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

Abstract

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.

Effect of Estradiol Supplementation on Luteal Support Following a Significant Reduction in Serum Estradiol Levels After hCG Triggering: A Prospective Randomized Controlled Trial

“…Estrogen, like progesterone, is a key hormone that regulates the development of the uterine lining. During the period when implantation of the embryo occurs, estrogens play a crucial role in preparing the uterus to accept the embryo by activating signaling pathways within the uterine lining [2]. Estrogens need to reach a certain level to start the physical and biological changes that make the uterine lining receptive to embryo implantation [9].…”

“…Therefore, optimal concentrations of both estrogen and progesterone are necessary for the adequate maturation of the endometrium before embryo implantation [1] (Lessey and Young, 2014). As estrogen operates through paracrine/autocrine signaling rather than direct regulation, it must reach a certain threshold to initiate morphological and biological changes that favor endometrial receptivity for embryo attachment and implantation maintenance [2]. In assisted reproduction cycles, serum estradiol levels reach their peak during follicular maturation.…”

Low Estradiol Level and Endometrial Thickness on the Day of Endometrial Transformation Influence Clinical Pregnancy After Intrauterine Insemination

“…It would be suggested that the individuals with low E 2 level may have premature menopause, premature ovarian failure, follicle development and other conditions that affect pregnancy. 23 Arzu Yavuz et al showed that lower level of E 2 significantly influenced the clinical pregnancy rate after IUI. 24 Dickey RP et al found that E 2 is associated with birth rate after IUI.…”

Estrogen and Progesterone Receptors Are Dysregulated at the BPH/5 Mouse Preeclamptic-Like Maternal–Fetal Interface

“…This study demonstrates for the first time that estrogen and progesterone receptors are spatially dysregulated pre-pregnancy and during the peri-implantation maternal–fetal interface of a unique model of superimposed preeclampsia, the BPH/5 mouse. Multiple clinical studies suggest lower concentrations of estrogens in the serum and maternal–fetal interface of preeclamptic women during late gestation, albeit conflicting findings have been reported [ 20 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 54 ]. The role of progesterone in preeclampsia is a subject of even greater controversy, with clinical studies pointing to either increased, similar, or decreased circulating levels in late-gestation preeclamptic pregnancies [ 29 , 30 , 32 , 34 , 35 ].…”

“…Nevertheless, studies to date have only investigated estrogen and progesterone receptor expression in third trimester preeclamptic placentas. Hence, such investigations neglect the dynamic expression pattern of sex hormones and receptors throughout pregnancy, as well as the intricate paracrine signaling between the placenta and adjacent decidua [ 54 ].…”