雌激素在妊娠初期的病理生理作用！

BACKGROUND

背景

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.

雌激素调节女性生理过程，确保生殖（功能）。雌激素水平及其信号通路的改变与妊娠失败和并发症风险增加有关，（这其中）包括高血压疾病和低出生体重婴儿。然而，雌激素在孕前和孕早期的作用仍未得到充分研究。

OBJECTIVE AND RATIONALE

目的和依据

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.

本综述旨在总结有关孕前期和自然受孕和辅助生殖技术后的妊娠早期母体雌激素作用的当前证据。详细描述了分子机制和相关的临床影响。

SEARCH METHODS

搜索方法

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’.

本叙述性综述的数据由Pubmed和Embase数据库上的7名研究人员独立确定。选择了以下关键词：“雌激素”或“雌激素水平(s)“或“血清雌二醇”或“雌二醇/雌激素浓度”，和“早期妊娠”或“妊娠前三个月”或“孕前期”、“辅助生殖技术”或“体外受精（IVF）“胚胎移植”或“冷冻胚胎移植”或“卵母细胞捐赠”或“卵子捐赠”、“流产”或“妊娠结局”或“子宫内膜”。

OUTCOMES

结果

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.

孕前期（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的容受性中起着至关重要的作用。在这个期间，雌激素失调似乎对自然受孕和辅助生殖技术后的妊娠都有害。低雌激素水平与自然妊娠中的非受孕周期相关。另一方面，在LH峰值时过高的超生理雌激素浓度与较低的活产率和更高的妊娠并发症风险相关。在早期妊娠中，雌激素主要通过调节血管生成因子的表达在胎盘形成中起着重要作用，并通过重塑子宫自然杀伤细胞和T辅助细胞的功能来发展免疫耐受的子宫微环境。较低的雌激素水平被认为会触发自然受孕妊娠中的异常胎盘形成，而雌激素过多似乎会加剧妊娠发育和结果的恶化。

WIDER IMPLICATIONS

更广泛的含义

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.

目前大多数现有证据支持孕前和孕早期雌激素水平与妊娠结局有关，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维持对发育中胎儿的局部耐受和对病原体免疫反应之间的微妙平衡仍不清楚。进一步研究确定雌激素反应的决定因素和辅助生殖技术中个性化雌激素给药方案的生物标志物是非常必要的。

参考文献：

F Parisi, C Fenizia, A Introini, A Zavatta, C Scaccabarozzi, M Biasin, V Savasi, The pathophysiological role of estrogens in the initial stages of pregnancy: molecular mechanisms and clinical implications for pregnancy outcome from the periconceptional period to end of the first trimester, Human Reproduction Update, Volume 29, Issue 6, November-December 2023, Pages 699–720, https://doi.org/10.1093/humupd/dmad016