BACKGROUND The measurement of circulating anti-Mullerian hormone (AMH) has been applied to a wide array of clinical applications, mainly based on its ability to reflect the number of antral and pre-antral follicles present in the ovaries. AMH has been suggested to predict the ovarian response to hyperstimulation of the ovaries for IVF and the timing of menopause, and to indicate iatrogenic damage to the ovarian follicle reserve. It has also been proposed as a surrogate for antral follicle count (AFC) in the diagnosis of polycystic ovary syndrome (PCOS). METHODS This paper is a summary of presentations at a European Society of Human Reproduction and Embryology campus workshop on AMH, with literature cited until September 2013. Published peer-reviewed medical literature about AMH was searched through MEDLINE and was subjected to systematic review and critical assessment by the panel of authors. RESULTS Physiologically, recent data confirm that AMH is a follicular gatekeeper limiting follicle growth initiation, and subsequently estradiol production from small antral follicles prior to selection. AMH assays continue to evolve and technical issues remain; the absence of an international standard is a key issue. The dynamics of circulating AMH levels throughout life can be split into several distinct phases, with a peak in the early 20s before a decline to the menopause, with a strong and positive correlation with non-growing follicle recruitment. There is a more complex rise during childhood and adolescence, which is likely to be more reflective of different stages of follicle development. AMH shows limited short-term variability, but the influence of states such as prolonged oral contraceptive use need to be considered in clinical assessment. There are only very limited data on relationships between AMH and natural fertility at different stages of reproductive life, and while it has a relationship to age at menopause the marked variability in this needs further exploration. AMH may be useful in assessing the need for fertility preservation strategies and detecting post-chemotherapy or surgical damage to the ovarian reserve. Long-term follow-up of patients to ascertain fully the value of post-cancer serum AMH in predicting long-term ovarian function is required. There is a linear relationship between AMH and oocyte yield after ovarian stimulation, which is of value in predicting ovarian hyperstimulation. AMH can also identify 'poor responders', but it seems inappropriate at present to withhold IVF purely on this basis. Women with PCOS show markedly raised AMH levels, due to both the increased number of small antral follicles and intrinsic characteristics of those granulosa cells, and this may contribute to anovulation. The value of AMH in the diagnosis of PCOS remains controversial, but it may replace AFC in the future. CONCLUSIONS For the first time in female reproductive biology, it is possible to measure the submerged part of the iceberg of follicle growth, i.e. the intrinsic, so-called 'acyclic' ovarian activity. An international standard for AMH and improved assay validity are urgently needed to maximize the clinical utility of this very promising biomarker of ovarian function in a large array of clinical situations, both in childhood and adulthood.

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

Inwomen,anti-Mu¨llerianhormone(AMH)isexclusivelyproducedbygranulosacellsofovarianfolliclesduringtheearlystagesof follicle development. After an initial increase until early adulthood, AMH concentrations slowly decrease with increasing age until becomingundetectable 5 years before menopause when the stock of primordial follicles is exhausted. However, major individual variability exists inthe pace of follicle pool depletion and the initial size of the follicle pool, reﬂected byawide range of age at menopause. Individual AMH serumconcentrationdoesaccuratelyreﬂectthesizeofthepoolofantralfollicles,representingthequantityoftheremainingprimordialfollicles.Accord-ingly,AMHlevelsmayvarysigniﬁcantlyinwomenofthesamechronologicalage,allowingAMHtopredicttheremaininglengthofawoman’sre-productive lifespan.

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Anti-Müllerian hormone: ovarian reserve testing and its potential clinical implications.

background: Chemotherapy treatment in premenopausal women is associated with an increased risk of premature ovarian failure (POF) but the exact mechanism through which this occurs is uncertain. In this review we examine the current evidence for the direct action of chemotherapeutic agents on the ovary and discuss possible molecular pathways through which follicle loss may occur. methods: A systemic search of the databases, PubMed and Google Scholar, was made for all English language articles through to 2011 in each subject area discussed. results: POF results from the loss of primordial follicles but this is not necessarily a direct effect of the chemotherapeutic agents. Instead, the disappearance of primordial follicles could be due to an increased rate of growth initiation to replace damaged developing follicles. Like- wise, the loss of oocytes need not necessarily be a direct result of damage: evidence suggests that chemotherapy drugs can also induce oocyte death indirectly via damage to somatic cells. Specific molecular mechanisms and likely ovarian targets are discussed for some of the anti-cancer drugs most commonly used to treat premenopausal women. Finally, we consider current and prospective methods of preserving fertility. conclusions: It is likely that different chemotherapeutic drugs act through a range of mechanisms and on different target cells. More research into the cellular mechanisms underpinning chemotherapy-induced follicle loss could lead to the generation of treatments specifically designed to prevent POF.

