Is there any correlation between Estradiol supplementation, as luteal phase support, and clinical pregnancy in ART cycles? A cross-sectional study


Background: Endometrial receptivity is one of the important factors in assisted reproductive technology (ART) success. In the luteal phase of an ART cycle, serum estradiol (E2) and progesterone are often placed in low levels. Supporting the luteal phase with progesterone is a usual method.

Objective: To evaluate the effects of E2 supplementation plus progesterone on the luteal phase support in the antagonist protocol who have undergone intracytoplasmic sperm injection-embryo transfer cycles.

Materials and Methods: In this cross-sectional study, 200 patients with antagonist stimulation protocol, who had undergone intracytoplasmic sperm injection treatment, were divided into two groups based on the use of E2 supplementation. In both groups, 400 mg progesterone suppositories (Cyclogest®), twice a day/vaginally, was administered starting from the day of oocyte collection until the fetal heart activity. However, in the E2 group, in addition to progesterone, 4 mg tablet of E2 was received daily. Beta hCG was checked 14 days after the embryo transfer, and the clinical pregnancy rate was the main endpoint.

Results: The patients’ characteristics were matched, and insignificant differences were observed, except for endometrial thickness. The clinical outcomes showed the rate of pregnancy was higher in the E2 group compared to the control group; nonetheless, statistically, there was no noticeable difference.

Conclusion: E2 supplementation had no beneficial effect in the luteal phase support of IVF cycles. Nevertheless, more studies are required to confirm the supportive role of E2 supplementation for embryo implantation and to improve the outcomes in ART cycles.

Key words: Luteal phase, Estradiol, Progesterone, ICSI, Pregnancy rate.

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

[2] Yılmaz NK, Kara M, Hançerlioğulları N, Erkılınç S, Coşkun B, Sargın A, et al. Analysis of two different luteal phase support regimes and evaluation of in vitro fertilizationintra cytoplasmic sperm injection outcomes. Turk J Obstet Gynecol 2018; 15: 217–221.

[3] Huang N, Situ B, Chen X, Liu J, Yan P, Kang X, et al. Metaanalysis of estradiol for luteal phase support in in vitro fertilization/intracytoplasmic sperm injection. Fertil Steril 2015; 103: 367–373.

[4] Zhao W, Liu Y, Xu P, Wu Y, Chen K, Guo X, et al. Effects of oestradiol for luteal phase support in fresh embryo transfer cycles: A retrospective cohort study. Clin Endocrinol 2018; 89: 194–201.

[5] Gelbaya TA, Kyrgiou M, Tsoumpou I, Nardo LG. The use of estradiol for luteal phase support in in vitro fertilization/intracytoplasmic sperm injection cycles: A systematic review and meta-analysis. Fertil Steril 2008; 90: 2116–2125.

[6] Beckers NGM, Macklon NS, Eijkemans MJ, Ludwig M, Felberbaum RE, Diedrich K, 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: 4186–4192.

[7] Eftekhar M, Zare Mehrjardi S, Molaei B, Taheri F, Mangoli E. The correlation between endometrial thickness and pregnancy outcomes in fresh ART cycles with different age groups: A retrospective study. Middle East Fertil Soc J 2019; 24: 1–6.

[8] Çakar E, Tasan HA, Kumru P, Cogendez E, Usal NT, Kutlu HT, et al. Combined use of oestradiol and progesterone to support luteal phase in antagonist intracytoplasmic sperm injection cycles of normoresponder women: a casecontrol study. J Obstet Gynaecol 2020; 40: 264–269.

[9] Serna J, Cholquevilque JL, Cela V, Martínez-Salazar J, Requena A, Garcia-Velasco JA. Estradiol supplementation during the luteal phase of IVF-ICSI patients: a randomized, controlled trial. Fertil Steril 2000; 90: 2190–2195.

[10] Drakakis P, Loutradis D, Vomvolaki E, Stefanidis K, Kiapekou E, Anagnostou E, et al. Luteal estrogen supplementation in stimulated cycles may improve the pregnancy rate in patients undergoing in vitro fertilization/intracytoplasmic sperm injection-embryo transfer. Gynecol Endocrinol 2007; 23: 645–652.

[11] Zhang XM, Lv F, Wang P, Huang XM, Liu KF, Pan Y, et al. Estrogen supplementation to progesterone as luteal phase support in patients undergoing in vitro fertilization: systematic review and meta-analysis. Medicine 2015; 94: e459: 1–12.

[12] Lin H, Li Y, Li L, Wang W, Zhang Q, Chen X, 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: 171–175.

[13] Munjal R, Gupta S. Addition of oestradiol to progesterone for luteal phase support in GnRh antagonist IVF/ICSI cycles. Fertility Science and Research 2019; 6: 35–39.

[14] Scheffer JB, Scheffer BB, de Carvalho RF, Aguiar AP, Lozano DHM, Labrosse J, et al. A comparison of the effects of three luteal phase support protocols with estrogen on in vitro fertilization-embryo transfer outcomes in patients on a GnRH antagonist protocol. JBRA Assist Reprod 2019; 23: 239–245.

[15] Pinheiro LMA, Candido PDS, Moreto TC, Almeida WGD, Castro EC. Estradiol use in the luteal phase and its effects on pregnancy rates in IVF cycles with GnRH antagonist: A systematic review. JBRA Assist Reprod 2017; 21: 247–250.

[16] Madkour WAI, Noah B, Abdel Hamid AM, Zaheer H, Al- Bahr A, Shaeer M, et al. Luteal phase support with estradiol and progesterone versus progesterone alone in GnRH antagonist ICSI cycles: A randomized controlled study. Hum Fertil 2016; 19: 142–149.

[17] Lukaszuk K, Liss J, Lukaszuk M, Maj B. Optimization of estradiol supplementation during the luteal phase improves the pregnancy rate in women undergoing in vitro fertilization-embryo transfer cycles. Fertil Steril 2005; 83: 1372–1376.

[18] Kasapoglu I, Düzok N, Şen E, Şen E, Çakır C, Avcı B, Uncu G. Luteal oestradiol for patients with serum oestradiol levels lower than expected per oocyte. Hum Fertil 2019: 1–7.

[19] Kutlusoy F, Guler I, Erdem M, Erdem A, Bozkurt N, Biberoglu EH, et al. Luteal phase support with estrogen in addition to progesterone increases pregnancy rates in in vitro fertilization cycles with poor response to gonadotropins. Gynecol Endocrinol 2014; 30: 363–366.