers E, Hessler S. et al. Activation of arcuate nucleus GABA neurons promotes luteinizing hormone secretion and reproductive dysfunction: Implications for polycystic ovary syndrome. EBioMedicine 2019; 44: 582-596
    CrossrefPubMedGoogle Scholar
  • 22 Roa J, Herbison AE. Direct regulation of GnRH neuron excitability by arcuate nucleus POMC and NPY neuron neuropeptides in female mice. Endocrinology 2012; 153 (11) 5587-5599
    CrossrefPubMedGoogle Scholar
  • 23 Prevot V, Croix D, Bouret S. et al. Definitive evidence for the existence of morphological plasticity in the external zone of the median eminence during the rat estrous cycle: implication of neuro-glio-endothelial interactions in gonadotropin-releasing hormone release. Neuroscience 1999; 94 (03) 809-819
    CrossrefPubMedGoogle Scholar
  • 24 Parkash J, Messina A, Langlet F. et al. Semaphorin7A regulates neuroglial plasticity in the adult hypothalamic median eminence. Nat Commun 2015; 6: 6385
    CrossrefPubMedGoogle Scholar
  • 25 García-Cáceres C, Balland E, Prevot V. et al. Role of astrocytes, microglia, and tanycytes in brain control of systemic metabolism. Nat Neurosci 2019; 22 (01) 7-14
    CrossrefPubMedGoogle Scholar
  • 26 Prevot V, Dehouck B, Sharif A, Ciofi P, Giacobini P, Clasadonte J. The versatile tanycyte: a hypothalamic integrator of reproduction and energy metabolism. Endocr Rev 2018; 39 (03) 333-368
    CrossrefPubMedGoogle Scholar
  • 27 Prevot V, Bellefontaine N, Baroncini M. et al. Gonadotropin-releasing hormone nerve terminals, tanycytes and neurohaemal junction remodelling in the adult median eminence: functional consequences for reproduction and dynamic role of vascular endothelial cells. J Neuroendocrinol 2010; 22 (07) 639-649
    CrossrefPubMedGoogle Scholar
  • 28 Sharif A, Baroncini M, Prevot V. Role of glia in the regulation of gonadotropin-releasing hormone neuronal activity and secretion. Neuroendocrinology 2013; 98 (01) 1-15
    CrossrefPubMedGoogle Scholar
  • 29 Tata B, Mimouni NEH, Barbotin AL. et al. Elevated prenatal anti-Müllerian hormone reprograms the fetus and induces polycystic ovary syndrome in adulthood. Nat Med 2018; 24 (06) 834-846
    CrossrefPubMedGoogle Scholar
  • 30 Teede HJ, Tay CT, Laven JJE. et al. Recommendations from the 2023 International Evidence-based Guideline for the Assessment and Management of Polycystic Ovary Syndrome. J Clin Endocrinol Metab 2023; 108 (10) 2447-2469
    CrossrefPubMedGoogle Scholar
  • 31 Sir-Petermann T, Maliqueo M, Angel B, Lara HE, Pérez-Bravo F, Recabarren SE. Maternal serum androgens in pregnant women with polycystic ovarian syndrome: possible implications in prenatal androgenization. Hum Reprod 2002; 17 (10) 2573-2579
    CrossrefPubMedGoogle Scholar
  • 32 Peigné M, Simon V, Pigny P. et al. Changes in circulating forms of anti-Müllerian hormone and androgens in women with and without PCOS: a systematic longitudinal study throughout pregnancy. Hum Reprod 2023; 38 (05) 938-950
    CrossrefPubMedGoogle Scholar
  • 33 Das M, Gillott DJ, Saridogan E, Djahanbakhch O. Anti-Mullerian hormone is increased in follicular fluid from unstimulated ovaries in women with polycystic ovary syndrome. Hum Reprod 2008; 23 (09) 2122-2126
    CrossrefPubMedGoogle Scholar
  • 34 Pigny P, Merlen E, Robert Y. et al. Elevated serum level of anti-Mullerian hormone in patients with polycystic ovary syndrome: relationship to the ovarian follicle excess and to the follicular arrest. J Clin Endocrinol Metab 2003; 88 (12) 5957-5962
    CrossrefPubMedGoogle Scholar
  • 35 Piltonen TT, Giacobini P, Edvinsson Å. et al. Circulating antimüllerian hormone and steroid hormone levels remain high in pregnant women with polycystic ovary syndrome at term. Fertil Steril 2019; 111 (03) 588-596.e1
    CrossrefPubMedGoogle Scholar
