Molecular Profile and Clinical Associations of Androgen Receptor Coactivators and Structural Genes in Benign Prostatic Hyperplasia and Metabolic Syndrome

Personalized Medicine for the Management of Benign Prostatic Hyperplasia

SERUM PROSTATE SPECIFIC ANTIGEN IS A STRONG PREDICTOR OF FUTURE PROSTATE GROWTH IN MEN WITH BENIGN PROSTATIC HYPERPLASIA

Society of Interventional Radiology Research Reporting Standards for Prostatic Artery Embolization

Benign prostatic hyperplasia (BPH) is one of the major public health concerns, which has a high prevalence rate and causes significant decline in men’s quality of life. BPH is highly related to sexual hormone metabolism and aging. In particular, dihydrotestosterone (DHT), to which testosterone is modified by 5α-reductase (5AR), has a significant effect on BPH development. DHT binds to an androgen receptor (AR) and steroid receptor coactivator 1 (SRC-1); then, it induces the proliferation of a prostate cell and expression of prostate specific antigen (PSA). Paecilomyces tenuipes (P. tenuipes) is a mushroom that has been popularized by the artificial cultivation of fruiting bodies based on silkworms by researchers from the Republic of Korea. In a previous study, we identified the effect of PE on PSA mRNA expression in LNCaP cells. This suggests that PE may have an inhibitory effect on androgen signaling. Therefore, we confirmed the expression of androgen signaling-related factors, such as AR, SRC-1, and PSA in LNCaP. Furthermore, we confirmed the androgen signaling inhibitory effect of PE using the testosterone propionate (TP)-induced BPH rat model. A BPH rat model was established with a four-week treatment of daily subcutaneous injections of testosterone propionate (TP, 3 mg/kg) dissolved in corn oil after castration. The rats in the treatment group were orally gavaged P. tenuipes extract (PE), finasteride (Fi), or saw palmetto extract (Saw) with TP injection. DHT induced an increase in the expression levels of AR, SRC-1, and PSA proteins in LNCaP cells. On the contrary, the PE treatment reduced the expression levels. In vivo, the BPH group showed an increase in prostate size compared with the control group. The PE gavaged group showed a decrease in prostate size compared with the BPH group. In addition, the protein expressions of AR, 5AR2, and PSA were significantly lower in the PE gavaged group than BPH group in prostate tissue. These results suggest the beneficial effects of PE on BPH via the modulation of AR signaling pathway.

Benign prostatic hyperplasia (BPH) cases in Indonesia frequently associated with high serum prostate specific antigen (PSA). To explore possible factors that could increase serum PSA level, we performed a retrospective, cross-sectional study on 805 consecutive patients in Sumber Waras and Dr. Cipto Mangunkusumo Hospitals from 1994 to 1997. Clinical manifestations were evaluated and prostate biopsies were performed if indicated. Complete histopathological data were only available in 82 BPH patients with no urinary retention from 1998-1999 and a thin section of paraffin blocks of BPH patients which still could be found from 1994-1999 was analyzed using flow cytometer to obtain the S-phase fraction as a parameter of proliferative activity, From 805 patients, 461 (57%) presented with urinary retention and need to be catheteized. Catheteization significantly increased PSA level if compared to noncatheterized patients (16.3 vs. 6,8 ng/mL, p= 0,000). Another data of 82 uncatheteized patients from 1998-1999 has revealed that 79 patients (96.3%) had chronic prostatitis and 19 (23.2%) showed the presence of prostatic-intraepithelial neoplasia (PIN) with an increase of PSA level (5.4 ng/mL). The S-phase fraction of BPH without PIN cases was significantly higher in cases with PSA > 4 ng/ml than patients with PSA < 4 ng/ml (I3.1% vs. 8.9%, p=0,008). As conclusion, the high serum PSA level was mostly due to urethral catheteization and increased prostate volume. There was a tendency of increasing PSA in subclinical inflammation and PIN. Cases with high PSA also showed high proliferative activities which is suggestive of mitogenic activity. (Med J Indones 2001; 10:22-8) Keywords: BPH, high PSA, PIN, proliferative activity, s-phase fraction

Prostate-specific antigen as an estimator of prostate volume in the management of patients with symptomatic benign prostatic hyperplasia.

