L26/P-324 Investigating the effect of oxytocin on the inner and outer layers of the pregnant and non-pregnant human myometrium

Abstract Study question Do uterotonics have different effects on the inner (IM) and outer (OM) layers of the human pregnant and non-pregnant myometrium? Summary answer Oxytocin dose-dependently augments contractions in the IM and OM of the pregnant and non-pregnant uterus, but a greater uterotonic effect is observed in the OM. What is known already Myometrial contractions serve several physiological functions including fertilisation, menstruation, and labour. Aberrant contractions have been linked to benign gynaecological disorders such as adenomyosis as well as obstetric complications including pre-term birth. The myometrium consists of three layers: the sub-endometrial IM, sub-serosal OM, and middle myometrium. Despite animal studies suggesting distinct contractile properties and physiological functions of the IM and OM, equivalent functional characterisation in humans is lacking. A better understanding of regional differences in contractions of the human myometrium, and their regulation, would support the development of novel targeted treatments for benign gynaecological disease as well as dysfunctional labour. Study design, size, duration Myometrial samples were collected from term-pregnant women undergoing elective caesarean section (n = 10) and non-pregnant women (n = 5) undergoing hysterectomy for benign gynaecological conditions at Liverpool Women’s Hospital with informed, written consent. Participants/materials, setting, methods Paired myometrial strips (5x2x1mm) were dissected from the inner and outer third myometrial layers and mounted in organ baths to record isometric tension. The contractile response of the IM and OM to increasing concentrations of oxytocin (10-10M-10-6M) were recorded. Change in contraction amplitude (mN), mean integral of force (MIF, a.u), frequency (contractions/hour), and duration (min) were assessed relative to spontaneous contractions (taken as 100%). Concentration-response curves determined Emax and OM and IM responses were compared. Main results and the role of chance Oxytocin augmented amplitude and MIF of contractions in the pregnant IM and OM in a concentration-dependent manner. Amplitude Emax was greater in the OM (256% of control, standard error (SE) 39.6) than the IM (163% of control SE 15.4) although not reaching significance (p=0.06). No significant difference (p=1.00) in MIF Emax was identified between OM (322% of control SE 51.0) and IM (328% of control SE 45.2). A dose-dependent reduction in contraction frequency and prolonged duration was observed in both layers, with no regional difference noted. Pilot investigation of the non-pregnant myometrium (IM; n = 2, OM; n = 4) demonstrated a stimulatory effect of oxytocin on contraction amplitude and MIF in both regions. The uterotonic effect in the non-pregnant uterus was reduced compared to both regions in the pregnant myometrium. But, similarly to pregnant, a trend toward increased amplitude in the non-pregnant OM was observed. An increased response to oxytocin in the pregnant myometrium and greater uterotonic effect in the OM supports the proposed role of the OM in facilitating the powerful contractions at labour. The same layer-specific sensitivity to OT in the non-pregnant uterus may indicate regional differences in receptor expression that are present even in the non-pregnant state. Limitations, reasons for caution Current findings are preliminary and ongoing, and limited to a single uterotonic. Investigating contractile response to steroid hormones and other known pharmacological modulators of contraction are warranted. Wider implications of the findings These findings highlight potential important differences between the IM and OM, supporting their distinct physiological roles in the pregnant and non-pregnant uterus. By delineating regional differences in contractile behaviour, we can begin to unravel the pathophysiological mechanisms, and guide treatment of conditions including adenomyosis, as well as improve pregnancy outcomes. Trial registration number No