Efficacy of Daily 50 mg Intramuscular Progesterone for Luteal Phase Support in Frozen Embryo Transfer Cycles: Analysis of Serum Levels and Pregnancy Outcomes
-
Robabeh Hatami
,
Ensieh Shahrokh Tehraninejad
,
Batool Hossein Rashidi
,
Fatemeh Keikha
,
Masoumeh Masoumi
,
Amirali Barkhordarioon
,
Azadeh Tarafdari
Abstract
Objective: To evaluate the efficacy of 50 mg/day intramuscular (IM) progesterone in achieving optimal serum P4 levels during endometrial preparation and investigate the association between serum P4 levels on ET day and subsequent fertility outcomes in hormone replacement therapy (HRT) frozen embryo transfer (FET) cycles.
Materials and methods: This prospective cohort study included 121 women (aged 22-45 years) undergoing HRT-FET at Imam Khomeini Hospital Complex from December 2022 to January 2024. Endometrial preparation began with oral estradiol valerate (6 mg/day) on cycle day 2. Once an endometrial thickness of ≥8 mm was achieved, daily IM P4 (50 mg) was initiated. Serum P4 levels were measured on ET day, and oral dydrogesterone (20 mg/day) was added for patients with P4 levels <10.0 ng/mL. Primary outcomes included chemical pregnancy, clinical pregnancy, miscarriage, and ongoing pregnancy rates.
Results: The mean serum P4 level on ET day was 22.8 ± 10.1 ng/mL, with 78.5% of participants achieving the target range (10-32.5 ng/mL) following IM P4 administration. Overall chemical pregnancy, clinical pregnancy, and ongoing pregnancy rates were 23.1%, 18.2%, and 14.1%, respectively, with a miscarriage rate of 5.0%. Multivariate analysis revealed that P4 levels >27.8 ng/mL were associated with reduced odds of chemical pregnancy (OR = 0.20; 95% CI: 0.05-0.86; p = 0.03), while no significant differences were observed in other pregnancy outcomes across P4 quartiles.
Conclusion: Daily administration of 50 mg IM P4 effectively achieved optimal serum P4 levels in most patients. While higher P4 levels (>27.8 ng/mL) were associated with reduced chemical pregnancy rates, the absence of significant correlations with other pregnancy outcomes highlights the multifactorial nature of embryo implantation success. These findings emphasize the need for further research to refine
P4 thresholds and identify additional predictive factors influencing pregnancy outcomes in FET cycles.
1. De Geyter C, Wyns C, Calhaz-Jorge C, de Mouzon J, Ferraretti AP, Kupka M, et al. 20 years of the European IVF-monitoring Consortium registry: what have we learned? A comparison with registries from two other regions. Hum Reprod. 2020;35(12):2832-49.
2. Mumusoglu S, Polat M, Ozbek IY, Bozdag G, Papanikolaou EG, Esteves SC, et al. Preparation of the Endometrium for Frozen Embryo Transfer: A Systematic Review. Front Endocrinol (Lausanne). 2021;12:688237.
3. Strauss III J, Williams C. The ovarian life cycle. Yen & Jaffe's reproductive endocrinology. Philadelphia: Saunders; 2009. p. 155-90.
4. Nawroth F, Ludwig M. What is the 'ideal' duration of progesterone supplementation before the transfer of cryopreserved-thawed embryos in estrogen/progesterone replacement protocols? Hum Reprod. 2005;20(5):1127-34.
5. Mackens S, Santos-Ribeiro S, van de Vijver A, Racca A, Van Landuyt L, Tournaye H, et al. Frozen embryo transfer: a review on the optimal endometrial preparation and timing. Hum Reprod. 2017;32(11):2234-42.
6. Kofinas JD, Blakemore J, McCulloh DH, Grifo J. Serum progesterone levels greater than 20 ng/dl on day of embryo transfer are associated with lower live birth and higher pregnancy loss rates. J Assist Reprod Genet. 2015;32(9):1395-9.
