Elsevier

Clinica Chimica Acta

Volume 476, January 2018, Pages 123-129
Clinica Chimica Acta

Review
Anti-Müllerian Hormone: genetic and environmental effects

https://doi.org/10.1016/j.cca.2017.11.027Get rights and content

Highlights

  • AMH plays a major role in assisted reproductive technology

  • AMH is considered as a reliable marker for ovarian reserve assessment

  • Genetic and environmental factors effects on AMH levels

Abstract

Anti-Müllerian hormone (AMH) is a homodimeric glycoprotein produced by granulosa cells of growing ovarian follicles. AMH appears to have an inhibitory effect on both primordial follicle recruitment and responsiveness of growing follicles to follicle-stimulating hormone (FSH). This hormone is considered to be a reliable marker of ovarian reserve; therefore, it is crucial to determine which factors influence AMH levels for prognostic and diagnostic purposes. In this review we intend to discuss the effect of genetic and environmental factors which may lead to AMH interindividual variability.

Introduction

Anti-Müllerian hormone (AMH), also recognized as Müllerian inhibiting substance, is a gonadal-specific glycoprotein that belongs to the transforming growth factor beta (TGF-β) superfamily. During fetal differentiation, testicular Sertoli cells begin to produce AMH at the 7th week of gestation, which leads to regression of Müllerian ducts and initiation of the male phenotypic development [1]. On the other hand, lack of AMH expression during embryogenesis allows the Müllerian duct to differentiate into the internal female genital organs such as the uterus, fallopian tubes, and upper two-thirds of the vagina [2], [3]. In females, AMH production is commenced by the granulosa cells of small growing follicles, particularly the primary and preantral follicles at the end of the third trimester of pregnancy (around the 36th week of gestation), and reaches a peak at about 25 years of age [4], [5]. Subsequently, AMH concentration declines progressively with age and becomes undetectable at menopause, which reflects the decline in a pool of primordial and developing follicles [6], [7]. In recent years, numerous researchers have mainly focused on the role of AMH as a marker of ovarian follicular reserve and ovarian aging [8], [9].

The biological actions of AMH are exerted through two membrane-bound receptors that have serine/threonine kinase activity - type II (specific receptor) and type I (general receptor) [10]. These receptors express in AMH target organs such as granulosa cells in the ovaries and Sertoli and Leydig cells in the testes [11]. Once AMH binds to the type II receptor, the intracellular domain of the type I receptor, which acts as threonine kinase, becomes phosphorylated and activates cytoplasmic Smad proteins. Subsequently, Smad proteins translocate to the nucleus to regulate expressions of numerous genes [12]. The pattern of AMH expression seems to be similar in mice and human ovaries [13]; therefore, studies that have analyzed the follicle pool in ovaries from AMH-deficient mice provide insight into the roles of AMH in folliculogenesis [14]. Primordial follicles in AMH deficient mice are recruited at a faster rate, which results in premature depletion of the primordial follicle pool at an earlier age [9]. This finding provides evidence that AMH inhibits the initial recruitment and growth of follicles by restricting stimulatory growth factors required for recruitment such as KIT ligand and basic fibroblast growth factor [15], [16]. This has been further substantiated by the fact that mouse ovaries cultured with AMH resulted in a 40%–50% decrease in growing follicle numbers [17]. AMH decreases the sensitivity of primordial follicles to follicle-stimulating hormone (FSH) and inhibits granulosa cell aromatase, which results in a decreased chance for the follicle to move toward cyclic recruitment and estrogen biosynthesis [18]. Several authors have hypothesized that AMH could be one of the factors involved in the modification of follicular responsiveness to FSH during cyclical recruitment [13], [19], [20].

Section snippets

AMH as a marker of ovarian reserve

The term ovarian reserve refers to a woman's reproductive potential, reflected as the quantity and quality of the ovarian follicle pool at any given time [21]. Since it is not possible to directly determine the number of follicles in vivo, indirect measurements of ovarian reserve can be achieved by assessments of biochemical and ultrasound markers [22]. Increasing evidence suggests that AMH is the best available test in terms of sensitivity and specificity compared to other parameters such as

AMH and response to fertility treatment

Prediction of ovarian response to gonadotropins is currently one of the ongoing challenges in assisted reproduction. In accordance with previous findings [37], [38], [39], both AFC and AMH levels are clinically invaluable in providing useful information about ovarian responsiveness to treatment. The higher intra- and inter-cycle variability of AFC [40] make it preferable to perform these measurements during the early follicular stage [41]. According to a numerous studies, AMH could predict

Factors that influence AMH levels

Although AMH is considered the best hormonal marker to assess ovarian reserves, it has been suggested that AMH expression and serum levels can be altered by genetic and environmental factors [62], [63], [64], [65]. The important role of AMH in the clinic setting makes it essential to know the factors that influence AMH levels. These factors enable better interpretation of AMH levels in clinical practice and optimization of treatment strategies to reduce possible clinical errors such as placing

Conclusion

Over the past few years, there have been numerous scientific developments in the field of reproductive medicine that improve both the management of patients who undergo infertility treatments and their safety. Despite these improvements, understanding the factors that influence AMH levels as an accurate marker of ovarian function has not been fully addressed. Considering the important role of AMH in clinic, it is crucial to know the molecular, genetic and environmental factors influencing its

References (128)

  • S.L. Broer et al.

