Medicine, Salt Lake, Kolkata, West Bengal, India

Transcription

1 Comparison of oral dydrogestrone with progesterone gel and micronized progesterone for luteal support in 1,373 women undergoing in vitro fertilization: a randomized clinical study Ashalatha Ganesh, M.B.B.S., M.M.S.T., Ph.D., a Nishant Chakravorty, M.B.B.S., M.M.S.T., a Rashmi Mukherjee, M.Sc., a Sourendrakanta Goswami, M.B.B.S., b Koel Chaudhury, Ph.D., a and Baidyanath Chakravarty, M.B.B.S., M.D. b a School of Medical Science and Technology, Indian Institute of Technology, Kharagpur; and b Institute of Reproductive Medicine, Salt Lake, Kolkata, West Bengal, India Objective: To compare the efficacy of oral dydrogesterone with that of micronized vaginal P gel and micronized P capsule for luteal supplementation. Design: Prospective, randomized clinical study. Setting: Institute of Reproductive Medicine, Kolkata, India. Patient(s): A total of 1,373 infertile women undergoing IVF participated. Intervention(s): Micronized P gel, P capsule, and oral dydrogesterone were administered for luteal support and compared. Main Outcome Measure(s): Demographic profile and pregnancy and miscarriage rates. Result(s): The overall pregnancy rate and miscarriage rate were comparable among the three groups. Conclusion(s): Oral dydrogesterone seems to be a promising drug for luteal support in woman undergoing IVF. (Fertil Steril Ò 2011;95: Ó2011 by American Society for Reproductive Medicine.) Key Words: Dydrogesterone, luteal-phase support, micronized vaginal progesterone, progesterone gel, progesterone supplementation Stimulated IVF cycles are associated with a defective luteal phase in almost all patients (1 3). Various factors, including pituitary downregulation with GnRH agonist, administration of hcg for final oocyte maturation (4), and aspiration of follicular fluid in assisted reproductive technology (ART) cycles may alter the estrogen/p ratio, resulting in luteal-phase defect (LPD) (1, 2). It is well established that luteal support causes considerable improvement in IVF outcome (5 8). Progesterone or hcg supplementation during the luteal phase of IVF cycles improves clinical pregnancy outcomes significantly as compared to cycles without treatment (5). Progesterone is usually the drug of choice for luteal support because the likelihood of ovarian hyperstimulation syndrome is more than twofold higher with hcg supplementation (7, 9). Different types of luteal-phase supplementation (LPS) with varying doses and duration have been extensively investigated to overcome LPD in stimulated IVF cycles (10, 11). It is suggested that exogenous P can be administered intramuscularly (IM), intravaginally, or orally for luteal support, regardless of the response to gonadotropin stimulation. The drug may be administered either as 17a-hydroxyprogesterone or micronized P or dydrogesterone (5, 12). Vaginal and IM P are reported to have comparable outcomes (11). Received October 20, 2010; revised January 18, 2011; accepted January 20, 2011; published online February 21, A.G. has nothing to disclose. N.C. has nothing to disclose. R.M. has nothing to disclose. S.G. has nothing to disclose. K.C. has nothing to disclose. B.C. has nothing to disclose. A.G. was supported by the Council of Scientific and Industrial Research [file no. 9/81(675)/08 EMR-I, dated March 25, 2008]. Reprint requests: Koel Chaudhury, Ph.D., School of Medical Science and Technology, Indian Institute of Technology, Kharagpur, West Bengal , India ( koel@smst.iitkgp.ernet.in). Contradictory reports exist regarding the optimal route of P supplementation. Dydrogesterone, a retro-progesterone, is closely related to endogenous P in its molecular structure and its pharmacologic effects, with good oral bioavailability (13). It is an optical isomer of P in which the methyl group in 10 carbon is located in a position (in natural P it is in b position), hydrogen attached to 9 carbon is in b position (in natural P it is in a position), and there is an extra double bond between carbon 6 and 7. These changes in configuration make dydrogesterone more stable and effective orally. It has excellent patient compliance and is devoid of local adverse effects. An ongoing pregnancy rate of 31% was obtained with dydrogesterone in a study in which oocyte donation was followed by IVF (14). In 2007, Patki and Pawar (15) found the pregnancy rate to be significantly higher with dydrogesterone than with micronized vaginal P and placebo treatment. The authors concluded that dydrogesterone is effective luteal-phase support in ART. However, there are limited reports on the use of dydrogesterone in ART cycles for luteal supplementation (16, 17). Because data from well-controlled clinical trials are insufficient, further studies are required to establish the type and dose of progestational agent for optimum outcome (18). A meta-analysis of randomized trials has shown lower clinical pregnancy and delivery rates associated with vaginal P over the IM route (6). In contrast, several trials comparing various routes of micronized P administration in ART cycles support vaginal therapy and have suggested it to be as good as IM therapy and superior to oral therapy (19 22). Painful IM injections and their complications, such as local soreness and inflammatory reactions, can be avoided by the vaginal route (23). Although vaginal gel and IM P are equally effective for luteal-phase support in IVF, vaginal gel is better tolerated by patients owing to ease of use, high tolerability, and fewer side effects (24, 25). Progesterone /$36.00 Fertility and Sterility â Vol. 95, No. 6, May doi: /j.fertnstert Copyright ª2011 American Society for Reproductive Medicine, Published by Elsevier Inc.

2 vaginal gel can be successfully used as an alternative to IM P for luteal support in IVF. One daily dose seems sufficient to support clinical pregnancies and live births at a rate comparable to IM supplementation (26). Several clinical trials have shown that among the different routes of P administration, the vaginal route is considered to be more convenient and effective than the IM or oral route (19, 12). In most ART centers worldwide, use of vaginal natural P has become routine practice. However, several research groups believe that the vaginal route is not very well accepted by all patients because of side effects such as vaginal irritation and discharge (27). In India, where 40,000 IVF cycles are performed every year, the oral route is preferred by the majority of women because they find this route of administration more convenient. In a study reported earlier, we compared the efficacy of oral dydrogesterone for LPS in 79 women undergoing IVF with vaginal micronized P (28) and found the results to be encouraging with oral dydrogesterone. This further motivated us to increase the sample size, to validate our earlier findings. Moreover, an extensive literature search showed no study comparing oral dydrogesterone, micronized vaginal P, and P gel for LPS. The main objective of this study was to compare the efficacy of oral dydrogesterone with that of vaginal micronized P and P gel in a large population of women undergoing IVF. MATERIALS AND METHODS Patient Selection This prospective, randomized, single-blinded and comparative study was carried out in a tertiary infertility care unit, the Institute of Reproductive Medicine, Kolkata, India. Approval was obtained from the research ethics committee of the Institute before the study. A total of 1,363 women (aged years) undergoing controlled ovarian stimulation for IVF treatment (fresh cycle) were included in the study. Women with a history of tubal factor, male factor infertility, idiopathic infertility, endometriosis-related infertility, and ovulatory disturbances were included. All women were euthyroid and normoprolactinemic. There was no case of dropout from any of the three groups. Women