  • 36 Köninger A, Kampmeier A, Mach P. et al. Tight interplay in early pregnancy between follistatin and anti-Mullerian hormone in women with polycystic ovarian syndrome (PCOS). Arch Gynecol Obstet 2018; 297 (05) 1307-1316
    CrossrefPubMedGoogle Scholar
  • 37 Detti L, Christiansen ME, Francillon L. et al. Serum anti-Müllerian hormone (AMH) in mothers with polycystic ovary syndrome (PCOS) and their term fetuses. Syst Biol Reprod Med 2019; 65 (02) 147-154
    CrossrefPubMedGoogle Scholar
  • 38 Valdimarsdottir R, Valgeirsdottir H, Wikström AK. et al. Pregnancy and neonatal complications in women with polycystic ovary syndrome in relation to second-trimester anti-Müllerian hormone levels. Reprod Biomed Online 2019; 39 (01) 141-148
    CrossrefPubMedGoogle Scholar
  • 39 Mimouni NEH, Paiva I, Barbotin AL. et al. Polycystic ovary syndrome is transmitted via a transgenerational epigenetic process. Cell Metab 2021; 33 (03) 513-530.e8
    CrossrefPubMedGoogle Scholar
  • 40 Rebar R, Judd HL, Yen SS, Rakoff J, Vandenberg G, Naftolin F. Characterization of the inappropriate gonadotropin secretion in polycystic ovary syndrome. J Clin Invest 1976; 57 (05) 1320-1329
    CrossrefPubMedGoogle Scholar
  • 41 Berga SL, Guzick DS, Winters SJ. Increased luteinizing hormone and alpha-subunit secretion in women with hyperandrogenic anovulation. J Clin Endocrinol Metab 1993; 77 (04) 895-901
    PubMedGoogle Scholar
  • 42 Taylor AE, McCourt B, Martin KA. et al. Determinants of abnormal gonadotropin secretion in clinically defined women with polycystic ovary syndrome. J Clin Endocrinol Metab 1997; 82 (07) 2248-2256
    PubMedGoogle Scholar
  • 43 Silva MSB, Decoster L, Delpouve G. et al. Overactivation of GnRH neurons is sufficient to trigger polycystic ovary syndrome-like traits in female mice. EBioMedicine 2023; 97: 104850
    CrossrefPubMedGoogle Scholar
  • 44 Goodman RL, Herbison AE, Lehman MN, Navarro VM. Neuroendocrine control of gonadotropin-releasing hormone: pulsatile and surge modes of secretion. J Neuroendocrinol 2022; 34 (05) e13094
    CrossrefPubMedGoogle Scholar
  • 45 Coyle C, Campbell RE. Pathological pulses in PCOS. Mol Cell Endocrinol 2019; 498: 110561
    CrossrefPubMedGoogle Scholar
  • 46 Ho EV, Shi C, Cassin J. et al. Reproductive deficits induced by prenatal antimüllerian hormone exposure require androgen receptor in Kisspeptin Cells. Endocrinology 2021; 162 (12) bqab197
    CrossrefPubMedGoogle Scholar
  • 47 Risal S, Pei Y, Lu H. et al. Prenatal androgen exposure and transgenerational susceptibility to polycystic ovary syndrome. Nat Med 2019; 25 (12) 1894-1904
    CrossrefPubMedGoogle Scholar
  • 48 Stener-Victorin E, Deng Q. Epigenetic inheritance of polycystic ovary syndrome - challenges and opportunities for treatment. Nat Rev Endocrinol 2021; 17 (09) 521-533
    CrossrefPubMedGoogle Scholar
  • 49 Liu Q, Li Y, Feng Y. et al. Single-cell analysis of differences in transcriptomic profiles of oocytes and cumulus cells at GV, MI, MII stages from PCOS patients. Sci Rep 2016; 6: 39638
    CrossrefPubMedGoogle Scholar
  • 50 Dumesic DA, Oberfield SE, Stener-Victorin E, Marshall JC, Laven JS, Legro RS. Scientific statement on the diagnostic criteria, epidemiology, pathophysiology, and molecular genetics of polycystic ovary syndrome. Endocr Rev 2015; 36 (05) 487-525
    CrossrefPubMedGoogle Scholar
  • 51 Vázquez-Martínez ER, Gómez-Viais YI, García-Gómez E. et al. DNA methylation in the pathogenesis of polycystic ovary syndrome. Reproduction 2019; 158 (01) R27-R40
    CrossrefPubMedGoogle Scholar
  • 52 Rellini AH, Stratton N, Tonani S, Santamaria V, Brambilla E, Nappi RE. Differences in sexual desire between women with clinical versus biochemical signs of hyperandrogenism in polycystic ovarian syndrome. Horm Behav 2013; 63 (01) 65-71
    CrossrefPubMedGoogle Scholar
