Reversible Effects of Oral Contraceptive Removal on Serotonergic Neurotransmission

NCT07511439 | Not Yet Recruiting Phase 4

• 2 other identifiers: REVERSEH-25059351
• Study Type: interventional
• Target: 60
• Locations: 1 country
• Sites: 1

Brief Summary

The goal of this study is to learn about potential reversible effects of combined oral contraceptive (COC) use on the serotonergic brain system. The main question it aims to answer is: \- If COC discontinuation results in an increase in serotonin 4 receptor binding in caudate, putamen, and hippocampus measured with Positron Emission Tomography from baseline to follow-up ≥ week 8 after discontinuation. The secondary question it aims to answer is: \- Over what timeframe the serotonin 4 receptor binding is restored after COC discontinuation to the level previously seen in a group of premenopausal women who had not used hormonal contraception before. Researchers will compare discontinuation with continuation of a 2nd generation COC containing 150 ug levonorgestrel and 30 microgram to see if COC discontinuation results in an increased serotonin 4 receptor level in the brain. \- Participants will:

• Be randomized to discontinue or continue their COC use for 1-52 weeks.
• Undergo an investigational program including brain scans, biological sampling, and neuropsychological testing at baseline and at follow-up. The study uses a group sequential design with two sequential analyses planned, including an interim analysis after 60% of the brain scans have been acquired, which will be used to decide the timing of the last 40% of the scans - this is performed to best determine when the recovery of the serotonin 4 receptor level occurs.

Conditions

Healthy Adult Females; The Focus of the Study is to Investigate Reversible Effects of Combined Oral Contraceptive Use on Serotonergic Neurotransmission

Outcome Measures

Primary Outcomes (1)

• Change in global serotonin 4 receptor (5-HT4R) brain binding across caudate, putamen, and hippocampus

  Serotonin 4 receptor (5-HT4R) brain binding is measured with positron emission tomography. Change in global 5-HT4R brain binding is estimated using a latent variable model with a latent variable pooling the change in log-transformed binding potentials from baseline to follow-up across caudate, putamen, and hippocampus after adjustment for change in injected tracer mass per kg body weight.

  1-52 weeks

Secondary Outcomes (18)

• Change in total Verbal Affective Memory Test-24 (VAMT-24) score

  1-52 weeks

• Difference in hippocampal activation during memory encoding

  1-52 weeks

• Change in brain insulin sensitivity

  1-52 weeks

• Change in hypothalamic blood-oxygen-level-dependent response to oral glucose

  1-52 weeks

• Change in peripheral insulin sensitivity

  1-52 weeks

Other Outcomes (44)

• Change in area under the curve of glucose during an oral glucose tolerance test (OGTT)

  1-52 weeks

• Change in area under the curve of insulin during an oral glucose tolerance test (OGTT)

  1-52 weeks

• Change in area under the curve of c-peptide during an oral glucose tolerance test (OGTT)

  1-52 weeks

Study Arms (2)

Combined oral contraceptive continuation (COCc)

ACTIVE COMPARATOR

COCc: between 1-52 weeks of second-generation combined oral contraceptive containing 150 microgram levonorgestrel and 30 microgram ethinylestradiol. Each cycle consists of 21 days of active pills and 7 days of placebo pills/pause days.

Drug: Continuation of 2nd generation combined oral contraceptive use

Combined oral contraceptive discontinuation (COCd)

EXPERIMENTAL

COCd: between 1-52 weeks.

Drug: Discontinuation of 2nd generation combined oral contraceptive use

Interventions

Continuation of 2nd generation combined oral contraceptive use DRUG

Continuation of 2nd generation combined oral contraceptive use

Combined oral contraceptive continuation (COCc)

Discontinuation of 2nd generation combined oral contraceptive use DRUG

Discontinuation of 2nd generation combined oral contraceptive use

Combined oral contraceptive discontinuation (COCd)

Eligibility Criteria

• Age: 18 Years - 39 Years
• Sex: female
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Healthy women (assigned female at birth) at 18-39 years of age
• Currently using a second-generation combined oral contraceptive containing 150 ug levonorgestrel and 30 ug ethinylestradiol for at least 3 months

You may not qualify if:

• Current or previous neurological or psychiatric disease, severe somatic disease, or consumption of medical drugs (including psychoactive medication) likely to influence the test results
• Non-fluent in Danish or pronounced visual or auditory impairments
• Current or past learning disability
• Pregnancy within the last year or previous pregnancy lasting into second or third trimester
• A wish to become pregnant within the following 12 months
• Participation in experiments with exposure to radioactivity (\> 10 mSv) within the last year or significant occupational exposure to radioactivity
• Contraindications for MRI (pacemaker, metal implants, claustrophobia)
• A history of head injury or concussion resulting in loss of consciousness for more than 2 min
• Alcohol or drug abuse
• Drug use other than tobacco and alcohol within the last 30 days
• Cannabis \> 50 x lifetime
• Recreational drugs other than cannabis \> 10 x lifetime (for each substance)
• Nicotine addiction
• Non-compliance to COC within the last 3 months (i.e., \> 2 missed pills in a cycle)
• Contraindication for use of combined oral contraception

Sponsors & Collaborators

• Rigshospitalet, Denmark: lead

Study Sites (1)

Neurobiology Research Unit (NRU)

Copenhagen, 2100, Denmark

Location

Study Officials

• Søren Vinther Larsen, MD, PhD

  Neurobiology Research Unit, Rigshospitalet

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Søren Vinther Larsen, MD, PhD

CONTACT

+45 35456708; soren.vinther@nru.dk

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: MD, PhD

Model Details: Randomized Controlled Trial (RCT)

Study Record Dates

• First Submitted: March 28, 2026
• First Posted: April 6, 2026
• Study Start: April 1, 2026
• Primary Completion (Estimated): December 31, 2030
• Study Completion (Estimated): December 31, 2030
• Last Updated: April 9, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will not share

Locations

DK (1)