From the Guidelines
Estradiol supplementation during letrozole treatment for infertility should typically be discontinued once ovulation has occurred or when pregnancy is confirmed, as the developing placenta will begin producing hormones to support the pregnancy, and continuing estradiol unnecessarily during early pregnancy is not recommended unless specifically prescribed for recurrent pregnancy loss or other specific conditions. In a standard protocol, estradiol (usually 1-2mg daily) is often started around day 8-10 of the menstrual cycle after completing the 5-day course of letrozole (2.5-7.5mg daily on cycle days 3-7) 1. The estradiol supplementation is then continued until either a positive pregnancy test or the onset of menstruation. The purpose of adding estradiol to letrozole treatment is to counteract the temporary estrogen-lowering effects of letrozole, which can thin the endometrial lining and reduce cervical mucus quality. By providing estrogen support after letrozole has stimulated follicle development, the protocol aims to create a more favorable environment for implantation while still allowing letrozole to effectively induce ovulation.
Key Considerations
- The use of letrozole does not reduce the number of mature oocytes obtained or their fertilisation capacity, and no effect on congenital abnormality rates in children has been observed 1.
- Ovarian stimulation with gonadotropins is required for oocyte and embryo cryopreservation, followed by follicle aspiration, and can be started at any time of the menstrual cycle (‘random start stimulation’) 1.
- The efficacy of oocyte and embryo cryopreservation to generate a subsequent pregnancy is tightly connected to the number of mature oocytes retrieved after ovarian stimulation, which is age-dependent and reduced in women with poor ovarian reserve 1.
Discontinuation Criteria
- Ovulation has occurred
- Pregnancy is confirmed
- Onset of menstruation It is essential to note that the decision to discontinue estradiol supplementation should be based on individual patient needs and circumstances, and should be made in consultation with a healthcare provider. Additionally, the most recent and highest quality study, published in 2020, provides the most up-to-date guidance on this topic 1.
From the Research
Discontinuation of Estradiol (E2) Therapy
- The decision to discontinue estradiol (E2) therapy after letrozole (Femara) for infertility treatment depends on various factors, including the type of fertility treatment and the individual patient's response to the medication.
- According to a study published in 2009 2, luteal phase support (LPS) should be stopped either on the day of pregnancy test or the first ultrasound (6-7 weeks pregnancy).
- There is no evidence to suggest that the addition of estrogen, such as estradiol, will improve pregnancy rates 2.
- Letrozole, an aromatase inhibitor, has been used in various infertility settings, including ovulation induction and intrauterine insemination (IUI) 3, 4, 5.
- The optimal duration of estradiol therapy after letrozole treatment is not clearly established, and further studies are needed to determine the best approach 6, 4.
Luteal Phase Support
- Luteal phase support (LPS) is an integral part of IVF cycles treated with gonadotropin-releasing hormone analogues 2.
- Progesterone is the preferred option for LPS, and it should start within 2 days from triggering ovulation and end on the day of beta human chorionic gonadotropin or the day of the first ultrasound (6-7 weeks pregnancy) 2.
- The use of estradiol in LPS is not recommended, as there is no evidence to suggest that it improves pregnancy rates 2.
Letrozole and Estradiol
- Letrozole suppresses serum estradiol levels, but its effect on uterine artery Doppler flow indices is not fully understood 6.
- The combination of letrozole and estradiol has not been extensively studied, and further research is needed to determine the optimal approach to using these medications together 3, 4.