Letrozole for OHSS Prevention Post-IVF Pickup
Letrozole administered during ovarian stimulation or immediately after oocyte retrieval reduces estradiol levels and may decrease the incidence of moderate-to-severe OHSS, though its effectiveness for preventing all grades of OHSS remains controversial.
Mechanism of Action
Letrozole is an aromatase inhibitor that works by blocking the conversion of androgens to estrogen, thereby reducing peak estradiol (E2) levels during and after ovarian stimulation 1. This reduction in estrogen exposure is the primary mechanism by which letrozole may prevent OHSS, as elevated estradiol levels are a key driver of increased vascular permeability and fluid shifts that characterize OHSS 2.
Evidence for OHSS Prevention
Effectiveness on Different OHSS Grades
Moderate-to-severe OHSS: Letrozole demonstrates significant benefit in reducing combined moderate and severe OHSS in high-risk women 3. One randomized trial found only 1 moderate case in the letrozole group versus 9 moderate cases in controls (p=0.04) 4.
Individual OHSS grades: A meta-analysis of 8 studies found no significant differences in the incidence of mild, moderate, or severe OHSS when analyzed individually, suggesting letrozole should not be considered first-line treatment for OHSS prevention 3.
Dose-dependent effects: Higher doses appear more effective—7.5 mg letrozole showed lower incidence of moderate and severe OHSS compared to controls (p<0.05), while 2.5 mg and 5 mg doses showed less consistent benefit 2.
Clinical Application
Timing and Dosing Protocols
During stimulation: Letrozole 5 mg daily can be added simultaneously with gonadotropins during the first 5 days of the IVF cycle, which significantly reduces total stimulation days and cumulative gonadotropin dose (p=0.00) 4.
Post-trigger administration: Letrozole 2.5 mg daily started the day before hCG trigger and continued until egg retrieval significantly lowers E2 levels on retrieval day (p<0.001), though OHSS reduction may not reach statistical significance 5.
Optimal dosing: 7.5 mg daily appears most effective for OHSS prevention in high-risk patients undergoing whole embryo frozen transfer 2.
Impact on IVF Outcomes
Letrozole does not compromise reproductive outcomes 1:
- Number of mature oocytes retrieved remains similar to conventional stimulation 1
- Fertilization capacity is preserved 1
- Clinical pregnancy rates are comparable between letrozole and control groups 4, 5
- No increase in congenital abnormalities in offspring 1
Hormonal Effects
From day 5 post-hCG trigger, letrozole causes 2:
- Progressive decrease in E2 levels (p<0.05)
- Increase in LH levels from day 8 onward (p<0.05)
- Decrease in progesterone levels from day 8 onward (p<0.05)
- Dose-dependent reduction in VEGF levels, a key mediator of OHSS (p<0.001)
Special Populations
Hormone-Sensitive Cancers
Letrozole is particularly valuable for women with estrogen receptor-positive breast cancer undergoing fertility preservation 1:
- Reduces peak estradiol levels to near-physiologic ranges while maintaining oocyte yield 1
- Randomized trials show similar mature oocyte yields with letrozole-gonadotropin versus tamoxifen-gonadotropin protocols (12±8.6 vs 11.6±7.5, p=0.81) 1
- Short-term follow-up shows no adverse impact on cancer-free survival 1
PCOS Patients
Women with PCOS are at particularly high risk for OHSS and may benefit most from letrozole 4:
- Significantly reduces estradiol levels on trigger day (p=0.04) 4
- Decreases total stimulation days and gonadotropin requirements (p=0.00) 4
- May reduce moderate OHSS incidence specifically in this population 4
Clinical Caveats and Limitations
When Letrozole May Not Be Sufficient
- Mild OHSS: No demonstrated benefit for preventing mild cases 3
- Individual severe cases: Effect on severe OHSS alone is not statistically significant when analyzed separately 3
- Variable response: Some studies show no significant OHSS reduction despite E2 lowering 5
Alternative Considerations
For patients with antiphospholipid antibodies or thrombophilia, letrozole-based protocols that yield lower peak estrogen levels may reduce thrombotic complications during ovarian stimulation 1, 6.
Practical Implementation
For high-risk OHSS patients (PCOS, high antral follicle count, previous OHSS):
- Consider letrozole 5-7.5 mg daily during first 5 days of stimulation 4, 2
- Monitor E2 levels; if peak E2 ≥4000 pg/ml, consider adding letrozole 2.5 mg daily from day before trigger until retrieval 5
- Plan for freeze-all strategy in conjunction with letrozole to eliminate early OHSS risk from pregnancy 2
- Continue monitoring VEGF levels if available, as dose-dependent reduction correlates with OHSS prevention 2
The evidence suggests letrozole is most beneficial for preventing moderate-to-severe combined OHSS rather than individual grades, with optimal benefit at higher doses (7.5 mg) in freeze-all cycles 3, 2.