Combined Therapy Shows Promise in Benign Prostatic Hyperplasia Management

Background

Benign prostatic hyperplasia (BPH) is a progressive disease that causes lower urinary tract symptoms (LUTS) that substantially affect the quality of life of many patients.

Men with BPH may have more severe SSLUTI, as well as other symptoms and events such as reduced urinary flow rate, increased incidence of urinary tract infection, acute urinary retention, and increased incidence of surgery for BPH, which have a greater negative impact on the patient’s quality of life.

Dihydrotestosterone (DHT) is the main androgen responsible for the excessive growth of the prostate that is characteristic of BPH, which is converted from testosterone by the catalysis of 5α-reductase (5AR) in the prostate gland.

Furthermore, 5AR may participate in steroid metabolism and have a close interaction with the testosterone androgen receptor. Excessive expression of DHT would trigger the proliferation of prostate epithelial and mesenchymal cells and lead to the development of BPH.

5AR inhibitors (5ARI) can decrease serum DHT concentration and control prostate development and BPH progression by inhibiting this enzyme.

Dutasteride , a selective inhibitor of 5ARI type 1 and type 2, is the most frequently prescribed drug. However, recent clinical trials have found that the effectiveness of dutasteride was limited by its side effects, mainly related to erectile dysfunction, ejaculation disorder and decreased libido.

Tamsulosin , as an effective α 1 receptor blocker, improves dysuria and other symptoms of BPH by selectively blocking the α 1A-adrenergic receptor in the prostate by relaxing the smooth muscles of the gland .

In view of the unique mechanism of tamsulosin and dutasteride, the combination of these two drugs was feasible and has already been examined in some clinical studies. Currently, there are no Evidence-Based Medicine data to explain the advantages and disadvantages of the combination of tamsulosin plus dutasteride compared to tamsulosin monotherapy.

We performed a meta-analysis to confirm the efficacy and safety of the combination of tamsulosin plus dutasteride compared with tamsulosin monotherapy in the treatment of benign prostatic hyperplasia (BPH) over a treatment course of at least 1 year.

Methods

Randomized controlled trials were searched using MEDLINE, EMBASE and the Cochrane Register of Controlled Trials.

The systematic review was conducted using the preferred reporting items for systematic reviews and meta-analyses. Data were evaluated and statistically analyzed using RevMan version 5.3.0.

Results

Five studies with 4348 patients were studied.

The analysis found that the combination group had a significantly greater effect on the International Prostate Symptom Score (mean difference [MD], −1.43; 95% confidence interval [CI], −2.20 to −0.66; P = 0.0003), prostate volume (MD, - 10.13; 95% CI, - 12.38 to - 7.88; P < 0.00001), transition zone volume (MD, - 3.18; 95% CI, - 3.57 to - 2.79 ; P < 0.0001), maximum urine flow rate (MD, 1.05; 95% CI, 0.82 to 1.29; P < 0.00001), prostate-specific antigen (MD, -0.54; 95%, - 0.80 to - 0.29; P <0.0001) and postvoid residual volume (MD, - 3.85; 95% CI, - 4.95 to - 2.76; P <0.00001 ) compared to the tamsulosin group.

In terms of safety, including adverse events, (odds ratio [OR], 2.06; 95% CI, 1.34 to 3.17; P = 0.001), erectile dysfunction (OR, 2.24; 95% CI, 1.73 to 2.92; P < 0.00001 ), ejaculation disorder (OR, 3.37; 95% CI, 1.97 to 5.79; P < 0.0001), retrograde ejaculation (OR, 2.30; 95% CI, 1.08 to 4.93; P = 0.03), decreased libido (OR, 2.25; 95% CI, 1.53 to 3.31; P < 0.0001), and loss of libido (OR, 3 .38; 95% CI, 1.94 to 5.88; P < 0.0001), the combination group showed poor tolerance relative to that of the tamsulosin alone group with the exception of dizziness (OR, 1.16 (95% CI, 0.75 to 1.80; P = 0.50).

The combination group significantly reduced the risk of clinical progression relative to the tamsulosin group, especially in the incidence of progression of BPH-related symptoms (OR, 0.56; 95% CI, 0.46 to 0.67; P <0.00001) and acute urinary retention (OR, 0.61; 95). %CI, 0.38 to 0.98; P = 0.04).

Discussion

BPH is a progressive condition characterized by prostate growth that is accompanied by lower urinary tract symptoms (LUTS) and sexual dysfunction. Clinical treatment of BPH with 5ARIs and/or α1 blockers has been the first-line treatment, and the two drugs showed different mechanisms of action to influence the progression of prostate hypertrophy.

Currently, the European Association of Urology (EAU) guidelines recommend offering combination treatment with an α1-blocker and a 5ARI for men with moderate to severe LUTS and an increased risk of disease progression (e.g., prostate volume > 40 ml).

The latest prospective study found that the combination of tamsulosin plus dutasteride was more efficient than placebo in the treatment of LUTS and may contribute to attenuating ejaculation disorders, especially in sexually active men with BPH.

We performed this meta-analysis for five studies including 4348 participants to compare the efficacy and safety of the combination of tamsulosin plus dutasteride compared with tamsulosin monotherapy in the treatment of BPH over a treatment cycle of at least 1 year.

Overall, the results suggested that tamsulosin plus dutasteride combination therapy was more effective than tamsulosin monotherapy in patients seeking symptom improvement.

Deslypere et al. found that the progression of BPH was inseparable from the variation of DHT which has a high affinity for the androgen receptor and an inhibitory effect on testosterone.

Previous studies have suggested that combination therapy markedly reduced the risk of progression of BPH-related symptoms and acute urinary retention relative to tamsulosin monotherapy.

Dutasteride inhibits two subtypes of 5AR, and has a 45-fold higher affinity for type I and a 2.5-fold higher affinity for type II than finasteride. As a result of this higher affinity, dutasteride effectively inhibits DHT much more rapidly than finasteride.

Our study found that dutasteride can also be used as an effective ingredient in combination medication that may be even superior to previous treatments.

For safety reasons, included in the randomized trials, erectile dysfunction, ejaculation disorder, retrograde ejaculation, decreased libido, loss of libido, the combination group had a higher incidence than the tamsulosin group , with the exception of vertigo.

These results indicated that the doctor should explain to patients the possible side effects of the long-term combination of tamsulosin plus dutasteride treatment before adopting this treatment.

One study demonstrated that long-term dutasteride therapy resulted in worsening erectile dysfunction, reduced testosterone levels, increased glucose, and altered lipid profiles, suggesting an induced imbalance of metabolic function and impaired gonadal function. .

Manohar et al. demonstrated that tamsulosin had better effectiveness in relieving BPH symptoms and in the frequency of a variety of adverse reactions, such as dizziness, decreased blood pressure, increased heart rate, occasional abdominal pain, nausea, and allergic reactions.

Regarding clinical progression after drug administration, combination therapy can significantly reduce the risk of progression of BPH-related symptoms and acute urinary retention compared with tamsulosin monotherapy.

In another evaluation of BPH-related clinical progression, which included urinary incontinence, urinary tract infection, and renal failure, no significant differences were found between the two treatment groups.

Tamsulosin can selectively block the α 1 adrenergic receptor in the prostate to relax the smooth muscles of the gland, expanding the prostatic part of the urethra, modifying urinary symptoms, and reducing the possibility of acute urinary retention.