From the Guidelines
The dose of letrozole should be increased in ovulation induction if a woman is not responding adequately to the initial dose, with the goal of achieving monofollicular or bifollicular growth to minimize the risk of multiple pregnancies and ovarian hyperstimulation syndrome (OHSS) 1. When using letrozole for ovulation induction, the initial dose is typically 2.5 mg daily for 5 days, but it can be increased to 5 mg or even 7.5 mg daily if needed, based on individual response and follicular development. The main reasons to increase the dose include:
- Failure to develop mature follicles
- Inadequate endometrial thickness
- Persistent anovulation despite treatment Letrozole works by temporarily reducing estrogen production, which triggers the pituitary gland to release more follicle-stimulating hormone (FSH), stimulating ovarian follicle development, as shown in studies on ovulation induction 1. Some women require higher doses to achieve sufficient estrogen suppression and subsequent FSH release, and monitoring through ultrasound and hormone testing helps determine if a dose increase is necessary. It is essential to balance the dose to achieve optimal follicular growth while minimizing the risk of multiple pregnancies and OHSS, which can be achieved by aiming for monofollicular or bifollicular growth, as supported by the study by van Rumste et al. (2008) cited in 1. If increasing the dose doesn't result in ovulation after 2-3 cycles, alternative treatments may be considered, and side effects may increase with higher doses, including hot flashes, headaches, and fatigue, but these are generally mild and temporary.
From the Research
Reason to Increase Letrozole Dose
- The reason to increase the letrozole dose when using it for ovulation induction is to potentially increase follicular growth and the number of predicted ovulations, as higher doses of the drug have been shown to offer benefits to patients 2.
- Increasing the dose of letrozole may be of value in women who fail to respond adequately to lower doses, as high-dose letrozole may be more effective in inducing ovulation 2.
- However, some studies have found that higher doses of letrozole do not necessarily produce better outcomes, and that the optimal dose for ovulation induction may be lower than previously thought 3.
Effects of Higher Doses of Letrozole
- One study found that letrozole at a dose of 5.0 mg/day produced a higher pregnancy rate and more mature follicles than a dose of 2.5 mg/day in women with PCOS 4.
- Another study found that letrozole at a dose of 7.5 mg/day did not produce significantly better outcomes than a dose of 5 mg/day in women with PCOS 3.
- A review of 41 RCTs found that letrozole was associated with higher live birth rates and pregnancy rates compared to SERMs, but that the optimal dose of letrozole was not clearly established 5.
Safety of Higher Doses of Letrozole
- High-dose letrozole has been shown to be safe and effective, with no detrimental effect on endometrial thickness 2.
- One study found that letrozole combined with low-dose highly purified HMG was an effective and safe choice for reducing hyperstimulation and increasing pregnancy rate in CC-resistant women with PCOS, with no severe OHSS or multiple pregnancy reported 6.