7. Yovich JL, Conceicao JL, Stanger JD, Hinchliffe PM, Keane KN. Mid-luteal serum progesterone concentrations govern implantation rates for cryopreserved embryo transfers conducted under hormone replacement. Reprod Biomed Online. 2015;31(2):180-91.
8. Labarta E, Mariani G, Holtmann N, Celada P, Remohí J, Bosch E. Low serum progesterone on the day of embryo transfer is associated with a diminished ongoing pregnancy rate in oocyte donation cycles after artificial endometrial preparation: a prospective study. Hum Reprod. 2017;32(12):2437-42.
9. Brady PC, Kaser DJ, Ginsburg ES, Ashby RK, Missmer SA, Correia KF, et al. Serum progesterone concentration on day of embryo transfer in donor oocyte cycles.
J Assist Reprod Genet. 2014;31(5):569-75.
10. Alyasin A, Agha-Hosseini M, Kabirinasab M, Saeidi H, Nashtaei MS. Serum progesterone levels greater than 32.5 ng/ml on the day of embryo transfer are associated with lower live birth rate after artificial endometrial preparation: a prospective study. Reprod Biol Endocrinol. 2021;19(1):24.
11. Gao H, Ye J, Ye H, Hong Q, Sun L, Chen Q. Strengthened luteal phase support for patients with low serum progesterone on the day of frozen embryo transfer in artificial endometrial preparation cycles: a large-sample retrospective trial. Reprod Biol Endocrinol. 2021;19(1):60.
12. Volovsky M, Pakes C, Rozen G, Polyakov A. Do serum progesterone levels on day of embryo transfer influence pregnancy outcomes in artificial frozen-thaw cycles? J Assist Reprod Genet. 2020;37(5):1129-35.
13. Gaggiotti-Marre S, Martinez F, Coll L, Garcia S, Álvarez M, Parriego M, et al. Low serum progesterone the day prior to frozen embryo transfer of euploid embryos is associated with significant reduction in live birth rates. Gynecol Endocrinol. 2019;35(5):439-42.
14. Polat M, Mumusoglu S, Bozdag G, Ozbek IY, Humaidan P, Yarali H. Addition of intramuscular progesterone to vaginal progesterone in hormone replacement therapy in vitrified-warmed blastocyst transfer cycles. Reprod Biomed Online. 2020;40(6):812-8.
15. Melo P, Chung Y, Pickering O, Price MJ, Fishel S, Khairy M, et al. Serum luteal phase progesterone in women undergoing frozen embryo transfer in assisted conception: a systematic review and meta-analysis. Fertil Steril. 2021;116(6):1534-56.
16. Hershko Klement A, Samara N, Weintraub A, Mitri F, Bentov Y, Chang P, et al. Intramuscular versus Vaginal Progesterone Administration in Medicated Frozen Embryo Transfer Cycles: A Randomized Clinical Trial Assessing Sub-Endometrial Contractions. Gynecol Obstet Invest. 2018;83(1):40-4.
17. Tehraninejad ES, Alizadeh S, Nekoo EA, Zargarzadeh N, Shariat M, Haghollahi F, et al. Comparing the outcomes of in-vitro fertilization in patients receiving vaginal, subcutaneous, and intramuscular progesterone for luteal phase support: a three-armed randomized controlled trial. BMC Womens Health. 2024;24(1):481.
18. 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(2):266-75.
19. 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):1464-9.
20. Delcour C, Robin G, Delesalle AS, Drumez E, Plouvier P, Dewailly D, et al. Weekly intramuscular progesterone for luteal phase support in women receiving oocyte donation is associated with a decreased miscarriage rate. Reprod Biomed Online. 2019;39(3):446-51.
21. Lorillon M, Robin G, Keller L, Cailliau E, Delcourt C, Simon V, et al.: Is oral dydrogesterone equivalent to vaginal micronized progesterone for luteal phase support in women receiving oocyte donation? Reprod Biol Endocrinol. 2024;22(1):154.
