PHARMACOLOGICAL AND TOXICOLOGICAL EFFECTS OF CHRONIC PORCINE GROWTH-HORMONE ADMINISTRATION IN DOGS

The purpose of this study was to evaluate the pharmacological and toxi cological effects of exogenous GH administration in normal adult dogs. Because porcine GH (pGH) is structurally identical to canine GH, pGH was selected for a 14-wk study in dogs. Thirty-two dogs (<2 yr) were r andomized to 4 groups (4 dogs/sex/group); 1 group was treated with the vehicle and 3 groups received pGH at 0.025, 0.1, or 1.0 IU/kg/day sub cutaneously. Daily clinical signs and weekly body weights were recorde d. Hematology, serum biochemistry, urinalyses, electrocardiograms, and ophthalmoscopic examinations were done. Serum GH, insulin-like growth factor-1 (IGF-1), insulin, thyroxine (T4), triiodothyronine (T3), and cortisol levels were determined. Necropsies were performed, organs we ighed, and tissues were fixed and processed for light microscopic exam ination. Porcine GH caused increased body weight gain (p less than or equal to 0.05) through the mid dose; the mean weight gains at study te rmination in mid-and high-dose groups were 2.8 kg and 4.7 kg, respecti vely, compared to 0.4 kg and 0.8 kg in control and low-dose groups, re spectively. Dose-related increased weights of liver, kidney, thyroid, pituitary gland, skeletal muscle, and adrenal gland were noted. In pGH -treated dogs, increased skin thickness seen grossly correlated histol ogically with increased dermal collagen. There was no gross or histomo rphological evidence of edema. There were dose-related increased serum IGF-1 levels (approximate to 2-10-fold; p less than or equal to 0.05) that correlated with the elevated serum GH levels in pGH-treated dogs . Also, increased serum insulin levels (p less than or equal to 0.05) through the mid dose were seen throughout the study. In high-dose dogs , the insulin levels remained elevated over 24 hr postdose. The serum glucose levels in fasted dogs remained within the control range and th ere was no chronic hyperglycemia based on glycosylated hemoglobin leve ls. Renal glomerular changes, significant polyuria with decreased urin e specific gravity, and increased serum insulin levels suggested that the dogs had early insulin-resistant diabetes. There was minimal or no biologically significant effect of pGH on serum T3, T4, and cortisol levels in dogs. Other serum biochemical changes in pGH-treated dogs in cluded decreased urea nitrogen and creatinine, and increased potassium , cholesterol, and triglycerides. Significant increases in serum calci um and phosphorous levels and alkaline phosphatase activity (bone isoz yme) correlated with the histological changes in bone. In pGH-treated dogs, there was a dose-related normochromic, normocytic, nonregenerati ve anemia. The changes described above, except for the anemia, are rel ated to either anabolic or catabolic effects of high doses of GH. Base d on this study, it is concluded that the dog is a good model in which to evaluate the safety of GH secretagogues as well as compounds with GH-like activity.