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PubMed2003

5 alpha-reductase inhibitors: what's new?

PURPOSE OF REVIEW: Medical therapy is now the first-line treatment for most men with symptomatic benign prostatic hyperplasia. This review aims to highlight the recent contributions to our understanding of 5 alpha-reductase inhibitor usage. RECENT FINDINGS: For the last decade, finasteride has been the only available 5 alpha-reductase inhibitor, acting upon the type 2 isoenzyme of 5-alpha reductase. Dutasteride is the first drug that can inhibit both isoenzymes and is soon to be available. Biochemically it achieves greater and more rapid dihydrotestosterone suppression compared with finasteride. Clinically, it appears to be at least as good in terms of improving symptoms and flow rates, and reducing the risk of acute urinary retention or the requirement for benign prostatic hyperplasia-related surgery. However, until these two drugs are formally compared, the true benefits of additional type 1 isoenzyme inhibition are unknown. The recently reported Medical Therapy of Prostatic Symptoms trial has convincingly demonstrated superior outcomes with combination therapy compared with monotherapy, unlike previous trials of shorter duration. The ability of 5 alpha-reductase inhibitors to prevent disease progression was also confirmed. Newer roles for 5 alpha-reductase inhibitors are also being defined. Finasteride has been shown to reduce and control benign prostatic hyperplasia-related haematuria, although its value in controlling perioperative bleeding is less clear. Their role as chemopreventive agents for prostate cancer is also under investigation. SUMMARY: Recent studies have both clarified and extended the roles of 5 alpha-reductase inhibitors in benign prostatic hyperplasia, and these may expand further if chemopreventive abilities are proved. In addition, dual isoenzyme inhibition will soon be available.

5-alpha Reductase Inhibitors↗
PubMed2004

Chemotherapeutic prevention studies of prostate cancer.

PURPOSE: Despite advances in the detection and management of prostate cancer, this disease remains a major cause of morbidity and mortality in men. Increasing attention has focused on the role of chemoprevention for prostate cancer, ie the administration of agents that inhibit 1 or more steps in the natural history of prostate carcinogenesis. We review prostate cancer chemoprevention studies in Europe. MATERIALS AND METHODS: Published studies were identified in a search of MEDLINE. Information about ongoing studies was provided by author access to protocols. RESULTS: A variety of chemoprevention studies have focused on the role of dietary factors, vitamins and trace elements in prostate cancer. Some of these studies have been prospective, randomized and double-blinded, while others have used retrospective or epidemiological approaches. Large scale randomized studies are also evaluating the role of 5alpha-reductase inhibitors, which inhibit the conversion of testosterone to the more potent androgen dihydrotestosterone. CONCLUSIONS: Robust evidence is lacking for the value of chemopreventive agents in prostate cancer. Current evidence does suggest that vitamin E and selenium may have a role in prostate cancer chemoprevention. Data from 2 studies, 1 examining the type 1 5alpha-reductase selective inhibitor finasteride and the other using the dual 5alpha-reductase inhibitor dutasteride, will determine the benefits of androgen inhibition strategies for prostate cancer chemoprevention.

Anticarcinogenic Agents↗
PubMed2004

Eliciting preferences for drug treatment of lower urinary tract symptoms associated with benign prostatic hyperplasia.

PURPOSE: There are 2 main medical preparations available for lower urinary tract symptoms resulting from benign prostatic hyperplasia (BPH). Choosing between an alpha-blocker and a 5alpha-reductase inhibitor requires trade-offs between their attributes or characteristics. We investigated the relative importance of and trade-offs between the attributes of the 5alpha-reductase inhibitor dutasteride and alpha-blockers in community dwelling men using a validated technique. MATERIALS AND METHODS: A discrete choice experiment was administered to 211 men older than 40 years who were randomly selected from the general United Kingdom population. Attributes investigated in the discrete choice experiment were time to symptom improvement, sexual and nonsexual side effects, the risks of acute urinary retention (AUR) and surgery, cost and prostate size decrease. Using regression analysis the relative importance of these attributes, the trade-offs that men are willing to make between these attributes and the willingness to pay for each attribute were estimated. RESULTS: All attributes were important to respondents. The most important attribute was side effects. The least preferred side effects was impotence, followed by decreased libido and dizziness. Respondents were willing to wait 13, 2 and 8 months longer for symptom improvement in exchange for decreased prostate size, and the risks of AUR and surgery, respectively. Men reporting moderate symptoms were less concerned about sexual side effects, time to symptom improvement and the risk of AUR compared with men reporting mild symptoms. CONCLUSIONS: Given the attribute levels of BPH medical treatment, overall community dwelling men preferred the 5alpha-reductase inhibitor over alpha-blockers. In the interests of shared decision making it is important to consider the importance of eliciting the preferences of patients with BPH.