22. Rashidi BH, Ghazizadeh M, Tehrani Nejad ES, Bagheri M, Gorginzadeh M. Oral dydrogesterone for luteal support in frozen-thawed embryo transfer artificial cycles: A pilot randomized controlled trial. APJR. 2016;5(6):490-4.
23. Neumann K, Masuch A, Vonthein R, Depenbusch M, Schultze-Mosgau A, Eggersmann TK, et al. Dydrogesterone and 20α-dihydrodydrogesterone plasma levels on day of embryo transfer and clinical outcome in an anovulatory programmed frozen-thawed embryo transfer cycle: a prospective cohort study. Hum Reprod. 2022;37(6):1183-93.
24. Sahereh A, Maryam E, Saeideh D, Nahid H, Elham N. Comparison of pregnancy outcome after adding oral or intramuscular progesterone to vaginal progesterone in frozen embryo transfer: A cross-sectional study. Int J Reprod Biomed. 2024;22(10).
25. Alvarez M, Gaggiotti-Marre S, Martinez F, Coll L, Garcia S, Gonzalez-Foruria I, et al. Individualised luteal phase support in artificially prepared frozen embryo transfer cycles based on serum progesterone levels: a prospective cohort study. Hum Reprod. 2021;36(6):1552-60.
26. González-Foruria I, Gaggiotti-Marre S, Álvarez M, Martínez F, García S, Rodríguez I, et al. Factors associated with serum progesterone concentrations the day before cryopreserved embryo transfer in artificial cycles. Reprod Biomed Online. 2020;40(6):797-804.
27. Cédrin-Durnerin I, Isnard T, Mahdjoub S, Sonigo C, Seroka A, Comtet M, et al. Serum progesterone concentration and live birth rate in frozen-thawed embryo transfers with hormonally prepared endometrium. Reprod Biomed Online. 2019;38(3):472-80.
28. Chen W, Xu Y, Liu X, Pan J, Cai B, Zhou C, et al. Serum Progesterone Level on the Day of Embryo Transfer Is Not a Reliable Predictor for Frozen-Thawed Embryo Transfer Outcomes With Euploid Blastocyst Transfer: A Retrospective Cohort Study. Bjog. 2025;132 Suppl 2:53-61
29. Ovarian Stimulation T, Bosch E, Broer S, Griesinger G, Grynberg M, Humaidan P, et al. ESHRE guideline: ovarian stimulation for IVF/ICSI. Hum Reprod Open. 2020;2020(2):hoaa009. Erratum in: Hum Reprod Open. 2020;2020(4):hoaa067.
30. 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):485-90.
31. Akbari Asbagh F, Ghasemzadeh F, Ebrahimi M, Davari-Tanha F, Feizabad E, Akbari Asbagh P, et al. Effect of intramuscular injection of human chorionic gonadotropin on endometrium preparation in frozen-thawed embryo transfer cycle: A randomized clinical trial. Caspian J Intern Med. 2023;14(2):185-91.
32. Eftekhar M, Rahsepar M, Rahmani E. Effect of progesterone supplementation on natural frozen-thawed embryo transfer cycles: a randomized controlled trial. Int J Fertil Steril. 2013;7(1):13-20.
33. Eslami Moayed M, Moini A, Kashani L, Farid Mojtahedi M, Rezaee T, Tabasizadeh H, et al.: Pregnancy outcomes in women with adenomyosis, undergoing artificial endometrial preparation with and without gonadotropin-releasing hormone agonist pretreatment in frozen embryo transfer cycles: An RCT. Int J Reprod Biomed. 2023;21(6):481-90.
34. Agha-Hosseini M, Hashemi L, Aleyasin A, Ghasemi M, Sarvi F, Shabani Nashtaei M, et al. Natural cycle versus artificial cycle in frozen-thawed embryo transfer: A randomized prospective trial. Turk J Obstet Gynecol. 2018;15(1):12-7.
