Vaginal Progesterone Supplementation in Women With PCOS Undergoing Ovulation Induction With Letrozole

February 23, 2018 updated by: Laurel Stadtmauer, Eastern Virginia Medical School

"Supplementation of the Luteal Phase With Vaginal Progesterone (Crinone 8%) in Women With Polycystic Ovary Syndrome Undergoing Ovulation Induction With Letrozole: A Prospective and Randomized Controlled Trial

Aromatase inhibitors such as letrozole are hypothesized to maintain normal hypothalamic/ pituitary feedback mechanisms and in the case of OI (ovulation induction) in women with PCOS, may act to increase follicular sensitivity to FSH by increasing intrafollicular androgen levels. Letrozole also may act to increase midluteal P levels presumably by induction of follicles and corpora lutea. The investigators are asking the question whether P supplementation with Crinone (8%) may have an additive beneficial effect on endometrial development in those women taking letrozole. Progesterone levels in the endometrium (tissue levels) have been documented to be significantly higher than serum levels after vaginal administration which may lead to higher pregnancy rates. In addition P has been shown to decrease LH pulse frequency which is elevated in PCOS and has been shown to down regulate endometrial androgen receptors. There have been retrospective studies showing progesterone supplementation seems to benefit both CC and letrozole treatment groups. In fact, this study showed the only pregnancies in the letrozole group were those in women who took P supplementation. However the number of cycles studied was small. There is a place for a randomized controlled trial (RCT) to determine if luteal phase P supplementation with Crinone should be used in all women using letrozole for Ovulation Induction (OI) in combination with Intrauterine Insemination (IUI) or Timed Intercourse (TI). This is currently not done in all clinical practices.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Approval of the study was obtained from the local IRB. Prospective volunteers had had an infertility workup including blood hormone levels (FSH, LH, E2, Progesterone, Prolactin, and Thyroid), partner's semen analysis, HSG, laparoscopy or hydrosonogram, plus a baseline evaluation including ultrasound of ovaries and uterus performed as standard of care. If the results of these tests and the remaining Inclusion/Exclusion criteria were met, the study consent was reviewed with participants and signatures were obtained. Participants contacted the clinic at the start of their menses (spontaneous or progesterone-induced) to start the treatment cycle. Eligibility criteria was reviewed, and Letrozole 2.5-7.5 mg day 3-7 was initiated based on BMI and prior response. An ultrasound was performed on cycle day 11 or 12 and repeated if needed to determine response until at least 1 follicle with mean diameter > 17mm in size was observed. When the appropriate follicle size was reached, participants were randomized into one of the two treatment groups as determined by a randomization table, and Ovidrel (250mcg) was administered. If there was no response identified by follicle growth on day 21, the participant was considered a letrozole failure, the cycle was stopped, and the participant was dropped from the study and was not included in subsequent cycles.

IUI/TI was performed at 24-48 hours after the Ovidrel (hCG) injection. If the participant was randomized to progesterone (Crinone), the luteal phase was supplemented once daily with vaginal progesterone (Crinone 8%) starting the second day after the IUI or TI and continued for 14 days. A urine or serum pregnancy test was performed as standard of care 16 days after the IUI/TI. If the test was positive, a confirmatory blood level (βhCG) was performed as standard of care X2 (1 week apart) and an ultrasound on post-hCG day 35-42 was done. Any pregnancies occurring in either treatment group were followed for delivery outcomes. Information regarding the delivery (induced, vaginal, cesarean section), date of birth, infant measurements (weight and length) and other important information regarding the infant's condition was obtained. Participants were allowed to undergo up to 3 cycles of letrozole as the pregnancy rates for the first 3 cycles have been shown to be similar. The participants were re-randomized each cycle. If the participant was pregnant, Crinone (8%) was continued until 10 weeks gestation in both groups.

Each participant was able to proceed with up to 3 cycles (consecutively, if desired) of OI over the next 6 months and was re-randomized each cycle.

Study Type

Interventional

Enrollment (Actual)

52

Phase

  • Phase 2
  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Virginia
      • Norfolk, Virginia, United States, 23507
        • Laurel A. Stadtmauer, MD, PhD

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

20 years to 40 years (Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

Female

Description

Inclusion Criteria:

  • Women who have anovulatory or oligoovulatory infertility who are undergoing ovulation induction for infertility with TI or IUI , with or without regular cycles defined as cycle length > 35 days, < 26 days or amenorrhea (no cycles in the past six months), and who meet 2 out of 3 of the Rotterdam Criteria (1. Chronic anovulation or irregular cycles, 2. Clinical or biochemical hyperandrogenism, 3. Polycystic appearing ovaries on ultrasound.)
  • Day 3 FSH(Follicle stimulating hormone)< 10 (obtained within 2 years prior to screening
  • Documented infertility for at least 1 year or documented anovulation
  • Willing to participate in up to 3 cycles of OI with letrozole and IUI or TI
  • Partner's or donor's SA> 5 million motile sperm within 2 years of screening
  • Patients may have received clomiphene citrate or letrozole treatment in the past.

