Recovery of Oxytocin Responsiveness in Pregnant Human Myometrial Explants After Oxytocin-Induced Desensitization: an In-vitro Analysis of Oxytocin Receptor Expression and Signaling

NCT02762669 | Terminated

• 1 other identifier: 16-05
• Study Type: interventional
• Target: 4
• Locations: 1 country
• Sites: 1

Brief Summary

Postpartum hemorrhage (PPH) is a leading cause of maternal mortality and morbidity worldwide, and is caused most commonly by poor uterine muscle contraction after delivery of the baby and placenta. The first line agent used in the prevention and treatment of PPH is oxytocin, which acts by binding with the oxytocin receptor (OTR) found on myometrial cells to cause uterine contraction. Oxytocin is also used for the augmentation of labor when spontaneous labor has been deemed ineffective. It is administered intravenously at progressively higher doses, until effective contractions are achieved and vaginal delivery results. However, if augmentation is determined to have failed, a Cesarean delivery (CD) is performed. One of the potential problems with oxytocin use during delivery is that it loses its effectiveness if the uterus has previously been pre-exposed to its high doses and/or for a prolonged duration during labor. This phenomenon is termed OTR desensitization, and can result in the attenuation of myometrial contractility induced by subsequent oxytocin administration, as well as PPH due to poor uterine tone. Furthermore, oxytocin can produce potentially fatal maternal hemodynamic adverse effects when administered at high doses, so it is advantageous to be able to use as low a dose as possible to obtain good uterine muscle tone. The objective of this study is to get a better understanding of the signaling pathways governing desensitization, resensitization and contractility in pregnant human myometrium. The investigators wish to investigate the effects of increasing recovery period on the expression patterns of the OTR and its signaling pathways in desensitized pregnant human myometrium. This study will help shed light on the molecular mechanisms responsible for desensitization and oxytocin-induced myometrial contractility, and will provide some insight into potential therapeutic targets to reduce the incidence of PPH and complications associated with using increasing concentrations of oxytocin. The hypothesis is that the expression and phosphorylation patterns of the OTR and downstream proteins will be altered in desensitized myometrium, and that these patterns will change with increasing rest periods and re-exposure to oxytocin.

Conditions

Postpartum Hemorrhage

Keywords

Uterine contraction; Oxytocin desensitization

Outcome Measures

Primary Outcomes (1)

• Oxytocin receptor (OTR) protein expression and localization

  Western blotting will be performed to detect expression levels of the OTR protein and its localization within the plasma membrane, cytoplasmic or nuclear cell fractions.

  24 hours

Secondary Outcomes (2)

• Oxytocin receptor (OTR) phosphorylation patterns

  24 hours

• Protein expression levels of PLC, MEK5 and ERK5

  24 hours

Study Arms (8)

Control (no oxytocin) + No recovery

NO INTERVENTION

A control experiment will be undertaken in which the myometrial explants will be exposed to PSS for 2-hours without any oxytocin. No recovery time.

Continuous oxytocin + No recovery

ACTIVE COMPARATOR

10-5M oxytocin for 2 hours. No recovery time.

Drug: Oxytocin

Continuous oxytocin + 30 minute recovery

ACTIVE COMPARATOR

10-5M oxytocin for 2 hours. After 2 hours, the solution will be drained from the organ baths, and any residual solution will be removed by washing three times with PSS. Following this, the strip will be exposed to PSS for 30 minutes.

Drug: Oxytocin

Continuous oxytocin + 60 minute recovery

ACTIVE COMPARATOR

10-5M oxytocin for 2 hours. After 2 hours, the solution will be drained from the organ baths, and any residual solution will be removed by washing three times with PSS. Following this, the strip will be exposed to PSS for 60 minutes.

Drug: Oxytocin

Control (no oxytocin) + No recovery + 10-7 oxytocin

ACTIVE COMPARATOR

A second control experiment will be undertaken in which the myometrial explants will be exposed to PSS for 2-hours without any oxytocin. After 2 hours, the solution will be drained from the organ baths, and replaced with fresh PSS. Following this, the strip will be exposed to 10-7 oxytocin for 10 minutes.

