This is a 12-week, prospective, randomized, parallel-group controlled clinical trial conducted at an academic tertiary-care center in Islamabad, Pakistan (July-October 2025). The trial compares the independent and combined effects of metformin, inositol, and calorie restriction on metabolic, anthropometric, hormonal, and reproductive outcomes in women with polycystic ovary syndrome (PCOS).
Participants A total of 192 reproductive-aged women (18-35 years) with PCOS diagnosed by Rotterdam criteria (≥2 of: oligo/anovulation, clinical/biochemical hyperandrogenism, polycystic ovarian morphology on ultrasound) will be enrolled. Key exclusions include thyroid dysfunction, hyperprolactinemia, congenital adrenal hyperplasia, Cushing syndrome, hepatic/renal impairment, pregnancy or lactation, and use of hormonal therapy or insulin-sensitizing agents within the preceding 3 months.
Randomization and masking Participants will be randomized in a 1:1:1:1 allocation (n=48 per group) using a computer-generated sequence, with allocation concealment using sequentially numbered, opaque, sealed envelopes. Due to the nature of interventions, participant blinding is not feasible; however, laboratory personnel and data analysts will remain blinded to group assignment.
Interventions (12 weeks) Group A (Metformin): metformin 1500-2000 mg/day orally, titrated according to gastrointestinal tolerance.
Group B (Inositol): myo-inositol 2 g plus D-chiro-inositol 50 mg, taken twice daily.
Group C (Calorie-restricted diet): individualized dietary counseling targeting 1200-1500 kcal/day with emphasis on low-glycemic carbohydrates, lean protein, and high-fiber foods.
Group D (Combination): metformin + inositol + calorie-restricted diet as above. Participants will be followed every two weeks for adherence assessment and adverse event monitoring. Medication adherence will be assessed by pill counts. Dietary adherence will be assessed using weekly dietary logs and summarized as percent compliance with prescribed caloric intake.
Outcomes
Primary outcomes assessed at baseline and 12 weeks include:
Anthropometric measures: weight, BMI, waist circumference; Metabolic measures: fasting glucose, fasting insulin, and insulin resistance (HOMA-IR; calculated as \[fasting insulin × fasting glucose\]/405); Menstrual regularity, defined as cycle length 21-35 days during the final four weeks of the intervention.
Secondary outcomes include serum total testosterone, LH, FSH, LH/FSH ratio, Ferriman-Gallwey score, adherence, and adverse events. Fasting blood samples will be collected and hormonal assays performed using standardized chemiluminescence immunoassay platforms.
Statistical approach Normality will be assessed using Shapiro-Wilk tests. Continuous variables will be summarized as mean ± SD. Within-group changes will be analyzed using paired t-tests. Between-group comparisons will use one-way ANOVA with Tukey HSD post-hoc testing. Effect sizes will be reported as partial eta-squared (η²). Categorical outcomes (e.g., menstrual regularity) will be compared using chi-square tests. Statistical significance will be defined as p \< 0.05. Analyses will follow CONSORT reporting principle
