Ferring Educational Programm

Ariel Weissman, MD

IVF Unit, Department of Obstetrics and Gynecology, Edith Wolfson Medical Center, Holon, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

Estrogens play a key role in uterine receptivity by regulating endometrial proliferation and influencing uterine perfusion and contractility. Far less is known on the role of E2 during the luteal phase, where it is believed to have a modulating effect on endometrial P receptors concentration and replenishment.

In the natural menstrual cycle E2 is continued to be secreted by the corpus luteum along with P throughout the luteal phase. The luteal phase of ART cycles is certainly different than that of the natural cycle and is assumed to be invariably abnormal. Controlled ovarian stimulation with either GnRH agonists or antagonists is associated with supra-physiological levels of E2 and P due to multi-follicular development that subsequently adversely affect pituitary function during the luteal phase. LH activity plays a crucial role in the luteal phase, since it stimulates implantation and is entirely responsible for the steroid activity of the corpus luteum. It is assumed that the high steroid levels have a negative feedback on the hypothalamic-pituitary axis, resulting in suppression of LH secretion, that leads to a drop in serum E2 and P to very low levels during the mid-luteal phase, resulting in reduced implantation and pregnancy rates.

Compared to P, relatively few studies have been conducted on E2 supplementation for luteal support, and conflicting results were reported. Four meta-analyses have been recently published on this subject (1-4), and all came to the same conclusion that there is no clear benefit in adding E2 to the luteal support regimens. This conclusion, however, should be evaluated with caution, since most studies included in the analyses suffer from a large degree of heterogeneity. For example, in the study of Farhi et al. (5), only high responder patients were included, and only in those stimulated on a long GnRH agonist protocol the addition of oral E2 was found beneficial. A significant increase in serum E2 levels was demonstrated in E2 treated patients. In the study by Lukaszuk et al.(6), several oral doses of E2 were used with an increasing beneficial effect of E2 supplementation in a dose-dependent manner. In the study by Engmann et al.(7), the vaginal route was used and very high serum E2 levels were achieved, which could be detrimental. In the study of Lewin et al. (8) a low dose of oral E2 was used, that did not result in different serum E2 levels in treated and non-treated patients.

Because of considerable differences in E2 doses, routes of administration, timing of treatment, patient populations and outcome variables reported, it is very difficult to include many of the eligible studies in meta-analyses in a comprehensive manner without causing significant bias. In addition, live birth rate as the major clinical determinant of success has only been reported in very few cycles, and the number of patients analyzed in eligible trials might be far below the sample size required to prove a clinically significant difference. Therefore, the validity of the conclusions of the meta-analyses should be questioned. In addition, hormone treatment during the luteal phase is conducted empirically and is rarely individualized. Lack of clearly defined morphologic or hormonal criteria that relate to appropriate endometrial preparation make the evaluation even more complex.

There is a certain need for further research in order to better understand the role of E2 during the luteal phase of ART cycles and to define patient-specific treatment criteria and goals. Only then properly designed RCTs can be carried out that will finally tell us whether the inclusion of E2 in luteal support protocols can increase the probability of pregnancy and live birth in ART.

---

1. 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. Fertility and sterility 2008;90:2116-25.
2. 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. Fertility and sterility 2010;93:428-36.
3. 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. Human Reproduction 2008;23:1346-54.
4. van der Linden M, Buckingham K, Farquhar C, Kremer JA, Metwally M. Luteal phase support for assisted reproduction cycles. Cochrane Database Syst Rev 2011:CD009154.
5. Farhi J, Weissman A, Steinfeld Z, Shorer M, Nahum H, Levran D. Estradiol supplementation during the luteal phase may improve the pregnancy rate in patients undergoing in vitro fertilization-embryo transfer cycles. Fertility and sterility 2000;73:761-6.
6. 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. Fertility and sterility 2005;83:1372-6.
7. Engmann L, DiLuigi A, Schmidt D, Benadiva C, Maier D, Nulsen J. The effect of luteal phase vaginal estradiol supplementation on the success of in vitro fertilization treatment: a prospective randomized study. Fertility and sterility 2008;89:554-61.
8. Lewin A, Benshushan A, Mezker E, Yanai N, Schenker JG, Goshen R. The role of estrogen support during the luteal phase of in vitro fertilization-embryo transplant cycles: a comparative study between progesterone alone and estrogen and progesterone support. Fertility and sterility 1994;62:121-5.