Luteal Phase Support in Assisted Reproduction

Middle East Fertility Society Journal Vol. 12, No. 3, 2007 © Copyright Middle East Fertility Society

DEBATE

Luteal phase support in assisted reproduction

Comment by: Mohamed Yehia, MD, FRCOG the most important source of progesterone Cairo, Egypt synthesis by the corpus luteum, thus disrupting the luteal phase (6). supraphysiological levels of steroids [related to the larger number of corpora 1- Is luteal support needed? lutea] during the early luteal phase could directly inhibit LH release via negative feedback actions at The first report of the combined use of pituitary the hypothalamic-pituitary axis (7). A meta- suppression and ovarian hyperstimulation in in- analysis comparing placebo with any form of luteal vitro fertilization (IVF) and embryo transfer support favored the addition of luteal support (8). programmes was published in 1984 (1). Since Vlaisavljevic (2007) compared natural IVF cycles then, the advantages of gonadotrophin hormone- with and without luteal support and concluded that releasing hormone analogues (GnRHa) have been even in a natural cycle IVF a higher pregnancy rate well documented; the cancellation rate has been was observed if HCG was administered after decreased through the prevention of premature embryo transfer (9). luteinizing hormone (LH) surge, follicular recruitment has improved, and the ovarian 2- What is the best regimen for luteal support? response to hyperstimulation has been better synchronized, thus facilitating the scheduling of Human chorionic gonadotropin (HCG), oocyte retrieval (OR). This pituitary suppression progesterone, with or without estrogen have been however, results in an impaired gonadotrophin used to support the luteal phase. production later on, and the output of LH remains blocked for at least 10 days after cessation of A- Is HCG superior to progesterone? GnRHa administration (2, 3). As gonadotrophins are necessary to maintain progesterone output by In comparing HCG and progesterone –both the corpus luteum, exogenous luteal support is intramuscular (I.M.) and vaginal- a meta-analysis mandatory. However several reports have shown preformed by Pritts and Atwood (2002) found no that corpus luteum function and luteal phase differences (10). However, in a recent meta- duration are shortened in IVF cycles regardless of analysis comparing progesterone versus human the protocol used for multifollicular induction. In chorionic gonadotropin (hCG) alone or in comparing HMG either alone or with the addition combination with progesterone, it was concluded of GnRH antagonist cetorolix, Tavaniotuo et al. that hCG was superior to progesterone as luteal 2001, have shown that LH concentration declines phase support with respect to pregnancy rates (8). at the mid luteal phase and without luteal The drawbacks of using hCG are the increased risk supplementation the corpus luteum function will of ovarian hyperstimulation and, in my opinion, be disturbed which results in a very low the other drawback stems from the long half life of implantation rate (4). The induction of multiple hCG in the circulation (about 8 days) which can follicle development per se could either directly occasionally lead to erroneous diagnosis of or indirectly influence the duration of the luteal pregnancy with its distressing psychological phase (5); the removal of large quantities of impact on the patient. granulosa cells at oocyte retrieval may diminish

158 Debate Luteal phase support in assisted reproduction MEFSJ B-Which route of progesterone administration cream is used once daily while micronized confers more reproductive benefit: oral, I.M. or progesterone requires multiple applications (2-3 vaginal? times/day).

While the oral route is the patients’ preference, the C-When to start luteal support? very high dose needed to be administered to reach a sufficient progesterone concentration in the Mochtar et al. (2006) compared the effect of the serum will lead to several problems. The onset of luteal support on pregnancy rate, and breakdown products from the metabolism of oral found no significant difference whether progesterone have been associated with sedation, progesterone support started at hCG injection, at drowsiness, and other hypnotic effects, as well as oocyte retrieval or at ET (18). flushing, nausea, and fluid retention. In addition, several studies have shown the superiority of D-How long should luteal support be vaginal progesterone (11, 12). In comparing administrated? vaginal and I.M routes, both have side effects. Intramuscular injections are not only painful, but There is no consensus regarding the duration of can also lead to inflammation and even sterile luteal support. Traditionally, progesterone is abscess formation at the injection site (13). Severe administrated for 8-10 weeks after positive allergic reactions to the oil used as a vehicle for pregnancy test, however no difference was found if progesterone injections have also been reported. progesterone was withdrawn immediately after Acute eosinophilic pneumonia was reported (14) positive pregnancy test or continued for 8 weeks. and can induce severe morbidity in otherwise (19, 20). healthy young women. Vaginal application of progesterone has also led to E-Adding estrogen some minor side-effects such as vaginal discharge and irritation. Although I.M. injections have lead Several investigators have noticed that the level of to higher serum levels of progesterone, the vaginal estrogen is low during the luteal phase in IVF formulations have been shown to have better cycles. The results of adding estrogen to synchronization effects upon the endometrium progesterone produced conflicting data; while (15). This is theorized to be due to a first pass Gorkemli et al. (2004) found an increased uterine effect leading to higher uterine tissue levels pregnancy rate (21), Fatemi et al. (2006) found no and lower systemic serum levels (16). In meta- differences in pregnancy rate or implantation rate analysis by Pritts and Atwood 2002, however, the (22). I.M. route conferred higher clinical pregnancy rate (CPR) and delivery rate (DR) than the vaginal route. Unfer et al. (2004) used 17 alpha- CONCLUSION hydroxyprogesterone caproate every 3 days (instead of the routine daily dose) versus At the present evidence points out the necessity of intravaginal progesterone in IVF-embryo transfer adding luteal support to any protocol of controlled cycles in a prospective randomized study and hyperstimulation; even if no agonist or antagonist found the former superior (17). A drawback in I.M. is used. HCG is equivalent to progesterone in progesterone is the prolongation of luteal phase efficiency but is associated with a higher incidence despite the absence of pregnancy. Bleeding of hyperstimulation syndrome. Progesterone eventually occurs, but patients often feel intramuscularly seems to yield a better pregnancy something is wrong when no menstruation occurs rate; however the side effects of intramuscular and she is not pregnant. Vaginal progesterone is progesterone make local vaginal progesterone available in micronized form, cream and tablets. At cream or suppository the most common form the present no definite significant difference utilized by patients. Estrogen addition does not between the 3 forms was found , however vaginal