35. Farid Mojtahedi M, Aref S, Moini A, Maleki-Hajiagha A, Kashani L. Natural cycle versus modified natural cycle for endometrial preparation in women undergoing frozen-thawed embryo transfer: An RCT. Int J Reprod Biomed. 2022;20(11):923-30.
36. Aflatoonian A, Mohammadi B. Subcutaneous progesterone versus vaginal progesterone for luteal-phase support in frozen-thawed embryo transfer: A cross-sectional study. Int J Reprod Biomed. 2021;19(2):115-20.
37. Omidi M, Halvaei I, Akyash F, Khalili MA, Agha-Rahimi A, Heydari L. The exact synchronization timing between the cleavage embryo stage and duration of progesterone therapy-improved pregnancy rates in frozen embryo transfer cycles: A cross-sectional study. Int J Reprod Biomed. 2021;19(3):227-34.
2. Mumusoglu S, Polat M, Ozbek IY, Bozdag G, Papanikolaou EG, Esteves SC, et al. Preparation of the Endometrium for Frozen Embryo Transfer: A Systematic Review. Front Endocrinol (Lausanne). 2021;12:688237.
3. Strauss III J, Williams C. The ovarian life cycle. Yen & Jaffe's reproductive endocrinology. Philadelphia: Saunders; 2009. p. 155-90.
4. Nawroth F, Ludwig M. What is the 'ideal' duration of progesterone supplementation before the transfer of cryopreserved-thawed embryos in estrogen/progesterone replacement protocols? Hum Reprod. 2005;20(5):1127-34.
5. Mackens S, Santos-Ribeiro S, van de Vijver A, Racca A, Van Landuyt L, Tournaye H, et al. Frozen embryo transfer: a review on the optimal endometrial preparation and timing. Hum Reprod. 2017;32(11):2234-42.
6. Kofinas JD, Blakemore J, McCulloh DH, Grifo J. Serum progesterone levels greater than 20 ng/dl on day of embryo transfer are associated with lower live birth and higher pregnancy loss rates. J Assist Reprod Genet. 2015;32(9):1395-9.
7. Yovich JL, Conceicao JL, Stanger JD, Hinchliffe PM, Keane KN. Mid-luteal serum progesterone concentrations govern implantation rates for cryopreserved embryo transfers conducted under hormone replacement. Reprod Biomed Online. 2015;31(2):180-91.
8. Labarta E, Mariani G, Holtmann N, Celada P, Remohí J, Bosch E. Low serum progesterone on the day of embryo transfer is associated with a diminished ongoing pregnancy rate in oocyte donation cycles after artificial endometrial preparation: a prospective study. Hum Reprod. 2017;32(12):2437-42.
9. Brady PC, Kaser DJ, Ginsburg ES, Ashby RK, Missmer SA, Correia KF, et al. Serum progesterone concentration on day of embryo transfer in donor oocyte cycles.
J Assist Reprod Genet. 2014;31(5):569-75.
10. Alyasin A, Agha-Hosseini M, Kabirinasab M, Saeidi H, Nashtaei MS. Serum progesterone levels greater than 32.5 ng/ml on the day of embryo transfer are associated with lower live birth rate after artificial endometrial preparation: a prospective study. Reprod Biol Endocrinol. 2021;19(1):24.
11. Gao H, Ye J, Ye H, Hong Q, Sun L, Chen Q. Strengthened luteal phase support for patients with low serum progesterone on the day of frozen embryo transfer in artificial endometrial preparation cycles: a large-sample retrospective trial. Reprod Biol Endocrinol. 2021;19(1):60.
12. Volovsky M, Pakes C, Rozen G, Polyakov A. Do serum progesterone levels on day of embryo transfer influence pregnancy outcomes in artificial frozen-thaw cycles? J Assist Reprod Genet. 2020;37(5):1129-35.
