Prostate specific antigen in hormonally treated stage D2 prostate cancer: is it always an accurate indicator of disease status? The clinical significance of serum prostate specific antigen (PSA) values in hormonally treated prostate cancer patients and the effect of hormonal therapy on the serum PSA concentration, independent of the response observed from its antitumor activity, are not well defined. To elucidate further the influence of antiandrogen therapy on serum PSA expression, 81 randomly selected patients with stage D2 prostate cancer were evaluated with respect to serum PSA concentration. These patients were divided into 2 groups on the basis of previous hormonal therapy. Group 1 consisted of 43 patients 55 to 89 years old (mean age 71 years) who had received no prior therapy for prostate cancer. Group 2 included 38 men 58 to 84 years old (mean age 72 years) who had received only androgen deprivation therapy with either bilateral orchiectomy or diethylstilbestrol. The mean interval between initiation of antiandrogen therapy and evaluation of these patients was 14 months (range 8 to 31 months). At the time of PSA determination both groups were similar in all respects, including tumor grade, disease symptoms and bone scan findings. The median serum PSA concentration was 96.0 ng./ml. in group 1 and 16.5 ng./ml. in group 2 (p less than 0.001), despite both groups having similar symptoms and widespread metastatic disease on radionuclide bone scan. In group 1 only 1 patient (2%) had a serum PSA level less than 4.0 ng./ml., whereas 13 men (34%) in group 2 had a serum PSA concentration below 4.0 ng./ml. (p less than 0.001). Of the patients in group 1, 2% and of the men in group 2, 45% had a serum PSA concentration less than 10 ng./ml. (p less than 0.001). These findings demonstrate that the serum PSA level in prostate cancer patients treated hormonally may have a significantly different meaning than the same serum PSA value in patients without hormonal therapy. In addition, these observations suggest that PSA expression may be under hormonal regulation and that androgen deprivation therapy may have a direct effect on the serum PSA concentration, independent of the response obtained from any antitumor activity. However, the exact mechanism of this androgenic influence on PSA expression awaits further investigation at the cellular level. 