Reply: Artificial cycle ‘per se’ or the specific protocol of endometrial preparation as responsible for obstetric complications of frozen cycle?
Reply: Artificial cycle ‘per se’ or the specific protocol of endometrial preparation as responsible for obstetric complications of frozen cycle?
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回复：人工周期“本身”还是子宫内膜准备的具体方案导致冷冻周期产科并发症？
DOI：
10.1093/humrep/dez221
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发表时间：
2019
影响因子：
6.1
通讯作者：
Irahara M and Saito H.
中科院分区：
文献类型：
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作者：
Saito K;Kuwahara A;Ishikawa T;Morisaki N;Miyado M;Miyado K;Fukami M;Miyasaka N;Ishihara O;Irahara M and Saito H.
先生，我们感谢Manno等人。S对我们最近的手稿感兴趣(Saito等人，2019年)。我们普遍同意他们对我们研究局限性的评估，即人工周期(AC)方案在接受AC-冷冻-解冻胚胎移植(FET)的患者中有所不同。我们也同意，这些激素差异会影响妊娠结局和产科并发症的风险。在这方面，我们的研究是基于国家登记，没有关于每个病例的详细治疗方案的数据。先前的几项研究表明，激素药物给药途径和剂量的不同会影响FET后的妊娠率(Casper和Yanushpolsky，2016)。因此，我们的研究结果表明，AC-FET与自然周期(NC)-FET相比，妊娠结局不同，妊娠率和活产率较低，自然流产率较高，这在一定程度上可能是由于方案不佳所致。虽然AC的最优方案尚未确定，但对每种AC方案进行比较将有助于澄清哪种方案是最有效的。然而，关于NC和AC之间的比较，我们不相信Manno等人提出的注射孕酮的AC会产生有信息的结果，因为NC有完整的黄体和AC没有内源性孕酮产生是不同的环境。考虑到孕酮的全身和局部效应，阴道孕酮与注射或口服药物相结合可能是一种更好的选择，因为这种方法使血液和局部孕酮水平更接近于NC。关于黄体酮的剂量，我们同意AC周期比NC周期需要更多的激素支持来补偿黄体的缺失。而曼诺等人。主要讨论孕酮补充，我们想强调雌激素与妊娠期高血压疾病(HDP)的重要性。先前的一项研究报告称，黄体期补充雌激素可改善FET周期的妊娠结局(Tonguc等人，2011年)。然而，在怀孕早期，黄体酮是治疗的重点，这可能是因为观察到，怀孕早期的黄体切除会导致流产，而单靠黄体酮替代就可以防止这种流产(Csao等人，1973)。因此，孕酮在AC-FET后的早期妊娠中被认为是必需的，因为黄体不存在。相反，黄体中的雌激素被认为是维持妊娠所必需的。然而，积累的证据表明，低水平的雌激素与HDP有关，可能是通过改变胎盘血管生成和子宫动脉血管扩张(Berkane等人，2017年)。虽然雌激素对维持妊娠可能是可有可无的，但对于胎盘的健康发育和避免HDP可能是必不可少的。值得注意的是，黄体-胎盘转换通常发生在妊娠6至8周之间，在此之前，黄体是雌二醇的唯一来源(Tal等，2000)。此外，胎盘缺乏细胞色素P17A1(17α羟基酶和17，20裂解酶)，这是一种将孕酮代谢为17-羟孕酮和雄烯二酮的酶，这是雌激素的前体(Tal等人，2000年)。因此，胎盘本身不能产生雌激素(Tal等人，2000年)。换句话说，如果没有黄体，补充黄体酮可能不能在AC-FET后的妊娠早期提供足够的雌激素。因此，雌激素的替代成为…
Sir, We appreciate Manno et al.’s interest in our recent manuscript (Saito et al., 2019). We are in general agreement with their assessment of the limitation of our study that the artificial cycle (AC) protocol varied among patients who underwent AC-frozen-thawed embryo transfer (FET). We also agree that these hormonal differences affect pregnancy outcomes and risk of obstetrical complications. In this regard, our study was based on the national registry, and data about detailed treatment protocols in each case were not available. Several previous studies have suggested that differences in administration route and dosage of hormonal agents affect pregnancy rates after FET (Casper and Yanushpolsky, 2016). Therefore, the results from our study indicating differences in pregnancy outcomes, lower rates of pregnancy and live births and a higher rate of spontaneous abortion among patients after AC-FET compared with those after natural cycle (NC)-FET are possibly due to suboptimal protocols to some extent. While the most optimal protocol of AC has not been determined, comparison between each AC protocol will be beneficial in clarifying which protocol is most effective. However, regarding the comparison between NC and AC, we are unconvinced that AC with progesterone injections, as suggested by Manno et al., would yield informative results because NC with an intact corpus luteum and AC without endogenous progesterone production are different milieu. Considering the systematic and local effects of progesterone, a combination of vaginal progesterone with injected or oral agents might be a better alternative because this method brings blood and local levels of progesterone closer to those in NC. Concerning the dose of progesterone, we agree that more hormonal support is required in AC than in NC cycles to compensate for the absence of the corpus luteum. While Manno et al. mainly discussed progesterone supplementation, we would like to highlight the significance of estrogen in association with hypertensive disorders of pregnancy (HDP). A previous study reported that estrogen supplementation during the luteal phase improved pregnancy outcomes in FET cycles (Tonguc et al., 2011). However, during early pregnancy, progesterone is the focus of treatment, likely due to observations that luteectomy in early pregnancy caused abortion and progesterone replacement alone prevented this abortion (Csapo et al., 1973). Consequently, progesterone is assumed to be essential during early pregnancy after AC-FET because no corpus luteum exists. In contrast, estrogen from the corpus luteum was presumed to be dispensable for maintenance of pregnancy. However, accumulated evidence has shown that low levels of estrogen are associated with HDP, potentially through altered placental angiogenesis and uterine artery vasodilation (Berkane et al., 2017). While estrogen might be dispensable for maintenance of pregnancy, it is likely essential for robust development of the placenta and avoiding HDP. Notably, until the luteal–placental shift, which typically occurs between 6 and 8 weeks of gestation, the corpus luteum is the exclusive source of estradiol (Tal et al., 2000). In addition, the placenta lacks CYP17A1 (17α-hydroxylase and 17, 20-lyase), an enzyme that metabolizes progesterone into 17-hydroxy progesterone and androstenedione, which are precursors of estrogen (Tal et al., 2000). Accordingly, the placenta is not able to produce estrogen by itself (Tal et al., 2000). In other words, without the corpus luteum, a progesterone supplement may not provide sufficient estrogen in early pregnancy after AC-FET. Therefore, replacement of estrogen as …