Progesterone Luteal Support in Unexplained Infertility Management (PLUIM)

The purpose of this study is to evaluate whether progesterone in women with unexplained infertility can increases live birth rate.

The main research question is:

Does luteal phase support with progesterone increase the live birth rate among couples with unexplained infertility?

The study compares progesterone with placebo to determine the effectiveness of progesterone in unexplained infertility.

Study participants will:

• Perform home ovulation tests and maintain a digital diary to record menstrual cycles and study medication use.10
• Take progesterone or placebo twice daily during the luteal phase of each menstrual cycle for up to six months.11
• Continue usual medical care. No additional hospital visits or invasive procedures are required as part of the study.

Study Overview

• Status: Not yet recruiting
• Conditions: Infertility; Subfertility; Subfertility, Female; Female Infertility; Infertility Primary; Infertility Secondary
• Intervention / Treatment: Drug: Utrogestan® 200 mg Soft Capsule; Drug: Placebo soft capsule 200 mg

Detailed Description

Rationale

Progesterone is a critical hormone in the luteal phase, facilitating endometrial secretory transformation, decidualization, implantation, and early pregnancy maintenance. A previous systematic review suggested that progesterone insufficiency may contribute to reduced implantation potential and lower pregnancy rates in women with unexplained infertility (UI). Additional support for the importance of luteal function in fertility is provided by studies demonstrating improved outcomes following progesterone supplementation in various fertility treatments, including intrauterine insemination (IUI) during mildly stimulated cycles, (natural)-cycle cryoembryo transfers and early gestation.

The present study aims to determine whether progesterone supplementation during the luteal phase in women with UI, managed expectantly through ovulation testing and timed intercourse, can increase live birth rates. A previous pilot randomised controlled trial (the PINC trial) indicated a potential benefit of luteal phase support (LPS) in this population (odds ratio 2.38, 95% CI 0.78-7.24), though the study was underpowered, included only three menstrual cycles, and lacked placebo blinding, thereby limiting the strength of the evidence and supporting the need for a large, high-quality study.

The hypothesis is that the addition of progesterone during expectant management in UI will lead to an absolute increase of 10% in cumulative live birth rate. LPS is expected to be cost-effective, by reducing the need for invasive fertility treatment such as IUI or IVF, thereby shortening time to pregnancy and decreasing the emotional, psychological, and financial burden of infertility care. Given the low cost and ease of home administration, the impact of LPS on total healthcare is expected to be minimal. The overall estimated budget impact of the addition of LPS in UI management is ±11.6 million euros per year.

Trial design

A randomised, controlled, double-blind, multicentre superiority trial will be conducted with two parallel, non-crossover treatment arms: (1) LPS and (2) placebo. All natural cycles occurring within 6 months after randomisation, monitored at home using LH-surge ovulation testing, are included in the study period. The follow up period continues for 12 months after end of the study period (i.e. up to 18 months after randomisation) to assess pregnancy outcomes and confirm live birth.

Trial population A total of 640 patients will be included, with 320 patients allocated to each treatment group.

Couples diagnosed with primary or secondary unexplained infertility, who have a good prognosis for achieving a live birth within the coming year (i.e. Hunault prognostic score ≥30%) and who are assigned to expectant management for at least six months in accordance with Dutch NVOG guidelines, are eligible for inclusion. Female eligibility criteria include an age range of 18-43 years and a body mass index (BMI) below 45kg/m2. A diagnosis of endometriosis will constitute an exclusion criterion.

Interventions

During six consecutive calendar months, participants will perform LH-surge testing via urinary ovulation tests at home, followed by progesterone or placebo treatment during the luteal phase of each menstrual cycle.

A dosage of 300 mg vaginal micronised progesterone twice daily (Utrogestan; Besins Healthcare, Ireland) will be administered in the treatment group, while matching vaginal placebo capsules will be administered in the control group.

Treatment will start on day 3 after a positive urinary LH-surge test and continue until the onset of menstruation, a negative pregnancy test performed 14 days after the positive LH-surge test, miscarriage, or a gestational age of 7+0 weeks. No additional hospital visits or laboratory tests will be required compared with standard care.

Participants are will be asked to use the vaginal capsules as prescribed and complete a medication diary to record compliance throughout the study period. In addition, participants receive short digital questionnaires: at randomisation (Q1, to assess baseline quality of life), at 6 months after randomisation (Q2, quality of life, compliance to therapy, side-effects), and 18 months after randomisation (Q3, determine pregnancy and neonatal outcomes of pregnancies achieved within 6 months after randomisation, determine use of ART treatment and conception during follow up period).

For pregnancies occurring during the six-month study period, the first pregnancy ultrasound will be scheduled at the hospital. Following confirmation of a viable pregnancy, additional antenatal care will be provided within the usual care setting, typically in primary care, unless medical indications require specialist care.

