Progesterone administration route in GnRH antagonist cycles

9 04 2010

To the Editor:

We read interest the paper of Kahraman et al. comparing the effectiveness of vaginal and intramuscular progesteron as luteal phase support among women undergoing IVF with intracytoplasmic sperm injection (ICSI) with gonadotropin-releasing hormone (GnRH) antagonist (1).

The authors conducted a prospective study and evaluated 426 women less than 37 years old undergoing ICSI-embryo transfer (ET) cycle with GnRH antagonist cetrorelix. Their results revealed similar clinical pregnancy, implantation and miscarriage rates among those women following either usage of vaginal or intramuscular progesterone as luteal phase support. In their article they admitted that route of progesterone administration was an important issue in patient compliance and discussed current data about luteal phase support in which only GnRH agonist analogues used. In this regard, the luteal phase support in GnRH antagonist cycles has not been elucidated clearly yet.

This paper is so far the first prospective but not randomized controlled trial conducted in GnRH antagonist protocols for the assessment of the type of luteal phase support. However, the results of this study should be interpreted cautiously since the design of the study has several drawbacks. The first one is the type of allocation of patients was quasi-randomization. There is a greater risk of selection bias in quasi-random trials where allocation is not adequately concealed compared with randomized controlled trials with adequate allocation concealment. Secondly, the study does not have enough statistical power to detect a clinical significant difference (such as pregnancy or miscarriage rates). Thirdly, it is very interesting that, authors did not experience any embryo transfer cancellation following oocyte retrievals in an 10-month period, therefore not even one drop-out was mentioned.

Last but not least, the authors failed to recognize and discuss the results of the first report on luteal phase support conducted in over 1400 patients in GnRH antagonist protocols (2). In this retrospective study, contradictory to the Kahraman et al. paper, significant differences were detected in terms of implantation and clinical pregnancy rates in favor of intramuscular progesterone injection compared to vaginal progesterone. Conceivably, we believe in that comparison of the mentioned report above with their results merits inclusion in the discussion.

Administration of progesterone for luteal phase has been subject of numerous studies, but all of them reported the results from GnRH agonist protocols. Both Kahraman et al. (quasi-randomization) and Bahceci and Ulug (retrospective) papers have limitations for interpretation of the results clearly. Therefore, the impact of progesterone route in GnRH antagonist cycles still warrants well powered prospective randomized clinical trials.

Mustafa Bahceci, M.D.
Ulun Ulug, M.D.
Bahceci Women Health Care Center
Istanbul, Turkey

References
1. Kahraman S, Karagozoglu SH, Karlikaya G. The efficiency of progesterone vaginal gel versus intramuscular progesterone for luteal phase supplementation in gonadotropin releasing hormone antagonist cycles: a prospective trial. Fertil Steril (in press)

2. Bahceci M, Ulug U. Route of progesterone administration for luteal phase support may affect outcome of controlled ovarian hyperstimulation for IVF with ICSI using GnRH antagonist. J. Assist. Reprod. Genet. 2008; 25:499-502.

Published online in Fertility and Sterility doi:10.1016/j.fertnstert.2010.04.014

The Authors Respond:

We would like to thank Drs. Bahceci and Ulug for their comments.

The result of our study demonstrated that the difference between the treatment outcomes of progesterone vaginal gel (PVG) and intramuscular progesterone (IMP) are statistically insignificant for luteal phase support after IVF-ET in GnRH-antagonist cycles (1).

In the present study, patients who underwent oocyte retrieval on odd days were included in the progesterone vaginal gel group and patients who underwent oocyte retrieval on even days were included in the intramuscular progesterone group. There was no significant difference between the treatment groups according to the baseline characteristic (age, duration of infertility, body mass index, day-3 FSH levels, mean day of stimulation, total gonadotrophin dose used and estradiol level on hCG day). The treatment groups were found to be comparable. The strict inclusion and exclusion criteria used ruled out the possibility of selection bias that might otherwise have occurred.

The number of patients needed to achieve a statistical comparison to the power of 80% was calculated as a minimum of 420, in this case a significant difference in pregnancy rate would be 13.2%. the number of patients included in our study was 426, 209 patients in the PVG group and 217 patients in the IMP group and the difference in pregnancy rate was 3% only suggesting that administration of PVG might be an alternative to IMP for luteal phase support in GnRH antagonist cycles.
The correspondence format did not allowed the inclusion of all details. The drop out rate was not significant (5 in PVG and 6 in IMP).

Our study was carried out over the period of January to October 2008 and its completion coincides with the publication by Bahçeci and Uluğ (2). Furthermore the latter is a retrospective study which was not designed to compare the effects of IMP and PVG on live birth rates, the gold standard of success in ART, whereas ours was a prospective study comparing the cycle outcomes of the same groups.

Our study was the first prospective randomized study comparing the efficiency of PVG versus IMP in GnRH antagonist cycles its conclusion indicate that prospective randomized studies with larger sample size would be beneficial.

Semra Kahraman, M.D.
Hale Karagozoglu, M.D.
Guvenc Karlikaya, M.D.
Istanbul Memorial Hospital
Istanbul, Turkey

References
1. Kahraman S, Karagozoglu SH, Karlikaya G. The efficiency of progesterone vaginal gel versus intramuscular progesterone for luteal phase supplementation in gonadotropin releasing hormone antagonist cycles: a prospective trial. Fertil Steril (in press)

2. Bahceci M, Ulug U. Route of progesterone administration for luteal phase support may affect outcome of controlled ovarian hyperstimulation for IVF with ICSI using GnRH antagonist. J. Assist. Reprod. Genet. 2008; 25:499-502.

Published online in Fertility and Sterility doi:10.1016/j.fertnstert.2010.04.015

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