by Dr. Sam Ward / Sint-Jan Clinic, Brussels, Head of the Urology Department – Medi-sfeer
Benign prostatic hyperplasia (BPH) and its associated symptoms are among the most common diagnoses seen by urologists. Previous studies show that more than half of men experience at least one symptom of lower urinary tract symptoms (LUTS), with prevalence increasing as the population ages, and the majority of men over the age of 70 developing BPH/LUTS (1).
An enlarged prostate in and of itself is not an indication for treatment; rather, it is the symptoms and their impact on quality of life (QoL) that lead patients to see a urologist. Although many of these symptoms may be mild, they have usually become bothersome by the time a man seeks care from a urologist. Although it was initially assumed that the primary problem associated with BPH was due exclusively to bladder outlet obstruction (BOO), we now know that LUTS is more complex and involves a combination of both voiding and storage problems. We refer to these as “voiding” and “storage” symptoms.
The gold standard for assessing LUTS is the International Prostate Symptom Score (IPSS), which has been extensively validated and includes both voiding and storage symptoms (e.g., overactive bladder). Although symptom relief and the patient’s perception of treatment effectiveness are inherently subjective, a 4-point improvement in the score is often considered a significant improvement in most men (2). Keeping a voiding diary is particularly helpful (and low-cost) for distinguishing between voiding and storage symptoms and nocturnal polyuria (voiding more than 60% of total volume at night). In a voiding diary, we record voiding frequency, bladder capacity, lifestyle habits, urgency, etc. We ask patients to complete the diary for at least two consecutive days.
When treating any medical condition, it is important to make the correct diagnosis and, furthermore, to prescribe a treatment with as few side effects as possible on quality of life (QoL). After all, an optimal QoL is the very reason why men consult a doctor. That is why phytotherapy is often recommended as a first-line treatment. But is there (sufficient) rationale for this?
Phytotherapy
Plant extracts have long been the most commonly used treatment for LUTS and BPH. The available preparations consist of roots, seeds, pollen, bark, or fruits. There are two types of plant preparations: single-ingredient preparations (monopreparations) and combination preparations. Phytosterols, β-sitosterol, fatty acids, and lectins are potentially relevant compounds. Plant extracts can have various effects in vitro. They exhibit anti-inflammatory, anti-androgenic, and estrogenic properties, as well as a reduction in the protein SHBG (sex hormone-binding globulin). In addition, plant extracts may also inhibit α-adrenoceptors, 5α-reductase, muscarinic acetylcholine receptors, dihydropyridine receptors, and vanilloid receptors.
The effects of these compounds in vivo are unknown, and the exact mechanism of action of plant extracts is also unknown.
A literature review focusing specifically on long-term controlled studies (study period ≥ 6 months) and the recommendations from BPH guidelines was published in 2007 in the renowned journal *European Urology*, the bible of urological research. Only a small number of the available studies met the criteria defined by the WHO-BPH Consensus Conference. The few placebo-controlled long-term studies (study period ≥ 6 months) suggest a positive effect of certain extracts (saw palmetto, β-sitosterol, stinging nettle, combination of saw palmetto/stinging nettle) on LUTS, while an effect on urine flow, post-void residual urine, prostate volume, and PSA was not consistently demonstrated. Due to the lack of prospective studies, which, according to the WHO-BPH recommendations, cannot serve as a substitute for prospective studies. None of the current BPH guidelines recommend plant extracts, but they do unanimously conclude that this is an interesting approach. We can therefore conclude that further prospective studies conducted according to WHO standards are needed to determine the role of plant extracts in the current management of LUTS and to assess their reliability (3).
Alpha-adrenergic antagonists or “alpha-blockers”
The smooth muscles of the prostate respond to alpha-adrenergic stimulation by increasing the resistance of the prostatic urethra. We can induce relaxation by blocking this stimulation, thereby reducing the resistance at the bladder outlet. The fact that the prostate and bladder contain primarily alpha-1 receptors is why we have an arsenal of selective blockers. Although most current alpha-1 blockers are well tolerated, they cause side effects in the prostate and systemically as a result of alpha blockade. Patients may generally experience retrograde ejaculation, rhinitis, and orthostatic hypotension. The bladder contains alpha receptors, which may explain why symptoms of overactive bladder (OAB) are less prevalent. Although the exact physiology behind this is unknown, it is believed to be related to alpha blockade, which increases detrusor blood flow (4).
The first selective alpha-1 blocker to be tested was prazosin, which demonstrated efficacy but required twice-daily dosing (5). Prazosin is no longer used for LUTS, but interestingly, it has found a role in the treatment of post-traumatic stress disorder. Doxazosin and terazosin are selective alpha-1 blockers administered once daily; they generally require a titration period to reach a full therapeutic dose and are not often used as first-line agents (6,7). Doxazosin is not available in Belgium.
