Dietary energy restriction abolishes development of prolactin-producing pituitary tumors in Fischer 344 rats treated with 17-βestradiol

Abstract

Reduction in energy consumption is known to inhibit development of a variety of spontaneous, carcinogen-induced, and hormone-dependent cancers, but the mechanism or mechanisms by which this occurs remain unknown. We hypothesize that energy consumption may modulate development of estrogen-dependent neoplasms by altering the manner in which target cells respond to estrogens. To test this hypothesis, ovariectomized female Fischer 344 rats were fed diets that allowed consumption of different amounts of energy, and the ability of 17beta-estradiol (E2), administered for 10 wk from subcutaneous Silastic implants, to promote development of prolactin-producing pituitary tumors was examined. A 40% restriction of energy consumption virtually abolished the ability of E2 to promote development of pituitary tumors and associated hyperprolactinemia. A 25% restriction of energy consumption appeared to slightly inhibit E2-induced pituitary growth and hyperprolactinemia, but the observed degree of inhibition was not statistically significant. Interestingly, dietary energy restriction did not inhibit induction by E2 of pituitary cell proliferation and lactotroph hyperplasia. Furthermore, E2 treatment inhibited expression of testosterone-repressed prostate message-2 mRNA, a cellular marker of apoptosis, and this inhibitory effect of E2 was blocked by 40% energy restriction. These data suggest that dietary energy restriction virtually abolished E2-induced development of prolactin-producing pituitary tumors, not by blocking the ability of E2 to induce cell proliferation but rather by blocking the ability of E2 to enhance cell survival. This study and the accompanying paper provide the first indication that dietary energy consumption may modulate estrogen action at the level of the target cell.

Estrogen induction of prolactin‐producing pituitary tumors in the Fischer 344 rat: Modulation by dietary‐energy but not protein consumption

“…First and foremost, DES fully induced anterior pituitary DNA synthesis and lactotroph hyperplasia in rats fed the EnRes diet, indicating that certain responses of the pituitary gland to administered estrogen were unaffected by energy restriction. Second, the results obtained in the study described here correlate well with the results from a subsequent study in our labo-ratory in which energy restriction markedly inhibited development of pituitary tumors that were induced in female F344 rats by treatment with 17β-estradiol; in that study, body weights of untreated and treated animals fed the EnRes diet did not differ significantly [29]. Finally, the inhibitory effect of dietary energy restriction on estrogen-induced pituitary tumorigenesis is rat-strain specific; no inhibitory effect on pituitary tumor development was observed in 17β-estradiol-treated ACI rats (manuscript in preparation).…”

“…These data strongly suggest that energy restric- tion did not inhibit the fraction of the anterior pituitary cell population in which DNA synthesis was occurring at the time of death. In a subsequent experiment described in the accompanying paper, we observed that treatment of female F344 rats with 17βestradiol increased the S-phase fraction within both the lactotroph and non-lactotroph populations and that energy restriction did not inhibit this induction of pituitary cell proliferation [29]. Taken together, these data suggest that energy restriction inhibited the ability of DES to increase pituitary mass in F344 rats by acting at a step after induction of lactotroph proliferation.…”

Caloric restriction

“…Many other cancers are impacted by CR, including cancers of the liver (Fu et al, 1994;Kolaja et al, 1996), pituitary (Spady et al, 1998;Stewart et al, 2005) skin (Stewart et al, 2005;Xie et al, 2007), colon (Wheatley et al, 2008) and lymph system. .…”