April 17, 2023

Estradiol effects on pregnancy rates in IVF cycles: A review of research

By Daniela Valle

Director’s Note: As research on the role of progesterone supplementation in pregnancy continues to emerge, physicians and other clinicians trained in restorative reproductive medicine may wonder whether supplementing estrogen during the luteal phase in women trying to conceive would increase pregnancy and implantation rates. In this review, FACTS elective student Daniela Valle summarizes research on the role of estradiol in the luteal phase within the context of IVF outcomes. Given that study participants only included women attempting to conceive using IVF, the results cannot be extrapolated to predict the utility of estrogen supplementation to improve pregnancy rates in women trying to conceive naturally. However, it does highlight the need for future research among FABM users and the need to investigate potential factors underlying infertility even before couples seek out assisted reproductive technology.

Introduction

In vitro fertilization (IVF) is a method of treating infertility in which an egg or ovum is fertilized by a sperm outside of a woman’s body in a laboratory, and the resultant embryo is placed inside the woman’s uterus so it can implant in the uterine endometrial lining. For women with luteal phase defects who are undergoing IVF or attempting to conceive naturally, supplementation with progesterone facilitates implantation and may prevent early pregnancy loss. Less is known about the importance of optimal estrogen levels to facilitate implantation and maintain a healthy pregnancy. This systematic review set out to answer the question, “Does supplementation with luteal phase estrogen during IVF cycles increase the rate of pregnancy and implantation?”

“For women with luteal phase defects who are undergoing IVF or attempting to conceive naturally, supplementation with progesterone facilitates implantation and may prevent early pregnancy loss.”

The first step of IVF is ovarian stimulation, in which drugs are used to make the ovary develop a greater number of oocytes than normal so they can be harvested. Several drug protocols exist to perform ovarian stimulation. This systematic review looked at GnRH antagonist IVF protocols, which use drugs that block the gonadotropin releasing hormone receptor; some of these medications include ganirelix acetate and cetrorelix acetate. [4] This blockage prevents LH release, which would cause ovulation of the egg into the fallopian tube, and enables the oocytes to be harvested. [2] During this type of ovarian stimulation protocol, serum progesterone in the luteal phase tends to be higher than normal, while there may be a decrease in serum estradiol.

Methodology

The authors analyzed studies published from 2000 to 2016 in Portugese, English, and Spanish using the key terms “luteal phase,” “estradiol,” and “in vitro fertilization.” The authors included randomized clinical trials which used the GnRH antagonist protocol, and compared the luteal phase support with progesterone alone vs. estradiol with progesterone. The women in these studies were 18 to 39 years of age and their body mass index (BMI) was 18-29. They had intact ovaries and a cycle start hormonal profile with estradiol <80 pg/mL and FSH <10. Patients with male factor infertility, poor response to hormones, or PCOS were excluded. Only four papers matched the inclusion and exclusion criteria.

Results

The researchers looked at both pregnancy and implantation rates comparing women treated with luteal progesterone (P) versus luteal progesterone plus estradiol (P+E).      In all four studies, there was no significant difference in the rate of pregnancy between the two groups. Only 3 of the 4 studies reported implantation rates. Of these, only one study found a significant difference in the implantation rate: the progesterone only group had an implantation rate of 15.8% vs. 26% in the ‘estrogen plus progesterone’ group.

Summary of studies analyzed

Key aspects of the four studies included in the systematic review are summarized below.

Study 1: Fatemi et al, 2006    

This was a prospective, randomized study with 201 study participants. In the control group, 90 women underwent embryo transfer and received 600 mg progesterone vaginally. In the experimental group, 92 women underwent embryo transfer and received 600 mg vaginal progesterone plus 4 mg estradiol valerate daily. There was no significant difference in implantation rate per embryo transferred (37.8% for the P group, 42.4% for the E+P group; p value 0.548).

Study 2: Ceyhan et al, 2006          

This was a prospective, randomized study of 60 women. In both control and experimental groups, women received 600 mg/day of micronized progesterone from the day of oocyte capture until the eighth week of pregnancy. In the experimental group, women additionally received transdermal estradiol 100 mg twice weekly. Study biases include the small sample size and overestimated pregnancy rates because in Turkey, public assistance infertility treatments are limited to 3 cycles per couple, so patients with poor quality embryos had their treatment cycles canceled prior to embryo transfer. There was no significant difference in pregnancy rate per embryo transferred (61.9% in the P group, 56.5% in the E+P group; p value 0.72). Implantation rates were not published.

Study 3:  Kwon et al, 2013

This was a randomized prospective study of 110 women. All women received 90 mg/day of vaginal progesterone (Crinone 8%) during the luteal phase from oocyte capture until the tenth week of pregnancy. In the experimental group, 55 women additionally received 4 mg/day of estradiol valerate orally until pregnancy was confirmed. This was the only study in which embryo implantation rate was significantly increased in the ‘progesterone plus estradiol’ group (15.8% in the P group vs. 26.0% in the E+P group; p value 0.035). However, there was no significant difference in pregnancy rates among the two groups (48.5% vs. 37%; p >0.05). In addition, the supplemental estradiol group had a significantly reduced incidence of luteal vaginal bleeding (7.4% vs. 27.8%; p value 0.010).

