Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, 6710B Rockledge Drive, MSC 7004, Bethesda, MD 20892, USA.
Department of Epidemiology and Environmental Health, University at Buffalo, 410 Kimball Tower, Buffalo NY 14214, USA.
Hum Reprod. 2017 Aug 1;32(8):1743-1750. doi: 10.1093/humrep/dex233.
How are concentrations of plasma homocysteine and serum folate associated with reproductive hormones and anovulation in regularly menstruating women?
Higher homocysteine was associated with sporadic anovulation and hormonal changes that may be indicative of impaired ovulatory function, but higher serum folate was associated only with higher luteal phase progesterone.
Higher folate levels as well as some variants in genes relevant to one-carbon metabolism, are associated with improved reproductive outcomes and responses to fertility treatment, but only a few small studies have explored the relationship between markers of one-carbon metabolism and menstrual cycle characteristics.
STUDY DESIGN, SIZE, DURATION: The BioCycle Study (2005-2007) is a prospective, longitudinal cohort of 259 regularly menstruating women not using hormonal contraceptives or dietary supplements who were followed for up to two menstrual cycles.
PARTICIPANTS/MATERIALS, SETTING, METHODS: Serum folate and reproductive hormones were measured up to eight times per cycle and plasma homocysteine up to three times. Linear mixed models were used to estimate associations between serum folate or plasma homocysteine and log-transformed reproductive hormone levels while accounting for multiple observations and cycles per woman. Generalized estimating equations were used to examine risk of sporadic anovulation. All models were adjusted for age, race, body mass index, cigarette and alcohol use, and energy and fiber intake.
Higher plasma homocysteine concentrations were associated with lower total estradiol across the cycle (adjusted percent change per unit increase in homocysteine [aPC] -2.3%, 95% CI: -4.2, -0.03), higher follicle stimulating hormone around the time of expected ovulation (aPC 2.4%, 95% CI: 0.2, 4.7) and lower luteal phase progesterone (aPC -6.5%, 95% CI: -11.1, -1.8). Higher serum folate concentrations were associated with higher luteal phase progesterone (aPC per unit increase in folate 1.0%, 95% CI: 0.4, 1.6). Higher homocysteine concentrations at expected ovulation were associated with a 33% increased risk of sporadic anovulation. We observed no risk associated with decreased folate concentrations, but a higher ratio of folate to homocysteine at ovulation was associated with a 10% decreased risk of anovulation.
LIMITATIONS, REASONS FOR CAUTION: Our results are generalizable to healthy women with adequate serum folate levels. The independent influence of homocysteine should be confirmed in larger cohorts and among women with folate deficiency or increased risks of anovulation.
If these findings are confirmed, it is possible that lowering homocysteine with B-vitamins through diet or supplementation could improve ovulatory function in some women.
STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (Contract numbers: HHSN275200403394C, HHSN275201100002I and Task one HHSN27500001). None of the authors has any conflicts of interest to disclose.
血浆同型半胱氨酸和血清叶酸浓度与月经正常的女性生殖激素和排卵障碍有何关联？
较高的同型半胱氨酸与散发性排卵障碍和可能表明排卵功能受损的激素变化有关，但较高的血清叶酸仅与黄体期孕酮水平升高有关。
较高的叶酸水平以及与一碳代谢相关的基因中的某些变体与改善生殖结局和对生育治疗的反应有关，但只有少数小型研究探讨了一碳代谢标志物与月经周期特征之间的关系。
研究设计、大小和持续时间：生物周期研究（2005-2007 年）是一项前瞻性、纵向队列研究，纳入了 259 名未使用激素避孕药或膳食补充剂的月经正常的女性，随访时间长达两个月经周期。
参与者/材料、设置、方法：在每个周期中最多测量 8 次血清叶酸和生殖激素，最多测量 3 次血浆同型半胱氨酸。线性混合模型用于估计血清叶酸或血浆同型半胱氨酸与对数转换的生殖激素水平之间的关联，同时考虑了多个观察值和每个女性的周期数。广义估计方程用于检查散发性排卵障碍的风险。所有模型均调整了年龄、种族、体重指数、吸烟和饮酒以及能量和纤维摄入。
较高的血浆同型半胱氨酸浓度与整个周期中的总雌二醇水平降低有关（单位同型半胱氨酸增加的调整后百分比变化[APC]-2.3%，95%CI：-4.2，-0.03），接近排卵时的卵泡刺激素升高（APC 2.4%，95%CI：0.2，4.7）和黄体期孕酮降低（APC-6.5%，95%CI：-11.1，-1.8）。较高的血清叶酸浓度与黄体期孕酮升高有关（APC 单位叶酸增加 1.0%，95%CI：0.4，1.6）。排卵时同型半胱氨酸浓度升高与散发性排卵障碍的风险增加 33%有关。我们没有观察到与叶酸浓度降低相关的风险，但在排卵时较高的叶酸/同型半胱氨酸比值与排卵障碍风险降低 10%有关。
局限性、谨慎的原因：我们的结果适用于血清叶酸水平充足的健康女性。同型半胱氨酸的独立影响应在更大的队列中并在叶酸缺乏或排卵障碍风险增加的女性中得到证实。
如果这些发现得到证实，那么通过饮食或补充剂降低同型半胱氨酸水平可能会改善一些女性的排卵功能。
研究资金/利益冲突：这项工作得到了美国国立儿童健康与人类发展研究所 Eunice Kennedy Shriver 国家研究所的内部研究计划的支持，美国国立卫生研究院（合同编号：HHSN275200403394C、HHSN275201100002I 和任务一 HHSN27500001）。所有作者均无利益冲突。