Vol. 12, No. 3, 2007 Debate Luteal phase support in assisted reproduction 159 seem to offer an advantage over progesterone 15. Bourgain , C., Smitz, J., Camus,M., Erard, P., DeVroey, P., alone in spite of sporadic reports of the contrary. Van Steirteghem, A.C. and Klopppel, G. Human endometrial maturation is markedly improved after luteal supplementation of gonadotrophin-releasing hormone analogue/human menopausal gonadotrophin stimulated REFERENCES cycles. Hum. Reprod. 1994, 9:32–40. 16. Ludwig, M. and Diedrich, K. Evaluation of an optimal luteal 1. Porter, R , Smith, W and Craft, I :Induction of ovulation for phase support protocol in IVF. Acta Obstet. Gynecol. Scand in vitro fertilization using buserelin and gonadotropins 2001., 80:452–66. Lancet, U.1984,1284-1285. 17. Unfer V; Casini ML; Costabile L; Gerli S; Baldini D; Di 2. Smitz J, Devroey P, Van Steirteghem AC Endocrinology in Renzo GC. 17 alpha-hydroxyprogesterone caproate versus luteal phase and implantation. Br Med Bull 1990,46:709–19 intravaginal progesterone in IVF-embryo transfer cycles: a 3. Broekmans FJ, Bernardus RE, Berkhout G, Schoemaker J. prospective randomized study. Reprod Biomed Online. Pituitary and ovarian suppression after early follicular and 2004; 9(1):17-21 mid-luteal administration of a LHRH agonist in a depot 18. Mochtar MH; Van Wely M; Van der Veen F:Timing luteal formulation: decapeptyl CR. Gynecol Endocrinol. 1992 phase support in GnRH agonist down-regulated IVF/embryo Sep;6(3):153-61. transfer cycles. Hum Reprod. 2006; 21(4):905-8 4. Tavaniotou A, Albano C, Smitz J, Devroey P. Comparison 19. Schmidt, K.L.T., Ziebe, S., Popovic, B., Lindhard, A., Loft, of LH concentrations in the early and mid-luteal phase in A. and Andersen, A.N. Progesterone supplementation during IVF cycles after treatment with HMG alone or in association early gestation after IVF has no effect on the delivery rates. with the GnRH antagonist Cetrorelix.. Hum Reprod. Fertil. Steril.,2001, 75:337–41. 2001;16(4):663-7. 20. Nyboe Andersen A; Popovic-Todorovic B; Schmidt KT; 5. Messinis IE, Templeton AA Disparate effects of Loft A; Lindhard A; Højgaard A; Ziebe S; Hald F; Hauge B; endogenous and exogenous estradiol on luteal phase Toft B.: Progesterone supplementation during early function in women. J Reprod Fertil 1987, 79:549–54 gestations after IVF or ICSI has no effect on the delivery 6. Garcia J, Jones GS, Acosta AA, Wright Jr GL :Corpus rates: a randomized controlled trial. Hum Reprod. 2002; luteum function after follicle aspiration for oocyte retrieval. 17(2):357-61. Fertil Steril , 1981 36:565–72 21. Gorkemli H; Ak D; Akyurek C; Aktan M; Duman S: 7. Fauser BC, Devroey P. Reproductive biology and IVF: Comparison of pregnancy outcomes of progesterone or ovarian stimulation and luteal phase consequences. Trends progesterone + estradiol for luteal phase support in ICSI-ET Endocrinol Metab 2003,14:236–242 cycles. Gynecol Obstet Invest. 2004; 58(3):140-4 . 8. Nosarka S, Kruger T, Siebert I, Grové D.Luteal phase 22. Fatemi HM; Kolibianakis EM; Camus M; Tournaye H; support in in vitro fertilization: meta-analysis of randomized Donoso P; Papanikolaou E; Devroey P: Addition of estradiol trials. Gynecol Obstet Invest. 2005;60(2):67-74. to progesterone for luteal supplementation in patients 9. Vlaisavljevic V, Embryo transfer and luteal support in stimulated with GnRH antagonist/rFSH for IVF: a natural cycles. Reprod Biomed Online. 2007; 14(6):686-92 randomized controlled trial. Hum Reprod. 2006; 10. Pritts EA, Atwood AK. Luteal phase support in infertility 21(10):2628-32 treatment: a meta-analysis of the randomized trials. Hum Reprod. 2002;17(9):2287-99.. 11. Pouly, J.L., Bassil, S., Frydman, R., Hedon, B., Nicollet, B., Prada, Y., Antoine, J.M., Zambrano, R. and Donnez, J. Mohamed Yehia, MD, FRCOG Luteal support after in-vitro fertilization: Crinone 8%, a sustained release vaginal progesterone gel, versus Professor of Obstetrics & Gynecology, Utrogestan, an oral micronized progesterone. Hum. Reprod., Faculty of Medicine, Ain Shams University .1996 ,11, 2085–9. Cairo, Egypt 12. Friedler, S., Raziel, A., Schachter, M., Strassburger, D., Bukovsky, I. and Ron-El, R. Luteal support with micronized progesterone following in-vitro fertilization using a down- regulation protocol with gonadotropin-releasing hormone Comment by: Bulent Urman, M.D. agonist: a comparative study between vaginal and oral M.D. administration. Hum. Reprod., 1999, 14:1944–8. Baris Ata, 13. Tavaniotou, A., Smitz, J., Bourgain, C. and Devroey, P. Istanbul, Turkey Comparison between different routes of progesterone administration as luteal phase support in infertility treatments. Hum. Reprod. Update, 2000,6:139–48. 14. Bouckaert Y, Robert F, Englert Y, De Backer D, De Vuyst Luteal phase support is an integral part of P, Delbaere A. Acute eosinophilic pneumonia associated assisted reproduction treatment. In natural cycles with intramuscular administration of progesterone as luteal the administration of pharmacological agents to phase support after IVF: case report.Hum Reprod. 2004; 19(8):1806-10. augment progesterone secretion from the corpus

