Optimizing Metformin Use in Polycystic Ovary Syndrome

INTRODUCTION Polycystic ovary syndrome (PCOS) remains a key public health burden as it is one of the most common endocrine and metabolic disorders affecting up to 13% of women globally. The Rotterdam diagnostic criteria were updated and internationally endorsed in the 2023 International PCOS guideline and include a) ovulatory and menstrual dysfunction, b) biochemical and/or clinical hyperandrogenism and c) polycystic ovary morphology (PCOM) at ultra-sound. For a diagnosis in adults two of three criteria are required, with PCOM remaining nonspecific for PCOS in adolescents.

Women with PCOS present with diverse features; metabolic (weight gain, obesity, insulin resistance and diabetes) reproductive (infertility and pregnancy complications), endocrine (hyperandrogenism, hirsutism and acne) and psychosocial (depression, anxiety and poor quality of life).

While lifestyle management is strongly recommended for weight management, for those with higher body mass index (BMI), sustainable efficacy for weight loss can be limited and additional pharmacological treatment may be needed. The 2023 Updated International PCOS Guideline recommends that metformin, in addition to lifestyle, should be considered in adults with PCOS and BMI ≥ 25 kg/m2 for prevention of weight gain and management of weight and metabolic disorders. Metformin may be considered in adults with BMI \< 25 kg/m2 and adolescents with PCOS, acknowledging more limited evidence.

The aim of this randomized controlled trial (RCT) is to evaluate whether a metformin dose of 1500 mg is inferior compared to a dose of 2250 mg per day for females 18-37 years of age with PCOS in:

1. improving biochemical and clinical outcomes 2. gastrointestinal side-effects 3. mental health and quality of life

MATERIALS AND METHODS A double-blind, randomized controlled trial, including adults (age 18-37 years) with PCOS and a BMI ≥ 25 kg/m2 will be carried out. The randomization will be computer-generated and performed by the hospital pharmacy with 1:1 allocation in random blocks. Power analysis has indicated that a total number of 184 females (92 in each group) will be needed to reveal a 4 kg weight reduction (equals 5% weight reduction for a person weighting 80 kg) with an 80% power. We estimated a 15% drop-out in our power analysis.

Potential participants for the study will be recruited from females referred to the Reproductive Medicine Unit at Helsinki University Hospital and by advertising via the patient organization for those with PCOS (Korento). The internationally indorsed Rotterdam criteria will be used to diagnose women with PCOS. Pregnant women, women breastfeeding, women with untreated thyroid disease, hyperprolactinemia, other conditions with hyperandrogenism or use of hormonal contraceptive during the last three months will be excluded.

Women willing to participate in the study will be randomized to metformin 1500mg or 2250 mg per day for a 6-month period. Blood samples (on hyperandrogenism and metabolism), clinical examination (anthropometry and hirsutism) and a questionnaire (menstrual cyclicity, mental health, quality of life, side-effects) will be performed before starting the metformin medication, as well as at 3 and 6 months after onset of medication. Polycystic ovary morphology will be evaluated by measuring anti-mullerian hormone levels (AMH) and by vaginal ultrasound.

• Body mass index (BMI) [Time frame: The investigators will measure change in outcomes from baseline to 14 and 26 weeks]
• Waist circumference (WC) [Time frame: The investigators will measure change in outcomes from baseline to 14 and 26 weeks]
• Waist-hip-ratio (WHR) [Time frame: The investigators will measure change in outcomes from baseline to 14 and 26 weeks]
• Body adiposity index (BAI) [Time frame: The investigators will measure change in outcomes from baseline to 14 and 26 weeks]
• Body composition [Time frame: The investigators will measure change in outcomes from baseline to 14 and 26 weeks]
• Blood pressure (BP) [Time frame: The investigators will measure change in outcomes from baseline to 14 and 26 weeks]
• Pulse [Time frame: The investigators will measure change in outcomes from baseline to 14 and 26 weeks]
• Fasting glucose [Time frame: The investigators will measure change in outcomes from baseline to 14 and 26 weeks]
• Fasting insulin [Time frame: The investigators will measure change in outcomes from baseline to 14 and 26 weeks]
• HbA1C [Time frame: The investigators will measure change in outcomes from baseline to 14 and 26 weeks]
• Lipids (cholesterol and its subclasses, triglycerides) [Time frame: The investigators will measure change in outcomes from baseline to 14 and 26 weeks]
• C-reactive protein (CRP) [Time frame: The investigators will measure change in outcomes from baseline to 14 and 26 weeks]