Androgens vs estrogens in prostate cancer
Androgens and increasing age are established risk factors associated with prostate cancer, Paradoxically, testosterone levels gradually decline with increasing age as the incidence of prostate cancer (PCa) rises in older men. Estrogens have been implicated in PCa as estrogen levels in older men remain relatively unchanged resulting in a decline in the ratio of androgens:estrogens with age. Thus the hormonal regulation of prostate cancer is not limited to a role for androgens and we propose that androgens in combination with estrogens are required for PCa. Our hypothesis is based on the following evidence. The estrogen deficient, ArKO, (aromatase knock out) mice have a life long elevation of androgens; the prostate is enlarged and leads to the development of BPH, but not PCa. Estrogens have systemic actions in the male that include the suppression of testicular androgen synthesis leading to prostatic atrophy. As well, estrogens have local, direct actions on the prostate gland. In many mammalian species, including mice and men, estrogens induce proliferative change to the epithelium leading to squamous metaplasia, an effect that is mediated via the ERalpha subtype. Prolonged exposure to high levels of estrogen initiate an inflammatory response probably mediated via the ERbeta subtype. In the absence of androgens, estrogens do not induce malignancy. We conclude that neither testosterone nor estrogen alone is sufficient to induce malignancy, but a combination of both is required for the development of PCa.