SDZ 200–110 Induces Leydig Cell Tumors By Increasing Gonadotropins in Rats

Abstract

The administration of 62.5 mg/kg/day of SDZ 200–110, a calcium channel blocker, for 2 years increased the incidence of Leydig cell tumors while decreasing pituitary tumors in Sprague-Dawley rats. Lower doses did not change the incidence of these tumors. No other endocrine tumors were seen in rats or mice of either sex. A single gavage dose of 62.5 mg/kg/day decreased serum testosterone levels by 90% 4 hr after dosing. In vitro testosterone production by Leydig cells from these animals was minimally decreased, which suggests that a direct inhibition of steroid synthesis was removed during cell isolation. Dietary administration of the drug for 10 weeks did not significantly alter levels of serum hormones or testicular luteinizing hormone (LH) and gonadotropin-releasing hormone (GnRH) receptors, although a significant elevation of testicular testosterone levels was seen. Increased serum levels of LH and follicle-stimulating hormone (FSH) were seen after 52 and 66 weeks, respectively, of dietary feeding of 62.5 mg/kg/day. The increase in serum LH was observed to week 104, while FSH levels returned to control levels by week 94. No effect on gonadotropin receptors was seen at the 6.25 mg/kg/day dosage. The age-related increase in serum prolactin was markedly reduced by 62.5 mg/kg/day of SDZ 200–110 in weeks 66 to 104 and to a lesser extent at the 6.25 mg/kg/day dosage. Testicular LH receptors were decreased by the high dose in animals sacrificed after 90–104 weeks. In conclusion, SDZ 200–110 increases the incidence of Leydig cell tumors by elevating levels of serum gonadotropins. The suggested mechanism for this increase in gonadotropins is a result of the effects of SDZ 200–110 on serum hormones and testicular LH receptors. The drug was judged not to pose a risk to humans since no change in gonadotropin levels was observed after chronic treatment.

Rodent Leydig Cell Tumorigenesis: A Review of the Physiology, Pathology, Mechanisms, and Relevance to Humans

“…Testosterone levels decline with age in most strains of rats (Chan et al, 1977) as well as in humans (Horton and Tait, 1967;Vermeulen et al, 1972). In rats, this decrease is probably secondary to declining LH levels (Pirke, 1979;Roberts et al, 1989;Prentice et al, 1992;Chen et al, 1994), although this is somewhat paradoxical because one would expect LH to increase in order to maintain testosterone levels. This is in contrast to the situation in man where LH levels tend to increase with age, presumably because of decreasing testosterone levels (Rubens et al, 1974;Vermeulen, 1978).…”

Evaluation of the genotoxicity potential and chronic inhalation toxicity of 1,1-dichloro-1-fluoroethane (HCFC-141 b)

“…Senility per se is also a significant contributor to the appearance of Leydig cell tumours in rats: for example, Fischer 344 rats have a 100% incidence of interstitial celt tumours by the end of their life. In the cases of mesulargine (Prentice et al, 1992) and isradipine (Roberts et al, 1989) the association of increased LH and reduced prolactin with the induction of Leydig cell tumours was demonstrated.…”

“…A wide variety of materials (including lactose and lactitol), and procedures have been shown to induce the formation of Leydig cell tumours (B/ir, 1992). It has been reported by B/Jr (1992) and Roberts et al (1989) that an increased incidence of interstitial cell tumours followed ligation of testicular blood vessels, intrasplenic grafting of the testis, gonadotrophin injection and radiation. Administration of a wide variety of unrelated drugs, such as cimetidine, hydralazine, gemfibrizol, carbamazepine, vidarabine, mesulargine, isradipine and metronidazole, has also resulted in elevated interstitial cell tumour masses (Griffith, 1988).…”

Toxicokinetic and Mechanistic Considerations in the Interpretation of the Rodent Bioassay

“…These testicular interstitial cell tumors have been shown to be as-TOXICOLOGIC PATHOLOGY sociated with long-term high dose exposure to a diverse group of chemicals. Treatment of rats with high doses of flutamide, cimetidine, gemfibrozil, and a calcium channel blocking agent, SDZ200-1 10, have all resulted in an increase in the incidence of Leydig cell hyperplasia and adenomas (32,69,87,95). Flutamide and SDZ200-110 have been shown to produce pertubations in the hypothalmic-pituitary-testicular axis leading to sustained elevations of LH (95,115).…”

“…Treatment of rats with high doses of flutamide, cimetidine, gemfibrozil, and a calcium channel blocking agent, SDZ200-1 10, have all resulted in an increase in the incidence of Leydig cell hyperplasia and adenomas (32,69,87,95). Flutamide and SDZ200-110 have been shown to produce pertubations in the hypothalmic-pituitary-testicular axis leading to sustained elevations of LH (95,115). Luteinizing hormone (LH), in turn, has been shown to be an important trophic hormone for the Leydig cell (30).…”