Possible mechanism for testicular focal necrosis induced by hCG in rats.
Possible mechanisms for testicular focal necrosis induced by human chorionic gonadotropin (hCG) were examined in Fischer 344 rats. A single s.c. injection of 2000 IU/kg hCG produced focal necrosis 2 days later in testicular tissues such as the seminiferous tubules in the frontal lower part of the testis (FLPT) of 11-week-old F344/Jcl rats. This hCG-induced necrosis was suppressed by an oral treatment (concomitant or delayed by 3 hr) with cyclooxygenase inhibitors (indomethacin, rofecoxib) or prostaglandin (PG) receptor blocker (AA-2414). Focal necrosis was also induced by intratesticular injection of PGF(2alpha) or PGE(2) with this necrosis suppressed by previous oral treatment with AA-2414, and the PGF(2) level in the testis increased 4 hr after hCG treatment. These findings suggested that de novo synthesis of PGs beginning at 3-4 hr was responsible for induction of necrosis. No necrosis was induced by hCG in the Leydig cell-devoid testis produced by ethane dimethanesulfonate treatment. Necrosis of spontaneously-induced Leydig cell tumor mass was also induced by hCG, suggesting that Leydig cells are responsible for induction of necrosis. An injection of dye into the testicular artery and laser Doppler flowmetry revealed a continuous reduction of blood flow at the FLPT at 6-48 hr after hCG treatment; contrary to this, the upper part showed an early recovery from the reduced flow. From these results, the mechanism of the hCG-induced necrosis was concluded to be: 1) hCG stimulates Leydig cells to synthesize PGs de novo; 2) PGs induce the intratesticular arteries to contract in the FLPT; and 3) obstruction of blood flow (ischemia) for more than 12 hr induced focal necrosis in the testis.
Chatani
Fumio
F
Development Research Center, Pharmaceutical Research Division, Takeda Pharmaceutical Co. Ltd., Osaka, Japan. Chatani_Fumio@takeda.co.jp
D000818:Animals; D006063:Chorionic Gonadotropin / Q000633:toxicity*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D008297:Male; D009336:Necrosis; D011448:Prostaglandin Antagonists / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D012039:Regional Blood Flow / Q000187:drug effects; D013737:Testis / Q000098:blood supply / Q000187:drug effects* / Q000473:pathology
D006063:Chorionic Gonadotropin; D016861:Cyclooxygenase Inhibitors; D011448:Prostaglandin Antagonists