Changes in Prostate Specific Antigen in Hypogonadal Men After 12 Months of Testosterone Replacement Therapy: Support for the Prostate Saturation Theory

The physiology of the male urogenital apparatus and reproductive function is critically dependent on a healthy prostate. Since growth and function of the prostate are governed by androgens, endocrine interventions with the synthesis, uptake, or metabolism of these hormones are major pharmacological/therapeutic strategies in prostate diseases, e.g. cancer of the prostate (CaP) and benign prostatic hyperplasia (BPH). Pharmacological interference with androgen metabolism is associated with inevitable adverse effects. Therefore, it is important that such treatment be exercised with caution and weighed against its potential effects on the symptoms and outcome of the disease. α-Adrenergic blockade is an alternative treatment in BPH since α1-adrenoceptors are localized in the prostate stromal structures and considered to mediate an increased infravesical obstruction. Cancer of the prostate (CaP) is the most common cancer in the western male population with the highest incidence in Nordic countries (115/100 000) and in the USA, particularly in black Americans [1]. The incidence increases with age. About 30 to 35% of Swedish men at the age of 50 years have microscopic adenocarcinoma whereas the corresponding figure is more than 50% at the age of 80 years [2]. It has been estimated that about 7% of Swedish men will develop clinical CaP before the age of 75 years [2]. The other major disease of the prostate is BPH which is a histopathological diagnosis leading to benign prostatic enlargement and finally to bladder outlet obstruction. For the sake of simplicity, the clinical syndrome will be referred to as BPH in the following review. BPH is symptomatic in more than 40% of the ageing male population [3]. Shown in Table 1 are some prevalence numbers for CaP and BPH. Given this situation, it is not surprising that diseases of the prostate have attracted considerable interest from the scientific community and the public. Compared with men from western societies, oriental men like the Japanese have a low incidence of CaP [4]. The higher incidence in oriental men living in the US compared with men in their native countries indicates that environmental as well as genetic factors influence the prevalence of this disease in the population. For BPH, development of effective pharmacological intervention therapies as well as new physical treatment modalities have challenged the classical surgical approaches to cure the disease. Even though the efficacy of drugs may be limited compared to surgical and physical means of treatment, they are often preferred because of the much lower complication risks [5]. A comparison of pharmacological and non-pharmacological treatments in terms of efficacy and complication risks is depicted in Figure 1. Efficacy of treatment methods for BPH in relation to risk of complications. Arbitrary dimensions on Y- and X-axes. TUMT=transurethral microwave treatment; TUNA=transurethral needle ablation; TUIP=transurethral incision of the prostate; TURP=transurethral resection of the prostate. Adopted after Carlsson & Spångberg [5] with due permission from authors and publisher. The scope of this article is to describe the current possibilities and ideas for pharmacological intervention strategies, and to discuss their limitations and basis for further development of more advanced treatment programs. The major conveyors of androgenic influence on the prostate are testosterone and its 5α-reduced metabolite dihydrotestosterone (DHT). They bind to and activate the androgen receptor, a nuclear transcription factor in the luminal epithelial cells, thereby modulating a set of genes of importance for prostate biology. The binding affinity is higher for DHT than for testosterone [6]. A complex concerted action of the androgen receptor and other proteins is then initiated to accomplish binding to the hormone response elements and activation of the gene transcription [7]. Only a few liganded androgen receptor activated genes are known so far, e.g. prostate-specific antigen, PSA [8]. Since the transcriptional activation by the testosterone/androgen receptor and DHT/androgen receptor complexes differs greatly, the latter being about 10 times more powerful [7], it is conceivable that the tissue-specific distribution of the ligands and the bioactivating 5α-red2 and 5α-red1 enzymes are of crucial importance for the physiological and the pathophysiological effects of androgens in the prostate and other organs. The testes are the major source of testosterone production. The synthesis takes place in the Leydig cells, the activity of which is governed by the pituitary luteinizing hormone (LH). The adrenals also produce small amounts of androgens, but their major contribution to the androgen pool is via secretion of androgen precursors such as dehydroepiandrosterone (DHA) and androstenedione (Figure 2). The opinion about the relative contribution of adrenal androstenedione, DHA and its sulphate, DHA-S, to the circulating androgenic activity varies and the contribution has been suggested to be between 5 and 10 [9, 10, 11], or up to 40% [12]. Adrenal synthesis and metabolism of steroids, and formation of precursors for extra-adrenal biotransformation to testosterone. CYP denotes cytochrome P450, 3βHSD 3β-hydroxysteroid dehydrogenase, 17βHSD 17β-hydroxysteroid dehydrogenase, DHA dehydroepiandrosterone, and A-dione androstenedione. 11-DOC and 11-DOCOL denote 11-deoxycorticosterone and 11-deoxycortisol, respectively. DHA and androstenedione are converted to potent androgens in the prostate (2-4), first to testosterone through the action of 3β-and 17β-hydroxysteroid dehydrogenase (3β-HSD, 17β-HSD) followed by bioactivation of testosterone to DHT. Bioactivation of the androgen precursors also takes place in other organs. Testosterone metabolism. For abbreviations, see Figure 2. Endocrine intervention therapy of prostate diseases. Therapeutic levels are shown at right. LH denotes luteinizing hormone, ACTH adrenocorticotropin, and DHA-S DHA-sulphate. Organ symbols indicate the testes (left) and adrenals (right). For other abbreviations, see Figure 2. The principal goal in treatment of CaP is to prevent the activation of androgen regulated genes. There are three major approaches to achieve this goal: First, to inhibit the synthesis of androgens, notably testosterone in the Leydig cells of the testes and the androgen precursors in the adrenals. Secondly, to inhibit androgen binding to the androgen receptor and formation of the ligand-receptor complex (Figure 4) and, thirdly, to inhibit the bioactivation of testosterone through the 5α-red2 and 5α-red1 enzymes. A multitude of pharmacological treatment strategies are currently in use for CaP (Table 2). Testicular androgen synthesis is traditionally abolished by surgical castration, which reduces serum testosterone dramatically and has a positive effect on CaP, at least initially. Obviously, irreversible castration has encountered psychological resistance which varies in different countries. The introduction of pharmacological castration by luteinizing hormone-releasing hormone (LHRH) analogues (Figure 4) was therefore well received, particularly since the effect is reversible and as effective as surgical castration in terms of effects on testosterone levels. These drugs mimic LHRH, also known as the gonadotropin-releasing hormone (GnRH), and act as false ligands at the pituitary receptors for GnRH. The natural activation of these receptors causes a stimulation of the secretion of follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Prolonged receptor-stimulation by LHRH analogues gives a desensitisation and down-regulation of the pituitary GnRH receptors, thereby decreasing testosterone levels in man to castration values, (and oestrogen levels in women to postmenopausal values). However, a transient flare of the CaP is often seen due to an initial stimulation of FSH and LH secretion. The flare may be prevented by concomitant administration of anti-androgens (see below). It is important that the LHRH agonists be