Bunzo Kashiwagi

Genetic polymorphisms of estrogen receptor alpha, CYP19, catechol-O-methyltransferase are associated with familial prostate carcinoma risk in a Japanese population.

Estrogen is one of the crucial hormones participating in the proliferation and carcinogenesis of the prostate glands. Genetic polymorphisms in the estrogen metabolism pathway might be involved in the risk of prostate carcinoma development. The authors evaluated the association between genetic polymorphisms in estrogen‐related enzymes and receptors and the risk of developing familial prostate carcinoma.

New quantification method for estradiol in the prostatic tissues of benign prostatic hyperplasia using liquid chromatography–tandem mass spectrometry

Estrogen is suspected to play a role in the pathogenesis of benign prostatic hyperplasia (BPH) and prostate cancer. To clarify the role of estradiol (E2) in the prostatic tissues (prostatic tissue E2) during the development of prostatic disorders, we developed a new sensitive and specific quantification method for prostatic tissue E2 using liquid chromatography-tandem mass spectrometry (LC-MS/MS). For the solid-phase extraction, E2 was purified by anion-exchange through an Oasis MAX cartridge. In addition, after the formation of 3-pentaflurobenzyl-17beta-pyridinium-estradiol derivative (E2-PFBPY), E2-PFBPY was purified by cation-exchange through an Oasis WCX cartridge. These processes in the LC-MS/MS method improved the specificity and sensitivity for prostatic tissue E2 measurement, compared to the radioimmunoassay (RIA) method. The validation tests showed that intra-day and inter-day precisions were both within +/-15% (except for 15.5% of the inter-day precision of the lowest concentration), with the accuracy ranging from 88 to 110%. The quantification limit of this assay was 0.15pg/tube in our method, which was 80-fold more sensitive than that of the RIA method. With the use of our present method, the median E2 levels in the prostatic tissues in patients with BPH (n=20, median age: 71 years) were 12.0pg/g tissue (95% confidence interval=9.1-22.6pg/g tissue). Furthermore, the E2 levels increased significantly with aging. These results showed that our present method would be useful for elucidating the role of prostatic tissue E2 in the development of prostatic disorders with a small amount of tissue samples.

Hormonal and morphologic evaluation of the effects of antiandrogens on the blood supply of the rat prostate

OBJECTIVES To clarify the basic aspects of the regulation of the prostatic blood supply by antiandrogens, their effect on the prostatic blood supply was studied for both androgen content and morphology of true capillaries in the rat ventral prostate. The effectiveness of antiandrogens on the control of hemorrhagic status in prostatic diseases has been previously reported. METHODS Androgen concentrations in the prostate were quantified after administration of chlormadinone acetate (CMA), finasteride, or flutamide. The prostatic blood supplies were measured after administration of CMA, finasteride, flutamide, or bicalutamide. The alpha-blockers, terazosin and tamsulosin, were included in the study as negative controls. The histologic changes in the capillaries of the ventral prostate were observed, and the luminal area was measured. RESULTS The prostate dihydrotestosterone concentrations were decreased by the administration of all antiandrogens. Treatment with CMA, finasteride, flutamide, or bicalutamide reduced the prostatic blood supply by 50% to 65%. The parallel reduction in luminal areas of the true capillaries was observed in rats treated with CMA. Treatment with alpha-blockers did not affect the prostate androgen content, prostatic blood supply, or capillary luminal area. CONCLUSIONS The reduction of the prostatic blood supply was suggested to be the result of a decrease in dihydrotestosterone content and the reduction in the luminal area of capillaries. The early reductive effect of antiandrogens on the prostatic blood supply suggests an alternative use for antiandrogens independent of their typical use for prostate volume regression. The results support the basic aspects of the advantage of preoperative treatment with CMA, flutamide, and bicalutamide, similar to finasteride, in reducing perioperative hemorrhage.

Development of prostate cancer in a patient with primary hypogonadism: intratumoural steroidogenesis in prostate cancer tissues

Intratumoural steroidogenesis may play a significant role in the progression of prostate cancer (PC) in the context of long‐term ablation of circulating testosterone (T). To clarify the mechanism accounting for the progression of PC in a 74‐year‐old man who had undergone bilateral orchiectomy when he was 5 years old, we performed immunohistochemical studies of androgen receptor (AR) and steroidogenic enzymes in the prostate. We also measured steroid hormone levels in the serum and prostate, as well as mRNA levels of genes mediating androgen metabolism in the prostate. Positive nuclear staining of AR was detected in malignant epithelial cells. The levels of androstenedione (Adione), T, and 5‐alpha dihydrotestosterone (DHT) in the serum of the patient were similar to those in PC patients receiving neoadjuvant androgen deprivation therapy (ADT), but were higher in the patients prostate than in PC patients not receiving ADT. The gene expression of CYP17A1 and HSD3B1 was not detected, whereas that of STS, HSD3B2, AKR1C3, SRD5A1, and SRD5A2 was detected. Moreover, cytoplasmic staining of HSD3B2, AKR1C3, SRD5A1, and SRD5A2 was detected in malignant epithelial cells. Hence, in the present case (a man with primary hypogonadism), steroidogenesis in PC tissues from adrenal androgens, especially dehydroepiandrosterone sulphate, was the mechanism accounting for progression of PC. This mechanism might help elucidate the development of castration‐resistant PC.