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How do chemotherapeutic agents damage the ovary

Background Androgens, FSH, anti-Mullerian hormone (AMH) and estradiol (E2) are essential in human ovarian folliculogenesis. However, the interactions between these four players is not fully understood. Objectives and rationale The purpose of this review is to highlight the chronological sequence of the appearance and function of androgens, FSH, AMH and E2 and to discuss controversies in the relationship between FSH and AMH. A better understanding of this interaction could supplement our current knowledge about the pathophysiology of the polycystic ovary syndrome (PCOS). Search methods A literature review was performed using the following search terms: androgens, FSH, FSH receptor, anti-Mullerian hormone, AMHRII, estradiol, follicle, ovary, PCOS, aromatase, granulosa cell, oocyte. The time period searched was 1980-2015 and the databases interrogated were PubMed and Web of Science. Outcomes During the pre-antral ('gonadotropin-independent') follicle growth, FSH is already active and promotes follicle growth in synergy with theca cell-derived androgens. Conversely, AMH is inhibitory by counteracting FSH. We challenge the hypothesis that AMH is regulated by androgens and propose rather an indirect effect through an androgen-dependent amplification of FSH action on granulosa cells (GCs) from small growing follicles. This hypothesis implies that FSH stimulates AMH expression. During the antral ('gonadotropin-dependent') follicle growth, E2 production results from FSH-dependent activation of aromatase. Conversely, AMH is inhibitory but the decline of its expression, amplified by E2, allows full expression of aromatase, characteristic of the large antral follicles. We propose a theoretical scheme made up of two triangles that follow each other chronologically. In PCOS, pre-antral follicle growth is excessive (triangle 1) because of intrinsic androgen excess that renders GCs hypersensitive to FSH, with consequently excessive AMH expression. Antral follicle growth and differentiation are disturbed (triangle 2) because of the abnormally persisting inhibition of FSH effects by AMH that blocks aromatase. Beside anovulation, this scenario may also serve to explain the higher receptiveness to gonadotropin therapy and the increased risk of ovarian hyperstimulation syndrome (OHSS) in patients with PCOS. Wider implications Within GCs, the balance between FSH and AMH effects is pivotal in the shift from androgen- to oestrogen-driven follicles. Our two triangles hypothesis, based on updated data from the literature, offers a pedagogic template for the understanding of folliculogenesis in the normal and polycystic ovary. It opens new avenues for the treatment of anovulation due to PCOS.

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Interactions between androgens, FSH, anti-Müllerian hormone and estradiol during folliculogenesis in the human normal and polycystic ovary

This paper represents an international collaboration of paediatric endocrine and other societies (listed in the Appendix) under the International Consortium of Paediatric Endocrinology (ICPE) aiming to improve worldwide care of adolescent girls with polycystic ovary syndrome (PCOS)1. The manuscript examines pathophysiology and guidelines for the diagnosis and management of PCOS during adolescence. The complex pathophysiology of PCOS involves the interaction of genetic and epigenetic changes, primary ovarian abnormalities, neuroendocrine alterations, and endocrine and metabolic modifiers such as anti-Mullerian hormone, hyperinsulinemia, insulin resistance, adiposity, and adiponectin levels. Appropriate diagnosis of adolescent PCOS should include adequate and careful evaluation of symptoms, such as hirsutism, severe acne, and menstrual irregularities 2 years beyond menarche, and elevated androgen levels. Polycystic ovarian morphology on ultrasound without hyperandrogenism or menstrual irregularities should not be used to diagnose adolescent PCOS. Hyperinsulinemia, insulin resistance, and obesity may be present in adolescents with PCOS, but are not considered to be diagnostic criteria. Treatment of adolescent PCOS should include lifestyle intervention, local therapies, and medications. Insulin sensitizers like metformin and oral contraceptive pills provide short-term benefits on PCOS symptoms. There are limited data on anti-androgens and combined therapies showing additive/synergistic actions for adolescents. Reproductive aspects and transition should be taken into account when managing adolescents.

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An International Consortium Update: Pathophysiology, Diagnosis, and Treatment of Polycystic Ovarian Syndrome in Adolescence.

Background: Anti-Mullerian hormone (AMH) is a product of growing ovarian follicles. The concentration of AMH in blood may also reflect the non-growing follicle (NGF) population, i.e. the ovarian reserve, and be of value in predicting reproductive lifespan. A full description of AMH production up to the menopause has not been previously reported. Methodology/Principal Findings: By searching the published literature for AMH concentrations in healthy pre-menopausal females, and using our own data (combined n~3,260) we have generated and robustly validated the first model of AMH concentration from conception to menopause. This model shows that 34% of the variation in AMH is due to age alone. We have shown that AMH peaks at age 24.5 years, followed by a decline to the menopause. We have also shown that there is a neonatal peak and a potential pre-pubertal peak. Our model allows us to generate normative data at all ages. Conclusions/Significance: These data highlight key inflection points in ovarian follicle dynamics. This first validated model of circulating AMH in healthy females describes a transition period in early adulthood, after which AMH reflects the progressive loss of the NGF pool. The existence of a neonatal increase in gonadal activity is confirmed for females. An improved understanding of the relationship between circulating AMH and age will lead to more accurate assessment of ovarian reserve for the individual woman.

