No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
Finasteride, not tamsulosin, increases severity of erectile dysfunction and decreases testosterone levels in men with benign prostatic hyperplasia
Abstract
5α-reductase inhibitors (5α-RIs) (finasteride and dutasteride) have been proven useful in treatment of lower urinary tract symptoms (LUTS) related to benign prostatic hyperplasia (BPH). However, these inhibitors exert undesirable sexual side effects and, in some cases, these effects are persistent. There is considerable disagreement with regard to whether the adverse side effects resolve with continuous treatment.
To investigate the long-term adverse effects of finasteride treatment in men with BPH on erectile function and to compare these adverse effects in men treated with the α1-adrenergic receptor blocker, tamsolusin.
In this retrospective registry study, a cohort of 470 men aged between 47 and 68 years (mean 57.78±4.81) were treated with finasteride (5 mg/day). A second cohort of 230 men aged between 52 and 72 years (mean 62.62±4.65) were treated with tamsulosin (0.4 mg). All men were followed up for 45 months. At intervals of 3 months and at each visit, plasma testosterone (T) levels and the international index of erectile function (IIEF-EF) questionnaire scores were determined.
Long-term treatment with finasteride therapy is associated with worsening of erectile dysfunction (ED) as shown by the significant decrease in the IIEF-EF scores in men treated with finasteride. No worsening of ED was observed in men treated with tamsulosin. The increase in ED due to finasteride did not resolve with continued treatment with finasteride. Most importantly, long-term finasteride therapy resulted in reduction in total T levels, contributing to a state of hypogonadism. On the contrary, no changes in T levels were noted in men treated with tamsolusin.
Our findings suggest that in men with BPH, long-term finasteride therapy but not tamsulosin results in worsening of ED and reduces total T concentrations. Clinicians are urged to discuss the impact of 5α-RIs therapy on sexual function with their patients before commencing this therapy.
... Traish et al., [129] investigated the impact of finasteride and tamsulosin on the severity of ED in BPH patients for a period of 45 months. In 470 patients, finasteride increased the severity of ED, as assessed by the International Index of Erectile Function (IIEF) and resulted in reduced total testosterone levels [129]. ...
... Traish et al., [129] investigated the impact of finasteride and tamsulosin on the severity of ED in BPH patients for a period of 45 months. In 470 patients, finasteride increased the severity of ED, as assessed by the International Index of Erectile Function (IIEF) and resulted in reduced total testosterone levels [129]. In contrast, in 280 patients treated with tamsulosin, no significant changes in the IIEF scale were noted nor there was a decrease in total testosterone. ...
... More importantly, the aging male symptom score (AMS) increased concomitant with increased activity of alanine amino transferase (ALT) and aspartate aminotransferase (AST) suggesting changes in liver function with finasteride but not with tamsulosin. More importantly, this report [129] demonstrates that the sexual side effects do not resolve with continuous treatment with finasteride as claimed previously [60,61,86]. ...
Steroids are important physiological orchestrators of endocrine as well as peripheral and central nervous system functions. One of the key processes for regulation of these molecules lies in their enzymatic processing by a family of 5α-reductase (5α-Rs) isozymes. By catalyzing a key rate-limiting step in steroidogenesis, this family of enzymes exerts a crucial role not only in the physiological control but also in pathological events. Indeed, both 5α-R inhibition and supplementation of 5α-reduced metabolites are currently used or have been proposed as therapeutic strategies for a wide array of pathological conditions. In particular, the potent 5α-R inhibitors finasteride and dutasteride are used in the treatments of benign prostatic hyperplasia (BPH), as well as in male pattern hair loss (MPHL) known as androgenetic alopecia (AGA). Recent preclinical and clinical findings indicate that 5α-R inhibitors evoke not only beneficial, but also adverse effects. Future studies should investigate the biochemical and physiological mechanisms that underlie the persistence of the adverse sexual side effects to determine why a subset of patients is afflicted with such persistence or irreversible adverse effects. Also a better focus of clinical research is urgently needed to better define those subjects who are likely to be adversely affected by such agents. Furthermore, research on the non-sexual adverse effects such as diabetes, psychosis, depression, and cognitive function are needed to better understand the broad spectrum of the effects these drugs may elicit during their use in treatment of AGA or BPH. In this review, we will summarize the state of art on this topic, overview the key unresolved questions that have emerged on the pharmacological targeting of these enzymes and their products, and highlight the need for further studies to ascertain the severity and duration of the adverse effects of 5α-R inhibitors, as well as their biological underpinnings.
... 5-ARIs are generally known not to cause hypogonadism because 5-ARIs do not decrease total testosterone (TT) [4][5][6][7][8]; decreased testosterone causes hypogonadism. In recent years, 2 reports suggested that 5-ARIs may decrease TT to cause symptoms of hypogonadism [9,10], but there is no report that 5-ARIs caused cold sensation and paresthesia of lower extremities. We here report a patient with strong cold sensation and paresthesia of lower extremities and symptoms of hypogonadism due to 2 types of oral 5-ARIs. ...
... 5α-Reductase inhibitors(5-ARIs); Cold sensation; Dihydrotestosterone; Dutasteride; Finasteride; Hypogonadism; Over-the-counter drugs; Paresthesia of lower extremities; Saw palmetto; Testosterone the patient's age. According to general guidelines, the cut-off value of TT is around 200 to 300 ng/dL [1][2][3][4][5][6][7][8][9][10][11][12], although the reference value is relatively higher in some young people [13]. 5-ARIs are known not to decrease TT. ...
... 5-ARIs are known not to decrease TT. Only two reports have shown that 5-ARIs (finasteride, dutasteride) statistically reduced TT [9,10]. One report suggested that 5-ARIs (dutasteride) tended to reduce TT [14], but it is statistically not significant. ...
Introduction Hypogonadism is a disease to cause decreased energy, libido loss, body hair loss, mood depression, muscle volume reduction, and hot flashes [1-3]. 5α-reductase inhibitors (5-ARIs) are administered orally for male pattern alopecia and benign prostatic hyperplasia due to decrease of dihydrotestosterone, a potent male hormone [4]. 5-ARIs are generally known not to cause hypogonadism because 5-ARIs do not decrease total testosterone (TT) [4-8]; decreased testosterone causes hypogonadism. In recent years, 2 reports suggested that 5-ARIs may decrease TT to cause symptoms of hypogonadism [9,10], but there is no report that 5-ARIs caused cold sensation and paresthesia of lower extremities. We here report a patient with strong cold sensation and paresthesia of lower extremities and symptoms of hypogonadism due to 2 types of oral 5-ARIs. The one was finasteride, an imported medicine for personal use, and the other was saw palmetto, an over-the-counter drug in Japan. Case Presentation A 28-year-old previously healthy man visited our hospital with strong cold sensation and paresthesia of lower extremities for 3 months, and additional symptoms included palpitations, headache, and fatigue. He had been taking 2 tablet-types of 5-ARIs (finasteride (1 mg/day) and saw palmetto (fruit extract 320 mg/day)) for alopecia prevention in the 4 months before his visit. On physical examination, we found no abnormalities in his thyroid gland and limbs. Laboratory testing revealed TT, follicle-stimulating hormone (FSH), and luteinizing hormone (LH) levels of 160 ng/dL, 2.4 mIU/mL, 8.4 mIU/mL, respectively. TT was under the lower end of the range for his age. We diagnosed him with hypogonadism due to a lack of testosterone secretion. Eight days after he stopped taking both drugs, TT, FSH and LH levels improved to 404 ng/dL, 2.3 mIU/mL and 5.1 mIU/mL, respectively. After a month, all symptoms were completely resolved. Discussion From our patient, we have learned the following: 5-ARIs can cause symptoms of hypogonadism. 5-ARIs can cause cold sensation and paresthesia of lower extremities. Medical professionals should review every drug as a potential source of symptoms. Firstly, 5-ARIs can cause symptoms of hypogonadism. In general, primary hypogonadism that develops after puberty is diagnosed by both decreases in TT value and its consistent symptoms [2]; however, it may be under diagnosed due to 2 reasons. First, signs and symptoms of hypogonadism are often unspecific [1]. Second, TT value should be evaluated considering Volume 1 Issue 3-2017 Abstract Hypogonadism causes libido loss, body hair loss, mood depression, muscle volume reduction, and hot flashes. These symptoms can be due to lack of testosterone secretion from the testes or of testosterone action in target organs. 5α-reductase inhibitors (5-ARIs), often contained in hair growth-promoting agent, are known not to cause hypogonadism because they reduce dihydrotestosterone and do not decrease total testosterone (TT). We here report a patient with strong cold sensation and paresthesia of lower extremities and hypogonadism caused by 5-ARIs taken orally. A 28-year-old man visited our hospital with fatigue and strong cold sensation and paresthesia of lower extremities. He was taking 2 tablet-types of 5-ARIs. The one was finasteride (1 mg/day), an imported medicine for personal use, and the other was saw palmetto (fruit extract 320 mg/ day), an over-the-counter drug in Japan. Laboratory testing revealed TT, follicle-stimulating hormone (FSH), and luteinizing hormone (LH) levels of 160 ng/dL, 2.4 mIU/mL and 8.4 mIU/mL, respectively. We diagnosed hypogonadism due to a lack of testosterone secretion. Eight days after discontinuing both drugs, TT, FSH and LH levels improved to 404 ng/dL, 2.3 mIU/mL and 5.1 mIU/mL, and his symptoms improved completely in a month. Physicians should consider 5-ARIs as a cause of cold sensation and paresthesia of lower extremities and carefully check every ingested drug including imported and over-the-counter drugs.
... In 2015, Traish et al [32] reported that long-term finasteride therapy results in worsening of EF and lower total testosterone levels in men with BPH. In their retrospective registry study, a cohort of 470 men aged between 47 and 68 years (mean: 57.78±4.81 ...
... The increase in ED due to finasteride was not resolved by continuing the treatment with finasteride. Most importantly, long-term finasteride therapy resulted in reduced total testosterone levels that contributed to a state of hypogonadism [32]. ...
Finasteride is primarily used to treat benign prostatic hyperplasia (BPH) and male androgenetic alopecia (MAA). Five-alpha reductase inhibitors (5α-RIs) could induce male sexual dysfunction due to their effects on testosterone and dihydrotestosterone. There is evidence suggesting that 5α-RIs may independently increase the risk of erectile dysfunction (ED). However, many investigators believe that side effects of 5α-RIs will disappear with continuous treatment. Considerable controversy exists regarding the severity and persistence of side effects of finasteride on ED. The aim of this review was to summarize current research studies on finasteride associated with ED. The search strategy used each term of finasteride and ED against PubMed database to identify related studies. ED data reported from available trials for finasteride were summarized and reviewed. Although there is not enough evidence to prove the relationship between finasteride and ED, most studies in this review found that finasteride for BPH was correlated with ED. However, most studies included in this review revealed that finasteride for MAA was not correlated with ED. On the other hand, some studies reported side effects of finasteride associated with sexual dysfunction, including ED, male infertility, ejaculation problem, and loss of libido, even in MAA patients. Well-designed randomized controlled trials are needed to further determine the mechanism and effects of finasteride on ED. However, physicians should discuss with their patients possible long-term effects of finasteride on sexual function, although we do not have evidence showing that adverse events of sexual dysfunction are absolutely associated with 5α-RIs.
... 5a-Rs play key physiological roles in regulation and development of male sexual differentiation and metabolism (1)(2)(3)(4)(5)(6)(7). 5a-Rs catalyze the transformation of multiple gonadal, adrenal and CNS steroid precursors into active functional hormones and neuroactive steroids (8)(9)(10)(11)(12)(13)(14)(15). ...
... A body of evidence exists supporting the presence of a constellation of sexual, physical, and psychological symptoms that develop during and/or after finasteride exposure and persist after drug discontinuation (83)(84)(85)(86). It is important to note that the sexual adverse side effects of finasteride have been reported in almost all clinical studies, albeit with varying degrees of severity (12,13,14,. Table 1 summarizes findings of studies with finasteride or dutasteride in the treatment of men with BPH or for prevention of prostate cancer (87, 88, 90, 95, 97-99, 106, 112, 115, 119-126). ...
Post-finasteride syndrome (PFS) is a constellation of serious adverse side effects manifested in clinical symptoms that develop and persist in patients during and/or after discontinuing finasteride treatment in men with pattern hair loss (androgenetic alopecia) or benign prostatic hyperplasia. These serious adverse side effects include persistent or irreversible sexual, neurological, physical and mental side effects. To date, there are no evidence-based effective treatments for PFS. Although increasing number of men report persistent side effects, the medical community has yet to recognize this syndrome nor are there any specific measures to address this serious and debilitating symptoms. Here we evaluate the scientific and clinical evidence in the contemporary medical literature to address the very fundamental question: Is PFS a real clinical condition caused by finasteride use or are the reported symptoms only incidentally associated with but not caused by finasteride use? One key indisputable clinical evidence noted in all reported studies with finasteride and dutasteride was that use of these drugs is associated with development of sexual dysfunction, which may persist in a subset of men, irrespective of age, drug dose or duration of study. Also, increased depression, anxiety and suicidal ideation in a subset of men treated with these drugs were commonly reported in a number of studies. It is important to note that many clinical studies suffer from incomplete or inadequate assessment of adverse events and often limited or inaccurate data reporting regarding harm. Based on the existing body of evidence in the contemporary clinical literature, the author believes that finasteride and dutasteride induce a constellation of persistent sexual, neurological and physical adverse side effects, in a subset of men. These constellations of symptoms constitute the basis for PFS in individuals predisposed to epigenetic susceptibility. Indeed, delineating the pathophysiological mechanisms underlying PFS will be of paramount importance to the understanding of this syndrome and to development of potential novel therapeutic modalities.
... Men with prostatic hyperplasia who were exposed to dutasteride had an increase over baseline of serum testosterone levels at one year (Hong et al., 2010). However, a long-term study found that men with prostatic hyperplasia who were exposed to finasteride had a progressive, and clinically significant, decline in testosterone over 45 months (Traish et al., 2015a). In men exposed to finasteride for one week, effective androgen levels in the prostate are similar to those in castrated men (Geller & Sionit, 1992). ...
... A report of a 5-year study found that about 10% of men with prostatic hyperplasia experienced erectile dysfunction (ED) with finasteride exposure but this report omitted mention of persistence of ED (Hudson et al., 1999). Another long-term study found a progressive and sustained worsening of erectile function in men with prostatic hyperplasia who had continued exposure to finasteride, with a clinically significant decline of six to eight points in international index of erectile function (IIEF)-EF score over 45 months (Traish et al., 2015a). ...
Importance
Case reports describe persistent erectile dysfunction (PED) associated with exposure to 5α-reductase inhibitors (5α-RIs). Clinical trial reports and the manufacturers’ full prescribing information (FPI) for finasteride and dutasteride state that risk of sexual adverse effects is not increased by longer duration of 5α-RI exposure and that sexual adverse effects of 5α-RIs resolve in men who discontinue exposure.
Objective
Our chief objective was to assess whether longer duration of 5α-RI exposure increases risk of PED, independent of age and other known risk factors. Men with shorter 5α-RI exposure served as a comparison control group for those with longer exposure.
Design
We used a single-group study design and classification tree analysis (CTA) to model PED (lasting ≥90 days after stopping 5α-RI). Covariates included subject attributes, diseases, and drug exposures associated with sexual dysfunction.
Setting
Our data source was the electronic medical record data repository for Northwestern Medicine.
Subjects
The analysis cohorts comprised all men exposed to finasteride or dutasteride or combination products containing one of these drugs, and the subgroup of men 16–42 years old and exposed to finasteride ≤1.25 mg/day.
