{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T18:41:44Z","timestamp":1790102504550,"version":"4.0.1"},"reference-count":59,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2025,11,13]],"date-time":"2025-11-13T00:00:00Z","timestamp":1762992000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Research, Development, and Innovation Office","award":["NKFIH_FK_132812"],"award-info":[{"award-number":["NKFIH_FK_132812"]}]},{"name":"National Research, Development, and Innovation Office","award":["TKP2021-NVA-15"],"award-info":[{"award-number":["TKP2021-NVA-15"]}]},{"name":"National Research, Development, and Innovation Office","award":["TKP2021-EGA-25"],"award-info":[{"award-number":["TKP2021-EGA-25"]}]},{"name":"Hungarian Hypertension Society"},{"name":"Dean of the Medical Faculty, Semmelweis University"},{"DOI":"10.13039\/501100002332","name":"Semmelweis University","doi-asserted-by":"publisher","award":["STIA-OTKA-2021"],"award-info":[{"award-number":["STIA-OTKA-2021"]}],"id":[{"id":"10.13039\/501100002332","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Janos Bolyai Research Scholarship"},{"name":"UNKP-22-5 Research Scholarship"},{"name":"Hungarian Research Network (HUN-REN), Multiomics Neurodegeneration Research Group"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Life"],"abstract":"<jats:p>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 (&gt;10 mU\/L at 0 min, &gt;50 mU\/L at 60 min, &gt;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-M\u00fcllerian hormone (AMH) &lt;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.<\/jats:p>","DOI":"10.3390\/life15111744","type":"journal-article","created":{"date-parts":[[2025,11,13]],"date-time":"2025-11-13T12:57:13Z","timestamp":1763038633000},"page":"1744","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Mitochondrial DNA Deletions and Plasma GDF-15 Protein Levels Are Linked to Hormonal Dysregulation and Multi-Organ Involvement in Female Reproductive Endocrine Disorders"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8633-3986","authenticated-orcid":false,"given":"Vera","family":"Varhegyi","sequence":"first","affiliation":[{"name":"Institute of Genomic Medicine and Rare Disorders, Semmelweis University, 1085 Budapest, Hungary"},{"name":"Department of Obstetrics and Gynecology, Semmelweis University, 1085 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-8505-8165","authenticated-orcid":false,"given":"Barnabas","family":"Banfi","sequence":"additional","affiliation":[{"name":"Institute of Genomic Medicine and Rare Disorders, Semmelweis University, 1085 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Domonkos","family":"Trager","sequence":"additional","affiliation":[{"name":"Institute of Genomic Medicine and Rare Disorders, Semmelweis University, 1085 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9883-7367","authenticated-orcid":false,"given":"Dora","family":"Gerszi","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Semmelweis University, 1085 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0517-1269","authenticated-orcid":false,"given":"Eszter Maria","family":"Horvath","sequence":"additional","affiliation":[{"name":"Department of Physiology, Semmelweis University, 1085 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-0827-6689","authenticated-orcid":false,"given":"Miklos","family":"Sipos","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Semmelweis University, 1085 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1919-1869","authenticated-orcid":false,"given":"Nandor","family":"Acs","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Semmelweis University, 1085 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9350-1864","authenticated-orcid":false,"given":"Maria Judit","family":"Molnar","sequence":"additional","affiliation":[{"name":"Institute of Genomic Medicine and Rare Disorders, Semmelweis University, 1085 Budapest, Hungary"},{"name":"HUN-REN Multiomics Neurodegeneration Research Group, Hungarian Research Network, 1085 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7109-6906","authenticated-orcid":false,"given":"Szabolcs","family":"Varbiro","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Semmelweis University, 1085 Budapest, Hungary"},{"name":"Department of Obstetrics and Gynecology, University of Szeged, 6725 Szeged, Hungary"},{"name":"Workgroup for Science Management, Doctoral School, Semmelweis University, 1085 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2059-5748","authenticated-orcid":false,"given":"Aniko","family":"Gal","sequence":"additional","affiliation":[{"name":"Institute of Genomic Medicine and Rare Disorders, Semmelweis University, 1085 Budapest, Hungary"},{"name":"HUN-REN Multiomics Neurodegeneration Research Group, Hungarian Research Network, 1085 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Adachi, T., Endo, M., and Ohashi, K. 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