Tamsulosin is probably the best-known alpha-1 blocker. It is not only alpha-1-selective but also uroselective, allowing it to maintain good symptom control with minimal side effects. In general, you can expect symptom relief within a few days to a week after starting therapy. Tamsulosin has been extensively studied and has been shown to reduce the IPSS by approximately 9.5 points (8). Tamsulosin is generally prescribed at a dose of 0.4 mg, preferably 30 minutes after the same meal each day.
Set Yourself Apart
Alfuzosin and silodosin are additional uroselective agents that can be administered once daily and have also been shown to be effective. Silodosin may be associated with more severe sexual side effects, but carries a lower risk of orthostatic hypotension (9–11).
What should be done in cases of acute urinary retention?
Alpha-blockers are often initiated following an episode of acute urinary retention. When initiating treatment with alpha-blockers following acute urinary retention, the AUA guidelines recommend continuing treatment for at least three days before attempting to remove the transurethral catheter (12). Of course, it remains important to treat the underlying causes as well (UTI, fecal impaction, etc.).
What else should you know about alpha-blockers?
What is important, however, is that patients must be informed that, at any time after starting alpha-1 blockers, they are at an increased risk of developing floppy iris syndrome during cataract surgery. This has been observed even years after discontinuing alpha-1 blockers, so any patient who has used alpha-1 blockers for some time may be at risk (13).
5-alpha-reductase inhibitors
BPH is almost exclusively hormonally mediated by dihydrotestosterone (DHT). The volume of the prostate decreases as a result of DHT suppression. Steroid 5-alpha-reductase converts testosterone into DHT. The body has two isoenzymes: steroid 5-alpha-reductase type 1 (found primarily in extraprostatic tissues) and steroid 5-alpha-reductase type 2 (found primarily in prostate tissues).
The two available 5-alpha-reductase inhibitors (5ARIs) are finasteride, a selective inhibitor of type 2 5-alpha-reductase, and dutasteride, a non-selective inhibitor of both isozymes. These medications significantly reduce symptoms by affecting hormonal expression in the prostate. Patients should expect a waiting period of approximately three to six months before changes occur. In addition, results are generally better for patients with a larger prostate. The best results are achieved after nine months (14).
Finasteride and dutasteride have been extensively studied, both independently and in comparative trials, and have been shown to lower IPSS scores and reduce prostate volume by approximately 30% (15,16). There is no difference in outcomes or side effects between the two drugs. Side effects are generally well tolerated and include erectile dysfunction (8.1%); decreased libido (6.4%), ejaculatory dysfunction (0.8%), and gynecomastia (0.5%), all of which appear to occur within the first year of treatment. This should be discussed in detail with the patient. Andrologists are often reluctant to prescribe such medications to young patients. Studies have shown that the incidence of side effects does not increase with longer treatment periods, with the exception of ejaculatory dysfunction, which worsens with prolonged treatment (17).
What about “post-finasteride syndrome”?
Patients are increasingly reporting that their symptoms persist after using alpha-reductase inhibitors; this is known as post-finasteride syndrome, which is characterized by sexual side effects and a depressed mood that persist despite discontinuation of the medication, regardless of the duration of treatment. The pathophysiology of this condition is unclear, and it is a current area of research (18).
The MTOPS study demonstrated the safety and efficacy of combination therapy with a 5-ARI and an alpha-1 antagonist, with men showing less symptom progression on combination therapy compared to monotherapy. Men who used finasteride alone or in combination showed a reduction in acute urinary retention and the need for surgical intervention compared with doxazosin monotherapy (16). It is believed that as men age, their prostate continues to grow, causing greater urethral pressure than the 5ARI can counteract and the reduced muscle relaxation caused by the alpha-1 antagonist (16); however, it should always be noted that as men age, they may develop more medical comorbidities that make them more susceptible to urinary retention, independent of their BPH.
The controversial use of 5-ARI’s has been associated with a reduction in prostatic blood loss related to BPH, either in cases of macroscopic hematuria with clot retention or preoperatively prior to transurethral resection of the prostate (TURP). Although there is considerable anecdotal evidence supporting this use, there is a lack of evidence-based data (19); however, some studies suggest that even short courses—on the order of 4 to 6 weeks—of 5ARIs may be clinically significant (20). Anecdotally, some urologists reportedly keep patients on 5-ARIs for several weeks postoperatively following a TURP and empirically initiate treatment in patients presenting with macroscopic hematuria and LUTS.
