BACKGROUND Estrogens regulate disparate female physiological processes, thus ensuring reproduction. Altered estrogen levels and signaling have been associated with increased risks of pregnancy failure and complications, including hypertensive disorders and low birthweight babies. However, the role of estrogens in the periconceptional period and early pregnancy is still understudied. OBJECTIVE AND RATIONALE This review aims to summarize the current evidence on the role of maternal estrogens during the periconceptional period and the first trimester of pregnancies conceived naturally and following ART. Detailed molecular mechanisms and related clinical impacts are extensively described. SEARCH METHODS Data for this narrative review were independently identified by seven researchers on Pubmed and Embase databases. The following keywords were selected: ‘estrogens’ OR ‘estrogen level(s)’ OR ‘serum estradiol’ OR ‘estradiol/estrogen concentration’, AND ‘early pregnancy’ OR ‘first trimester of pregnancy’ OR ‘preconceptional period’ OR ‘ART’ OR ‘In Vitro Fertilization (IVF)’ OR ‘Embryo Transfer’ OR ‘Frozen Embryo Transfer’ OR ‘oocyte donation’ OR ‘egg donation’ OR ‘miscarriage’ OR ‘pregnancy outcome’ OR ‘endometrium’. OUTCOMES During the periconceptional period (defined here as the critical time window starting 1 month before conception), estrogens play a crucial role in endometrial receptivity, through the activation of paracrine/autocrine signaling. A derailed estrogenic milieu within this period seems to be detrimental both in natural and ART-conceived pregnancies. Low estrogen levels are associated with non-conception cycles in natural pregnancies. On the other hand, excessive supraphysiologic estrogen concentrations at time of the LH peak correlate with lower live birth rates and higher risks of pregnancy complications. In early pregnancy, estrogen plays a massive role in placentation mainly by modulating angiogenic factor expression—and in the development of an immune-tolerant uterine micro-environment by remodeling the function of uterine natural killer and T-helper cells. Lower estrogen levels are thought to trigger abnormal placentation in naturally conceived pregnancies, whereas an estrogen excess seems to worsen pregnancy development and outcomes. WIDER IMPLICATIONS Most current evidence available endorses a relation between periconceptional and first trimester estrogen levels and pregnancy outcomes, further depicting an optimal concentration range to optimize pregnancy success. However, how estrogens co-operate with other factors in order to maintain a fine balance between local tolerance towards the developing fetus and immune responses to pathogens remains elusive. Further studies are highly warranted, also aiming to identify the determinants of estrogen response and biomarkers for personalized estrogen administration regimens in ART.

中文翻译：

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雌激素在妊娠初期的病理生理作用：从围孕期到妊娠早期结束妊娠结局的分子机制和临床意义


背景 雌激素调节不同的女性生理过程，从而确保繁殖。雌激素水平和信号传导的改变与妊娠失败和并发症的风险增加有关，包括高血压疾病和低出生体重婴儿。然而，雌激素在围孕期和妊娠早期的作用仍未得到充分研究。客观和基本原理 本综述旨在总结目前关于母体雌激素在围孕期和自然受孕和接受ART的妊娠早期作用的证据。详细分子机制和相关临床影响被广泛描述。检索方法 本叙述性综述的数据由 7 名研究人员在 Pubmed 和 Embase 数据库上独立确定。选择了以下关键词：“雌激素”或“雌激素水平”或“血清雌二醇”或“雌二醇/雌激素浓度”，以及“早孕”或“妊娠早期”或“孕前期”或“ART”或“体外受精（IVF）”或“胚胎移植”或“冷冻胚胎移植”或“卵母细胞捐赠”或“卵子捐赠”或“流产”或“妊娠结局”或“子宫内膜”。结果 在围孕期 （此处定义为受孕前 1 个月开始的关键时间窗口），雌激素通过激活旁分泌/自分泌信号，在子宫内膜容受性中起关键作用。在此期间脱轨的雌激素环境似乎对自然妊娠和 ART 受孕都是有害的。低雌激素水平与自然妊娠中的非受孕周期有关。 另一方面，在 LH 高峰期超生理雌激素浓度过高与较低的活产率和较高的妊娠并发症风险相关。在怀孕早期，雌激素主要通过调节血管生成因子表达在胎盘中发挥重要作用，并通过重塑子宫自然杀伤细胞和 T 辅助细胞的功能在免疫耐受子宫微环境的发育中发挥重要作用。在自然受孕中，较低的雌激素水平被认为会引发胎盘异常，而雌激素过量似乎会使妊娠发育和结局恶化。更广泛的意义 目前可用的大多数证据都支持围孕期和孕早期雌激素水平与妊娠结局之间的关系，进一步描述了优化妊娠成功的最佳浓度范围。然而，雌激素如何与其他因素合作，以便在对发育中的胎儿的局部耐受性和对病原体的免疫反应之间保持微妙的平衡仍然难以捉摸。进一步的研究是非常必要的，其目的也是为了确定 ART 中雌激素反应的决定因素和个体化雌激素给药方案的生物标志物。