Role of growth factors in benign prostatic hyperplasia.

Benign prostatic hyperplasia (BPH) is a common condition among older men. Although surgery is the most effective treatment for patients with severe symptoms of bladder outlet obstruction, many patients with less severe symptoms will benefit from pharmacological intervention. Traditional medical therapies have involved hormonal manipulation. However, evidence has now emerged that prostate growth is under the immediate control of specific growth factors and only indirectly modulated by steroids. In this review we present a hypothesis of the mechanism of action of these growth factors in the developmental of BPH. Many of the more bothersome symptoms of BPH are not directly caused by the outlet obstruction, but only the resulting bladder hypertrophy. The development of the rabbit model of partial bladder outlet obstruction has allowed investigation of the bladder changes likely to occur in BPH. These studies have revealed the important role of growth factors in the development of bladder hypertrophy. Therefore, targeting growth factors potentially represents a direct therapeutic approach to the regulation of abnormal enlargement of the prostate and the amelioration of other symptoms associated with BPH.

Regional concentration of basic fibroblast growth factor in normal and benign hyperplastic human prostates.

Basic fibroblast grown factor (bFGF) is a potent mitogen for mesenchymal cells, including fibroblasts cultured from prostate, and has been postulated to play a role in the development of benign prostatic hyperplasia (BPH). If this is the case, it might be expected that bFGF levels would be elevated in the adenomas of BPH and in the periurethral region of the prostate where BPH is believed to arise. This study was undertaken to test this hypothesis. The concentration of bFGF was evaluated in 31 prostates, 13 normal glands and 18 with BPH. A method for quantitating bFGF by radioimmunoassay was developed that enabled growth factor levels to be correlated to the geographic region of the prostate and the histopathology of the specimen. A 2- to 3-fold higher concentration of bFGF (ng./g. of tissue) was noted in the benign hyperplastic prostates when compared with the adult normal glands. Pubertal specimens demonstrated low growth factor levels comparable to those observed in the normal adult group. Two prepubertal prostates analyzed had high levels similar to those measured in the hyperplastic glands. While the levels of bFGF in the normal adult prostates were highest in the periurethral region, statistical analysis failed to demonstrate a significant difference. Similarly, quantitative morphometric evaluation failed to demonstrate any significant differences in bFGF concentration related to the proportion of stromal, epithelial, or lumenal elements in the tissue sections.

Three-dimensional reconstruction of anatomic structures using serial sectional images.

Precise three-dimensional modeling and visualization of human anatomy and pathology are important in medicine. Three-dimensional models have applications in the training of medical students and residents and aid physicians evaluate and determine appropriate clinical management of patients. Three-dimensional reconstructions of radiographic images have been available for some time now. However, electronic reconstruction of these images often requires the utilization of large computer systems or workstations and also requires highly trained and specialized technicians to perform the task. This paper presents a technique for precise three-dimensional reconstruction of the human anatomy and pathology using an 80486 IBM compatible personal computer and commercially available software. We reconstructed the images from computed tomography scans. Implementation of this technique does not require extensive training and shows good results after a short learning curve.

Experience with macroscopic vasectomy reversal at the Medical College of Wisconsin.

Thirty-two men underwent vasectomy reversal using loupe magnification at the Medical College of Wisconsin between 1984 and 1991. Semen analysis and pregnancy data were available for 27 of them, and sperm were present in the ejaculate of 24, representing a patency rate of 89%. Pregnancy was established by 11, for a pregnancy rate of 41%. These results suggest that vasovasostomy using loupe magnification provides acceptable rates of patency and pregnancy, although the pregnancy rate appears to be somewhat lower than that reported for microsurgical repair. The lower cost of macroscopic vasectomy reversal may outweigh the potential statistical advantages for some couples.