13. Gaggiotti-Marre S, Martinez F, Coll L, Garcia S, Álvarez M, Parriego M, et al. Low serum progesterone the day prior to frozen embryo transfer of euploid embryos is associated with significant reduction in live birth rates. Gynecol Endocrinol. 2019;35(5):439-42.
14. Polat M, Mumusoglu S, Bozdag G, Ozbek IY, Humaidan P, Yarali H. Addition of intramuscular progesterone to vaginal progesterone in hormone replacement therapy in vitrified-warmed blastocyst transfer cycles. Reprod Biomed Online. 2020;40(6):812-8.
15. Melo P, Chung Y, Pickering O, Price MJ, Fishel S, Khairy M, et al. Serum luteal phase progesterone in women undergoing frozen embryo transfer in assisted conception: a systematic review and meta-analysis. Fertil Steril. 2021;116(6):1534-56.
16. Hershko Klement A, Samara N, Weintraub A, Mitri F, Bentov Y, Chang P, et al. Intramuscular versus Vaginal Progesterone Administration in Medicated Frozen Embryo Transfer Cycles: A Randomized Clinical Trial Assessing Sub-Endometrial Contractions. Gynecol Obstet Invest. 2018;83(1):40-4.
17. Tehraninejad ES, Alizadeh S, Nekoo EA, Zargarzadeh N, Shariat M, Haghollahi F, et al. Comparing the outcomes of in-vitro fertilization in patients receiving vaginal, subcutaneous, and intramuscular progesterone for luteal phase support: a three-armed randomized controlled trial. BMC Womens Health. 2024;24(1):481.
18. 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(2):266-75.
19. 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):1464-9.
20. Delcour C, Robin G, Delesalle AS, Drumez E, Plouvier P, Dewailly D, et al. Weekly intramuscular progesterone for luteal phase support in women receiving oocyte donation is associated with a decreased miscarriage rate. Reprod Biomed Online. 2019;39(3):446-51.
21. Lorillon M, Robin G, Keller L, Cailliau E, Delcourt C, Simon V, et al.: Is oral dydrogesterone equivalent to vaginal micronized progesterone for luteal phase support in women receiving oocyte donation? Reprod Biol Endocrinol. 2024;22(1):154.
22. Rashidi BH, Ghazizadeh M, Tehrani Nejad ES, Bagheri M, Gorginzadeh M. Oral dydrogesterone for luteal support in frozen-thawed embryo transfer artificial cycles: A pilot randomized controlled trial. APJR. 2016;5(6):490-4.
23. Neumann K, Masuch A, Vonthein R, Depenbusch M, Schultze-Mosgau A, Eggersmann TK, et al. Dydrogesterone and 20α-dihydrodydrogesterone plasma levels on day of embryo transfer and clinical outcome in an anovulatory programmed frozen-thawed embryo transfer cycle: a prospective cohort study. Hum Reprod. 2022;37(6):1183-93.
24. Sahereh A, Maryam E, Saeideh D, Nahid H, Elham N. Comparison of pregnancy outcome after adding oral or intramuscular progesterone to vaginal progesterone in frozen embryo transfer: A cross-sectional study. Int J Reprod Biomed. 2024;22(10).
25. Alvarez M, Gaggiotti-Marre S, Martinez F, Coll L, Garcia S, Gonzalez-Foruria I, et al. Individualised luteal phase support in artificially prepared frozen embryo transfer cycles based on serum progesterone levels: a prospective cohort study. Hum Reprod. 2021;36(6):1552-60.
26. González-Foruria I, Gaggiotti-Marre S, Álvarez M, Martínez F, García S, Rodríguez I, et al. Factors associated with serum progesterone concentrations the day before cryopreserved embryo transfer in artificial cycles. Reprod Biomed Online. 2020;40(6):797-804.
