Nutrition and Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Department of Clinical Nutrition and Dietetics, Faculty of Nutrition and Food Technology, National Nutrition and Food Technology Research Institute, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Hum Reprod. 2021 Feb 18;36(3):721-733. doi: 10.1093/humrep/deaa279.
Which metabolites are associated with varying rates of ovarian aging, measured as annual decline rates of anti-Müllerian hormone (AMH) concentrations?
Higher serum concentrations of metabolites of phosphate, N-acetyl-d-glucosamine, branched chained amino acids (BCAAs), proline, urea and pyroglutamic acid were associated with higher odds of fast annual decline rate of AMH.
Age-related rate of ovarian follicular loss varies among women, and the factors underlying such inter-individual variations are mainly unknown. The rate of ovarian aging is clinically important due to its effects on both reproduction and health of women. Metabolomics, a global investigation of metabolites in biological samples, provides an opportunity to study metabolites or metabolic pathways in relation to a physiological/pathophysiological condition. To date, no metabolomics study has been conducted regarding the differences in the rates of ovarian follicular loss.
STUDY DESIGN, SIZE, DURATION: This prospective study was conducted on 186 reproductive-aged women with regular menstrual cycles and history of natural fertility, randomly selected using random case selection option in SPSS from the Tehran Lipid and Glucose Study.
PARTICIPANTS/MATERIALS, SETTING, METHODS: AMH concentrations were measured at baseline (1999-2001) and the fifth follow-up examination (2014-2017), after a median follow-up of 16 years, by immunoassay using Gen II kit. The annual decline rate of AMH was calculated by dividing the AMH decline rate by the follow-up duration (percent/year). The women were categorized based on the tertiles of the annual decline rates. Untargeted metabolomics analysis of the fasting-serum samples collected during the second follow-up examination cycle (2005-2008) was performed using gas chromatography-mass spectrometry. A combination of univariate and multivariate approaches was used to investigate the associations between metabolites and the annual decline rates of AMH.
After adjusting the baseline values of age, AMH and BMI, 29 metabolites were positively correlated with the annual AMH decline rates. The comparisons among the tertiles of the annual decline rate of AMH revealed an increase in the relative abundance of 15 metabolites in the women with a fast decline (tertile 3), compared to those with a slow decline (tertile 1). There was no distinct separation between women with slow and fast decline rates while considering 41 metabolites simultaneously using the principal component analysis and the partial least-squares discriminant analysis models. The odds of fast AMH decline was increased with higher serum metabolites of phosphate, N-acetyl-d-glucosamine, BCAAs, proline, urea and pyroglutamic acid. Amino sugar and nucleotide sugar metabolism, BCAAs metabolism and aminoacyl tRNA biosynthesis were among the most significant pathways associated with the fast decline rate of AMH.
LIMITATIONS, REASONS FOR CAUTION: Estimating the annual decline rates of AMH using the only two measures of AMH is the main limitation of the study which assumes a linear fixed reduction in AMH during the study. Since using the two-time points did not account for the variability in the decline rate of AMH, the annual decline rates estimated in this study may not accurately show the trend of the reduction in AMH. In addition, despite the longitudinal nature of the study and statistical adjustment of the participants' ages, it is difficult to distinguish the AMH-related metabolites observed in this study can accelerate ovarian aging or they are reflections of different rates of the aging process.
Some metabolite features related to the decline rates of AMH have been suggested in this study; further prospective studies with multiple measurements of AMH are needed to confirm the findings of this study and to better understand the molecular process underlying variations in ovarian aging.
STUDY FUNDING/COMPETING INTEREST(S): This study, as a part of PhD thesis of Ms Nazanin Moslehi, was supported by Shahid Beheshti University of Medical Sciences (10522-4). There were no competing interests.
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哪些代谢物与抗苗勒管激素（AMH）浓度的年下降率变化有关，可作为卵巢衰老速度的衡量标准？
血清中磷酸盐、N-乙酰-d-葡萄糖胺、支链氨基酸（BCAAs）、脯氨酸、尿素和焦谷氨酸等代谢物的浓度较高与 AMH 年下降率较高的可能性相关。
女性的卵巢卵泡丢失率随年龄的增长而变化，导致这种个体间差异的因素主要未知。由于其对女性生殖和健康的影响，卵巢衰老的速度在临床上很重要。代谢组学是对生物样本中代谢物的全面研究，为研究与生理/病理生理状况相关的代谢物或代谢途径提供了机会。迄今为止，尚无关于卵巢卵泡丢失率差异的代谢组学研究。
研究设计、大小和持续时间：这项前瞻性研究在 186 名具有规律月经周期和自然生育史的育龄妇女中进行，使用 SPSS 中的随机案例选择选项随机选择，来自德黑兰血脂和血糖研究。
参与者/材料、设置、方法：在基线（1999-2001 年）和第五次随访检查（2014-2017 年）时测量 AMH 浓度，中位随访时间为 16 年，使用第二代试剂盒进行免疫测定。通过将 AMH 下降率除以随访时间（每年%）来计算 AMH 的年下降率。根据 AMH 年下降率的三分位数对妇女进行分类。在第二次随访检查周期（2005-2008 年）中收集空腹血清样本进行非靶向代谢组学分析，使用气相色谱-质谱联用。使用单变量和多变量方法相结合的方法来研究代谢物与 AMH 年下降率之间的关系。
在调整基线年龄、AMH 和 BMI 值后，有 29 种代谢物与 AMH 的年下降率呈正相关。与下降速度较慢的（三分位 1）相比，下降速度较快的（三分位 3）妇女的 AMH 年下降率的相对丰度增加了 15 种代谢物。在同时考虑 41 种代谢物时，主成分分析和偏最小二乘判别分析模型并没有明显区分下降速度较慢和较快的妇女。较高的血清磷酸盐、N-乙酰-d-葡萄糖胺、BCAAs、脯氨酸、尿素和焦谷氨酸代谢物与 AMH 快速下降的几率增加有关。与 AMH 快速下降率相关的最重要的途径包括氨基糖和核苷酸糖代谢、BCAAs 代谢和氨酰 tRNA 生物合成。
局限性、谨慎的原因：使用 AMH 的仅两次测量来估计 AMH 的年下降率是该研究的主要限制，该研究假设在研究期间 AMH 呈线性固定减少。由于使用两次测量没有考虑 AMH 下降率的可变性，因此本研究中估计的年下降率可能无法准确显示 AMH 减少的趋势。此外，尽管研究具有纵向性质且对参与者的年龄进行了统计调整，但仍难以区分本研究中观察到的与 AMH 相关的代谢物是否可以加速卵巢衰老，或者它们是否反映了不同的衰老过程。
本研究提出了一些与 AMH 下降率相关的代谢物特征；需要进一步进行具有多次 AMH 测量的前瞻性研究，以证实本研究的发现，并更好地了解卵巢衰老变化背后的分子过程。
研究资金/利益冲突：作为 Ms Nazanin Moslehi 博士论文的一部分，本研究由沙希德贝赫什蒂大学医学科学（10522-4）支持。没有竞争利益。
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