[Interpretation of results of clinical trials in benign prostatic hyperplasia]. / Interpretación de resultados de ensayos clínicos en hiperplasia benigna prostática.

The random clinical trial (RCT) is the most suitable study to evaluate the treatment effectiveness in the benign prostatic hyperplasia (BPH). Although most of the urologists will not collaborate in a RCT development, they will treat BPH patients, so it is very important to know if a CRT in BPH is well designed and their conclusions are correct. The aim of this article is to give the basic elements of analysis that urologists need in order to evaluate the quality and the level of evidence of a RCT in BPH. This article emphasizes the three main elements of a RCT: to check if the study has been correctly performed (internal validity), to evaluate if the treatment achieves an important clinical improvement (relevance of the results) and the applicability of the results in our patients (external validity). The article shows that to analyse these elements common sense and clinical judgment are needed rather than statistical knowledge.

Interpretación de resultados de ensayos clínicos en hiperplasia benigna prostática / Interpretation of clinical trial results on benign prostatic hyperplasia

El ensayo clínico aleatorio (ECA) es el estudio más adecuado para evaluar la eficacia de un tratamiento en hiperplasia benigna de próstata (HBP). Aunque la mayoría de urólogos no colaborarán en el desarrollo de un ECA, sí que van a tratar pacientes afectos de HBP, por lo que tiene gran interés saber discernir si un trabajo sobre un ECA en HBP está bien diseñado y sus conclusiones son correctas. El objetivo de este artículo es proporcionar los elementos básicos de análisis que permitan a un urólogo evaluar la calidad y el grado de evidencia de un ECA en HBP. El trabajo gira entorno de los tres pilares básicos de cualquier ECA: comprobar si el estudio se ha realizado de forma correcta (validez interna), evaluar si el tratamiento consigue mejoría clínica importante (relevancia de los resultados) y la aplicabilidad de los resultados del estudio a nuestros pacientes (validez externa). Como se comprobará para analizar estos elementos no se requieren grandes conocimientos estadísticos sino el uso del juicio clínico y del sentido común (AU)

[Prevalence of prostatic intraepithelial neoplasia in Spain]. / Prevalencia de la neoplasia intraepitelial prostática en España.

OBJECTIVE: To study the prevalence of high grade prostatic intraepithelial neoplasia in a Spanish population and to compare it with the prevalence in Caucasians of other countries and Afro-Americans. METHODS: 162 prostates obtained at autopsy from Spanish men aged 20-80 years, were fixed in 10% formalin and slices perpendicular to the posterior margin were made every 3-4 mm along its entire length. All blocks were embedded in paraffin and examined microscopically. Mapping of focality and site of the high grade prostatic intraepithelial neoplasia was done for each case. The Wayne University autopsy study was used for comparison of the prevalence in other countries and races. RESULTS: 146 prostates from men with a mean age of 48.5 years were considered valid for histological analysis. There were 42 high grade prostatic intraepithelial neoplasia; 20 were focal and 22 multifocal. By age group, the prevalence of high grade prostatic intraepithelial neoplasia were 7.1%, 14.7%, 28.5%, 33.3%, 45.4% and 51.8% for the 3rd, 4th, 5th, 6th, 7th, and 8th decades. CONCLUSIONS: High grade prostatic intraepithelial neoplasia begins to manifest in the Spanish population after the 3rd decade. It is usually focal and peripheral, and significantly increases with age and becomes multifocal. Its prevalence in the Spanish population is moderately lower than in American Caucasians and significantly lower than in Afro-Americans.

[Morphologic course of prostatic hyperplasia]. / Evolución morfológica de la hiperplasia de próstata.