PIP: 32 men underwent vasectomy reversal using 2.0x to 4.0x loupe magnification at the Medical College of Wisconsin between 1984 and 1991. The mean patient age was 36 years. The mean interval from vasectomy to reversal was 6.4 years (range 1 to 18 years). All procedures were performed on an outpatient basis, using local anesthesia with intravenous sedation. Anastomoses were completed using a modification of the technique described by Middleton. A semen analysis was obtained 1 to 3 months postoperatively. The medical record of each patient was reviewed to determine data for semen quality. Patients were contacted by telephone to determine pregnancy status as of July 1993. Semen analysis and pregnancy data were available for 27 of the 32 men (84%) who underwent vasectomy reversal between 1984 and 1991. Sperm were present in the ejaculate of 24 men, representing a patency rate of 89%. 11 men (41%) established pregnancies during the study interval. A complete semen analysis including sperm count, percent motility, and morphology was performed in 23 patients. Semen quality was determined according to World Health Organization standards for normal. 5 men (22%) had normal postoperative semen quality in all 3 parameters. 15 (65%) men were subfertile in one or more parameters. Three patients (13%) had no sperm present in the ejaculate. Regarding pregnancy according to semen quality, 60% (3 of 5) of the men with normal postoperative semen analyses established a pregnancy, while 40% (6 of 15) of the patients with subfertile semen quality produced pregnancies. Vasovasostomy using loupe magnification provides acceptable rates of patency and pregnancy as compared to microsurgical repair, although the pregnancy rate appears to be slightly better with microsurgery. Because of the potential cost benefits to both the patient and the surgeon, the relatively simple macroscopic vasovasostomy will continue to play a role in the management of postvasectomy male infertility.

Polycystic renal disease.

Renal cystic disease is a relatively common disorder whose development and progression currently appear to be due to an interaction between an abnormal basement membrane matrix, a potentially immature, hyperproliferative epithelium, and an abnormal epithelial secretory apparatus. RCC risk in cystic kidneys is the most controversial sequela of PKD. Currently, RCC risk in ESRD patients appears to be close to that present in the general population and only coincidentally associated with renal cysts. Screening of all ESRD patients for RCC and prophylactic native nephrectomy in dialysis and transplant patients does not seem to be indicated.

Quantitation of potentially undiagnosed incidental carcinoma of the prostate in patients treated non-surgically for benign prostatic hyperplasia.

Prostatectomy is the standard treatment for benign prostatic hyperplasia (BPH) and non-surgical treatment of prostatism would reduce the detection of Stage A prostate cancer. We wished to identify the number of potentially undiagnosed cancers resulting if non-surgical therapy were used to treat a presenting complaint of BPH. We also sought to identify the age group which would most clearly benefit from treatment of Stage A prostate cancer. Our series of transurethral prostatectomy specimens showed 92/996 patients (9.2%) positive for incidental carcinoma; 26/92 patients (28%) received further treatment and 25 of the 26 patients had Stage A2 disease. After evaluating life-tables and survival data on untreated A2 disease, the population aged < or = 72 years had a relative benefit of treatment ratio > 1.0, i.e. had a greater likelihood of dying from prostate cancer than from natural causes; 17/616 (2.8%) of the population aged < 72 years had their A2 disease treated and would have potentially been denied early cancer treatment if non-surgical management of BPH had been employed. The above figures assume 100% non-surgical treatment of BPH and no screening for prostate cancer pre-treatment. Stage A2 patients in this study demonstrated no significant difference in cause-specific survival rates between treated and untreated study groups (both 0%) or between treated study patients and untreated historical patients. Treated A2 patients demonstrated a significantly lower 5-year progression rate (0 vs 32%) relative to untreated patients reported in the literature, and a trend toward a significantly lower progression rate (0 vs 25%) relative to untreated study patients.

Influence of transforming growth factor beta 1 and other growth factors on basic fibroblast growth factor level and proliferation of cultured human prostate-derived fibroblasts.

Basic fibroblast growth factor (bFGF) has been identified in the human prostate. The level of bFGF has been reported to be elevated in benign prostatic hyperplasia (BPH), compared with normal prostate, suggesting that the growth factor may play a role in this disease of the prostate. Basic FGF is a mitogen for cultured human prostate-derived fibroblasts (PF). PF also synthesize bFGF, suggesting that growth regulation of these cells may be under autocrine control. The current study was undertaken to identify factors that affect PF proliferation and bFGF expression. Transforming growth factor beta 1 (TGF-beta 1) inhibited PF proliferation. The inhibition by TGF-beta 1 was partially overcome by bFGF but not by epidermal growth factor (EGF), platelet-derived growth factor (PDGF), insulin-like growth factor type 1 (IGF-1), or insulin. Incubation of PF with TGF-beta 1 increased bFGF mRNA and immunoreactive bFGF levels in a dose- and time-dependent fashion. None of the other growth factor studies affected bFGF levels. PF were also found to express TGF-beta 1 mRNA, the level of which was increased two- to fivefold by TGF-beta 1. These observations suggest that PF proliferation is controlled by the interaction of two different growth factors. It is possible that bFGF/TGF-beta imbalance in favor of cell proliferation promotes prostatic stromal hyperplasia.

