Estrogen deficiency reversibly induces telomere shortening in mouse granulosa cells and ovarian aging in vivo

Abstract

Estrogen is implicated as playing an important role in aging and tumorigenesis of estrogen responsive tissues; however the mechanisms underlying the mitogenic actions of estrogen are not fully understood. Here we report that estrogen deficiency in mice caused by targeted disruption of the aromatase gene results in a significant inhibition of telomerase maintenance of telomeres in mouse ovaries in a tissue-specific manner. The inhibition entails a significant shortening of telomeres and compromised proliferation in the follicular granulosa cell compartment of ovary. Gene expression analysis showed decreased levels of proto-oncogene c-Myc and the telomerase catalytic subunit, telomerase reverse transcriptase (TERT), in response to estrogen deficiency. Estrogen replacement therapy led to increases in TERT gene expression, telomerase activity, telomere length and ovarian tissue growth, thereby reinstating ovary development to normal in four weeks. Our data demonstrate for the first time that telomere maintenance is the primary mechanism mediating the mitogenic effect of estrogen on ovarian granulosa cell proliferation by upregulating the genes of c-Myc and TERT in vivo. Estrogen deficiency or over-activity may cause ovarian tissue aging or tumorigenesis, respectively, through estrogen regulation of telomere remodeling.

Plasticity of granulosa cells: on the crossroad of stemness and transdifferentiation potential

“…During antral differentiation only GCs close to the antrum and cumulus cells maintained the TERT expression [66]. Telomerase activity seems to be highly related to the estrogen metabolism since estrogen showed mitogenic effects on GCs proliferation by up-regulation of TERT gene [4], suggesting that infertile patients with estrogen deficiency are not suitable for research of their GCs stemness. Recently, more on the impact of steroid hormones, antiestrogens and aromatase inhibitors on telomerase activity was reviewed by Chronowska [13].…”

Early Telomere Shortening and Genomic Instability in Tubo-Ovarian Preneoplastic Lesions—Letter

“…In addition, estrogen deficiency has been found to decrease telomerase activity and shorten telomere length in the ovary of mice (4). Unfortunately, no information about age or menopausal status was supplied in the present study.…”

Leukocyte telomere length and age at menopause

“…This assumption could be faulty if, for example, the attrition rate accelerates after menopause, perhaps in response to a decrease in estrogen and its putative telomereprotective effects. 37 Such a difference could artificially exaggerate the results based on using post-menopausal telomere length as a surrogate for pre-menopausal length. This is because women with earlier menopause would experience a longer amount of time to undergo telomere attrition at a faster rate and thus might have shorter telomere length compared with women who had similar age-adjusted telomere length premenopausally but later age at menopause.…”