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DOI: 10.1055/s-0035-1545363
Luteal Phase Support in In Vitro Fertilization
Publication History
Publication Date:
03 March 2015 (online)
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Abstract
It has been well demonstrated that luteal phase physiology is disrupted in in vitro fertilization (IVF) cycles conducted with either gonadotropin-releasing hormone (GnRH) agonists or antagonists, and that supplementation of the luteal phase with either exogenous progesterone or human chorionic gonadotropin (hCG) is necessary to optimize IVF cycle outcomes. Though both progesterone and hCG supplementation resulted in comparable pregnancy rates, hCG supplementation was associated with increased risk for ovarian hyperstimulation syndrome (OHSS). For that reason progesterone has been used for luteal support by most IVF programs around the world. Vaginal progesterone preparations have been shown definitively to be equally efficacious and better tolerated by patients than intramuscular progesterone injections, but new data on the subcutaneous and oral progesterone are also emerging. New evidence has been accumulating on the benefits of low-dose luteal hCG supplementation in GnRH-antagonist cycles where GnRH agonists are used for the final maturation trigger. New approaches to luteal phase support as well as new formulations of progesterone have been developed since the last comprehensive review was published in 2011. In this article, we examine current evidence for efficacy, dosing, and timing of progesterone preparations as well as the role of hCG for luteal support in IVF cycles triggered with GnRH agonists. We also discuss the data on the role of estrogen supplementation in the luteal phase, optimal duration of progesterone support in early pregnancy, and progesterone replacement in frozen embryo transfer cycles and donor egg recipient cycles.
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References
- 1 Filicori M, Butler JP, Crowley Jr WF. Neuroendocrine regulation of the corpus luteum in the human. Evidence for pulsatile progesterone secretion. J Clin Invest 1984; 73 (6) 1638-1647
- 2 Yanushpolsky E. Evidence-based use of progesterone in IVF. In: Racowsky C, Carrell DT, Schlegel PN, Fauser BC, , eds. Biennial Review of Infertility (Volume 2). New York, NY: Springer; 2011: 79-90
- 3 Jones GS, Garcia J, Acosta A. Luteal phase evaluation in in-vitro fertilization. In: Edwards RG, Purdy JM, , eds. Human Conception In Vitro. London, UK: Academic Press; 1982: 297-310
- 4 Tavaniotou A, Devroey P. Luteal hormonal profile of oocyte donors stimulated with a GnRH antagonist compared with natural cycles. Reprod Biomed Online 2006; 13 (3) 326-330
- 5 Beckers NG, Macklon NS, Eijkemans MJ , et al. Nonsupplemented luteal phase characteristics after the administration of recombinant human chorionic gonadotropin, recombinant luteinizing hormone, or gonadotropin-releasing hormone (GnRH) agonist to induce final oocyte maturation in in vitro fertilization patients after ovarian stimulation with recombinant follicle-stimulating hormone and GnRH antagonist cotreatment. J Clin Endocrinol Metab 2003; 88 (9) 4186-4192
- 6 Hubayter ZR, Muasher SJ. Luteal supplementation in in vitro fertilization: more questions than answers. Fertil Steril 2008; 89 (4) 749-758
- 7 van der Linden M, Buckingham K, Farquhar C, Kremer JA, Metwally M. Luteal phase support for assisted reproduction cycles. Cochrane Database Syst Rev 2011; (10) CD009154