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A Validated Model of Serum Anti-Müllerian Hormone from Conception to Menopause

Background: Anti-Mullerian hormone (AMH) is a product of growing ovarian follicles. The concentration of AMH in blood may also reflect the non-growing follicle (NGF) population, i.e. the ovarian reserve, and be of value in predicting reproductive lifespan. A full description of AMH production up to the menopause has not been reported. Methodology/Principal Findings: By searching the published literature for AMH concentrations in healthy pre-menopausal females, and using our own data (combined n = 3,260) we have generated and robustly validated the first model of AMH concentration from conception to menopause. This model shows that 34% of the variation in AMH is due to age alone. We have shown that AMH peaks at age 24.5 years, followed by a decline to the menopause. We have also shown that there is a neonatal peak and a potential pre-pubertal peak. Our model allows us to generate normative data at all ages. Conclusions/Significance: These data highlight key inflection points in ovarian follicle dynamics. This first validated model of circulating AMH in healthy females describes a transition period in early adulthood, after which AMH reflects the progressive loss of the NGF pool. The existence of a neonatal increase in gonadal activity is confirmed for females. An improved understanding of the relationship between circulating AMH and age will lead more accurate assessment of ovarian reserve for the individual woman.

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

Human ovarian physiology is still poorly understood, with the factors and mechanisms that control initiation of follicular recruitment and loss remaining particularly unclear. Conventional hypothesis-led studies provide new data, results and insights, but datasets from individual studies are often small, allowing only limited interpretation. Great power is afforded by the aggregation of data from multiple studies into single datasets. In this paper, we describe how modern computational analysis of these datasets provides important new insights into ovarian function and has generated hypotheses that are testable in the laboratory. Specifically, we can hypothesize that age is the most important factor for variations in individual ovarian non-growing follicle (NGF) populations, that anti-Mullerian hormone (AMH) levels gen- erally rise and fall in childhood years before peaking in the mid-twenties, and that there are strong correlations between AMH levels and both NGF populations and rates of recruitment towards maturation, for age ranges before and after peak AMH levels.

Data-driven assessment of the human ovarian reserve.

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The natural history of asbestosis and idiopathic pulmonary fibrosis according to HRCT phenotype

<h3>Background</h3> Despite minimal evidence regarding utility, and no national guidelines, MDTMs are embedded within palliative care. However they are costly so efficiency must be maximised (De Leso et al, 2013).<sup>2</sup> The function of MDTMs includes coordinating care for complex patients (Borgstrom et al, 2021).<sup>1</sup> This project aimed to review completeness of local electronic MDTM documentation and assess staff’s views of the meeting’s purpose and associated documentation. <h3>Methods</h3> <h3>Mixed methods project</h3> 1) Retrospective data analysis of completeness of digital data entries in palliative care MDTMs over a 6-month period at a tertiary referral cancer centre. 2) Survey of MDTM members to understand what they felt the role of the MDTM was, what it should be, and how to best capture the data electronically. <h3>Results</h3> MDTM entries from 329 patients were reviewed. While some domains were completed for the majority of patients eg. Phase of Illness and Performance Status (&gt;95% of patients), other domains were poorly completed, eg. estimated prognosis (33%) and preferred place of death (24%). The survey was completed by 27 MDTM members from 7 disciplines. Members felt that the sharing and receiving of information was the purpose of the MDT – both currently and ideally. However while members felt that allowing shared decision making was important in their ideal MDT, they didn’t feel the current MDT fulfilled that purpose as strongly. In addition while members reported feeling comfortable contributing to discussion, some members thought there should be more discussion from different disciplines. <h3>Conclusions</h3> MDTM members felt that the main purpose of the meetings was to discuss complexity, and that meetings had a positive impact overall, with more of a positive impact on MDTM members than patients. MDTM members value the MDT but feel that there could be more discussion amongst members to avoid it feeling like a ‘box-ticking’ exercise. <h3>References</h3> Borgstrom E, Cohn S, Driessen A, <i>et al</i>. ‘Multidisciplinary team meetings in palliative care: an ethnographic study’. <i>BMJ Supportive &amp; Palliative Care</i>. 2021 [Online] Available at: https://spcare.bmj.com/content/early/2021/09/29/bmjspcare-2021-003267 (Accessed 14th September 2022) De Leso PB, Coward JI, Letsa U, Schick U, Nandhabalan M, Frentzas S, Gore ME. ‘A study of the decision outcomes and finacial cots of multidisciplinary team meetings (MDMs) in oncology’. <i>British Journal of Cancer</i>, 2013;<b>109</b>:2295–2300 

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130 Mixed-methods study to understand and improve the value of digital Palliative Care Multi-Disciplinary Team Meetings (MDTMs) in a tertiary oncology centre

Phoebe Wright

Papers

A Validated Model of Serum Anti-Müllerian Hormone from Conception to Menopause

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

Data-driven assessment of the human ovarian reserve.

The natural history of asbestosis and idiopathic pulmonary fibrosis according to HRCT phenotype

130 Mixed-methods study to understand and improve the value of digital Palliative Care Multi-Disciplinary Team Meetings (MDTMs) in a tertiary oncology centre