Main outcome and measures
Our main outcome measure was diagnosis of PED beginning after first 5α-RI exposure, continuing for at least 90 days after stopping 5α-RI, and with contemporaneous treatment with a phosphodiesterase-5 inhibitor (PDE 5 I). Other outcome measures were erectile dysfunction (ED) and low libido. PED was determined by manual review of medical narratives for all subjects with ED. Risk of an adverse effect was expressed as number needed to harm (NNH).
Results
Among men with 5α-RI exposure, 167 of 11,909 (1.4%) developed PED (persistence median 1,348 days after stopping 5α-RI, interquartile range (IQR) 631.5–2320.5 days); the multivariable model predicting PED had four variables: prostate disease, duration of 5α-RI exposure, age, and nonsteroidal anti-inflammatory drug (NSAID) use. Of 530 men with new ED, 167 (31.5%) had new PED. Men without prostate disease who combined NSAID use with >208.5 days of 5α-RI exposure had 4.8-fold higher risk of PED than men with shorter exposure (NNH 59.8, all p < 0.002). Among men 16–42 years old and exposed to finasteride ≤1.25 mg/day, 34 of 4,284 (0.8%) developed PED (persistence median 1,534 days, IQR 651–2,351 days); the multivariable model predicting PED had one variable: duration of 5α-RI exposure. Of 103 young men with new ED, 34 (33%) had new PED. Young men with >205 days of finasteride exposure had 4.9-fold higher risk of PED (NNH 108.2, p < 0.004) than men with shorter exposure.
Conclusion and relevance
Risk of PED was higher in men with longer exposure to 5α-RIs. Among young men, longer exposure to finasteride posed a greater risk of PED than all other assessed risk factors.
... The duration of these reported adverse effects is debated with evidence for a significant increase only during the first year of treatment and/or resolution upon drug discontinuation, 10,14,15,[22][23][24] as well as for worsening with time and persistence after medication is discontinued. [25][26][27][28][29] Those studies which suggest that symptoms of sexual dysfunction increase over time and/or persist after finasteride treatment has been ceased are usually retrospective, contain a patient population recruited from a related website and lack placebo controls. Thus, the results are subject to selection bias, possible placebo effects due to unknown prior counselling and recall bias as many had been experiencing sexual side effects for more than 3 years. ...
... Analysing clinical trial data, it is uncommon for a patient to leave a study due to sexual side effects, suggesting there is still benefit. [7][8][9]18,28,40 To complicate the issue, physicians must be careful in patient counsel as this could increase chances of symptom development. It is therefore strongly recommended that an accurate identification of risk factors for the development of sexual dysfunction be determined to allow for the safe continuation of finasteride use in the treatment of AGA. ...
Background:
Post-marketing reports suggest that finasteride causes sexual dysfunction despite a low incidence reported in clinical trials. Therefore, the extent of risk remains unknown.
Objective:
To determine whether the risk of sexual dysfunction is higher among individuals treated with finasteride compared to a baseline risk for all other drugs using the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) database.
Methods:
A case by non-case disproportionality approach was used whereby a Reporting Odds Ratio (ROR) with 95% confidence interval (CI) was calculated. The National Ambulatory Medical Care Survey (NAMCS) was used to confirm results.
Results:
A significant disproportionality in reporting of sexual dysfunction with the use of finasteride was observed whether finasteride was indicated for hair loss (ROR = 138.17, 95% CI: 133.13, 143.4), prostatic hyperplasia (ROR= 93.88, 95% CI: 84.62, 104.16) or any indication (ROR= 173.18, 95% CI: 171.08, 175.31). When these results were stratified by age, disproportionality was strongest at 31-45 years.
Conclusion:
Use of finasteride has led to an increase in reports of sexual dysfunction where it is believed to be the primary suspect. This article is protected by copyright. All rights reserved.
... A recent study (Stanczyk et al., 2013) also observed significant increases from baseline in testosterone levels at 1, 3, 6 and 12 months in 5 mg finasteride daily treated patients having elevated serum PSA (>4.0 ng/mL). However, a very recent study investigating the long-term adverse effects of finasteride treatment in men with BPH found reduction in TT levels, apparently contributing to a state of hypogonadism (Traish et al., 2015a). It is to note that studies performed in BPH patients were not designed to investigate hormonal levels after discontinuation of the drug. ...
Concern regarding adverse effects of finasteride is increasing. We aimed to determine the type and frequency of symptoms in men having long-term sexual and non-sexual side effects after finasteride treatment (a condition recently called post-finasteride syndrome, PFS) against androgenetic alopecia (AGA). Subjects were recruited at the Urology Unit of the Trieste University-Hospital, and from a dedicated website. Out of 79 participants, 34% were white Italians, mean age was 33.4 ± 7.60 years, mean duration of finasteride use was 27.3 ± 33.21 months; mean time from finasteride discontinuation was 44.1 ± 34.20 months. Symptoms were investigated by an ad hoc 100 questions' questionnaire, and by validated Arizona Sexual Experience Scale (ASEX) and Aging Male Symptom Scale (AMS) questionnaires. By ASEX questionnaire, 40.5% of participants declared getting and keeping erection very difficult, and 3.8% never achieved; reaching orgasm was declared very difficult by 16.5%, and never achieved by 2.5%. By the ad hoc questionnaire, the most frequent sexual symptoms referred were loss of penis sensitivity (87.3%), decreased ejaculatory force (82.3%), and low penile temperature (78.5%). The most frequent non-sexual symptoms were reduced feeling of life pleasure or emotions (anhedonia) (75.9%); lack of mental concentration (72.2%), and loss of muscle tone/mass (51.9%). We contributed to inform about symptoms of PFS patients; unexpectedly loss of penis sensitivity was more frequent than severe erectile dysfunction and loss of muscle tone/mass was affecting half of the subjects. Further studies are necessary to investigate the pathophysiological and biochemical pathways leading to the post-finasteride syndrome.
... corrected p-value 0.014, and right thalamus ([15,?27,9]; peak z-score ?3.3; corrected p-value 0.008). Positive correlation was identified in the right mid cingulate cortex ([9, 6, 48]; peak z-score 3.55; corrected p-value 0.005). In the corresponding plots with regression lines (center figures), individual patient's differential BOLD neural activation changes in the erotic vs. nonerotic doi: 10.1210/jc.2016-2726 ...
Context:
Some men who use finasteride for hair loss report persistent sexual and other symptoms after discontinuing finasteride therapy.
Objective:
To determine whether these persistent symptoms after discontinuation of finasteride use are due to androgen deficiency, decreased peripheral androgen action, or persistent inhibition of steroid 5?-reductase (SRD5A) enzymes.
Participants:
Finasteride-users, who reported persistent sexual symptoms after discontinuing finasteride (group 1); age-matched finasteride-users who did not report sexual symptoms (group 2); and healthy men who had never used finasteride (group 3).
Outcomes:
Sexual function, mood, affect, cognition, hormone levels, body-composition, functional magnetic resonance imaging (fMRI) response to sexually and affectively-valenced stimuli, nucleotide sequences of androgen receptor (AR), SRD5A1 and SRD5A2; expression levels of androgen-dependent genes in skin Setting: Academic medical center Results: Symptomatic finasteride-users were similar in body composition, strength, and nucleotide sequences of AR, SRD5A1 and SRD5A2 genes to asymptomatic finasteride-users and nonusers. Symptomatic finasteride-users had impaired sexual function, higher depression scores, a more negative affectivity balance, and more cognitive complaints than men in groups 2 and 3, but had normal objectively-assessed cognitive function. Testosterone, DHT, 5?-androstane-3?,17|gb-diol glucuronide, testosterone-to-DHT and androsterone glucuronide-to-etiocholanolone glucuronide ratios, and markers of peripheral androgen action, and expression levels of AR-dependent genes in skin did not differ among groups. fMRI BOLD responses to erotic and nonerotic stimuli revealed abnormal function in brain circuitry linked to sexual arousal and major depression.
Conclusions:
We found no evidence of androgen deficiency, decreased peripheral androgen action, or persistent peripheral inhibition of SRD5A in men with persistent sexual symptoms after finasteride use. Symptomatic finasteride-users revealed depressed mood and fMRI findings consistent with those observed in depression.
... [7] Therefore, androgen receptor, enzymes involved in androgens and estrogens metabolism, and DNA repair-related genes are critical for PC progression. [2,[8][9][10] In addition to hormone-related metabolites and genes, micro-RNAs (miRNAs) also play critical roles in PC progression. MiRNAs are small regulatory RNAs which post-transcriptionally repress the expression of target genes by binding to mRNA sequences and promoting mRNA degradation. ...
Prostate cancer (PC) is a common neoplasm, and metastatic PC remains incurable. The study aims to screen key microRNAs (miRNAs) and transcription factors (TFs) involved in PC.
The miRNA expression profile dataset (GSE45604) was downloaded from Gene Expression Omnibus database, including 50 PC and 10 normal specimens. Differentially expressed miRNAs (DEmiRNAs) were identified through limma package in R, and DEmiRNA–DEmiRNA co-regulation network was constructed based on the number of co-regulated target genes. Functional enrichment analysis of co-regulated target genes was performed using clusterProfiler package in R, and miRNA interactions sharing at least 1 functional term were used to construct a DEmiRNA–DEmiRNA functional synergistic network (MFSN). Based on Transcriptional Regulatory Element Database, cancer-related TFs which were co-regulated by DEmiRNAs were utilized to construct a DEmiRNA–TF regulation network.
A total of 66 DEmiRNAs were identified, including 7 up-regulated miRNAs with 18,642 target genes and 59 down-regulated miRNAs with 130,694 target genes. Then, the DEmiRNA–DEmiRNA co-regulation network was constructed, including 66 DEmiRNAs and 2024 co-regulation relationships. In MFSN, hsa-miR-1184, hsa-miR-1207-5p, and hsa-miR-24 had significant functional synergistic relationships. The DEmiRNA–TF network contained 6 up-regulated DEmiRNAs and 4 of them were highlighted, as hsa-miR-1184, hsa-miR-1207-5p, hsa-miR-182, and hsa-miR-183. In subnetwork of the 4 miRNAs, peroxisome proliferative activated receptor, alpha (PPARA) and cyclic AMP-responsive element modulator (CREM) were the critical regulated TFs.
Four up-regulated miRNAs (hsa-miR-1207-5p, hsa-miR-1184, hsa-miR-182, and hsa-miR-183) and 2 TFs (PPARA and CREM) were identified as key regulators in PC progression. The above 4 miRNAs might participate in PC progression by targeting PPARA and CREM.
... This relieves the clinical symptoms of benign prostatic hyperplasia and improves the lower urinary tract symptoms regardless of whether they receive surgery (5). At this time, a variety of selective α 1 -receptor blockers are available for clinical use (6). However, it is unclear which specific agents can improve lower urinary tract symptoms, male sexual function, and quality of life. ...
The purpose of the present study was to compare the effectiveness of two common α1-receptor blockers, alfuzosin and tamsulosin, on lower urinary tract symptoms, sexual function, and quality of life in young and middle-aged people with benign prostatic hyperplasia. We recruited 80 young and middle-aged patients with benign prostatic hyperplasia and divided them into two groups that received either the non-selective α1-receptor blocker alfuzosin or the selective α1A-receptor blocker tamsulosin for 18 consecutive days. After intervention, maximum urinary flow, bladder compliance, maximum detrusor pressure, maximum urethral pressure, 72 h urination frequency and urination frequency at night, average urinary volume, residual urinary volume, urinary symptom distress score were significantly better in the tamsulosin group than in the alfuzosin group. Also, sperm density, sperm motility, sperm activity, and sperm DNA fragmentation index were significantly better in the tamsulosin group compared to the alfuzosin group. Finally, international index of erectile function-5 scores, increased libido and erection, retrograde ejaculation, and the quality of life were significantly better in the tamsulosin group compared to the alfuzosin group. Overall, tamsulosin effectively relieved the lower urinary tract symptoms, improved semen quality, and increased sexual life and quality of life in young and middle-aged patients with benign prostatic hyperplasia.
... Table 1 summarizes some of the symptoms of post-finasteride syndrome (PFS) that most clearly align with evidence of its demasculinizing and feminizing effects. Post-finasteride syndrome is a condition characterized by altered circulating and brain steroid levels and adverse physical and psychological effects that occur even after finasteride treatment is ceased [50,54,[58][59][60][61][62]. ...
Purpose of Review
Here, we summarize current knowledge of androgens’ action gained over the recent years.
Recent Findings
Neurosteroids are produced in the brain and peripheral nerves, independent of endocrine glands have been investigated for how they are regulated, and have actions via non-steroid receptor targets to mediate social, affective, and cognitive behavior and to protect the brain. Androgens’ organizing actions in the peri-natal period have effects throughout the lifetime that may be recapitulated later in life during critical periods and at times of challenge. Developmental changes in androgens occur during mid-childhood, adrenarche, puberty, adolescence, young adulthood, middle age, and andropause. Changes in androgens with a 5α-reductase inhibitor, such as finasteride, result in disruptions in organizational and activational functions of androgens that can be unremitting.
Summary
Normal developmental or perturbation in androgens through other means can cause changes in androgen-sensitive phenotypes throughout the lifespan, in part through actions of neurosteroids.
... ± 4.8 years) or tamsulosin 0.4 mg (n = 230, mean age = 62.6 ± 4.7 years). The men treated with finasteride had an increased rate of erectile dysfunction (a 6-8 point reduction in IIEF scores) than the men treated with tamsulosin [18]. In contrast, Stojanovic et al. found the highest rates of diminished orgasmic and ejaculatory dysfunction in patients treated for BPH with tamsulosin alone compared to tamsulosin + finasteride or finasteride alone (n = 156, p < 0.01) [19]. ...
Purpose of Review
A constellation of persistent adverse effects—collectively termed post-finasteride syndrome (PFS)—after 5α-reductase inhibitor treatment for benign prostatic hyperplasia (BPH) and androgenic alopecia (AGA) has recently been described. The severity of these sexual, physical, neurological, and psychiatric side effects raises important concerns regarding the treatment of these conditions, especially given the prevalence of indications for these medications. Here we review the literature exploring the symptoms, proposed mechanisms, and potential disease modulating factors for PFS.
Recent Findings
While the persistent sexual side effects associated with PFS are well documented, research on the physical, neurological, and psychiatric adverse effects is much less ubiquitous. Though the mechanisms leading to PFS have been proposed, a clear treatment plan for these patients has not been established. In the treatment of BPH and AGA with 5α-reductase inhibitors, the risks of PFS should be considered.
Summary
The occurrence of persistent adverse sexual, physical, neurological, and psychiatric side effects after 5α-reductase inhibitor is well supported by the existing data. While additional studies are needed to better evaluate the role of 5α-reductase inhibitors in the manifestation of the symptoms of PFS, the risks of PFS should be critically evaluated when treating patients with BPH or AGA.
... The findings of our prospective trial indicate that the IIEF-5 score decreased from baseline in the BSM (tamsulosin and finasteride) group after 6-month standard medical treatment. The adverse effect of finasteride may be the main cause (22). Interestingly, the IIEF-5 score increased moderately from baseline in the curcumin + BSM group. ...
Background:
To perform a prospective, randomized, single center study to investigate the efficacy of combined use of curcumin, an anti-inflammatory agent, with the best standard management (BSM, tamsulosin and finasteride) in benign prostatic hyperplasia (BPH) patients.