OBJECTIVE: To find a morphologic model of the development of prostate hyperplasia. METHODS: Study of the transitional zone in 60 patients (30 with infravesical obstruction, 30 with no obstructive symptoms) and quantification of the involved surface, number of pure stromal and glandular-stromal nodes, node area for each of them, and non-nodular area of the transitional zone, correlating each parameter to age based on clinical status. RESULTS: The greater transitional zone area is seen in patients with obstruction: 1376.83 +/- 408.17 mm2 vs 321.39 +/- 151.49 mm2 in asymptomatic patients, mainly due to a higher number of glandular-stromal nodes (17 vs 2.2) and their size, with a correlation to age (p = 0.03). Moderate increases of non-nodular areas are also found. CONCLUSIONS: These findings suggest that onset of prostate hyperplasia may be due to a consistent increase of the transitional area, and that in some patients, probably because of local factors, nodular development occurs as a result of both an increase in nodes number and size.

[Quality of life and symptomatology in benign prostate hyperplasia in active Spanish population]. / Calidad de vida y sintomatología en la hiperplasia prostática benigna en población activa española.

BACKGROUND: Due to the lack of existing data regarding urinary symptoms and quality of life secondary to benign prostate hyperplasia (BPH) in the active Spanish population, and with the objective to evaluate the QoL in patients with lower urinary tract symptoms suggestive of BPH, we decided to conduct a national study which included 2,312 men employed by the National Railway Association (RENFE). SUBJECTS AND METHODS: 14 cities were selected and clinical histories, physical examinations, IPSS-L questionnaires and prostate echographies were conducted following the diagnostic guidelines of the Third International Committee by the WHO. RESULTS: Almost 20% of the men participating in the study had moderate or severe symptoms according to the IPSS and almost 15% were unsatisfied with their urinary situation. 3 out of every 4 men between the age of 50-65 years with moderate-severe symptoms have their urinary quality of life affected. The most prevalent symptoms were: filling, nicturia in almost 60% of the subjects, and emptying, the force and flow of the urinary stream diminishing in one out of every 3 participants. CONCLUSIONS: With an increase in age there is a higher prevalence of symptoms as dimmed by the IPSS, a poorer urinary quality of life, and a larger prostate volume as measured by echography.

[Benign prostatic hyperplasia and evidence based medicine: its approach in clinical practice]. / Hiperplasia prostática benigna y medicina basada en la evidencia: su aproximación a la práctica clínica.

The contribution of evidence based medicine (EBM) methodology to the clinical practice of symptomatic benign prostatic hyperplasia (BPH) patients may be very helpful. Otherwise its development is incipient. BPH is still a high prevalent and far-reaching clinicopathologic entity. In the last few years, new drug and surgical therapies have emerged that have significantly changed BPH clinical management. In this article, the elements that make feasible the application of EBM to the clinical management of BPH patients are reviewed, with the aim of making this relation part of the vast extension of EBM in the different medical specialties. This objective is an answer to the double interest, on one hand, in defining the importance of this new concept of medical practice and, on the other hand, in making clinical practice suitable for solving the queries of a disease with such a variable influence in patient's welfare and quality of life. We therefore conclude that application of EBM methodology to BPH management is relevant and necessary.

Evolución morfológica de la hiperplasia de próstata / Morphologic evolution of prostate hyperplasia

OBJETIVO: Hallar un modelo morfológico del desarrollo de la hiperplasia prostática. MÉTODOS: Se estudia la zona de transición de 60 pacientes (30 con obstrucción infravesical, y otros 30 sin síntomas obstructivos), cuantificándose la superficie de dicha zona, el número de nódu-los estromales puros y glándulo-estromales, el área nodular de cada uno de ellos, y el área no nodu-lar de la zona de transición, correlacionando cada uno de estos parámetros con la edad, de acuerdo a la situación clínica. RESULTADOS: La mayor área de la zona de transición se observa en los pacientes obstruidos, que es de 1376,83 ñ 408,17 mm2 frente a los 321,39 ñ 151,49 mm2 en los asintomáticos, y, a expensas, sobre todo, al incremento del número de nódulos glándulo-estromales (17 vs 2.2), y de su tamaño, correlacionándose con la edad (p = 0,03). También hay un moderado incremento del área no nodular. CONCLUSIONES: Estos hallazgos sugieren que el inicio de la hiperplasia prostática puede ser un incremento homogéneo de la zona de transición, y que en algunos pacientes, probablemente por fac-tores locales, se produce el desarrollo nodular, preferentemente glándulo-estromal, tanto por el aumento del número de nódulos como de su tamaño (AU)