administered in a non-pulsatile fashion, since the pulsatile administration, typical of the endogenous hormone, does not lead to desensitisation of the gonadotrophs. The peptide LHRH agonists are poorly absorbed after oral administration. This has called forth the development of pharmaceutical preparations for intramuscular, subcutaneous, or nasal administration. In recent years, depot formulations have also been introduced to optimise the drug administration. Oestrogen therapy (Table 2), which has been partly abandoned in favour of the LHRH agonists in CaP, clearly reduces the adrenal secretion of androgen precursors [13]. However, oestrogens cause water retention which may be deleterious to patients with compromised cardiovascular function. Cardiovascular complications may also occur. Another, although not fully evaluated therapeutic alternative is to block the adrenal cytochrome P450-dependent 17,20-lyase [14] which catalyses the final cleavage of the C-17,20 carbon to yield DHA and androstenedione from the 17α-hydroxylated precursors (Figure 2). This results in a decrease in the formation of testosterone and oestrogens (2, 3). The enzyme blockade may be achieved by ketoconazole, but other newly synthesised compounds may be better because of a more favourable side effect profile. However, the role of aromatase inhibitors to decrease oestrogen biosynthesis has not yet proven clinically useful [14]. Different means to block the synthesis of the androgen ‘bypass’ from the adrenals in castrated patients or the peripheral oestrogen synthesis contribute only marginally to the therapeutic effect. The second approach is to block the androgen action on the androgen receptor and the ultimate receptor gene activation, irrespective of the source of the ligands. For this purpose a number of anti-androgens have been developed. Some of these compounds are listed in Table 3. The steroidal compounds have an intrinsic androgenic activity and a mixed mechanism of action. In addition to androgen receptor blockade, they also inhibit the pituitary LH secretion, thereby decreasing the levels of testosterone and DHT. The non-steroidal agents are generally preferred to achieve a pure anti-androgenic effect [15]. The intrinsic androgenic action of some blockers on tumour growth has limited their use in progressing prostate cancer since a discontinuation of therapy may give a fall in PSA. Clinical studies of androgen receptor blockers, when used as a complement to castration, or when compared with LHRH agonists, have demonstrated varying effects [12]. At present, inhibition of 5α-reductase is not an alternative in treatment of CaP, and the prophylactic effect of such treatment has to await the results of the large American trial on finasteride (Prostate Cancer Prevential Trial) that is run by the National Cancer Institute (USA). Early clinical observations in the nineteenth and the beginning of the twentieth century demonstrated the dependence of the prostate on androgens. Castrates do not develop CaP or BPH [16], and castration of men with urinary obstructive problems was early noted to relieve the symptoms [17, 18]. It is interesting from an aetiological point of view that the intraprostatic levels of DHT and androgen receptors are maintained in senescent men even though the circulating androgens are decreasing [19, 20]. The importance of androgens for the growth, differentiation and function of the prostate is the rationale behind the therapeutic intervention with the androgen endocrinology. Inhibition of synthesis, or binding of androgens to the androgen receptor leads to clinical retardation or temporary regression of CaP. It is also known that castration leads to apoptosis of the glandular epithelial cells both in malignant and benign prostatic tissue [21, 22]. In the early phase, most cancers are androgen-dependent and sensitive to hormonal deprivation. However, most cancers eventually progress and become hormone-refractory, probably by a series of genetic changes in the tumour cells [23]. The ‘hormone escape’ phenomenon is a therapeutic challenge that has raised questions about the best therapeutic approach to CaP—partial or maximal androgen blockade. The efficacy of deferred hormonal treatment vs early treatment is also discussed. There is a scientific controversy over the efficacy of different androgen deprivation strategies in respect of time to progression and survival time. Clinical trials designed to compare the effect of partial vs maximal androgen blockade do not show consistent results. Table 4 lists some of the key comparative trials and the respective outcomes. It is a major challenge to understand the molecular mechanisms of the ‘hormone escape’ phenomenon and to find therapeutic alternatives that are effective in treatment of progressing prostate cancer. The growth-promoting effect of androgens on the prostate is the rationale behind the (intraprostatic) inhibition of the bioactivating 5α-reduction step that converts testosterone to the more potent DHT [24]. Binding to the androgen receptor, which is preferentially localised in the epithelial cells, triggers different reactions intrinsic to the epithelial cells in terms of cell division and apoptosis. When this machinery works in favour of prostate hyperplasia, a pharmacological reduction of the androgen influence is beneficial. The 5α-reductase is present in at least two isoforms. Studies in cDNA libraries from human and rat prostate revealed the presence of a type 1 [25] and a type 2 enzyme [26, 27] which were found to be two separate gene products. These isoforms are not only biochemically distinct (Table 5) but have different tissue distribution and pathophysiological roles in androgen-associated diseases. 5α-red2 is the major and abundant catalyst of DHT formation in prostate, whereas the 5α-red1 enzyme is only sparsely expressed in this organ [28]. 5α-red2 is also present in skin and liver and is subject to developmental regulation during ontogenesis [29]. The 5α-red1 enzyme is predominantly expressed in skin and liver. Failure to develop normal external genitalia and prostate in pseudohermaphroditic individuals is often due to deleterious mutations in the 5α-red2 gene [24]. The 5α-red2-specific enzyme blocker finasteride is highly specific for the 5α-red2 enzyme and has only a marginal effect on the 5α-red1 enzyme. Whereas the androgen receptors are localised to the epithelial cells, the 5α-red2 enzyme is present only in the stromal and basal epithelial cells of the prostate [28]. This implicates a paracrine rather than an autocrine effect of DHT. However, as already mentioned, 5a-reductase enzyme activity is present also in non-target tissues [30], thereby allowing an endocrine mechanism for androgen effects on the prostate. The relative importance of intraprostatic vs extraprostatic formation of DHT for the effects on the prostate is not fully known. Stromal cells in hyperplastic regions seem to contain somewhat more 5α-red2 enzyme than stromal cells in adjacent normal tissue as visualised immunohistochemically [31]. Consistent with this we have demonstrated a higher average rate of formation of DHT from testosterone in biopsies from BPH compared with cancerous prostatic tissue [32] which predominantly contains epithelial structures. Recent results in our laboratory have revealed a 10-fold variation in 5α-red2-specific mRNA in biopsies from prostate specimens (Söderström et al., unpublished), using solution hybridisation for quantitation of the transcript [33]. This is interesting from the point of view of variation in therapeutic response and therapeutic resistance. We also found a high correlation between DHT formation rate and 5α-red2-specific mRNA, indicating a transcriptional regulation of the enzyme. In view of the clinical variation in response to finasteride, it is of obvious interest to know if the therapeutic outcome is related to gene expression and/or activity of the 5α-red2 target enzyme. This is currently under investigation. Even though 5α-red2 blockade leads to prostate involution and improvement of clinical symptoms in BPH, the hypothesis is not exclusive of other possible pathogenic factors such as