Is neonatal uterine bleeding responsible for early-onset endometriosis?

Abstract

Background It has been hypothesized that the origin of early-onset endometriosis could be from endometrial mesenchymal stem cells (eMSCs) in neonatal uterine blood (NUB). There is no information on the possible mechanistic basis linking an association between NUB/neonatal endometrium and development of early-onset endometriosis. In this study we performed a series of experiments to clarify the mechanistic link between NUB and/or neonatal endometrium and development of early-onset endometriosis. Methods We retrospectively collected postmortem neonatal endometria (n = 15) and prospectively collected NUB (n = 18) of female babies for the analysis of different biological markers including eMSCs. Immunohistochemical analysis of neonatal endometria was performed to examine the expression patterns of ovarian steroid receptors (ER/PGR), decidualization (prolactin, IGFBP1), pre-decidualization (Glycodelin A, α-SMA), proliferation (Ki-67 index), vascularity (CD31 + cells), immunocompetent CD68+, CD45+, CD56 + cells and some putative markers of eMSCs. Cell transfer method and immunocytochemistry were used to investigate the eMSCs and/or endometrial cells in NUB. Results Immunohistochemical analysis of postmortem neonatal endometria revealed variable staining response to ER/PGR, decidual markers, and substantial proliferative and angiogenic activity. A moderate to strong immunoexpression of Glycodelin-A was found in both neonatal and adult endometria. The tissue infiltration of CD56+, CD45 + and CD68 + immunocompetent cells was significantly low in neonatal endometria than that in adult endometria (p = 0.0003, p < 0.0001, p = 0.034, respectively). No eMSCs or even endometrial cells were detected in NUB. However, a variable expression of some phenotypes of eMSCs (CD90/CD105) was found in neonatal endometria. Conclusions Based on our serial experiments we did not find any supporting evidence for the role of NUB in early-onset endometriosis. Neonatal endometria showed variable expression of ovarian steroid receptors, decidualization, and a substantial amount of proliferative and angiogenic activity. As an alternative mechanism, a significantly less tissue accumulation of immunocompetent cells in neonatal endometria may explain the survival of ER + and PGR + cells should they make entry into the pelvis and consequent development of early endometriosis with the onset of ovarian function. Future study with large sample size and application of modified technological tools is warranted to test the NUB hypothesis and to clarify their biological or clinical significance. Trial registration not applicable.

Is Neonatal Uterine Bleeding Involved in Early-Onset Endometriosis?

“…Another reason for caution in relation to the conclusions drawn by Ogawa et al [52] is the finding of variable expression of some phenotypes of eMSCs. The presence of stem cells in neonatal endometrium supports the hypothesis first put forward by Gargett et al [10] "that stem/progenitor cells present in shedding endometrium may have a role in the pathogenesis of early-onset endometriosis through retrograde neonatal uterine bleeding".…”

“…In a recent study, Ogawa et al [52] set out to evaluate the hypothesis that NUB is responsible for EOE. The study examined neonatal endometria (n = 15) obtained postmortem and blood collected from diapers from neonates with NUB (n = 18).…”

“…Standardization of MenSC isolation protocols and culture conditions are challenging, but most have relied on collection of a volume of menstrual blood using a cup device. The technique adopted by Ogawa et al [52] relied on the extraction of blood and menstrual debris from diapers, and can be affected by factors such as time, contamination, cell adhesion to the diapers, and cell viability. The tiny volume of biological material obtained was then subjected to pelleting, cell transfer, further fractionation, and processing through immunohistochemistry without antigen retrieval.…”

“…Study of postmortem uteri has long been hampered by the difficulty of obtaining suitable tissue for study. Ogawa et al [52] collected 15 samples from fetuses/neonates ranging between 27-40 weeks' gestation who died 0-32 days after birth. The timing from death to tissue harvesting is critical to the quality of the material used for the study, but routine autopsy can take several hours, if not days, resulting in autolysis.…”

“…Importantly, over a century ago, Halban [56] observed the presence of endometrial breakdown and microscopic blood extravasation in 8 out of 21 neonatal uteri examined at autopsy. Given the observation by Ogawa et al [52], endometrial debris remain to be accounted for. Proving or disproving the hypothesis that NUB has a role in the genesis of EOE requires the presence, rare as it may be, of endometrial shedding after birth, i.e., that the endometrium refluxes, implants, and remains dormant in the peritoneal cavity till stimulated.…”