27. Cédrin-Durnerin I, Isnard T, Mahdjoub S, Sonigo C, Seroka A, Comtet M, et al. Serum progesterone concentration and live birth rate in frozen-thawed embryo transfers with hormonally prepared endometrium. Reprod Biomed Online. 2019;38(3):472-80.
28. Chen W, Xu Y, Liu X, Pan J, Cai B, Zhou C, et al. Serum Progesterone Level on the Day of Embryo Transfer Is Not a Reliable Predictor for Frozen-Thawed Embryo Transfer Outcomes With Euploid Blastocyst Transfer: A Retrospective Cohort Study. Bjog. 2025;132 Suppl 2:53-61
29. Ovarian Stimulation T, Bosch E, Broer S, Griesinger G, Grynberg M, Humaidan P, et al. ESHRE guideline: ovarian stimulation for IVF/ICSI. Hum Reprod Open. 2020;2020(2):hoaa009. Erratum in: Hum Reprod Open. 2020;2020(4):hoaa067.
30. 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):485-90.
31. Akbari Asbagh F, Ghasemzadeh F, Ebrahimi M, Davari-Tanha F, Feizabad E, Akbari Asbagh P, et al. Effect of intramuscular injection of human chorionic gonadotropin on endometrium preparation in frozen-thawed embryo transfer cycle: A randomized clinical trial. Caspian J Intern Med. 2023;14(2):185-91.
32. Eftekhar M, Rahsepar M, Rahmani E. Effect of progesterone supplementation on natural frozen-thawed embryo transfer cycles: a randomized controlled trial. Int J Fertil Steril. 2013;7(1):13-20.
33. Eslami Moayed M, Moini A, Kashani L, Farid Mojtahedi M, Rezaee T, Tabasizadeh H, et al.: Pregnancy outcomes in women with adenomyosis, undergoing artificial endometrial preparation with and without gonadotropin-releasing hormone agonist pretreatment in frozen embryo transfer cycles: An RCT. Int J Reprod Biomed. 2023;21(6):481-90.
34. Agha-Hosseini M, Hashemi L, Aleyasin A, Ghasemi M, Sarvi F, Shabani Nashtaei M, et al. Natural cycle versus artificial cycle in frozen-thawed embryo transfer: A randomized prospective trial. Turk J Obstet Gynecol. 2018;15(1):12-7.
35. Farid Mojtahedi M, Aref S, Moini A, Maleki-Hajiagha A, Kashani L. Natural cycle versus modified natural cycle for endometrial preparation in women undergoing frozen-thawed embryo transfer: An RCT. Int J Reprod Biomed. 2022;20(11):923-30.
36. Aflatoonian A, Mohammadi B. Subcutaneous progesterone versus vaginal progesterone for luteal-phase support in frozen-thawed embryo transfer: A cross-sectional study. Int J Reprod Biomed. 2021;19(2):115-20.
37. Omidi M, Halvaei I, Akyash F, Khalili MA, Agha-Rahimi A, Heydari L. The exact synchronization timing between the cleavage embryo stage and duration of progesterone therapy-improved pregnancy rates in frozen embryo transfer cycles: A cross-sectional study. Int J Reprod Biomed. 2021;19(3):227-34.
| Files | ||
| Issue | Vol 19, No 3 (September 2025) | |
| Section | Original Articles | |
| DOI | https://doi.org/10.18502/jfrh.v19i3.20059 | |
| Keywords | ||
| Frozen Embryo Transfer Luteal Phase Support Intramuscular Progesterone Dydrogesterone Pregnancy-Related Outcomes Hormone Replacement Therapy | ||
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How to Cite
1.
Hatami R, Tehraninejad ES, Rashidi BH, Keikha F, Masoumi M, Barkhordarioon A, Tarafdari A. Efficacy of Daily 50 mg Intramuscular Progesterone for Luteal Phase Support in Frozen Embryo Transfer Cycles: Analysis of Serum Levels and Pregnancy Outcomes. J Family Reprod Health. 2025;19(3):216-225.
