Effect of a dopamine agonist on the development of Leydig cell hyperplasia in Sprague-Dawley rats

Dopamine agonists are known to increase the incidence of Leydig cell hyperplasia/adenomas when administered to rats over periods of 1-2 years. We have examined the early changes in factors affecting Leydig cell growth/hyperplasia after chronic oral administration of one of these dopamine agonists, Mesulergine (CU32-085) [N-(1-6-dimethylergolin-8 alpha-yl)-N,N-dimethylsulphamide hydrochloride), to Sprague-Dawley (SD) rats. Eight-week-old rats were given the dopamine agonist (2 mg/kg body weight/day) in food for 5 or 57 weeks. The dopamine agonist treatment had no significant effect on food intake, body weight, and testis and seminal vesicle size, but significantly decreased testicular interstitial fluid volume at 5 weeks (by 51%). Leydig cells isolated from rats treated with the dopamine agonist for 5 weeks exhibited an increase in the rate of protein synthesis compared with the controls (by 28%). This treatment, however, had no significant effect on the number of Leydig cells or macrophages as assessed by histological examination of testicular sections. Treatment with the dopamine agonist for 57 weeks caused a 36 and 28% increase in the number of Leydig cells and macrophages, respectively. Nodules of Leydig cells, indicating the first signs of tumor development, were present in testes from the 57- but not the 5-week-treated animals or the controls of both groups, although an increase in the number of Leydig cells occurred with aging. Thick-walled arterioles were found in the intertubular spaces of the testis sections from rats treated for 57 weeks. These findings suggest that chronic treatment of male SD rats with the dopamine agonist causes hypertrophy of Leydig cells within 5 weeks (as assessed by [3H]methionine incorporation), followed by hyperplasia within 2 years, prior to the development of Leydig cell adenomas, which occur within 1-2 years after the initiation of treatment.