Servy Institute of Reproductive Endocrinology, 812 Chafee Avenue, Augusta, GA, 30904, USA.
Cabinet d endocrinologie, 40 Bd de Courcelles, 75017, Paris, France.
J Assist Reprod Genet. 2018 Aug;35(8):1431-1435. doi: 10.1007/s10815-018-1225-2. Epub 2018 Jun 7.
To evaluate the possibility of correcting metabolic defects in gametes and embryos due to methylene tetra hydrofolate reductase (MTHFR) isoforms C677T and A1298C, by supplementation with 5-methyl THF instead of synthetic folic acid. In these couples, high doses of folic acid lead to UMFA (un-metabolized folic acid) syndrome.
Thirty couples with fertility problems lasting for at least 4 years, such as recurrent fetal loss, premature ovarian insufficiency, or abnormal sperm parameters, with two thirds of them having failed assisted reproductive technology (ART) attempts were included in this program. For all couples, at least one of the partners was a carrier of one of the two main MTHFR isoforms. Most of the women had been previously treated unsuccessfully with high doses of folic acid (5 mg/day), according to what is currently proposed in the literature. The couples carrying one of the isoforms were treated for 4 months with 5-MTHF, at a dose of 600 micrograms per day, before attempting conception or starting another attempt at ART. The duration of treatment corresponding to an entire cycle of spermatogenesis is approximately 74 days.
In this first series of 33 couples, one couple was not followed-up, and two are still currently under treatment. No adverse effects were observed. Thirteen of the couples conceived spontaneously, the rest needing ART treatment in order to achieve pregnancy. Only three couples have, so far, not succeeded.
The conventional use of large doses of folic acid (5 mg/day) has become obsolete. Regular doses of folic acid (100-200 μg) can be tolerated in the general population but should be abandoned in the presence of MTHFR mutations, as the biochemical/genetic background of the patient precludes a correct supply of 5-MTHF, the active compound. A physiological dose of 5-MTHF (800 μg) bypasses the MTHFR block and is suggested to be an effective treatment for these couples. Moreover, it avoids potential adverse effects of the UMFA syndrome, which is suspected of causing immune dysfunction and other adverse pathological effects such as cancer (especially colorectal and prostate).
评估通过补充 5-甲基四氢叶酸（5-MTHF）而非合成叶酸来纠正亚甲基四氢叶酸还原酶（MTHFR）同工型 C677T 和 A1298C 引起的配子和胚胎代谢缺陷的可能性。在这些夫妇中，高剂量叶酸会导致未代谢叶酸（UMFA）综合征。
30 对患有生育问题的夫妇，包括复发性胎儿丢失、卵巢早衰或精子参数异常，其中三分之二的夫妇曾尝试过辅助生殖技术（ART）但失败，纳入本研究。对于所有夫妇，至少有一方是两种主要 MTHFR 同工型之一的携带者。大多数女性之前曾根据文献建议接受过高剂量叶酸（5mg/天）治疗，但效果不佳。携带其中一种同工型的夫妇在尝试受孕或开始另一次 ART 尝试前，接受了 4 个月的 5-MTHF 治疗，剂量为每天 600 微克。治疗持续时间大约相当于整个精子发生周期的 74 天。
在这一系列的 33 对夫妇中，有一对未随访，还有两对仍在治疗中。未观察到不良反应。13 对夫妇自然受孕，其余夫妇需要接受 ART 治疗才能怀孕。迄今为止，只有三对夫妇尚未成功。
常规使用大剂量叶酸（5mg/天）已不再适用。普通人群可以耐受常规剂量的叶酸（100-200μg），但在存在 MTHFR 突变的情况下应避免使用，因为患者的生化/遗传背景排除了正确供应 5-MTHF（活性化合物）的可能性。生理剂量的 5-MTHF（800μg）绕过 MTHFR 阻断，被建议作为这些夫妇的有效治疗方法。此外，它避免了 UMFA 综合征的潜在不良反应，UMFA 综合征被怀疑会引起免疫功能障碍和其他不良病理效应，如癌症（特别是结直肠癌和前列腺癌）。