Methods:
One hundred and twenty-two consecutive patients were randomized to receive tamsulosin 0.2 mg, finasteride 5 mg, and curcumin 2,250 mg once a day (curcumin + BSM group, n=61) versus tamsulosin 0.2 mg, finasteride 5 mg, and placebo (BSM group, n=61) for 6 months. The safety of treatments and their efficacy on improving waist circumference (WC), periprostatic fat thickness (PPFT), lower urinary tract symptoms (LUTS), and sexual function were assessed at baseline and month 6.
Results:
One hundred and sixteen patients completed the whole procedure (116/122, 95.1%). There were significant improvements in prostate volume (PV), maximum flow rate (Qmax), the International Prostate Symptom Score (IPSS), IPSS-voiding subscore (IPSS-V), IPSS-storage subscore (IPSS-S), and quality of life (QoL) from baseline after treatment in both groups. Additionally, both WC and PPFT decreased significantly after treatments than those at baseline in the curcumin + BSM group. Also, WC and PPFT in the curcumin + BSM group were significantly lower than those in the BSM group. In addition, IPSS-S, QoL score, and the 5-item version of the International Index of Erectile Function (IIEF-5) in the curcumin + BSM group improved significantly compared with those in the BSM group.
Conclusions:
We conclude that curcumin combined with tamsulosin and finasteride has more beneficial effects in reducing PPFT, protecting erectile function, improving urinary retention symptoms, and QoL scores in BPH patients compared to tamsulosin and finasteride alone.
Trial registration:
Chinese Clinical Trial Registry ChiCTR2100043800.
... As DHT is the most active androgen hormone, the reduced levels of this hormone is associated with prostatic volume reduction [7][8][9][10]. However, DHT is also responsible for other metabolic functions, and treatment with 5ARI is associated with adverse effects such as erectile dysfunction (ED) decreased libido and decreased ejaculation [11][12][13]. ...
Objective: The aim of this study was to investigate whether concomitant treatment of dutasteride and sildenafil could prevent structural changes in the penis of a BPH rodent model.
Methods: Thirty-two adult male rats were divided into the following groups: Ctrl, untreated control rats; BPH, untreated spontaneously hypertensive rats (SHRs); BPH + D, SHRs treated with dutasteride; and BPH + DS, SHRs treated with dutasteride and sildenafil. All treatments were performed during 40 days, following which the penises were collected for histomorphometrical analysis. The results were compared via one-way ANOVA with Bonferroni’s post-test, considering p values <.05 as significant.
Results: The smooth muscle density decreased by 28.6% and 21.4% in BPH + D and BPH + DS, respectively, when compared to the BPH group. The sinusoid space density reduced by 32.2% in BPH, when compared to the Ctrl group; this density was also reduced by 22.6% in BPH + D, when compared to the BPH group. The density of the elastic fibers increased 51.6% and 65.6% in BPH + D and BPH + DS, when compared to the BPH group.
Conclusion: Treatment with dutasteride promoted morphological changes in the corpus cavernous of this BPH model. Concomitant treatment with sildenafil did not prevent the morphological changes caused by dutasteride; on the contrary, it also promoted a further increase in elastic fibers.
... Two observational studies in humans have shown that longer exposure to finasteride posed a greater risk of ED and worsening ED [13,14]. This study aimed to investigate the effects of dutasteride treatment duration on causing persistent ED even after discontinuation of treatment in a rat model. ...
Purpose: The current study is aimed to assess whether a longer duration of 5α-reductase inhibitor (5α-RI) exposure was asso-ciated with higher rate of permanent erectile dysfunction (ED) in a rat model.
Materials and Methods: Male Sprague-Dawley rats (n=76) were assigned to five groups: (i) normal control group; (ii) dutaste-ride (0.5 mg/rat/d) for 4-weeks group; (iii) dutasteride for 4-weeks plus 2-weeks of resting group; (iv) dutasteride for 8-weeks group; and (v) dutasteride for 8-weeks plus 2-weeks of resting group. In vivo erectile responses to electrical stimulation, and changes of fibrotic factors and smooth muscle/collagen contents in the corpus cavernosum were evaluated in each group.
Results: Dutasteride administration for 4 and 8 weeks significantly decreased erectile parameters compared with the control group. Reduced erectile responses were recovered during 2 weeks of drug-free time in the 4-week treatment group, but were not in the 8-week group. Protein levels of fibrosis-related factors transforming growth factor (TGF)-β1, TGF-β2, and p-Smad/Smad (Smad 2/3) in the corpus cavernosum showed no significant change after 4 weeks of dutasteride oral administration, but were enhanced after 8 weeks. Dutasteride markedly decreased smooth muscle content and increased collagen after 4 and 8 weeks of use, but no nuclear size changes; however, neither group showed significant improvement in the smooth muscle to collagen ratio after the rest period.
Conclusions: Our study showed that recovery from ED depended on the duration of medication, and administration of dutas-teride for more than 8-weeks in rats could result in irreversible ED even after discontinuation of medication.
... [24][25][26] As noted elsewhere, the undesirable sexual side effects of finasteride can negatively impact the IIEF-5 score. 27 Interestingly, we found that patients with BPH and high PPFT may have more severe ED and undesirable sexual side effects than patients with BPH and low PPFT. As a result, the combination therapy for patients with BPH with high PPFT should include tadalafil, which is often used to treat ED in men. ...
This study investigated the correlation between periprostatic fat thickness (PPFT) measured on magnetic resonance imaging and lower urinary tract symptoms, erectile function, and benign prostatic hyperplasia (BPH) progression. A total of 286 treatment-naive men diagnosed with BPH in our department between March 2017 and February 2019 were included. Patients were divided into two groups according to the median value of PPFT: high (PPFT >4.35 mm) PPFT group and low (PPFT <4.35 mm) PPFT group. After the initial evaluation, all patients received a combination drug treatment of tamsulosin and finasteride for 12 months. Of the 286 enrolled patients, 244 completed the drug treatment course. Patients with high PPFT had larger prostate volume (PV; P = 0.013), higher International Prostate Symptom Score (IPSS; P = 0.008), and lower five-item version of the International Index of Erectile Function (IIEF-5) score (P = 0.002) than those with low PPFT. Both high and low PPFT groups showed significant improvements in PV, maximum flow rate, IPSS, and quality of life score and a decrease of IIEF-5 score after the combination drug treatment. The decrease of IIEF-5 score was more obvious in the high PPFT group than that in the low PPFT group. In addition, more patients in the high PPFT group underwent prostate surgery than those in the low PPFT group. Moreover, Pearson's correlation coefficient analysis indicated that PPFT was positively correlated with age, PV, and IPSS and negatively correlated with IIEF-5 score; however, body mass index was only negatively correlated with IIEF-5 score.
... And it was found that dutasteride increased the severity of erectile dysfunction in the treatment of BPH [17]. In light of this, Traish AM et al. revealed that finasteride aggravates the symptoms of ED and could decrease the testosterone levels for patients with BPH; however, they could not find the side effect for tamsulosin [18]. And the α1-blockers have been investigated potential therapeutic for ED [19]. ...
Purpose:
The purpose of this study was to compare the relative safety and efficacy of different types of phosphodiesterase type 5 inhibitors (PDE5-Is) with tamsulosin for the treatment of lower urinary tract symptoms (LUTS) secondary to benign prostate hyperplasia (BPH) (BPH-LUTS) with or without erectile dysfunction (ED).
Methods:
We use the Stata version 13.0 to conduct the network meta-analysis (NMA) with a random effects model of the Bayesian framework. The International Prostate Symptom Score (IPSS), Maximum Urinary Flow Fate (Qmax), International Index of Erectile Function (IIEF), and their credible intervals (CI) were used to compare the efficacy and safety of every medical intervention, including sildenafil plus tamsulosin, tadalafil plus tamsulosin, and vardenafil plus tamsulosin.
Results:
Seven RCTs including 531 participants with seven interventions were analyzed. The results of NMA SUCRA showed that compared with different doses or types of PDE5-Is combined with tamsulosin (0.4 mg qd), the sildenafil (25 mg qd) combined with tamsulosin (0.4 mg qd) group had the greatest probabilities of being the best in the achievement of improving IIEF. The sildenafil (25 mg 4 days per week) combined with tamsulosin (0.4 mg qd) group had the greatest probabilities of being the best in the achievement of improving Qmax, whereas sildenafil (25 mg qd) combined with tamsulosin (0.4 mg qd) ranked the best for the safety outcomes.
Conclusions:
This meta-analysis indicates that sildenafil combined with tamsulosin is the best effective and tolerated treatment option for BPH-LUTS with or without ED. Further RCTs are strongly required to provide more direct evidence.
... Concurrently, there is a correlation between patients with ejaculatory disorders after the use of α-blockers, whose explanation is that blockade of α-adrenergic receptors in the urinary tract causes relaxation of the smooth muscle of the epididymis, seminal ducts, and vas deferens, which can lose the power of contraction and, therefore, of semen ejection. The ejaculatory disorder resulting from tamsulosin is characterized as retrograde ejaculation [33,[42][43][44][45][46][47][48][49][50][51]. ...
In the United States, tamsulosin is the most prescribed drug for benign prostatic hyperplasia (BPH) treatment. However, less is known about the adverse effects and mechanism of action of the drug in the organism. So, the aim of this review is to evaluate the benefits and harms of tamsulosin therapy in patients with BPH. A literature analysis was realized using the database of the National Center for Biotechnology Information (NCBI) MEDLINE®. The data collection was carried out in a retrospective of 10 years from 2008. Thus, we considered some measurements parameters used in different studies for a reliable comparison of the works. Tamsulosin has been characterized as an effective treatment for BPH. However, some studies demonstrate that the epithelial elements remain proliferative even after the administration of the drug and may be involved in the continuous growth of the gland. Also, tamsulosin can directly impact on the ejaculation process, cognitive functions and mental health of men. BPH affects approximately 50% of men between 50 and 60 years old. Beyond that, 90% of men in their eighth decade of life will present anatomical evidence of BPH. Therefore, the treatment with tamsulosin, an α1-adrenergic antagonist that promotes the relaxation of the prostate smooth muscle, is essential to diminish the gland size and restore the urinary flow. However, its administration must be assessed for a better response and lower risk of adverse effects in those patients.
5α-Reductase inhibitors (5α-RIs) such as finasteride and dutasteride have proven useful in clinical management of lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH) and also in treatment of androgenetic alopecia (AGA). However, these drugs have serious and, in some patients, persistent or irreversible sexual side effects. These agents interfere with the biosynthesis and metabolism of neurosteroids and may adversely affect mood, stress, and anxiety and potentiate the onset of depression. Data from preclinical and clinical studies have provided substantial evidence that these agents cause loss or reduction of libido, increase the risk of erectile dysfunction and ejaculatory dysfunction, and may contribute to the onset of depression. It is imperative that clinicians give serious considerations to these adverse effects and their impact on patients’ health and engage their patients in an open and honest discussion regarding the potential harm of these agents prior to prescribing them.
Circulating androgens can profoundly influence target cutaneous structures such as the pilosebaceous unit (hair follicle and sebaceous gland), and play a central role in the pathogenesis of cutaneous disorders of hyperandrogenism (CHA) which include androgenetic alopecia (AGA), acne vulgaris, and hirsutism. Therapeutically, two main categories of drugs affect androgens and their activity. The first are ‘antiandrogens’ which are agents that block the androgen receptor (AR) and include spironolactone, flutamide, and cyproterone acetate. The second are ‘androgen inhibitors,’ which block androgen synthesis, and include finasteride and dutasteride (these are specific 5-α reductase inhibitors, that inhibit formation of dihydrotestosterone [DHT]), as well as leuprolide, (which is a gonadotropin-releasing hormone (GnRH) agonist, and works at the level of the ovary and pituitary). In this chapter ‘antiandrogens’ is the term used for specific AR blockers, and the term ‘androgen inhibitors’ will be used to distinguish those compounds that work by suppressing or inhibiting the formation of DHT. Other agents such as progestins and combined oral contraceptives (COC) are both antiandrogens and androgen inhibitors. The various drugs discussed in this chapter are categorized by their most important clinical mode of action. This chapter provides an overview of various antiandrogens (drugs that block the AR) and androgen inhibitors (enzyme inhibitors and other mechanisms). How these specific compounds work, their approved and off-label indications, dosing, and adverse effects will be presented. Particular emphasis is given to spironolactone, finasteride, dutasteride, and oral contraceptives.
Introduction:
5α-Reductase inhibitors (5ARIs) are widely used for the treatment of benign prostatic hyperplasia (BPH) and androgenetic alopecia (AGA).
Aim:
To review all the available data on the effect of 5ARIs on sexual function and assess whether 5ARIs increase the risk of sexual dysfunction.
Methods:
A systematic search of the literature was conducted using the Medline, Embase, and Cochrane databases. The search was limited to articles published in English and up to October 2015. Article selection proceeded according to the search strategy based on Preferred Reporting Items for Systematic Reviews and Meta-analyses criteria. Data were analyzed using Stata 12.0. A fixed- or a random-effects model was used to calculate the overall combined risk estimates. Publication bias was assessed using Begg and Egger tests.
Main outcome measures:
Sexual dysfunction, erectile dysfunction, and decreased libido.
Results:
After screening 493 articles, 17 randomized controlled trials with 17,494 patients were included. Nine studies evaluated the efficacy of 5ARIs in men with BPH. The other eight reported using 5ARIs in the treatment of men with AGA. The mean age of participants was 60.10 years across all studies. We included 10 trials (6,779 patients) on the efficacy and safety of finasteride, 4 trials (6,222 patients) on the safety and tolerability of dutasteride, and 3 trials (4,493 patients) using finasteride and dutasteride for AGA. The pooled relative risks for sexual dysfunction were 2.56 (95% CI = 1.48-4.42) in men with BPH and 1.21 (95% CI = 0.85-1.72) in men with AGA; those for erectile dysfunction were 1.55 (95% CI = 1.14-2.12) in men with BPH and 0.66 (95% CI = 0.20-2.25) in men with AGA; and those for decreased libido were 1.69 (95% CI = 1.03-2.79) in men with BPH and 1.16 (95% CI = 0.50-2.72) in men with AGA. Estimates of the total effects were generally consistent with the sensitivity analysis. No evidence of publication bias was observed.
Conclusion:
Evidence from the randomized controlled trials suggested that 5ARIs were associated with increased adverse effects on sexual function in men with BPH compared with placebo. However, the association was not statistically significant in men with AGA. Well-designed randomized controlled trials are indicated to study further the mechanism and effects of 5ARIs on sexual function.
Post-finasteride syndrome (PFS) has been claimed to occur in men who have taken oral finasteride to treat either hair loss or benign prostatic hyperplasia, independent of age, dosage, or indication. By definition, the condition is characterized by sexual dysfunction, somatic symptoms, and psychological disorders that persist after cessation of finasteride treatment. As yet, the condition is not recognized by the medical community, although individuals who suffer from PFS present with relatively homogenous symptoms. The concept of PFS has emerged from reports of non-dermatologists, neuroendocrinological research and reflections, and uncontrolled studies of low quality and with a strong bias selection, while a significant nocebo effect among patients informed about possible side effects of finasteride is recognized. There are no predictive factors for the risk of development of PFS. Nevertheless, it has been suggested that a patient history of preexisting mental health disorder, particularly depression, may put patients at an increased risk. We report the first case of PFS in a long-standing (over 20 years) dermatotrichological practice with frequent finasteride prescription observed in a 25-year-old male following dutasteride treatment for male androgenetic alopecia. There was circumstantial evidence that PFS may represent a delusional disorder of the somatic type, possibly on a background of a histrionic personality disorder, which would explain the refractoriness of the condition and a high degree of suggestibility.