- 8 Licciardi FL, Kwiatkowski A, Noyes NL, Berkeley AS, Krey LL, Grifo JA. Oral versus intramuscular progesterone for in vitro fertilization: a prospective randomized study. Fertil Steril 1999; 71 (4) 614-618
- 9 Friedler S, Raziel A, Schachter M, Strassburger D, Bukovsky I, Ron-El R. Luteal support with micronized progesterone following in-vitro fertilization using a down-regulation protocol with gonadotrophin-releasing hormone agonist: a comparative study between vaginal and oral administration. Hum Reprod 1999; 14 (8) 1944-1948
- 10 Salehpour S, Tamimi M, Saharkhiz N. Comparison of oral dydrogesterone with suppository vaginal progesterone for luteal-phase support in in vitro fertilization (IVF): a randomized clinical trial. Iran J Reprod Med 2013; 11 (11) 913-918
- 11 Ganesh A, Chakravorty N, Mukherjee R, Goswami S, Chaudhury K, Chakravarty B. 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. Fertil Steril 2011; 95 (6) 1961-1965
- 12 Iwase A, Ando H, Toda S , et al. Oral progestogen versus intramuscular progesterone for luteal support after assisted reproductive technology treatment: a prospective randomized study. Arch Gynecol Obstet 2008; 277 (4) 319-324
- 13 Patki A, Pawar VC. Modulating fertility outcome in assisted reproductive technologies by the use of dydrogesterone. Gynecol Endocrinol 2007; 23 (Suppl. 01) 68-72
- 14 Scifres CM, Iams JD, Klebanoff M, Macones GA. Meta-analysis vs. large clinical trials: which should guide our management?. Am J Obstet Gynecol 2009; 200: 484.e1-484.e5
- 15 Timmermans S, Mauck A. The promises and pitfalls of evidence-based medicine. Health Aff (Millwood) 2005; 24 (1) 18-28
- 16 Atkins D, Best D, Briss PA , et al; GRADE Working Group. Grading quality of evidence and strength of recommendations. BMJ 2004; 328 (7454) 1490
- 17 Papaleo E, Quaranta L, Molgora M. Intramuscular vs intravaginal natural progesterone in patients undergoing in vitro fertilization-embryo transfer cycles. A retrospective observational, case-control study. Eur Rev Med Pharmacol Sci 2010; 14 (2) 103-106
- 18 Ho CH, Chen SU, Peng FS, Chang CY, Yang YS. Luteal support for IVF/ICSI cycles with Crinone 8% (90 mg) twice daily results in higher pregnancy rates than with intramuscular progesterone. J Chin Med Assoc 2008; 71 (8) 386-391
- 19 Bouckaert Y, Robert F, Englert Y, De Backer D, De Vuyst P, Delbaere A. Acute eosinophilic pneumonia associated with intramuscular administration of progesterone as luteal phase support after IVF: case report. Hum Reprod 2004; 19 (8) 1806-1810
- 20 Veysman B, Vlahos I, Oshva L. Pneumonitis and eosinophilia after in vitro fertilization treatment. Ann Emerg Med 2006; 47 (5) 472-475
- 21 Phy JL, Weiss WT, Weiler CR, Damario MA. Hypersensitivity to progesterone-in-oil after in vitro fertilization and embryo transfer. Fertil Steril 2003; 80 (5) 1272-1275
- 22 Van Steirteghem AC, Smitz J, Camus M , et al. The luteal phase after in-vitro fertilization and related procedures. Hum Reprod 1988; 3 (2) 161-164
- 23 Smitz J, Devroey P, Camus M , et al. The luteal phase and early pregnancy after combined GnRH-agonist/HMG treatment for superovulation in IVF or GIFT. Hum Reprod 1988; 3 (5) 585-590
- 24 Devroey P, Palermo G, Bourgain C, Van Waesberghe L, Smitz J, Van Steirteghem AC. Progesterone administration in patients with absent ovaries. Int J Fertil 1989; 34 (3) 188-193
- 25 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 (2) 168-175
