The polypeptide growth factors insulin-like growth factor I (IGF-I), epidermal growth factor (EGF), and transforming growth factor-alpha (TGF-alpha); second-messenger cyclic adenosine monophosphate (cAMP): protein kinase activators; and neurotransmitters were found to activate the estrogen (ER), progesterone (PR), and glucocorticoid receptor (GR) either in the absence of their natural ligands or synergistically with the respective hormone. There is now evidence of coupling of signaling pathways involving the androgen receptor (AR). Three polypeptide growth factor, IGF-I, keratinocyte growth factor (KGF), and EGF, stimulated AR-mediated reporter-gene transcription in the absence of androgen in DU-145 cells, which were cotransfected with the reporter gene and an AR expression vector. IGF-I effects were observed irrespective of the promoter driving the reporter gene. This growth factor increased the prostate-specific antigen (PSA) level in LNCaP cells, which contain endogenous AR. In CV-1 cells, which transiently express the AR, second-messenger cAMP potentiated effects of testosterone in stimulation of AR-mediated reporter-gene activity. Inhibition of androgen-stimulated chloramphenicol acetyltransferase (CAT) activity in the LNCaP cell line was achieved with retinoic acid. Stimulation and inhibition of prostatic carcinoma cell growth by polypeptide growth factors and cellular regulators may depend on the presence of the AR in an androgen-depleted environment.