oestrogens. The long-term efficacy of 5α-red2 inhibition therapy may well be confounded by other metabolic changes in the prostate. A recent controversy over the long-term efficacy of 5α-red2 blockers [34, 35] has highlighted the importance of patient stratification in respect of prostate size. The effect of finasteride treatment seems to be most pronounced in patients with initial prostate size of at least 40 ml. However, clinical trials of drugs for BPH should also focus on other clinical endpoints. Symptom scores are perhaps more relevant than urine flow measurements. An important difference in the regulation of 5α-red2 in the epididymis and the prostate has been found. In the former organ, expression of the enzyme is abolished upon androgen ablation in CaP patients as assessed by immunoblotting [31]. In contrast, the expression in the prostate of CaP patients does not seem to be compromised by maximal androgen blockade, at least not after 10–13 weeks of treatment. After orchidectomy, the enzyme was still present in the prostate after 6 months, although at a lower level [31]. This feature of the enzyme regulation is interesting in that the substrate availability does not seem to affect the expression of the enzyme. Similarly, blockade of the enzyme itself by finasteride did not influence the enzyme expression, as judged from immunoblotting results from three patients treated with finasteride for 2 weeks, 6 months, and 3 years, respectively [31]. This is different from the situation in the rat prostate where a ‘feed-forward’ regulation of the enzyme is exerted by DHT [36]. The insensitivity of the 5α-red2 enzyme to manipulation of its substrate availability, or to blockade, are interesting features from a therapeutic perspective. Current investigations of gene transcription of the enzyme under similar clinical conditions will help to explain the mechanisms of these observations. The BPH-associated bladder outflow obstruction is associated with morphological as well as functional changes in the bladder, detrusor, urethra, and prostate [37]. The bladder outlet obstruction has a static and a dynamic component. The effect of α-adrenoceptor blockade on the symptoms of BPH was early identified [38], and it is now well recognised that the dynamic component is responsive to such blockade. Initial promising treatment results were obtained with the non-selective phenoxybenzamine [38] which was shown to increase urinary flow rate and to improve many of the symptoms of BPH. However, the well-known adverse effects of phenoxybenzamine have prevented its further use. Pharmacological and physiological observations have demonstrated that the tension of the prostatic smooth muscle is mediated by α1-adrenoceptors (for review see 37), leading to an increase in the infravesical obstruction. The α1-adrenoceptor type is abundant in prostatic tissue, particularly in the stromal elements, whereas α2-adrenoceptors are localised to the vasculature [39]. Receptor-blockade decreases both obstructive and irritative lower urinary tract symptoms (LUTS). With the advancement of molecular biology it has been possible to identify different subgroups of the α1-adrenoceptors in the prostate. The presence of multiple subtypes of α1-adrenoceptors has been demonstrated through receptor cloning [40] and studies of receptor binding function [41]. Consensus on classification and nomenclature has recently been reached [42] and three α1-adrenoceptor subtypes designated α1A, α1B, and α1D, are now recognised [43]. All of them have been found in the prostate. It is important to consider this reclassification in review of old data, in order to avoid confusion. A group with low affinity for prazosin has also been described and designated α1L [44], but its role in the prostate is unclear. The α1A-receptor type is considered to be the major mediator of contraction of the smooth muscle in prostatic tissue and has therefore become the target receptor for development of effective antiadrenergic agents for use in BPH (for review see 45). Although the α1-adrenoceptors seemingly account for a substantial part of the disease symptoms, a role of other, hitherto unknown adrenergic receptors, or a central nervous α1-mechanism cannot be ruled out at the present time [46]. On this basis, drug manufacturers have striven to develop as ‘uroselective’α1-adrenoceptor agents as possible in order to avoid untoward effects on the vasculature. The use of α1-adrenoceptor blockers is associated with a number of cardiovascular and central nervous side-effects. Therefore, attempts to develop drugs with selective effects on the prostate receptors have been made to increase the ‘uroselectivity’. This concept is not easily defined since it may refer to pharmacological, physiological, or clinical aspects of selectivity [47]. The presence of other α1-adrenoceptors in the prostate may confound a pharmacological definition of uroselectivity. Physiological effects on blood pressure may occur concomitant with effects on the prostate or even without effects on the prostate. Such agents have limited usefulness in BPH. Obviously, physiological uroselectivity implicates effects on the prostate without or with minimal effects on the cardiovascular or central nervous system. Because of the difficulties to find an easy definition, the term ‘clinical uroselectivity’ was coined to account for the independence between functional dynamic obstruction, LUTS, and side-effects. It may be defined as: ‘the desired effects on obstruction and LUTS related to adverse effects’ [48]. Theoretically, an ideal drug would exhibit selectivity for α1A-over α1B, as well as α1D receptors. Any such drug is, however, not yet marketed for use in man. Although currently used α1-adrenoceptor blockers exhibit binding to these receptors, none has any selectivity [47]. α1A-over selectivity in has been for This drug is also a potent of and has a higher selectivity for α1-adrenoceptors in the prostate compared with this has any importance for the of symptoms in comparison with other drugs has yet to be in comparative clinical with the for are to drugs with to easy administration blockers that these and which be (Table questions in relation to α1-adrenoceptor blockade also to be This more on the relative contribution of different receptors to (see and more on the effect of α1-adrenoceptor In the α1-adrenoceptor blockers are now considered to be in treatment of patients with clinical symptoms of BPH [37]. However, the long-term of in comparison with other therapeutic strategies has yet to be The of therapy in BPH on a series of It is to be noted that of is more with the α1-adrenoceptor blockers than the 5α-reductase A response is, however, only a relative in the of long-term treatment of the disease. Since the efficacy to relieve LUTS seems to be between the α1-adrenoceptor blockers and the 5α-reductase the may most important to the patients for of and are of They be weighed against the adverse effects of α1-adrenoceptor blockade which and if the patient from α1-adrenoceptor blockade has an In to α1-adrenoceptor blockers, finasteride may lower PSA by 50% which may confound the results of PSA for prostate cancer. approaches for pharmacological treatment of BPH and CaP will on new about and endocrine changes as a cause or of prostate diseases. methods for studies of genes and gene expression as well as function of receptors, or other of response in the organ will help to improve our of the and of and or of untoward endocrine or paracrine influence on the about factors growth of the prostate. The development of hormone resistance is also a which may be due to genetic changes of the or approaches to block androgenic influence at the or different (Figure 4) may be and such have already been by drug The presence in the prostate of metabolic enzymes not in androgen such as P450, will also be important to Such enzymes are present at varying levels in the prostate and may well with the androgen metabolism. They may also be on therapeutic drugs and/or of importance in the of This is poorly but further studies may on mechanisms for development of prostate diseases. for and and for on the of the was by the Swedish Cancer