- 26 Bourgain C, Devroey P, Van Waesberghe L, Smitz J, Van Steirteghem AC. Effects of natural progesterone on the morphology of the endometrium in patients with primary ovarian failure. Hum Reprod 1990; 5 (5) 537-543
- 27 Perino M, Brigandì FG, Abate FG, Costabile L, Balzano E, Abate A. Intramuscular versus vaginal progesterone in assisted reproduction: a comparative study. Clin Exp Obstet Gynecol 1997; 24 (4) 228-231
- 28 Artini PG, Volpe A, Angioni S, Galassi MC, Battaglia C, Genazzani AR. A comparative, randomized study of three different progesterone support of the luteal phase following IVF/ET program. J Endocrinol Invest 1995; 18 (1) 51-56
- 29 Porcu E. Intramuscular versus vaginal progesterone in assisted reproduction. Fertil Steril 2003; 80 (Suppl. 03) S131
- 30 Pritts EA, Atwood AK. Luteal phase support in infertility treatment: a meta-analysis of the randomized trials. Hum Reprod 2002; 17 (9) 2287-2299
- 31 Daya S, Gunby J. Luteal phase support in assisted reproduction cycles. Cochrane Database Syst Rev 2004; (3) CD004830
- 32 Propst AM, Hill JA, Ginsburg ES, Hurwitz S, Politch J, Yanushpolsky EH. A randomized study comparing Crinone 8% and intramuscular progesterone supplementation in in vitro fertilization-embryo transfer cycles. Fertil Steril 2001; 76 (6) 1144-1149
- 33 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 (3) 361-367
- 34 Yanushpolsky E, Hurwitz S, Greenberg L, Racowsky C, Hornstein MD. Comparison of Crinone 8% intravaginal gel and intramuscular progesterone supplementation for in vitro fertilization/embryo transfer in women under age 40: interim analysis of a prospective randomized trial. Fertil Steril 2008; 89 (2) 485-487
- 35 Bulletti C, de Ziegler D, Flamigni C , et al. Targeted drug delivery in gynaecology: the first uterine pass effect. Hum Reprod 1997; 12 (5) 1073-1079
- 36 Cicinelli E, de Ziegler D, Bulletti C, Matteo MG, Schonauer LM, Galantino P. Direct transport of progesterone from vagina to uterus. Obstet Gynecol 2000; 95 (3) 403-406
- 37 Miles RA, Paulson RJ, Lobo RA, Press MF, Dahmoush L, Sauer MV. Pharmacokinetics and endometrial tissue levels of progesterone after administration by intramuscular and vaginal routes: a comparative study. Fertil Steril 1994; 62 (3) 485-490
- 38 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 (7) 2596-2599
- 39 Schoolcraft WB, Hesla JS, Gee MJ. Experience with progesterone gel for luteal support in a highly successful IVF programme. Hum Reprod 2000; 15 (6) 1284-1288
- 40 Zarutskie PW, Phillips JA. A meta-analysis of the route of administration of luteal phase support in assisted reproductive technology: vaginal versus intramuscular progesterone. Fertil Steril 2009; 92 (1) 163-169
- 41 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 (2) 761-763
- 42 Stadtmauer L, Silverberg KM, Ginsburg ES, Weiss H, Howard B. Progesterone vaginal ring versus vaginal gel for luteal support with in vitro fertilization: a randomized comparative study. Fertil Steril 2013; 99 (6) 1543-1549
- 43 Baker VL, Jones CA, Doody K , et al. A randomized, controlled trial comparing the efficacy and safety of aqueous subcutaneous progesterone with vaginal progesterone for luteal phase support of in vitro fertilization. Hum Reprod 2014; 29 (10) 2212-2220
- 44 Gibbons WE, Toner JP, Hamacher P, Kolm P. Experience with a novel vaginal progesterone preparation in a donor oocyte program. Fertil Steril 1998; 69 (1) 96-101