Purpose of Review
Post-finasteride syndrome (PFS) is a disorder characterized by a set of clinical symptoms experienced during use or after drug discontinuation. This cluster of symptoms encompasses overall sexual dysfunction (SD), erectile dysfunction (ED), loss of libido, depression, suicidal ideation, anxiety, panic attacks, insomnia, and cognitive dysfunction. To date, there is lack of comprehensive understanding of the biochemical and pathophysiological mechanisms responsible for the adverse effects of finasteride. More importantly, there is lack of knowledge and effective clinical tools for treatments of this condition, resulting in outright dismissal of complaints by individuals afflicted with this syndrome. Psychological symptoms and cognitive dysfunction of PFS are far more serious and difficult to treat than sexual dysfunction symptoms and may lead young men to contemplate, attempt, or even commit suicide. Therefore, an urgent need exists to fill the knowledge gap in physiology, pathophysiology, and clinical management of patients with PFS.
Recent Findings
Finasteride treatment impairs biosynthesis and function of neurosteroids, which are critical regulators of central (CNS) as well as peripheral nervous system functions and modulate a host of neurotransmitter receptors, such as gamma amino butyric acid receptors. Thus, finasteride-induced neuroendocrine disruption of biosynthesis of critical signaling molecules results in pathophysiological states, which contribute to inhibition of biochemical pathways responsible for a host of physiological functions, ranging from sexual activity, mood, and cognition. In addition, finasteride-induced epigenetic changes in gene expression, including upregulation of androgen receptors (AR), increased histone acetylation, and methylation results in undesirable biological outcomes such as impairment of dopaminergic signaling and modulation of other neurotransmitter receptors, may be the underlying mechanism causing persistent or permanent adverse effects, manifested in anxiety, depression, and suicidal ideation.
Summary
The medical community has an obligation not to turn a blind eye on this rare yet debilitating condition in young men. Patients with this condition should not be stereotyped or stigmatized by untrained and unprepared clinicians, due to lack of awareness and knowledge pertaining to this new and rare syndrome. Greater awareness and education is needed among the medical and scientific communities in order to develop better approaches for managing men with PFS. It is paramount that steps are taken to develop better understanding of the underlying mechanisms contributing to the onset and progression of PFS and to promote educational and training programs to increase awareness and improve management of this condition.
Background
Dutasteride has been successfully used in treatment of lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH). However, dutasteride inhibits 5α-reductase type 1 and type 2 enzymes and may compromises glucocorticoids and androgen metabolism and alters metabolic function resulting in undesirable metabolic and sexual adverse side effects.
Aim
The aim of this study was to investigate the long-term adverse effects of dutasteride therapy in men with BPH on: i) blood glucose, ii) glycated hemoglobin (HbA
Methods
A retrospective registry study, with a cohort of 230 men aged between 47 and 68 years (mean 57.78 ± 4.81) were treated with dutasteride (0.5 mg/day) for LUTS, secondary to BPH. A second cohort of 230 men aged between 52 and 72 years (mean 62.62 ± 4.65) were treated with tamsulosin (0.4 mg). All men were followed up for 36–42 months. At intervals of 3–6 months, and at each visit, plasma glucose, HbA
Results
Long-term treatment with dutasteride therapy is associated with significant improvements in LUTS, as assessed by reduction in prostate volume, IPSS and prostate specific antigen (PSA). Long-term dutasteride therapy, however, resulted in increased blood glucose, HbA
Conclusion
Our findings suggest that long-term dutasteride therapy produces worsening of ED, reduced T levels and increased glucose, HbA
Background:
Prescription medications are among the most common causes of sexual dysfunction, and patients are often hesitant to seek help when experiencing these symptoms.
Objective:
In this review, we identify the available evidence of sexual adverse effects in men using systemic dermatologic medications and suggest screening protocols and actions that may improve a patient's symptoms where possible.
Methods:
A systematic review was conducted of all articles in the PubMed database published from the time of inception to May 2018 to identify studies evaluating the use of systemic dermatologic medications in men with evidence of sexual adverse effects. Subsequently, a secondary in-depth literature review was performed for each individual medication.
Results:
There were 5497 articles reviewed in the primary systematic review, and 59 articles covering 11 systemic dermatologic medications met inclusion criteria. We identified level 1 evidence for sexual adverse effects as a primary outcome in patients taking finasteride.
Limitations:
Many included studies were limited by sample size and methodology.
Conclusion:
The information in this review may serve as a reference of adverse effects when deciding on a therapeutic agent and a guide to help identify patients to screen for sexual dysfunction.
Androgens are steroid hormones with pleotropic and diverse biochemical and physiological functions, and androgen deficiency exerts a negative impact on human health. Testosterone (T) either directly or via its transformation into the more potent metabolite 5α-dihydrotestosterone (5α-DHT) or via aromatization into estradiol (E2) modulates important biochemical signaling pathways of human physiology and plays a critical role in the growth and/or maintenance of functions in a host of tissues and organs. T and 5α-DHT play an important role in regulating physiology of the muscle, adipose tissue, liver, bone, and central nervous system, as well as reproductive and sexual functions. Thus, androgen deficiency (also referred to as hypogonadism) is a well-recognized medical condition and if remained untreated will have a negative impact on human health and quality of life.
The 5ARIs, finasteride and dutasteride, are used to treat benign prostate hyperplasia and lower urinary tract symptoms. At much lower doses, 5ARI treatment reduces male hair loss. These drugs inhibit the conversion of testosterone to the more active dihydrotestosterone (DHT). In men taking these medications, DHT levels are reduced by some 90% while testosterone levels remain relatively stable. Well known for their negative effects on libido and erectile function, 5ARIs also cause ejaculatory dysfunction in some men, having the potential to decrease semen quality. In fact, some studies of men treated with these drugs have reported lower total sperm count, along with lower sperm motility, although the changes are probably insufficient to reduce fertility in men with normal semen before treatment. There is a population of men with more severely decreased sperm numbers; as low as 10% of pretreatment values. Fewer studies have looked at the lower doses used for male alopecia, indicating little affect in men with normal semen quality, but a negative effect on sperm numbers in men with oligozoospermia. There have been no studies looking at fertility endpoints for these medications.
Our research objective is to understand more, through subjective, self-reports on discussion boards/forums, persons' experiences associated with the use of drugs that alter androgen metabolism, such as finasteride. Finasteride is an orally active, specific inhibitor of 5α-reductase, which is localized to many androgen-dependent tissues. Finasteride inhibits the conversion of testosterone (T) to dihydrotestosterone (DHT), and is commonly used to treat benign prostatic hypertrophy (BPH) and male pattern baldness (MPB), both disorders associated with elevated DHT levels and 5α-reductase activity in the prostate and hair follicles, respectively. It is now acknowledged that long-term use and discontinuation of finasteride has adverse effects (AEs); however, these claims have not been well documented. In this study, discussion board posts (forums) were analyzed as self-reports of what finasteride users indicate is problematic for them. Reports were categorized by the age of subjects as well as the types of AEs described: antiandrogenic, estrogenic, central, and nonspecific/severe. A total of 244 cases were recorded and analyzed on the discussion forum on propeciahelp.com . Among these, 74 (32%) cases reported antiandrogenic affects, 43 (19%) reported estrogenic effects, 70 (30%) reported central effects, 11 (5%) reported nonspecific/severe AEs, and 31 (14%) reported AEs in all categories. The categorization of AEs may prompt further investigation into the pathophysiology of post-finasteride syndrome (PFS). Also, subjective reports may engender greater understanding of the perceived lasting AEs of finasteride.
The post-Finasteride syndrome (PFS) has been claimed to occur in men who have taken oral finasteride to treat hair loss or benign prostatic hyperplasia. While the incidence of persistent sexual, mental, and physical side effects despite quitting finasteride is unknown, and the condition is not recognized by the scientific community, individuals who suffer from PFS do present with very distinctive and homogenous symptoms. The concept has emerged from reports of nondermatologists, neuroendocrinological research, case reports, and uncontrolled studies. These have been scrutinized by hair experts who found that persistent sexual side effects were only documented in low-quality studies with a strong bias selection and a significant nocebo effect. Others totally dispute the credibility of the PFS. In any case, the PFS is a problem that has to be dealt with. Low-quality studies neither confirm nor refute the condition as a valid nosologic entity. Therefore, it is as inappropriate to dismiss the condition, as it would be to demonize finasteride for the treatment of male pattern hair loss. Whether the PFS represents a nocebo reaction or a real drug adverse event is irrelevant, while the best way to alleviate the emotional distress related to hair loss is to effectively treat the condition causing the problem. It is not sufficient to only discuss the plausibility of the PFS. There is a need for practical recommendations to include such important issues as patient selection and risk assessment, appropriate patient information, how to react in case of drug-related adverse events, issues of fertility and malignancy, management of the PFS, and alternatives, specifically the use of topical finasteride. It is the aim of this commentary to provide the respective information. © 2019 International Journal of Trichology | Published by Wolters Kluwer - Medknow.
Purpose of review:
The use of 5-alpha reductase inhibitors (5ARIs) for the treatment of benign prostatic hyperplasia (BPH) and other diseases has been proposed and studied. However, the controversy about its benefits and harms for other diseases has persisted. In this review, we will discuss the newly identified effects of 5ARIs based on recently published studies.
Recent findings:
These drugs are currently recommended in clinical guidelines for BPH. However, the reporting of adverse effects, including sexual dysfunction as well as neurologic, endocrine, and cardiovascular effects, have been controversial. There are reports of additional effects of 5ARI in prostate cancer and bladder cancer. Although 5ARIs have been prescribed for the treatment of androgenic alopecia (AGA), postfinasteride syndrome can result, with symptoms that range from sexual dysfunction to muscle atrophy.
Summary:
Clinical applications of 5ARIs have been established for the treatment of BPH and AGA from a series of randomized controlled trials. The adverse effects of 5ARIs affect only a small proportion of treated patients and can be resolved with discontinued treatment. It will be necessary to establish the mechanism by which 5ARIs elicit these effects through better designed studies.
Objective:
Finasteride, a selective inhibitor of type 2 5-alpha reductase isoenzyme, inhibits the conversion of testosterone to dihydrotestosterone (DHT) and is indicated in the treatment of male androgenetic alopecia. The study objective was to evaluate a newly developed finasteride 0.25% topical solution in comparison to the marketed finasteride 1 mg tablet, with respect to finasteride pharmacokinetics and suppressive effects on plasma DHT.
Methods:
24 healthy men with androgenetic alopecia were randomized in a single center, open-label, parallel-group, exploratory study, and received either multiple scalp applications of the topical solution b.i.d. or oral doses of the reference tablet o.d. for 7 days. Plasma finasteride, testosterone and DHT concentrations were determined.
Results:
After multiple doses, mean (± SD) finasteride Cmax and AUC0-t corresponded to 0.46 ± 0.28 ng/mL and 6.64 ± 7.50 ng/mL x h for the topical solution and to 6.86 ± 1.78 ng/mL and 57.93 ± 29.38 ng/mL x h for the tablet. Plasma DHT was reduced by ~ 68 - 75% with the topical solution and by ~ 62 - 72% with the tablet. No relevant changes occurred for plasma testosterone with either treatment. No clinically significant adverse events occurred.
Conclusions:
A strong and similar inhibition of plasma DHT was found after 1 week of treatment with the topical and tablet finasteride ormulations, albeit finasteride plasma exposure was significantly lower with the topical than with the oral product (p < 0.0001).
With aging, abnormal benign growth of the prostate results in benign prostate hyperplasia (BPH) with concomitant lower urinary tract symptoms (LUTS). Because the prostate is an androgen target tissue, and transforms testosterone into 5α-dihydrotestosterone (5α-DHT), a potent androgen, via 5α-reductase (5α-R) activity, inhibiting this key metabolic reaction was identified as a target for drug development to treat symptoms of BPH. Two drugs, namely finasteride and dutasteride were developed as specific 5α-reductase inhibitors (5α-RIs) and were approved by the U.S. Food and Drug Administration for the treatment of BPH symptoms. These agents have proven useful in the reducing urinary retention and minimizing surgical intervention in patients with BPH symptoms and considerable literature exists describing the benefits of these agents. In this review we highlight the adverse side effects of 5α-RIs on sexual function, high grade prostate cancer incidence, central nervous system function and on depression. 5α-Rs isoforms (types 1-3) are widely distributed in many tissues including the central nervous system and inhibition of these enzymes results in blockade of synthesis of several key hormones and neuro-active steroids leading to a host of adverse effects, including loss of or reduced libido, erectile dysfunction, orgasmic dysfunction, increased high Gleason grade prostate cancer, observed heart failure and cardiovascular events in clinical trials, and depression. Considerable evidence exists from preclinical and clinical studies, which point to significant and serious adverse effects of 5α-RIs, finasteride and dutasteride, on sexual health, vascular health, psychological health and the overall quality of life. Physicians need to be aware of such potential adverse effects and communicate such information to their patients prior to commencing 5α-RIs therapy.
Finasteride is a synthetic 5-α reductase inhibitor, which prevents the conversion of testosterone to dihydrotestosterone and has been used for more than 20 years in the treatment of male pattern hair loss. Randomized, controlled trials have associated finasteride with both reversible and persistent adverse effects. In this pilot study, we sought to characterize sexual and nonsexual adverse effects that men reported experiencing at least 3 months after stopping the medication. Based on previous research on persistent side effects of finasteride, we constructed an Internet survey targeting six domains: physical symptoms, sexual libido, ejaculatory disorders, disorders of the penis and testes, cognitive symptoms, and psychological symptoms and was e-mailed to patients who reported experiencing symptoms of side effects of finasteride. Responses from 131 generally healthy men (mean age, 24 years) who had taken finasteride for male pattern hair loss was included in the analysis. The most notable finding was that adverse effects persisted in each of the domains, indicating the possible presence of a "post-finasteride syndrome."
Patients with critical illness or hepatic failure exhibit impaired cortisol responses to ACTH, a phenomenon known as 'relative adrenal insufficiency'. A putative mechanism is that elevated bile acids inhibit inactivation of cortisol in liver by 5α-reductases type 1 and 2 and 5β-reductase, resulting in compensatory down-regulation of the hypothalamic-pituitary-adrenal axis and adrenocortical atrophy. To test the hypothesis that impaired glucocorticoid clearance can cause relative adrenal insufficiency we investigated the consequences of 5α-reductase type 1 deficiency in mice. In adrenalectomised male mice with targeted disruption of 5α-reductase type 1 compared with wild type control mice, clearance of corticosterone was lower after acute or chronic (8-fold, p<0.05) administration. In intact 5α-reductase deficient male mice, although resting plasma corticosterone levels were maintained, corticosterone responses were impaired after ACTH administration (26% lower, p<0.05), handling stress (2.5-fold lower, p<0.05) and restraint stress (43% lower, p<0.05) compared with wild type mice. mRNA levels of GR, CRH and AVP in pituitary or hypothalamus were altered, consistent with enhanced negative feedback. These findings confirm that impaired peripheral clearance of glucocorticoids can cause 'relative adrenal insufficiency' in mice, an observation with important implications in patients with critical illness or hepatic failure, and in patients receiving 5α-reductase inhibitors for prostatic disease.
Context:
5α-Reductase (5αR) types 1 and 2 catalyze the A-ring reduction of steroids, including androgens and glucocorticoids. 5α-R inhibitors lower dihydrotestosterone in benign prostatic hyperplasia; finasteride inhibits 5αR2, and dutasteride inhibits both 5αR2 and 5αR1. In rodents, loss of 5αR1 promotes fatty liver.