• Study Type: Interventional
• Enrollment (Estimated): 640
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Julie C.M. van de Wal, MD; Phone Number: +31650177981; Email: j.c.m.vandewal-15@umcutrecht.nl
• Study Contact Backup: Name: Katja C.E. Drechsel, MD, PhD; Email: K.C.E.Drechsel-2@umcutrecht.nl

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Primary or secondary infertility for at least a period of 1 year Participants whose previous pregnancy was achieved through MOH-IUI or IVF are eligible to join the study, provided they are willing to continue expectant management for at least six months before considering any further fertility interventions

• Diagnosis of UI after infertility work-up, i.e.

  • regular menstrual cycle ranging between 21-35 days,
  • total motile sperm count ≥ 10 million/ml,
  • no risk of tubal pathology (or in case of increased risk, tubal pathology uitgesloten middels tubal patency testing)
• A Hunault prognostic score ≥ 30% (calculated using the Hunault prediction model7, based on key prognostic factors including female age, subfertility duration, type of subfertility (primary or secondary), sperm motility and referral status),
• Assignment to expectant management during at least six months, in accordance with Dutch NVOG Guidelines (4).
• Female age ≥18 years old Female
• BMI <45 kg/m2

Exclusion Criteria:

• Uncorrected uterine factors, such as endometrial polyps or submucosal fibroids,
• Insufficient knowledge or understanding of the Dutch or English language and not willing or able to receive study information via a certified translator
• Not able or willing to provide (written) informed consent
• Contraindications for vaginal progesterone, in particular: females with allergy to peanuts or soya.
• Formal diagnosis of endometriosis

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 1. The Progesterone Arm; Female participants apply vaginal micronized progesterone (Utrogestan) during the luteal phase of their cycle, at a dosage of 300 mg twice daily	Drug: Utrogestan® 200 mg Soft Capsule; progesteron versus placebo
Placebo Comparator: 2. The Placebo (Control) Arm; Female participants apply a vaginal capsule (placebo) during the luteal phase of their cycle, at a dosage of 300 mg twice daily	Drug: Placebo soft capsule 200 mg; placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Pregnancy occurring within 6 months after randomisation, leading to a live birth.	within 6 months after randomisation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical pregnancy		within 6 months after randomisation
Ongoing pregnancy		within 6 months after randomisation
Biochemical pregnancy loss		within 6 months after randomisation
Miscarriage rates		within 6 months after randomisation
Multiple pregnancy rate	of all achieved (ongoing) pregnancies	within 6 months after randomisation
Time to pregnancy	Of all achieved (ongoing) pregnancies	Within 6 months after randomisation
Pregnancy loss	of all achieved (ongoing) pregnancies	within 6 months after randomisation
Pregnancy complications	of all achieved (ongoing) pregnancies	within 6 months after randomisation
Perinatal outcomes	Of all achieved (ongoing) pregnancies	within 6 months after randomisation
Type of delivery	of all achieved (ongoing) pregnancies	within 6 months after randomisation
Side effects	Assessed using a monthly medication diary and a questionnaire administered 6 months after randomisation.	During the 6-month study period
Compliance to therapy	Assessed using a monthly medication diary and a questionnaire administered 6 months after randomisation.	During the 6-month study period
Number of adverse events and serious adverse events.		During the 6-month study period
Quality of life assessed at time of randomisation, and 6 and 18 months after randomisation	using the FertiQoL questionnaire	assessed at time of randomisation, and 6 and 18 months after randomisation
Progression to (MOH)IUI/IVF/ICSI		within six months after randomisation
Use of ART and (ongoing) pregnancy achieved		after the six-month study period and within 12 months follow up.
Budget impact		over the 6-month study period
Cost-effectiveness analyses using live birth rates and costs		over the 6-month study period

Collaborators and Investigators

• Sponsor: Simone Broer
• Collaborators: ZonMw: The Netherlands Organisation for Health Research and Development
• Investigators: Principal Investigator: Simone L. Broer, Gynaecologist, PhD, UMC Utrecht

Study record dates

Study Major Dates

• Study Start (Estimated): August 1, 2026
• Primary Completion (Estimated): August 1, 2030
• Study Completion (Estimated): January 1, 2031

Study Registration Dates

• First Submitted: July 22, 2026
• First Submitted That Met QC Criteria: July 27, 2026
• First Posted (Actual): July 30, 2026

Study Record Updates

• Last Update Posted (Actual): July 30, 2026
• Last Update Submitted That Met QC Criteria: July 27, 2026
• Last Verified: July 1, 2026

More Information

Terms related to this study

• Keywords: infertility; Unexplained Infertility; Expectant Management; Luteal Phase Support (LPS); progesteron luteal support; progesteron; Progesterone (Utrogestan®)
• Additional Relevant MeSH Terms: Urogenital Diseases; Genital Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Genital Diseases, Female; Infertility; Infertility, Female; Utrogestan
• Other Study ID Numbers: V0003925; 2026-525747-33-00 (Ctis)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No