The physiology of the male urogenital apparatus and reproductive function is critically dependent on a healthy prostate. Since growth and function of the prostate are governed by androgens, endocrine interventions with the synthesis, uptake, or metabolism of these hormones are major pharmacological/therapeutic strategies in prostate diseases, e.g. cancer of the prostate (CaP) and benign prostatic hyperplasia (BPH). Pharmacological interference with androgen metabolism is associated with inevitable adverse effects. Therefore, it is important that such treatment be exercised with caution and weighed against its potential effects on the symptoms and outcome of the disease. α-Adrenergic blockade is an alternative treatment in BPH since α1-adrenoceptors are localized in the prostate stromal structures and considered to mediate an increased infravesical obstruction. Cancer of the prostate (CaP) is the most common cancer in the western male population with the highest incidence in Nordic countries (115/100 000) and in the USA, particularly in black Americans [1]. The incidence increases with age. About 30 to 35% of Swedish men at the age of 50 years have microscopic adenocarcinoma whereas the corresponding figure is more than 50% at the age of 80 years [2]. It has been estimated that about 7% of Swedish men will develop clinical CaP before the age of 75 years [2]. The other major disease of the prostate is BPH which is a histopathological diagnosis leading to benign prostatic enlargement and finally to bladder outlet obstruction. For the sake of simplicity, the clinical syndrome will be referred to as BPH in the following review. BPH is symptomatic in more than 40% of the ageing male population [3]. Shown in Table 1 are some prevalence numbers for CaP and BPH. Table 1 Prevalence of diseases of the prostate in relation to age. Given this situation, it is not surprising that diseases of the prostate have attracted considerable interest from the scientific community and the public. Compared with men from western societies, oriental men like the Japanese have a low incidence of CaP [4]. The higher incidence in oriental men living in the US compared with men in their native countries indicates that environmental as well as genetic factors influence the prevalence of this disease in the population. For BPH, development of effective pharmacological intervention therapies as well as new physical treatment modalities have challenged the classical surgical approaches to cure the disease. Even though the efficacy of drugs may be limited compared to surgical and physical means of treatment, they are often preferred because of the much lower complication risks [5]. A comparison of pharmacological and non-pharmacological treatments in terms of efficacy and complication risks is depicted in Figure 1. Figure 1 Efficacy of treatment methods for BPH in relation to risk of complications. Arbitrary dimensions on Y- and X-axes. TUMT=transurethral microwave treatment; TUNA=transurethral needle ablation; TUIP=transurethral incision of the prostate; TURP=transurethral ... The scope of this article is to describe the current possibilities and ideas for pharmacological intervention strategies, and to discuss their limitations and basis for further development of more advanced treatment programs.

