Effect of a dopamine agonist on luteinizing hormone receptors, cyclic AMP production and steroidogenesis in rat Leydig cells.
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 luteinizing hormone (LH)-controlled signal transduction pathways and steroidogenesis in Leydig cells in vitro after chronic oral administration of one of these dopamine agonists, Mesulergine (CU327-085) (N-(1-6,dimethylergolin-8a-yl)-N',N'-dimethylsulphamide hydrochloride) to Sprague-Dawley (SD) rats. Eight-week-old rats were given this dopamine agonist (2 mg/kg body wt/day) in food for 1, 5, or 12 weeks. The Leydig cells from control and treated rats were purified by elutriation and density gradient centrifugation. The dopamine agonist treatment was found to decrease the specific binding of 125I-human chorionic gonadotrophin (hCG) binding to the Leydig cells: a decrease was detected as early as 1 week after treatment and was more pronounced after 5 and 12 weeks. This was found to be due to a decrease in the LH/hCG receptor numbers and not to a decrease in LH/hCG-receptor binding affinity. Both basal and LH-stimulated cAMP and testosterone production were also decreased; cAMP production was decreased by approximately 50% by all concentrations of LH added whereas testosterone production was only decreased with submaximum stimulating concentrations of LH. The formation of testosterone in response to dibutyryl cAMP was also decreased by approximately 50%, indicating additional lesions in the signal transduction pathway. The addition of the cell permeant 22R-hydroxycholesterol (22R) demonstrated that testosterone but not pregnenolone production was decreased by treatment with the dopamine agonist, thus indicating that the 17 alpha-hydroxylase/C17-20 lyase may have been inhibited. Supporting evidence for this was found because the dopamine agonist also increased aromatase activity in the Leydig cells and thus the potential to produce estrogens; previous studies have shown that estradiol is an inhibitor of the 17-20 lyase enzyme. The addition of the dopamine agonist directly to the Leydig cells did not inhibit cAMP production or testosterone production except at high concentrations. It is concluded that treatment of rats with the dopamine agonist indirectly (i.e., via the pituitary) affects Leydig cell function resulting in a rapid decrease in LH receptors and cAMP and testosterone production. Aromatase activity is increased and thus the capacity to produce estrogens. These early changes in the signal transduction pathways and steroidogenesis may be involved in the Leydig cell hyperplasia/adenoma formation that subsequently occurs.
Dirami
G
G
Department of Biochemistry and Molecular Biology, Royal Free Hospital School of Medicine, London, England, United Kingdom.
Cooke
B A
BA
D000284:Administration, Oral; D000818:Animals; D001141:Aromatase / Q000378:metabolism; D002469:Cell Separation; D006063:Chorionic Gonadotropin / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism*; D018491:Dopamine Agonists / Q000008:administration & dosage / Q000633:toxicity*; D004873:Ergolines / Q000008:administration & dosage / Q000633:toxicity*; D006888:Hydroxycholesterols / Q000378:metabolism; D007457:Iodine Radioisotopes; D007985:Leydig Cells / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D011284:Pregnenolone / Q000096:biosynthesis*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011974:Receptors, LH / Q000187:drug effects* / Q000378:metabolism; D012702:Serotonin Antagonists / Q000008:administration & dosage / Q000633:toxicity*; D015398:Signal Transduction / Q000187:drug effects; D013739:Testosterone / Q000096:biosynthesis*
D006063:Chorionic Gonadotropin; D018491:Dopamine Agonists; D004873:Ergolines; D006888:Hydroxycholesterols; D007457:Iodine Radioisotopes; D011974:Receptors, LH; D012702:Serotonin Antagonists; C003585:22-hydroxycholesterol; D013739:Testosterone; D011284:Pregnenolone; D000242:Cyclic AMP; D001141:Aromatase; C031649:mesulergine