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ORIGINAL ARTICLE
http://dx.doi.org/10.5653/cerm.2013.40.3.131
pISSN 2233-8233 · eISSN 2233-8241
Luteal estradiol supplementation in gonadotropin-
releasing hormone antagonist cycles for infertile
patients in vitro fertilization
Su-Kyoung Kwon1, Chung-Hoon Kim1, Kyung-Hee Lee1, Il Kyung Jeon1, Jun-Woo Ahn2, Sung-Hoon Kim1, Hee-Dong Chae1,
Byung-Moon Kang1
Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, 1Asan Medical Center, University of Ulsan College of
Medicine, Seoul; 2Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea
Objective: To evaluate the effect of the addition of estradiol to luteal progesterone supplementation in GnRH antagonist cycles for infertile pa-
tients undergoing IVF/ICSI.
Methods: One hundred and ten infertile patients, aged 28 to 39 years, were recruited for this prospective randomized study. They were ran-
domly assigned to receive vaginal progesterone gel (Crinone) along with 4 mg estradiol valerate (group 1, n=55) or only Crinone (group 2,
n=55) for luteal support. A GnRH antagonist multiple dose protocol using recombinant human FSH was used for controlled ovarian stimula-
tion (COS) in all of the subjects. The COS results and pregnancy outcomes of the two groups were compared.
Results: Group 1 and 2 were comparable with respect to the patient characteristics. The COS and IVF results were also comparable between
the two groups. There were no differences in the clinical pregnancy rate (PR) and multiple PR between the two groups. However, the embryo
implantation rate were significantly higher in group 1 than that in group 2 (22.2% vs. 13.3%, p=0.035). The incidence of luteal vaginal bleeding
(LVB) was significantly lower in group 1 (7.4% vs. 27.8%, p=0.010).
Conclusion: The addition of estradiol to luteal progesterone supplementation in GnRH antagonist cycles reduces the incidence of LVB and in-
creases the embryo implantation rate in infertile patients undergoing IVF/ICSI.
Keywords: Luteal progesterone supplementation; Gonadotropin-releasing hormone antagonist; Addition of estradiol; In vitro fertilization; In-
tracytoplasmic sperm injection
Introduction
Luteal supplementation is important for successful embryo implan- Luteal phase supplementation after controlled ovarian stimulation tation after COS for IVF. Progesterone supplementation in the luteal (COS) for IVF-ET has been current practice, because stimulated IVF phase after COS is widely accepted, and the role of progesterone in cycles are associated with luteal phase defect (LPD) due to very low luteal support in COS cycles is well established. However, it has been shown that mid-luteal estradiol levels decrease under progesterone Received: Jun 11, 2013 ∙ Revised: Jul 19, 2013 ∙ Accepted: Aug 2, 2013 supplementation alone. This might be associated with a decrease in Corresponding author: Chung-Hoon Kim
pregnancy rates [2]. In addition, luteal vaginal bleeding (LVB) can de- Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Asan Medical Center, University of Ulsan College of Medicine, velop more frequnetly in patients supplemented with progesterone 86 Asanbyeongwon-gil, Songpa-gu, Seoul 138-736, Korea vaginal gel, or vaginal suppositories containing micronized proges- Tel: +82-2-3010-3639, Fax: +82-2-3010-6944, E-mail: [email protected] terone compared with those who receive intramuscular progester- This is an Open Access article distributed under the terms of the Creative Commons Attribution
Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits
one [3], although it is very easy and convenient to use progesterone unrestricted non-commercial use, distribution, and reproduction in any medium, provided the
original work is properly cited.