160 Debate Luteal phase support in assisted reproduction MEFSJ luteum or to administer the progesterone hormone aspirated during oocyte retrieval in agonist or itself has not been shown to improve the pregnancy antagonist cycles (19). Secretion of progesterone outcome. However, this is not true for assisted recovered earlier in response to stimulation with reproduction treatment (ART) cycles. It has been hCG in the antagonist cycles compared to agonist long recognized that not supporting the luteal cycles. Furthermore morphometric characteristics phase in women undergoing ART is associated and hCG localization following immunoperoxidase with significantly lower pregnancy and delivery staining were different in agonist and antagonist rates (1-4). cycles (20). Contrary to initial beliefs that antagonists do not disrupt the luteal phase their use The etiology of luteal phase insufficiency in has been similarly associated with lower LH levels ART cycles and a shorter luteal phase (21, 22). Friedler et al. studied luteal phase secretion of estradiol and Defective luteal phase in assisted reproduction progesterone in nonconception cycles of patients cycles has been attributed to adverse effects of stimulated with FSH combined with agonist or controlled ovarian hyperstimulation, suppression antagonist for suppression of the premature LH of the pituitary LH release by GNRH analogues, surge (22). Conception cycles were not studied to and to depletion of granulosa cells during follicle obviate the effect of endogenous hCG. The aspiration (5-11). The latter, however, has been concentration of estradiol and progesterone was challenged as aspiration of the dominant follicle in found to be similar in both groups thus lending a natural cycle did not result in shortening of the discredit to the notion that antagonists do not luteal phase or a decreased secretion of adversely affect the luteal phase. progesterone (12). The most likely mechanism for luteal phase Controlled ovarian hyperstimulation (COH) has insufficiency is a disturbance of pituitary function been shown to advance endometrial maturation thus due to the use of GnRH analogues (agonists and disrupting the delicate mechanism of embryo- antagonists), possibly in conjunction with an endometrium interaction (13, 14). In the setting of elevated serum estradiol concentration following COH estradiol concentrations are ovarian stimulation as a result of multiple follicular supraphysiological due to multifollicular maturation development. (15). Furthermore, immediately after ovulation estradiol concentrations decrease to a greater extent Why and how to support the luteal phase due to follicular aspiration and early progesterone rise is more pronounced due to formation of It is evident that the luteal phase is defective in multiple corpora lutea. However, Hung Yu Ng et al. ART cycles thus necessitating the administration did not find an adverse effect of rapidly declining of exogenous agents to overcome this problem. estradiol levels during the midluteal phase (16). Several agents and various routes of administration Controlled ovarian hyperstimulation also may result are available to the practicing physician. HCG is a in a short follicular phase compared to the natural time honored hormone that has been and is still cycle further augmenting the problem of defective being used for luteal phase support. Due to the luteal phase (17). increased risk of hyperstimulation, however, it has The use of GnRH agonists and antagonists has largely been replaced by progesterone. been implicated in the pathogenesis of defective Progesterone can be administered orally, vaginally, luteal phase after IVF treatment (10, 11). or intramuscularly. Several other agents have been The use of agonists may result in decreased mainly used as adjuncts to progesterone. These are progesterone and estradiol production during the hCG, estradiol, GnRH agonists, aspirin, and luteal phase (18). Furthermore, agonists cause various others. Despite the widely adopted practice significant reduction in the length of the luteal of luteal phase support there is still the need for phase, impairment of GnRH secretion and properly designed and adequately powered premature luteolysis. Lin et al. studied randomized studies to determine the agents/s that progesterone secretion from granulosa-lutein cells are associated with higher implantation rates.