Adrenergic alpha-Antagonists↗
PubMed2004

An update on the use of 5alpha-reductase inhibitors.

Twelve years ago, finasteride, the first 5alpha-reductase inhibitor, was introduced as drug therapy for benign prostatic hyperplasia, and more recently dutasteride has emerged as an alternative. The efficacy, safety and ability of these 5alpha-reductase inhibitors to reverse the natural progression of benign prostatic hyperplasia have been convincingly demonstrated and both drugs are now well established in the medical armamentarium against the disease. Given the multifactorial etiology of benign hyperplasia, the usefulness of 5alpha-reductase inhibitors in combination with alpha adrenergic blockers has also been investigated and justified in select patients. Wider applications of 5alpha-reductase inhibitors are also emerging, though their perhaps most important new role as chemopreventive agents remains unclear.

Adrenergic alpha-Antagonists↗
PubMed2006

Update on prostate cancer chemoprevention.

BACKGROUND: Prostate cancer is the most common type of cancer and the second leading cause of cancer-related deaths in American men. Its high rate of occurrence and long lead time to clinically significant disease make prostate cancer an ideal disease for pharmacologic or nutritional chemoprevention. METHODS: To identify the various chemoprevention strategies for prostate cancer, a MEDLINE search (from 1967-2005) and bibliographic search of the English-language literature were conducted. RESULTS: Epidemiologic and retrospective studies have assessed the effect of carotenoids (e.g., lycopene), vitamins, selenium, and nonsteroidal antiinflammatory drugs (NSAIDs) on the rate of occurrence of prostate cancer. The few published prospective trials evaluated prostate cancer as a secondary end point. Lycopene (as beta-carotene) and selenium supplementation have been associated with a reduced risk of prostate cancer in nested case-control studies, but only in subgroups of men with low baseline plasma lycopene (or beta-carotene) and selenium levels respectively. The Prostate Cancer Prevention Trial prospectively evaluated finasteride, a 5-alpha-reductase inhibitor, as chemoprevention. The results showed a 25% relative risk reduction in prostate cancer, albeit at an increased risk of invasive tumors. CONCLUSION: Data regarding lycopene, vitamin E, and selenium as chemoprevention for prostate cancer appear promising. Prospective trials such as the Selenium and Vitamin E Cancer Prevention Trial (SELECT) will clarify the role of these agents in prostate cancer prevention. The role of NSAIDs is unclear, and the long-term toxicity associated with NSAIDs may limit their usefulness. Although finasteride has decreased overall prostate cancer occurrence, the risk of invasive tumors may outweigh the benefit of this agent. The continuing Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial may help define a role for the 5-alpha-reductase inhibitors in cancer chemoprevention. At this time, nothing has been proven effective as chemoprevention against clinically significant prostate cancer.

5-alpha Reductase Inhibitors↗
PubMed2006

Treatment of lower urinary tract symptoms in benign prostatic hyperplasia and its impact on sexual function.

