Letrozole Extended vs Traditional Therapy for Ovulation Induction in Women With PCOS (PROLEx-PCOS)

Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder and one of the leading causes of anovulatory infertility worldwide. Letrozole, an aromatase inhibitor, has emerged as the preferred first-line pharmacological agent for ovulation induction in women with PCOS. Despite its widespread use, there is ongoing debate regarding the optimal duration of therapy to maximize ovulatory and pregnancy outcomes.

This randomized clinical trial is designed to evaluate whether an extended regimen of letrozole provides superior reproductive outcomes compared with the standard regimen. The extended protocol consists of daily administration of 5 mg letrozole from cycle day 2 through day 12, whereas the standard regimen involves 5 mg daily from cycle day 2 through day 6. Ovulatory response will be monitored through serial transvaginal ultrasound and biochemical markers of ovulation.

The trial aims to generate high-quality evidence on the efficacy and safety of extended letrozole therapy. The findings may inform future clinical guidelines on ovulation induction strategies in women with PCOS and contribute to optimizing treatment protocols for anovulatory infertility.

• Traditional Letrozole Therapy (Drug): Traditional therapy group: 5 mg/day of letrozole for 5 days (cycle days 2-6).
• Extended Letrozole Therapy (Drug): Extended therapy group: 5 mg/day of letrozole for 10 days (cycle days 2-12)

Primary outcomes

• Ovulation rate [Assessed within one treatment cycle (up to 6 weeks from the start of medication).]: Proportion of participants achieving ovulation, defined as the presence of a dominant follicle ≥18 mm on transvaginal ultrasound with confirmation by urinary LH surge and/or visualization of corpus luteum.

Secondary outcomes

• Clinical Pregnancy Rate [Assessed within 8 weeks after the start of treatment.]: Proportion of participants achieving clinical pregnancy, defined as visualization of a gestational sac by transvaginal ultrasound.
• Number of Mature Follicles [Assessed during one treatment cycle (up to 6 weeks).]: Number of follicles ≥18 mm observed by transvaginal ultrasound in the stimulated cycle.
• Follicular Size [Assessed during one treatment cycle (up to 6 weeks).]: Maximum diameter (in millimeters) of the leading follicle(s) observed by transvaginal ultrasound.
• Miscarriage Rate [Assessed up to 12 weeks of gestation.]: Proportion of participants with spontaneous pregnancy loss within the first trimester (<12 weeks of gestation).
• Multiple Pregnancy Rate [Assessed within 8 weeks after the start of treatment.]: Proportion of participants with multiple gestations, confirmed by transvaginal ultrasound.
• Incidence of Ovarian Hyperstimulation Syndrome (OHSS) [Assessed within one treatment cycle (up to 6 weeks).]: Proportion of participants presenting clinical or ultrasound signs of OHSS during treatment.

Sex: Female, ages: 18 Years to 40 Years, accepts healthy volunteers

Inclusion Criteria:

* Women aged 18 to 40 years;
* BMI between 18,5 and 31 kg/m2
* Diagnosis of Polycystic Ovary Syndrome (PCOS) according to the Rotterdam criteria (2003) (presence of at least two of the following: oligo/anovulation, clinical and/or biochemical hyperandrogenism, polycystic ovarian morphology on ultrasound);
* Active desire for pregnancy at the time of enrollment;
* Ability and willingness to provide written informed consent (ICF).

Exclusion Criteria:

* Age <18 or >40 years;
* Presence of confirmed bilateral tubal factor, severe male factor infertility, premature ovarian insufficiency, uncontrolled hyperprolactinemia or thyroid dysfunction);
* Congenital or acquired uterine malformations;
* History of gynecologic or breast cancer;
* Known hypersensitivity to, or contraindication for, letrozole;
* Severe uncontrolled systemic disease (e.g., cardiovascular, renal, or hepatic disorders);
* Pregnancy or breastfeeding at the time of screening.

• Gabriel M Pinheiro, MD, Study director, Universidade Santo Amaro
• Katherine Ann R Miller, Medical student, Principal investigator, Universisty of Santo Amaro