Herbert Lepor

The Relative Proportion of Stromal and Epithelial Hyperplasia is Related to the Development of Symptomatic Benign Prostate Hyperplasia

The specific features of the prostate adenoma predisposing to the development of symptomatic benign prostatic hyperplasia (BPH) are unknown. Our objective was to determine whether the histological composition of the prostate adenoma is related to the development of symptomatic BPH. Prostate adenomas were obtained from men with asymptomatic BPH undergoing cystoprostatectomy for invasive transitional cell carcinoma, and from men with symptomatic BPH undergoing open prostatectomy, transurethral resection of the prostate and pharmacotherapy. The severity of bladder outlet obstruction was evaluated with the Boyarsky symptom score and uroflowmetry. The percentages of stroma, epithelium and glandular lumen were determined in the prostate adenomas via quantitative image analysis on a computer-assisted morphometry system. The prostate adenomas from the 33 men with symptomatic BPH contained 62 +/- 1%, 15 +/- 1% and 23 +/- 1 of stroma, epithelium and glandular lumen, respectively. The prostate adenomas from 6 men with asymptomatic disease contained 54 +/- 1%, 21 +/- 1% and 25 +/- 1% of stroma, epithelium and glandular lumen, respectively. The ratios of stromal-to-epithelial hyperplasia in the prostate adenomas from men with symptomatic and asymptomatic disease were 4.6 +/- 0.3 and 2.7 +/- 0.1, respectively. The differences in percentage of stroma and epithelium, and the stromal-to-epithelial ratio in the prostate adenomas from men with symptomatic and asymptomatic BPH were statistically significant. Our study suggests that the histological composition of the prostate adenoma is related to the development of symptomatic BPH.

Autonomic receptors in human prostate adenomas.

Radioligand receptor binding techniques were used to characterize alpha 1 adrenergic, alpha 2 adrenergic and muscarinic cholinergic (MCh) binding sites in human prostate adenomas obtained from men with symptomatic and asymptomatic benign prostatic hyperplasia (BPH). Prostate adenoma specimens were obtained from nine men with asymptomatic BPH undergoing cystoprostatectomy, 11 men with symptomatic BPH undergoing open prostatectomy, and 11 men with symptomatic BPH undergoing transurethral resection of the prostate (TURP). A quantitative symptoms score analysis and urinary flow rate determinations documented the absence of bladder outlet obstruction in men undergoing cystoprostatectomy and confirmed the presence of bladder outlet obstruction in men undergoing prostatectomy. The mean equilibrium dissociation constants (Kd) and the mean densities of 125I-Heat (alpha 1 adrenergic) and 3H-NMS (MCh) binding sites were similar in tissue homogenates obtained from men with asymptomatic and symptomatic BPH. The mean Kd of 3H-Rauwolscine (3H-Ra) was significantly greater in the prostatectomy specimens obtained from men with symptomatic BPH compared to the specimens obtained from men with asymptomatic BPH (p less than 0.05). The density of 3H-Ra (alpha 2 adrenergic) binding sites was significantly greater in the prostate adenomas obtained from men with symptomatic BPH compared to the prostate adenomas obtained from men with asymptomatic BPH (p less than 0.05). The difference in alpha 2 adrenoceptor density was accounted for by an increased receptor density in the open prostatectomy specimens. There was no significant correlation between alpha 2 adrenergic, alpha 1 adrenergic, and MCh receptor densities and prostate weight or patient age. This study indicates that the development of infravesical obstruction in men with BPH is not related to upregulation or altered binding affinity of alpha 1 adrenergic or MCh receptor binding sites. The significance of the observed upregulation of alpha 2 adrenoreceptors in the prostate adenomas obtained from men undergoing open prostatectomy is unknown, and requires further investigation.

Alpha 1 adrenergic receptors in canine lower genitourinary tissues: insight into development and function.

Radioligand receptor binding methods were used to characterize the alpha 1-adrenergic receptor in the bladder body, bladder base, prostate and urethra of the male dog. Saturation experiments were performed in tissue homogenates using [125iodine]-Heat, an alpha 1-adrenergic antagonist of high specific activity (2,200 Ci. per mmol.). The equilibrium dissociation constant Kd for [125iodine]-Heat binding in the bladder body (0.56 pM.), bladder base (0.81 +/- 0.11 pM.), prostate (0.86 +/- 0.19 pM.) and urethra (0.55 pM.) was similar, suggesting homogeneity of alpha 1-adrenergic binding sites in lower genitourinary tissues. The receptor density in the bladder body, bladder base, prostate and urethra, expressed as fmol. per mg. wet weight, was 0.22 +/- 0.02, 0.82 +/- 0.09, 0.55 +/- 0.06 and 0.27 +/- 0.06, respectively (mean +/- standard error of mean). Competitive binding experiments with [125iodine]-Heat and unlabeled prazosin and clonidine confirmed the selectivity of Heat for alpha 1-adrenergic binding sites. Anatomical dissections have revealed that a major component of the smooth muscle of the bladder base and prostate originates from the ureter, whereas a major component of the smooth muscle of the urethra originates from the bladder. The measured alpha 1-adrenergic receptor densities support these developmental theories.

