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：从围孕期到妊娠头三个月末妊娠结局的分子机制和临床意义

背景技术雌激素调节不同的女性生理过程，从而确保生殖。雌激素水平和信号的改变与妊娠失败和并发症（包括高血压和低出生体重婴儿）的风险增加有关。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。目的和基本原理本综述旨在总结关于母体雌激素在围孕期和自然受孕妊娠前三个月以及辅助生殖技术后的作用的现有证据。详细的分子机制和相关的临床影响得到了广泛的描述。搜索方法 本叙述性综述的数据由七名研究人员在 Pubmed 和 Embase 数据库中独立确定。选择以下关键词：“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“怀孕早期”或“怀孕头三个月”或“受孕前期”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“妊娠结果”或“子宫内膜”。结果 在围孕期（这里定义为从受孕前 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发挥着至关重要的作用。这一时期雌激素环境的失调似乎对自然妊娠和人工受孕都是有害的。低雌激素水平与自然妊娠的非受孕周期有关。另一方面，LH 峰值时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。在妊娠早期，雌激素主要通过调节血管生成因子的表达在胎盘形成中发挥重要作用，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展中发挥重要作用。较低的雌激素水平被认为会引发自然受孕妊娠中的胎盘异常，而雌激素过多似乎会恶化妊娠发育和结果。更广泛的影响 目前大多数现有证据都支持围孕期和妊娠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率的最佳浓度范围。然而，雌激素如何与其他因素合作以维持对发育中胎儿的局部耐受性和对病原体的免疫反应之间的良好平衡仍然难以捉摸。进一步的研究非常有必要，旨在确定雌激素反应的决定因素和 ART 中个性化雌激素给药方案的生物标志物。