with baseline FSH >12 IU and adenomyosis were excluded. All women received a daily SC injection of 500 mg GnRH agonist, leuprolide acetate (Lupride 4; Sun Pharmaceuticals, Mumbai, India), followed by recombinant FSH, IU (Gonal-F; Serono, Aubonne, Switzerland). Ovarian follicular development was monitored by transvaginal ultrasonography, which started from day 6 of stimulation. Human chorionic gonadotropin injection (Profasi; Serono, Geneva, Switzerland; 10,000 IU) was administered IM when the leading follicle reached R18 mm in diameter and there were at least two or more follicles R17 mm in diameter. This occurred approximately between days 9 and 13 of stimulation. Serum peak E 2 was assessed on the day of hcg administration. Oocytes were retrieved transvaginally under ultrasound guidance hours after hcg injection. Subsequently, conventional IVF was performed when the semen sample of the male partner was normal. Intracytoplasmic sperm injection was the choice of treatment in case of azoospermia or severe oligoasthenospermia. An average of three embryos was transferred between 40 and 44 hours after insemination. Luteal support began on the day of ET. The enrolled participants were counseled, and informed consent was obtained before randomization, as per the institution s protocol. Sequentially numbered sealed envelopes were prepared and provided by the study coordinator, according to random-number tables. Single-blinding was achieved by keeping the person enrolling participants, study investigators, ultrasound technicians, and clinicians unaware of the type of protocol used. Only the statisticians had access to the unblinded data. A double-blind study protocol was not possible because the drug delivery method in the three groups was different. Group A (n ¼ 422) received 10 mg dydrogesterone twice daily (Duphaston; Solvay Pharma India, Mumbai), group B (n ¼ 482) received 90 mg micronized vaginal P gel per day (Crinone 8%; Merck Serono, Fleet Laboratories, Watford, United Kingdom), and group C (n ¼ 459) received 200 mg micronized P capsule three times daily vaginally (Utrogestan; Solvay Pharma India). The serum b-hcg level was estimated 13 days after ET. Luteal support was continued up to 12 weeks of pregnancy. Outcome in the three groups was evaluated in terms of clinical pregnancy and miscarriage rates. Clinical pregnancy was defined when an ultrasound scan, performed 7 weeks after ET, revealed the presence of a viable fetus. The presence of at least one viable fetus at 12 weeks gestation was classified as ongoing pregnancy. Further, the three groups were graded according to factors including age >37 years, FSH >9 12 IU/mL, dense pelvic adhesions, distorted uterine shape and size, basal antral follicular count fewer than six, body mass index (BMI) >25 kg/m 2, and duration of infertility >7 years. These factors were considered to be unfavorable for IVF outcome. Each factor was given a score of 1 if unfavorable, or 0 otherwise. The subjects were graded depending on the total scores. Grade 0 (score 0), grade I (scores 1 3), and grade II (scores 3 5) corresponded to highly favorable, unfavorable, and highly unfavorable categories, respectively. Immunoassay of Hormones Serum levels of LH and FSH were assayed using a two-site chemiluminescent sandwich immunoassay system (ACS: 180; Bayer Diagnostics, Tarrytown, NY). Patients serum samples were assayed immediately upon sample acquisition. All samples were assayed in duplicate. The LH and FSH values were expressed in terms of the reference standards (World Health Organization [WHO] 2nd International Standard [IS] 94/632 and WHO 2nd IS 80/552, respectively). Assay sensitivity for FSH was 0.3 miu/ml and for LH was 0.07 miu/ml. Estradiol levels were measured by a fully automated enzyme-linked fluorescence assay system (Vidas; biomerieux, Marcy l Etoile, France). The minimum detection limit was 9 pg/ml. The intraand interassay coefficients of