The Influence of Baseline Parameters on Changes in International Prostate Symptom Score with Dutasteride, Tamsulosin, and Combination Therapy among Men with Symptomatic Benign Prostatic Hyperplasia and an Enlarged Prostate: 2-Year Data from the CombAT Study

This article is available from http://www.labmedonline.org 2014, Laboratory Medicine Online This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Background: Baseline prostate volume (PV) is related with the progression of benign prostatic hyperplasia (BPH). Although recent studies have reported the relationship between BPH and metabolic syndrome, the findings are inconsistent. Thus, this study was performed to investigate the association of PV with metabolic factors and prostate-specific antigen (PSA) in individuals with normal PV and clarify the factors associated with benign prostate enlargement (BPE), including PSA. Methods: We selected 3,915 health examinees aged >40 yr with a PSA level <4 ng/mL who underwent ultrasonography of the prostate as part of a routine health check-up. These individuals were classified into two groups according to PV: normal PV (PV <30 mL) and BPE (PV ≥30 mL). We investigated the association of PV with metabolic factors and PSA using multiple linear regression analysis, and clarified the factors associated with BPE using logistic regression analysis. Results: The factors associated with PV were PSA, age, and waist circumference in individuals with normal PV. The factors associated with BPE were age, body mass index (BMI), and PSA. The logistic regression analysis adjusted for age and confounding factors showed that individuals with a BMI of 23-24.9 kg/m, 25-29.9 kg/m, and ≥30 kg/m had higher odds ratios of 1.580 (95% confidence interval, 1.171-2.131; P =0.003), 1.767 (1.332-2.344; P <0.001), and 2.024 (1.042-3.933; P =0.038), respectively, for BPE than individual with a BMI <23 kg/m. Conclusions: Abdominal obesity was significantly associated with PV in individuals with normal PV, whereas obesity was an associated metabolic factor of BPE. PSA level was positively associated with PV.