Exclusion Criteria:

  • Untreated thyroid or prolactin abnormalities
  • Pregnancy in the last 3 months
  • BMI< 18 or >40kg/m2
  • Abnormal uterine bleeding of undetermined origin
  • Contraindications to pregnancy
  • Progesterone sensitivity
  • Uterine anomalies seen on ultrasound (performed within 6 months prior to screening) that can affect pregnancy chances such as submucosal uterine fibroids or polyps
  • Three or more previous consecutive pregnancy losses
  • Blocked fallopian tubes X2 (documented by HSG, laparoscopy, or hydrosonogram completed within past 3 years)
  • More than 3 failed monitored letrozole cycles prior to enrolling

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Other
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Single

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Other: # 1- no progesterone therapy
Letrrozole 2.5 to 5 mg oral tablet cycle day 3-7.Pelvic ultrasound at cycle day 11 or 12 and repeat if needed until leading follicle is >17 mm. Ovidrel 250 mcg injected sq. Timed intercourse or intrauterine insemination. No supplemental progesterone therapy in luteal phase
Drug: Letrozole Oral Tablet
letrozole oral tablet 2.5 mg or 5 mg administered cycle day 3-7 for ovulation induction
Diagnostic test: pelvic ultrasound
pelvic ultrasound performed at cycle day 11 or 12 and repeated as necessary until leading follicle size is >17 mm in diameter
Drug: Ovidrel 250 MCG Per 0.5 ML Prefilled Syringe
ovidrel 250 mcg given when leading follicle size is > 17 mm in diameter
Other Names:
  • recombinant hCG 250 mcg
Other: Intrauterine insemination or timed intercourse
Intrauterine insemination or timed intercourse (depending on semen parameters) performed 36-40 hours after Ovidrel
Active Comparator: # 2 - Progesterone Vaginal Gel 8%
Letrrozole 2.5 to 5 mg oral tablet cycle day 3-7. Pelvic ultrasound at cycle day 11 or 12 and repeat if needed until leading follicle is >17 mm. Ovidrel 250 mcg injected sq. Timed intercourse or intrauterine insemination.Crinone 8% (progesterone) vaginal therapy was provided in luteal phase for 14 days .Administration was started the second day after intrauterine insemination or timed intercourse.
Drug: Letrozole Oral Tablet
letrozole oral tablet 2.5 mg or 5 mg administered cycle day 3-7 for ovulation induction
Diagnostic test: pelvic ultrasound
pelvic ultrasound performed at cycle day 11 or 12 and repeated as necessary until leading follicle size is >17 mm in diameter
Drug: Ovidrel 250 MCG Per 0.5 ML Prefilled Syringe
ovidrel 250 mcg given when leading follicle size is > 17 mm in diameter
Other Names:
  • recombinant hCG 250 mcg
Other: Intrauterine insemination or timed intercourse
Intrauterine insemination or timed intercourse (depending on semen parameters) performed 36-40 hours after Ovidrel
Drug: Progesterone Vaginal Gel 8%
progesterone supplementation for luteal phase support administered with vaginal applicators and used instead of progesterone intramuscular injections or progesterone vaginal suppositories.
Other Names:
  • Crinone 8% vaginal gel

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Clinical pregnancy rates
Time Frame: Per initiated cycle of treatment. At the end of Cycle 1, 2, and 3 (each cycle is 28 days) and if pregnant up to 8 weeks after completion of cycle
The primary endpoint of the trial is the Clinical Pregnancy Rate per cycle initiated
Per initiated cycle of treatment. At the end of Cycle 1, 2, and 3 (each cycle is 28 days) and if pregnant up to 8 weeks after completion of cycle

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Live birth rates
Time Frame: Up to 1 year or until delivery
The secondary endpoint is the Live Birth Rate per cycle initiated (each cycle is 28 days)
Up to 1 year or until delivery

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Eastern Virginia Medical School

Collaborators

Watson Pharmaceuticals

Investigators

  • Principal Investigator: Laurel A Stadtmauer, MD, PhD, Eastern Virginia Medical School

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

July 6, 2012

Primary Completion (Actual)

November 2, 2016

Study Completion (Actual)

December 30, 2017

Study Registration Dates

First Submitted

February 7, 2018

First Submitted That Met QC Criteria

February 14, 2018

First Posted (Actual)

February 22, 2018

Study Record Updates

Last Update Posted (Actual)

February 26, 2018

Last Update Submitted That Met QC Criteria

February 23, 2018

Last Verified

February 1, 2018

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • IRB 12-07-FB-0170

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

Yes

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

Yes

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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