variation were 3.4% and 5.2% for FSH, 4.4% and 3.2% for LH, and 5.6% and 4.2% for E 2, respectively. Statistical Analysis All data were analyzed using the commercially available software packages KyPlot version 2.0 b13 (software developed by Koichi Yoshioka and available online: and SPSS version 10.0 (SPSS, Chicago, IL). Pregnancy rates and miscarriage rates in the three groups were statistically compared using a c 2 test with Yates correction. All values are presented as mean SD or percentage unless otherwise stated. Differences were considered to be significant at P%.05. Power analysis suggested a sample size of 389 patients per group. The parameters used to determine sample size were based on assuming the pregnancy rate to be 30% for oral dydrogesterone and 20% for the vaginal P gel. Sample size calculation was based on a two-sided significance level a of 0.05 and a power of 90% to detect significant differences between the compared groups. RESULTS Demographic data, including mean age, BMI, and baseline characteristics of patients belonging to groups A, B, and C are summarized TABLE 1 Scoring system adopted for favorable and unfavorable IVF outcome. Factor Favorable (score [ 0) Unfavorable (score [ 1) Age (y) %37 >37 BMI (kg/m 2 ) %25 >25 Baseline FSH (miu/ml) %9 >9 Basal antral follicle count R6 <6 Pelvic adhesions Absent Present Uterine shape Normal Abnormal Total score 0 6 Note: Grading: grade 0 (total score 0), highly favorable; grade I (total score 1 3), unfavorable; grade II (total score 4 6), highly unfavorable Ganesh et al. Oral dydrogesterone as luteal support Vol. 95, No. 6, May 2011

3 TABLE 2 Demographic data of patients randomly subjected to three different luteal supplementation protocols. Demographic parameter Oral dydrogesterone protocol, group A (n [ 422) Micronized vaginal P gel, group B (n [ 482) Vaginal P capsules, group C (n [ 459) Mean age (y) Mean BMI (kg/m 2 ) FSH (miu/ml) LH (miu/ml) E 2 (pg/ml) Basal antral follicle Endometrial thickness Pregnancy rate (121/422) a (138/482) a (104/459) a Miscarriage rate (14/121) a (18/138) a (19/104) a Note: Data presented as mean SD or percentage (number). a Not significant. in Table 1. The overall pregnancy rate was 28.67%, 28.63%, and 22.65% for groups A, B, and C, respectively, and found to be comparable. The miscarriage rate was also comparable among the three groups (Table 2). The overall pregnancy rates and miscarriage rates were found to be comparable in the subgroups grade 0, grade I, and grade II of groups A, B, and C (Table 3). DISCUSSION Luteal-phase supplementation is necessary for optimal success in IVF stimulated cycles. It is suggested that P supplementation yields significantly higher pregnancy rates as compared with unsupported IVF-ET cycles (29). Presently, IM and transvaginal routes are the two conventional methods of P administration (30). As mentioned earlier, there are very few studies in which comparison of oral dydrogesterone with natural P for luteal support in ART cycles is documented. In the present study, we have assessed the clinical efficacy of oral dydrogesterone for LPS in 422 stimulated IVF cycles and compared the pregnancy and miscarriage rates with those of women using vaginal micronized P and vaginal P gel. Our earlier study on LPS in women undergoing IVF showed no significant differences in pregnancy rates, miscarriage rates, or viable delivery rates between women receiving oral dydrogesterone and vaginal micronized P (28). The present findings on a larger subpopulation are in agreement with our earlier results. Pregnancy and miscarriage rates were found to be comparable among the three groups. Our results are supported by other researchers who observed similar efficacy with dydrogesterone and natural micronized P in women undergoing IVF-ET (29, 31, 32). Further, a prospective randomized study comparing vaginal gel and vaginal capsules for LPS showed the ongoing pregnancy rate to be comparable