Drug: Oxytocin

Continuous oxytocin + No recovery + 10-7 oxytocin

ACTIVE COMPARATOR

10-5M oxytocin for 2 hours. After 2 hours, the solution will be drained from the organ baths, and any residual solution will be removed by washing three times with PSS. Following this, the strip will be exposed to 10-7 oxytocin for 10 minutes.

Drug: Oxytocin

Continuous oxytocin + 30 minute recovery + 10-7 oxytocin

ACTIVE COMPARATOR

10-5M oxytocin for 2 hours. After 2 hours, the solution will be drained from the organ baths, and any residual solution will be removed by washing three times with PSS. Following this, the strip will be exposed to PSS for 30 minutes. The strip will then be exposed to 10-7 oxytocin for 10 minutes.

Drug: Oxytocin

Continuous oxytocin + 60 minute recovery + 10-7 oxytocin

ACTIVE COMPARATOR

10-5M oxytocin for 2 hours. After 2 hours, the solution will be drained from the organ baths, and any residual solution will be removed by washing three times with PSS. Following this, the strip will be exposed to PSS for 60 minutes. The strip will then be exposed to 10-7 oxytocin for 10 minutes.

Drug: Oxytocin

Interventions

Oxytocin DRUG

Oxytocin, 10-7mol/L to 10-5mol/L

Also known as: pitocin

Continuous oxytocin + 30 minute recovery; Continuous oxytocin + 30 minute recovery + 10-7 oxytocin; Continuous oxytocin + 60 minute recovery; Continuous oxytocin + 60 minute recovery + 10-7 oxytocin; Continuous oxytocin + No recovery; Continuous oxytocin + No recovery + 10-7 oxytocin; Control (no oxytocin) + No recovery + 10-7 oxytocin

Eligibility Criteria

• Age: 16 Years - 40 Years
• Sex: female
• Healthy Volunteers: Yes
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Patients who give written consent to participate in this study
• Patients with gestational age 37-41 weeks
• Non-laboring patients, not exposed to exogenous oxytocin
• Patients requiring primary Cesarean delivery or first repeat Cesarean delivery

You may not qualify if:

• Patients who refuse to give written informed consent
• Patients who require general anesthesia
• Patients who had previous uterine surgery or more than one previous Cesarean delivery
• Patients with any condition predisposing to uterine atony and postpartum hemorrhage, such as abnormal placentation, multiple gestation, preeclampsia, macrosomia, polyhydramnios, uterine fibroids, bleeding diathesis, chorioamnionitis, or a previous history of postpartum bleeding
• Emergency Cesarean section in labor
• Patients on medications that could affect myometrial contractility, such as nifedipine, labetolol or magnesium sulphate.

Sponsors & Collaborators

• Samuel Lunenfeld Research Institute, Mount Sinai Hospital: lead

Study Sites (1)

Mount Sinai Hospital

Toronto, Ontario, M5G1X5, Canada

Location

MeSH Terms

Conditions

Postpartum Hemorrhage

Interventions

Oxytocin

Condition Hierarchy (Ancestors)

Obstetric Labor Complications; Pregnancy Complications; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Puerperal Disorders; Uterine Hemorrhage; Hemorrhage; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Pituitary Hormones, Posterior; Pituitary Hormones; Peptide Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Peptides; Amino Acids, Peptides, and Proteins

Study Officials

• Mrinalini Balki, MD

  MOUNT SINAI HOSPITAL

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 3, 2016
• First Posted: May 5, 2016
• Study Start: August 3, 2016
• Primary Completion: December 31, 2023
• Study Completion: December 31, 2023
• Last Updated: August 27, 2024

Record last verified: 2024-03

Data Sharing

• IPD Sharing: Will not share

Locations

CA (1)