Addition of intramuscular to vaginal progesterone for luteal phase support in fresh embryo transfer cycles: A cross-sectional study


Background: Luteal phase deficiency is common in assisted reproductive technology and is characterized by inadequate progesterone production. Various studies have shown that administration of progesterone in fresh embryo transfer cycles increases the rate of clinical pregnancy and live birth rate. Progesterone administration has variable types: oral, vaginal, oil-based intramuscular, and subcutaneous.

Objective: This study aims to compare the effect of adding intramuscular progesterone to the vaginal progesterone for luteal phase support in the fresh embryo transfer cycle.

Materials and Methods: This study reviewed the information related to 355 women who had a fresh embryo transfer between March 2020 and February 2021 at the Yazd Reproductive Sciences Institute, Yazd, Iran. The participants population were divided into 2 groups based on the type of luteal phase support regime: group I (n = 173) received 400 mg vaginal progesterone alone twice a day from the day of ovum pick up; and group II (n = 182) received 50 mg IM of progesterone in addition to vaginal progesterone 400 mg twice a day from the day of ovum pick up. Chemical and clinical pregnancy rates were compared between groups.

Results: The basic characteristics of groups were statistically similar. The rates of chemical and clinical pregnancy were higher in the vaginal plus IM progesterone group than in the vaginal progesterone group. Moreover, chemical pregnancy showed a significant difference between the groups (p = 0.011).

Conclusion: Our findings demonstrated that the addition of IM progesterone to the vaginal progesterone improves the chemical pregnancy rate in fresh embryo transfer.

Key words: Luteal phase, Progesterone, Assisted reproductive technology, Embryo transfer.

[1] Check JA. Luteal phase support for in vitro fertilization-embryo transfer-present and future methods to improve successful implantation. Clin Exp Obstet Gynecol 2021; 39: 422–428.

[2] Lu B-J, Lin C-J, Lin B-Z, Huang L, Chien L-T, Chen C-H. ART outcomes following ovarian stimulation in the luteal phase: A systematic review and meta-analysis. J Assist Reprod Genet 2021; 38: 1927–1938.

[3] Daya S. Luteal support: Progestogens for pregnancy protection. Maturitas 2009; 65: S29–S34.

[4] 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: 2596–2599.

[5] van der Linden M, Buckingham K, Farquhar C, Kremer JA, Metwally M. Luteal phase support for assisted reproduction cycles. Cochrane Database Syst Rev 2015; 2015: CD009154.

[6] Miller CE, Zbella E, Webster BW, Doody KJ, Bush MR, Collins MG. Clinical comparison of ovarian stimulation and luteal support agents in patients undergoing GnRH antagonist IVF cycles. J Reprod Med 2013; 58: 153–160.

[7] del Carmen Nogales M, Cruz M, de Frutos S, Martínez EM, Gaytán M, Ariza M, et al. Association between clinical and IVF laboratory parameters and miscarriage after single euploid embryo transfers. Reprod Biol Endocrinol 2021; 19: 186.

[8] Vaisbuch E, de Ziegler D, Leong M, Weissman A, Shoham Z. Luteal-phase support in assisted reproduction treatment: Real-life practices reported worldwide by an updated website-based survey. Reprod Biomed Online 2014; 28: 330–335.

[9] Lee Ch-I, Chen H-H, Huang C-C, Lin P-Y, Lee T-H, Lee M-S. Early progesterone change associated with pregnancy outcome after fresh embryo transfer in assisted reproduction technology cycles with progesterone level of > 1.5 ng/ml on human chorionic gonadotropin trigger day. Front Endocrinol 2020; 11: 653.

[10] Mohammed A, Woad KJ, Mann GE, Craigon J, Raine- Fenning N, Robinson RS. Evaluation of progestogen supplementation for luteal phase support in fresh in vitro fertilization cycles. Fertil Steril 2019; 112: 491–

[11] Acharya KS, Acharya CR, Bishop K, Harris B, Raburn D, Muasher SJ. Freezing of all embryos in in vitro fertilization is beneficial in high responders, but not intermediate and low responders: An analysis of 82,935 cycles from the society for assisted reproductive technology registry. Fertil Steril 2018; 110: 880–887.

