Craig A. Peters

The Effect of Nafarelin Acetate, a Luteinizing-Hormone–Releasing Hormone Agonist, on Benign Prostatic Hyperplasia

We examined the influence of androgens on benign prostatic hyperplasia, using nafarelin acetate, a potent luteinizing-hormone-releasing hormone agonist, to achieve reversible androgen deprivation in men with benign prostatic hyperplasia. Nine patients with bladder-outlet obstruction due to benign prostatic hyperplasia were treated with subcutaneous nafarelin acetate (400 micrograms per day) in an open trial for six months. In all patients, serum testosterone decreased to castrate levels. Objective observations included uroflowmetry, measurement of residual urine volume, determination of prostatic size by ultrasonography, and prostatic biopsy. In all patients, the prostate regressed to a mean (+/- SEM) of 75.8 +/- 3 percent of the initial size (range, 52 to 86; P less than 0.005); the regression reached a plateau after four months. Morphologic analysis of biopsy specimens showed regression of glandular epithelium. Three of nine patients had clinical improvement with treatment. Six months after the cessation of treatment, plasma testosterone levels had returned to normal and the size of the prostate had increased to 99 +/- 5.5 percent of the initial size. These findings suggest that androgens have an important supportive role in established benign prostatic hyperplasia and that testicular suppression will benefit some patients. However, this form of treatment could be applicable only in carefully selected patients who were not surgical candidates, and it would need to be maintained indefinitely.

The Influence of Reversible Androgen Deprivation on Serum Prostate-Specific Antigen Levels in Men with Benign Prostatic Hyperplasia

This study was designed to investigate the relationship of serum prostate-specific antigen to prostatic size and hormonal stimulation. Seven patients with benign prostatic hyperplasia were treated for six months with nafarelin acetate and then followed for an additional six months. Nafarelin acetate is a potent luteinizing-hormone-releasing hormone agonist which causes reversible testosterone deprivation resulting in involution of the prostate. During therapy and follow up, serum prostate-specific antigen correlated with: 1) serum testosterone (p less than 0.001); 2) quantity of prostatic epithelium (p less than 0.001); and 3) prostatic size (p less than 0.05). Before therapy, serum prostate-specific antigen (mean +/- SD) was 0.43 +/- 0.2 ng./ml. per gram of epithelium. This did not change significantly after six months of androgen deprivation (0.48 +/- 0.36), although the ratios of prostate-specific antigen to testosterone and to prostatic size each changed significantly. Despite testosterone levels in the castrate range at six months, five of seven patients had serum prostate-specific antigen concentrations above the female range and three of seven patients had prostatic biopsies containing columnar epithelium which stained positively for prostate-specific antigen. These results demonstrate that serum prostate-specific antigen is related to prostatic size, prostatic epithelial weight, and testosterone stimulation. However, prostatic size is not a good predictor of serum prostate-specific antigen because there is tremendous variation in the relative amount of epithelium in a prostate; in this study the ratio of prostatic size to epithelial weight varied threefold. Furthermore, although testosterone determines prostatic size and amount of prostatic epithelium, it may not totally control prostate-specific antigen production.

Endoscopic injection of glutaraldehyde cross-linked bovine dermal collagen for correction of vesicoureteral reflux.

From November 1986 through May 1989, a Food and Drug Administration approved investigational study was done to assess the safety and efficacy of glutaraldehyde cross-linked bovine dermal collagen in the endoscopic treatment of vesicoureteral reflux. Over-all, 57 patients (92 ureters) were treated. The majority of ureters (68.5%) had grade II to III/V vesicoureteral reflux (international classification). One treatment was given in 61.4% of the patients, while 33.3% required 2 and 5.3% required 3 treatments. Nonduplicated/primarily refluxing ureters comprised 68.5% of the total, while 13% were duplex/primarily refluxing and 18.5% were surgical failures. The procedures were performed on an outpatient basis in all but 3 patients. Patients were evaluated by voiding cystourethrogram and renal/bladder sonography before and after treatment at 1 month and 1 year. Cure at 1 month after the last treatment was achieved in 75% of the ureters. Among the ureters cured at 1 month the cure persisted in 79% at 1 year after treatment. Cure at 1 year was achieved in 65% of all ureters evaluated, regardless of the status at 1 month. Procedure-related morbidity was minimal and there were no adverse reactions to the implant substance. Thus, glutaraldehyde cross-linked bovine dermal collagen appears to be safe and effective in the endoscopic treatment of vesicoureteral reflux.