Introduction: Benign prostatic hyperplasia (BPH) is a progressive condition characterized by prostate enlargement accompanied by lower urinary tract symptoms (LUTS). Benign prostatic hyperplasia arises in the periurethral and transition zones of the prostatic gland and represents an inevitable phenomenon for the ageing male population. An estimated 75% of men&gt;50 years of age have symptoms arising from benign prostatic hyperplasia, and 20–30% of men reaching 80 years of age require surgical intervention for the management of BPH. Prostate specific antigen (PSA) is a serine protease produced by the prostate epithelium and periurethral glands in male. Serum PSA elevation occurs as a result of disruption of normal prostatic architecture that allows PSA to diffuse into prostatic tissue and gain access to the circulation. Benign prostatic hyperplasia, prostatic carcinoma and prostatitis are three common diseases where PSA in the serum is raised.&#x0D; Aims and objectives: To evaluate the PSA level and To find out the relationship between serum PSA level and the volume of prostate in Benign hyperplasia of prostate.&#x0D; Material and Methods: This is a Hospital based prospective study which was conducted in the Department of Surgery at Nepalgunj Medical College Teaching Hospital, th th Kohalpur, for a duration of 1 year from 13th July 2015 to 12th July 2016. A total of 30 cases were studied. Patients were chosen for the study on the basis of clinical history and DRE. Patient with LUTS symptoms and enlarged Prostate on DRE were further subjected to PSA screening through blood examination and Transabdominal ultrasound for measuring prostatic volume. Patients were explained about procedure and following consent, patients were subjected for TURP under spinal anesthesia/general anesthesia. Specimen was sent to the Department of Pathology, Nepalgunj Medical College for Histopathological evaluation.&#x0D; Results: Out of 30 patients, one patient was of 44 years of age, rest of them were above 50 years of age and the mean age was 63.9±8.64 years. All the patients had voiding problems, of which 28 patients (94%) had obstructive symptoms and 27 patients (90%) had irritative symptoms. Most patients had history of nocturia which was present in 24 patients (83%). Mean PSA level was 6.36 ng/ml with a range of 3.2-12 ng/ml. Mean prostate volume measured by TAUS was 60.30 ml. and that by DRE was 38.33 ml. There was statistically significant positive correlation between PSA level and prostate volume measured by TAUS with Pearson's correlation coefficient (r=0.679).&#x0D; Conclusion: The analysis of present study consisting of 30 patients showed that mean PSA and prostate volume increased with advancing age, and the correlation between PSA and prostate volume estimated by TAUS in BPH as found to be statistically significant (p&lt; 0.05). DRE underestimated the volume of prostate with a mean difference 21.97 ml. The correlation of age of the patient with PSA and prostate volume are (r=0.128) and (r=0.036) respectively. The above value shows that both are statistically weekly positive but the association between age of patient and PSA seems to be higher in comparison to age of the patient and prostate volume.