[Comparative population-based survey as evaluation method of prostate disease changes]. / Estudio poblacional comparativo mediante encuesta como método de evaluación de las modificaciones sobre la patología prostática.

A survey-based comparative study was conducted to evaluate the changes on the prostate pathology in two male populations separated by a time interval of two years (1st and 3rd Week of Prostate Health). A total of 2056 respondents in the 1st Week, and 2126 in the 3rd Week were evaluated. The questionnaire included questions relative to prostate awareness, impact of urinary complaints on daily like activities, Spanish validated IPSS and selective questions for prostate patients. The comparison between both surveys disclosed visits to the urologist at earlier age and longer-standing symptoms. The most prevalent symptoms continue to be decreased calibre of the urinary stream, pollakiuria and urgency. IPSS/L and IPSS/age ratios remained unchanged. There was increased number of visits by mildly symptomatic patients (IPSS < 8), increased periodical revisions, and in the number of patients seen and treated by the urologist. A significant approximation to the diagnostic testing criteria established by the WHO for BPH was demonstrated. The number of patients who received treatment raised and there was also a significant improvement in the outcome. Comparative populational studies could allow to assess changes in the awareness status of the prostate, changes in symptomatic levels and quality of life of the population requesting health care, as well as changes in the diagnostic and therapeutical schemes in patients suspected of having BPH.

Expression of basic fibroblast growth factor and its receptors FGFR1 and FGFR2 in human benign prostatic hyperplasia treated with finasteride.

BACKGROUND: The development of benign prostatic hyperplasia (BPH) is an androgen-dependent process which may be mediated by a number of locally produced growth factors. One of these, the basic fibroblast growth factor (bFGF or FGF2), has a mitogenic effect on prostatic stroma. High expression levels of bFGF have been reported in BPH. FGFR1 and FGFR2 receptors, that exhibit affinity for bFGF, have been identified in normal and hyperplastic prostate. Finasteride, a 5alpha-reductase inhibitor, is an effective drug in the treatment of BPH, inducing regressive changes in the prostate of treated patients, even though its mechanisms of action are not yet completely elucidated. This study was designed to assess the effects of finasteride on the expression levels of bFGF, FGFR1, and FGFR2 in patients with BPH. METHODS: The expression levels of bFGF, FGFR1, and FGFR2 in 9 patients with prostatic hyperplasia treated with finasteride were assessed by immunohistochemistry and reverse transcription-polymerase chain reaction (RT-PCR) analysis of mRNA expression and were compared with those of 9 control patients with untreated BPH. RESULTS: Immunohistochemistry showed strong bFGF immunoreactivity in the prostatic stroma of untreated patients, this being somewhat weaker in the epithelium. In treated patients, epithelial immunoreactivity was practically negative, and a considerable reduction in stromal immunoreactivity was seen. These findings were also confirmed by RT-PCR. FGFR1 showed a weak immunoreactivity in the stroma and in basal epithelial cells. FGFR1 showed a weak immunoreactivity in the stroma and in basal epithelial cells. FGFR2 exhibited strong stromal immunoreactivity, becoming weaker in the basal epithelium. No differences were seen in the expression of both receptors between the groups of treated and untreated patients. CONCLUSIONS: A marked reduction in bFGF levels is seen in BPH treated with finasteride in comparison to untreated BPH. In our opinion, finasteride may act as a negative regulator of bFGF expression, counteracting the role of bFGF in the development of BPH.

