{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T13:53:03Z","timestamp":1791208383264,"version":"4.1.0"},"reference-count":228,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2023,6,24]],"date-time":"2023-06-24T00:00:00Z","timestamp":1687564800000},"content-version":"vor","delay-in-days":1,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,11,2]]},"abstract":"Abstract<\/jats:title>\n \n BACKGROUND<\/jats:title>\n 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.<\/jats:p>\n <\/jats:sec>\n \n OBJECTIVE AND RATIONALE<\/jats:title>\n 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.<\/jats:p>\n <\/jats:sec>\n \n SEARCH METHODS<\/jats:title>\n Data for this narrative review were independently identified by seven researchers on Pubmed and Embase databases. The following keywords were selected: \u2018estrogens\u2019 OR \u2018estrogen level(s)\u2019 OR \u2018serum estradiol\u2019 OR \u2018estradiol\/estrogen concentration\u2019, AND \u2018early pregnancy\u2019 OR \u2018first trimester of pregnancy\u2019 OR \u2018preconceptional period\u2019 OR \u2018ART\u2019 OR \u2018In Vitro Fertilization (IVF)\u2019 OR \u2018Embryo Transfer\u2019 OR \u2018Frozen Embryo Transfer\u2019 OR \u2018oocyte donation\u2019 OR \u2018egg donation\u2019 OR \u2018miscarriage\u2019 OR \u2018pregnancy outcome\u2019 OR \u2018endometrium\u2019.<\/jats:p>\n <\/jats:sec>\n \n OUTCOMES<\/jats:title>\n During the periconceptional period (defined here as the critical time window starting 1\u2009month 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\u2014and 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.<\/jats:p>\n <\/jats:sec>\n \n WIDER IMPLICATIONS<\/jats:title>\n 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.<\/jats:p>\n <\/jats:sec>","DOI":"10.1093\/humupd\/dmad016","type":"journal-article","created":{"date-parts":[[2023,6,24]],"date-time":"2023-06-24T23:17:27Z","timestamp":1687648647000},"page":"699-720","source":"Crossref","is-referenced-by-count":131,"title":["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"],"prefix":"10.1093","volume":"29","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2017-7869","authenticated-orcid":false,"given":"F","family":"Parisi","sequence":"first","affiliation":[{"name":"Department of Woman, Mother and Neonate, \u2018V. Buzzi\u2019 Children Hospital, ASST Fatebenefratelli Sacco , Milan, via L. 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Castelvetro 32, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0424-6035","authenticated-orcid":false,"given":"C","family":"Scaccabarozzi","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Clinical Sciences, \u201cL.Sacco\u201d Hospital, University of Milan , Milan, via G.B. Grassi 74, Milan 20157, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3671-4235","authenticated-orcid":false,"given":"M","family":"Biasin","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Clinical Sciences, \u201cL.Sacco\u201d Hospital, University of Milan , Milan, via G.B. 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