Color Doppler sonography in the evaluation of the adult acute scrotum.

Color Doppler sonography (CDS) was used to evaluate 35 adult males with acute scrotal discomfort. Correlative nuclear scintigraphy was performed in 15 patients. Surgical correlation was available in 10 patients with clinical follow-up in the remaining 25. The complete absence of intratesticular color flow was used as our criterion for testicular ischemia. This was found to be 100% sensitive and 100% specific in 8 patients with surgically confirmed testicular ischemia. Spontaneous detorsion was noted in one patient with hyperemia demonstrated by color imaging. Increased color flow was found in 20 patients with the clinical impression of scrotal inflammation. Nuclear scintigraphy and color Doppler imaging had 100% agreement in 15 patients. Color Doppler sonography is a useful and highly accurate diagnostic method in the evaluation of patients with the acute scrotal syndrome. Color flow imaging is comparable to nuclear scintigraphy in the diagnosis of testicular ischemia.

Chromosomal defects in renal cell carcinoma.

Numerous chromosomal defects have been identified in hereditary and sporadic renal cell carcinoma (RCC) tumor cells. Current data indicate that visible, and/or submicroscopic lesions on the 3p are fundamental to RCC development; other chromosomal abnormalities are identified less frequently and may be secondarily involved in RCC production in some cases. Oncogenesis may be initiated via inactivation of suppressor allele pairs, or through activation of oncogenes via translocation to areas of increased gene expression, migration to a chromosomal breakpoint, or gene amplification.

Color Doppler ultrasonography in the evaluation of the acute scrotum.

Color Doppler ultrasonography was used to assess 20 patients with the acute onset of scrotal pain. Patients were categorized into 3 groups according to the initial clinical impression of the examining physician: ischemia, inflammation or trauma. Color Doppler ultrasonography correctly predicted the need for surgery in 8 of 9 operated patients (89%) and correctly predicted the outcome in all 11 nonoperated patients (100%). The anatomical resolution possible, as well as information regarding blood flow made color Doppler ultrasonography a useful tool in the assessment of acute scrotal processes.

Chronic effects of focused electrohydraulic shock waves on renal function and hypertension.

The chronic effects of focused electrohydraulic shock waves were studied in a minipig model. Fifteen animals underwent a unilateral nephrectomy and compensatory renal hypertrophy was allowed to take place over a minimum of six months. Baseline studies were then carried out consisting of 1) serum creatinine, blood urea nitrogen, and plasma renin levels 2) intra-arterial blood pressure measurement and 3) 3H-inulin clearance. Ten of the animals then underwent 8 shockwave treatments (2500 shocks per treatment), alternately to the upper and lower pole of the kidney, at two weeks intervals. A total of 20,000 shock waves were administered to each minipig over the four month period. The five control pigs underwent sham procedures. The renal function and blood pressure evaluations were then repeated. No significant decrease in renal function was noted in the experimental animals when compared to the controls. In addition, renin mediated hypertension was not observed despite the excessive number of total shock waves delivered to the kidney.

Development and testing of second generation extracorporeal shock-wave lithotriptor.

The Northgate SD-3 extracorporeal shock-wave lithotriptor is a second generation device that utilizes an ultrasound-guided computer-assisted system for calculus localization. Focused electrohydraulic shock waves are generated in a movable membrane-covered ellipsoidal reflector. Pressure wave characteristics and energy output of the SD-3 and the Dornier HM-3 were tested and found to be comparable. The ultrasound unit was capable of identifying radiolucent calculi as well as calculus fragments 2-3 mm in size. The computer-assisted aiming system was found to be accurate to within 1 mm. The overall successful calculus fragmentation rate using an animal model was 80 percent with an 87.5 percent rate following machine modifications resulting in increased energy output.