- 45 Jobanputra K, Toner JP, Denoncourt R, Gibbons WE. Crinone 8% (90 mg) given once daily for progesterone replacement therapy in donor egg cycles. Fertil Steril 1999; 72 (6) 980-984
- 46 Doody KJ, Schnell VL, Foulk RA , et al. Endometrin for luteal phase support in a randomized, controlled, open-label, prospective in-vitro fertilization trial using a combination of Menopur and Bravelle for controlled ovarian hyperstimulation. Fertil Steril 2009; 91 (4) 1012-1017
- 47 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 (1) 83-87
- 48 Ludwig M, Schwartz P, Babahan B , et al. Luteal phase support using either Crinone 8% or Utrogest: results of a prospective, randomized study. Eur J Obstet Gynecol Reprod Biol 2002; 103 (1) 48-52
- 49 Geber S, Moreira AC, de Paula SO, Sampaio M. Comparison between two forms of vaginally administered progesterone for luteal phase support in assisted reproduction cycles. Reprod Biomed Online 2007; 14 (2) 155-158
- 50 Polyzos NP, Messini CI, Papanikolaou EG , et al. Vaginal progesterone gel for luteal phase support in IVF/ICSI cycles: a meta-analysis. Fertil Steril 2010; 94 (6) 2083-2087
- 51 Sohn SH, Penzias AS, Emmi AM , et al. Administration of progesterone before oocyte retrieval negatively affects the implantation rate. Fertil Steril 1999; 71 (1) 11-14
- 52 Mochtar MH, Van Wely M, Van der Veen F. Timing luteal phase support in GnRH agonist down-regulated IVF/embryo transfer cycles. Hum Reprod 2006; 21 (4) 905-908
- 53 Williams SC, Oehninger S, Gibbons WE, Van Cleave WC, Muasher SJ. Delaying the initiation of progesterone supplementation results in decreased pregnancy rates after in vitro fertilization: a randomized, prospective study. Fertil Steril 2001; 76 (6) 1140-1143
- 54 Nyboe Andersen A, Popovic-Todorovic B, Schmidt KT , et al. Progesterone supplementation during early gestations after IVF or ICSI has no effect on the delivery rates: a randomized controlled trial. Hum Reprod 2002; 17 (2) 357-361
- 55 Aboulghar MA, Amin YM, Al-Inany HG , et al. Prospective randomized study comparing luteal phase support for ICSI patients up to the first ultrasound compared with an additional three weeks. Hum Reprod 2008; 23 (4) 857-862
- 56 Kohls G, Ruiz F, Martínez M , et al. Early progesterone cessation after in vitro fertilization/intracytoplasmic sperm injection: a randomized, controlled trial. Fertil Steril 2012; 98 (4) 858-862
- 57 Kyrou D, Fatemi HM, Zepiridis L , et al. Does cessation of progesterone supplementation during early pregnancy in patients treated with recFSH/GnRH antagonist affect ongoing pregnancy rates? A randomized controlled trial. Hum Reprod 2011; 26 (5) 1020-1024
- 58 Goudge CS, Nagel TC, Damario MA. Duration of progesterone-in-oil support after in vitro fertilization and embryo transfer: a randomized, controlled trial. Fertil Steril 2010; 94 (3) 946-951
- 59 Liu XR, Mu HQ, Shi Q, Xiao XQ, Qi HB. The optimal duration of progesterone supplementation in pregnant women after IVF/ICSI: a meta-analysis. Reprod Biol Endocrinol 2012; 10: 107
- 60 Damewood MD, Shen W, Zacur HA, Schlaff WD, Rock JA, Wallach EE. Disappearance of exogenously administered human chorionic gonadotropin. Fertil Steril 1989; 52 (3) 398-400
- 61 Delvigne A, Rozenberg S. Epidemiology and prevention of ovarian hyperstimulation syndrome (OHSS): a review. Hum Reprod Update 2002; 8 (6) 559-577
- 62 Galindo A, Bodri D, Guillén JJ, Colodrón M, Vernaeve V, Coll O. Triggering with HCG or GnRH agonist in GnRH antagonist treated oocyte donation cycles: a randomised clinical trial. Gynecol Endocrinol 2009; 25 (1) 60-66
