Evidence for Corpus Luteal and Endometrial Origins of Adverse Pregnancy Outcomes in Women Conceiving with or Without Assisted Reproduction

Abstract

Preeclampsia may arise from impaired decidualization in some women. Transcriptomics of mid-secretory biopsy endometrial stromal cells decidualized in vitro and of early gestation choriodecidua from women who experienced preeclampsia with severe features overlapped significantly with the classical endometrial disorders giving rise to the concept of "endometrium spectrum disorders". That is, recurrent implantation failure and miscarriage, endometriosis, normotensive intrauterine growth restriction, preeclampsia and preterm birth may all lie on a continuum of decidual dysregulation, in which phenotypic expression is determined by the specific molecular pathway(s) disrupted and severity of disruption. Women conceiving by programmed IVF protocols showed widespread dysregulation of cardiovascular function and increased rates of adverse pregnancy outcomes including preeclampsia. Programmed cycles preclude development of a corpus luteum (CL), a major regulator of endometrial function. Lack of circulating CL product(s) that are not replaced in programmed cycles (eg, relaxin) could adversely impact the maternal cardiovascular system directly and/or compromise decidualization, thereby increasing preeclampsia risk.

Keywords: Autologous frozen embryo transfer; Decidua; Endometrium spectrum disorders; In vitro fertilization; Preeclampsia; Relaxin; Trophoblast.

Figure 1.. Aberrant decidualization in the late secretory phase and during early pregnancy may play a role in the development of preeclampsia for some women.

See refs.^, for details. From Conrad KP, Rabaglino MB, Post Uiterweer ED. Emerging role for dysregulated decidualization in the genesis of preeclampsia. Placenta 2017;60:125; with permission.

Figure 2.. Principal component analysis of genes belonging to the cytokine-cytokine receptor interaction pathway.

Principal component plots show that normal endometrial samples obtained from healthy women (shades of green, n=36), decidual tissues obtained post-delivery from women with preeclampsia (shades of pink, n=8) and normal pregnancies (shades of yellow n=8) formed a distinct cluster. Endometrial samples from women with pathologic endometrium (shades of red, n=25) and samples from non-decidualized endometrium (nonDEC) or proliferative endometrium (PrE; shades of blue, n=9) formed another distinct cluster. The analysis was applied to 264 genes belonging to the cytokine-cytokine receptor interaction pathway. LSE: late-secretory endometrium. DEC: ~9 week gestational endometrium with confluent decidualization. FC: mid-secretory endometrium from fertile controls. ESCs: endometrial stromal cells isolated from mid-secretory biopsies of healthy women, cultured, and decidualized in vitro. PE-and NP-CVS: chorionic villous samples obtained from women ~11.5 gestational weeks who developed preeclampsia with severe features or experienced normal pregnancy. PE- and NP-DEC: mid-secretory endometrial biopsies obtained from women between 1 and 5 years after a pregnancy either complicated by PE with severe features or an uncomplicated pregnancy. Endometrial stromal cells were subsequently isolated, cultured and decidualized in-vitro. PE-and NP-DB: decidual tissue obtained by placental bed biopsy after cesarean section. PE- and NP-BP: decidual tissue harvested from the basal plate of delivered placentas. IF: secretory endometrium from women with recurrent implantation failure. RM: secretory endometrium from women with recurrent miscarriage. OSIS: endometrial stromal cells isolated from ovarian endometriomas, cultured and decidualized in vitro. From Rabaglino MB, Conrad KP. Evidence for shared molecular pathways of dysregulated decidualization in preeclampsia and endometrial disorders revealed by microarray data integration. FASEB J. 2019 Nov;33(11):11682–11695; with permission.

Figure 3.. Endometrium spectrum disorders.

A significant number of differentially expressed genes that were either up- or downregulated in chorionic villous samples from women who experienced preeclampsia with severe features compared to normal pregnancy demonstrated overlap with, and the same directional change as differentially expressed genes in recurrent implantation failure (RIF), recurrent miscarriage (RM) and endometriosis (OSIS) relative to their respective control tissues. Similarly, a significant number of differentially expressed genes that were either up- or downregulated in cultured endometrial stromal cells decidualized in vitro derived from mid-secretory biopsies of women who experienced severe preeclampsia compared to normal pregnancy demonstrated overlap with, and the same directional change as differentially expressed genes in recurrent implantation failure (RIF), recurrent miscarriage (RM) and endometriosis (OSIS) compared to their respective control tissues. These findings gave rise to the notion of endometrium spectrum disorders, in which disease phenotype may be determined in part by which endometrial molecular pathways are disrupted and the severity of the disruption.