between the two groups (33, 34). Another group observed identical pregnancy rates between the gel and micronized P intravaginal capsules. They also found the gel to be far more tolerable than vaginal capsules, in terms of lesser side effects (35). Luteal-phase supplementation with vaginal gel is associated with better clinical pregnancy and implantation rates than vaginal capsules in IVF/intracytoplasmic sperm injection blastocyst transfer cycles (36). On comparing vaginal with IM P supplementation for TABLE 3 Comparison of pregnancy rates and miscarriage rates between groups A, B, and C for grade 0, grade I, and grade II. Parameter Oral dydrogesterone protocol, group A Progesterone vaginal gel, group B Vaginal P capsules, group C P value Grade 0 n Pregnancy rate 31.5 (23/73) (27/79) (24/83) NS Miscarriage rate 13 (3/23) (3/27) (4/24) NS Grade I n Pregnancy rate (89/315) (107/389) (77/357) NS Miscarriage rate (10/89) (14/107) (14/77) NS Grade II n Pregnancy rate (9/34) (4/14) (3/19) NS Miscarriage rate (1/9) 25.0 (1/4) (1/3) NS Note: Data presented as percentage (number). NS ¼ not significant. Fertility and Sterility â 1963

4 LPS after IVF-ET, there was no significant differences in treatment outcomes between vaginal and IM P supplementation, yielding similar clinical pregnancy, miscarriage, and live birth rates (37). In the present study, we found comparable results with oral dydrogsesterone and the vaginal gel application. Most of these women undergoing IVF have multiple causes of infertility and different demographic profiles. In infertility clinics, very few patients are encountered with a highly favorable profile, and most of the time clinicians are challenged with infertile women having factors that are unfavorable for IVF. Our aim was to evaluate whether oral dydrogesterone is as effective as micronized P in poor-profile patients. Therefore, these women were classified retrospectively according to the demographic profiles that we commonly encounter in our infertility clinic. Factors including age (>37 years), FSH (>9 12 IU/mL), dense pelvic adhesions, distorted uterine shape and size, basal antral follicular count (fewer than six), BMI (>25 kg/m 2 ), and duration of infertility (>7 years) were considered unfavorable for IVF outcome. Each factor was given a score of 1 if unfavorable, or 0 otherwise. The subjects were graded depending on the total scores. The grading criteria showing grade 0 (score 0), grade I (scores 1 3), and grade II (scores 3 5) corresponding to highly favorable, unfavorable, and highly unfavorable categories, respectively, are summarized in Table 1. Pregnancy and miscarriage rates for each grade were compared among groups A, B, and C. The results are summarized in Table 3. No significant differences were observed when comparing the three groups for specific grades. It is evident from our study that oral dydrogesterone is effective in infertile women undergoing IVF, irrespective of the cause of infertility or the number of factors contributing to infertility. Our results suggest that oral dydrogesterone is as effective as micronized P for LPS in women undergoing IVF. Several potential benefits of dydrogesterone have led us to believe that this drug may be considered as an alternative to vaginal P for LPS. Dydrogesterone, an optical isomer of P, has a high affinity for P receptors, and its conformational structure makes it a metabolically stable and orally effective drug. In patients diagnosed with LPD, dehydrogesterone has been successfully used to induce normal endometrial maturation (38, 39). It is hypothesized that dydrogesterone, through its preferential affinity for P receptor A, has a better potentiality to generate endothelial nitric oxide synthetase and release nitric oxide, thereby enhancing endometrial vascularity (35). It is also suggested that dydrogesterone restores normal concentration of P-induced blocking factors in T lymphocytes and