Alpha-Lipoic Acid Supplementation and IVF Outcomes in Women of Advanced Maternal Age

Female Infertility Due to Diminished Ovarian Reserve

Alpha-lipoic acid, In vitro fertilization, Advanced maternal age, Oocyte quality, Mitochondrial function, Cumulus cells

Female fertility declines with advancing age, largely because of deteriorating oocyte quality driven by mitochondrial dysfunction and oxidative stress within the ovarian microenvironment. Alpha-lipoic acid (ALA) is a potent antioxidant that crosses cell and mitochondrial membranes, regenerates other antioxidants (vitamin C, vitamin E, glutathione, coenzyme Q10), and supports mitochondrial respiratory chain activity and ATP production. This prospective study will enroll 60 infertile women aged 35-45 years undergoing in vitro fertilization (IVF) treatment. Thirty participants will receive oral ALA 600 mg/day for two months before their IVF cycle, and thirty will proceed directly to IVF without supplementation. The study will compare oocyte and embryo quality, cumulus cell mitochondrial function and metabolic gene expression, and clinical pregnancy and live birth rates between the two groups.

Oocyte quality declines markedly after age 35, with chromosomal abnormality rates rising from approximately 25% at age 35 to over 50% at age 40, paralleling a fall in IVF success rates from roughly 35-45% under age 35 to 5-15% after age 40. The mechanistic core of this decline is mitochondrial dysfunction: mature oocytes contain 100,000-600,000 mitochondria to meet exceptionally high energy demands for maturation, fertilization, and early embryogenesis, and oocyte ATP content correlates with fertilization rate, blastocyst formation, and implantation. With aging, oocyte mitochondria accumulate mtDNA mutations, show reduced respiratory chain activity and ATP output, generate excess reactive oxygen species (ROS), and exhibit lower membrane potential - a self-reinforcing cycle of oxidative damage and bioenergetic failure that disrupts meiotic spindle formation and chromosome segregation. ALA is a disulfide-containing fatty acid that exists in interconvertible oxidized (ALA) and reduced (dihydrolipoic acid) forms. Its dual hydrophilic-lipophilic structure allows it to penetrate cell and mitochondrial membranes and scavenge superoxide, hydroxyl, and peroxide radicals directly, while also regenerating other components of the antioxidant network and chelating transition metals (iron, copper) that drive Fenton-reaction oxidative damage. As a cofactor for pyruvate dehydrogenase and α-ketoglutarate dehydrogenase, ALA participates directly in the TCA cycle, stabilizes mitochondrial membrane potential, enhances electron transport chain activity, reduces electron leakage and ROS generation, and upregulates PGC-1α-driven mitochondrial biogenesis. Animal studies (Tarín et al.; Liu et al.; Ben-Meir et al.) have shown that ALA supplementation in aged female mice improves oocyte mitochondrial distribution, lowers ROS, raises ATP content and membrane potential, reduces aneuploidy, and increases cleavage and blastocyst rates. In humans, evidence is currently limited to PCOS cohorts - a randomized trial by Genazzani et al. (600 mg/day, 6 months) showed improved insulin sensitivity, lower androgen levels, and higher ovulation rates - while prospective trials of ALA in IVF patients of advanced maternal age are lacking. This study addresses that gap. Sixty women aged 35-45 years planning IVF will be assigned to an ALA group (oral ALA 600 mg/day for 2 months before the IVF cycle) or a control group (standard IVF without supplementation) in a 1:1 ratio. Cumulus-oocyte complexes will be collected at retrieval; cumulus cells will be isolated by hyaluronidase digestion and mechanical separation, then assessed for mitochondrial ROS (DCFDA, MitoSOX), mitochondrial mass/membrane potential (MitoTracker Green), and ATP content (fluorescent ATP live-cell dye) by fluorescence microscopy and flow cytometry, alongside qPCR profiling of mitochondria-related metabolic gene expression (normalized to RNU6-1). Clinical endpoints - oocyte and embryo quality, clinical pregnancy rate, and live birth rate - will be compared between groups to determine whether ALA supplementation translates improved cumulus cell bioenergetics into better IVF outcomes in this age group.

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