Hyperprolactinaemia as an adverse effect in regulatory and clinical toxicology: role in breast and prostate cancer.
Historically, hyperprolactinaemia has been considered of low toxicological relevance when detected in toxicity studies, and even mammary carcinogenesis induced in the rat by prolactin excess has been considered of no relevance to humans. However, recent findings from human epidemiology and molecular biology suggests that prolactin is a risk factor for human breast cancer, and probably prostate cancer. Therefore, this new evidence should be considered in the various decisions to develop and license a new drug or chemical if the compound causes hyperprolactinaemia. This emerging evidence suggests that prolactin can also be produced locally from human breast cancer cells, and that, regardless of source (ie, pituitary or autocrine/paracrine production from cancer cells), prolactin is mitogenic, stimulates proliferation and suppresses apoptosis in breast and prostate cancer cells. This review outlines the evidence that hyperprolactinaemia should be considered a toxicological adverse effect and concludes that prolactin-induced rodent mammary carcinogenesis is relevant to humans and is not species-specific. The effects of prolactin on the prostate gland are also discussed; hyperprolactinaemia may be an additional risk factor for prostate cancer and this also requires consideration in toxicological risk assessments. The implications of increased prolactin secretion as an adverse effect for regulatory toxicology of drugs and chemicals, and in high risk patients receiving therapeutic drugs with hyperprolactinaemic side effects, is discussed. Alteration of prolactin level is also a novel mechanism that requires consideration in endocrine disruption research, since both endogenous oestrogens and also xenoestrogens stimulate prolactin secretion or affect prolactin receptors.
Harvey
P W
PW
Department of Toxicology, Covance Laboratories Ltd., Harrogate, North Yorkshire, UK. philip.harvey@covance.com
Everett
D J
DJ
Springall
C J
CJ
D000818:Animals; D001943:Breast Neoplasms / Q000097:blood / Q000209:etiology* / Q000378:metabolism; D015197:Carcinogenicity Tests; D018492:Dopamine Antagonists / Q000009:adverse effects* / Q000633:toxicity; D005260:Female; D006801:Humans; D006966:Hyperprolactinemia / Q000097:blood / Q000209:etiology* / Q000378:metabolism; D008297:Male; D011388:Prolactin / Q000097:blood / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000097:blood / Q000209:etiology* / Q000378:metabolism; D011981:Receptors, Prolactin / Q000378:metabolism; D018570:Risk Assessment; D012307:Risk Factors
D018492:Dopamine Antagonists; D011981:Receptors, Prolactin; D011388:Prolactin