endometrial cells, which induces a favorable immunologic environment for implantation (40). To summarize, dydrogesterone is a promising drug for luteal support in woman undergoing IVF and seems to be as effective as micronized P for LPS in women undergoing IVF. Oral dydrogesterone can be considered for routine luteal support because the side effects, such as vaginal irritation and discharge, can be avoided. Acknowledgment: The authors thank Mrs. Sharmista for assisting in data collection. REFERENCES 1. Ubaldi F, Bourgain C, Tournaye H, Smitz J, Van Steirteghem A, Devroey P. Endometrial evaluation by aspiration biopsy on the day of oocyte retrieval in the embryo transfer cycles in patients with serum progesterone rise during the follicular phase. Fertil Steril 1997;67: Macklon NS, Fauser BC. Impact of ovarian hyperstimulation on the luteal phase. J Reprod Fertil Suppl 2000;55: Kolibianakis EM, Bourgain C, Platteau P, Albano C, Van Steirteghem AC, Devroey P. Abnormal endometrial development occurs during the luteal phase of nonsupplemented donor cycles treated with recombinant follicle-stimulating hormone and gonadotropin-releasing hormone antagonists. Fertil Steril 2003;80: Van Der Gaast MH, Beckers NG, Beier-Hellwig K, Beier HM, Macklon NS, Fauser BC. Ovarian stimulation for IVF and endometrial receptivity the missing link. Reprod Biomed Online 2002;5(Suppl 1): Soliman S, Daya S, Collins J, Hughes EG. The role of luteal phase support in infertility treatment: a meta-analysis of randomized trials. Fertil Steril 1994;61: Pritts EA, Atwood AK. Luteal phase support in infertility treatment: a meta-analysis of the randomized trials. Hum Reprod 2002;17: Daya S, Gunby J. Luteal phase support in assisted reproduction cycles. Cochrane Database Syst Rev; 2004:CD Nosarka S, Kruger T, Siebert I, Grove D. Luteal phase support in in vitro fertilization: meta-analysis of randomized trials. Gynecol Obstet Invest 2005;60: Araujo E, Bernadini L, Frederick JL, Asch RH, Balmaceda JP. Prospective randomized comparison of human chorionic gonadotropin versus intramuscular progesterone for luteal phase support in assisted reproduction. J Assist Reprod Genet 1994;11: Pouly JL, Bassil S, Frydman R, Hedon B, Nicollet B, Prada Y, et al. Luteal support after in-vitro fertilization: Crinone 8%, a sustained release vaginal progesterone gel, versus Utrogestan, an oral micronized progesterone. Hum Reprod 1996;11: Fatemi HM, Popovic-Todorovic B, Papanikolaou E, Donoso P, Devroey P. An update of luteal phase support in stimulated IVF cycles. Hum Reprod Update 2007;13: Smitz J, Devroey P, Faguer B, Bourgain C, Camus M, Van Steirteghem AC. A prospective randomized comparison of intramuscular or intravaginal natural progesterone as a luteal phase and early pregnancy supplement. Hum Reprod 1992;7: Coelingh Bennink HJT, Boerrigter PJ. Use of dydrogesterone as a progestogen for oral contraception. Steroids 2003;68: Abu-Musa A, Hannoun A, Khalil A, Masaad Z, Karam K. Artificial endometrial preparation for oocyte donation using synthetic estrogen and progestogen. Clin Exp Obstet Gynecol 1998;25: Patki A, Pawar VC. Modulating fertility outcome in assisted reproductive technologies by the use of dydrogesterone. Gynecol Endocrinol 2007;23: Belaisch-Allart J, Testart J, Fries N, Forman RG, FrydmanR. The effectofdydrogesterone supplementation in an IVF programme. HumReprod 1987;2: Kupferminc MJ, Lessing JB, Amit A, Yovel I, David MP, Peyser MR. A prospective randomized trial of human chorionic gonadotrophin or dydrogesterone support following in-vitro fertilization and embryo transfer. Hum Reprod 1990;5: Daya S. Luteal support: progestogens for pregnancy protection. Maturitas 2009;65(Suppl 1):S Tavaniotou A, Smitz J, Bourgain C, Devroey P. Comparison between different routes of progesterone administration as luteal phase support in infertility treatments. Hum Reprod Update 2000;6: Levine H, Watson N. Comparison of the pharmacokinetics of