Objective:
Our objective was to test the hypothesis that inhibition of 5αR1 causes metabolic dysfunction in humans.
Design, setting, and participants:
This double-blind randomized controlled parallel group study at a clinical research facility included 46 men (20-85 years) studied before and after intervention.
Intervention:
Oral dutasteride (0.5 mg daily; n = 16), finasteride (5 mg daily; n = 16), or control (tamsulosin; 0.4 mg daily; n = 14) was administered for 3 months.
Main outcome measure:
Glucose disposal was measured during a stepwise hyperinsulinemic-euglycemic clamp. Data are mean (SEM).
Results:
Dutasteride and finasteride had similar effects on steroid profiles, with reduced urinary androgen and glucocorticoid metabolites and reduced circulating DHT but no change in plasma or salivary cortisol. Dutasteride, but not finasteride, reduced stimulation of glucose disposal by high-dose insulin (dutasteride by -5.7 [3.2] μmol/kg fat-free mass/min, versus finasteride +7.2 [3.0], and tamsulosin +7.0 [2.0]). Dutasteride also reduced suppression of nonesterified fatty acids by insulin and increased body fat (by 1.6% [0.6%]). Glucose production and glycerol turnover were unchanged. Consistent with metabolic effects of dutasteride being mediated in peripheral tissues, mRNA for 5αR1 but not 5αR2 was detected in human adipose tissue.
Conclusion:
Dual inhibition of 5αRs, but not inhibition of 5αR2 alone, modulates insulin sensitivity in human peripheral tissues rather than liver. This may have important implications for patients prescribed dutasteride for prostatic disease.
Sexual adverse events (AEs), a major cause for discontinuing 5α-reductase inhibitor (5ARI) therapy for benign prostatic hyperplasia (BPH), are known to occur most frequently early in therapy and appear to decline over time. The aim of this study was to investigate the changes in sexual function occurring with dutasteride treatment during a 1-year follow-up period in Korean men.
Using the International Index of Erectile Function, we prospectively evaluated, after 1, 3, 6, 9, and 12 months of treatment, the changes in sexual function of 55 outpatients (mean age 62.3±7.2 years) with BPH (mean volume 48.9±16.0 g) who had relatively good erectile function (EF) and were treated with dutasteride for at least 1 year.
EF scores showed the most significant decrease at 1 month (p<0.01). Function gradually recovered thereafter but was still significantly decreased after 12 months of treatment (p<0.05). The scores for orgasmic function and sexual desire also showed the most significant reduction at 1 month but were restored to the baseline level at 6 months. No significant correlation was observed between changes in sexual function and prostate-specific antigen level, prostate volume, or International Prostate Symptom Scores.
After 1 month of treatment, dutasteride therapy resulted in a significant reduction in all investigated sexual functions. Overall, recovery in sexual function was noted at 3 months, and orgasmic function and sexual desire were restored to baseline levels at 6 months. However, EF was still significantly reduced at 12 months.
Two isozymes (types 1 and 2) of 5 alpha-reductase (5 alpha R; EC 1.3.99.5), with differential tissue distribution, have been identified in humans. These enzymes catalyze the reduction of testosterone (T) to dihydrotestosterone (DHT). The contributions of each of these isozymes to serum and tissue concentrations of DHT remain to be fully defined. Finasteride, a selective inhibitor of type 2 5 alpha R, lowers circulating DHT levels by approximately 70% in men after treatment with 5 mg daily. MK-386 (4,7 beta-dimethyl-4-aza-5 alpha-cholestan-3-one) is a new selective inhibitor of type 1 5 alpha R. A single rising dose, alternating panel, trial in 16 healthy males (age range, 21-25 yr) studied the effect of 0.1-100 mg MK-386. DHT was maximally reduced by 20-30% relative to placebo at MK-386 doses of 10 mg or more, orally, by 24 h posttreatment (P < 0.01 vs. placebo). No consistent effect on T concentrations was evident. In a second trial, finasteride (5 mg) was given for 19 days to 10 healthy young men (age r...
An oral 5-mg dose of finasteride, a 5 alpha-reductase inhibitor, was administered for 3 months to 10 hirsute women to determine the effect on gonadotropin secretion, on basal and stimulated androgen secretion, and on hair growth. Hair growth was assessed by the Ferriman-Gallwey score. All of the above determinations were evaluated before and after 1 and/or 3 months of finasteride treatment. Basal and GnRH-stimulated gonadotropin secretions were not affected. Indeed, finasteride did not modify the pulsatility of LH secretion. No change was seen in estradiol, PRL, free testosterone, androstenedione, dehydroepiandrosterone sulfate, and sex hormone-binding globulin concentrations. Serum concentrations of cortisol (F) were significantly reduced after 1 month of finasteride treatment. The F levels returned to pretreatment levels after 3 months. Plasma levels of dihydrotestosterone and 3 alpha-androstanediol glucuronide significantly decreased during finasteride treatment. A significant increase in testosterone ...
From studies undertaken in this laboratory and elsewhere, a model for the mechanism of action of androgens may be proposed (Fig. 1).
The findings about possible sexual adverse effects of finasteride therapy as reported by Belknap and colleagues¹ in this issue of JAMA Dermatology are best understood as 3 separate issues woven together: (1) What is the evidence that use of finasteride for androgenetic alopecia (AGA) impairs male sexual function, especially persistently? (2) How adequate were clinical trials for assessing these harms? (3) How well reported was this evidence in scientific journals, especially in meta-analyses?
Two meta-analyses conclude that finasteride treatment of androgenic alopecia (AGA) is safe but do not assess quality of safety reporting.
To assess safety reporting for clinical trial reports of finasteride for AGA.
MEDLINE, ClinicalTrials.gov, and a clinical data repository for an academic medical center.
Published clinical trial reports for finasteride treatment of AGA.
For each trial, we assessed quality of adverse event reporting, extracted the number and type of adverse events in treatment and placebo groups, and assessed duration of safety evaluation and adequacy of blinding. Two observers independently extracted the data; differences were resolved by consensus. We assessed generalizability in a large cohort of men prescribed finasteride, 1.25 mg/d or less, by assessing for eligibility in the finasteride-AGA pivotal trials.
Quality was assessed as adequate, partially adequate, inadequate, or no events reported. We used funnel plots of the hazard ratio to assess bias.
Of 34 clinical trials, none had adequate safety reporting, 19 were partially adequate, 12 were inadequate, and 3 reported no adverse events. Funnel plots were asymmetric with a bias toward lower odds ratio for sexual adverse effects, suggesting systematic underdetection. No reports assessed adequacy of blinding, 18 (53%) disclosed conflicts of interest, and 19 (56%) received funding from the manufacturer. Duration of drug safety evaluation was 1 year or less for 26 of 34 trials (76%). Of 5704 men in the clinical data repository who were treated for AGA with finasteride, 1.25 mg/d or less, for AGA, only 31% met inclusion criteria for the pivotal trials referenced in the manufacturer's full prescribing information and 33% took finasteride for more than 1 year.
Available toxicity information from clinical trials of finasteride in men with AGA is very limited, is of poor quality, and seems to be systematically biased. In a cohort of men prescribed finasteride for routine treatment of AGA, most would have been excluded from the pivotal studies that supported US Food and Drug Administration approval for AGA. Published reports of clinical trials provide insufficient information to establish the safety profile for finasteride in the treatment of AGA.
Penile erection is a nitric oxide (NO)-mediated process that has been shown to be androgen dependent in rats. Castration reduces the activity of the penile enzyme involved in NO synthesis, nitric oxide synthase (NOS). To determine whether adrenal androgens and/or corticosteroids contribute to this control, the following groups of Fischer 344 adult male rats (n = 5–7) were studied: 1) intact, 2) castrated, 3) adrenalectomized alone, 4) castrated/adrenalectomized, 5) castrated/adrenalectomized with aldosterone (1.25 mg/kg, sc) and hydrocortisone (12 mg/kg, sc), 6) castrated/adrenalectomized with dihydrotestosterone (1.2-cm SILASTIC-brand tubing pellet; Dow Corning, Midland, MI), 7) castrated/adrenalectomized with dehydroepiandrosterone (2-cm tubing), 8) castrated/adrenalectomized with aldosterone (1.25 mg/kg, sc), and 9) castrated/adrenalectomized with hydrocortisone (12 mg/kg, sc). After 1 week, EFS was applied, and the maximal intracavernosal pressure (MIP) and mean arterial pressure (MAP) were recorded. The MIP/MAP ratio in the adrenalectomized group (0.37) was reduced to values found in the castrated group (0.40). The values in both groups were significantly less than those in intact controls (0.75). The most significant reduction in MIP/MAP was seen in the adrenalectomized/castrated group (0.16). Erectile response in animals submitted to adrenalectomy and castration was restored close to intact values with the administration of hydrocortisone and aldosterone (0.63). Similar results were obtained by the administration of either of the substances alone (0.56 and 0.67, respectively). Penile NOS activity assayed by the l-arginine/citrulline conversion was decreased by 55% in the castrated group compared with that in the intact group, but was not further reduced in the adrenalectomized/castrated or adrenalectomized groups. Penile neuronal NOS protein content, estimated by Western blot, was decreased only in the adrenalectomized/castrated animals (35%), and endothelial NOS content was not affected. These data suggest that the rat adrenal gland contributes to the maintenance of the erectile mechanism and may affect neuronal NOS content in the penis in the rat model. The possibility that hypotension may play a role in the erectile dysfunction observed in adrenalectomized rats cannot be discarded.
Objective
To investigate whether a fixed-dose combination of 0.5 mg dutasteride and 0.4 mg tamsulosin (FDC) is more effective than watchful waiting with protocol-defined initiation of tamsulosin therapy if symptoms did not improve (WW-All) in treatment-naïve men with moderately symptomatic benign prostatic hyperplasia (BPH) at risk of progression.Patients and methodsThis was a multicentre, randomised, open-label, parallel-group study (NCT01294592) in 742 men with an International Prostate Symptom Score (IPSS) of 8–19, prostate volume ≥30 cc and total serum PSA ≥1.5 ng/ml. Patients were randomised to FDC (n = 369) or WW-All (n = 373) and followed for 24 months. All patients were given lifestyle advice. The primary endpoint was symptomatic improvement from baseline to 24 months, measured by IPSS. Secondary outcomes included BPH clinical progression, impact on quality of life (QoL), and safety.ResultsThe change in IPSS at 24 months was significantly greater for FDC than WW-All (–5.4 vs. –3.6 points, P < 0.001). With FDC, the risk of BPH progression was reduced by 43.1% (P < 0.001); 29% and 18% of men in the WW-All and FDC groups had clinical progression, respectively, comprising symptomatic progression in most patients. Improvements in QoL (BPH Impact Index and question 8 of the IPSS) were observed in both groups but were significantly greater with FDC (P < 0.001). The safety profile of FDC was consistent with established profiles of dutasteride and tamsulosin.ConclusionFDC therapy with dutasteride and tamsulosin, plus lifestyle advice, caused rapid and sustained improvements in men with moderate BPH symptoms at risk of progression with significantly greater symptom and QoL improvements and a significantly reduced risk of BPH progression compared with WW plus initiation of tamsulosin as per protocol.
Abstract 5α-reductases, a unique family of enzymes with a wide host of substrates and tissue distributions, play a key role in the metabolism of androgens, progestins, mineralocorticoids and glucocorticoids. These enzymes are the rate-limiting step in the synthesis of a host of neurosteroids, which are critical for central nervous system function. Androgens and glucocorticoids modulate mitochondrial function, carbohydrate, protein and lipid metabolism and energy balance. Thus, the inhibition of these regulatory enzymes results in an imbalance in steroid metabolism and clearance rates, which leads to altered physiological processes. In this report, we advance the hypothesis that inhibition of 5α-reductases by finasteride and dutasteride alters not only steroid metabolism but also interferes with the downstream actions and signaling of these hormones. We suggest that finasteride and dutasteride inhibit 5α-reductase activities and reduce the clearance of glucocorticoids and mineralocorticoids, potentiating insulin resistance, diabetes and vascular disease.
Introduction:
Tadalafil (TAD) 5 mg coadministered with finasteride (FIN) 5 mg significantly improves lower urinary tract symptoms (LUTS) in men with benign prostatic hyperplasia (BPH) and prostatic enlargement. However, its effects on erectile/sexual function have yet to be fully described.
Aim:
Assess the effects of TAD/FIN coadministration (compared with placebo [PBO]/FIN) on erectile and sexual function in sexually active men with LUTS and prostatic enlargement secondary to BPH with or without baseline comorbid erectile dysfunction (ED).
Methods:
A randomized, double-blind, PBO-controlled study of 695 men (610 sexually active; 450 with baseline ED; 404 sexually active with baseline ED) conducted at 70 sites in 13 countries. TAD 5 mg or PBO once daily coadministered with FIN 5 mg once daily for 26 weeks.
Main outcome measures:
International Index of Erectile Function (IIEF) domain and single-item scores; proportions of patients who demonstrated minimal clinically important differences (MCIDs) in IIEF-Erectile Function domain scores (IIEF-EF; MCID defined as ≥4-point improvement); and sexual dysfunction adverse events (AEs).
Results:
Compared with PBO/FIN, TAD/FIN resulted in improvements for all IIEF domain and single-item scores assessed among patients with baseline ED (P ≤ 0.002 for all measures) and among patients without baseline ED (P ≤ 0.041 for all measures). Compared with PBO/FIN, significantly larger percentages of sexually active men with baseline ED treated with TAD/FIN achieved an IIEF-EF MCID after 4, 12, and 26 weeks of therapy (P < 0.001 for odds ratio comparisons between TAD/FIN and PBO/FIN at all 3 three postbaseline timepoints). The incidence of sexual AEs was low: five TAD/FIN patients and seven PBO/FIN patients reported sexual AEs, including ED, decreased/lost libido, and ejaculation disorders.
Conclusions:
TAD/FIN coadministration for the treatment of men with LUTS and prostatic enlargement secondary to BPH concurrently leads to statistically significant improvements in erectile/sexual function and is well-tolerated, regardless of the presence/absence of ED at treatment initiation.
5α-Reductase 1 (5αR1) catalyses A-ring reduction of androgens and glucocorticoids in liver, potentially influencing hepatic manifestations of the Metabolic Syndrome.Male mice, homozygous for a disrupted 5α-R1 allele (5αR1-KO), were studied following metabolic (high fat diet) and fibrotic (carbon-tetrachloride) challenge. The effect of the 5α-reductase inhibitor, finasteride, on metabolism was investigated in male obese Zucker rats.On high fat diet male 5αR1-KO mice demonstrated greater weight gain (21.6±1.4 vs 16.2±2.4 g), hyperinsulinaemia (insulin AUC during glucose tolerance test, 609±103 vs 313±66 ng.ml(-1).min) and hepatic steatosis (liver triglycerides: 136.1±17.0 vs 89.3±12.1 micromol.g(-1)). mRNA transcript profiles in liver were consistent with decreased fatty acid β-oxidation and increased triglyceride storage. 5αR1-KO male mice were more susceptible to fibrosis after CCl4 (37% increase in collagen staining). The non-selective 5α-reductase inhibitor finasteride induced hyperinsulinaemia and hepatic steatosis (10.6±1.2 vs 7.0±1.0 micromol.g(-1)) in obese male Zucker rats, both intact and castrated.5α-R1 deficiency induces insulin resistance and hepatic steatosis, consistent with intra-hepatic accumulation of glucocorticoids, and predisposes to hepatic fibrosis. Hepatic steatosis is independent of androgens in rats. Variations in 5αR1 activity in obesity and with non-selective 5α-reductase inhibition in men with prostate disease may have important consequences for onset and progression of metabolic liver disease.