vaginal gel. The importance of estradiol levels during the luteal phase Copyright 2013. THE KOREAN SOCIETY FOR REPRODUCTIVE MEDICINE
Clin Exp Reprod Med 2013;40(3):131-134
or the addition of luteal estradiol to progesterone supplementation Woking, Surrey, UK) with interassay and intraassay variances of <10% for luteal support in the IVF cycle is controversial [4]. and 5%, respectively, and transvaginal ultrasonographic evidence of This prospective, randomized study was performed to evaluate the a gestational sac. Estradiol valerate supplementation was discontin- effect of the addition of estradiol to luteal vaginal suppositories con- ued on the day of the first pregnancy test, 11 days after ET. All of the taining micronized progesterone supplementation in GnRH antago- patients who had increased serum β-hCG were administered vaginal nist cycles for infertile patients undergoing IVF/ ICSI. progesterone gel continuously until 10 weeks of gestation. Material and methods
3. Statistical analysis
The mean value was expressed as the mean±SD. The Student’s t- 1. Patient population
test was used to compare the mean values between the two groups. This prospective randomized study was performed at a university- The chi-squared test and Fisher’s exact test were used for the com- based infertility clinic at Asan Medical Center, Seoul, Korea. The study parison of fractions, where applicable. Statistical significance was de- population consisted of 110 infertile patients who had undergone fined as p<0.05. Al analyses were performed using the SPSS ver. 110 IVF cycles. Patients were randomized to receive progesterone vaginal gel (Crinone 8%, Merck-Serono SA, Geneva, Switzerland), progesterone vaginal gel along with estradiol valerate (Progynova, Bayer-Schering, Berlin, Germany) (group 1) or only progesterone vaginal gel (group 2). They were in good health with normal thyroid, Group 1 and 2 were comparable with respect to the patient’s char- hepatic and renal functioning. The Institutional Review Board of our acteristics such as the age of patients, infertility duration, the propor- center approved the study (2006-0446) and all of the patients pro- tion of nullipara, body mass index (BMI), antral follicle count (AFC) Each group 1 and 2 consisted of 55 cycles initiated corresponding 2. Ovarian stimulation protocols
to 55 patients. In group 1, 1 out of 55 cycles initiated (1.8%) was can- The GnRH antagonist multiple dose protocol (MDP) using recombi- celled before ET, because no oocytes were obtained despite a follicu- nant human follicle stimulating hormone FSH (rhFSH) was used for lar aspiration for oocyte retrieval. In group 2, 1 out of 55 cycles initiat- COS in al of the subjects. On cycle day 3, ovarian stimulation was ed (1.8%) was cancelled after oocyte retrieval due to a high risk of commenced using rhFSH (Gonal-F, Merck-Serono SA) of 150 to 225 ovarian hyperstimulation syndrome (OHSS). There was no significant IU/day after establishing ovarian and uterine quiescence using vagi- difference in the cycle cancellation rate between the two groups. Ta- nal ultrasound. The rhFSH dose was adjusted according to the ovari-an response, every 3 to 4 days. GnRH antagonist (Cetrotide, 0.25 mg; Table 1. Patient characteristics
Merck-Serono SA) was started when the leading follicle reached an average of 14 mm in diameter, and was continued daily until the day of hCG administration. Recombinant hCG (rhCG, Ovidrel, Merck-Sero- no SA) of 250 μg was injected to induce follicular maturation when one or more follicles reached a mean diameter of ≥18 mm. Oocyte retrieval was performed 35 to 36 hours after hCG injection and one to three embryos were transferred into the uterus on the third day after oocyte retrieval. For group 1, 90 mg of vaginal progesterone gel (Crinone 8%) once daily and estradiol valerate orally 4 mg daily were administrated for luteal phase support from the day of oocyte re- trieval. For group 2, only 90 mg of vaginal progesterone gel was ad- ministered during the same period. The serum level of β-hCG was measured 11 days after embryo transfer (ET). On the day of the first pregnancy test, patients were asked by the clinician in our fertility clinic if they had experienced any bleeding. Clinical pregnancy was Values are presented as mean±SD or number (%).
E defined as an increased serum β-hCG concentration, as measured by 2, estradiol; P, progesterone; FSH, follicle stimulating hormone; NS, not sig- radioimmunoassay using a hCG MAIAclone kit (Serono Diagnostics, aStudent’s t-test; bChi-squared test or Fisher’s exact test.
http://dx.doi.org/10.5653/cerm.2013.40.3.131
SK Kwon et al. Luteal estradiol supplementation in GnRH antagonist cycles
Table 2. Comparison of controlled ovarian stimulation results and
Discussion
COS has contributed to improving assisted reproductive technolo- gy (ART) outcomes. However, COS frequently results in luteal phase defect (LPD). The luteal function could be attributed to COS, resultant altered hormone levels and the process of oocyte retrieval. The eleva- tion of serum estradiol to supraphysiologic levels by COS was prone to alter endometrial receptivity by causing an imbalance of the estra- diol/progesterone ratio. Follicular fluid aspiration for oocyte retrieval may disrupt and reduce the number of granulosa cells undergoing luteinization, thereby diminishing the corpus luteal function and re- ducing progesterone levels. Luteal function can be suppressed by the direct effect of GnRH agonist on the corpus luteum in a GnRH ag- onist long protocol [5]. Applying GnRH antagonist co-treatment in IVF cycles has also shown that luteolysis is initiated prematurely, re- sulting in a significant reduction in the length of the luteal phase [5]. Multiple PR per clinical pregnancy (%) 30.8 (8/26) In these conditions, LPD can be overcome by supplementation of hCG or progesterone, a concept referred to as luteal phase support, and this modality has been the standard for luteal phase support Values are presented as mean±SD or number (%).