Study 4: Madkour et al, 2016          

This was a prospective, randomized study that included 220 study participants. All 220 women received vaginal progesterone 90 mg/day, while 110 women also received 2 mg estradiol twice per day. There was no significant difference in pregnancy, implantation or spontaneous abortion rates between the groups (implantation rates were 19.25% in the P group vs. 23.44% in the P+E group; p value 0.2).

Discussion

Although implantation rates are a more patient-oriented and relevant measure of success than pregnancy rates, the live birth rate is the most patient-oriented outcome. Future studies on luteal phase estrogen plus progesterone supplementation should follow patients longitudinally to determine differences in live birth rate rather than implantation rate.

The authors conclude there is weak evidence to support supplementation with estrogen added to progesterone during the luteal phase in women undergoing IVF with GnRH antagonist protocols. One study supporting this practice is not enough to recommend its widespread use; more research is needed. Furthermore, hormone levels should be measured with treatment given only if a deficiency of estrogen or progesterone is proven. In IVF cycles with multiple follicles and very high hormone levels throughout the process, it seems unlikely hormone deficiency is contributing to IVF failure.

“There is weak evidence to support supplementation with estrogen added to progesterone during the luteal phase in women undergoing IVF with GnRH antagonist protocols.”

Users of fertility awareness-based methods (FABMs) may wonder whether estrogen supplementation during the luteal phase in women trying to conceive naturally would result in a higher pregnancy and implantation rate. Estrogen promotes endometrial proliferation and production of cervical mucus conducive to sperm passage. Progesterone optimizes transport of the developing embryo through the fallopian tube, increases receptiveness of the endometrium to implantation, maintains pregnancy, inhibits uterine contractions, and (like estrogen) stimulates secretory function of the endometrium and spiral artery development.[3]

Given all that is known about estrogen’s vital role during pregnancy for fetal development and uterine wall growth, the idea that optimal estrogen levels would result in higher implantation and live birth rates seems like a plausible hypothesis. It is unclear how estrogen supplementation might improve pregnancy rates in users attempting to conceive naturally, since this systematic review only looked at women trying to conceive using IVF, but it does suggest more research is needed to determine potential applications of luteal estrogen in FABM users. One study of patients with infertility found that 63% had suboptimal luteal phase estrogen levels after evaluation with the Creighton Model’s Natural Procreative Technology. Beyond assessing for a deficiency in estradiol and progesterone, it is important to determine why hormone levels are low. If it is due to poor follicle function or an inadequate corpus luteum, it may be better to treat with follicle stimulation rather than just luteal phase support.

“It is unclear how estrogen supplementation might improve pregnancy rates in users attempting to conceive naturally, but it does suggest more research is needed to determine potential applications of luteal estrogen in FABM users.”

References

[1] Pinheiro, L. M., Cândido, P. da, Moreto, T. C., Almeida, W. G., &amp; Castro, E. C. (2017). Estradiol use in the luteal phase and its effects on pregnancy rates in IVF cycles with GnRH antagonist: A systematic review. JBRA Assisted Reproduction, 21(3), 247–250. https://doi.org/10.5935/1518-0557.20170046.

[2] Ovarian stimulation for IVF in low responders. Advanced Fertility Center of Chicago. (2020, December 15). Retrieved December 17, 2021, from https://advancedfertility.com/2020/09/18/ovarian-stimulation-for-ivf-in-low-responders/.

[3]  Burton GJ, Hempstock J, Jauniaux E. Nutrition of the Human Fetus during the First Trimester—A Review. Placenta. 2001; 22: pp. S70–S77. doi: 10.1053/plac.2001.0639.

[4]  Tavaniotou, A., &amp; Devroey, P. (2006). Luteal hormonal profile of oocyte donors stimulated with a GnRH antagonist compared with natural cycles. Reproductive BioMedicine Online, 13(3), 326–330. https://doi.org/10.1016/s1472-6483(10)61435-6.

[5]  Stanford JB, Parnell TA, Boyle PC. Outcomes from treatment of infertility with natural procreative technology in an Irish general practice [published correction appears in J Am Board Fam Med. 2008 Nov-Dec;21(6):583]. J Am Board Fam Med. 2008;21(5):375-384. doi:10.3122/jabfm.2008.05.070239.

About the Author

Daniela Valle

Daniela Valle is a fourth-year medical student at Rowan School of Osteopathic Medicine in Stratford, NJ. She plans to specialize in family medicine. Her professional interests include obstetrics, breastfeeding medicine, osteopathic manipulative medicine, NaProTechnology, pediatrics, and medication assisted treatment. She completed undergraduate studies in biomedical engineering at the New Jersey Institute of Technology Albert Dorman Honors College. She first became interested in FABMs after shadowing a NaProTech family physician prior to medical school, and completed this review as part of the FACTS elective for medical students.