crinone 8% administered vaginally versus Prometrium administered orally in postmenopausal women(3). Fertil Steril 2000;73: Penzias AS, Alper MM. Luteal support with vaginal micronized progesterone gel in assisted reproduction. Reprod Biomed Online 2003;6: Ng EHY, Chan CCW, Tang OS, Ho PC. A randomized comparison of side effects and patient convenience between CyclogestÒ suppositories and EndometrinÒ tablets used for luteal phase support in IVF treatment. Eur J Obstet Gynecol Reprod Biol 2007;131: Penzias AS. Luteal phase support. Fertil Steril 2002;77: Yanushpolsky E, Hurwitz S, Greenberg L, Racowsky C, Hornstein M. Crinone vaginal gel is equally effective and better tolerated than intramuscular progesterone for luteal phase support in in vitro fertilization-embryo transfer cycles: a prospective randomized study. Fertil Steril 2010;94: 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 clinical trial. Fertil Steril 2010;94: Dal Prato L, Bianchi L, Cattoli M, Tarozzi N, Flamigni C, Borini A. Vaginal gel versus intramuscular progesterone for luteal phase supplementation: a prospective randomized trial. Reprod Biomed Online 2008;16: Schoolcraft WB, Hesla JS, Gee MJ. Experience with progesterone gel for luteal support in a highly successful IVF programme. Hum Reprod 2000;15: Chakravarty BN, Shirazee HH, Dam P, Goswami SK, Chatterjee R, Ghosh S. Oral dydrogesterone versus intravaginal micronised progesterone as luteal phase 1964 Ganesh et al. Oral dydrogesterone as luteal support Vol. 95, No. 6, May 2011

5 support in assisted reproductive technology (ART) cycles: results of a randomised study. J Steroid Biochem Mol Biol 2005;97: Inizi STA, Asaad M, Schick J. Luteal phase support in in-vitro fertilization. Middle East Fertil Soc J 2006;11: Chang SP. Comparison of Crinone 8% intravaginal gel and intramuscular progesterone for luteal support in in vitro fertilization. J Chin Med Assoc 2008;71: Norman TR, Morse CA, Dennerstein L. Comparative bioavailability of orally and vaginally administered progesterone. Fertil Steril 1991;56: Domitrz JWS, Syrewicz M, Szamatowicz J, Kuezyanski W, Corochowski D, Szamatowicz M. The comparison of efficiency of supplement of the second phase in the program IVF-ET by dydrogesterone and progesterone. Ginekol Pol 1999;70: Ludwig M, Schwartz P, Babahan B, Katalinic A, Weiss JM, Felberbaum R, et al. Luteal phase support using either CrinoneÒ 8% or UtrogestÒ: results of a prospective, randomized study. Eur J Obstet Gynecol Reprod Biol 2002;103: Kleinstein J. Efficacy and tolerability of vaginal progesterone capsules (Utrogest 200) compared with progesterone gel (Crinone 8%) for luteal phase support during assisted reproduction. Fertil Steril 2005;83: Simunic V, Tomic V, Tomic J, Nizic D. Comparative study of the efficacy and tolerability of two vaginal progesterone formulations, Crinone 8% gel and Utrogestan capsules, used for luteal support. Fertil Steril 2007;87: Wang LJ, Huang FJ, Kung FT, Lin PY, Chang SY, Lan KC. Comparison of the efficacy of two vaginal progesterone formulations, Crinone 8% gel and Utrogestan capsules, used for luteal support in blastocyst stage embryo transfers. Taiwan J Obstet Gynecol 2009;48: Khan N, Richter KS, Newsome TL, Blake EJ, Yankov VI. Matched-samples comparison of intramuscular versus vaginal progesterone for luteal phase support after in vitro fertilization and embryo transfer. Fertil Steril 2009;91: Balasch J, Vanrell JA, Marquez M, Burzaco I, Gonzalez-Merlo J. Dehydrogesterone versus vaginal progesterone in the treatment of the endometrial luteal phase deficiency. Fertil Steril 1982;37: Jacobs MH, Balasch J, Gonzalez-Merlo JM, Vanrell JA, Wheeler C, Strauss JF 3rd, et al. Endometrial cytosolic and nuclear progesterone receptors in the luteal phase defect. J Clin Endocrinol Metab 1987;64: Szekeres-Bartho J, Polgar B. PIBF: the double edged sword. Pregnancy and tumor. Am J Reprod Immunol 2001;64: Fertility and Sterility â 1965