Comparison of intracycle Extended Letrozole Regimen and Gonadotropins for Letrozole-Resistant Polycystic Ovary Syndrome Patients Undergoing Ovulation Induction-A randomized controlled pilot study

Polycystic Ovary Syndrome (PCOS) is the most common endocrinopathy affecting women of reproductive age. The prevalence ranges from 6 to 21 percent in the global population, depending on phenotype and ethnicity. In 2018, new evidence-based international consensus guidelines for women with PCOS highlighted the use of letrozole (LE) as the first-line treatment for OI to improve pregnancy rates while reducing adverse effects and gonadotropins as the second line of treatment.

Traditional LE treatment protocol involves administering a daily dosage of 2.5 mg or 5 mg for 5 days. However, follicular development varies among patients, with 20–30 percent of women failing to ovulate despite traditional letrozole therapy. According to current guidelines, gonadotrophins and laparoscopic ovarian drilling are recommended as second-line treatment options. Alternative strategies include extending the duration of letrozole therapy in subsequent cycles.  Recent studies show that extending the duration of LE treatment in patients with PCOS, who have not ovulated with the standard 5-day LE regimen, can enhance follicular development and achieve ovulation. In a randomized controlled trial, the extended letrozole regimen (5 mg for 7 days) resulted in a significantly higher ovulation rate of 78–82 percent**,** compared to 60–65 percent in the conventional regimen (5 mg for 5 days). A retrospective study further supported these findings, showing improved ovulation rates and endometrial thickness in patients who received extended or individualized letrozole dosing (5 mg for 10 days), especially among those resistant to standard treatment. These findings collectively suggest that an extended letrozole protocol may be more effective in enhancing ovulation outcomes in women with PCOS.

Another alternative for ovulation induction is the use of gonadotropins; however, this approach is more expensive, requires intensive monitoring, and carries an increased risk of ovarian hyperstimulation and multiple pregnancies. In our population, where cost-effectiveness and accessibility to fertility treatment are crucial, particularly for women residing in remote areas with limited access to regular clinic visits, treatment protocols must be optimized accordingly.

Our analysis of ovulation induction data and letrozole response revealed that among patients resistant to standard letrozole therapy, 83 percent responded favorably to an extended letrozole regimen within the same cycle. In women who fail to develop a greater than 10 mm follicle by day 10 of the stimulation cycle, extending ovarian stimulation rather than abandoning the cycle may improve outcomes.

Therefore, we propose a randomized controlled trial to compare the safety and efficacy of an extended letrozole regimen with that of a gonadotropin protocol in women with polycystic ovary syndrome (PCOS) who exhibit inadequate response to first-line letrozole therapy (5 mg for 5 days) during ovulation induction