Huggins and Hodges<sup>18 Huggins C., Hodges C.V. Studies on prostatic cancer, effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate Cancer Res 1941 ;  1 : 293-297

Cliccare qui per andare alla sezione Riferimenti</sup> described the relationship between androgens and prostate cancer proliferation by showing that castration by medical or surgical means resulted in tumor regression. Since that time, androgen ablation has been one of the mainstays of treatment for metastatic prostate cancer. More recently, the concept of complete androgen ablation has been popularized by Labrie and colleagues,<sup>22 Labrie F., Belanger A., Simard J. , e al. Combination therapy for prostate cancer: Endocrine and biologic basis for its choice as new standard first-line therapy [abstract] Cancer 1993 ;  71 : 1059  [cross-ref]

Cliccare qui per andare alla sezione Riferimenti</sup> which involves the simultaneous suppression of testicular and adrenal androgens using a GnRH analog or orchiectomy in combination with a nonsteroidal antiandrogen, such as flutamide. This approach remains controversial, as is the management of patients once they have progressed on primary hormonal therapy. To many physicians, patients who have progressed on complete androgen blockade were considered to be resistant to further hormonal manipulations and traditionally have been treated with nonhormonal approaches or chemotherapy as the next appropriate therapy.

In 1993,<sup>19 Kelly W.K., Scher H.I. Prostate specific antigen decline after antiandrogen withdrawal J Urol 1993 ;  149 : 607-609

Cliccare qui per andare alla sezione Riferimenti</sup> we initially described four patients with progressive metastatic prostate cancer on combined androgen blockade who after selective discontinuation of the antiandrogen, flutamide, showed subjective, biochemical, and objective improvement. Although withdrawal responses to tamoxifen and progesterones in advanced breast cancer were recognized,<sup>17 Howell A., Dodwell D.J., Anderson H. , e al. Response after withdrawal of tamoxifen and progestens in advanced breast cancer Ann Oncol 1992 ;  3 : 611-617

Cliccare qui per andare alla sezione Riferimenti</sup> this was the first report of the phenomenon in prostate cancer. As more patients with progressive prostate cancer on combined androgen blockade were taken off antiandrogen and monitored for response, it became apparent that this was not an isolated occurrence but in fact therapeutic for a significant proportion of the patients.<sup>4 Collinson M.P., Daniel F., Tyrell C.J. , e al. Response of carcinoma of the prostate to withdrawal of flutamide Br J Urol 1993 ;  72 : 662-663  [cross-ref]

Cliccare qui per andare alla sezione Riferimenti, 9 Dupont A., Gomez J., Cusan L. , e al. Response to flutamide withdrawal in advanced prostate cancer in progression under combination therapy J Urol 1993 ;  150 : 908-913

Cliccare qui per andare alla sezione Riferimenti, 16 Herrada J., Dieringer P., Logothetis C.J. Characterization of patients with androgen-independent prostatic carcinoma whose serum prostate specific antigen decreased following flutamide withdrawal J Urol 1996 ;  155 : 620-623  [cross-ref]

Cliccare qui per andare alla sezione Riferimenti</sup> As the awareness of the syndrome evolved, it became a routine clinical practice to discontinue the antiandrogen and observe before initiating more toxic therapies. It now is recognized that this is a more generalized phenomenon, not limited to antiandrogens alone, and more appropriately renamed the steroid hormone withdrawal syndrome.