Renal transplantation in a child with primary oxalosis.

Primary hyperoxaluria (oxalosis) is an autosomal recessive disorder due to an inherited deficiency of the peroxisomal alanine:glyoxylate aminotransferase characterized by increased production and urinary excretion of oxalate and glycolate resulting in renal failure due to oxalate deposition. Because of the risk of continuing oxalate deposition in the transplanted kidney, oxalosis had been considered a contraindication for transplantation. A 5-year-old boy with oxalosis, maintained on peritoneal dialysis, received a haploidentical qiving-related transplant. The preoperative management included donor-specific transfusions and daily hemodialysis to remove a maximum amount of oxalate. The immunosuppression consisted of azathioprine and prednisone. Aggressive fluid management including noncalciuric diuretics (hydrochlorothiazide) kept urine output high. Pyridoxine, magnesium, neutral phosphate and sodium benzoate were used to prevent deposition of oxalate in the transplanted kidney. Two acute rejection episodes responded to steroid boluses. A kidney biopsy during the second rejection episode confirmed the diagnosis but also revealed oxalate deposits in the transplanted kidney. More than 4 years after transplantation, the patient has catch-up growth and his serum creatinine is 1.4 mg/dl. In conclusion, oxalosis is not an absolute contraindication to renal transplantation. Transplantation can be performed successfully utilizing living-related donor kidneys and aggressive medical management. The risks of deterioration of function and oxalate deposition in the transplant kidney are offset by improvement in quality of life.

Benign prostatic hyperplasia and growth factors.

A great deal of work has been accomplished in the attempt to determine the cause of benign prostatic hyperplasia (BPH). Early work by morphologists suggests that BPH starts as a stromal disease and that the hyperplastic stroma secretes a substance that stimulates the growth of epithelial cells. The quantitative morphometric data also suggest that BPH is primarily a stromal disease. Experimental embryology data have shown that the basic fibroblast growth factor, bFGF, is involved in early embryogenesis and is the primary inducer of mesodermal tissue. Work in mouse embryos has shown that a powerful inducer for prostatic epithelial growth is elaborated by the urogenital mesenchyme. Both of these findings fit the hypothesis that stromal hyperplasia may be initiated by a growth factor and that a second growth factor stimulates epithelial growth. Work in our laboratory has established that bFGF is the primary growth factor present in human BPH. We have also found that bFGF is synthesized by prostate fibroblasts and bFGF may be in higher concentration in the periurethral tissues of BPH. At this time, no definite link between growth factors and hyperplastic growth of the prostate has been established. However, circumstantial evidence has lead us to formulate several hypothesis regarding the role of growth factors in BPH. Hopefully, these hypothesis will be of some assistance in guiding future work on growth factors and BPH.

Juxtaglomerular cell tumor with elevation of serum erythropoietin.

Juxtaglomerular cell tumor of the kidney is an uncommon neoplastic cause of surgically curable hypertension. We report a case of erythrocytosis due to elevated serum erythropoietin with a renin secreting juxtaglomerular cell tumor.

Biliary lithotripsy. Determination of stone fragmentation success and potential tissue injury in swine.

Application of extracorporeal shock wave lithotripsy to gallbladder stones was studied in 37 adult female swine. Twenty-two sows underwent cholecystostomy with implantation of human gallstones. In 20 animals, after a 10-day recovery period, extracorporeal shock wave lithotripsy, 2000 shocks (an amount determined in preliminary water bath studies to be effective), was performed. In 10 of these implanted swine, frequent focal point refocusing and biplanar ultrasonography were employed. Two animals served as operative controls. Fifteen other animals without gallstone implantation were studied for adverse effects of extracorporeal shock wave lithotripsy on tissue. These animals (unimplanted) received 5000 shocks; 7 animals were killed 1 to 4 days after treatment and the others were killed after 4 weeks. Biochemical tests (total bilirubin, alkaline phosphatase, lipase, amylase, alanine aminotransferase, and lactate dehydrogenase determinations) were performed on all animals at entry and every second or third day until they were killed. Successful fragmentation, defined as all residual gallstone fragments being less than or equal to 4 mm in greatest dimension, was achieved in 14 of 20 animals overall, but in 10 of 10 animals in which focal point refocusing had been used. Slight perivascular hemorrhage and minimal coagulation necrosis were seen histologically only in the liver parenchyma adjacent to the gallbladder bed. The remainder of the liver was grossly and histologically normal. No injuries to the colon, duodenum, common bile duct, or pancreas were observed. No alterations suggesting injury or altered function occurred in any of the biochemical tests.