In vivo proton magnetic resonance spectroscopy of diseased prostate: spectroscopic features of malignant versus benign pathology.

In vivo Proton Magnetic Resonance Spectroscopy appears potentially useful for non-invasive discrimination between benign prostatic hyperplasia (BPH) and prostate carcinoma (PC). Aiming to delimit the range within which spectra from one or the other pathology should occur, and establish extreme spectroscopic features of malignant versus benign prostate disease, we performed endorectal proton MR spectroscopy on 20 patients severely affected of either benign prostatic hyperplasia (BPH) (n = 10) or prostate cancer (PC) (n = 10). They were selected on the basis of the large volume and homogeneity of their lesions, which were histologically confirmed after spectroscopy. Consequently, high-quality short-TE proton spectra with well-resolved metabolite signals, and practically free of volume averaging issues were obtained in all cases. Apart from the typical citrate, creatine, and choline signals of prostate spectra, both BPH and PC spectra showed a peak centered at 3.6 ppm which was assigned to myo-inositol. The intensity of this contribution was found significantly increased in PC cases compared to BPH. Possible relationships between neoplastic transformation and the metabolic pathways in which myo-inositol participates are discussed. Average spectroscopic profiles were calculated for both advanced pathologies, and showed obvious differentiated features. In quantitative terms, the ratio of citrate to choline peak areas as well as that of creatine to myo-inositol appeared as the most convenient to discriminate between advanced PC cases (both ratios below 1.0) and advanced BPH cases (both ratios above 1.0).

Gains of the relative genomic content of erbB-1 and erbB-2 in prostate carcinoma and their association with metastasis.

Prostate carcinoma (PC) is the second leading cause of cancer death in men in the western world. Although the role of oncogenes and growth factors in prostate carcinoma is still unclear, overexpression of the epidermal growth factor receptor (erbB-1) and the proto-oncogene erbB-2 have been reported in prostate tumors, and erbB-2 related to poor prognosis and distant metastasis. Recent allelotyping studies in prostate cancer have shown chromosomal gains in 7p and 17q, regions where erbB-1 and erbB-2 are localized respectively, although no direct evidence of an increased gene copy number of either erbB-1 or erbB-2 has been reported. To address this question, we analyzed 20 benign prostatic hyperplasia (BPH) samples and 36 samples of metastatic and non-metastatic PC by means of semiquantitative PCR. Thus, 64% (11/17) and 52% (10/19) of metastatic and non-metastatic tumors respectively showed gains of the relative genomic content of erbB-1 and an association of erbB-1 with prostate cancer but not with metastasis. Additionally, 41% (7/17) of metastatic samples showed gains of erbB-2 genomic content, suggesting an association of erbB-2 with metastasis and poor prognosis (p<0.005). No gains of erbB-1 or erbB-2 genomic content were detected in the BPH samples.

Regressive changes in finasteride-treated human hyperplastic prostates correlate with an upregulation of TGF-beta receptor expression.

BACKGROUND: Prostatic atrophy has been documented histologically as a consequence of finasteride action on human hyperplastic prostates. An increase in apoptotic rates has also been reported in androgen-deprived hyperplastic prostates. Transforming growth factor beta (TGF-beta) signaling is implicated in apoptotic cell death. TGF-betas have been detected in normal and diseased human prostate. In the normal prostate, TGF-beta acts as a predominantly negative growth regulator. TGF-beta signaling receptors TbetaRI and TbetaRII have been shown to be negatively regulated by androgens. METHODS: We studied the histological changes in 9 selected finasteride-treated patients with benign prostatic hyperplasia (BPH), and analyzed the levels of expression and localization of TGF-beta receptor types TbetaRI and TbetaRII in these patients as compared to selected BPH controls. RESULTS: The prostatic epithelial compartment seemed to be a primary target site for finasteride action, since we observed moderate to severe glandular atrophy after 4-6 months of treatment. TGF-beta receptors were upregulated in treated cases. We assessed a twofold increase in TbetaRII mRNA levels in treated cases as compared to controls. An increase in both TbetaRI and TbetaRII at the protein level by immunostaining was observed, which also provided a helpful means for detecting glands undergoing regression. CONCLUSIONS: We conclude that finasteride may modulate the TGF-beta signaling system to promote changes leading to apoptosis of epithelial cells and prostatic glandular atrophy.

