Metformin Might Quell Age-Associated Ovarian Fibrosis

By David Douglas

October 17, 2019

NEW YORK (Reuters Health) - Studies in mice and in human tissue suggest that metformin abrogates age-related ovarian fibrosis and thus conceivably might be of use in preventing ovarian cancer, according to Canadian researchers.

"This is the first study to report that human ovaries become fibrotic with age and develop changes that are more conducive to tumour growth," Dr. Barbara Vanderhyden of the University of Ottawa told Reuters Health by email. "The most interesting finding is that postmenopausal ovaries from women on metformin had no evidence of ovarian fibrosis."

Writing in Clinical Cancer Research, online October 9, Dr. Vanderhyden and colleagues note, "The ovarian cancer risk factors of age and ovulation are curious since ovarian cancer incidence increases in postmenopausal women, long after ovulations have ceased."

To investigate, the team first validated previous findings in mice, identifying age-associated ovarian fibrosis in 70% of animals greater than 20 months old.

Other mice were randomized to treatment with 4-vinylcyclohexene diepoxide (VCD) to accelerate and model ovarian aging, or to phosphate-buffered saline.

VCD induced age-associated changes by destroying ovarian follicles over a 60-day period. At blinded necropsy, no ovarian fibrosis was found in VCD-treated ovaries, suggesting the development of fibrosis might have more to do with cumulative ovulations than with follicle loss, the authors say.

Moving on to human ovaries, the team examined normal non-cancerous ovarian samples acquired via oophorectomy in women ages 21 to 71. Eight of these came from pre-menopausal women, five from post-menopausal women, and five from women who were post-menopausal and also used metformin. The researchers also studied an independent validation cohort of three pre-menopausal and six menopausal ovaries

Across both the original and the independent cohorts, three of 11 pre-menopausal ovaries were fibrotic compared to nine of 11 post-menopausal ovaries. This reveals "a significant association between age and fibrosis," the team writes.

None of the ovaries from women taking metformin (for type 2 diabetes) were fibrotic.

The researchers cite a large Taiwanese study that found an adjusted hazard ratio for ovarian cancer for ever-users versus never-users of metformin of 0.658 - or, as Dr. Vanderhyden and colleagues put it, "up to an astonishing 88% reduction in ovarian cancer incidence" with higher cumulative doses of metformin.

This and other work, say the researchers, "led us to hypothesize that metformin use prevents age-associated ovarian fibrosis, thereby preventing the development of a tumor-permissive niche and decreasing the risk of ovarian cancer."

"This study was about putting two and two together," Dr. Vanderhyden said in a statement, "Now we’re doing more research to learn how fibrosis develops in the ovaries, and how metformin stops it from happening."

One aspect currently being assessed, she told Reuters Health, is "whether women at high risk of developing ovarian cancer also develop ovarian fibrosis prematurely. If the research is successful, the implication is that, in the future, women at high risk may be able to take metformin as a means to slow the development of ovarian fibrosis and the potential risk of ovarian cancer."


Clin Cancer Res 2019.