BACKGROUND: Benign prostatic hyperplasia (BPH) is a common disorder in older men and may be associated with lower urinary tract symptoms (LUTS) and sexual dysfunction. Men who present with symptomatic BPH and LUTS are at increased risk for sexual dysfunction, including erectile dysfunction (ED) and ejaculatory dysfunction (EjD). OBJECTIVE: This review describes treatment options recommended by the 2003 American Urological Association (AUA) guideline panel for the relief of LUTS associated with BPH, with a focus on the effects of each treatment on ED and EjD. METHODS: Relevant articles were identified via MEDLINE searches of all English-language articles published from January 1984 to January 2005 using the following search terms: benign prostatic hyperplasia and sexual dysfunction, lower urinary tract symptoms and sexual dysfunction, alfuzosin, doxazosin, terazosin, tamsulosin, dutasteride, finasteride, transurethral resection of prostate, erectile dysfunction, and ejaculatory dysfunction. Data on the effects of BPH treatments on sexual function were extracted from the articles and summarized. Because properly designed, adequately powered, direct-comparator studies have not yet been conducted, the AUA's report provides the most comprehensive analyses regarding the efficacy and safety of the current BPH treatment options. RESULTS: LUTS are an independent risk factor for sexual dysfunction in aging men, even after controlling for age and comorbidities. Although surgery, minimally invasive therapies, and pharmacologic therapies can all improve LUTS and the peak urinary flow rate, some can cause or exacerbate ED (incidence rates: surgery, 10%; minimally invasive therapies, 1%-3%; pharmacologic monotherapy or combination therapy, 3%-10%) and EjD (incidence rates: surgery, 65%; minimally invasive therapies, 4%-16%; pharmacologic monotherapy or combination therapy, 0%-10%). Among pharmacologic therapies for BPH, the frequency of EjD appears to be greater with tamsulosin (10%) than with other alpha(1)-blockers (0%-1%) or the 5alpha-reductase inhibitor finasteride (4%), based on data from a single-arm meta-analysis conducted by the AUA. CONCLUSION: Sexual function should be assessed and discussed with the patient when contemplating the appropriate management strategy for LUTS associated with BPH, as well as when evaluating the patient's response to treatment.

Adrenergic alpha-Antagonists↗
PubMed2005

Chemoprevention of prostate cancer.

Prostate cancer is an attractive target for chemoprevention because of its ubiquity, treatment-related morbidity, long latency between premalignant lesions and clinically evident cancer, and defined molecular pathogenesis. Prevention of this disease would have a major impact on disease-associated cost, morbidity, and mortality for a large segment of the population. A major advance in prevention of prostate cancer came in 2003 with the publication of the Prostate Cancer Prevention Trial (PCPT). This overview summarizes the results of that trial, the design of other large-scale trials, and advances in understanding of the molecular mechanisms underlying the effect of other promising agents, including dutasteride, selenium, Vitamin E, Vitamin D, COX-2 inhibitors, lycopene, and green tea.

Anticarcinogenic Agents↗
PubMed2005

Sexual dysfunction and lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH).

Sexuality is an essential aspect of a couple's relationship and has a significant impact on life satisfaction. Benign prostatic hyperplasia (BPH) is a condition that commonly affects older men and is often associated with lower urinary tract symptoms (LUTS) and sexual dysfunction. Men with moderate-to-severe LUTS are at increased risk for sexual dysfunction, including moderate-to-severe erectile dysfunction (ED), ejaculatory dysfunction (EjD), and hypoactive desire (HD). The results of several recent large-scale studies have shown a consistent and strong relationship between LUTS and both ED and EjD. It appears that the pathophysiological mechanisms of LUTS and the related prostatic enlargement of BPH as well as certain treatments for this condition may have an impact on both the erection and ejaculation components of the sexual response. Validated questionnaires that assess sexual function provide clinicians with valuable information to help guide treatment selection decisions. Effective medical therapies for LUTS associated with BPH include alpha(1)-adrenergic receptor antagonists (i.e., alfuzosin, doxazosin, tamsulosin, and terazosin) and 5alpha-reductase inhibitors (i.e., finasteride and dutasteride). The side effects of these medications, including sexual dysfunction, are important distinguishing features. The successful management of patients with LUTS associated with BPH should include assessments of sexual function and monitoring of medication-related sexual side effects. For men with LUTS and sexual dysfunction, an appropriate integrated management approach, based on each patient's symptoms and outcome objectives, is warranted.

Humans↗
PubMed2003

The role of dihydrotestosterone in benign prostatic hyperplasia.

