Fabio Ghezzi

The etiopathogenesis of endometriosis is a multifactorial process resulting in a heterogeneous disease. Considering that endometriosis etiology and pathogenesis are still far from being fully elucidated, the current review aims to offer a comprehensive summary of the available evidence. We performed a narrative review synthesizing the findings of the English literature retrieved from computerized databases from inception to June 2019, using the Medical Subject Headings (MeSH) unique ID term "Endometriosis" (ID:D004715) with "Etiology" (ID:Q000209), "Immunology" (ID:Q000276), "Genetics" (ID:D005823) and "Epigenesis, Genetic" (ID:D044127). Endometriosis may origin from Müllerian or non-Müllerian stem cells including those from the endometrial basal layer, Müllerian remnants, bone marrow, or the peritoneum. The innate ability of endometrial stem cells to regenerate cyclically seems to play a key role, as well as the dysregulated hormonal pathways. The presence of such cells in the peritoneal cavity and what leads to the development of endometriosis is a complex process with a large number of interconnected factors, potentially both inherited and acquired. Genetic predisposition is complex and related to the combined action of several genes with limited influence. The epigenetic mechanisms control many of the processes involved in the immunologic, immunohistochemical, histological, and biological aberrations that characterize the eutopic and ectopic endometrium in affected patients. However, what triggers such alterations is not clear and may be both genetically and epigenetically inherited, or it may be acquired by the particular combination of several elements such as the persistent peritoneal menstrual reflux as well as exogenous factors. The heterogeneity of endometriosis and the different contexts in which it develops suggest that a single etiopathogenetic model is not sufficient to explain its complex pathobiology.

OBJECTIVE: To determine whether there is a relationship between the presence of histological signs of inflammation in the extraplacental membranes and umbilical cord and the concentrations of fetal plasma interleukin-6 (IL-6). METHODS: The study examined a cohort of patients who were admitted with preterm labor or preterm premature rupture of the membranes (PROM) and who underwent cordocentesis. Inclusion criteria included fetal plasma available for IL-6 determination, histological examination of the umbilical cord and placenta, and delivery within 48 h of the procedure. This last criterion was used to preserve a meaningful temporal relationship between fetal plasma IL-6 and the results of histological examination of the placenta. Fetal plasma IL-6 was determined by a high sensitivity ELISA. Forty-five patients were available for study: 18 patients had preterm labor with intact membranes and 27 had preterm PROM. RESULTS: The incidence of funisitis was 44.4% (20/45): 27.8% (5/18) in patients with preterm labor and intact membranes and 55.6% (15/27) in patients with preterm PROM. The median values of fetal plasma IL-6 in patients with funisitis, chorioamnionitis without funisitis, and non-inflamed membranes were 51.4, 18.4 and 5.2 pg/ml, respectively. After log transformation of the fetal plasma IL-6 concentration, the means differed significantly from each other (ANOVA, p < 0.02). There was no difference in log fetal plasma IL-6 concentration between patients with funisitis and those with chorioamnionitis without funisitis. The difference in mean concentration of log fetal plasma IL-6 between patients with funisitis or chorionic vasculitis and those without inflammation was highly significant (post-hoc test, p = 0.01 and p < 0.01, respectively). Fetuses with fetal plasma IL-6 > 11 pg/ml had a significantly higher rate of histological signs of inflammation in the extra-placental membranes and umbilical cord than those with fetal plasma IL-6 < 11 pg/ml (funisitis: 55.6% (15/27) vs. 27.8% (5/18), p < 0.05; chorionic vasculitis: 55.6% (15/27) vs. 12.5% (2/16), p < 0.01; chorioamnionitis only: 25.9% (7/27) vs. 16.7% (3/18), p < 0.05; no inflammation: 18.5% (5/27) vs. 55.6% (10/18), p < 0.05, respectively). Fetuses with funisitis had significantly higher rates of clinical and histological chorioamnionitis, and neonatal infectious morbidity (proven + suspected sepsis) than fetuses without funisitis (40% (8/20) vs. 8% (2/25), 90% (18/20) vs. 36% (9/25), and 40% (8/20) vs. 4% (1/25), respectively; p < 0.01 for each). Fetuses with chorionic vasculitis had significantly higher rates of clinical and histological chorioamnionitis as well as neonatal infectious morbidity (proven + suspected sepsis) than fetuses without chorionic vasculitis (100% (17/17) vs. 42.3% (11/26), p < 0.01; 82.4% (14/17) vs. 50.0% (13/26), p = 0.05; and 41.2% (7/17) vs. 7.7% (2/26), p = 0.01). CONCLUSION: Fetal plasma IL-6 concentration is significantly associated with the presence of inflammatory lesions in the extraplacental membranes and umbilical cord. Fetuses with fetal plasma IL-6 > 11 pg/ml had a significantly higher rate of funisitis and/or chorionic vasculitis than fetuses with fetal plasma IL-6 < 11 pg/ml. These findings suggest that funisitis/chorionic vasculitis is the histological manifestation of the fetal inflammatory response syndrome.