Abstract
Primary ovarian insufficiency (POI) is a critical fertility defect characterized by an anticipated and silent impairment of the follicular reserve, but its pathogenesis is largely unexplained. The frequent maternal inheritance of POI together with a remarkable dependence of ovarian folliculogenesis upon mitochondrial biogenesis and bioenergetics suggested the possible involvement of a generalized mitochondrial defect. Here, we verified the existence of a significant correlation between blood and ovarian mitochondrial DNA (mtDNA) content in a group of women undergoing ovarian hyperstimulation (OH), and then aimed to verify whether mtDNA content was significantly altered in the blood cells of POI women. We recruited 101 women with an impaired ovarian reserve: 59 women with premature ovarian failure (POF) and 42 poor responders (PR) to OH. A Taqman copy number assay revealed a significant mtDNA depletion (P<0.001) in both POF and PR women in comparison with 43 women of similar age and intact ovarian reserve, or 53 very old women with a previous physiological menopause. No pathogenic variations in the mitochondrial DNA polymerase γ (POLG) gene were detected in 57 POF or PR women with low blood mtDNA content. In conclusion, blood cell mtDNA depletion is a frequent finding among women with premature ovarian aging, suggesting that a still undetermined but generalized mitochondrial defect may frequently predispose to POI which could then be considered a form of anticipated aging in which the ovarian defect may represent the first manifestation. The determination of mtDNA content in blood may become an useful tool for the POI risk prediction.
Highlights
Primary ovarian insufficiency (POI) is a critical fertility defect characterized by an anticipated impairment of the follicular reserve [1,2]
This process is generally silent without evident menstrual irregularity so that women are diagnosed with POI due to the premature cessation of menses before 40 years of age in the stage of complete follicular depletion
We observed a significant correlation between ovarian and blood mitochondrial DNA (mtDNA) content and found a diminished mtDNA copy number in peripheral blood cells of women with an impaired ovarian reserve compared to controls
Summary
Primary ovarian insufficiency (POI) is a critical fertility defect characterized by an anticipated impairment of the follicular reserve [1,2]. This process is generally silent without evident menstrual irregularity so that women are diagnosed with POI due to the premature cessation of menses (secondary amenorrhea, SA) before 40 years of age in the stage of complete follicular depletion (premature ovarian failure, POF or overt POI). The maternal inheritance of the ovarian defect is prevalent (about 60%) [5,6] This observation together with the known association of POF with X-chromosomal abnormalities have prompted studies on the possible involvement of X-linked genes in POI pathogenesis [4,7,8]. Mitochondrial defects are strongly associated with physiological or pathological tissue aging, and can lead to altered metabolism, impaired activity and/or accelerated degeneration [9,10]
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