since late the 1980s [6]. A recent meta-analysis demonstrated that IVF, in vitro fertilization; E2, estradiol; P, progesterone; ET, embryo transfer; ICSI, the effect of hCG is comparable to progesterone for luteal phase sup- intracytoplasmic sperm injection; rhFSH, recombinant human follicle stimu-lating hormone; PR, pregnancy rate; NS, not significant. port with respect to clinical PR [6]. Nevertheless, progesterone is of- aChi-squared test or Fisher’s exact test; bStudent’s t-test. ten favored, because hCG is closely related to the development of OHSS. Various preparations of progesterone including oral, intramus- ble 2 presents the comparison of COS results and IVF outcomes be- cular (IM) and vaginal forms are currently available. A recent meta- tween groups 1 and 2. The two groups were similar in total the days analysis investigating possible differences in ART outcomes between and dose of rhFSH required for COS. There were no significant differ- the different progesterone preparations have shown that IM and ences between the two groups with respect to the numbers of oo- vaginal progesterone are equally effective for luteal phase support cytes retrieved, mature oocytes, fertilized oocytes, grade I or II em- [7]. IM progesterone is often associated with many side effects such bryos, embryos transferred and embryos frozen (Table 2). There were as painful injection, skin rash, urticaria and inflammatory reactions. also no differences in the clinical pregnancy rate (PR) and multiple PR Therefore, vaginal progesterone is frequently favored. However, a between the two groups (Table 2). However, the embryo implanta- few studies have reported a higher incidence of LVB in patients sup- tion rate was significantly higher in group 1, 26.0% (38/146) com- plemented with the vaginal progesterone gel, Crinone compared pared with 15.8% (24/152) in group 2 (p=0.033) (Table 2). The inci- with those supplemented with IM progesterone [3]. The clinical sig- dence of luteal vaginal bleeding (LVB) was significantly lower in group nificance of LVB remains unclear. In patients who received only Cri- 1 than in group 2 (5.6% vs. 24.1% respectively, p=0.013) (Table 2). In none in our study, LVB occurred more frequently in the nonpregnant group 1, LVB occurred with equal frequency in the pregnant and subgroup than in the pregnant subgroup (35.3% vs. 5.0%, respec- nonpregnant subgroups (3.8% vs. 7.1%, respectively). There were no tively). In addition, in patients who received Crinone with estradiol in differences in the pregnancy rate between patients who experienced our study, LVB occurred more frequently in the nonpregnant sub- LVB and those who did not (33.3% [1/3] vs. 49.0% [25/51], respec- group than in the pregnant subgroup (7.1% vs. 3.8%, respectively). In tively). However, in group 2 supplemented with only Crinone, the in- a recent study, Yanushpolsky et al. [8] reported the incidence of LVB cidence of LVB was significantly higher in the nonpregnant subgroup, in pregnant patients who were supplemented with estradiol was sig- at 35.3% (12/34) compared with 5.0% (1/20) in the pregnant sub- nificantly lower than in those who were supplemented with only group (p=0.019). Those who experienced LVB had significantly lower progesterone (10% vs. 23.9%, respectively). It is unknown whether pregnancy rates than those who did not experience LVB (7.7% [1/13] LVB is the cause or result of embryo implantation failure. However, vs. 46.3% [19/41] respectively, p=0.019).
LVB may be an ominous sign of implantation failure and be disquiet- ing to both patients and physicians. Therefore, an effort to reduce www.eCERM.org
Clin Exp Reprod Med 2013;40(3):131-134
LVB is needed. Actually, in the present study, the addition of estradiol References
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No potential conflict of interest relevant to this article was reported.
http://dx.doi.org/10.5653/cerm.2013.40.3.131

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