James P. Karr

Serum Prostatic Antigen Measurement in Localized Prostatic Cancer: Correlation with Clinical Course

Serial serum prostatic antigen measurements were performed on patients treated for localized prostatic carcinoma. There was good correlation of mean serum prostatic antigen levels and the surgical stage of the disease. Among patients treated by radical prostatectomy there was good correlation of an elevated serum prostatic antigen and the development of metastatic disease. It appears that serum prostatic antigen is a good indicator and predictor of the development of distant metastasis in this group of patients.

The possibility of aromatization of androgen in human prostate

Aromatase in human prostate tissue was determined in homogenized human prostate (three BPH and two normal specimens) incubated with [1-beta-3H]androstenedione (radiometric method) or [1,2,6,7-3H]androstenedione (estrogen production analysis method) in the presence of NADPH. Using the former procedure, significant amounts of 3H2O, resulting from the release of 3H at the C-1 position during aromatization, were measured and these increased with incubation time and amount of tissue, whereas the amount of estrone and estradiol-17 beta resulting from the latter method and calculated from the 3H/14C ratio in preparations of purified crystal was very small. The preliminary results, which suggest that an androgen aromatase system exists in the human prostate, point to the need to further investigate the identity and properties of the metabolic products resulting from the conversion of androgen to estrogens and other metabolites.

Correlation of histochemical and biochemical analyses of androgen binding in prostatic cancer: Relation to therapeutic response

A histochemical technique for the detection of androgen binding in prostatic cancer was performed on specimens from 108 patients and compared with a biochemical method in a double blind study of 77. Statistical analyses showed a significant agreement between the two assay systems for the qualitative and quantitative presence or absence of specific androgen binding, as well as for the subcellular localization of binding in nucleus and/or cytoplasm. Although the number of cases studied was too small for statistical analysis, there appeared to be good correlation between histochemical androgen binding results and clinical response, or lack of response to hormonal manipulation in 20 patients with Stage C and Stage D carcinoma. No correlation was evident between androgen binding and tumor grade or clinicopathologic stage of disease by either histochemistry or biochemistry.

Estrogen and progestin receptors in human prostatic carcinoma.

Cytosol receptors for estrogens (ER) and progestins (PR) were assayed in human prostatic carcinoma (CaP) and benign prostatic hyperplasia (BPH). Specimens were obtained from either the peripheral or the periurethral zone of the prostate. Stringent criteria were used to identify and measure 7‐8S specific receptor using sucrose gradient analysis in a vertical tube rotor. Progesterone receptor was found in 14 BPH samples assayed and in 12 of 13 prostate cancers. In contrast, the 7‐8S estrogen receptor was found in none of the nine benign samples assayed and in all prostate cancers. BPH samples were taken from either peripheral or periurethral zones and gave similar results. The histology of individual specimens did not correlate with either the ER or PR present, and, in the cancers, there was no correlation between the pathologic stage or the Gleason score and receptor content.

Steroid hormone receptors in the prostate.

Specific receptors for dihydrotestosterone and estradiol-17-beta have been identified in cytosols of the human and baboon prostate. Binding of radioactive estradiol-17-beta to the 0.4 M potassium chloride extractable component of human prostate nuclei also was demonstrated. Cyproterone acetate and diethylstilbestrol, agents of known high affinity for dihydrotestosterone and estradiol-17-beta receptors, respectively, did not bind significantly to sex hormone binding globulin and, therefore, were useful as competitors in distinguishing binding of dihydrotestosterone and estradiol-17-beta to sex hormone binding globulin and to their specific receptors. Displacement of [3H]-estradiol-17-beta binding by diethylstilbestrol in cytosols of 11 needle biopsy specimens (mean equals 16.8 mg.) from prostatic cancer patients was analyzed. These preliminary data indicated a trend towards greater competition by diethylstilbestrol for high affinity binding sites in differentiated tumor specimens from men who were not receiving estrogen therapy. Objective and subjective responses to hormone therapy were recorded in these patients, whereas the disease in those men with low displacement assay values progressed.

Effects of Diethylstilbestrol and Estramustine Phosphate on Serum Sex Hormone Binding Globulin and Testosterone Levels in Prostate Cancer Patients

Serum testosterone-estradiol binding globulin and total testosterone were measured in 2 groups of male controls (less than 50 and more than 65 years old) and in 7 groups of prostatic cancer patients treated with various endocrine manipulation procedures, including orchiectomy, and estramustine phosphate and diethylstibestrol therapy. There were 133 individuals studied. Total serum testosterone levels were significantly higher in the younger versus the older control group and testosterone-estradiol binding globulin levels were significantly higher in the older men. Whereas orchiectomy reduced serum testosterone to low concentrations (72 plus or minus 11 ng. per 100 ml.) testosterone-estradiol binding globulin levels were not altered. In contrast, estramustine phosphate and diethylstilbestrol therapy, when administered to intact or castrated patients, resulted in depressed testosterone and markedly elevated testosterone-estradiol binding globulin serum levels, particularly in those patients receiving estramustine phosphate (less than 35 ng. per 100 ml. and more than 6 micrograms per 100 ml., respectively). These studies led to the conclusion that diethylstilbestrol or estramustine phosphate therapy is significantly more effective than orchiectomy in eliciting a concomitant elevation of testosterone-estradiol binding globulin and a depression of total testosterone. Even though free serum testosterone was not measured in the present study the law of mass action would indicate that in those patients with high testosterone-estradiol binding globulin (more than 5 microgram. per 100 ml.) and low total testosterone levels (less than 80 ng. per 100 ml.) the availability of biologically active (unbound steroid) testosterone would be negligible.