    The role of antimullerian hormone in prediction of outcome after IVF: comparison with the antral follicle count

    Fertil. Steril.

    (2009)
  • L.G. Nardo et al.

    Circulating basal anti-Mullerian hormone levels as predictor of ovarian response in women undergoing ovarian stimulation for in vitro fertilization

    Fertil. Steril.

    (2009)
  • J.G. Wang et al.

    The association between anti-Mullerian hormone and IVF pregnancy outcomes is influenced by age

    Reprod. BioMed. Online

    (2010)
  • A. Hazout et al.

    Serum antimüllerian hormone/müllerian-inhibiting substance appears to be a more discriminatory marker of assisted reproductive technology outcome than follicle-stimulating hormone, inhibin B, or estradiol

    Fertil. Steril.

    (2004)
  • A. Kedem et al.

    Ongoing pregnancy rates in women with low and extremely low anti mullerian hormone (AMH) levels

    Fertil.

    (2013)
  • D.E. Reichman et al.

    Value of antimullerian hormone as a prognostic indicator of in vitro fertilization outcome

    Fertil. Steril.

    (2014)
  • B.P. Halloran et al.

    Effect of vitamin D deficiency on fertility and reproductive capacity in the female rat

    J. Nutr.

    (1980)
  • A.V. Krishnan et al.

    Novel pathways that contribute to the anti-proliferative and chemopreventive activities of calcitriol in prostate cancer

    J. Steroid Biochem. Mol. Biol.

    (2007)
  • D.A. DeUgarte et al.

    Surrogate obesity negatively impacts pregnancy rates in third-party reproduction

    Fertil. Steril.

    (2010)
  • E.W. Freeman et al.

    Association of anti-mullerian hormone levels with obesity in late reproductive-age women

    Fertil. Steril.

    (2007)
  • A.Z. Steiner et al.

    Antimullerian hormone and obesity: insights in oral contraceptive users

    Contraception

    (2010)
  • E. Buyuk et al.

    Elevated body mass index is associated with lower serum anti-mullerian hormone levels in infertile women with diminished ovarian reserve but not with normal ovarian reserve

    Fertil. Steril.

    (2011)
  • S. Halawaty et al.

    Effect of obesity on parameters of ovarian reserve in premenopausal women

    J. Obstet. Gynaecol. Can.

    (2010)
  • K. Rustemeier et al.

    Evaluation of the potential effects of ingredients added to cigarettes. Part 2: chemical composition of mainstream smoke

    Food Chem. Toxicol.

    (2002)
  • A.P. Sobinoff et al.

    Jumping the gun: smoking constituent BaP causes premature primordial follicle activation and impairs oocyte fusibility through oxidative stress

    Toxicol. Appl. Pharmacol.

    (2012)
  • T. Freour et al.

    Active smoking compromises IVF outcome and affects ovarian reserve

    Reprod. BioMed. Online

    (2008)
  • A. Munsterberg et al.

    Expression of the mouse anti-mullerian hormone gene suggests a role in both male and female sexual differentiation

    Development

    (1991)
  • M.M. Lee et al.

    Mullerian inhibiting substance: a gonadal hormone with multiple functions Mullerian inhibiting substance: a gonadal hormone with multiple functions *

    Endocr. Rev.

    (1993)
  • I. Zec et al.

    Anti-Mullerian hormone: a unique biochemical marker of gonadal development and fertility in humans

    Biochem. Med.

    (2011)
  • T.W. Kelsey et al.

    A validated model of serum anti-Müllerian hormone from conception to menopause

    PLoS One

    (2011)
  • A. La Marca et al.

    Anti-Mullerian hormone in premenopausal women and after AMH and ART 127 spontaneous or surgically induced menopause

    J. Soc. Gynecol. Investig.

    (2005)
  • J.A. Visser et al.

    Anti-Müllerian hormone: a new marker for ovarian function

    Reproduction

    (2006)
  • A.L.L. Durlinger et al.

    Control of primordial follicle recruitment by anti-Müllerian hormone in the mouse ovary

    Endocrinology

    (1999)
  • A. La Marca et al.

    Anti-Müllerian hormone (AMH) in female reproduction: is measurement of circulating AMH a useful tool?

    Clin. Endocrinol.

    (2006)
  • J. Massague et al.

    Smad transcription factors

    Genes Dev.

    (2005)
  • C. Weenen et al.

    Anti-Müllerian hormone expression pattern in the human ovary: potential implications for initial and cyclic follicle recruitment

    Mol. Hum. Reprod.

    (2004)
  • D. Dewailly et al.

    The physiology and clinical utility of anti-Mullerian hormone in women

    Hum. Reprod. Update

    (2014)
  • E. Nilsson et al.