Over-expression of epidermal growth factor receptor and c-erbB2/neu but not of int-2 genes in benign prostatic hyperplasia by means of semi-quantitative PCR.

It is well established that activation of cellular genes may trigger uncontrolled cell growth and cancer development. Previous reports suggest that the epidermal growth factor receptor (EGFr), c-erbB2/neu and int-2, fibroblast growth factor-3, may be implicated in the development of benign prostatic hyperplasia (BPH). Using the polymerase chain reaction technique, we have assessed the amplification and expression of these molecular markers in 30 prostate samples from patients with BPH as well as from 5 normal donors. We detected mRNA over-expression of EGFr and c-erbB2/neu in 36% and 63%, respectively, of the BPH samples, but no gene amplification was found. No amplification or over-expression of int-2 was detected in any of the samples analyzed, suggesting that int-2 is not involved in BPH. Our results thus suggest a role for EGFr and c-erbB2/neu but not for int-2 in the development of BPH.

Androgen-independent basal cell re-epithelialization, c-erbB-2 mRNA expression and androgen-dependent EGFr mRNA expression in benign prostatic hyperplasia explant cultures treated with finasteride.

We have analyzed the effects of the 5alpha-reductase inhibitor, finasteride (MK906), on the mRNA expression of the epidermal growth factor receptor and c-erbB-2 genes, in benign prostatic hyperplasia explant cultures treated with testosterone and with testosterone plus finasteride. A decrease of the epithelial cell content and an androgen-independent basal cell re-epithelialization was observed during the first 10 days of culture, suggesting a role of basal cells as stem cells involved in androgen-independent epithelial regeneration. Using a semi-quantitative reverse transcription polymerase chain reaction technique, we observed a significant decrease in expression of the epidermal growth factor receptor in the cultures treated with finasteride whereas no effect of finasteride on c-erbB-2 transcription was detected, although the expression of both genes was increased by dihydrotestosterone.

Prevalence of benign prostatic hyperplasia in Spanish men 40 years old or older.

PURPOSE: We estimate the prevalence of benign prostatic hyperplasia (BPH) according to symptoms as well as prostate obstruction determined by uroflowmetry and prostate size. MATERIALS AND METHODS: A cross-sectional study was performed at the autonomous community of Andalusia in 1,106 men 40 years old or older. The International Prostate Symptom Score (I-PSS) questionnaire was used to establish symptoms, abdominal and transrectal ultrasonography was done to measure prostate size and uroflowmetry was performed to measure urinary flow obstruction. RESULTS: The prevalence of moderate or severe symptoms was 24.94% and it increased with age. Of the 1,106 subjects 4.19% had severe prostatism, while 12.45% had poor quality of life (I-PSS greater than 3). Average prostate size was greater than 30 gm. in men 60 years old or older. Maximum urine flow was less than 10 and 15 ml. per second in 25.97 and 55.67% of the men, respectively. The prevalence of BPH, defined as I-PSS greater than 7, maximum flow less than 15 ml. per second and prostate size greater than 30 gm., was 11.77% (range 0.75 to 30 at ages 40 to 49 and greater than 70 years, respectively). CONCLUSIONS: The prevalence of BPH increases with age. Moderate prostatism is perceived as resulting in poor quality of life by young subjects and good quality of life by some older subjects. In some men there were symptoms and obstruction but no prostate enlargement. This percentage persists with age after 50 years, when the prevalence of BPH starts to increase.

