Hormonal imbalance in umbilical vein cord blood of pregnant women with endometriosis: a propensity score-matched analysis

Background: Pregnancy involves a fine-tuned hormonal interplay between the fetus, placenta, and mother, which shapes long-term developmental outcomes. Endometriosis has been hypothesized to originate in utero due to altered fetal exposure to sex steroids. This study investigates differences in umbilical cord estradiol and androgen levels in female fetuses born to women with and without endometriosis, exploring a potential role of altered in utero hormone exposure in the intergenerational transmission of endometriosis risk. Methods: This is a case-control study nested within a cohort of women delivering singleton females at our institution between June 2022 and June 2023. Cases were women with endometriosis (diagnosed via imaging or surgery before pregnancy) and controls were women without endometriosis. Analyses were performed before and after propensity-score matching (PSM) at a 1:3 ratio to control for maternal age, gestational age, and delivery mode. Umbilical cord blood was collected at delivery, and hormonal levels of corticosteroids, progestins, androgens, and estradiol (E2) were measured using liquid chromatography-tandem mass spectrometry. Estradiol-to-androgens ratios were calculated, with 95% confidence intervals (CIs) determined using the bootstrapping method. Results: The total cohort included 160 women, 17 (10.6%) of whom had endometriosis. After 1:3 matching, 51 controls without endometriosis were included. Women with endometriosis had higher E2 levels compared to controls, both before PSM (6.8 [4.3–9.1] mcg/L vs. 3.6 [1.4–8.6] mcg/L, p = 0.03) and after PSM (2.4 [1.1–6.6] mcg/L, p = 0.002). Estradiol-to-androgens ratios indicated a higher-estrogen and lower-androgens hormonal status in endometriosis, with higher E2-to-testosterone (p < 0.001), E2-to-androstenedione (p = 0.001), E2-to-dehydroepiandrosterone (DHEA) (p < 0.001), and E2-to-DHEA sulfate (DHEAS) ratios (p < 0.001) compared to controls. After PSM, the E2-to-testosterone, E2-to-androstenedione, E2-to-DHEA, and E2-to-DHEAS ratios were 4.38 (95% CI: 2.28–6.49), 3.28 (95% CI: 1.29–5.28), 2.52 (95% CI: 1.32–3.72), and 4.57 (95% CI: 1.86–7.27) times higher, respectively. Conclusions: This is the first study showing that female newborns of women with endometriosis are exposed to higher in utero estradiol compared to controls. This high estrogen low androgens environment may influence fetal programming of reproductive traits and might drive the in utero susceptibility to endometriosis.