Colorectal tumor prevention by the progestin medroxyprogesterone acetate is critically dependent on postmenopausal status
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Bartolomeus J. Meijer1,*, Mattheus C.B. Wielenga1,*, Patricia B. Hoyer3, James M. Amos-Landgraf4, Theodorus B.M. Hakvoort1, Vanesa Muncan1, Jarom Heijmans1,2 and Gijs R. van den Brink1,2,5
1Tytgat Institute for Liver and Intestinal Research and Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands
2Department of Internal Medicine, Academic Medical Center, Amsterdam, The Netherlands
3Department of Physiology, University of Arizona, Tucson, AZ, USA
4Department of Veterinary Pathobiology, University of Missouri, Columbia, MO, USA
5GlaxoSmithKline, Medicines Research Center, Stevenage, UK
*These authors have contributed equally to this work
Gijs R. van den Brink, email: firstname.lastname@example.org
Keywords: colon cancer; chemoprevention; animal models; menopause; hormone replacement
Received: January 30, 2018 Accepted: June 01, 2018 Published: July 17, 2018
The large randomized placebo controlled trials of the Women’s Health Initiative have shown that the combination of estrogen and progestin medroxyprogesterone acetate (MPA) protects from colorectal cancer in postmenopausal women. No effect was observed in women treated with estrogen alone. This suggests that progesterone, or more specifically the progestin MPA may have chemopreventive activity. The effect of MPA on colorectal carcinogenesis has been difficult to study in animal models. Most models are not affected by either depleting female hormones by ovariectomy or treatment with MPA. Importantly, an ovariectomy fails to reproduce one of the hall marks of the postmenopausal state in women with intact ovaries. That is, the continued production of androgens by the atrophic postmenopausal ovaries. Here we show that adenoma incidence is increased in the vinyl cylcohexene diepoxide (VCD) mouse model of the menopause compared to age matched fertile female mice. Treatment with MPA protected VCD treated mice from adenomagenesis, but had no effect on adenoma numbers in age-matched fertile female mice. Our data show that the protective effect of MPA depends on the postmenopausal state and suggest that MPA monotherapy may be studied as a chemopreventive agent in postmenopausal women.
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