Effects of the aromatase inhibitor testolactone on human benign prostatic hyperplasia

The aromatase inhibitor testolactone was used for endocrine treatment of benign prostatic hyperplasia (BPH). Thirteen patients (mean age 79 years) with complete urinary retention (BPH stage IV) without improvement after 4 weeks of bladder drainage by suprapubic catheter were treated with testolactone 100 mg, b.i.d., for 6 months. Nine men (mean age 80 years) with identical conditions who did not receive hormonal therapy served as controls. Results, treatment group: In 7 patients spontaneous micturation reoccurred after an average treatment period of 8 weeks (group A); 6 patients continued to need the catheter (group B). Prostatic volume decreased in all patients, and an average volume reduction of 26% was found in group A, whereas in group B the decrease averaged 15%. Finally, the testosterone/estradiol ratio significantly increased in all patients during treatment. Control group: Prostatic volume did not change nor did spontaneous micturation occur during the whole observation period.     

Estrogens and benign prostatic hyperplasia: the basis for aromatase inhibitor therapy

Benign prostatic hyperplasia is generally regarded as being a hormone-dependent disorder. The inductive action of stromal elements on the glandular epithelium and the demonstrable estrogen sensitivity of the stroma suggest that estrogens may play a role in the etiology of prostatic hyperplasia. This hypothesis forms the theoretical basis for the proposed use of aromatase inhibitors in treatment of this disorder.     

Metabolism of androgens in human benign prostatic hyperplasia: aromatase and its inhibition

As an extension of our studies on androgen metabolism in epithelium and stroma of human benign prostatic hyperplasia (BPH) tissue our attempts to demonstrate the presence of aromatase are described. Additionally, the question is raised whether the aromatase inhibitor 17 alpha-oxa-D-homoandrosta-1.4-diene-3.17-dione (testolactone) might also act by inhibition of 17 beta-hydroxysteroid dehydrogenase (17 beta-HSDH). In vitro metabolism and inhibition were analyzed by TLC. The main results were: (1) Two aromatase assays (estrone formation and tritium release) were tested with placenta microsomes. Identical results were obtained (Km = 43 +/- 7 nmol/l n = 5; Vmax = 100 resulted in recovery of the aromatase activity added. (3) In BPH tissue alone, formation of estrone from androstenedione could not be detected (less than 7 x 10(-17) mol/min per mg protein, n = 8). (4) 4-Hydroxyandrostenedione inhibited placental aromatase (Ki = 37 nmol/l) distinctly better than 17 beta-HSDH from human BPH (Ki = 18 mumol/l), whereas the Ki values for testolactone (3.7 and 29 mumol/l, respectively) were more similar. It is concluded that aromatization of androgens is not an important pathway in BPH tissue. An alternative mode of action of testolactone by inhibition of 17 beta-HSDH is discussed.     

Evaluating men with benign prostatic hyperplasia

The clinical manifestations of benign prostatic hyperplasia (BPH) include lower urinary tract symptoms (LUTS), poor bladder emptying, urinary retention, detrusor instability, urinary tract infection, hematuria, and renal insufficiency. However, the majority of men with BPH present with LUTS only. Because LUTS can indicate a variety of conditions, evaluation of symptomatic men must first aim to identify or exclude BPH and, if present, assess its severity. It is important to assess symptom severity at baseline and during follow-up, using the American Urological Association Symptom Index or the International Prostate Symptom Score. Further testing can then be tailored to narrow the diagnosis and guide treatment decisions. Factors such as patient age and concomitant malignancy will also affect management, but the main goal of treatment remains the improvement of quality of life for the patient.     

Medical treatment of benign prostatic hyperplasia

Medical therapy for the treatment of benign prostatic hyperplasia (BPH) became an accepted standard of care in the 1990s following the reports of randomized, double-blind, placebo-controlled studies showing that finasteride, a 5-α reductase inhibitor, and terazosin, an α-blocker, significantly improved lower urinary tract symptoms and increased peak urinary flow rates in men with BPH. This article reviews novel approaches to the pharmacological treatment of BPH.     

Clinical evaluation of benign prostatic hyperplasia

Benign prostatic hyperplasia (BPH) is the most common neoplastic condition afflicting men and constitutes a major factor impacting male health. Clinical evaluation to assess the presence and degree of voiding dysfunction and/or the role of BPH in its presence has an increasingly broad spectrum of treatment goals. The goals of the evaluation of such men are to identify the patient's voiding or, more appropriately, urinary tract problems, both symptomatic and physiologic; to establish the etiologic role of BPH in these problems; to evaluate the necessity for and probability of success and risks of various therapeutic approaches; and to present the results of these assessments to the patient so he can make an informed decision about management recommendations and available alternatives.     

Atamestane: An aromatase inhibitor for the treatment of benign prostatic hyperplasia. A short review

Benign prostatic hyperplasia (BPH) is the most common neoplastic growth in men and is the most frequent cause of urinary flow obstruction at the bladder neck. In addition to the clear evidence in favor of the androgen dependency of BPH, the involvement of the stroma, stromal-epithelial interaction and the role of estrogens have gained much interest in connection with the pathogenesis of this disease. For this reason, specific aromatase inhibitors such as atamestane (1-methyl-1,4-androstadiene-3,17-dione) have recently attracted attention due to their potential use in the treatment of BPH. The pharmacological action of atamestane as a new competitive and irreversible inhibitor of estrogen biosynthesis has been evaluated in mice, rats, rabbits, dogs, monkeys and in man. In all species tested so far, atamestane lacks other intrinsic hormonal or antihormonal activities and shows no inhibition of other cytochrome-P₄₅₀ dependent enzymes of adrenal steroidogenesis. However, it inhibits the estrogen-related negative feed-back. The extent and consequence of the induced counter-regulation of the pituitary-hypothalamic axis show major sex- and species-specific differences. In BPH animal models, atamestane is highly effective in inhibiting estrogen-induced hyperplastic changes in the fibromuscular stroma of the prostate in androstenedione-treated dogs and monkeys. In male volunteers and BPH patients, atamestane induces an expected dose-dependent reduction of serum estrogen concentrations with slight increases in androgen level. In conclusion, all available results indicate that atamestane is a selective (no inhibition of adrenal function), pure (= specific—no endocrine side-effects) and highly effective steroidal aromatase inhibitor with excellent safety profile. Based on our preliminary results aromatase inhibitors seem to be promising compounds for the treatment of BPH.     