Vol. 12, No. 3, 2007 Debate Luteal phase support in assisted reproduction 161 hCG to support the luteal phase associated with bothersome side effects that include drowsiness, flushing and nausea. Meta The initial agent of choice to support the luteal analysis of studies that compared oral progesterone phase has been hCG, however, due to an increased with placebo or no treatment showed no difference risk of ovarian hyperstimulation syndrome (OHSS) in pregnancy rates (COR=1.0; 95% CI=0.77-1.44) it has been largely replaced by progesterone (5, 23- (29). However, more recently dydrogesterone a 25). HCG is simple to use and has been associated retroprogesterone that has good bioavailability has with respectable pregnancy rates. Four studies that been compared with micronized vaginal compared hCG administration with placebo or no progesterone. The authors found no difference in treatment in ART cycles where GnRH analogues pregnancy rates (37). were not used showed no difference in clinical The route of choice for progesterone delivery in pregnancy rates (COR=1.08; 95% CI=0.67-1.73) Europe is vaginal. Progesterone can be (26-28). However, when GnRH agonists were used administered vaginally in several forms that hCG was superior to placebo or no treatment include tablets, suppositories and gels. A relatively (COR=1.94; 95% CI=1.25-3.01). Prospective dated meta-analysis showed slightly decreased randomized studies comparing hCG with ongoing pregnancy rates (COR=0.73; 95% progesterone have shown similar results in term of CI=0.56-0.96), however, similar clinical pregnancy pregnancy and miscarriage rates (29). A more rates (COR=0.82; 95% CI=0.67-1.01) when recent meta analysis showed hCG to be superior to vaginal progesterone was compared with progesterone in terms of clinical pregnancy and intramuscular progesterone for LPS (29). More delivery rates (30). The favorable effect of hCG may recent comparative studies revealed similar be in part due stimulation of the corpora lutea and the pregnancy and delivery rates (38). Vaginal secretion of various growth factors and cytokines in administration of progesterone may mimic more addition to progesterone that in turn optimizes closely the physiological secretory endometrial implantation (31). However, as stated previously the transformation rendering implantation more administration of hCG may cause OHSS even in efficient (39, 40). Furthermore, vaginal moderately overstimulated subjects. It is generally administration through higher local progesterone agreed that hCG during the luteal phase should not be levels decreased uterine peristaltic activity at the administered when the peak estradiol level exceeds time of embryo transfer (41). Different routes of 2500 pg/ml and there are more than 10 mature vaginal progesterone use appear to yield similar follicles at the time of oocyte retrieval (32-34). results. Capsules, gel, and suppositories have been There appears to be no consensus regarding the compared with each other that showed no dosage and frequency of hCG administered to difference in the studied clinical outcomes (42-44). support the luteal phase. There is no consensus on the optimal dose of Recently hCG has been administered in small vaginal progesterone that should be administered doses to overstimulated women who received GnRH for LPS. Different dose of vaginal tablets (300-900 analogues for final induction of follicular maturation mg/day), vaginal suppositories (200-400 mg/day) (35). This strategy has been associated with high and gel (90-180 mg) have been used with similar pregnancy rates and no cases of OHSS and may be outcomes. Unfortunately dosage aspects of vaginal an option for overstimulated subjects. progesterone for LPS have not been studied. Itching and local skin irritation has been reported Progesterone to support the luteal phase with vaginal progesterone but otherwise the drug is well tolerated and preferred by the patients. Progesterone can be administered orally, In North America the preferred route of transvaginally or intramuscularly. Oral progesterone delivery is intramuscular. administration is not preferred due to decreased Intramuscular progesterone injections result in bioavailability from hepatic first pass effect higher serum progesterone levels and in earlier resulting in low tissue concentrations of the studies were associated with higher pregnancy medication (36). Furthermore, oral use has been rates compared with vaginal progesterone (45, 46).