Electrohydraulic shock wave induced renal injury.

The pathological effects of focused electrohydraulic shock waves on renal parenchyma were studied using a porcine model. Testing was carried out using the Northgate SD-3 and Dornier HM-3 shock wave lithotripters. Pigs received 3,000, 5,000 or 6,000 shocks at energy levels equivalent to 18 to 20 KV on the Dornier HM-3. The animals were sacrificed one or four weeks post treatment and evaluated for renal injury. Kidneys were serially sectioned and injury volume calculations carried out. The predominant injury pattern was interstitial and perivascular fibrosis with chronic lymphoid infiltration. Dense areas of fibrosis ranged from less than 0.01% to 0.13% and from less than 0.01% to 1.04% of renal volume in those kidneys treated on the SD-3 and HM-3 respectively. Surrounding areas of perivascular and interstitial fibrosis intercalated with areas of normal appearing parenchyma were noted and were more extensive than the central scar. While the calculated volumes of parenchymal scarring are probably insignificant with respect to renal function, the surrounding areas of partial injury may be related to the development of hypertension.

Cultured human prostate-derived fibroblasts produce a factor that stimulates their growth with properties indistinguishable from basic fibroblast growth factor.

Fibrostromal proliferation is believed to be important in the development of benign prostatic hyperplasia (BPH). We found that a mitogen for cultured mesodermal-derived cells was present in extracts of BPH tissue. The mitogen was identified as basic fibroblast growth factor (bFGF). Previous studies did not determine the cell population(s) responsible for bFGF production in the prostate. This information is important to the understanding of the role of bFGF in the etiology of BPH. Human prostate-derived fibroblasts (PF) were initiated in culture. Recombinant bFGF and PF lysates stimulated tritiated thymidine uptake by quiescent PF cells. Greater than 90% of the mitogen in PF lysates bound to heparin-Sepharose and had the same elution profile and apparent molecular weight as bFGF isolated from BPH tissue. The growth factor in PF lysates competed with recombinant iodinated bFGF for binding to antiserum to (1-24)bFGF. Cultured PF incorporated 35S-methionine into protein that was precipitated by antiserum to bFGF. The apparent molecular weight of the radiolabeled protein, about 17,000, was similar to authentic bFGF. The observations are consistent with the interpretation that cultured PF synthesize a growth factor that stimulates their growth with properties that are indistinguishable from bFGF.

A growth factor in bovine and human testes structurally related to basic fibroblast growth factor.

Homogenates of human testes, epididymides and prostate, and calf testes and epididymides are mitogenic for cultured human foreskin fibroblasts. The growth factors appear similar in that they are inactivated by boiling and acid, but not by treatment with reducing agent. The growth factor in human and bovine testes was partially purified from tissue homogenates, prepared in high ionic strength buffer (pH 7.6) containing protease inhibitors, by ammonium sulfate precipitation and two cycles of heparin-Sepharose chromatography. The growth factor in calf testes was also partially purified from tissue extracted in ammonium sulfate without protease inhibitors, acidified to pH 4.5, and precipitated by ammonium sulfate followed by two cycles of heparin-affinity chromatography. A predominant 17,500 molecular weight (MW) growth factor was identified from alkaline homogenates of human and calf testes by its reactivity with antisera prepared against synthetic peptides whose sequences corresponded to residues 1-12 (amino-terminal), 33-43 (internal) and 136-145 (carboxy-terminal) of bovine basic fibroblast growth factor (bFGF). A slightly smaller 16,600 MW peptide from acidic extracts of calf testes also reacted with antisera to the three synthetic peptides. A 15,500 MW peptide, lacking immunoreactivity with antiserum to the amino-terminal synthetic peptide, was also seen. These findings suggest that a growth factor is present in human and calf testes that is structurally related to bFGF. The structure of the growth factors appears to be altered during the isolation procedure.