Transrectal Ultrasonography in the Diagnosis and Staging of Carcinoma of the Prostate

Transrectal prostatic ultrasonography is a potentially valuable means to evaluate the prostate of men with suspected carcinoma. We studied 118 patients with this modality before histological evaluation of the prostate (20 underwent radical prostatectomy, 75 core needle biopsy and aspiration cytology, and 23 transurethral resection of the prostate). Transrectal ultrasonography was more efficient than digital rectal examination in the staging of carcinoma of the prostate before radical prostatectomy. The value of transrectal ultrasonography in the diagnosis of prostatic cancer in men with an abnormal-feeling prostate on digital rectal examination is less certain, since 10 of 75 patients (13 per cent) in this group had a falsely positive scan. The predictive value of a scan positive for malignancy was 37 per cent. Further refinements in the technique of transrectal prostatic ultrasonography are needed to realize fully the diagnostic potential of this imaging modality.

The alpha adrenergic binding properties of terazosin in the human prostate adenoma and canine brain.

Clinical trials are currently underway to evaluate the efficacy of terazosin for the treatment of symptomatic benign prostatic hyperplasia (BPH). Terazosin is a potent and selective alpha 1 adrenergic blocking agent structurally similar to prazosin. The alpha adrenergic binding properties of terazosin were studied in human prostate adenomas and canine brains using radioligand receptor binding methods. Saturation analyses were performed at varying concentrations of [125I]-Heat and [3H]rauwolscine [( 3H]Ra) in human prostate adenomas and canine brains. The binding of [125I]-Heat and [3H]Ra in the human prostates and canine brains was consistently saturable and of high affinity. The equilibrium dissociation constant (Kd) for [125I]-Heat binding in the canine brains and human prostate adenomas was 84.4 +/- 4.3 pM and 65.4 +/- 19.2 pM, respectively (p greater than 0.05). The (Kd) for [3H]Ra binding in the human prostate adenomas and canine brains was 1.21 +/- 0.23 nM and 1.52 +/- 0.28 nM, respectively (p greater than 0.05). The density of alpha 1 (0.37 +/- 0.15 fmol/mg. wet wt.) and alpha 2 (0.29 +/- 0.09 fmol/mg. wet wt. adrenergic binding sites in the human adenomas were similar (p greater than 0.05). The IC50 corrected (IC50 corr) of terazosin for [125I]-Heat and [3H]Ra binding sites in the human prostate was 2.5 nM and 1.0 micron., respectively. The IC50 corr of terazosin for [125I]-Heat and [3H]Ra binding sites in the canine brain was 2.0 nM and 0.8 microM, respectively. The competitive binding assays indicate that terazosin binds selectively to alpha 1 adrenergic binding sites in the human prostate and canine brain.

Muscarinic Cholinergic Receptors in Normal Pediatric and Myelodysplastic Bladberi

Radioligand receptor binding experiments and in vitro muscle contractile studies were performed to determine the binding and functional properties of detrusor muscarinic cholinergic receptors in control and myelodysplastic bladders. Control bladder tissue was obtained from 8 children with primary vesicoureteral reflux undergoing ureteral reimplantation and 1 child at the time of organ transplant harvesting. Bladder specimens also were obtained from 10 children with myelomeningocele undergoing augmentation cystoplasty. Preoperative cystograms revealed that all children with vesicoureteral reflux had a smooth-walled bladder with normal capacity, whereas those with myelomeningocele undergoing augmentation cystoplasty had a small capacity bladder with trabeculations. Experiments were performed on detrusor tissue obtained from the bladder body in all cases. Radioligand receptor binding experiments with the 3H-N-methylscopolamine revealed that the equilibrium dissociation constant in control and myelodysplastic bladders was 0.44 +/- 0.09 and 0.40 +/- 0.10 nM., respectively. The equilibrium dissociation constant was similar in control and myelodysplastic bladders. The muscarinic cholinergic receptor density (Bmax) in control and myelodysplastic bladders was 0.66 +/- 0.12 and 0.24 +/- 0.03 fmol. per micrograms, protein, respectively. The significantly lower density of muscarinic cholinergic receptors in the myelodysplastic bladders may be explained by either a down regulations or by the histologically observed development of fibrosis. Concentration response experiments were performed on 7 control and 6 myelodysplastic bladders using carbachol and potassium chloride. The carbachol and potassium chloride concentrations producing half of the maximal response were similar in the control and myelodysplastic bladders, suggesting that detrusor dysfunction in myelodysplasia is not associated with detrusor supersensitivity. The maximal response (Emax) for potassium chloride was less in the myelodysplastic bladders than in the control bladders but the carbachol Emax was not significantly different. Concentration inhibitory experiments with oxybutynin and imipramine demonstrated that the myelodysplastic and control bladders were identically inhibited by these antagonists. Radioligand receptor binding studies and in vitro contractile experiments indicate that the detrusor dysfunction associated with myelomeningocele is not mediated by changes in the binding or functional properties of detrusor muscarinic cholinergic receptors.