162 Debate Luteal phase support in assisted reproduction MEFSJ More recent studies showed similar outcomes Lukazsuk et al supplemented the luteal phase with compared with vaginal progesterone (38, 47). 2, 4, or 6 mg of estradiol valerate and found only Intramuscular progesterone use is associated with the 6 mg dose to be beneficial (62). In a recent painful injections, allergic reactions, and sterile study that is in press, Engmann et al. administered abscess formation at the injection site, and more 4 mg estrace during the luteal phase in women recently two cases of acute eosinophilic pneumonia stimulated with either the agonist or antagonist (48). As with vaginal progesterone the optimal protocols (63). The authors found significantly dose (50-100 mg/day) of intramuscular decreased pregnancy rates in the long GnRH progesterone is not known. Due to the side effects agonist group supplemented with estradiol. Our and similar outcomes reported with vaginal experience with oral estrogen supplementation progesterone we prefer the latter for LPS. during the luteal phase has not been favorable. A Progesterone has been combined with hCG randomized study using transdermal estrogens is with the aim to benefit from the best of both currently underway in our institution. worlds. A meta analysis of studies that compared GnRH agonists have also been proposed as a novel progesterone with progesterone and hCG showed form of luteal phase support. Two studies showed no difference in pregnancy rates (COR=1.1; 95% an improvement in pregnancy rates with a single CI=0.84-1.43) (29). However, OHSS rates dose GnRH agonist administration in mid luteal increased significantly when hCG was added to phase (64). A recent prospective randomized progesterone for LPS. placebo controlled double blind study performed in our institution showed no additional benefit from Adjuvant treatments during the luteal phase the addition of GnRH agonists on progesterone for LPS in patients undergoing ICSI who were Several adjuvants together with mainly stimulated with a long agonist protocol. We progesterone have been administered during the believe that this seemingly simple strategy should luteal phase with the aim to increase the be further explored prior to its incorporation into implantation rate. The addition of ascorbic acid or routine practice. prednisolone have not been found to be beneficial (49, 50). Aspirin has been advocated both to increase ovarian responsiveness and implantation. CONCLUSION Although some studies showed increased clinical pregnancy rates with the use of aspirin during 1. Luteal phase is deficient in women undergoing ovarian stimulation and the subsequent luteal phase ART treatment. This is true for women stimulated others did not corroborate these results (51-54). A with agonist or antagonists combined with very recent meta-analysis of the prospective gonadotropins. randomized studies showed that aspirin did not 2. Support of the luteal phase is essential. increase pregnancy and delivery rates in the ART 3. LPS with HCG yields satisfactory pregnancy setting (55). rates but carries the risk of OHSS. In selected Estrogen has been advocated as an adjuvant to patients, however, it is simple to use and should be progesterone for LPS. Estrogen can be given further consideration particularly in light of administered either orally or transdermally. While recent evidence that it may be more effective than two earlier randomized trials showed a beneficial progesterone. effect of estrogen in terms of pregnancy rates, 4. Progesterone is preferred for LPS by almost all recent studies failed to corroborate these results IVF centers and appears to be the current agent of (33, 56-60). One study found a significant benefit choice from the use of phytoestrogens and this strategy is 5. Vaginal progesterone should be preferred as its worthwhile further exploration (61). In one other is as effective as intramuscular progesterone and is study transdermal estrogen was used and found to associated with less side effects-effective and more be beneficial (57). However, this study suffered user friendly from low pregnancy rates in the control group.

