211 - Limited contribution of sex and sex hormones to regulation of the mouse ductus arteriosus (DA) and human PDA

Poster Number: 211
Publication Number: 211.220

Naoko H. Boatwright, Vanderbilt University Medical Center, Nashville, TN, United States; Claire Sorenson, Monroe Carell Jr. Children's Hospital at Vanderbilt, Nashville, TN, United States; Shani Israel, Monroe Carell Jr. Children's Hospital at Vanderbilt, Bellaire, TX, United States; Michael T. Yarboro, Vanderbilt University, Nashville, TN, United States; Rachel Su, Monroe Carell Jr. Children's Hospital at Vanderbilt, Tampa, FL, United States; Chelsea D. Tolentino, University of Cincinnati College of Medicine, Ewa Beach, HI, United States; Bibhash C. Paria, Vanderbilt University School of Medicine, Brentwood, TN, United States; Reese H. Clark, MEDNAX, Myrtle Beach, SC, United States; Elaine L. Shelton, Vanderbilt University Medical Center, Nashville, TN, United States; Jeff Reese, Vanderbilt University Medical Center, Nashville, TN, United States

Background: Preterm males have greater risks for multiple neonatal morbidities. Patent ductus arteriosus (PDA) is felt to be more common in male than female preterm infants, however only limited evidence for this supposition exists. The pregnancy hormones estrogen (E2) and progesterone (P4) have vasoactive properties and shift in predominance as birth approaches, suggesting potential effects on DA patency.

Objective: We hypothesized that: 1) E2 and P4 signaling affects DA tone, 2) male and female DAs respond differently to vasoactive stimuli, and 3) male-female PDA ratios are different between early- and late-preterm infants.      

Design/Methods: E2 and P4 receptor expression in the mouse DA was examined by RT-PCR. The effects of E2, P4, and vasoconstrictors/dilators on term (e18.5) and preterm (e16.5) fetal DAs were studied by ex vivo pressure myography. Published PDA RCTs were re-examined for male-female dimorphism. Data from the Pediatrix clinical data warehouse (CDW) were examined to determine if any report of a PDA occurred more often in male compared to female infants. Data were analyzed by t-test, ANOVA, and multivariate logistic regression as appropriate.      

Results: Membrane P4 receptors (Pgrmc1, 2) were more highly expressed than nuclear receptors (Pgr or Esr1, 2); Esr1 was greater in female DAs. E2 induced minor DA relaxation (6%) that was not inhibited by ICI 182,780 (ESR antagonist); P4 induced modest DA relaxation (28%) that was unaffected by RU486 (PGR antagonist). There was no difference in male and female mouse DA responses to constrictors (O2, KCl, U-46619), dilators (PGE2, SNP, distending pressure) or myogenic tone in term or preterm DAs. Of the 62 most-cited PDA RCTs, most did not report sex, or no sex difference was found (n=13). Among 244,109 inborn, non-anomalous infants in the CDW (2016-2019), the reported rates of any PDA by sex were similar across all gestational ages. When evaluated by gestational groups and corrected for EGA, birth weight, and antenatal steroid exposure, the odds of PDA were higher in females than males for the most immature infants (Figure; 1.4 1.2-1.7, p< 0.0001).Conclusion(s): P4 non-genomic signaling via membrane receptors may contribute to fetal DA relaxation prior to birth. Thus, hormone withdrawal may be a mechanism for postnatal DA constriction, but requires further study. Contrary to expectation, no difference in DA reactivity exists between male and female mouse DAs at term or preterm gestation. Likewise, only limited data support sexual dimorphism in human preterm PDA, with observational evidence that females, not males, are at marginally higher risk.
Gender-specific Adjusted Odds Ratio (Female/Male) For PDA