  • 53 Steinberg Weiss M, Roe AH, Allison KC. et al. Lifestyle modifications alone or combined with hormonal contraceptives improve sexual dysfunction in women with polycystic ovary syndrome. Fertil Steril 2021; 115 (02) 474-482
    CrossrefPubMedGoogle Scholar
  • 54 Stovall DW, Scriver JL, Clayton AH, Williams CD, Pastore LM. Sexual function in women with polycystic ovary syndrome. J Sex Med 2012; 9 (01) 224-230
    CrossrefPubMedGoogle Scholar
  • 55 Pastoor H, Both S, Laan ETM, Laven JSE. Sexual dysfunction in women with PCOS: a case control study. Hum Reprod 2023; 38 (11) 2230-2238
    CrossrefPubMedGoogle Scholar
  • 56 Pastoor H, Timman R, de Klerk C, MBramer W, Laan ET, Laven JS. Sexual function in women with polycystic ovary syndrome: a systematic review and meta-analysis. Reprod Biomed Online 2018; 37 (06) 750-760
    CrossrefPubMedGoogle Scholar
  • 57 Pastoor H, Mousa A, Bolt H. et al. Sexual function in women with polycystic ovary syndrome: a systematic review and meta-analysis. Hum Reprod Update 2024; 00 (00) 1-18
    PubMedGoogle Scholar
  • 58 Donaldson NM, Prescott M, Ruddenklau A, Campbell RE, Desroziers E. Maternal androgen excess significantly impairs sexual behavior in male and female mouse offspring: perspective for a biological origin of sexual dysfunction in PCOS. Front Endocrinol (Lausanne) 2023; 14: 1116482
    CrossrefPubMedGoogle Scholar
  • 59 Yang CF, Chiang MC, Gray DC. et al. Sexually dimorphic neurons in the ventromedial hypothalamus govern mating in both sexes and aggression in males. Cell 2013; 153 (04) 896-909
    CrossrefPubMedGoogle Scholar
  • 60 Singh R, Pervin S, Shryne J, Gorski R, Chaudhuri G. Castration increases and androgens decrease nitric oxide synthase activity in the brain: physiologic implications. Proc Natl Acad Sci U S A 2000; 97 (07) 3672-3677
    CrossrefPubMedGoogle Scholar
  • 61 Clasadonte J, Poulain P, Beauvillain JC, Prevot V. Activation of neuronal nitric oxide release inhibits spontaneous firing in adult gonadotropin-releasing hormone neurons: a possible local synchronizing signal. Endocrinology 2008; 149 (02) 587-596
    CrossrefPubMedGoogle Scholar
  • 62 Hanchate NK, Parkash J, Bellefontaine N. et al. Kisspeptin-GPR54 signaling in mouse NO-synthesizing neurons participates in the hypothalamic control of ovulation. J Neurosci 2012; 32 (03) 932-945
    CrossrefPubMedGoogle Scholar
  • 63 Meng C. Nitric oxide (NO) levels in patients with polycystic ovary syndrome (PCOS): a meta-analysis. J Int Med Res 2019; 47 (09) 4083-4094
    CrossrefPubMedGoogle Scholar
  • 64 Krishna MB, Joseph A, Thomas PL, Dsilva B, Pillai SM, Laloraya M. Impaired arginine metabolism coupled to a defective redox conduit contributes to low plasma nitric oxide in polycystic ovary syndrome. Cell Physiol Biochem 2017; 43 (05) 1880-1892
    CrossrefPubMedGoogle Scholar
  • 65 Masha A, Manieri C, Dinatale S, Bruno GA, Ghigo E, Martina V. Prolonged treatment with N-acetylcysteine and L-arginine restores gonadal function in patients with polycystic ovary syndrome. J Endocrinol Invest 2009; 32 (11) 870-872
    CrossrefPubMedGoogle Scholar
  • 66 Mahran A, Abdelmeged A, Shawki H, Moheyelden A, Ahmed AM. Nitric oxide donors improve the ovulation and pregnancy rates in anovulatory women with polycystic ovary syndrome treated with clomiphene citrate: a RCT. Int J Reprod Biomed (Yazd) 2016; 14 (01) 9-14
    CrossrefPubMedGoogle Scholar
  • 67 Bédécarrats GY, O'Neill FH, Norwitz ER, Kaiser UB, Teixeira J. Regulation of gonadotropin gene expression by Mullerian inhibiting substance. Proc Natl Acad Sci U S A 2003; 100 (16) 9348-9353
    CrossrefPubMedGoogle Scholar
  • 68 Devillers MM, Petit F, Cluzet V. et al. FSH inhibits AMH to support ovarian estradiol synthesis in infantile mice. J Endocrinol 2019; 240 (02) 215-228
    CrossrefPubMedGoogle Scholar