Anticholinergics
The detrusor muscle of the bladder is innervated by parasympathetic fibers and mediated via muscarinic receptors, which in turn regulate bladder capacity and involuntary detrusor contractions, which may contribute to “storage” LUTS. By inhibiting these contractions with muscarinic receptor antagonists (anticholinergics), we can reduce involuntary detrusor contractions, which in turn leads to improved urinary storage capacity (and thus less frequent urination). Since we are inhibiting detrusor contractions, there is a theoretical risk of urinary retention, especially in patients with “voidings” LUTS(22).
Oxybutynin, solifenacin, propiverine hydrochloride, and tolterodine are four of the most commonly prescribed anticholinergics. Although they play a role in patients with only symptoms of an overactive bladder, patients with BPH often have a combination of voiding and storage-related LUTS. For this reason, anticholinergics are often not used as monotherapy, as studies have shown that this can be much less effective than combination therapy (23).
Although acute urinary retention (AUR) is often cited as a side effect of anticholinergic drugs, the actual incidence rates of AUR reported in the literature are quite low, likely in the order of 0.3% (24). In general, a post-void residual volume (PVR) cutoff of 200 cc is used as a mild contraindication for initiating anticholinergic therapy, which must, of course, be discontinued if a patient develops AUR. If a patient develops AUR, another anticholinergic is generally not tried. The most common side effects are dry mouth, constipation, and blurred vision. It is important to note that central nervous system (CNS) side effects, such as confusion and delirium, are more common in older men and men with pre-existing neurological conditions and should therefore be used with caution. There is evidence suggesting that CNS side effects vary depending on the medication, with one study showing that oxybutynin was associated with more severe CNS side effects compared to darifenacin (25).
Combination therapy with anticholinergics and alpha-1 antagonists has proven successful with many different drug combinations. Tamsulosin and tolterodine ER were each studied as monotherapy, in combination therapy, and compared to placebo. Combination therapy was found to provide the most significant reduction in symptoms, with a greater reduction in storage symptoms, without affecting urinary retention rates (23). This is further supported by a meta-analysis of multiple studies of various combinations of anticholinergics and alpha-1-antagonists, which confirm that patients with storage-related LUTS experience a significant reduction in symptoms without an increase in urinary retention rates, suggesting that more than 100 patients would need to be treated with combination therapy to cause one additional case of urinary retention (26).
Phosphodiesterase type 5 inhibition
Phosphodiesterase type 5 inhibitors (PDE5i) are best known as a treatment for erectile dysfunction (ED) due to their vasodilatory effect, which results from blocking cGMP breakdown and promoting nitric oxide production. Patients taking PDE5i have reported a reduction in LUTS. Although the general mechanism underlying this is unclear, possible theories include increased oxygenation of the bladder and prostate, as well as potential relaxation of the bladder neck and prostatic smooth muscles (27,28). ED and LUTS often co-occur in aging men, so a medication that can treat both would be ideal for this population.
Sildenafil was the first PDE5 inhibitor to be studied (29), and further research showed that among men with a baseline IPSS score greater than 10, taking sildenafil an average of twice a week was associated with a statistically significant 4.6-point decrease in the IPSS score (30). Given sildenafil’s “on-demand” dosing, this treatment regimen may be difficult for men to adhere to, a challenge further compounded by sildenafil’s poor absorption, which requires it to be taken on an empty stomach. Thus, although the reduction in LUTS can be viewed as a potential additional benefit, a more stable medication would be preferred for the primary treatment of LUTS.
This is where tadalafil has an advantage, as it has a much longer half-life in the body and can be taken daily. After tadalafil was shown to be effective in reducing LUTS (31), a randomized, controlled dose-finding study was conducted in which tadalafil 2.5, 5, 10, and 20 mg daily was tested over a 12-week period. All men showed a reduction in IPSS scores, but a daily dose of 5 mg was found to have the most favorable risk-benefit profile (32). Currently, tadalafil at a dose of 5 mg per day is the only PDE5i with FDA/EMA approval for the treatment of BPH/LUTS. It is recommended to take it at the same time every day, and it can be taken with or without food. Although 5 mg is the most common dose, it can be titrated for men with refractory ED or LUTS.
Side effects of tadalafil are generally well tolerated by most men and include headache, flushing, dyspepsia, nasal congestion, myalgia, and back pain. The side effect profile is similar to that of sildenafil; however, myalgia and back pain may occur more frequently with tadalafil (33). Since tadalafil does not cause the ejaculatory dysfunction side effects associated with alpha-blockers, this may make it a more attractive first-line treatment for younger men who prioritize sexual function.
Although tadalafil has not been studied as extensively in combination therapies as drugs in other classes, a recent meta-analysis (34) of tamsulosin and tadalafil combination therapy showed very positive results, demonstrating that combination therapy leads to an improvement in IPPS (primarily with improvement in voiding symptoms), an increase in Qmax, as well as a mitigating effect on the ejaculatory dysfunction associated with tamsulosin monotherapy when used in combination therapy. The study did note, however, that more patients had to discontinue treatment due to side effects in the combination therapy groups. In general, tadalafil and tamsulosin can be recommended to patients, but a discussion regarding the possibility of worsening side effects and a potential contingency plan to revert to monotherapy is necessary.
