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The Effects of Ad Libitum Overfeeding and Moderate and Marked Dietary Restriction on Age-Related Spontaneous Pituitary Gland Pathology in Sprague—Dawley Rats

Merck Sharp & Dohme-Chibret Laboratories, Research Center, Department of Safety Assessment, route de Marsat, Riom 63963 Clermont-Ferrand Cedex 9, France, sylvain_molonnoblot{at}merck.com

Philippe Laroque

Merck Sharp & Dohme-Chibret Laboratories, Research Center, Department of Safety Assessment, route de Marsat, Riom 63963 Clermont-Ferrand Cedex 9, France

John B. Coleman

Merck Research Laboratories, Department of Safety Assessment, West Point, Pennsylvania 19486, USA

Chao-Min Hoe

Merck Research Laboratories, Department of Biometrics, West Point, Pennsylvania 19486, USA

Kevin P. Keenan

Merck Research Laboratories, Department of Safety Assessment, West Point, Pennsylvania 19486, USA

This study compared the effects of ad libitum (AL) overfeeding and moderate or marked dietary restriction (DR) on the pathogenesis of aged-related pituitary gland changes in Sprague—Dawley (SD) rats. SD rats were fed Purina Certified Rodent Diet AL (group 1), DR at 72—79% of AL (group 2), DR at 68—72% of AL (group 3) or DR at 47—48% of AL (group 4) for 106 weeks. Interim necropsies were performed at 13, 26, and 53 weeks, after a 7-day 5-bromo-2-deoxyuridine (BrdU)-filled minipump implantation. Body weights, organ weights and insulin-like growth factor 1 (IGF-1) serum levels were measured at interim and final necropsies. Serum levels of prolactin (PRL), progesterone, estradiol, luteinizing hormone (LH) and follicle stimulating hormone (FSH) were measured at 53 and/or 106 weeks. In addition to the routine histopathologic examination, determination of 7 stereologic parameters after pituitary immunohistochemistry of PRL, growth hormone (GH) and BrdU was done in both sexes at 13, 26, and 53 weeks. Body and pituitary weights were proportional to the food intake. In AL-fed rats, hyperplastic and neoplastic changes developed early and progressed with age, affecting almost all animals by 106 weeks. These changes were associated with high PRL serum levels. Pituitary adenomas were the most common cause of death in both sexes. In DR rats, a delayed onset and a decreased incidence of pituitary tumors were observed in association with decreased serum IGF-1, PRL, estradiol, and LH levels. The results of the stereological analysis demonstrated that, compared to AL-fed rats, pituitary glands from DR rats contained lower PRL and GH secreting cell volumes, and a lower epithelial cell BrdU labeling index, which correlated with a lower incidence of pituitary tumors at study termination. Moderate and marked degrees of DR delayed the onset of pituitary tumors in a temporal-and dose-related manner. In contrast to marked DR, which dramatically reduced the incidence of hyperplastic and neoplastic pituitary gland changes, moderate DR delayed the onset but did not prevent the development of pituitary tumors.

Key Words: Dietary restriction • aging • adenohypophysis • pituitary hormones • pituitary neoplasms.

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Toxicologic Pathology, Vol. 31, No. 3, 310-320 (2003)
DOI: 10.1080/01926230390204351


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