A frank discussion of risks and benefits
Benign prostatic hyperplasia (BPH) is one of the most common disorders affecting men as they grow older. Yet there is much confusion about the best way to treat this disorder, in part because men taking medications for BPH are also likely to be taking other drugs for common medical problems, which may lead to adverse interactions and exacerbated side effects.
Harvard editors invited three Harvard experts to participate in a roundtable discussion to share their thoughts about the relative benefits and risks of current BPH medications. Participants included:
- Dr. Kevin Loughlin, professor of surgery (urology) at Harvard Medical School, who is senior surgeon and director of urologic research at Brigham and Women’s Hospital and staff urologist at Harvard University Health Services, a large university health program that serves the needs of Harvard students, faculty, employees, and their families.
- Dr. Abraham Morgentaler, associate clinical professor of surgery (urology) at Harvard Medical School and director of Men’s Health Boston. Dr. Morgentaler specializes in diseases of the prostate and has a particular interest in treating erectile dysfunction, low testosterone levels, and BPH. He has published widely on the issue of erectile dysfunction.
- Dr. Martin Sanda, associate professor of surgery (urology) at Harvard Medical School and director of the Prostate Care Center at Beth Israel Deaconess Hospital. Dr. Sanda has extensive experience in prostate cancer and BPH and has devoted much of his professional research to evaluating prostate-related treatment outcomes and developing new therapies.
Here, you’ll learn what they think about who needs to be treated, what medications should be prescribed, and what side effects you need to be aware of. In short, after reading this article, you’ll become a more discerning critic of the statements made during BPH drug advertisements that air during televised sporting events — and much more able to work with your doctor to make your own treatment decisions.
Who needs to be treated
|In brief: One of the most vexing issues for people with BPH is deciding whether to begin treatment for urinary difficulties and other symptoms. Studies of the natural history of BPH over a period of up to five years show that, even without treatment, symptoms will not worsen in 16% of men, and they will actually improve in 38% of men.
What criteria do you use in determining whether to recommend treatment?
Morgentaler: One of the issues we’re always struggling with is who really needs to be treated at all. Some men may have relatively mild symptoms, in the spectrum of what we see, but they really are bothered by them and want to be treated, while other men may have really bad symptoms and are not interested in treatment at all. BPH treatment really comes down to patient preference and the impact of the condition on a person’s life.
Sanda: I agree. When we talk about treatment, we’re really talking about symptom management and symptom relief. The only time we’d urge someone without symptoms to begin medical treatment for BPH is if he began to suffer adverse consequences, such as infection due to retained urine or acute urinary retention, or if tests reveal scarring of the bladder, or any other sign that some type of irreversible damage is occurring in the bladder or kidneys. In such situations, we’d recommend treatment even if the patient is not particularly bothered by symptoms.
Loughlin: There’s actually a fairly narrow spectrum of absolute indications to treat BPH. Most people, probably more than 90%, are coming for relief of symptoms.
What medications should be prescribed
|In brief: Two classes of medication are available to treat BPH: alpha-1 blockers and 5–alpha-reductase inhibitors. It is not always apparent which medication is best for which patient.
What criteria do you use in determining the type of BPH medication to recommend?
Loughlin: In general, alpha-1 blockers are best used in men with smaller prostates, 35 grams and smaller, and 5–alpha-reductase inhibitors are better for men with larger prostates, 55 grams and larger. This approach has been endorsed by several respected studies. Now, it’s not absolute. There’s judgment involved on the part of the urologist and the patient, but I think it’s a useful way to think of it, that with smaller glands you tend to use alpha-1 blockers, and with larger glands you tend to use 5–alpha-reductase inhibitors.
How is the size of the prostate best determined?
Loughlin: Your doctor can provide you with a rough estimate by doing a digital rectal exam. The other way to find out is to undergo a transrectal ultrasound — although that is usually ordered only if prostate cancer is suspected.
Of course, prostate size isn’t the only issue. Something else to consider is that alpha-1 blockers have a very rapid onset of action, days to weeks. 5–alpha-reductase inhibitors have a slow onset of action, three to six months. So in addition to size of the prostate gland, you need to understand from the patient how bothered he is by his symptoms and how long he can wait for relief.
Morgentaler: Definitely one factor that drives the choice of medication is how quickly a patient wants to see results. It’s very difficult to take a medication day after day, when it may not really have much impact for a few months. I think part of what drives the choice of alpha-1 blockers is that a patient will get relief fairly soon. On the other hand, if a patient wants to reduce the size of his prostate, then 5–alpha-reductase inhibitors are the better choice.
Is there a correlation between prostate gland size and symptoms?
Sanda: Well, that’s an interesting question, because the studies that have looked carefully at that issue have not found a great deal of correlation between prostate size and symptoms. But as Kevin mentioned, the size of the prostate helps determine whether a 5–alpha-reductase inhibitor has any role or not.
In my practice, I generally recommend alpha-1 blockers as the first line of treatment because of the immediacy of effect. And although the effectiveness of 5–alpha-reductase inhibitors is limited to men with large prostates, the converse is not true. In other words, alpha-1 blockers seem just as effective in men with larger prostates as in those with smaller prostates. So they have a broad spectrum of action, which is another reason why I tend to recommend alpha-1 blockers as a first-line therapy. I reserve 5–alpha-reductase inhibitors for those patients who, for one reason or another, do not get sufficient symptom relief from an alpha-1 blocker, and who have a large prostate, are not in an emergency situation, and have the patience to wait for several months before the medication takes effect.