Blood transfusion and anesthetic practices in radical retropubic prostatectomy

We have attempted to lessen blood transfusion requirements during radical retropubic prostatectomy. The influence of temporary occlusion of the hypogastric arteries, anesthetic techniques and autologous blood transfusions were studied in 93 men undergoing radical retropubic prostatectomy with pelvic lymph node dissection. Operations performed with the patient under general or regional anesthesia with hypogastric artery clamping required significantly less blood replacement than those performed without hypogastric artery clamping (1.8 plus or minus 0.3 versus 3.5 plus or minus 0.3 units, respectively, mean plus or minus standard error). Preoperative autologous banking of blood eliminated the need for heterologous transfusions in 10 of 15 patients in whom any autologous blood was banked (2 to 4 units per person). We conclude that temporary hypogastric artery clamping can reduce significantly the need for blood product replacement in radical retropubic prostatectomies during the perioperative period. We also are encouraging the preoperative banking of autologous blood to lessen further exposure to heterologous blood products with their attendant risks.

A new method for labeling and autoradiographic localization of androgen receptors.

We have used a novel receptor labeling and autoradiographic technique to localize androgen receptors in the intact rat ventral prostate at the morphological level. Frozen slide-mounted prostate tissue sections (10 micron thick) were incubated with increasing concentrations of [3H]-R1881 in the absence and presence of excess unlabeled R1881. Tissue sections labeled in this way were subjected to concurrent biochemical and autoradiographic analysis. After incubation and washing to remove free [3H]-steroid, some of the sections were wiped from the slides for scintillation counting in order to characterize and quantitate [3H]-R1881 binding. Androgen receptors could indeed be labeled in slide-mounted tissue sections, and specific [3H]-R1881 binding to these receptors was high-affinity (Kd = 1 nM), saturable, and androgen-specific. All cellular androgen receptors appear to be retained, because receptor content in sections was comparable to the sum of receptors in subcellular fractions of homogenized tissue. Replicate labeled slide-mounted tissue sections were dried rapidly, apposed to dry emulsion-coated coverslips, and exposed in the dark for autoradiography. Silver grains were counted over nuclei or cytoplasm of epithelium or stroma to evaluate specific androgen receptor location. Autoradiographic analysis demonstrated androgen receptor localization almost exclusively in the epithelial nuclei, with little or none in the stroma. We discuss here the unique features and advantages of labeling androgen receptors in slide-mounted frozen tissue sections for autoradiographic localization.

Androgen receptor localization in the human prostate: Demonstration of heterogeneity using a new method of steroid receptor autoradiography

We have used a novel receptor labeling and autoradiographic technique to identify the cell types in human benign prostatic hyperplasia (BPH) that contain androgen receptors, and we have found that androgen receptor localization is heterogeneous. Prostatic androgen receptors were labeled by incubating slide-mounted frozen tissue sections (10 micron thickness) with [3H]R1881 in vitro. Tissue sections labeled in this way were subjected to concurrent biochemical and autoradiographic analysis. Some of the sections were wiped from the slides for scintillation counting to validate that the procedure indeed measures total cellular androgen receptors of appropriate high affinity and androgen steroid specificity. Replicate labeled slide-mounted tissue sections were dried rapidly, apposed to dry emulsion-coated coverslips, and exposed in the dark for autoradiography. Autoradiograms were developed, fixed, and stained; silver grains were counted over nuclei or cytoplasm of epithelium or stroma to evaluate specific androgen receptor location. Autoradiographic analysis of human glandular BPH demonstrated androgen receptor localization almost exclusively in the epithelial nuclei, with little or none in the stroma. We anticipate that data obtained using this new method of steroid receptor autoradiography may provide fresh insight into the mechanism of hormonal regulation of the prostate.

Epispadias and Incontinence: The Challenge of the Small Bladder

The 12-year experience at our hospital with epispadias and incontinence is reviewed and attention is focused on the approach to patients with a small bladder capacity. Of 29 children 20 had incontinence associated with the epispadias (13 boys and 7 girls). A total of 15 patients underwent definitive management of the incontinence with a Young-Dees bladder neck reconstruction with or without ureteral reimplantation and they are evaluable. Nine patients (6 boys and 3 girls) had a bladder capacity that was believed to be inadequate for satisfactory bladder neck reconstruction (less than 60 ml.). To date, 7 of these children have undergone staged reconstruction with urethroplasty for epispadias as the initial operation. Bladder capacity increased 95 ml. on the average (range 60 to 140 ml.) after the urethroplasty. No child had hydronephrosis before or after bladder neck reconstruction. Review of the results of bladder neck reconstruction in all patients with a mean followup of 2.9 years (range 7 months to 13 years) demonstrates an 87 per cent satisfactory continence rate (9 of 9 boys and 4 of 6 girls). In the patients who underwent staged reconstruction the results were similar, with a 100 per cent continence rate in evaluable patients (5 of 5 boys and 2 of 2 girls). In conclusion, urethroplasty before bladder neck reconstruction in the epispadiac child with a small bladder allows an increase in capacity, thus, obviating for the most part the need for procedures such as bladder augmentation in the majority of these patients.

Unilateral nerve-sparing radical prostatectomy and hemicystectomy in management of prostate sarcoma]

A patient with sarcoma of the prostate was treated with radical prostatectomy including wide excision of the ipsilateral neurovascular bundle and hemicystectomy. Six years postoperatively he is free of disease, continent with a bladder capacity of 350 cc, voids to completion, and is potent.