Identification and Characterization of Alpha1 Adrenergic Receptors in the Canine Prostate Using [125I]-Heat

We have recently utilized radioligand receptor binding methods to characterize muscarinic cholinergic and alpha adrenergic receptors in human prostate adenomas. The primary advantages of radioligand receptor binding methods are that neurotransmitter receptor density is quantitated, the affinity of unlabelled drugs for receptor sites is determined, and receptors can be localized using autoradiography on slide-mounted tissue sections. Recently, [125I]-Heat, a selective and high affinity ligand with high specific activity (2200 Ci/mmole) has been used to characterize alpha 1 adrenergic receptors in the brain. In this study alpha 1 adrenergic receptors in the dog prostate were characterized using [125I]-Heat. The Scatchard plots were linear indicating homogeneity of [125I]-Heat binding sites. The mean alpha 1 adrenergic receptor density determined from these Scatchard plots was 0.61 +/- 0.07 fmol/mg. wet wt. +/- S.E.M. The binding of [125I]-Heat to canine prostate alpha 1 adrenergic binding sites was of high affinity (Kd = 86 +/- 19 pM). Steady state conditions were reached following an incubation interval of 30 minutes and specific binding and tissue concentration were linear within the range of tissue concentrations assayed. The specificity of [125I]-Heat for alpha 1 adrenergic binding sites was confirmed by competitive displacement assays using unlabelled clonidine and prazosin. Retrospective analysis of the saturation experiments demonstrated that Bmax can be accurately calculated by determining specific [125I]-Heat binding at a single ligand concentration. [125I]-Heat is an ideal ligand for studying alpha 1 adrenergic receptors in the prostate and its favorable properties should facilitate the autoradiographic localization of alpha 1 adrenergic receptors in the prostate.

Muscarinic Cholinergic Receptors in the Normal and Neurogenic Human Bladder

Bladder dysfunction secondary to neurologic conditions occurs in all age groups and is associated with significant morbidity. The role of neuroreceptors in the development of detrusor dysfunction has not been studied previously. Control bladder tissue specimens were obtained from eight children with ureterovesical reflux undergoing ureteral reimplantation and 14 adults with bladder carcinoma undergoing cystectomy. Neurogenic bladder specimens were obtained from 10 children with myelomeningocele and five adults with neurogenic bladder dysfunction undergoing augmentation cystoplasty. Saturation experiments using 3H-N-methylscopolamine (3H-NMS) were performed in these control and neurogenic bladder homogenates. The mean equilibrium dissociation constants in the neurogenic and control bladders were 0.41 nM and 0.55 nM, respectively. The mean density of muscarinic cholinergic (MCh) receptor binding sites in the neurogenic and control bladders was 0.34 fmol/mg wet wt. and 0.65 fmol/mg. wet wt., respectively. Competitive binding experiments with 3H-NMS and various unlabelled MCh antagonists indicated that the pharmacology of MCh binding sites was similar in neurogenic and control bladders. Age was not significantly correlated with MCh receptor density in the control and neurogenic bladders. Muscarinic cholinergic binding sites are homogeneous in neurogenic and control bladders. The lower density of MCh receptors in the neurogenic bladders may represent down regulation of MCh receptors or a replacement of smooth muscle by fibrosis.

The stereospecificity of LY253352 for α1-adrenoceptor binding sites in the brain and prostate

1 The stereospecificity of the enantiomers of LY253352, a potent and selective α1‐adrenoceptor antagonist, were studied in the human prostate and canine brain using radioligand receptor binding methods. 2 The mean equilibrium dissociation constant (KD) in the canine brain and human prostatic adenoma was 84.4 pM and 65.4 pM, respectively. 3 The α1‐adrenoceptor density in the canine brain was approximately eight fold greater than in the human prostatic adenoma. 4 The mean Ki values of (−)‐LY253352 and (+)‐LY253352 in the prostate were 0.19 nM and 5.79 nM, respectively. 5 The mean Ki values of (−)‐LY253352 and (+)‐LY253352 in the brain were 0.29 nM and 34.7 nM, respectively. 6 This study indicates that the stereochemical specificity of the optical isomers of LY253352 is a manifestation of differential affinities of the enantiomers for α1‐adrenoceptor binding sites. 7 The differential affinities of (+)‐LY253352 in the brain and prostate are suggestive of subtle unique properties of adrenoceptor binding sites in these tissues.

Innovative Surgical Management of Idiopathic Retroperitoneal Fibrosis

Idiopathic retroperitoneal fibrosis is a rare entity usually treated with exploratory laparotomy, deep biopsies of the fibrotic process and uretrolysis. Innovative surgical management occasionally is required for ureteral obstruction. We report the use of dismembered pyeloplasty, autorenal transplantation and bilateral psoas hitch ureteral reimplantation for the management of ureteral obstruction associated with idiopathic retroperitoneal fibrosis.