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Morphological Changes in the Pituitary Gland of Dogs Chronically Exposed to Exogenous Growth Hormone

Merck Sharp & Dohme-Chibret Laboratories, Research Center, Department of Safety Assessment BP 134, route de Marsat, 63203 Riom, France

Sylvain Molon-Noblot

Merck Sharp & Dohme-Chibret Laboratories, Research Center, Department of Safety Assessment BP 134, route de Marsat, 63203 Riom, France

Srinivasa Prahalada

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

Lea G. Stabinski

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

Chennekatu P. Peter

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

Pierre Duprat

Merck Sharp & Dohme-Chibret Laboratories, Research Center, Department of Safety Assessment BP 134, route de Marsat, 63203 Riom, France

Matthew J. van Zwieten

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

Growth hormone (GH) synthesis and release from the pituitary is regulated by hypothalamic releasing hormone, insulin-like growth factor-1 (IGF-1), and somatostatin. However, the potential effects of pharmacological doses of exogenous GH on the pituitary are not well studied. To determine the potential chronic effects of exogenous GH on pituitary morphology in dogs, porcine GH (pGH) was administered subcutaneously to 3 groups of dogs (4 animals/sex/group) at doses of 0.025, 0.1, and 1.0 IU/kg/day for 14 wk. A group (4/sex) of dogs served as the vehicle control. The pituitaries from all dogs were weighed and fixed in appropriate fixatives for light and electron microscopic examination; in addition, cells of the pars distalis were quantitated by a point counting method following immunostaining to identify cells containing GH, prolactin (PRL), and adrenocorticotrophic (ACTH) hormones. Administration of pGH resulted in a statistically significant (p 0.05) increased pituitary weight through the high dose. By light microscopy (LM), hypertrophy of pars distalis cells was evident in mid- and high-dose female dogs. The pituitaries of dogs given the lowest dose (0.025 IU/kg/day) of pGH were not remarkable based on weight and LM findings. In addition, transmission electron microscopic (TEM) examination of the pituitary gland of high-dose dogs demonstrated, in both sexes, pituitary cells with variably dilated rough endoplasmic reticulum and decreased numbers of secretory granules; some of these cells reacted positively to GH immunostaining. Quantitative analysis of the pituitary gland of high-dose males and females showed an increase in the absolute volume of all cell populations studied: GH-, PRL-, and ACTH-positive cells. Based on the LM and TEM findings, the increased volume of the cell populations studied is likely related to cellular hypertrophy. The expected elevation in serum GH levels following repeated administration of pGH and an associated elevation in serum IGF-1 levels resulted in morphologic changes in the pituitary gland of dogs given high doses (0.1 IU/kg/day) of pGH; these observations differed from the reported findings in pituitaries of transgenic mice secreting large quantities of bovine GH.

Key Words: Somatotrophs • lactotrophs • adrenocorticotrophs • transmission electron microscopy • quantitative analysis

Toxicologic Pathology, Vol. 26, No. 2, 201-206 (1998)
DOI: 10.1177/019262339802600202


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