Elie A. Benaim

Alpha-blockade downregulates myosin heavy chain gene expression in human benign prostatic hyperplasia

OBJECTIVES Smooth muscle (SM), a major component of prostate stroma, plays an important role in the pathogenesis of benign prostatic hyperplasia. In many muscle systems, steroid hormones and alpha(1)-adrenergic neurotransmitters tightly regulate expression of contractile proteins. In this study, SM content and the expression of myosin heavy chain (MHC) in tissues from patients with benign prostatic hyperplasia treated with androgen ablation or alpha-blockade were compared with untreated controls. METHODS Prostatic periurethral tissue specimens from patients receiving luteinizing hormone-releasing hormone analogues (n = 12), alpha-blocking agents (n = 12), and no treatment (n = 13) were examined. The samples were analyzed for SM MHC mRNA expression using competitive reverse transcription-polymerase chain reaction. SM content was measured by morphometric analysis of trichrome-stained sections. RESULTS Stromal SM constituted 45.4% +/- 8.6%, 48.1% +/- 18.4%, and 45.9% +/- 10.8% of the total tissue in androgen ablated, alpha-blocked, and untreated tissues, respectively. No significant difference was observed among these three groups (P = 0.84, analysis of variance). However, SM MHC mRNA expression was markedly decreased in the alpha-blockade group (0.15 +/- 0.02 attomole/mg tissue) compared with the androgen-ablated (0.58 +/- 0.15 attomole/mg tissue) or control (0.44 +/- 0.10 attomole/mg tissue) groups. The relationship between SM content and expression of SM MHC significantly differed among the groups (P = 0.02, analysis of variance). CONCLUSIONS Androgen ablation and alpha-blockade do not appear to alter the histologic characteristics of prostate stroma in men with symptomatic benign prostatic hyperplasia. However, contractile protein gene expression in stromal SM cells is significantly altered after alpha-blockade. These data suggest that, in addition to the simple relaxation of muscle tone, alpha-blocking agents may affect the phenotypic expression of contractile proteins in prostate SM cells.

Characterization of prostate size, PSA and endocrine profiles in patients with spinal cord injuries

Aims of this study: From cross-sectional and longitudinal population based studies as well as from autopsy studies it is well documented that total prostate volume increases with advancing age. However, it is not well known (1) which factors are ultimately responsible for this growth phenomenon; or (2) at what time in a persons life the growth tends to occur. At present at least a permissive role for testicular androgens is assumed to be involved in growth regulation. Other factors such as growth factors, epithelial-mesenchymal interaction, and the role of intact neural pathways are still poorly understood. We aimed to study a group of men with spinal cord injuries to determine whether the pattern of prostate enlargement would be different in men with partially or completely interrupted innervation of the pelvis and the prostate gland.Materials and methods: Forty-three men from the Spinal Cord Injury (SCI) Service at the VA North Texas Health Care System ranging in age from 27–73 y (mean 51 y) were recruited to participate in this study. Time since SCI ranged from 2–47 (mean 19 y). All patients underwent standardized questionnaire, physical examination, transrectal ultrasonography (TRUS) measurements of total and transition zone volume of the prostate, serum PSA, testosterone (T), dihydrotestosterone (DHT), FSH and LH measurements, some had TRUS guided biopsies taken.Results: By all the measured criteria there were no abnormalities regarding the pituitary-gonadal axis observed in these men. Testicular volume, serum T, DHT and LH were within normal ranges, and when the patients were stratified by age, no differences were identified. There was an age related increase in FSH which has been described in neurologically intact men. Serum PSA increased slightly with advancing age. While total (TPV) and transition zone (TZV) prostate volume increased with age, the groupwise differences by decades of life were not significant. Moreover, when compared to a group of community dwelling men without known prostatic diseases and a clinic cohort of men with BPH, TPV was substantially lower for each decade of life except for men in their 40s, while TZV was substantially lower for men in their 60s.Conclusions: We observed normal age related changes regarding serum PSA and serum FSH without significant changes in other hormonal parameters. All parameters behaved consistent with changes described in neurologically intact populations. However, we did not observe the typical increase in TPV and TZV of the prostate as seen in population, autopsy and clinic patient studies. This interesting finding indicates that factors other than an intact pituitary-gonadal axis and male steroid hormones may be responsible for the normal age related growth of the prostate. Further studies in larger cohorts are needed to corroborate our findings.