[Relationship of prostatic carcinoma of the peripheral zone with glandular atrophy and prostatic intraepithelial neoplasia]. / Relación del carcinoma prostático de la zona periférica con la atrofia glandular y la neoplasia intraepitelial prostática.

The study of the prostate's peripheral area in 32 patients, with age ranging between 48 to 75 years (mean, 61.4 +/- 6.7), demonstrates the frequency of certain morphological changes such as glandular atrophy (46.8%), which are neither related to age (p = 0.8) or the carcinoma (p = 0.8). A very different issue is the prostatic intraepithelial neoplasia, which although not statistically related to age in this series (p = 0.3) (probably due to the absence of young adults), appears to develop in earlier stages than cancer, is associated in 88.8% carcinomas (p = 0.03) and has a close topographic correlation to latent microscopic foci of adenocarcinoma of the prostate's peripheral area, anatomic proximity of both lesions occurring in 55.5% cases.

[Primary care physicians and prostatic disease. National survey. Members of the Spanish Council of Prostatic Health]. / Los médicos de atención primaria y la patología prostática. Encuesta nacional. Miembros del Consejo Español de Salud Prostática.

The paper presents the results of a survey distributed to 15,000 primary care physicians (PCP) asking about their management of prostate conditions. From the 3.265 surveys completed, the following information was obtained. The number of visits for "prostatism" is low, 3.92 + 3.99 per week. Most PCPs inquired for symptoms related to prostate conditions regardless the initial reason for the visit. 95% refer the patient directly to the urologist, either with no further investigation or after a diagnostic evaluation or initial therapy. Vegetable extracts are the pharmacological group most commonly used by PCPs. They would accept to monitor the patient's evolution, after diagnosis and treatment by the urologist, and always with the specialist's regular supervision. Most show little sensitivity toward prostatic conditions and are aware of slight of null urological education received during their graduation. They are by a majority also ready for a retraining in urology permitting them one active participation in this pathology.

[The urologist and prostatic disease. National survey. Members of the Spanish Council of Prostatic Health]. / El urólogo y la patología prostática. Encuesta nacional. Miembros del Consejo Español de la Salud Prostática.

Analysis of the results of a survey answered by 290 urologists on their relationship with primary care physicians (PCP), as well as the diagnostic and therapeutical approach to "prostatism". According to urologists, the PCPs attitude towards these patients shows a low profile, and they lack the necessary urological training to undertake diagnosis and treatment. With regard to the urological diagnostic approach, it is surprising that 73% of urologists who work outside the hospital milieu, usually do not perform digital examination. Likewise, urography is initially requested by 47.9% of the respondents. The symptoms questionnaire are used by only part of the hospital urologist and is never used by those who have no direct relation with hospital. These tendencies are in conflict with the recommendations established by the WHO for diagnosis of the condition.

Neuroendocrine cells in peripheral prostatic zone: age, prostatic intraepithelial neoplasia and latent cancer-related changes.

The neuroendocrine cells (NCs) in the peripheral prostatic zone of 32 patients without prostatic symptoms and with an average age of 61.4 +/- 6.7 (range 48-75) years were studied, and it was found that most are closed-type cells (95.8%) and that there is a gradual fall both in their total number and the number per square millimeter (p = 0.03) with advancing age. There were microscopic foci of high-grade prostatic intraepithelial neoplasia (PIN) in 59.3% of the patients and occult carcinomas in 28.1%, but no statistical relationship was found between these lesions and the number of NCs (p = 0.35 and p = 0.9, respectively). The gradual increase in NCs in the peripheral zone of normal prostates as of adolescence, reported in the literature, would appear to support a possible androgenic action on these cells. Our finding of a decrease in patients with foci of PIN and carcinoma from the fifth decade suggests that this decrease in NCs may make the prostate more susceptible to carcinogenic factors.