This article examines the role of the androgen dihydrotestosterone (DHT) in the healthy and diseased prostate and considers the implications of the data on DHT for therapeutic approaches to benign prostatic hyperplasia (BPH). Development and maintenance of the normal prostate, as well as development of BPH, depend on a functional androgen-signaling axis, components of which include: (1) testosterone synthesis in the testes and adrenal glands; (2) conversion of testosterone to DHT; (3) transport of DHT to target tissues; and (4) binding of DHT to the androgen receptor with consequent modulation of genes. DHT plays a beneficial role in the developing prostate but it can be detrimental in the adult prostate in that it causes pathologic prostate growth. The role of DHT in other adult tissues is uncertain. DHT has not been shown to perform beneficial functions unique from testosterone in the adult male, and it is believed that its fundamental effect is to amplify testosterone's weaker hormonal signal. Increased understanding of the cellular mechanisms by which the androgen-signaling axis functions has led to advances in treatment for prostate disease. In BPH, the 5alpha-reductase inhibitors--the only class of therapy to act at the pathophysiologic substrate of the disease--arrest the disease process, reduce prostate volume, improve symptoms, and reduce the risk of acute urinary retention and BPH-related surgery. The availability of dutasteride, the first dual (Type 1/Type 2) 5alpha-reductase inhibitor, offers the opportunity for rapid and consistent inhibition of DHT.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed2006

Drug Insight: 5alpha-reductase inhibitors for the treatment of benign prostatic hyperplasia.

Benign prostatic hyperplasia (BPH) is a common problem among older men, which is characterized by an enlarged prostate, lower urinary tract symptoms, and decreased flow of urine. It is a progressive disease that can lead to complications such as acute urinary retention (AUR) or a need for BPH-related surgery in some men. Dihydrotestosterone is the primary androgen involved in both normal and abnormal prostate growth and 5alpha-reductase inhibitors (5ARIs) inhibit the conversion of testosterone to dihydrotestosterone. There are two 5ARIs licensed for the treatment of BPH; dutasteride, which inhibits both type 1 and type 2 isoenzymes of 5alpha reductase, and finasteride, which inhibits the type 2 isoenzyme. Both 5ARIs have been shown to decrease prostate volume, improve urinary flow and lower urinary tract symptoms and reduce the risk of AUR and BPH-related surgery. The prevention of disease progression, by treating the underlying cause, and the alleviation of symptoms are important aims of BPH therapy. 5ARIs are the only currently available medical therapy that can reduce the risk of AUR and BPH-related surgery while providing long-term symptom control. This provides a mandate for their use in men with enlarged prostates (volume >or=30 ml), who are at increased risk of disease progression.

5-alpha Reductase Inhibitors↗
PubMed2003

The Finnish version of The National Institutes Of Health Chronic Prostatitis Symptom Index correlates well with the visual pain scale: translation and results of a modified linguistic validation study.

UNLABELLED: Authors from Finland have assessed a version in their language of the National Institutes of Health-Chronic Prostatitis Symptom Index; they found that their translated version was valid and easily understandable in the management of the symptoms of chronic pelvic pain syndrome. They felt it should be used as a primary outcome measure in studies with these patients. There are three papers in this issue relating to the effect of drugs on LUTS; the first of these is a pooled analysis of three double-blind placebo-controlled studies into the safety and efficacy of the 10 mg dose of alfuzosin. The second evaluates the effect on quality-of-life issues of treatment with dutasteride. Finally, authors from Australia compare the effect of a Serenoa repens extract with placebo for LUTS. OBJECTIVES: To provide a fluent and easily comprehensible Finnish version of the National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) and to study its linguistic validity and correlation with a visual pain scale (VAS). PATIENTS AND METHODS: The double-back translation method with two interim modifications was used to produce the Finnish version of the NIH-CPSI. The validity was tested by presenting the questionnaire to 155 men with clinically confirmed chronic pelvic pain syndrome (CPPS) and 12 controls with no previous urological symptoms. Convergent validity of the NIH-CPSI was tested by determining the correlation between the Finnish NIH-CPSI and VAS. Patients' and urologists' opinions about the utility of the Finnish NIH-CPSI were also reviewed. RESULTS: The total Finnish NIH-CPSI scores and the pain domain and voiding symptom domain scores differed significantly (P < 0.001) between the groups, suggesting good discriminant validity of the symptom index. The NIH-CPSI scores correlated well with the VAS (Pearson's correlation 0.76). The preciseness and comprehensibility of the questionnaire were consistently evaluated to be 'good' or 'excellent' both by patients and urologists. CONCLUSIONS: The Finnish version of the NIH-CPSI is valid and easily comprehensible for measuring CPPS symptoms. In addition, it provides good discriminant and convergent validity in distinguishing CPPS symptoms and should be used as primary outcome measure in CPPS studies.

