Hormones and steroid metabolism by rat mammary tumours
The hormonal control of 5a- reductase activity in DMBA ( 7 ,12- dimethylbenz[a]anthracene)- induced rat mammary tumours and its relationship to tumour growth have been studied by measuring tumour growth, tumour metabolism of testosterone and plasma hormone levels in rats of differing endocrine status.The hormonal control of 5a- reductase activity in DMBA ( 7 ,12- dimethylbenz[a]anthracene)- induced rat mammary tumours and its relationship to tumour growth have been studied by measuring tumour growth, tumour metabolism of testosterone and plasma hormone levels in rats of differing endocrine status.Female Sprague -Dawley rats bearing actively grow- ing tumours, induced by an intragastric administration of 30 mg DMBA at 50 days of age, were allocated to one of the following treatment groups : - 1) Intact Control (IC), 2) Intact + Perphenazine (IP), 3) Intact + Bromocryptine methanesulphonate (IB), 4) Ovariectomised Control (OC), 5) Ovariectomised + Perphenazine (OP). Animals received a daily s.c. dose of drug (5 mg /kg body weight) or corn oil vehicle (controls), over an average treatment period of 12 days. The effects of the treatment regimes on pl4sma prolactin and plasma oestradiol levels were measured in the individual tumour -bearing rats and also in greater detail in non -tumour -bearing rats. At the end of treatment (dioestrus in cycling rats), a whole tissue homogenate of tumour was incubated under fixed conditions with [7a -3H] testosterone in the presence of an NADPH -generating system. 5a- Reduction was deter- mined as the sum of 5a- dihydrotestosterone and total 5a- androstanediol production. Plasma prolactin levels were raised to the same extent in both IP and OP groups and were lowered in IB and OC groups. Plasma oestradiol levels were lowered in the OC, OP and IP groups, but not the IB group. The OC, OP and IP groups were in constant dioestrus, whereas rats in the IB group cycled normally. Tumour growth was, on average, inhibited in the IB group and tumours regressed rapidly in the OC group. Tumour growth was stimulated in the IP group, but, in general, was not maintained in the OP group. In comparison with the IC group tumour 5a- reduction was significantly higher in the IP group, unaltered in the IB group, and numerically but not significantly lower in the OC group. Whilst tumour 5a- reductase in the OP group was significantly higher than that of the OC group it did not differ significantly from that of the IC group and was significantly less than that of the IP group. Although, in comparison with their respective control groups, the groups with elevated plasma prolactin levels showed a higher capacity for tumour 5a- reduction, other intergroup comparisons indicate that ovarian hormones may also be involved in regulating tumour 5a- reductase activity. A study of testosterone metabolism in actively growing DMBA- induced mammary tumours, taken from un- treated rats at different stages of a 4 -day oestrous cycle, revealed that 5a- reductase was highest in tumours removed in metoestrus and lowest in tumours removed in proestrus. However the differences in 5a- reduction levels between tumours from the 4 stages of the cycle did not attain significance. Evidence is presented to indicate that DMBA -induced rat mammary tumours convert testosterone to 4- androstene- 3a,17ß -diol. The daily s.c. administration (1 mg /rat) of 5a- dihydrotestosterone and 5a- androstane- 3a,17ß -diol but not 5u.- androstane- 3ß,17ß -diol induced a state of constant dioestrus and regression of DMBA- induced rat mammary tumours. The effects may be associated with a decreased secretion of oestradiol and prolactin - Tumour incidence was higher in rats given DMBA in proestrus and lower in those given DMBA in dioestrus. At all stages of the cycle the mean plasma prolactin levels at the time of DMBA administration were higher in rats which subsequently bore tumours than in those which did not.