- 63 Kolibianakis EM, Schultze-Mosgau A, Schroer A , et al. A lower ongoing pregnancy rate can be expected when GnRH agonist is used for triggering final oocyte maturation instead of HCG in patients undergoing IVF with GnRH antagonists. Hum Reprod 2005; 20 (10) 2887-2892
- 64 Humaidan P, Ejdrup Bredkjaer H, Westergaard LG, Yding Andersen C. 1,500 IU human chorionic gonadotropin administered at oocyte retrieval rescues the luteal phase when gonadotropin-releasing hormone agonist is used for ovulation induction: a prospective, randomized, controlled study. Fertil Steril 2010; 93 (3) 847-854
- 65 Humaidan P, Alsbjerg B. GnRHa trigger for final oocyte maturation: is HCG trigger history?. Reprod Biomed Online 2014; 29 (3) 274-280
- 66 Bermejo A, Cerrillo M, Ruiz-Alonso M , et al. Impact of final oocyte maturation using gonadotropin-releasing hormone agonist triggering and different luteal support protocols on endometrial gene expression. Fertil Steril 2014; 101 (1) 138-146.e3
- 67 Toner JP. Vaginal delivery of progesterone in donor oocyte therapy. Hum Reprod 2000; 15 (Suppl. 01) 166-171
- 68 Berger B, Phillips J. A retrospective analysis of pregnancy outcomes in recipients of anonymously donated oocytes at a large ART center. Fertil Steril 2007; 89: S11-S12
- 69 Berger B, Phillips J. A retrospective analysis of pregnancy outcomes in recipients of frozen/thawed embryos (FET) from donated oocytes at a large assisted reproductive technology (ART) center. Fertil Steril 2008; 90: S459
- 70 Williams SC, Donahue J, Muasher SJ. Vaginal progesterone therapy during programmed cycles for frozen embryo transfer: an analysis of serum progesterone levels and pregnancy rates. Fertil Steril 2000; 74 (Suppl. 01) S209
- 71 Kaser DJ, Ginsburg ES, Missmer SA, Correia KF, Racowsky C. Intramuscular progesterone versus 8% Crinone vaginal gel for luteal phase support for day 3 cryopreserved embryo transfer. Fertil Steril 2012; 98 (6) 1464-1469
- 72 Shapiro DB, Pappadakis JA, Ellsworth NM, Hait HI, Nagy ZP. Progesterone replacement with vaginal gel versus i.m. injection: cycle and pregnancy outcomes in IVF patients receiving vitrified blastocysts. Hum Reprod 2014; 29 (8) 1706-1711
- 73 Muasher S, Acosta AA, Garcia JE, Jones GS, Jones Jr HW. Luteal phase serum estradiol and progesterone in in vitro fertilization. Fertil Steril 1984; 41 (6) 838-843
- 74 Sharara FI, McClamrock HD. Ratio of oestradiol concentration on the day of human chorionic gonadotrophin administration to mid-luteal oestradiol concentration is predictive of in-vitro fertilization outcome. Hum Reprod 1999; 14 (11) 2777-2782
- 75 Kolibianakis EM, Venetis CA, Papanikolaou EG, Diedrich K, Tarlatzis BC, Griesinger G. Estrogen addition to progesterone for luteal phase support in cycles stimulated with GnRH analogues and gonadotrophins for IVF: a systematic review and meta-analysis. Hum Reprod 2008; 23 (6) 1346-1354
- 76 Jee BC, Suh CS, Kim SH, Kim YB, Moon SY. Effects of estradiol supplementation during the luteal phase of in vitro fertilization cycles: a meta-analysis. Fertil Steril 2010; 93 (2) 428-436
- 77 Elgindy EA, El-Haieg DO, Mostafa MI, Shafiek M. Does luteal estradiol supplementation have a role in long agonist cycles?. Fertil Steril 2010; 93 (7) 2182-2188
- 78 Lin H, Li Y, Li L , et al. Oral oestradiol supplementation as luteal support in IVF/ICSI cycles: a prospective, randomized controlled study. Eur J Obstet Gynecol Reprod Biol 2013; 167 (2) 171-175