AMH in Reproductive Medicine

Paolo Giacobini, PhD

Since the discovery of anti-Mullerian hormone (AMH), significant strides have been made in elucidating its roles in male and female gonadal function, as well as its implications in infertility syndromes. In clinical practice, over the past two decades, the use of AMH measurement has evolved significantly. Initially utilized mainly as an indicator of ovarian function, it has since emerged as a valuable tool for assessing ovarian aging and reserve, in predicting fertility preservation outcomes, diagnosing PCOS, and measuring fertility treatment efficacy. Furthermore, over the past decade, several studies have unveiled the presence of AMH receptors throughout the hypothalamic–pituitary–gonadal axis, suggesting that AMH may serve as a pivotal neuroendocrine regulator of fertility.

This issue of Seminars in Reproductive Medicine features six reviews discussing key advancements regarding the role of AMH in reproductive medicine.

In this issue, Hamza Benderradji et al describe the role of AMH in male reproduction and sperm motility. Benderradji and colleagues review the current literature on the role of AMH in male fertility, in physiological and pathological conditions, starting from the gonadal differentiation period and continuing to the maturation stage from the neonatal period to adulthood. This review discusses the use of serum AMH measurement by pediatric endocrinologists, who employ it as a specific indicator of immature Sertoli cell count and functionality in childhood. Conversely, in adult men, specialists in male reproduction are exploring its prospective utility as a fertility marker. Furthermore, recent research highlights a potential new physiological role of circulating AMH in negatively regulating follicle-stimulating hormone secretion, potentially by influencing gonadotropic cell activity in the pituitary gland. Additionally, the authors discuss how the expression of AMH receptor type 2 in human spermatozoa could be involved in regulating sperm motility.

Over the years, the focus on AMH has transitioned from its involvement in male sexual differentiation to its role in female gonadal function. In their article, Sena Yildiz, Loes Moolhuijsen, and Jenny Visser discuss the role of AMH in ovarian function, as a gatekeeper of folliculogenesis, describing the latest insights regarding AMH processing, signaling pathways, and its temporal and spatial regulation, while also scrutinizing the knowledge gap in the transcriptional control of AMH within the ovary. Herein, the authors also discuss the effects of AMH genetic variants on ovarian function. Indeed, accumulating evidence proposes that genetic variants in AMH, its receptor, or downstream signaling molecules are likely to impact ovarian AMH function, leading to subfertility and hormonal disturbances in women.

In their article, Inès Sellami et al provide an overview of the current understanding of AMH assessment in reproductive medicine, with a specific focus on its predictive role in spontaneous pregnancy, outcomes in assisted reproductive techniques, and in fertility preservation. Does measuring AMH help anticipate the response to oral ovulation inducers in PCOS? Is AMH measurement effective in predicting the response to pulsatile gonadotropin-releasing hormone (GnRH) therapy and/or gonadotropins in hypogonadotropic hypogonadism? Can serum AMH levels be used to predict the response to controlled ovarian stimulation? These are just a few of the major clinical inquiries tackled by the authors in this review.

Ludovica Cotellessa and Paolo Giacobini describe the role of AMH in the central regulation of fertility. Recently, AMH has been shown to be implicated in the periodic remodeling of the GnRH neuronal terminals by modulating the tanycytic plasticity at the level of the median eminence. These findings highlight the potential role of this hormone in influencing hypothalamic function and its impact on reproductive health. This review focuses on the emerging roles of AMH on hypothalamic neuronal and glial cell types involved in the central control of reproduction and discusses its potential implications in reproductive physiology. Additionally, Cotellessa and Giacobini review recent preclinical and clinical studies pointing to the role of aberrant levels of AMH as a potential contributor to the pathophysiology of polycystic ovary syndrome (PCOS). These findings underscore the intricate interplay between AMH and the neuroendocrine system, offering new avenues for understanding the mechanisms underlying fertility and reproductive disorders.

David Abbott, Beverly Hutcherson, and Daniel Dumesic discuss the role of AMH in the etiology of PCOS. PCOS is the most common endocrinopathy, estimated to affect 8 to 13% of women of reproductive age globally. PCOS is also recognized for its significant impact on metabolic and psychological well-being of affected women. Despite significant advancements since its initial description by Stein and Levanthal in 1935, the exact origin of PCOS remains largely elusive. In this review, Abbott and colleagues discuss in detail the role of AMH as a crucial element within the androgen receptor–regulated pathways that underlie the hyperandrogenic origin of PCOS, the genetic and epigenetic contributions to AMH-related pathogenesis and PCOS, and the neuroendocrine role of AMH in the control of ovarian function potentially contributing to PCOS pathogenesis. Lastly, the authors provide an in-depth examination of various preclinical animal models of PCOS presently employed to elucidate mechanistic aspects pertaining to the syndrome's etiology.

Finally, Terhi T. Piltonen and colleagues discuss the utility of serum AMH measurement as part of PCOS diagnosis. The 2023 international evidence-based guideline update for the assessment and management of PCOS recommends using the Rotterdam criteria for the diagnosis of PCOS. This updated guideline provides evidence-based recommendations for diagnosis, now incorporating serum AMH measurement as an alternative to gynecological ultrasound for diagnosing polycystic ovary morphology (PCOM). In this review, the authors discuss the factors influencing AMH levels and its utility in PCOS diagnosis. The authors thoroughly present several studies reporting various cutoffs for AMH in diagnosing PCOM. Importantly, Piltonen et al present arguments advocating for the inclusion of age and platform-specific references to enhance the effectiveness of AMH use in the PCOS diagnosis process.

It is clear that there remain significant gaps in our understanding in the transcriptional control of AMH, in the indirect effects of ovarian AMH through hypothalamic cellular networks, and in the potential role of AMH on different extragonadal organs expressing its receptors. Emerging techniques, such as single-cell multiomics, patient-specific iPSC cells, and organoids, represent a promising tool to gain a better understanding of the altered regulation of AMH expression in physiological and pathological reproductive conditions.

It is with great honor that I introduce this special issue focusing on AMH in reproductive medicine, which sheds light on recent developments and considerations that have emerged in recent years. I sincerely hope that both academic and clinical readers will find the articles featured in this issue compelling, and that this collection of articles will serve as a catalyst for further research, ultimately advancing clinical progress in reproductive biology.

Publikationsverlauf

Artikel online veröffentlicht:
18. Juli 2024