150 IU vs. 225 IU FSH in Normal Responders: The OPTIMAL-DOSE Trial

OPTIMAL-DOSE: A Randomized, Open-Label, Non-Inferiority Trial Comparing Fixed Daily Doses of 150 IU Versus 225 IU of Follicle-Stimulating Hormone in Predicted Normal Responders Undergoing In Vitro Fertilization/Intracytoplasmic Sperm Injection

This is a single-center, randomized, open-label, non-inferiority trial comparing two fixed daily doses of follicle-stimulating hormone (FSH): 150 IU versus 225 IU in women with predicted normal ovarian response undergoing in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) with a gonadotropin releasing hormone (GnRH) antagonist protocol. The primary objective is to determine whether the 150 IU dose is noninferior to the 225 IU dose regarding the cumulative live birth rate per initiated cycle. Secondary objectives include comparing oocyte yield, incidence of OHSS, treatment costs, and patient-reported outcomes.

Background: Controlled ovarian stimulation (COS) with exogenous FSH is a cornerstone of IVF treatment. The optimal starting dose of FSH for women with normal ovarian reserve remains controversial, with doses ranging from 150 IU to 300 IU used in clinical practice.

Both 150 IU and 225 IU are widely used, but no randomized controlled trial has directly compared these two specific doses in predicted normal responders.

Objective: To determine if a fixed daily dose of 150 IU FSH is non-inferior to 225 IU FSH with respect to cumulative live birth rate per initiated cycle.

Methods: A total of 440 women (220 per group) will be randomized 1:1 to receive either 150 IU or 225 IU of FSH daily, starting on day 2-3 of the menstrual cycle. All participants will follow a standard GnRH antagonist protocol. The primary outcome is cumulative live birth rate, defined as the delivery of at least one live-born infant at ≥24 weeks of gestation from the first fresh or any subsequent frozen embryo transfer from a single stimulation cycle. The non-inferiority margin is set at -10% (absolute difference).

Significance: If 150 IU is proven non-inferior, this would support the use of a lower dose, potentially reducing treatment costs and the risk of ovarian hyperstimulation syndrome (OHSS) without compromising efficacy.

Inclusion Criteria:

1. Body Mass Index (BMI) 18-30 kg/m².
2. Predicted normal ovarian reserve:
3. Anti-Müllerian Hormone (AMH) 1.2-3.5 ng/mL (measured within 12 months), AND Antral Follicle Count (AFC) 8-20 (both ovaries combined, measured on day 2-5 of the cycle).
4. First or second IVF/ICSI cycle.
5. Planned GnRH antagonist protocol.
6. Both ovaries present and accessible.
7. Written informed consent provided voluntarily.

Exclusion Criteria:

1. Predicted poor or high ovarian response (AMH <1.2 or >3.5 ng/mL; AFC <8 or >20).
2. Polycystic Ovary Syndrome (PCOS) according to Rotterdam criteria.
3. Severe endometriosis (Stage III-IV per ASRM).
4. Severe uterine abnormalities affecting implantation.
5. Previous complete fertilization failure (fertilization rate <30%).
6. Severe male factor (sperm count <5 million/mL, or requirement for donor sperm/TESE).
7. Uncontrolled endocrine disorders (uncontrolled hypothyroidism, hyperprolactinemia, diabetes).
8. Contraindications to pregnancy or gonadotropins.
9. Participation in another clinical trial within 30 days.
10. Inability to provide informed consent.