Vol. 12, No. 3, 2007 Debate Luteal phase support in assisted reproduction 163

6. The role adjuvants such as estrogen and GnRH 16. Hung Yu Ng E, Shu Biu Yeung W, Yee Lan Lau E, Wai Ki analogues should be further explored So W, Chung Ho P. A rapid decline in serum estradiol concentrations around the mid-luteal phase had no adverse effect on outcome in 763 assisted reproduction cycles. Hum Reprod, 2000; 15: 1903-8. REFERENCES 17. Pabuccu R and Akar ME. Luteal phase support in assisted reproductive technology. Curr Opin Obstet Gynecol, 2005; 1. Buvat J, Marcolin G, Herbaut JC, Dehaene JL, Verbecq P, 17: 277-81. Fourlinnie JC. A randomized trial of human chorionic 18. Sheehan K, Casper R, Yen S. Luteal phase defects induced gonadotropin support following in vitro fertilization and by an agonist of luteinizing hormone-releasing factor: a embryo transfer. Fertil Steril, 1988; 49: 458-61. model for fertility control. Science, 1982; 215: 170-172. 2. Daya S. Efficacy of progesterone support in the luteal phase 19. Lin Y, Kahn JA, Hillensjo T. 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Fertil Steril, 2000; 74: Levran D. Estradiol supplementation during the luteal phase 836-837. may improve the pregnancy rate in patients undergoing in 48. Bouckaert Y, Robert F, Englert Y, De Backer D, De Vuyst vitro fertilization-embryo transfer cycles. Fertil Steril, 2000; P, Delbaere A. Acute eosinophilic pneumonia associated 73: 761-6. with intramuscular administration of progesterone as luteal 34. Araujo E, Jr., Bernardini L, Frederick JL, Asch RH, phase support after IVF: case report. Hum Reprod, 2004; 19: Balmaceda JP. Prospective randomized comparison of 1806-10. human chorionic gonadotropin versus intramuscular 49. Griesinger G, Franke K, Kinast C, Kutzelnigg A, Riedinger progesterone for luteal-phase support in assisted S, Kulin S, et al. Ascorbic acid supplement during luteal reproduction. J Assist Reprod Genet, 1994; 11: 74-8. phase in IVF. J Assist Reprod Genet, 2002; 19: 164-8. 35. Krause BT and Ohlinger R. Safety and efficacy of low dose 50. Ubaldi F, Rienzi L, Aniballo S, Iacobelli M, Cobellis L, hCG for luteal support after triggering ovulation with a Greco E. Low dose prednisolone administration in routine GnRH agonist in cases of polyfollicular development. Eur J ICSI patients does not improve pregnancy and implantation Obstet Gynecol Reprod Biol, 2006; 126: 87-92. rates. Hum Reprod, 2002; 17: 1544-1547. 36. Penzias AS. Luteal phase support. Fertil Steril, 2002; 77: 51. Pakkila M, Rasanen J, Heinonen S, al e. Low dose aspirin 318-23. does not improve ovarian responsiveness or pregnancy rate 37. Chakravarty BN, Shirazee HH, Dam P, Goswami SK, in IVF and ICSI patients: a randomized, placebo controlled Chatterjee R, Ghosh S. Oral dydrogesterone versus double blind study. Hum Reprod, 2004; 20: 2211-2214. intravaginal micronised progesterone as luteal phase support 52. Hurst B, Bhojwani J, Marshburn P, al e. Low dose aspirin in assisted reproductive technology (ART) cycles: results of does not improve ovarian stimulation, endometrial response, a randomised study. J Steroid Biochem Mol Biol, 2005; 97: or pregnancy rates for in vitro fertilization. J Exp Clin Assist 416-20. Reprod, 2005; 2: 8-12. 38. Manno M, Marchesan E, Cicutto D, Zadro D, Favretti C, 53. Rubinstein M, Marazzi A, Polak_de_Fried E. Low-dose Tomei F. Greater implantation and pregnancy rates with aspirin treatment improves ovarian responsiveness, uterine vaginal progesterone in intracytoplasmic sperm injection but and ovarian blood flow velocity, implantation, and not in in vitro fertilization cycles: a retrospective study. Fertil pregnancy rates in patients undergoing in vitro fertilization: a Steril, 2005; 83: 1391-1396. prospective, randomized, double-blind placebo-controlled 39. Chantilis SJ, Zeitoun KM, Patel SI, Johns DA, Madziar VA, assay. Fertility and Sterility, 1999; 71: 825-9. McIntire DD. Use of Crinone vaginal progesterone gel for 54. Urman B, Mercan R, Alatas C, Balaban B, Isiklar A, luteal support in in vitro fertilization cycles. Fertil Steril, Nuhoglu A. Low-dose aspirin does not increase implantation 1999; 72: 823-9. rates in patients undergoing intracytoplasmic sperm 40. Schoolcraft WB, Hesla J, Gee M. Experience with injection: a prospective randomized study. Journal of progesterone gel for luteal phase support in a highly Assisted Reproduction and Genetics, 2000; 17: 586-90. successful IVF programme. Hem Reprod, 2000; 15: 1284- 55. Gelbaya T, Kyrgiou M, Stern C, Nardo L. Low dose aspirin 1288. for in vitro fertilization: a systematic review and meta- 41. Tavaniotou A, Smitz J, Bourgain C, Devroey P. Comparison analysis. Hum Reprod Update, 2007; 13: 357-364. between different routes of progesterone administration as 56. Unfer V, Casini ML, Gerli S, Costabile L, Mignosa M, Di luteal phase support in infertility treatments. Hum Reprod Renzo GC. Phytoestrogens may improve the pregnancy rate Update, 2000; 6: 139-48. in in vitro fertilization-embryo transfer cycles: a prospective, 42. Kleinstein J. Efficacy and tolerability of vaginal controlled, randomized trial. Fertil Steril, 2004; 82: 1509-13. progesterone capsules (Utrogest 200) compared with 57. Gorkemli H, Ak D, Akyurek C, Aktan M, Duman S. progesterone gel (Crinone 8%) for luteal phase support Comparison of pregnancy outcomes of progesterone or during assisted reproduction. Fertil Steril, 2005; 83: 1641-9. progesterone + estradiol for luteal phase support in ICSI-ET 43. Geber S, Moreira AC, de Paula SO, Sampaio M. cycles. Gynecol Obstet Invest, 2004; 58: 140-4. Comparison between two forms of vaginally administered 58. Fatemi HM, Kolibianakis EM, Camus M, Tournaye H, progesterone for luteal phase support in assisted reproduction Donoso P, Papanikolaou E, et al. Addition of estradiol to cycles. Reprod Biomed Online, 2007; 14: 155-158. progesterone for luteal supplementation in patients 44. Simunic V, Tomic V, Tomic J, Nizic D. Comparative study stimulated with GnRH antagonist/rFSH for IVF: a of the efficacy and tolerability of two vaginal progesterone randomized controlled trial. Hum Reprod, 2006; 21: 2628- formulations, Crinone 8% gel and Utrogestan capsules, used 32. for luteal support. Fertil Steril, 2007; 87: 83-7. 59. Lewin A, Benshushan A, Mezker E, Yanai N, Schenker JG, 45. Damario MA, Goudas VT, Session DR, Hammitt DG, Goshen R. The role of estrogen support during the luteal Dumesic DA. Crinone 8% vaginal progesterone gel results phase of in vitro fertilization-embryo transplant cycles: a

