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Frozen embryo transfer: Endometrial preparation by letrozole versus hormone replacement cycle: A randomized clinical trial

Abstract Background The endometrial preparation with stimulating natural cycles for frozen embryo transfer (FET) have benefits like lower cost and ease of use. Objective Comparing the clinical outcome of letrozole versus hormone replacement (HR) for endometrial preparation in women with normal menstrual cycles for FET in artificial reproduction techniques. Materials and Methods A total of 167 participants who had frozen embryos and regular ovulatory cycles were randomly divided into two groups for endometrial preparation. One group (82 women) was stimulated with letrozole 5mg/day and the other group (85 women) was hormonally stimulated by oral estradiol valerate (2 mg three times a day). All participants were followed serially by ultrasonography. Any patient who did not reach optimal endometrial thickness was excluded from the study. Implantation, biochemical and clinical pregnancy and abortion rate were reported. Results There was no significant difference in the mean age, duration, and primary or secondary infertility, cause of the infertility, number, and quality of transferred embryos between the groups. The mean estradiol level on the day of transfer was 643 ± 217 in the HR group and 547 ± 212 in the letrozole group (P = 0.01), which was significantly different. The clinical pregnancy rate was 38.7 in the letrozole group, higher than the HR group (25.3) but not significantly different (P = 0.06). Conclusion For endometrial preparation in women with a normal cycle, letrozole yields higher pregnancy rate although it is not significant; due to its cost, ease in use, and lower side effects, letrozole is a good choice.


Introduction
Frozen-thawed embryo transfer (FET) in in-vitro fertilization (IVF) cycles is a critical step to increase the rate of pregnancy and to prevent ovarian hyper stimulation syndrome (OHSS) (1). Improved laboratory techniques by transferring fewer embryos in the fresh transfer cycles have led to an increase in the number of FET cycles (2).
One of the main principles in FET is endometrial preparing for implantation of the thawed embryos Letrozole is an aromatase inhibitor which does not decrease estrogen receptors. The normal central feedback system is not affected by letrozole and ovulation stays intact. It has no negative effect on endometrium (8).
Letrozole cause increasing FSH by not allowing estrogen making in granulosa cells from androgen.
Its half-life is ± 2 days while clomiphene citrate half-life ± 2 wk; hence, antiestrogenic adverse effects of letrozole does not affected endometrium and cervix, and in comparison, to clomiphene citrate letrozole might have more ovulation induction properties like follicular growth and endometrial development (9). Therefore, mono ovulation with letrozole reduces the effect of high estradiol on the endometrium and embryo (10).
Considering the benefits, letrozole can be an effective endometrial preparing drug for FET cycles, its need more studies for clinical efficacy. The purpose of this study was to compare pregnancy outcome in stimulating with hormone replacement and endometrial preparation in patients with regular menstrual cycles with letrozole who were routinely candidate for the artificial cycle in our center.

Setting
This study was conducted as a randomized

Letrozole group
Participants were prescribed 5 mg letrozole/day from the third day to the seventh day of the menstrual cycle. Follicular development was monitored by vaginal ultrasonography starting on the 10th day of the menstrual cycle; if the follicular diameter was ≥ 17 mm and the endometrial thickness reached 7-9 mm, they were given 10,000 unit of HCG, and 36-48 hr after that, they were progesterone ampule 100 mg was given intramuscularly/day for three to five days depending on the embryo's age. Then, the embryos were transferred and progesterone 100 mg/IM per day was continued for three days after the transfer and then changed to progesterone suppository 400 mg Q12 hr (rectal or vaginal) 14-16 days after the transfer.
If on the 10th day of the cycle, the dominant follicle was ≥ 14 mm to < 17 mm, a serial vaginal ultrasonography (every other day) was repeated without adding any medication until the follicle reached 17 mm or more or the endometrial thickness was 7-9 mm. After that, HCG was administered and like the first method progress was continued.
However, if on the 10th day, the dominant follicle size was < 14 mm, HMG was injected daily for three to four days until the follicular diameter was > 17 mm or the endometrial thickness was 7-9 mm, and then HCG was injected. If by the 17th day of the cycle, the dominant follicle did not reach 17 mm or if the endometrial thickness was < 7 mm, the cycle was canceled.

HRT group
The participants were prescribed oral estradiol valerate (2 mg three times a day) starting on the second to the third day of menstrual cycle, and on the 10th day, the endometrial thickness was monitored by vaginal ultrasonography. If the endometrial thickness was 7-9 mm and three-line pattern, estrogen was continued and progesterone therapy was initiated 100 mg IM/day for three to five days depending on the embryo's age. Then, it was continued after the embryo transfer for three days and then changed to progesterone suppository 400 mg Q 12 hr.

Statistical analysis
Date were analyzed using the Statistical Package for the Social Sciences, version 22, SPSS Inc, Chicago, Illinois, USA. The mean was compared using one-way analysis of variance (ANOVA) and two-sample t-tests. The proportion for the two groups was compared using the x2-test, p < 0.05 was considered to be statistically significant.

Results
This was a prospective trial comparing the outcome of endometrial preparation in frozen embryos transfer cycle by letrozole and hormone replacement. In the letrozole group, 82 women were followed, the analysis was limited to 80 women, since 2 of them (2.5%) were excluded due  As shown in Table III The clinical pregnancy rate was higher in the letrozole group (38.7%) than in the artificial group (25.3%) but not significant. Furthermore, the first trimester abortion rate was non-significantly lower in the letrozole group (Table IV).

International Journal of Reproductive BioMedicine
Endometrial preparation in embryo transfer In this study, 20 patients who participated in the HR group and failed to reach pregnancy were scheduled to use letrozole in the next menstrual cycle, and of them, 35% became pregnant (7/ 20), but three had an early abortion (45% of clinical pregnancy).

Discussion
In this study we detected that the clinical and chemical pregnancy rate was higher in the letrozole group although it was not significant. There has been no protocol for endometrial preparing by letrozole.

Conclusion
For endometrial preparation in women with a normal cycle, letrozole yields higher pregnancy rate although it is not that significant; due to its benefit, lower side effects, and the patient's comfort in the use of medication, letrozole is a better choice for endometrial preparation.