Pharmacotherapy for benign prostatic hyperplasia.

Benign prostatic hyperplasia is a benign neoplasm of the prostate seen in men of advancing age. Microscopic evidence of the disorder is seen in about 70% of men by 70 years of age, whereas symptoms requiring some form of surgical intervention occur in 30% of men during their lifetime. Although the exact cause of benign prostatic hyperplasia is not clear, it is well recognized that high levels of intraprostatic androgens are required for the maintenance of prostatic growth. In recent years, extensive surveys of patients undergoing transurethral resection of the prostate reveal an 18% incidence of morbidity that has essentially not changed in the past 30 years. This procedure is also the second highest reimbursed surgical therapy under Medicare. These findings have resulted in an intensive search for alternative therapies for prostatic hyperplasia. An alternative that has now been well defined is the use of alpha-adrenergic blockers to relax the prostatic urethra. This is based on findings that a major component of benign prostatic hyperplasia symptoms is spasm of the prostatic urethra and bladder neck, which is mediated by the alpha-adrenergic nerves. A second approach is to block androgens involved in maintaining prostate growth. Several such drugs are now available for clinical use, and we discuss their side effects and use. We also include the newer recommendations on evaluating benign prostatic hyperplasia that are cost-effective yet comprehensive.     

Role of inflammation in benign prostatic hyperplasia

Inflammation of the prostate may represent a mechanism for hyperplastic changes to occur in the prostate. There are a variety of growth factors and cytokines that may lead to a proinflammatory process within the prostate. There are several proposed mechanisms that lead to both the intrinsic and extrinsic basis of inflammation. Prostatic inflammation may represent an important factor in influencing prostatic growth and progression of symptoms. This article reviews the recent literature on inflammation leading to chronic prostatic diseases, such as benign prostatic hyperplasia.     

Effects of estrogen deprivation on human benign prostatic hyperplasia

Sex steroids are thought to play an essential role in the pathogenesis of human benign prostatic hyperplasia (BPH). Since recent studies in animal models and in men have shown that estrogens might be causally linked to the onset and maintenance of BPH, we examined the effect of 1-methyl-androsta-1,4-diene-3,17-dione (Atamestane), a newly developed aromatase inhibitor, in men with BPH. In an open multicenter study 49 men (mean age 70.1 years, range 55 to 84) with obstructive BPH were treated with atamestane (3 × 200 mg/day) for 3 months. Of the 49 patients 44 completed the treatment period; the other patients discontinued the study for reasons unrelated to treatment. With treatment BPH-related symptoms such as daytime voiding frequency, nycturia, peak flow and residual urine improved considerably; however, these parameters did not reach statistical significance. The mean prostatic volume decreased significantly from 74.2 ± 31.7 to 64.0 ± 31 ml (mean ± SD). Serum estrogen levels decreased markedly during treatment. In addition intraprostatic estrogen concentration decreased with treatment as compared to estrogen levels in hyperplastic prostates from untreated patients. The following conclusions can be drawn from this study: first, estrogens appear to have an important supportive role in established BPH, and second, estrogen deprivation improved BPH-related symptoms and reduced significantly prostatic volume.     

Urinary hormone excretion in benign prostatic hyperplasia

The urinary excretion of LH, low polar oestrogens (oestrone + oestradiol-17β), dehydroepiandrosterone, androsteone, aetiocholanolone, pregnanediol and total 17-keto-and 17-ketogenic steroids has been determined in 30 men aged 60–84 years with benign prostatic hyperplasia and in 39 healthy men aged 60–79 years. The results show a significantly elevated oestrogen excretion in benign prostatic hyperplasia as compared with the control group. No other significant differences were found in the urinary hormone excretion. It is speculated that the increased oestrogen levels might stimulate the prostate growth mainly by facilitating the transport of peripheral testosterone into prostate cell.     

Prostate development and growth in benign prostatic hyperplasia

The etiology of benign prostatic hyperplasia [BPH] in elderly men has intrigued anatomists, pathologists and scientists for centuries. Studies of morbid anatomy, clinical observations and contemporary cellular biology have contributed to an evolving interpretation of the causality of the disease. Insights into the detailed microanatomy and ductal architecture of the prostate during stages of fetal and early postnatal development suggest that mechanisms involved in the early growth period become aberrantly expressed in elderly men. Age, hormones and epithelial-mesenchymal interactions are all contributing factors to the pathogenesis of BPH. Control of the microenvironment in normal and abnormal growth is a multifactorial process. Susceptibility to the disease may include clinical comorbid diseases, region-specific changes in cell-cell interactions and a variety of signaling pathways including a novel hypothesis regarding the role of the primary cilium as a regulator of signal transduction mechanisms. Recent work in animal models has shown that there are region-specific differences within the prostate that may be significant because of the dynamic and intricate interplay between the epithelium and mesenchyme. Because of the focal nature of BPH a closer examination of normal morphogenesis patterns, which defines the gland's architecture, may facilitate a detailed understanding of the atypical growth patterns.