Local Metabolism of Progesterone Regulates Cervical Remodelling and Timing of Labour Onset

• Main Author: Nadeem, Amna
• Format: Dissertation
• Language: English
• Published: ProQuest Dissertations & Theses 01-01-2023
• Subjects: Biology; Medicine; Obstetrics; Physiology
• ISBN: 9798379769635

Withdrawal of pro-gestational hormone progesterone (P4) is necessary for labour onset in human and rodents. In murine cervix P4 withdrawal is mediated by enzymes 5-alpha-reductase (Srd5a1) and 20-alpha-hydroxysteroid-dehydrogenase (20αHSD/Akr1c18). I hypothesize that 1) inflammation (physiologic or infection-induced) alters the levels of both enzymes in mouse cervix, impacting local P4-metabolism; 2) Selective Progesterone Receptor Modulator (SPRM), Promegestone (aka R5020), non-metabolizable by 20αHSD, can prevent preterm labour (PTL) in mice by maintaining P4 signaling. I found significant induction (p<0.01) of Srd5a1 and Akr1c18 mRNA and protein levels during infectious (Lipopolysaccharide (LPS)-induced) PTL in mice which was inhibited by prophylactic R5020 administration. Transcript levels of cervical ripening enzymes Adamts1 and Has2, as well as pro-inflammatory markers Il1b, Il6, Cxcl1, and Ccl2 were induced during PTL (p<0.05) and inhibited with R5020 pre-treatment (p<0.05). I concluded that prophylactic R5020 administration prevents LPS-induced inflammation and cervical ripening in mice, thus presenting a promising novel therapeutic for women at risk of preterm birth.