Effect of Intramuscular Progesterone Supplementation on Clinical and Ongoing Pregnancy Rates in Patients With Low Serum Progesterone Levels on the Day of Embryo Transfer in Artificial Frozen Cycles

March 15, 2022 updated by: Abdelfatah Mohamed Kamel Eldesouky, Cairo University
The aim of this study is to investigate whether intramuscular progesterone supplementation will improve clinical pregnancy rates and ongoing pregnancy rates in patients with decreased serum progesterone levels on the day of embryo transfer in artificial frozen cycles.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Cryopreservation of frozen-thawed embryos has become a cardinal procedure in assisted reproductive therapies. This can be attributed to the development of the vitrification process and the improvement of embryo survival rates after thawing, leading to the progressive increase in the use of frozen embryo transfer (FET).

The need for FET has also increased greatly due to the implementation of a single embryo transfer policy in many areas of the world to reduce multiple pregnancies. This has led to an increase in surplus embryos derived from ovarian stimulation cycles. Moreover, although the 'freeze all' technique or elective embryo cryopreservation was mainly developed for patients with an increased risk of developing ovarian hyperstimulation syndrome, its use has now been extended to cover other indications, such as cycles involving pre-implantation genetic diagnosis, late-follicular progesterone elevation and embryo-endometrial asynchrony.

Despite this increased need for FET, there still exists debate over the best method to implement the practice. The two most common used treatment regimens to prepare the endometrium for embryo transfer are the so-called natural cycle (NC) and the hormone replacement therapy (HRT) cycle.

In a NC FET, there is no medical intervention apart from ultrasound monitoring during the proliferative phase, to schedule the transfer when the endometrium is synchronized to the developmental stage of the embryo. Although the advantage is the absence of estrogen supplementation, this protocol entails more frequent visits to the clinic and less cycle control. Despite this, there is still an ongoing debate whether frozen embryos transferred in a 'more physiologic' non-stimulated endometrium, may not only result in higher pregnancy rates, but also potentially decrease maternal and neonatal morbidity.

On the other hand, in the HRT cycle, also referred to as an artificial cycle, exogenous administration of estrogens and progesterone is used to mimic a natural cycle and therefore endometrial development. Although originally developed to allow embryo transfers in recipients of donated oocytes, the HRT protocol has proven to be successful in the general population as well.

The advantage of this protocol is the easy scheduling and minimal cycle monitoring. There are however, potential disadvantages associated with its widespread usage, including the increased expense and risks of estrogen supplementation such as thromboembolic events.

Generally speaking, in HRT cycles, progesterone supplementation begins once the proliferation of the endometrium with the administration of estrogens is considered sufficient. Progesterone is initiated to promote the final phase of endometrial preparation prior to embryo transfer, however, there is little agreement on the ideal route or dose of progesterone supplementation itself.

As regards the route of administration, when compared to intramuscular (IM) injections, patients seem to prefer the vaginal route owing to its quick, easy and painless administration. Despite this, there is limited data comparing IM versus vaginal progesterone administration, with some being in favour of the IM route and others showing no significant differences in terms of outcome.

However, the more recent focus on intramuscular rather than the traditional transvaginal progesterone supplementation, stems from newer mounting evidence that transvaginal supplementation not only increases vaginal discharge, but also has a limited effect in increasing serum progesterone levels.

Boynukalin et al., 2019 explored the idea of intramuscular progesterone supplementation in HRT FET cycles further, by substituting the traditional vaginal progesterone with 100mg of daily IM progesterone during endometrial preparation and thereafter till the 10th week of pregnancy. They found that the mean progesterone level on the day of ET was significantly higher in patients who later had an ongoing pregnancy (28 ng/ml) than those who did not have an ongoing pregnancy (16.4 ng/ml) with a p-value of 0.039. They did however conclude, that further investigation is needed for the individualization of intramuscular progesterone doses to reach optimal pregnancy rates.

Thus, more attention has been given recently to measuring serum progesterone during HRT FET cycles. Kofinas et al., 2015 suggested that progesterone levels >20 ng/ml (possibly due to an escape ovulation and subsequent embryo-endometrial asynchrony) on the day of transfer have been associated with decreased ongoing pregnancy and live birth rates. On the other hand, Yovich, et al., 2015 proposed an optimal mid-luteal progesterone range between 22 and 31 ng/ml.

Most recently, Labarta et al., 2017 investigated the relationship between serum progesterone levels on the day of embryo transfer (ET) and ongoing pregnancy rate (OPR). Their study recommended a minimum serum progesterone threshold (9.2 ng/ml) to optimize OPR in artificial cycles using transvaginal progesterone and this value could theoretically be used to decide if ET should be postponed or not.

Extrapolating from this data, we intend to investigate whether intramuscular progesterone supplementation can help improve OPR rates in the aforementioned patients with decreased serum progesterone on the day of ET. In other words, we intend to investigate further the concept of individualizing luteal phase support in HRT FET cycles.

Study Type

Interventional

Enrollment (Actual)

354

Phase

  • Not Applicable

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

  • Egypt
      • Cairo, Egypt, 11956
        • Cairo University, Faculty of Medicine, Department of Obstetrics and Gynecology
      • Cairo, Egypt, 12611
        • AlBoshra IVF & Infertility Treatment Centre

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:

  1. Age range 20-40 years
  2. BMI < 40 kg/m2
  3. Endometrial thickness >7mm
  4. Double embryo transfer (Day 5), Grade 1 or 2.

Exclusion Criteria:

  1. Autoimmune diseases
  2. Uncontrolled medical conditions
  3. Recurrent implantation failure
  4. Anatomical uterine abnormalities as polyps, fibroids or Müllerian anomalies.

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: Non-Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Serum Progesterone Levels >9.2 ng/ml
These patients will receive only twice-daily vaginal progesterone supplementation following embryo transfer
Drug: Twice-daily transvaginal progesterone supplementation
Patients with serum progesterone levels >9.2 ng/ml on the day of embryo transfer in artificial frozen cycles will receive the traditional twice-daily vaginal progesterone supplementation till 12 weeks gestation.
Active Comparator: Serum Progesterone Levels <9.2 ng/ml
These patients will receive twice-weekly intramuscular progesterone supplementation in addition to the twice-daily vaginal supplementation following embryo transfer
Drug: Twice-weekly intramuscular + Twice-daily transvaginal progesterone supplementation
Patients with serum progesterone levels <9.2 ng/ml on the day of embryo transfer in artificial frozen cycles will receive the twice-daily vaginal progesterone in addition to twice-weekly intramuscular progesterone supplementation till 12 weeks gestation.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Clinical pregnancy rates
Time Frame: 4 weeks after the day of embryo transfer
Detected via ultrasound
4 weeks after the day of embryo transfer

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Ongoing pregnancy rates
Time Frame: 12 weeks after the day of embryo transfer
Detected via ultrasound
12 weeks after the day of embryo transfer

Collaborators and Investigators

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

Sponsor

Cairo University

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 27, 2021

Primary Completion (Actual)

March 1, 2022

Study Completion (Actual)

March 15, 2022

Study Registration Dates

First Submitted

April 6, 2021

First Submitted That Met QC Criteria

April 6, 2021

First Posted (Actual)

April 8, 2021

Study Record Updates

Last Update Posted (Actual)

March 17, 2022

Last Update Submitted That Met QC Criteria

March 15, 2022

Last Verified

March 1, 2022

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • Progesterone in HRT FET cycles

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

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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