Case-Control Studies↗
PubMed2006

[Drug therapy for benign prostatic syndrome (BPS)].

Alpha1-receptor blockers (alfuzosin, doxazosin, tamsulosin and terazosin), 5alpha-reductase inhibitors (dutasteride and finasteride) and combinations thereof are used in the drug treatment of benign prostatic syndrome. As before, there is still no evidence supporting the use of plant extracts, the use of anticholinergic substances alone or in combination with other BPS drugs is currently under investigation and should not be attempted outside of clinical trials. For all drugs the placebo effect is considerable. Accordingly, deviations from the recommended doses are rapidly associated with an activity loss over that of placebo. alpha1-Receptor blockers show a rapid onset of action and are slightly superior to 5alpha-reductase inhibitors with regard to the relief of symptoms. All alpha1-receptor blockers are similarly effective at adequate doses, however, quantitative differences are seen in the side effect profiles. 5alpha-reductase inhibitors also provide relief from BPS-associated symptoms with the relief being volume-dependent. Prostate volume-dependent complications of BPS (operation risk and risk of acute urine retention) can be reduced by 5alpha-reductase inhibitors. Long-term drug studies have demonstrated the superiority of combination therapies over monotherapies with alpha1-receptor blockers and 5alpha-reductase inhibitors in patients with a high risk for progression. This superiority is accompanied by a combination of the respective side-effect profiles and their absolute increase. Besides poorer tolerability, combination therapies also result in higher costs. Thus, it is important to decide at an early stage which patients are to be treated with drugs and which by surgery.

5-alpha Reductase Inhibitors↗
PubMed2004

Preventing diseases of the prostate in the elderly using hormones and nutriceuticals.

The prostate has only one function, namely to secrete fluid containing substances that are needed for reproduction. This requires an extremely high concentration of androgens in the tissues. Benign prostatic hypertrophy (BPH) seems to be related to the long-term exposure of the prostate to the strong androgen 5alpha-dihydrotestosterone (DHT) and, possibly, to estrogens. The relation between prostate cancer and androgens is suggested to be U-shaped, with both extremes of androgen concentrations being associated with increased risk of invasive cancer. In the treatment of patients with BPH, the lipidic liposterolic extracts of Serenoa repens were as effective as the pharmaceutical inhibitors of the 5alpha-reductase enzyme or alpha1-adrenergic blockers in relieving urinary symptoms. In addition to moderately inhibiting the 5alpha-reductase activity, Serenoa seems to exert anti-inflammatory and complementary cellular actions with beneficial effects on the prostate. Unlike the pharmaceutical 5alpha-reductase inhibitors, finasteride and dutasteride, Serenoa does not suppress serum PSA, facilitating the follow-up and the early detection of prostate cancer. We suggest a strategy to prevent prostate cancer that aims at providing men with partial androgen deficiency correct testosterone substitution with a sustained release buccal bio-adhesive tablet. In addition, food supplementation with extracts of Serenoa repens and a combination of the antioxidants selenium, (cis)-lycopene and natural vitamin E, together with fish oil rich in long-chain polyunsaturated essential fatty acids of the omega-3 group seems warranted. Clearly, a holistic approach including careful clinical and biological monitoring of the aging man and his prostate remains mandatory.

Aged↗
PubMed2000

Biochemical and pharmacogenetic dissection of human steroid 5 alpha-reductase type II.

