There is no literature available about the growth differentiation factor-15 (GDF-15) biomarker in combination with mitochondrial DNA (mtDNA) deletions in insulin resistance (IR), and polycystic ovary syndrome (PCOS); however, it would be useful to achieve optimal metabolic status and improve pregnancy success. In this study, the role of GDF-15 and mtDNA deletions as biomarkers in the pathogenesis of IR and PCOS was investigated. In our study, 81 female patients who were treated for IR and/or PCOS and 41 healthy controls were included. GDF-15 levels in patients showed a marked increase compared to controls. Elevated GDF-15 levels were found in 12 patients; all of them had a BMI > 25 kg/m², which is associated with reactive hyperinsulinemia. The presence of mitochondrial dysfunction was mainly observed in the IR-only subgroup. The increase in plasma levels of GDF-15 and the prevalence of mtDNA deletions is directly proportional to body mass index. The more marked metabolic abnormalities required more intensive drug therapy with a parallel increase in plasma GDF-15 levels. Elevated levels of GDF-15 and the presence of mitochondrial DNA deletions may be a consequence of carbohydrate metabolism disorders in patients and thus a predictor of the process of accelerated aging.

Mitochondrial dysfunction contributes to female reproductive endocrine disorders and is frequently associated with multisystem symptoms. Insulin resistance (IR) is a common metabolic disorder strongly linked to polycystic ovary syndrome (PCOS), while premature ovarian insufficiency (POI) also impairs fertility. Mitochondrial DNA (mtDNA) deletions and the stress-responsive cytokine growth differentiation factor 15 (GDF-15) have recently emerged as complementary biomarkers of mitochondrial impairment. In this retrospective observational study, we examined reproductive hormones, plasma GDF-15, mtDNA deletions, and clinical symptoms in insulin-resistant women, including those with PCOS or POI. Eighty-one patients were divided into three subgroups: IR-only (n = 49), IR-PCOS (n = 19), and IR-POI (n = 13). IR was defined based on elevated insulin levels during oral glucose tolerance testing (>10 mU/L at 0 min, >50 mU/L at 60 min, >30 mU/L at 120 min) according to national gynecological endocrinology guidelines, acknowledging that IR is not universally accepted as a distinct clinical entity. POI was defined as reduced ovarian reserve before age 40 with anti-Müllerian hormone (AMH) <1.0 ng/mL. Clinical symptoms were assessed using a questionnaire, medical record, and physical examination. MtDNA deletions were detected by long-range PCR, and GDF-15 was measured by ELISA. Free thyroxine (T4) emerged as an independent predictor of GDF-15, suggesting that thyroid function modulates mitochondrial stress signaling in insulin-resistant women. MtDNA deletions and/or elevated GDF-15 correlated with endocrine, gastrointestinal, and neuropsychiatric symptoms, and reduced AMH/FSH ratios indicated impaired ovarian function. Cross-sectional analysis further revealed lower AMH and AMH/FSH ratios in older women with mtDNA deletions, consistent with a trend toward accelerated reproductive aging. Overall, these findings support the role of GDF-15 and mtDNA deletions as complementary biomarkers of mitonuclear stress, with potential relevance for both systemic and reproductive health.