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comparative study between progesterone alone and estrogen necessary for successful implantation of the and progesterone support. Fertil Steril, 1994; 62: 121-5. embryo (1). 60. Smitz J, Devroey P, Faguer B, Bourgain C, Camus M, Van Steirteghem AC. [A randomized prospective study The second mechanism of luteal phase deficiency comparing supplementation of the luteal phase and early is caused by gonadotropin releasing hormone pregnancy by natural progesterone administered by agonist (GnRH-a) used in the ovarian stimulation intramuscular or vaginal route]. Rev Fr Gynecol Obstet, regimen to prevent premature LH surge. This 1992; 87: 507-16. 61. Unfer V, Casini ML, Costabile L, Gerli S, Baldini D, Di results in persistent block of the LH output for at Renzo GC. 17 alpha-hydroxyprogesterone caproate versus least ten days after discontinuing GnRH-a, which intravaginal progesterone in IVF-embryo transfer cycles: a can result in impairment of progesterone secretion prospective randomized study. Reprod Biomed Online, by the corpus luteum (2). This increases estrogen/ 2004; 9: 17-21. progesterone ratio, which is associated with an 62. Lukaszuk K, Liss J, Luakzsuk M, Maj B. Optimization of estradiol supplementation during the luteal phase improves inhibitory effect on embryo implantation. the pregnancy rate in women undergoing in vitro fertilization In an attempt to enhance the probability of embryo transfer cycles. Fertil Steril, 2005; 83: 1372-1376. pregnancy, different doses, durations and types of 63. Engmann L, Diluigi A, Schmidt D, Benadiva C, Maier D, treatments for LPS have been evaluated. There is, Nulsen J. The effect of luteal phase vaginal estradiol supplementation on the success of in vitro fertilization however, no agreement regarding the optimal treatment: a prospective randomized study. Fertil Steril, supplementation scheme (3). Some authors 2007. suggested IM progesterone-in-oil as the best 64. Tesarik J, Hazout A, Mendosa-Tesarik R, Mendosa N, method of luteal phase support (4). Others Mendosa C. Beneficial effect of luteal phase GnRH agonist suggested vaginal progesterone (5) while some administration on embryo implantation after ICSI in both GnRH agonist and antagonist treated ovarian stimulation claimed that both hCG and intra-vaginal cycles. Hum Reprod, 2006; 21: 2572-2579. progesterone are equally effective (6). GnRH agonist was recently suggested as a novel luteal phase support. The mechanism of the Bulent Urman, M.D. presumed beneficial effect of luteal-phase GnRH Baris Ata, M.D. agonist administration is not clear and may be due Assisted Reproduction Unit, American Hospital to the drug action at multiple levels. It was Guzelbahce Sokak No: 20 hypothesized that GnRH agonist may support the Nisantasi Istanbul 34365 Turkish Republic corpus luteum by stimulating the secretion of LH Tel: +90 212 311 20 00 ext. 1660 by pituitary gonadotrophin cells or by acting Email: [email protected] directly on the endometrium through the locally

expressed GnRH receptors (7). Tesarik et al.