Beta-3-adrenergic agonists
Beta-3-adrenergic receptors are present in the bladder, and their activation leads to relaxation of the smooth muscles in the detrusor. By activating these receptors, we can relax the bladder and inhibit microcontractions of the bladder, leading to an increase in storage capacity and a decrease in storage-related LUTS (35). Animal studies suggest that beta-3 agonists also induce relaxation of the urethra (36), which offers a possible physiological explanation for the relief of voiding LUTS. Since beta-3 agonists employ a completely different mechanism of action than their anticholinergic counterparts, we can treat storage-related LUTS with a different side effect profile.
Mirabegron is the primary beta-3 agonist available, and although it was initially studied in men and women with OAB, there are specific data examining this drug in men with BPH and storage symptoms. Mirabegron was compared with solifenacin and was found to provide comparable relief from urgency, frequency, and incontinence (37)/ Mirabegron doses of 50 mg and 100 mg showed no difference from placebo in terms of worsening of BOO, as patients’ detrusor pressure and maximum urinary flow rate remained unchanged compared with placebo. Patients experienced reduced frequency and urgency while taking mirabegron (38).
Although mirabegron is well tolerated, previous studies have shown that it can cause an increase in systolic blood pressure, and it should be avoided in patients with difficult-to-control hypertension. In addition, the patient’s blood pressure should be monitored during initiation and titration.
Vibegron received FDA approval in 2020 for use in OAB and has demonstrated promising results and safety; the EMPOWUR clinical trial compared vibegron with tolterodine ER and showed a greater reduction in urge incontinence and a comparable reduction in urgency (39). The study was extended to 40 weeks and demonstrated sustained safety and efficacy (40). Vibegron is currently being studied for use in BPH with storage-related LUTS. A marketing authorization application has been submitted, and vibegron may soon be available in Belgium.
What if medication isn't helpful enough?
Although medication is often the first step, surgical intervention may be necessary for patients who do not respond to medication or who experience severe symptoms or side effects from conventional medication. The main surgical procedures include:
- Transurethral resection of the prostate (TURP): the gold standard for surgical treatment of BPH, in which excess prostate tissue is removed. Fully reimbursed in Belgium. Retrograde ejaculation.
- Holmium Laser Enucleation of the Prostate (HoLEP): an effective, less invasive technique for larger prostates. Fully reimbursed in Belgium. Retrograde ejaculation.
- REZUM®: a newer technique that uses steam therapy to reduce the size of prostate tissue. For the time being, it is no longer fully reimbursed in Belgium. Only the device itself is reimbursed. There is no longer a nomenclature number for it. Retrograde ejaculation is almost never observed.
- Very recent new options: procedures such as iTind®, Aquablation®, and Optilume® are promising new techniques that are less invasive and designed to promote rapid recovery.
- Urolift®: a minimally invasive procedure that uses implants to pull the prostate lobes to the side. Although this technique is used less frequently in Belgium, it can be a good option for selected patients.
What should I do?
Due to the wide range of drug classes and medications within each category, there is variation in treatment approaches among urologists. This variability underscores the importance of a personalized approach, in which treatment is tailored to the patient’s specific needs and preferences. It is crucial to consider the potential side effects of the chosen therapies and to work with the patient to make an informed decision that focuses not only on symptom relief but also on maintaining quality of life. After all, for many men, ejaculation may still be important. Thorough counseling is therefore necessary and ensures a personalized approach every time.
Don't hesitate to ask a urologist for advice. If you want to refer a patient, ask them to keep a voiding diary. It helps a lot.
Key Points
– LUTS can be quantified using the IPSS, which allows for more objective monitoring of symptoms during treatment. – Uroselective alpha-1 antagonists (tamsulosin, alfuzosin, silodosin) are well tolerated and are effective first-line treatments for LUTS. – 5-alpha-reductase inhibitors (e.g., finasteride, dutasteride) are slow-acting medications indicated for men with enlarged prostates and have been shown to reduce the incidence of urinary retention. 5-alpha-reductase inhibitors are effective as monotherapy or in combination therapy for men with enlarged prostates and/or urinary retention. – Anticholinergics are ideal for combination therapy in patients with refractory storage LUTS, generally carrying a low risk of developing acute urinary retention in men with a baseline PVRS of less than 200 cc. – Patients presenting with LUTS and erectile dysfunction may start with daily treatment with tadalafil. – Patients should be aware that as they age, they may “outgrow” their current therapy and may need to switch to combination therapies or consider surgical intervention.