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Mutations in mitochondrial DNA (mtDNA) are maternally inherited and can cause fatal or debilitating mitochondrial disorders. The severity of clinical symptoms is often associated with the level of mtDNA mutation load or degree of heteroplasmy. Current clinical options to prevent transmission of mtDNA mutations to offspring are limited. Experimental spindle transfer in metaphase II oocytes, also called mitochondrial replacement therapy, is a novel technology for preventing mtDNA transmission from oocytes to pre-implantation embryos. Here, we report a female carrier of Leigh syndrome (mtDNA mutation 8993T > G), with a long history of multiple undiagnosed pregnancy losses and deaths of offspring as a result of this disease, who underwent IVF after reconstitution of her oocytes by spindle transfer into the cytoplasm of enucleated donor oocytes. A male euploid blastocyst wasobtained from the reconstituted oocytes, which had only a 5.7% mtDNA mutation load. Transfer of the embryo resulted in a pregnancy with delivery of a boy with neonatal mtDNA mutation load of 2.36-9.23% in his tested tissues. The boy is currently healthy at 7 months of age, although long-term follow-up of the child's longitudinal development remains crucial.

These data suggest that vit D3 alters AMH signaling and steroidogenesis in human cumulus GCs, possibly reflecting a state of GC luteinization potentiation.

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In women with PCOS, vit D3 might exert a protective effect against the inflammatory action of AGEs by increasing circulating sRAGE. The normalization in serum AMH induced by vit D3 replacement suggests an improvement in folliculogenesis.

Leptin may program abnormal AMH signaling, thereby resulting in ovarian dysfunction. This study opens a new perspective for understanding the low ovarian reserve seen in obese women and provides new insights into potential mechanisms that explain the lower AMH seen in obese women. Whether our findings explain the worse response to ovulation induction observed in obese women needs to be further elucidated.

American Society for Reproductive Medicine New Investigator Award and University of Vermont College of Medicine Internal Funds. No competing interests.

No abstract