(2004) evaluated 138 women who were assigned to

receive a single injection of 0.1 triptorelin 6 days

after ICSI treatment or to receive placebo. In their Comment by: Hesham Al Inany, M.D. series, they reported a significantly higher Cairo, Egypt implantation and pregnancy rates in the GnRH

agonist treated group compared with the placebo

(8). Moreover, Pirard et al. (2005) investigating Luteal phase supplementation or support is a whether the intranasal administration of 100 µg of common practice in IVF treatment. It significantly buserelin to 23 patients who underwent IVF improves the embryo implantation rate, pregnancy treatment, found that E2 and P concentrations were and delivery rates as ovarian superstimulation sustained and the implantation and pregnancy rates during IVF is commonly associated with luteal were significantly improved with increased doses phase deficiency. The aspiration of the granulosa and frequency of GnRH-a administration. These cells that surround the oocyte and the use of findings may suggest a direct effect of GnRH gonadotropin releasing hormone agonists (GnRHa) agonist on the embryo (7). In a prospective during assisted reproduction technology (ART) randomized study, Tesarik et al. evaluated the treatment can interfere with the production, during effect of GnRH agonist (0.1 mg triptorelin) the luteal phase, of progesterone, which is

166 Debate Luteal phase support in assisted reproduction MEFSJ administration in the luteal phase on outcomes in a down regulation protocol with gonadotropin releasing both GnRH agonist (n = 300) and GnRH hormone agonist: a comparative study between vaginal and oral administration. Hum Reprod 1999; 14 (8), 1944-1948. antagonist (n = 300) ovarian stimulation protocols 5. Martinez F, Coroleu B, Parera N. Human chorionic (9). They were randomly assigned to receive a gonadotropin and intra-vaginal natural progesterone are single injection of GnRH agonist (study group) or equally effective for luteal phase support in IVF. Gynecol placebo (control group) 6 days after ICSI. The PR Endorinol. 2000; 14(5): 316-320. 6. Soliman S, Daya S, Collins J. The role of luteal phase were enhanced for both protocols, in long GnRH support in infertility treatment: a meta analysis of agonist protocol the clinical implantation rate were randomized trials. Fertil Steril. 1994; 61, 1068-1076. 29.8 versus 18.2% respectively (P < 0.05). 7. Pirard C, Donnez J, Loumaye E. GnRH agonist as luteal Ongoing PR were 46.8 versus 38.0% respectively phase support in assisted reproduction technique cycles: (P = NS). In patients treated with the GnRH results of a pilot study. Hum Reprod. 2006 Jul;21(7):1894- 900. antagonist protocol, clinical implantation rates 8. Tesarik J, Hazout A, Mendoza C. (2004) Enhancement of were 27.1 versus 17.4% respectively (P < 0.05) embryo developmental potential by a single administration and ongoing PR were 44.8 versus 31.9% of GnRH agonist at the time of implantation. Hum Reprod respectively (P < 0.05). 19:1176–1180 9. Tesarik J, Hazout A, Mendoza-Tesarik R, Mendoza N, Luteal-phase GnRH agonist administration Mendoza C. Beneficial effect of luteal-phase GnRH agonist additionally increased the luteal-phase serum hCG, administration on embryo implantation after ICSI in both E2 and progesterone concentrations in both ovarian GnRH agonist- and antagonist-treated ovarian stimulation stimulation regimens. It was postulated that the cycles. Hum Reprod. 2006 Oct;21(10):2572-9 beneficial effect may have resulted from a 10. Lambalk CB, Homburg R. GnRH agonist for luteal support in IVF? Setting the balance between enthusiasm and caution. combination of effects on the embryo and on the Hum Reprod. 2006 Oct;21(10):2580-2 corpus luteum (9). 11. Elefant E, Biour B, Blumberg-Tick J, Roux C, Thomas F. Despite these encouraging results, this way of Administration of a gonadotropin-releasing hormone agonist supplementation was not widely adopted as great during pregnancy: follow-up of 28 pregnancies exposed to triptorelin. Fertil Steril. 1995 May;63(5):1111-3. concern exists about possible adverse effects on 12. Wilshire GB, Emmi AM, Gagliardi CC, Weiss G. oocytes and, more importantly, on embryos (10). Gonadotropin-releasing hormone agonist administration in However, the incidence of miscarriage and the early human pregnancy is associated with normal outcomes. long term follow-up of children born after Fertil Steril. 1993 Dec;60(6):980-3. inadvertent administration of GnRH-a in early pregnancy do not appear to be altered (11, 12). In order to establish a potential positive role of GnRH agonist administration in the luteal phase of stimulated IVF cycles, further large prospective trials are needed.

REFERENCES

1. Daya S, Gunby J. Luteal phase support in assisted reproduction cycles. Cochrane Database Syst Rev. 2004;(3):CD004830. 2. Damario MA, GoudasVT, Session DR., Hammitt DG, Dumesic DA. Crinone 8% vaginal progesterone gel results in lower embryonic implantation efficiency after in vitro fertilization- embryo transfer. Fertil Steril. 1999; 72 (5), 829- 836. 3. 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 Nov- Dec;13(6):581-90. 4. Friedler S, Raziel A, Schachter M. Luteal support with micronized progesterone following in vitro fertilization using

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