Human prostatic steroid 5alpha-reductase, encoded by the SRD5A2 gene on chromosome band 2p23, catalyses the irreversible conversion of testosterone to dihydrotestosterone (DHT), the most active androgen in the prostate, with NADPH as its cofactor. This enzyme has never been purified but a number of competitive inhibitors have been developed for this enzyme since increased steroid 5alpha-reductase activity may cause benign prostatic hypertrophy and prostate cancer. We report here the detailed biochemical and pharmacogenetic dissection of the human enzyme by analysing 10 missense substitutions and three double mutants which are all naturally found in humans. Nine of these 13 mutants reduce activity (measured as Vmax) by 20% or more, three increase steroid 5alpha-reductase by more than 15% and one results in essentially unaltered kinetic properties suggesting that it is a truly neutral ('polymorphic') amino acid substitution. Substantial pharmacogenetic variation among the mutants was also observed when three competitive inhibitors, finasteride, GG745 (dutasteride) and PNU157706, were investigated. Our studies not only define the substrate and cofactor binding sites of human steroid 5alpha-reductase, but also have significant consequences for the pharmacological usage of steroid 5alpha-reductase inhibitors in human patients treated for prostatic conditions.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed2004

Pharmacological therapy of benign prostatic hyperplasia/lower urinary tract symptoms: an overview for the practising clinician.

Less than 10 years ago surgery and watchful-waiting were the only widely accepted management options for lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (BPH) and benign prostatic obstruction (BPO). There has been an enormous decline in the popularity of surgery and it is now apparent that medication is the most frequently used treatment for BPH/LUTS; this has arguably therefore been the most major change in urological clinical practice in the last decade. Currently alpha(1)-adrenoceptor antagonists are the commonest medical therapy, and are thought to act by relaxing prostatic smooth muscle, the neural or so-called 'dynamic' component of BPO. 5alpha-reductase inhibitors (finasteride, dutasteride) are another option for BPH/LUTS, which reduce prostatic mass and therefore the mechanical or 'static' component of BPO. In the last 10 years there have been four direct comparative studies between alpha(1)-adrenoceptor antagonists and finasteride, including their combination, the results of which, and their implications for therapy, are discussed. Another group of agents are the phytotherapeutic extracts, which act via various mechanisms, many as yet poorly defined. This review critically assesses existing publications relating to the medical management of BPH/LUTS.

Adrenergic alpha-Antagonists↗
PubMed2006

Impact of medical treatments for benign prostatic hyperplasia on sexual function.

Lower urinary tract symptoms (LUTS) and male sexual dysfunction are highly prevalent in ageing men, and are strongly linked. Various treatment strategies for benign prostatic hyperplasia (BPH)/LUTS may affect sexuality, with differences between drug classes and between drugs within a same class. The 5alpha-reductase inhibitors, finasteride and dutasteride, are associated with a greater risk of erectile dysfunction (ED), ejaculatory dysfunction (EjD) and decreased libido than is placebo. Alpha1-adrenoceptor blockers (alfuzosin, doxazosin, tamsulosin, terazosin) show an incidence of decreased libido and ED closely similar to placebo, but differ in their impact on ejaculation, tamsulosin being associated with a higher incidence of EjD (10%) than other alpha1-adrenoceptor blockers (0-1%) and placebo (1%), which is unrelated to retrograde ejaculation or higher efficacy. A randomized, placebo-controlled, cross-over study conducted in healthy volunteers showed that tamsulosin 0.8 mg once daily markedly decreased mean ejaculate volume in almost 90% of subjects, with 35% having no ejaculation. By contrast, there was no lack of ejaculation in subjects receiving alfuzosin 10 mg once daily or placebo. Sperm concentrations in urine after ejaculation were similar for the three treatment groups, confirming that the EjD with tamsulosin was unrelated to retrograde ejaculation. It may be related to a peripheral effect on seminal vesicles and/or the vas deferens. A central effect is also plausible, as tamsulosin shows a strong affinity for 5HT1A- and D2-like receptors, both of which are involved in the central command of ejaculation. In conclusion, because treatment options for managing BPH have different effects on sexuality, the sexual dimension should be considered when assessing patients' expectations and the choice of treatment.

5-alpha Reductase Inhibitors↗
PubMed2006

Combination of phosphodiesterase-5 inhibitors and alpha-blockers in patients with benign prostatic hyperplasia: treatments of lower urinary tract symptoms, erectile dysfunction, or both?