[12] Movahedi S, Aleyasin A, Agahosseini M, Safdarian L, Abroshan S, Khodaverdi S, et al. Endometrial preparation for women undergoing embryo transfer frozen-thawed embryo transfer with and without pretreatment with gonadotropin releasing hormone agonists. J Family Reprod Health 2018; 12: 191–196.

[13] Pabuçcu EG, Pabuçcu R, Evliyaoglu Ozdegirmenci O, Bostancı Durmus A, Keskin M. Combined progesterone (IM+ V) versus vaginal progesterone for luteal support in cleavage-stage embryo transfer cycles of good prognosis patients. Gynecol Endocrinol 2016; 32: 366–369.

[14] Venturella R, Vaiarelli A, Buffo L, D’alessandro P, Colamaria S, Pedri S, et al. Progesterone for preparation of the endometrium for frozen–thawed blastocyst transfer in vitro fertilization cycles: A prospective study on patients’ opinions on a new subcutaneous formulation. Gynecol Endocrinol 2018; 34: 766–771.

[15] Dashti S, Eftekhar M. Luteal-phase support in assisted reproductive technology: An ongoing challenge. Int J Reprod BioMed 2021; 19: 761–772.

[16] Czyzyk A, Podfigurna A, Genazzani AR, Meczekalski B. The role of progesterone therapy in early
pregnancy: From physiological role to therapeutic utility. Gynecol Endocrinol 2017; 33: 421–424.

[17] Zhao J, Hao J, Li Y. Individualized luteal phase support after fresh embryo transfer: unanswered questions, a review. Reprod Health 2022; 19: 19.

[18] Tulic L, Tulic I, Bila J, Nikolic L, Dotlic J, LazarevicSuntov M, et al. Correlation of progesterone levels on the day of oocyte retrieval with basal hormonal status and the outcome of ART. Sci Rep 2020; 10: 22291.

[19] Andersen CY, Andersen KV. Improving the luteal phase after ovarian stimulation: Reviewing new options. Reprod Biomed Online 2014; 28: 552–559.

[20] de Ziegler D, Pirtea P, Andersen CY, Ayoubi JM. Role of gonadotropin-releasing hormone agonists, human chorionic gonadotropin (hCG), progesterone, and estrogen in luteal phase support after hCG triggering, and when in pregnancy hormonal support can be stopped. Fertil Steril 2018; 109: 749–755.

[21] Labarta E, Rodríguez C. Progesterone use in assisted reproductive technology. Best Pract Res Clin Obstet Gynaecol 2020; 69: 74–84.

[22] Griesinger G, Blockeel C, Sukhikh GT, Patki A, Dhorepatil B, Yang D-Z, et al. Oral dydrogesterone versus intravaginal micronized progesterone gel for luteal phase support in IVF: A randomized clinical trial. Hum Reprod 2018; 33: 2212–2221.

[23] Khan AM, Jariwala S, Lieman HJ, Klapper P. Acute eosinophilic pneumonia with intramuscular progesterone after in vitro fertilization. Fertil Steril 2008; 90: 1200.

[24] Ahuja A, Ikladios O. Progesterone as a cause of eosinophilic pneumonia after in vitro fertilization. J Community Hosp Intern Med Perspect 2017; 7: 366– 368.

[25] Devine K, Richter KS, Widra EA, McKeeby JL. Vitrified blastocyst transfer cycles with the use of only vaginal
progesterone replacement with endometrin have inferior ongoing pregnancy rates: Results from the planned interim analysis of a three-arm randomized controlled noninferiority trial. Fertil Steril 2018; 109: 266-275.

[26] Glujovsky D, Pesce R, Fiszbajn G, Sueldo C, Hart RJ, Ciapponi A. Endometrial preparation for women undergoing embryo transfer with frozen embryos or embryos derived from donor oocytes. Cochrane Database Syst Rev 2010; 1: CD006359.