ESTRAMUSTINE PHOSPHATE WITHDRAWAL SYNDROME WITH DRAMATIC PAIN RELIEF

A 65-year-old man with hormone refractory prostatic cancer was admitted to our hospital for severe pain of the pelvis and inferior limb due to multiple bone metastases 31 months after initial treatment with luteinizing hormone releasing hormone (LH-RH) agonist depot combined with flutamide. Flutamide was stopped after 2 months because of liver dysfunction. After hospitalization, he was treated with 250 to 375 mg. diethylstilbestrol phosphate intravenously daily and LH-RH. Serum PSA concentration decreased until 13 weeks after treatment and then it gradually increased. Diethylstilbestrol phosphate was stopped after 21 weeks (total dose 41.5 gm.), and the patient started taking 560 mg. estramustine phosphate orally daily. However, PSA level declined for only 2 weeks and then began to elevate. After 6 weeks of estramustine phosphate all hormonal therapy was stopped except for LH-RH. At the current hospitalization the patient was given 180 mg. morphine sulfate daily for pain relief and this dose was increased based on patient complaints to the maximum dose of 960 mg. at 18 weeks. Other treatment for pain relief, including spot irradiation, minor tranquilizers and dexamethasone, were also tried but complete relief of pain was not achieved. The course of treatment, levels of serum PSA and morphine sulfate dose are shown in figure 1. After estramustine phosphate withdrawal PSA concentration declined greatly and the pain was relieved dramatically. Daily dose of morphine sulfate was reduced gradually to a final dose of 0, 8 weeks after estramustine phosphate withdrawal (fig. 2). The patient was discharged home without morphine sulfate and is now followed as outpatient.

Time-dependent effects of castration on the bladder function and histological changes in the bladder and blood vessels

We examined the effect of androgens on bladder blood flow (BBF), bladder function and histological changes in castrated male rats. Male Wistar rats were classified into unoperated group (control group), groups castrated at the age of 8 weeks (group 8wPC) and groups castrated at the age of 4 weeks (group 4wPC). Each rat was used at the age of 20 weeks. BBF was measured using fluorescent microspheres. Bladder cystometry was performed without anesthesia or restraint; the bladder was first irrigated with saline and then with 0.25% acetic acid (AA) solution. Maximum voiding pressure and voiding interval were measured. The bladder and iliac artery were histologically examined for differences in smooth muscle and quantity of collagen fiber to analyze the effect of castration on the smooth muscle content. No differences were noted in BBF following castration. The voiding intervals for all groups were shortened (P < 0.001) following AA irrigation. No significant difference was noted in the maximum voiding pressure. Histological changes were observed in bladder and iliac artery. Smooth muscle/collagen ratio at the bladder was lower in groups 8wPC and 4wPC compared to the control group (P< 0.01), while that at the iliac artery was decreased in group 4wPC compared to the control group (P< 0.001). In conclusion, our findings indicate that castration does not alter BBF, but leads to histological changes in the bladder as well as its associated blood vessels.

Influence of castration on bladder blood flow and function during the rapid phase of androgen deprivation

Abstract Objective. This study examined the effects of androgen deprivation on bladder blood flow (BBF) and bladder function during the acute phase in castrated rats. Material and methods. Nine-week-old male Wistar rats were divided into six groups as follows: 24 h post-sham-operation (24hPS), no operation (control), 24 h post-castration (24hPC), 48 h post-castration (48hPC), 7 days post-castration (7dPC) and 12 weeks post-castration (12wPC). BBF was measured in the 24hPS, control, 24hPC, 48hPC, 7dPC and 12wPC groups, and prostate blood flow was measured in the control, 24hPC, 48hPC and 7dPC groups using laser Doppler methods. In select groups, BBF was measured using the fluorescent microsphere method. Bladder function was tested in the 24hPS, control, 24hPC and 12wPC groups. The bladder was irrigated with saline and 0.25% acetic acid. Maximum voiding pressure and voiding intervals were measured. Results. BBF significantly increased within 24 h after castration (p < 0.001); these changes did not persist beyond 24 h. However, prostate blood flow decreased significantly within 24 h after castration (p < 0.001). Shortening of the voiding interval upon acetic acid stimulation was significantly suppressed in group 24hPC compared to the control group (p < 0.001). The maximum voiding pressure did not significantly change in the 24hPS, control, 24hPC and 12wPC groups. Conclusions. During the acute phase of androgen deprivation following castration, BBF significantly increased and the bladder became receptive to stimulation. This temporary increase may be because of a decrease in the prostate blood flow, indicating that androgens do not directly affect the BBF.