ReviewAnti-Müllerian Hormone: genetic and environmental effects
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
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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 BiologyAge-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 GynecologyCitation 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 ToxicologyCitation 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 MethodsCitation 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 ScienceCitation 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