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.

Keywords: ART; endometrial receptivity; estrogens; implantation; infertility; inflammation; pregnancy; steroid hormones.

The impact of method of conception and serum estrogen levels on pregnancy outcome. FGR, fetal growth restriction; E2, estradiol.

Figure 1.

Serum estrogen concentration in women at time of the LH surge in natural conception cycles compared to autologous ART conception and oocyte donation. E2, estradiol; FET, frozen embryo transfer; OD-FET, oocyte-donation FET.

Figure 2.

Studies reporting serum estradiol levels in women on the day of hCG administration in IVF pregnancies. The pregnancies were described as adequate for pregnancy development and progression (green line) or at high risk for pregnancy complications (red line). E2, estradiol.

Figure 3.

Influence of estrogen levels on appropriate placentation and pregnancy progression. The schematic represents crucial determinants of the development of human placental insufficiency diseases and compares the effects of adequate and supraphysiologic E2 levels on vascular remodeling and angiogenesis at the materno-fetal interface. E2, estradiol; VEGF, vascular endothelial growth factor; NO, nitric oxide; uNK, uterine natural killer.

Figure 4.

Synoptic representation of the main effects of estrogens on immune cells, both locally in syncytiotrophoblast/placenta and systemically in the peripheral blood. uNK, uterine natural killer; Treg, T-regulatory lymphocytes.