Recent postmarketing studies and the US Food and Drug Administration have found that finasteride, 1 mg, for androgenic alopecia has been associated with persistent sexual and nonsexual adverse effects.¹ The mechanisms of these symptoms in humans are unknown. Finasteride, 1 mg, has been associated with male infertility, and 5% of men taking a 5α-reductase inhibitor had a dramatic decline in total sperm count to below 10% of baseline.²,3 The present study was designed to assess whether otherwise healthy former users of finasteride with persistent sexual adverse effects have a higher prevalence of low serum androgens and spermatogenic deficits compared with reference populations.
Purpose:
Although there is no evidence that testosterone therapy increases the risk of prostate cancer, there is a paucity of long-term data. We determined whether the incidence of prostate cancer is increased in hypogonadal men receiving long-term testosterone therapy.
Materials and methods:
In 3 parallel, prospective, ongoing, cumulative registry studies 1,023 hypogonadal men received testosterone therapy. Two study cohorts were treated by urologists (since 2004) and 1 was treated at an academic andrology center (since 1996). Patients were treated when total testosterone was 12.1 nmol/l or less (350 ng/dl) and symptoms of hypogonadism were present. Maximum followup was 17 years (1996 to 2013) and median followup was 5 years. Mean baseline patient age in the urological settings was 58 years and in the andrology setting it was 41 years. Patients received testosterone undecanoate injections in 12-week intervals. Pretreatment examination of the prostate and monitoring during treatment were performed. Prostate biopsies were performed according to EAU guidelines.
Results:
Numbers of positive and negative biopsies were assessed. The incidence of prostate cancer and post-prostatectomy outcomes was studied. A total of 11 patients were diagnosed with prostate cancer in the 2 urology settings at proportions of 2.3% and 1.5%, respectively. The incidence per 10,000 patient-years was 54.4 and 30.7, respectively. No prostate cancer was reported by the andrology center. Limitations are inherent in the registry design without a control group.
Conclusions:
Testosterone therapy in hypogonadal men does not increase the risk of prostate cancer. If guidelines for testosterone therapy are properly applied, testosterone treatment is safe in hypogonadal men.
Benign prostatic hyperplasia (BPH) affects over 50 percent of men by age 60 and is the cause of millions of dollars of healthcare expenditure for treatment of lower urinary tract symptoms (LUTS) and urinary obstruction. Despite the widespread use of medical therapy, there is no universal therapy that treats all men with symptomatic BPH, and at least 30% of patients do not respond to medical management and a subset require surgery. Significant advances have been made in understanding the natural history and development of the prostate, such as elucidating the role of the enzyme 5α reductase Type 2 (5AR2), and advances in genomics and biomarker discovery offer the potential for a more targeted approach to therapy. We review the current understanding of BPH progression as well as key genes and signaling pathways implicated in the process such as 5α reductase. We also explore the potential of biomarker screening and gene-specific therapies as tools to risk stratify BPH patients and identify those with symptomatic or medically resistant forms.
A PubMed® literature search of current and past peer-reviewed literature on prostate development, lower urinary tract symptoms, BPH pathogenesis, targeted therapy, biomarkers, epigenetics, 5AR2 and personalized medicine was performed. An additional Google Scholar™ search was conducted to broaden the scope of the review. Relevant reviews and original research articles were examined as well as their cited references, and a synopsis of original data was generated with the goal of informing the practicing urologist of these advances and their implications.
BPH is associated with a state of hyperplasia of both the stromal and epithelial compartments, with 5AR2 and androgen signaling playing key roles in development and maintenance of the prostate. Chronic inflammation, multiple growth factor and hormonal signaling pathways, and medical comorbidities play an intricate role in prostate tissue homeostasis as well as its evolution into the clinical state of BPH. Resistance to medical therapy with finasteride may occur through silencing of the 5AR2 gene by DNA methylation, leading to a state in which 30% of adult prostates do not express 5AR2. Novel biomarkers such as single nucleotide polymorshisms may be used to risk stratify patients with symptomatic BPH and identify those at risk of progression or failure of medical therapy. Several inhibitors of the androgen receptor and other signaling pathways have recently been identified which appear to attenuate BPH progression and may offer alternative targets for medical therapy.
Progressive worsening of LUTS and bladder outlet obstruction secondary to BPH is the result of multiple pathways including androgen receptor signaling, pro-inflammatory cytokines and growth factor signals. New techniques in genomics, proteomics and epigenetics have led to the discovery of aberrant signaling pathways, novel biomarkers, DNA methylation signatures and potential gene-specific targets. As personalized medicine continues to grow, the ability to risk stratify patients with symptomatic BPH, identify those at higher risk of progression, and seek alternative therapies for those likely to fail conventional options will become the standard of targeted therapy.
To determine the efficacy and safety of dutasteride, alone or in combination, versus a placebo or control, used for the treatment of benign prostatic hyperplasia.
Pubmed(®) and the Cochrane Library were searched for randomized controlled trials longer than 6 months in duration. The subjects in the trials were men aged 40 or over, with moderate to severe symptoms of benign prostatic hyperplasia (BPH) as determined by International Prostate Symptom Score (IPSS). We pooled data from a total of nine different clinical trials.
Dutasteride was superior to placebo in improving urinary symptoms measured by IPSS (∆ = -1.78, 95 % CI -3.01 to -0.55), peak urinary flow (Q max) (∆ = 1.27 mL/s, 95 % CI 0.97-1.57), and change in total prostate volume (TPV) (∆ = -17.40 cm(3), 95 % CI -25.77 to -9.02) while it resulted in more frequent drug-related adverse events (RR 1.35, 95 % CI 1.19-1.54). Combination therapy with dutasteride and tamsulosin resulted in significantly greater improvements in IPSS and Q max than tamsulosin monotherapy (∆ = -1.80 mL/s, 95 % CI -1.81 to -1.79 and ∆ = 1.60 mL/s, 95 % CI 1.59-1.61, respectively). When comparing dutasteride with finasteride, no significant differences in symptom improvement or the rate of adverse events were observed.
Dutasteride can be used to improve urinary symptoms (IPSS and Q max) and reduce TPV but with awareness of its potential adverse events. Combination therapy with tamsulosin can be considered when further improvements in symptoms are desired.
We investigate the impact of dutasteride on prostate specific antigen (PSA) and prostate volume in men receiving testosterone (T) therapy. Twenty-three men on stable dose T therapy were randomised to receive either dutasteride or placebo for 12 months. Serum levels of PSA, T and dihydrotestosterone (DHT) and responses to the International Index of Erectile Function (IIEF) and Male Sexual Health Questionnaire (MSHQ) questionnaires were determined at baseline and at 3, 6, 9 and 12 months. Prostate volume (PV) was measured using transrectal ultrasound (TRUS) at baseline and again after 12 months. A total of 22 men (mean age 57.3) completed the study, with 11 men receiving placebo and 11 receiving dutasteride. Men receiving dutasteride had a significant decrease in PSA (-0.46 ± 0.81 ng ml(-1) ; P = 0.04) and in PV (-6.65 ± 11.0%; P = 0.03) from baseline over 12 months. DHT decreased significantly for men on dutasteride compared with men receiving placebo (P = 0.02). When compared with men who received placebo, men who received dutasteride demonstrated nonsignificant trends towards decreased PSA (-0.46 versus 0.21 ng ml(-1) ; P = 0.11), PV (-6.65% versus 3.4%; P = 0.08) and MSHQ scores (-10.2 versus 5.6; P = 0.06). Dutasteride reduces PSA and PV for men on T therapy, but perhaps less so than in men without T therapy.
Dihydrotestosterone is the main androgen causative of androgenetic alopecia, a psychologically and physically harmful condition warranting medical treatment.
We sought to compare the efficacy and safety of dutasteride (type 1 and 2 5-alpha reductase inhibitor) with finasteride (type 2 5-alpha reductase inhibitor) and placebo in men with androgenetic alopecia.
Men aged 20 to 50 years with androgenetic alopecia were randomized to receive dutasteride (0.02, 0.1, or 0.5 mg/d), finasteride (1 mg/d), or placebo for 24 weeks. The primary end point was hair count (2.54-cm diameter) at week 24. Other assessments included hair count (1.13-cm diameter) and width, photographic assessments (investigators and panel), change in stage, and health outcomes.
In total, 917 men were randomized. Hair count and width increased dose dependently with dutasteride. Dutasteride 0.5 mg significantly increased hair count and width in a 2.54-cm diameter and improved hair growth (frontal view; panel photographic assessment) at week 24 compared with finasteride (P = .003, P = .004, and P = .002, respectively) and placebo (all P < .001). The number and severity of adverse events were similar among treatment groups.
The study was limited to 24 weeks.
Dutasteride increased hair growth and restoration in men with androgenetic alopecia and was relatively well tolerated.
IntroductionRecent studies have reported persistent sexual and nonsexual adverse effects associated with the 5α-reductase inhibitor finasteride. AimsThe first aim was to review the clinical studies of persistent sexual and nonsexual adverse effects associated with finasteride in younger men who took the medication for treatment of male pattern hair loss. The second aim was to place these findings into context with what is known from basic and clinical studies about the hormones and neurosteroids affected by finasteride. Methods
Relevant published literature on the topic was reviewed. Clinical symptomatology in humans was correlated with findings from rodent models to investigate possible underlying mechanisms. Main Outcome MeasuresPersistent sexual and nonsexual adverse effects were summarized. ResultsTwo clinical studies have described persistent side effects associated with finasteride use in otherwise healthy younger men. The sexual side effects are typically present in multiple domains that include erectile dysfunction, low libido, and decreased orgasms. Erectile dysfunction may be related to low levels of dihydrotestosterone, which has been shown to be an important androgen in both human and animal studies. Nonsexual side effects include depression and decreased alcohol consumption that are linked to the neurosteroid allopregnanolone in both human and animal studies. Three men with persistent side effects associated with finasteride were found to have lower plasma and cerebrospinal fluid levels of several neurosteroids. Conclusions
Persistent adverse effects of finasteride in younger men include erectile dysfunction, low libido, lack of orgasms, depression, and decreased alcohol consumption. One study has found lower levels of several neurosteroids in this population. Out of the various persistent side effects, erectile dysfunction and decreased alcohol consumption have been the most studied in animal models. Further research is needed on who is susceptible to the persistent adverse side effects of finasteride and on the underlying mechanisms of the medication. Irwig MS. Persistent sexual and non-sexual adverse effects of finasteride in younger men. Sex Med Rev **;**:**–**.
To examine the effects of doxazosin, finasteride and combined therapy among men with lower urinary tract symptoms associated with benign prostatic hyperplasia (LUTS/BPH) on sexual function assessed by the Brief Male Sexual Function Inventory (BMSFI) over 4 years.
The Medical Therapy of Prostatic Symptoms (MTOPS) Study was a multi-center, randomized, double-blind, placebo-controlled clinical trial with a primary outcome of time-to-BPH progression. Change in sexual function was a secondary outcome. A total of 2,783 men enrolled in the MTOPS Study who completed the BMSFI at baseline and at least once during follow-up were analyzed.
Among men enrolled in the MTOPS Study, sexual function declined over time. Overall, men assigned to finasteride and combined therapy experienced statistically significant but small worsening of ejaculatory function compared with placebo. Men assigned to combined therapy also experienced significant worsening in erectile function and sexual problem assessment. There was no significant difference in changes in any of the BMSFI domains among men assigned to doxazosin alone compared to placebo.
This study significantly extends understanding of the effects of long-term treatment with these drugs on sexual function in men with LUTS/BPH. Treatment with finasteride or combined therapy was associated with worsening of sexual function whereas treatment with doxazosin alone was associated with minimal, if any, negative impact. Physicians should discuss the possible long-term effects of these drugs for LUTS/BPH on sexual function with their patients.
To investigate the effects and mechanisms of long-term treatment of 5α-reductase inhibitors (5ARIs) on erectile organ structure and function in aged rats.
Thirty 16-month-old male rats were assigned to 2 groups: untreated or treated with 5ARIs. After 16 weeks, the erectile function was measured after electrical stimulation of the cavernous nerve. The weights and histopathologic features of the corpus cavernosum were examined. The levels of autophagy, apoptosis, and protein expression were also recorded.
In the 5ARI-treatment group, the plasma and intraprostatic dihydrotestosterone concentration was lowered by 52.1% and 57.3%, respectively, and the weight of the corpus cavernosum and prostate had decreased by 22.4% and 35.6%, respectively. The in vivo erectile response to electrical stimulation of the cavernous nerve had decreased significantly in the 5ARI-treatment group (P <.001). Masson's staining, immunohistochemistry, and Western blot all demonstrated decreased smooth muscle and increased collagen deposition and decreased endothelial nitric oxide synthase and LC3-II protein expression in the corpus cavernosum of the 5ARI-treatment group. Using transmission electron microscopy and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling, decreased autophagy, aggravated ultrastructural injury of mitochondria, and increased apoptosis were observed in the cavernous smooth muscle cells from the rats in the 5ARI-treatment group.
Long-term 5ARI treatment did attenuate the erectile function of aged rats. The mechanisms might have been the decreased rate of autophagy and an increased rate of apoptosis in the cavernous smooth muscle cells, suggesting a new role for androgen in maintaining the structural and functional integrity of the erectile organ. Additional studies are necessary to demonstrate the mechanisms of dihydrotestosterone in regulating the autophagy and apoptosis of the cavernous smooth muscle cells.
The inhibition of testosterone 5α-reductase activity by 3-oxo-4-androstene-17β-carboxylic acid in the male reproductive organs of the rat was demonstrated . The medium for incubation of caput epididymis showed the highest concentration of 5α-dihydrotestosterone (5α-DHT) whereas the highest concentration of testosterone (T) was recorded in medium for incubation of decapsulated testis after two hours of incubation. The 3-oxo-4-androstene-17β-carboxylic acid (1.58 × 10−5M) inhibited the conversion of T to 5α-DHT in all the organs tested (testis, caput and cauda epididymis and ventral prostate) under identical incubation conditions.
Because increasing numbers of men are seeking treatment for benign prostatic hyperplasia (BPH) from primary care physicians, we sought to assess the efficacy and tolerability of finasteride in a primary care setting. In this randomized, double-masked study, 2112 men with symptomatic BPH received either finasteride (n = 1589) or placebo (n = 523) for 1 year. At 3, 6, 9, and 12 months, urinary symptoms were measured using the American Urological Association Symptom Index (AUASI). Quality of life was assessed using the BPH Impact Index (BII), which assessed bother, worry, physical discomfort, and restriction in activities. Both patients and investigators assessed overall urologic status. Investigators assessed the effect of the drug on plasma lipids in a subset of patients. Patients treated with finasteride had a statistically significant mean decrease in AUASI scores compared with patients treated with placebo beginning at month 6 and continuing throughout the study. At month 12, adjusted mean decreases in AUASI scores were −4.96 for finasteride versus −3.71 for placebo. Statistically significant differences in favor of finasteride were also noted on BII at months 9 and 12. Patient and investigator overall assessments showed greater improvement in the finasteride group beginning at month 6. The incidence of drug-related sexual adverse experiences was significantly greater in finasteride-treated patients but led to withdrawal in only 2.2% of these patients. Overall lipid profile was not significantly altered in either group. Based on improvement in symptoms and quality of life, and on its favorable tolerability profile, finasteride should be considered by primary care physicians for management of symptomatic BPH.