As the prevalence of both erectile dysfunction (ED) and lower urinary tract symptoms (LUTS) increases with age, physicians could be in the position to manage these two conditions simultaneously. Moreover, medical therapies for either one of these conditions can affect the other and this should be carefully considered when making treatment decisions. Pharmacotherapy for benign prostatic hyperplasia (BPH)/LUTS can cause side-effects affecting sexual function. Hence, 5alpha-reductase inhibitors such as finasteride and dutasteride are associated with a greater risk of ED, ejaculatory disorders (EjD) and decreased libido than is placebo. Among alpha1-adrenergic blockers, tamsulosin is associated with an increased risk of EjD. However, some alpha1-adrenergic blockers can also have a positive impact on erection. This is the case for alfuzosin, which has been shown to enhance erectile function in experimental models, probably by reducing the sympathetic tone and thus relaxing corpus cavernosum smooth muscle cells. Phosphodiesterase 5 (PDE-5) inhibitors are commonly used to treat ED. There is increasing evidence that they might also have a beneficial effect on LUTS, probably through the nitric-oxide pathway. Nitric oxide is an important mediator of the relaxation of isolated bladder and urethral smooth muscle, and could modulate prostatic smooth muscle tone. Alpha1-adrenergic blockers and PDE-5 inhibitors can therefore have a positive impact on both ED and LUTS. Although placebo-controlled studies are needed to confirm the impact of these drugs, alone or combined, on both ED and LUTS, this reinforces the need for a common approach to managing these two highly prevalent and bothersome conditions.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed2026

Thyroid-stimulating hormone receptor mediates peripheral-central neuroimmune crosstalk in autoimmune thyroid diseases.

BACKGROUND: Organ-specific autoimmune diseases, particularly Graves' disease (GD) and its extrathyroidal manifestation, Graves' orbitopathy (GO), are characterized by systemic autoimmunity that may extend its impact to the central nervous system (CNS). While thyroid-stimulating hormone receptor (TSHR) is the primary driver of pathological remodeling in the thyroid and orbital tissues, emerging evidence suggests it is also expressed in the brain and may participate in neuroimmune signaling. However, the molecular mechanisms linking peripheral TSHR-driven autoimmunity to these extended systemic features remain unclear. Thus, GD and GO provide a unique window to investigate how peripheral autoantibodies influence CNS involvement as part of its broader pathological spectrum. METHODS: Genome-wide association studies (GWAS) and post-GWAS analyses were integrated with bulk RNA sequencing, single-cell and spatial transcriptomics, and brain imaging phenotypes to comprehensively characterize peripheral and central alterations in GD and GO. Mendelian randomization was applied to test causal relationships between genetic variants and brain signatures. Structural biology analyses were further conducted including protein-protein docking, small-molecule docking, and normal mode dynamics to identify prospective modulators of TSHR. Immunofluorescence staining was performed in a GO mouse model to validate the colocalization of potential interacted proteins in the specific brain region. RESULTS: Brain imaging-derived phenotypes (IDPs) alterations in GO and GO were systematically analyzed to identify neuroanatomical and functional alterations. TSHR was further identified as a shared genetic driver across peripheral and central compartments. TSHR was expressed in spiny projection neurons, microglia, and peripheral T cells, with cell-cell communication analyses highlighting TSHR-mediated interactions among neurons, endothelial cells, and microglia. Immunofluorescence staining in a GO mouse model confirmed the colocalization of TSHR with FN1 and GNAS in the basal ganglia, providing tissue-level validation of the computationally predicted ligand-receptor interactions. Immune profiling further showed immune alterations in GD and GO. Structural modeling supported plausible physical interfaces between TSHR and interacting proteins, and small-molecule screening identified three repurposable compounds - venetoclax, irinotecan, and dutasteride - with predicted favorable docking scores and stable binding poses in our simulations. CONCLUSIONS: These findings demonstrate that TSHR acts as a molecular hub mediating peripheral-central neuroimmune crosstalk in GD and GO. The results support a broader "disease-molecule axis" framework that links genetic susceptibility with multi-level immune and neural mechanisms. This work provides mechanistic insights relevant to the development of TSHR-targeted therapies, with implications for both peripheral immune modulation and central regulation. However, the limited sample size, lack of longitudinal follow-up, and absence of in vivo validation warrant cautious interpretation and further investigation.

Receptors, Thyrotropin↗