    Actions of anti-Mullerian hormone on the ovarian transcriptome to inhibit primordial to primary follicle transition

    Reproduction

    (2007)
  • E.E. Nilsson et al.

    Roles of gremlin 1 and gremlin 2 in regulating ovarian primordial to primary follicle transition

    Reproduction

    (2014)
  • H.I.A. Durlinger et al.

    AMH inhibits initiation of primordial follicle growth in the mouse ovary

    Endocrinology

    (2002)
  • L. Pellatt et al.

    Anti-Müllerian hormone reduces follicle sensitivity to follicle-stimulating hormone in human granulosa cells

    Fertil. Steril.

    (2011)
  • Z. Kollmann et al.

    Anti-Müllerian hormone and progesterone levels produced by granulosa cells are higher when derived from natural cycle IVF than from conventional gonadotropin-stimulated IVF

    Reprod. Biol. Endocrinol.

    (2015)
  • A.L.L. Durlinger et al.

    AMH attenuates the effects of FSH on follicle development in the mouse ovary

    Endocrinology

    (2001)
  • N. Gleicher et al.

    Defining ovarian reserve to better understand ovarian aging

    Reprod. Biol. Endocrinol.

    (2011)
  • C.B. Lambalk et al.

    A systematic review of tests predicting ovarian reserve and IVF outcome

    Hum. Reprod. Update

    (2006)
  • I.A.J. Van Rooij et al.

    Serum anti-Müllerian hormone levels: a novel measure of ovarian reserve

    Hum. Reprod.

    (2002)
  • R. Fanchinm et al.

    Serum anti-Mullerian hormone is more strongly related to ovarian follicular status than serum inhibin B, estradiol, FSH and LH on day 3

    Hum. Reprod.

    (2003)
  • A. La Marca et al.

    How much does AMH really vary in normal women?

    Int. J. Endocrinol.

    (2013)
  • A. La Marca et al.

    Anti-Müllerian hormone (AMH): what do we still need to know?

    Human

    (2009)
  • D.B. Seifer et al.

    Early follicular serum mu substance levels are associated with ovarian response during assisted reproductive technology cycles

    Fertil. Steril.

    (2002)
  • Cited by (33)

    • Can Anti-Müllerian Hormone levels predict future pregnancy outcomes in recurrent pregnancy loss?

      2023, European Journal of Obstetrics and Gynecology and Reproductive Biology
    • Age-specific random day serum antimüllerian hormone reference values for women of reproductive age in the general population: a large Chinese nationwide population-based survey

      2022, American Journal of Obstetrics and Gynecology
      Citation Excerpt :

      The AMH levels of the women in our study were similar to that of Chinese women in other studies,25 lower than that of White women at older age,27,32 and higher than that of Latina women.27,32 Moreover, these differences between different countries and ethnicities may result from their differences in genes,34,35 ethnicities,27,32,33 lifestyles,36–38 and environmental exposures.39,40 Our study used the GAMLSS method to establish the AMH reference values.

    • The impact of isotretinoin on the pituitary-ovarian axis: An interpretative review of the literature

      2021, Reproductive Toxicology
      Citation Excerpt :

      One of the good markers of ovarian physiology and reserve is anti-Müllerian hormone (AMH). AMH is a homodimeric glycoprotein secreted by granulosa cells of growing ovarian follicles [21,22]. AMH is secreted by the primary, secondary, and small antral follicles up to about 4 mm in diameter [23].

    • Establishment of a homogeneous immunoassay-light-initiated chemiluminescence assay for detecting anti-Müllerian hormone in human serum

      2021, Journal of Immunological Methods
      Citation Excerpt :

      During fetal differentiation, production of AMH induces the regression of Müllerian ducts and the development of male embryo-phenotype. On the contrary, lack of AMH leads the Müllerian duct to differentiate into uterus, fallopian tubes and the upper part of the vagina (La Marca et al., 2010; Shahrokhi et al., 2018). Disorders of sex development, such as ambiguous genitalia, are usually associated with disorders in the secretion or action of AMH (Freire et al., 2018).

    • Exposure of dairy cows to high environmental temperatures and their lactation status impairs establishment of the ovarian reserve in their offspring

      2020, Journal of Dairy Science
      Citation Excerpt :

      Nevertheless, because the experimental design of this study did not allow to control for several managerial and environmental variables, the observed differences in the ovarian follicular population of the offspring cannot be exclusively attributed to the environmental conditions in early pregnancy. Vitamin D is a steroid hormone whose deficiency has been associated with a 25% fertility reduction in rats (Halloran and DeLuca, 1980), and recent evidence suggests that low vitamin D levels have a negative effect on the ovarian reserve in women (Shahrokhi et al., 2018). Cattle synthetize vitamin D3 (cholecalciferol) following exposure to sunlight, and obtain both vitamin D2 (ergocalciferol) and D3 through dietary sources (Hidiroglou et al., 1985; Hymøller and Jensen, 2010).

    • Ovarian reserve

      2020, Subfertility: Recent Advances in Management and Prevention
    View all citing articles on Scopus
    View full text