Prediction of premature ovarian insufficiency: foolish fallacy or feasible foresight?

Abstract

Prediction of premature ovarian insufficiency (POI) would be of substantial individual benefit, but being a heterogeneous and fluctuating condition, with an extensive range of complex etiologies and arbitrary diagnostic criteria, might make this seem foolhardy. However, contemporary and complementary genetic strategies assessing consanguineous and large POI pedigrees and cohorts with age at natural menopause have shown strong enrichment in genes regulating DNA damage repair, homologous recombination, and meiosis, processes that are critical to oogenesis and folliculogenesis. Recognition of the molecular architecture of POI and its contribution to baseline genotypic risk may enable these estimates to be refined further by estimation of the residual ovarian reserve. Increasing data derived from spontaneous and gonadotoxic-induced POI cohorts demonstrate the utility of anti-Müllerian hormone (AMH) to predict POI. This review presents current understanding of how genetics in combination with AMH may facilitate the prediction of POI.

预测早发性卵巢功能不全:愚蠢的谬论还是可行的远见？ 摘要

预测早发性卵巢功能不全 (POI) 对个人有很大的好处, 但作为一种异质性和波动性的疾病, 具有广泛的复杂病因和不确定的诊断标准, 可能会使预测看起来很草率。然而, 一项当代互补遗传策略评估了自然绝经年龄的近亲和大型 POI 谱系和队列, 结果显示调节 DNA 损伤修复、同源重组和减数分裂的基因有很强的富集, 这些过程对卵子发生和卵泡生成至关重要。对 POI 的分子结构及其对基线基因型风险的认识可能使这些预测能够通过估计剩余卵巢储备进一步完善。来自特发性和性腺毒性诱导 POI 队列越来越多的数据证明了抗缪勒管激素 (AMH) 可用于预测 POI。本综述介绍了目前对遗传学与 AMH 相结合如何促进 POI 预测的理解。

Keywords:

• Premature ovarian insufficiency
• ovarian reserve
• genetics
• anti-Müllerian hormone
• prediction models

Acknowledgements

The views expressed in this publication are those of the authors and not necessarily those of the National Health Service, the National Institute for Health Research, or the Department of Health and Social Care, or any other funders mentioned here.

Potential conflict of interest

S. M. Nelson reports personal fees from Access Fertility, Merck, Modern Fertility, and The Fertility Partnership, and grants and personal fees from Ferring and Roche Diagnostics, outside the submitted work. R. A. Anderson has participated in Advisory Boards and received speakers or consultancy fees from Roche Diagnostics, Ferring Pharmaceuticals, IBSA, Merck Serono, KaNDy Therapeutics, and Sojournix Inc., outside the submitted work.

Additional information

Funding

The authors’ work in this field is supported by grants from the Medical Research Council (MRC) [G1100357 to R.A.A.], [MR/N022556/1 to the MRC Centre for Reproductive Health].