Objective To examine the safety of finasteride as used in general medical practice to treat benign prostatic hypertrophy (BPH).
Patients and methods Information was collected on 14 772 patients who were included in an observational cohort study conducted using Prescription-Event Monitoring.
Results Finasteride was reported to have been effective in 60% of the patients in whom an opinion on efficacy was recorded. Impotence or ejaculatory failure was reported in 2.1% of the patients, decreased libido in 1% and gynaecomastia and related conditions in 0.4%. Impotence was the most frequent reason for stopping treatment with finasteride and was the most commonly reported adverse reaction to the drug. Of the patients included in the elderly cohort involved in this study, 819 (5.5%) died; none of these deaths was attributed to finasteride.
Conclusion Impotence or ejaculatory failure, decreased libido and gynaecomastia in a small proportion of patients were associated with the use of finasteride. The results of this study strongly suggest that this drug is acceptably safe when used in accordance with the current prescribing information.
Background Finasteride is known to improve urinary symptoms in men with benign prostatic hyperplasia, but the extent to which the benefit is sustained and whether finasteride reduces the incidence of related events, including the need for surgery and the development of acute urinary retention, are not known. Methods In this double-blind, randomized, placebo-controlled trial, we studied 3040 men with moderate-to-severe urinary symptoms and enlarged prostate glands who were treated daily with 5 mg of finasteride or placebo for four years. Symptom scores (on a scale of 1 to 34), urinary flow rates, and the occurrence of outcome events were assessed every four months in 3016 men. Prostate volume was measured in a subgroup of the men. Complete data on outcomes were available for 2760 men. Results During the four-year study period, 152 of the 1503 men in the placebo group (10 percent) and 69 of the 1513 men in the finasteride group (5 percent) underwent surgery for benign prostatic hyperplasia (reduction in ris...
Introduction:
In the light of post-marketing reports of persistent sexual dysfunction with the use of finasteride, analysis of the extent of risk associated with 5α-reductase inhibitor treatment for androgenetic alopecia (AGA) is warranted. This study sought to evaluate the efficacy of 5α-reductase inhibitors using the outcomes hair count, global photographic assessment and patient self-assessment and evaluate the benefits of treatment versus the risk of global sexual dysfunction.
Methods:
A systematic review identified all relevant randomized controlled trials of finasteride 1 mg, 5 mg and dutasteride 0.5 mg. The efficacy outcome hair count was analyzed using pair-wise meta-analysis, while the efficacy outcomes global photographic assessment and patient self-assessment as well as the safety outcome global sexual dysfunction were analyzed through network meta-analyses. A benefit-risk assessment was also performed.
Results:
The active interventions were not significantly different than each other in efficacy and were not significantly different from placebo in eliciting sexual dysfunction. Benefit-risk analysis resulted in an arbitrary ranking due to the lack of statistically significant difference between active treatments.
Discussion:
Analysis results reiterate the efficacy and safety of 5α-reductase inhibitors for the treatment of AGA and may support the approval of dutasteride 0.5 mg as an additional treatment option, following further study.
The synthetic steroid methyltrienolone (R 1881) binds specifically with high affinity to intracellular androgen receptors and is not metabolized to androstanediol. Administration of R 1881 (1 mg/day) to castrated male rats facilitated intromission in significantly more animals than did 5α-dihydrotestosterone (DHT) (1 mg/day); however, the percentage of animals ejaculating and the pattern of behavior displayed were equivalent in the two groups. Combined administration of estradiol benzoate (EB) (2 μg/day) plus either R 1881 or DHT further facilitated males' sexual performance to levels previously seen in castrated male rats of the same strain when given testosterone propionate (TP). The results suggest that conversion of DHT to 3α- or 3β-androstanediol neither detracts from nor contributes to its ability to activate sexual behavior in the male rat.
Background:
There is a robust literature in rodents, but not in humans, on the interaction between finasteride and alcohol, particularly as it relates to neurosteroids. Finasteride has been shown to reduce alcohol intake and suppress alcohol preference in male mice. This study examines the role of finasteride in alcohol consumption in humans with male pattern hair loss.
Methods:
The subjects were 83 otherwise healthy men who developed persistent sexual side effects associated with finasteride, despite the cessation of this medication for at least 3 months. Information from standardized interviews was collected regarding medical histories, sexual function, and alcohol consumption before and after finasteride use.
Results:
Of the 63 men who consumed at least 1 alcoholic beverage/wk prior to starting finasteride, 41 (65%) noted a decrease in their alcohol consumption after stopping finasteride. This reduction typically began before discontinuing finasteride. Twenty men (32%) reported no change in their alcohol consumption, and 2 men (3%) reported an increase in their alcohol consumption. For the 63 consumers of alcohol, the mean number (± SE) of alcoholic beverages/wk declined from 5.2 ± 0.7 before finasteride to 2.0 ± 0.3 after finasteride (p < 0.0001). A major study limitation is the lack of a comparison group.
Conclusions:
In former male users of finasteride who developed persistent sexual side effects, 65% noticed a decline in their alcohol consumption as compared to baseline. This finding is consistent with finasteride's ability to modulate alcohol intake in rodents. Further research is needed on the central nervous system effects of finasteride in humans.
Studies show that treatment of men with 5α-reductase inhibitors such as finasteride is effective for the primary prevention of prostate cancer. Although it is known that finasteride treatment suppresses serum levels of dihydrotestosterone (DHT) and its distal metabolite, 5α-androstane-3α,17β-diol glucuronide (3α-diol G), and increases serum testosterone (T) levels, little is known about its effect on other precursors and metabolites of DHT, as well as on the relationship of these androgens to prostate specific antigen (PSA), a marker of prostatic intraepithelial neoplasia. The present study provides new data on the effect of finasteride on precursors and metabolites of DHT. Fifty-three men, ages 57-79 years, with elevated PSA levels (>4ng/ml), were randomized to treatment with finasteride (5mg/day) or observation (controls) for 12 months. Blood samples were obtained at baseline, 1, 3, 6 and 12 months for measurement of PSA, androstenedione (A), T, DHT, 3α-diol G, androsterone glucuronide (ADT G) and DHT sulfate (DHT S) in serum by validated, highly specific radioimmunoassays. Statistical analysis was carried out using mixed model ANOVA and t-tests. In the control group, PSA and androgen levels were unchanged throughout the 12 months of treatment. In the finasteride group, PSA, DHT, DHT S, 3α-diol G and ADT G decreased from baseline to 1 month by 23.2%, 78.7%, 71.0%, 75.7% and 43.0%, respectively. The change in PSA decreased further to 46.1% and 55.1% at 3 and 12 months of treatment, respectively, whereas the decrease in androgens observed at 1 month did not change by more than 6.9% for DHT, DHT S and 3α-diol G in the subsequent months of sampling. However, the decline in ADT G was only 22.2% at month 3, and remained essentially at this level after that time. In contrast, T and A increased significantly from baseline, and the increase in A of approximately 34.5% was about 1.9 times the increase in T (approximately 18.3%). The present data suggest that either 3α-diol G or DHT S may serve as a potential diagnostic marker of intraprostatic 5α-reductase activity during treatment of patients with 5α-reductase inhibitors.
5α-Reductase inhibitors (5α-RI) act by inhibiting the conversion of testosterone to dihydrotestosterone (DHT), thereby preventing DHT induced benign prostatic hyperplasia. The existing 5α-RIs can be classified into two types: competitive and noncompetitive. Currently, limited evidence is available concerning the effect differences between the two types of 5α-RI on androgens. The purpose of this study was to assess the effects of competitive and noncompetitive 5α-RIs on serum and intra-prostatic androgens in beagle dogs.
Twenty beagles with spontaneous benign prostatic hyperplasia were randomly allocated into two groups: epristeride group (n = 10) in which beagles were treated with epristeride at 1 mg/kg once a day for 3 months, and finasteride group (n = 10) in which beagles were treated with finasteride at 1 mg/kg once a day for 3 months. The levels of intra-prostatic testosterone and DHT were measured before treatment and on day one after three months medication. Serum levels of testosterone and DHT were measured at the same time points. Changes in androgen levels before and after treatment were analyzed, and comparisons were made within each treatment group and between treatment groups.
After 3-month treatment, serum and intra-prostatic DHT levels all decreased significantly in both the epristeride and finasteride groups. The change of DHT in serum was significantly higher in the finasteride group (-14% and -43% in epristeride and finasteride groups respectively, with P < 0.001); however there was no significant difference in the changes of intra-prostatic DHT between the two groups (-47% and -51% in epristeride and finasteride groups, respectively, P = 0.304). The decreases in DHT levels were accompanied by reciprocal increases in serum and intra-prostatic testosterone levels. Changes of testosterone were significantly higher in finasteride group both in serum (20% and 42% in epristeride and finasteride groups, respectively, P < 0.001) and in prostate tissue (18% and 29% in epristeride and finasteride groups, respectively, P = 0.004).
Two types of 5α-RI have similar effects in reducing DHT in prostate tissue in beagles. Competitive 5α-RI may reduce serum DHT to a greater scale, and significantly increase testosterone in beagle serum and prostate.
Purpose:
We examined the effects of doxazosin, finasteride and combination therapy among men with benign prostatic hyperplasia on quality of life assessed with MOS-SF-36 (Medical Outcomes Study Short-Form 36) and 2 disease specific instruments (BII, benign prostatic hyperplasia Impact Index and I-PSS-QoL, International Prostate Symptom Score-QoL) during 4 years.
Materials and methods:
The MTOPS (Medical Therapy of Prostatic Symptoms) study was a multicenter, randomized, double-blind, placebo controlled clinical trial with a primary outcome of time to benign prostatic hyperplasia progression. Change in quality of life was a secondary outcome. A total of 2,872 men enrolled in the MTOPS study who had 3 baseline quality of life measures and at least 1 followup measure by any of the quality of life instruments were analyzed.
Results:
Compared with men assigned to placebo, men assigned to doxazosin and combination experienced a statistically significant improvement in the BII at year 4. Men assigned to each of the drug groups also experienced a significant improvement in the I-PSS-QoL compared with those assigned to placebo. Considering longitudinal changes during 4 years, a significant improvement in BII and I-PSS-QoL scores was observed in men assigned to the drug groups compared with those assigned to placebo. However, there were no significant differences for the MOS-SF-36 subscales and summary scores when drug groups were compared with the placebo group.
Conclusions:
The quality of life of men treated with doxazosin, finasteride, and the drugs combined generally improved when assessed with the BII and the I-PSS-QoL compared with those treated with placebo. Quality of life did not show improvement when measured by the MOS-SF-36.
Objective
5a-reductases are a family of isozymes expressed in a wide host of tissues including the central nervous system (CNS) and play a pivotal role in male sex ual differentiation, development and physiology.
Methods
A comprehensive literature search from 1970 to 2011 was made through PubMed and the relevant information was summarized.
Results
5a reductases convert testosterone, proges terone, deoxycorticosterone, aldosterone and corticoste rone into their respective 5a-dihydro-derivatives, which serve as substrates for 3a-hydroxysteroid dehydrogenase enzymes. The latter transforms these 5a-reduced metabo lites into a subclass of neuroactive steroid hormones with distinct physiological functions. The neuroactive steroid hormones modulate a multitude of functions in human physiology encompassing regulation of sexual differen tiation, neuroprotection, memory enhancement, anxiety, sleep and stress, among others. In addition, 5a -reductase type 3 is also implicated in the N-glycosylation of pro teins via formation of dolichol phosphate. The family of 5a-reductases was targeted for drug development to treat pathophysiological conditions, such as benign prostatic hyperplasia and androgenetic alopecia. While the clinical use of 5a-reductase inhibitors was well established, the scope and the magnitude of the adverse side effects of such drugs, especially on the CNS, is still unrecognized due to lack of knowledge of the various physiological functions of this family of enzymes, especially in the CNS.
Conclusion
There is an urgent need to better under stand the function of 5a-reductases and the role of neuro active steroids in human physiology in order to minimize the potential adverse side effects of inhibitors targeting 5a-reductases to treat benign prostatic hyperplasia and androgenic alopecia. (Endocr Pract. 2012;18:965-975)
Introduction:
Treatment with 5-alpha reductase inhibitors (5ARI) is commonly utilized for the treatment of benign prostatic hyperplasia (BPH). The true prevalence of sexual side effects with 5ARI treatment is currently unknown.
Areas covered:
The current article reviews the reported adverse effects of 5ARI in regard to erectile function, sexual desire and ejaculation. A PubMed search was performed of all articles from 1990 to present, which reported any sexual side effects with finasteride or dutasteride. Preference was given to more recent and human studies where available.
Expert opinion:
Clinical trials with 5ARI report prevalence rates of de novo erectile dysfunction of 5 - 9%. Decreased circulating dihydrotestosterone (DHT) resulting from 5ARI use is associated with diminished sexual desire and/or orgasm. The presence of adverse sexual effects is associated with decreased self-esteem, quality of life and ability to maintain an intimate relationship. Inhibition of 5ARI additionally influences progesterone and deoxycorticosterone levels and may alter psychological functions, including increased depression, melancholy and loss of general well being. Ejaculatory dysfunction has not been well studied in patients using 5ARI. Patients receiving therapy with 5ARI should be counseled as to potential sexual and psychological adverse effects. Future clinical studies are needed to further investigate the sexual side effects associated with this class of drugs.
Objective:
We evaluated 5-year safety, efficacy and prostate volume data from BPH patients treated with finasteride or dutasteride.
Methods:
A retrospective analysis of 378 consecutive men treated with 5α-reductase inhibitor monotherapy between January 2004 and September 2009 (197 on finasteride and 211 on dutasteride) in a single clinic was performed. Efficacy assessments included International Prostate Symptom Score (IPSS), peak urinary flow rate (Qmax), postvoid residual urine volume (PVR), prostate-specific antigen (PSA) and prostate volume (PV). Safety assessments included International Index of Erectile Function (IIEF) and adverse events. Patients were evaluated at 3 months, 1 year and yearly thereafter.
Results:
Mean age of the group was 58.7 ± 6.7 years. Maintenance of therapy at 5 years was 57.4% and 42.5% for the finasteride and dutasteride groups respectively. Changes in IPSS, Qmax, PVR, PV and PSA were similar for both groups at 5 years. The incidence of erectile dysfunction, ejaculatory dysfunction and decreased libido resulting in discontinuation from therapy was significantly (p < 0.01) higher in the dutasteride (5.1%, 2.4%, 2.7% respectively) compared with the finasteride (2.1%, 1.8%, 1.4% respectively) group. In addition, the incidence of self-reported breast tenderness and/or enlargement was significantly (p < 0.01) greater in the dutasteride (3.5%) compared with the finasteride (1.2%) group.
Conclusions:
In this retrospective analysis of data from consecutive patients treated at a single clinic, both finasteride and dutasteride were effective therapies for the management of lower urinary tract symptoms. However, dutasteride resulted in significantly more sexual side effects and breast complications than finasteride.
Finasteride, a commonly prescribed medication for male pattern hair loss, has recently been associated with persistent sexual side effects. In addition, depression has recently been added to the product labeling of Propecia (finasteride 1 mg). Finasteride reduces the levels of several neuroactive steroids linked to sexual function and depression. This study assesses depressive symptoms and suicidal thoughts in former users of finasteride who developed persistent sexual side effects despite the discontinuation of finasteride.
