Classic Citations: Studies on Prostatic Cancer I. The Effect of Castration, of Estrogen and of Androgen Injection on Serum Phosphatases in Metastatic Carcinoma of the Prostate* by Charles Huggins and Clarence V. Hodges

Abstract

I n 1941, Huggins and Hodges [1] published this classical article which established for the first time the relationship between testosterone (T) and prostate cancer (PCa). The goals of Huggins and Hodges were to present the values of serum phosphatases in normal men and patients with carcinoma of the prostate. Furthermore, they wanted to demonstrate that the serum levels of acid phosphatase were reduced in metastatic PCa by decreasing the activity of androgens and increased after androgens injections. Authors argued that there were evidences that the activity of phosphatases, mainly the acid one, in serum was found to provide objective indices of activity of PCa [2]. They evaluated alkaline and acid phosphatases of 40 normal men who served as controls to determine the normal range of enzymes levels, 21 men with benign prostatic hypertrophy, and of 47 men with carcinoma of the prostate. Eight patients who had carcinoma of the prostate with bone metastases and with moderate or great elevation of both phosphatases levels were submitted to bilateral orchiectomy. Five patients were injected with stilbestrol 1 mg or estradiol benzoate 1.66 to 3.32 mg daily, and two patients were injected with T propionate 1.25 mg daily before castration. In one patient, T was injected after castration. They also evaluated phosphatase levels in the cerebrospinal fluid of three patients and in the spermatocele fluid of one patient concurrently with the serum levels. They made serial observations of serum phosphatases 1 week before and 4 weeks after bilateral orchiectomy in four normal adult dogs. They found that of the 47 patients with PCa with or without bone metastases, 23 had both phosphatases levels in the range of the controls. Of the remaining 24, all had elevated levels of both alkaline and acid phosphatases. Of 25 patients with radiographic evidence of bone metastasis, 19 had elevated levels of both phosphatases. Alkaline phosphatase alone was increased in two cases, while acid phosphatase was within normal limits, and neither enzyme was increased in other four cases. There was no X-ray evidence of metastasis in 20 patients; in 16 men, both acid and alkaline phosphatases were normal; in three men, alkaline phosphatase was elevated, but in none of this group, the acid phosphatase level was increased. The authors did not report phosphatase levels in men with benign prostatic hypertrophy. After bilateral orchiectomy, the levels of acid phosphatase rapidly decreased (7 to 12 days); its levels usually persisted in a range slightly above or below the upper limits of the normal values and it was maintained at this value with slight fluctuation during the period of observation which in the longest case was 180 days. A rise was always observed in the value of alkaline phosphatase following castration followed by a decrease to or toward normal range. Serum phosphatases were within normal range in four dogs and therewere no changes after castration. © 2010 International Society for Sexual Medicine