Effects of Oral Magnesium Supplementation on DNA Damage, Obesity, Insulin Resistance, and Intracellular Magnesium in Women With Polycystic Ovary Syndrome

Technical Summary: Effects of Oral Magnesium Supplementation on DNA Damage, Obesity, Insulin Resistance, and Intracellular Magnesium in Women With Polycystic Ovary Syndrome

Problem Statement
Polycystic ovary syndrome (PCOS) is a heterogeneous endocrine disorder characterized by metabolic comorbidities, including obesity, insulin resistance, and dyslipidemia. While disturbances in magnesium (Mg) homeostasis are hypothesized to contribute to these metabolic abnormalities, clinical evidence regarding the efficacy of Mg supplementation in PCOS remains limited and heterogeneous. Specifically, the impact of Mg replacement on circulating glucose transporter type 4 (GLUT-4), selected adipokines (chemerin, betatrophin), and oxidative stress markers (8-OHdG) in women with PCOS is insufficiently characterized. Previous studies have reported mixed findings on anthropometric and metabolic outcomes, necessitating further investigation into whether correcting low serum Mg concentrations can improve metabolic, hormonal, and molecular biomarkers in this population.

Methodology
This study employed a prospective, nonrandomized, open-label controlled intervention design. The protocol was approved by the Clinical Research Ethics Committee of Van Yüzüncü Yıl University.

• Participants: 60 women (aged 18–40) diagnosed with PCOS according to the Rotterdam criteria were enrolled. After exclusions and withdrawals (due to pregnancy or pandemic-related inability to attend), 46 participants (23 per group) completed the 12-week follow-up.
• Group Allocation: Allocation was nonrandomized and based strictly on baseline serum Mg concentration:
  • Low-Mg Intervention Group (n=30 initially): Baseline serum Mg 1.2–1.7 mg/dL. Participants received oral Mg supplementation (365 mg/day of MgCl₂, MgO, or Mg(OH)₂) for 12 weeks.
  • Normomagnesemic Comparison Group (n=30 initially): Baseline serum Mg 1.8–2.4 mg/dL. Participants received no supplementation and underwent routine follow-up.
• Data Collection: Assessments were conducted at baseline (Week 0), Week 6, and Week 12. Measurements included anthropometrics (BMI, waist-to-hip ratio), lipid profiles, glycemic indices (glucose, insulin, HbA1c, HOMA-IR), hormonal profiles (FSH, LH, testosterone, SHBG, etc.), and specific molecular biomarkers.
• Biomarker Analysis: Serum concentrations of GLUT-4, chemerin, betatrophin, leptin, 8-hydroxy-2′-deoxyguanosine (8-OHdG), total antioxidant status (TAS), and total oxidative stress (TOS) were measured via ELISA. Intracellular Mg was measured in erythrocytes using atomic absorption spectrophotometry.
• Statistical Analysis: Data were analyzed using IBM SPSS Statistics. Between-group comparisons utilized independent-samples t-tests, while within-group changes were assessed using paired-samples t-tests and repeated-measures ANOVA.

Key Results

• Magnesium Status: Serum Mg concentrations increased significantly in the intervention group by Week 6 (p=0.001), though they remained statistically lower than the comparison group at Week 12 (p=0.013). Intracellular Mg also showed significant differences between groups at baseline and follow-up.
• Metabolic and Lipid Profiles: At baseline, the low-Mg group exhibited higher total cholesterol and LDL cholesterol. Both groups showed numerical declines in these values by Week 12, but the between-group differences were no longer statistically significant. Crucially, Mg supplementation was not associated with statistically significant improvements in HOMA-IR, HbA1c, or BMI over the 12-week period.
• Hormonal and Molecular Biomarkers:
  • GLUT-4: Circulating GLUT-4 concentrations were significantly lower in the low-Mg intervention group compared to the normomagnesemic group at all time points (p<0.05).
  • Adipokines: Chemerin and betatrophin concentrations were significantly higher in the normomagnesemic comparison group than in the low-Mg group at multiple time points.
  • Oxidative Stress: 8-OHdG levels showed similar patterns between groups, while TAS was significantly higher in the comparison group at Week 6.
  • Other Hormones: The low-Mg group had significantly higher Parathyroid Hormone (PTH) levels and lower Calcium levels compared to the comparison group. Estradiol was significantly higher in the low-Mg group at Week 6.

Significance and Claims
The authors conclude that oral Mg supplementation successfully corrected low serum Mg concentrations in women with PCOS but did not produce statistically significant improvements in glycemic indices (HOMA-IR, HbA1c), BMI, or lipid profiles over 12 weeks.

The paper explicitly states that its nonrandomized design, which allocated participants based on pre-existing baseline Mg status, precludes separating the effects of the treatment from inherent group differences. Consequently, the authors assert that the observed differences in molecular markers (such as lower GLUT-4 in the low-Mg group) cannot be causally attributed to Mg supplementation.

The study positions its findings as hypothesis-generating rather than definitive evidence of clinical efficacy. The authors emphasize that larger, randomized controlled trials with placebo controls and prespecified mechanistic outcomes are required to determine whether Mg supplementation can effectively improve lipid, hormonal, or molecular outcomes in PCOS. They caution against interpreting the numerical changes in BMI or lipids as evidence of a treatment effect without further validation.