Early indicators for carcinogenesis in sex-hormone-sensitive organs.

Hormones induce tumours in various target tissues in different species of laboratory animals in long-term toxicity studies. Examples of such tumours are: mammary gland tumours in beagle dogs after long-term treatment with progestogens or progestogen/oestrogen combinations; pituitary and mammary gland tumours in rats and mice after long-term treatment with oestrogens or progestogens with an oestrogenic partial effect; interstitial cell tumours in rats after chronic overstimulation by endogenous luteinising hormone; endometrial carcinomas in rats after chronic treatment with dopamine agonists. As a rule every hormone when given in excessive doses over prolonged periods can induce a tumour in the relevant target organs. Drugs or chemicals which stimulate or inhibit the endogenous hormone production of certain endocrine organs can have the same effect. Tumour induction can be a direct or indirect effect involving specific regulatory mechanisms. In general, the induction is preceded by excessive hyperplasia of the target tissue concerned or with regard to the pituitary where excess production of the stimulating hormone occurs. Tumour induction in chronic toxicity studies can usually be predicted by determining hormone levels in short-term studies. Hormones and drugs or chemicals which induce tumours when given in doses high enough to induce hyperplasia are unlikely to do so by a genotoxic mechanism.