Estrogen receptors and clinical correlations with human prostatic disease

Measurement of estrogen binding in human prostate using high-pressure liquid chromatography (HPLC) revealed the presence of cytosolic estrogen receptors (ER) both in benign prostatic hyperplasia (BPH) and adenocarcinoma. Receptor concentrations correlated with several histopathologic features in the specimens analyzed. Estrogen receptor levels generally were higher in BPH than in cancer specimens although there was a subgroup of patients with poorly differentiated carcinoma with levels higher than those of BPH, HPLC can be used for measuring ER in 50 microliters of cytosol, and thus needle biopsy specimens will be analyzed routinely for ER with this micromethod.

Effects of testosterone and estradiol on ventral prostate and body weights of castrated rats

Abstract Administration of 100 μg of testosterone (T) daily for 14 and 28 days to 7-day castrate rats restored the weight of the ventral prostate to a level which slightly exceeded that of the controls. Ventral prostate weight in groups receiving estradiol-17β (E2) doses of 10, 50, 100, 200, or 500 μg administered simultaneously with 100 μg of T did not differ significantly from intact controls, although the weights were lower at E2 levels greater than 100 μg. Body weights of the castrated rats receiving 100 μg of T did not differ from those of sham castrated controls. However, mean body weights of all groups which received E2 (10 to 500 μg) simultaneously with 100 μg of T were significantly less than (p

Prostatic binding of estradiol-17β in the baboon

A specific receptor for estradiol-17β (E2) has been identified in the caudal and cranial lobes of the baboon prostate. Following in vivo infusion of [3H]-E2 into the hypogastric arteries of castrated and intact baboons, the prostate, particularly the cranial lobe, concentrated more radioactivity than any other tissue or fluid not involved in the metabolism or excretion of E2. Sucrose density gradient centrifugation of in vivo and in vitro labeled cytosols showed that the bound E2 complex had a sedimentation coefficient of ∼-4S. Sephadex G-25 filtration of cytosols and 0.4 M KCl nuclear extracts of caudal and cranial lobe preparations from intact and 40 h castrates infused with [3H]-E2 showed bound radioactivity in all cases. Analysis of nuclear residues resistant to 0.4 M KCl extraction revealed significant concentrations of radioactivity. Testosterone (T) and dihydrotestosterone (DHT) did not compete in vitro with [3H]-E2 for the estrogen receptors, but E2 and diethylstilbestrol (DES) were effective competitors. Nafoxidine, and to some extent estracyt, displaced labeled E2 from cytosol binding sites. Analysis of cytosols and nuclear preparations following in vitro incubations of prostatic tissues revealed further evidence of specific cytosol binding and demonstrated nuclear translocation of a [3H]-E2 bound complex. Scatchard and double reciprocal plots indicated Ka and Ka values for the E2 binding to be about 1.2 × 109 M and 8.3 × 10−10M for the caudal lobe and 7.7 × 109 M and 1.3 × 10−10 M for the cranial lobe, respectively.

The potential significance of aromatase in the etiology and treatment of prostatic disease

Prior to the present conference on aromatase, reports in the literature on prostatic aromatase have been scattered over time, few in number, and the results have been widely divergent. Moreover, several participants at this conference have reported unpublished data that failed to detect the existence of androgen aromatase in the prostate of man and other species. While papers and posters presented at this conference have added new information to this field, there would still appear to be no consensus as to the biological significance, if any, of the putative androgen aromatase system or the practical importance of inhibitors of prostatic and/or peripheral aromatase as a treatment modality for benign prostatic hyperplasia (BPH). Thus, it would be difficult to predict at this time the ultimate impact which current prostatic aromatase investigations will eventually have on our understanding and treatment of prostatic disease. To summarize the status of our current understanding of aromatase as it relates to prostatic function and disease, it would be safe to note that this field is virtually wide open for researchers to explore, both in terms of the future role that aromatase inhibitors may have in clinical investigations and in terms of the functional significance of aromatase, if any, in the normal prostate as well as in the pathogenesis of BPH and prostate cancer. Clearly, the widely divergent results currently available in the literature must reflect, in part, differences in methodology, anatomy, tissue types, the relative amounts of stroma and epithelium in specimens analyzed, the cellular and tissular (normal, BPH, and carcinomatous) heterogeneity encountered in clinical specimens, and the pharmacologic features of aromatase inhibitors tested.