Change in prostate specific antigen following androgen stimulation is an independent predictor of prostate cancer diagnosis.

PURPOSE We tested the hypothesis that a single exogenous androgen injection in men with low prostate specific antigen would provoke a differential prostate specific antigen response that would correlate with the presence and volume of cancer at biopsy. MATERIALS AND METHODS Following institutional review board approval 40 men with prostate specific antigen between 2.5 and 4.0 ng/ml were given 1 intramuscular injection of 400 mg testosterone cypionate at the start of the study. Prostate specific antigen and early morning serum testosterone were measured at baseline, 48 hours, and weeks 1, 2 and 4. All men underwent 12-core transrectal ultrasound guided biopsy at week 4. RESULTS Of the 40 men 18 (45%) were diagnosed with prostate cancer. The mean change in prostate specific antigen from baseline to 4 weeks was 3.1 to 3.4 ng/ml (9.7%) in men found to have benign findings on biopsy compared to a mean increase of 2.9 to 3.8 ng/ml (29%) in those with prostate cancer (p = 0.006). The change in prostate specific antigen following androgen stimulation was significantly associated with the percent of tissue involved with cancer and it was an independent predictor of cancer diagnosis on univariate and multivariate analysis. CONCLUSIONS An increase in prostate specific antigen following androgen stimulation in men with prostate specific antigen between 2.5 and 4.0 ng/ml was highly predictive of the subsequent diagnosis of prostate cancer and it correlated with disease volume. If these findings are corroborated, prostate specific antigen provocation may become an important strategy to identify men at risk for harboring prostate cancer and minimize the number undergoing unnecessary biopsies.

Intraluminal crystalloids are highly associated with prostatic adenocarcinoma on concurrent biopsy specimens

Prostatic crystalloids are intraluminal eosinophilic structures with variable size and shape. Their presence has been described in conjunction with the occurrence of prostatic adenocarcinoma (pCA). We herein report the association of crystalloids and pCA in a prospective trial utilizing an extended multi-site transrectal ultrasound-guided (TRUS) prostate biopsy protocol. Three hundred and forty-four consecutive patients were prospectively enrolled at the Dallas Veterans Administration Hospital from November 2002 to September 2003. Indications for biopsy included a prostate-specific antigen (PSA) ⩾4 ng/ml and/or abnormal digital rectal exam. A single pathologist evaluated all biopsy cores and documented the presence or absence of significant histopathologic features. Univariate and multivariate logistic regression analysis were applied to test the association of these features with the presence of pCA on concurrent biopsy. Median number of core biopsies per patient was 12 (range 3–36). Overall cancer detection rate was 42.7%. pCA was diagnosed in 66 (81.5%) of 81 patients with crystalloids, 70 (69.3%) of 101 patients with high-grade prostatic intraepithelial neoplasia (HGPIN), and 32 (84.2%) of 38 patients with both HGPIN and crystalloids on biopsy. Multivariate analysis identified crystalloids (RR 4.53, 95% CI 2.30–8.88) and HGPIN (RR 3.20, 95% CI 1.84–5.57) as independent predictors of the presence of cancer on concurrent biopsy (P<0.001). In this prospective analysis, crystalloids were significantly associated with pCA on concurrent biopsy and more predictive of the presence of pCA than HGPIN. These findings suggest that the presence of crystalloids alone or in combination with HGPIN in prostate biopsies may be a more compelling indication for repeat biopsy than HGPIN alone.