Anti-Müllerian hormone (AMH) is a novel biomarker of ovarian reserve, or the size of the ovarian follicle pool. Follicle stimulating hormone (FSH) and inhibin B have been the gold standard measures of ovarian reserve. However, changes in FSH and inhibin B levels are not detectable in serum until there is a significant reduction in the follicle pool (Steiner, 2013), making timely detection and intervention challenging. Several studies have explored the influence of both reproductive and lifestyle determinants on AMH concentrations (Dolleman et al., 2013; Freeman et al., 2007; La Marca et al., 2010; La Marca, Stabile, Artenisio, & Volpe, 2006; Malhotra, Bahadur, Singh, Kalaivani, & Mittal, 2013; Nelson, Stewart, Fleming, & Freeman, 2010; Steiner, Stanczyk, Patel, & Edelman, 2010; Tsepelidis et al., 2007). A systematic review of factors associated with AMH levels has not been conducted. A high level summary of the evidence is needed to evaluate the usefulness of AMH as a biomarker of ovarian reserve.
Ovarian reserve is established during fetal life. At birth, the number of primordial follicles is estimated at 1 million. This number decreases steadily during a female’s lifespan and is reduced to approximately 300,000-500,000 at menarche. Throughout a female’s reproductive years, follicles are recruited from the primordial pool and progress through the various stages of follicular growth. At the start of each menstrual cycle, one dominant follicle is selected for ovulation (Visser, de Jong, Laven, & Themmen, 2006). While it has proven challenging to quantify ovarian reserve, a new biomarker, anti-Müllerian hormone (AMH), has shown considerable promise (Dewailly et al., 2014). AMH is secreted by growing follicles, and is therefore reflective of the size of the primordial follicular pool. Measurable in serum, AMH offers a promising non-invasive marker of ovarian reserve. In addition, AMH levels are the earliest detectable change that occurs in the sequence of events associated with ovarian aging (Sills, Alper, & Walsh, 2009). The hormone is also ideal as a research and clinical measure because concentrations do not fluctuate across the menstrual cycle, and are independent of FSH, LH, and E2 levels (La Marca et al., 2010; Shaw et al., 2011; Tran, Cedars, & Rosen, 2011).
While ovarian reserve naturally declines with age, age alone is not predictive of ovarian age or reproductive status. The decline of ovarian reserve is primarily due to apoptotic loss of oocytes (programmed cell death) rather than ovulation (Tremellen, Kolo, Gilmore, & Lekamge, 2005). Thirty-four percent of the variation in AMH concentrations is due to age, meaning that the remaining 66% is due to other factors (Kelsey, Wright, Nelson, Anderson, & Wallace, 2011). Identifying these factors may help to elucidate predictors of reproductive dysfunction and disease. Understanding factors that influence AMH levels in normo-ovulatory women will also help to establish reliable normative age ranges for use in clinical practice and research. While numerous studies have examined factors associated with AMH concentrations, the sensitivity of the biomarker depends on an understanding of the complex interplay of factors that influence its concentrations. The purpose of this systematic review is to provide a high level summary of the evidence on the factors associated with AMH concentrations and to develop a conceptual model based on the strengths of association for future hypothesis testing.
Methods:
This systematic review will be conducted according to the PRISMA guidelines. A comprehensive literature search will be conducted using “anti-Müllerian hormone” as the search term in PubMed. Studies will be included if they meet the follow criteria: 1) published in the last 10 years, 2) human subjects research, 3) research conducted with healthy females. Reference lists of selected studies will also be searched in order to identify any relevant studies missed in the primary search.
Results:
Two researchers will read and independently judge all selected studies. Studies will be grouped by the factors that emerge from the systematic review. Once all relevant factors have been reviewed, a conceptual model will be developed based on the strengths of association. If there is contradicting evidence, several potential models may be proposed.
Conclusion:
The conceptual models developed through this systematic review will provide the foundation for future hypothesis testing, and may improve the usefulness of AMH as a biomarker of ovarian reserve.
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