In 2010-2011, former users of finasteride (n = 61) with persistent sexual side effects for ≥ 3 months were administered standardized interviews that gathered demographic information, medical and psychiatric histories, and information on medication use, sexual function, and alcohol consumption. All former users were otherwise healthy men with no baseline sexual dysfunction, chronic medical conditions, current or past psychiatric conditions, or use of oral prescription medications before or during finasteride use. A control group of men (n = 29), recruited from the community, had male pattern hair loss but had never used finasteride and denied any history of psychiatric conditions or use of psychiatric medications. The primary outcomes were the prevalence of depressive symptoms and the prevalence of suicidal thoughts as determined by the Beck Depression Inventory II (BDI-II); all subjects self-administered this questionnaire at the time of the interview or up to 10 months later.
Rates of depressive symptoms (BDI-II score ≥ 14) were significantly higher in the former finasteride users (75%; 46/61) as compared to the controls (10%; 3/29) (P < .0001). Moderate or severe depressive symptoms (BDI-II score ≥ 20) were present in 64% (39/61) of the finasteride group and 0% of the controls. Suicidal thoughts were present in 44% (27/61) of the former finasteride users and in 3% (1/29) of the controls (P < .0001).
Clinicians and potential users of finasteride should be aware of the potential risk of depressive symptoms and suicidal thoughts. The preliminary findings of this study warrant further research with controlled studies.
Introduction:
Finasteride has been associated with sexual side effects that may persist despite discontinuation of the medication. In a clinical series, 20% of subjects with male pattern hair loss reported persistent sexual dysfunction for ≥6 years, suggesting the possibility that the dysfunction may be permanent. These subjects also reported a wide range of symptoms including changes in cognition, ejaculate quality, and genital sensation. Other medications have been associated with irreversible neurological effects, such as phenothiazines with tardive dyskinesias.
Aim:
To prospectively study whether the persistent sexual side effects associated with finasteride resolve or endure over time.
Methods:
Subjects (N = 54) with persistent sexual side effects associated with finasteride were reassessed after 9-16 months (mean 14 months). All subjects were otherwise healthy young men without any baseline sexual dysfunction, medical conditions, psychiatric conditions, or use of oral prescription medications prior to taking finasteride for male pattern hair loss.
Main outcome measure:
Scores from the Arizona Sexual Experience Scale (ASEX).
Results:
The participation rate was 81%. At reassessment persistent sexual side effects continued to be present in 96% of subjects. According to the ASEX scores, 89% of subjects met the definition of sexual dysfunction. Neither the length of finasteride use nor the duration of the sexual side effects correlated to changes in scores of sexual dysfunction.
Conclusion:
In most men who developed persistent sexual side effects (≥3 months) despite the discontinuation of finasteride, the sexual dysfunction continued for many months or years. Although several rat studies have shown detrimental changes to erectile function caused by 5 alpha reductase inhibitors, the persistent nature of these changes is an area of active research. Prescribers of finasteride and men contemplating its use should be made aware of the potential adverse medication effects.
OBJECTIVE Since it is not clear whether testosterone or dihydrotestosterone is the active hormone in bone metabolism, we wished to assess the effect of finasteride, a 5α-reductase inhibitor, on vertebral bone mineral density and parameters of bone and mineral metabolism.
DESIGN Patients were treated in a randomized, double-blind controlled study with either placebo, 1 or 5 mg/day finasteride.
PATIENTS Twenty-three men with benign prostatic hyper-plasla (BPH) were included in this study; eight received placebo, seven were allocated to treatment with 1 mg/day, and eight to 5 mg/day finasteride for 12 months.
MEASUREMENTS Vertebral bone mineral density was measured at the lumbar spine by dual energy X-ray bone densltometry. Serum calcium, phosphorus, parathyroid hormone, osteocalcln and vitamin D metabolites were measured regularly. Urinary calcium and creatinlne excretion were monitored as well.
RESULTS Finasteride caused a significant decrease in serum dlhydrotestosterone after 6 and 12 months, but no effect on serum testosterone. Vertebral bone mineral density remained unaltered. None of the other parameters monitored were affected except for a small unexplained increase in 1,25-dihydroxyvitamin D in the group receiving 5 mg finasteride/day.
CONCLUSIONS Testosterone is probably the active hormone in bone metabolism. However, oestradiol, the product of testosterone aromatization (which remains unaltered under finasteride) may yet be another possible responsible steroid in the maintenance of bone density. We can also not rule out that the small amount of dihydrotestosterone remaining under finasteride administration is sufficient for maintaining normal bone metabolism.
The association of 5-alpha reductase inhibitor (5ARI) therapy and sexual dysfunction has been reported. Some patients claim persistent erectile dysfunction despite long-term discontinuation of 5ARI treatment. The aim of this study was to assess erectile function after cessation of 5ARI therapy using a rat model.
Twenty-six adult male Sprague-Dawley rats were randomized into three groups: (i) control (N = 10); (ii) 8-week dutasteride treatment (0.5 mg/rat/day, in drinking water, N = 8); and (iii) 6-week dutasteride treatment followed by a 2-week washout period (N = 8). The experiments were performed after 8 weeks from the initiation of treatment in all groups. In vivo erectile activity and in vitro contractile and relaxant responses of cavernosal smooth muscle were investigated.
In vivo erectile activity (intracavernosal pressure [ICP]/mean arterial pressure [MAP] and total ICP) in treatment groups were significantly decreased compared with controls (ICP/MAP: P < 0.001 for 2.5 v, 5 v, and 7.5 v; total ICP: P < 0.001 for 5 v and P < 0.01 for 7.5 v). Acetylcholine-induced relaxations were diminished in treatment groups (P < 0.05). Relaxant responses to electrical field stimulation (EFS) were decreased in the 8-week treatment group (P < 0.05) but were similar to controls in the washout group. Sodium nitroprusside (SNP)-induced endothelium-independent relaxations were reduced in the 8-week dutasteride treatment group (P < 0.01), while these responses were restored in the washout group. The contractile responses to the alpha1-adrenergic agonist phenylephrine were decreased in treatment groups compared with controls (P < 0.01). Direct neurogenic contractile responses in the dutasteride groups were significantly lower than controls between 1 and 15 Hz frequencies (but not at 20 Hz) and washout partially restored the responses at 10 and 15 Hz.
Discontinuation of dutasteride improved the relaxant responses to EFS and SNP, while cholinergic and adrenergic responses remained depressed. Our findings suggest a time-dependent detriment of dutasteride on erectile function. The withdrawal/washout effect of 5ARIs on parameters of human sexual function warrants further investigation.
The effects of various androgen agonists and antagonists on the restoration of penile erection in long-term castrated male rats were investigated. Erections were evaluated in spinally intact animals held in a supine position with the penile sheath retracted. Mating behavior was measured by placing the male in an observation arena with a receptive female. Both testosterone and dihydrotestosterone (DHT) were very effective in restoring penile erections. Testosterone was also effective in restoring mating behavior, but DHT was totally ineffective. Estradiol was incapable of restoring erections but was effective in stimulating mounting behavior. The non-steroidal antiandrogen flutamide inhibited the testosterone-induced restoration of penile erections, when administered alone, it had a slight excitatory effect. The latency for restoration of erections by testosterone was quite rapid, with a substantial increase within 24 hr. It is suggested that: (1) the androgen-induced restoration of penile erection derives more from neural changes than growth of somatic tissues; and (2) the neural elements regulating erection demonstrate different response characteristics to various hormones than those regulating mounting.
Background:
Dutasteride is a dual inhibitor of type I and type II 5α-reductases and provides nearly complete suppression of dihydrotestosterone, which plays a key role in the aetiology and development of benign prostatic hyperplasia (BPH). Most knowledge about the efficacy and safety of dutasteride in BPH derives from three pivotal phase III studies conducted primarily in Caucasian populations.
Objective:
This study aimed to evaluate the efficacy and safety of dutasteride in Chinese adults with symptomatic BPH.
Methods:
This was a randomized, double-blind, parallel-group, placebo-controlled study conducted over 6 months, followed by an open-label extension of 12 months. A total of 253 BPH subjects with a total prostate volume (TPV) of ≥30 cm3, a maximal urinary flow rate (Q(max)) between 5 and 15 mL/s, and an American Urology Association Symptom Index (AUA-SI) score of ≥12 units were randomized to dutasteride 0.5 mg/day orally or matching placebo treatment in a 1:1 ratio. After 6 months, eligible subjects who volunteered to enter the open-label extension received dutasteride 0.5 mg/day orally. Changes in TPV, Q(max) and AUA-SI as well as drug safety were evaluated.
Results:
Dutasteride significantly reduced mean TPV compared with placebo at 3 and 6 months (both p < 0.05). At 6 months, mean TPV decreased by 17.14% versus 3.71% in the dutasteride and placebo groups, respectively. Numerically higher improvements in Q(max) and AUA-SI were observed in the dutasteride group at 3 and 6 months, but there was no statistically significant difference between treatment groups. However, ad hoc analysis indicated that, at 6 months, significantly higher proportions of subjects in the dutasteride group experienced a Q(max) improvement of ≥3 mL/s, or an AUA-SI improvement of ≥1 unit, compared with the placebo group (both p < 0.05). According to these criteria, the Q(max) responder rates were 33.63% and 19.83% in the dutasteride- and placebo-treated groups, respectively, and the AUA-SI responder rates were 87.61% and 76.92%, respectively. During the open-label extension, continuous improvements in TPV, Q(max) and AUA-SI were noted in both groups. Dutasteride was well tolerated with a low incidence of treatment-related adverse events over 18 months.
Conclusion:
Dutasteride was effective compared with placebo in the treatment of symptomatic BPH among Chinese patients. The efficacy data from trials involving subjects of different ethnic origins showed some similarities. Dutasteride was generally well tolerated during the study period.
Despite widespread adoption of the six-item erectile function (EF) domain of the International Index of Erectile Function (IIEF) as a clinical trial end point, there are currently no objective data on what constitutes a minimal clinically important difference (MCID) in the EF domain.
Estimate the MCID for the IIEF EF domain.
Anchor-based MCIDs were estimated using data from 17 randomized, double-blind, placebo-controlled, parallel-group clinical trials of the phosphodiesterase type 5 inhibitor (PDE5-I) tadalafil for 3345 patients treated for 12 wk.
The anchor for the MCID is the minimal improvement measure calculated using change from baseline to 12 wk on IIEF question 7: "Over the past 4 weeks, when you attempted sexual intercourse how often was it satisfactory for you?" MCIDs were developed using analysis of variance (ANOVA)- and receiver operating characteristic (ROC)-based methods in a subset of studies (n=11) by comparing patients with and without minimal improvement (n=863). MCIDs were validated in the remaining six studies (n=377).
The ROC-based MCID for the EF domain was 4, with estimated sensitivity and specificity of 0.74 and 0.73, respectively. MCIDs varied significantly (p<0.0001) according to baseline ED severity (mild: 2; moderate: 5; severe: 7). MCIDs consistently distinguished between patients in the validation sample classified as no change or minimally improved overall and by geographic region, ED etiology, and age group. MCIDs did not differ by age group, geographic region, or ED etiology. Current analyses were based on 17 clinical trials of tadalafil. Results need to be replicated in studies using other PDE5-Is or in nonpharmacologic intervention studies.
The contextualization of treatment-related changes in terms of clinically relevant improvement is essential to understanding treatment efficacy, to interpreting results across studies, and to managing patients effectively. This analysis provides, for the first time, anchor-based estimates of MCIDs in the EF domain score of the IIEF.
Numerous clinical series have reported an association between 5-alpha-reductase inhibitors (5ARIs) and sexual dysfunction, but there are limited preclinical data available.
To further investigate the mechanisms of erectile dysfunction (ED) related to 5ARI therapy using a rat model.
Outcome measures include serum dihydrotestosterone (DHT), relaxant and contractile properties of cavernosal muscle, and nitric oxide synthase expression.
Twenty adult male Sprague-Dawley rats were randomized into control (N = 10) and dutasteride (0.5 mg/rat/day, in drinking water, N = 10) groups. Serum samples were obtained at baseline, from which DHT was measured after 30 days of treatment via radioimmunoassay (Beckman Coulter, Fullerton, CA, USA). Before the terminal blood draw, erectile response was measured using cavernosal nerve stimulation. The relaxant and contractile properties of cavernosal muscle strips were evaluated in tissue baths, and immunohistochemical (IHC) staining for nitric oxide synthase (NOS) and collagen deposition was performed.
Mean serum DHT was suppressed by 86.5% (range 64.2-94.8%) after 30 days of 5ARI treatment and was statistically significant (P = 0.0024). In vivo erectile response in the dutasteride treated group decreased significantly compared with control (P < 0.001). While electrical field stimulation (EFS)-induced and acetylcholine-induced relaxation was decreased, EFS-induced and phenlyephrine-induced adrenergic contraction was significantly enhanced in the dutasteride group (P < 0.01). IHC studies demonstrated increased collagen deposition in the treatment arm as well as altered expression of neuronal NOS (nNOS) and inducible NOS (iNOS).
The 5ARIs, as demonstrated in these rat cavernosal smooth muscle studies, have a detrimental effect on erectile function. Enhanced iNOS expression may protect penile smooth muscle from fibrosis. The effect of 5ARIs on human sexual function warrants further investigation.
Finasteride has been associated with reversible adverse sexual side effects in multiple randomized, controlled trials for the treatment of male pattern hair loss (MPHL). The Medicines and Healthcare Products Regulatory Agency of the United Kingdom and the Swedish Medical Products Agency have both updated their patient information leaflets to include a statement that "persistence of erectile dysfunction after discontinuation of treatment with Propecia has been reported in post-marketing use."
We sought to characterize the types and duration of persistent sexual side effects in otherwise healthy men who took finasteride for MPHL.
We conducted standardized interviews with 71 otherwise healthy men aged 21-46 years who reported the new onset of sexual side effects associated with the temporal use of finasteride, in which the symptoms persisted for at least 3 months despite the discontinuation of finasteride.
The types and duration of sexual dysfunction and the changes in perceived sexual frequency and sexual dysfunction score between pre- and post-finasteride use.
Subjects reported new-onset persistent sexual dysfunction associated with the use of finasteride: 94% developed low libido, 92% developed erectile dysfunction, 92% developed decreased arousal, and 69% developed problems with orgasm. The mean number of sexual episodes per month dropped and the total sexual dysfunction score increased for before and after finasteride use according to the Arizona Sexual Experience Scale (P<0.0001 for both). The mean duration of finasteride use was 28 months and the mean duration of persistent sexual side effects was 40 months from the time of finasteride cessation to the interview date. Study limitations include a post hoc approach, selection bias, recall bias for before finasteride data, and no serum hormone levels.
Physicians treating MPHL should discuss the potential risk of persistent sexual side effects associated with finasteride.
5α-reductase inhibitors (5α-RIs), finasteride and dutasteride, have been approved for treatment of lower urinary tract symptoms, due to benign prostatic hyperplasia, with marked clinical efficacy. Finasteride is also approved for treatment of hair loss (androgenetic alopecia). Although the adverse side effects of these agents are thought to be minimal, the magnitude of adverse effects on sexual function, gynecomastia, depression, and quality of life remains ill-defined.
The goal of this review is to discuss 5α-RIs therapy, the potential persistent side effects, and the possible mechanisms responsible for these undesirable effects.
We examined data reported in various clinical studies from the available literature concerning the side effects of finasteride and dutasteride.
Data reported in the literature were reviewed and discussed. Results. Prolonged adverse effects on sexual function such as erectile dysfunction and diminished libido are reported by a subset of men, raising the possibility of a causal relationship.
We suggest discussion with patients on the potential sexual side effects of 5α-RIs before commencing therapy. Alternative therapies may be considered in the discussion, especially when treating androgenetic alopecia.