The aim of the study is to investigate the effects of glutathione S-transferase P1 (GSTP1) gene polymorphism and metabolic syndrome (MS) on lower urinary tract symptoms (LUTS) attributed to benign prostatic hyperplasia (BPH). This study included 195 patients diagnosed with LUTS secondary to BPH as case group, divided into simple BPH group (S-BPH group) and combined with MS group (MS-BPH group). Control group included 200 healthy elderly men without LUTS. Use peripheral blood samples detected the GSTP1 gene polymorphism (Ile 105 Val A → G polymorphism) by polymerase chain reaction-restriction fragment length polymorphism. Recorded age, GSTP1 gene polymorphism, international prostate symptom score (IPSS), prostate volume (PV), residual urine volume (RV), maximal urinary flowrate (Qmax), and prostate-specific antigen (PSA) to statistical analysis. Pairwise compared between control group, S-BPH group and MS-BPH, the PV (P < 0.001), PSA (P < 0.001), RV (P < 0.001), Qmax (P < 0.001), IPSS (P < 0.001), frequencies of GSTP1 gene (P < 0.05) were shown significant different, and MS-BPH group had larger PV, and more severe LUTS. In case group, variation genotypes (GSTP1 A/G + G/G) always had larger PV, higher PSA and IPSS, more RV and lower Qmax than homozygote (GSTP1 A/A) and the comparison were significant different (P < 0.05). Variation genotypes were positively correlated with PV (β = 0.092, P < 0.001), RV (β = 0.228, P = 0.004), IPSS (β = 0.274, P = 0.038), PSA (β = 1.243, P < 0.001) and negatively correlated with Qmax (β = -0.362, P = 0.025). In patients with BPH, GSTP1 variation genotypes and MS might be potential risk factors for faster progression of benign prostatic enlargement and LUTS, which might increase the surgical rate. ChiCTR-IPR-14005580.

Dutasteride Reduces Prostate Size and Prostate Specific Antigen in Older Hypogonadal Men With Benign Prostatic Hyperplasia Undergoing Testosterone Replacement Therapy

Prostate Specific Antigen and Human Glandular Kallikrein 2 in Early Detection of Prostate Cancer