Deciding which alpha-1 blockers are best
|In brief: Two types of alpha-1 blockers are available. The first generation, nonselective alpha-1 blockers — doxazosin (Cardura, generic) and terazosin (Hytrin, generic) — affect not only the prostate but the heart and blood vessels, and so have an impact on blood pressure. The second generation, selective alpha-1 blockers — alfuzosin (Uroxatral), silodosin (Rapaflo), and tamsulosin (Flomax, generic) — mainly affect the prostate, and so have less of an impact on blood pressure, but sometimes create ejaculation difficulties.
Do you prescribe the nonselective alpha-1 blockers anymore? Or just the selective alpha-1 blockers?
Sanda: The clear advantage of the selective alpha-1 blockers is that they are simpler to use and they take effect more quickly, because you don’t have to worry about titrating the dose. The first-generation nonselective drugs have to be titrated gradually. How long that takes depends on how much the drug affects that particular person’s blood pressure, and that’s quite variable. Some patients can reach a therapeutic dose of terazosin or doxazosin almost immediately without much effect on their blood pressure, but others need the dose increased much more slowly.
I also try to avoid the nonselective drugs because of their impact on blood pressure, but if I do prescribe them, I advise patients that if they experience lightheadedness and fatigue, or just feel washed out, that might indicate that their blood pressure is being affected too drastically by the medicine.
Morgentaler: I’m so glad that we have the newer selective alpha-1 blockers because I’ve found that titrating of doses is very confusing for patients. There are certainly times when the nonselective alpha-1 blockers might be useful, but there’s no question in my mind that the new medications that generally have a single dose are simpler to prescribe, simpler to explain, and simpler for the patients to take.
Loughlin: I agree. A single-dose regimen is easier for the patient. If you ask someone who’s in his 80s and who’s already on six or seven other medications to titrate an alpha-1 blocker, you’re just asking for a drug error.
Morgentaler: I do prescribe the nonselective drugs for men if they’ve been on one of the drugs for a long time and they’ve been satisfied with it; then I’ll just renew the prescription. A second issue is cost. Every now and again there are some formulary issues, where a health plan will only cover the nonselective alpha-1 blockers because they are less expensive.
Sanda: If cost is a concern, then I mention that both of the nonselective alpha-1 blockers are available in generic forms, which are cheaper than the prescription drugs.
Side effects of alpha-1 blockers
|In brief: The main concern about the nonselective alpha-1 blockers is that they may cause orthostatic hypotension when used in conjunction with other blood pressure medications or erectile dysfunction drugs. But the selective alpha-1 blockers are apparently more likely to cause ejaculatory difficulties.
How do you advise patients who are taking antihypertensives?
Sanda: Certainly with the nonselective alpha-1 blockers there’s a great concern in terms of adjusting other antihypertensives. I think it’s much less of a concern with the selective alpha-1 blockers, such as Flomax.
Morgentaler: The one big issue that comes up with men who are on Flomax, although it can happen on any of the alpha-1 blockers, is the issue of ejaculatory dysfunction. This hasn’t shown up so much in the studies, or in the manufacturer’s materials, but we hear a lot about it from patients. Some men aren’t bothered at all, but others are really affected a lot.
Is ejaculatory dysfunction just a problem for the selective alpha-1 blockers, or do you also see it with the nonselective ones?
Morgentaler: This problem may have happened occasionally in men taking Cardura and Hytrin, but the complaints really increased when Flomax came out. I mean, it’s fairly routine now to have a patient talk to me about this problem. They say things like, “Doc, I have an orgasm and nothing comes out. There must be something terribly wrong with me.” I find that if men are aware of this possibility ahead of time, so that they can anticipate it, they can deal with it. But when a man isn’t prepared, and when he’s still very interested in his sexuality, and his definition of potency includes ejaculatory potency, then it can become a problem.
Uroxatral is supposed to cause less ejaculatory disturbances. Have you found that to be the case?
Morgentaler: I personally have very little experience so far with Uroxatral. The data suggest that it’s not as much of a problem as it is with Flomax, but it’s still there.
Loughlin: I also tend to prescribe far more Flomax than Uroxatral, but that’s probably because Flomax has been around longer and my patients have been satisfied with it. But I think they’re probably about the same in terms of efficacy.
Are there any other key side effects that you see in people who take alpha-1 blockers for years?
Morgentaler: Every medication has risks, but over all, these medications are remarkably safe. The one thing that I do hear from patients, and it does show up in the literature as well, is that some people just don’t tolerate these medicines well. They feel lousy, weak, they don’t feel like themselves. But I think the number of men who experience that is fairly small.
And what do you do in those circumstances?
Morgentaler: Whenever I give a patient a medication, I try to alert him to the most common side effects. And I also tell him, you know, some guys just don’t tolerate certain kinds of medicine, and so you may feel weak or lousy. If it only lasts for a day or two, I advise them to try and get through it, but if they feel awful or the discomfort persists, I ask them to stop the medication and give me a call, and we can try something else.
Using BPH and erectile dysfunction drugs
|In brief: Many men who are taking alpha-1 blockers for BPH are also taking erectile dysfunction medications, known as PDE-5 inhibitors. The FDA has approved three: sildenafil (Viagra), tadalafil (Cialis), and vardenafil (Levitra). Because these medications widen arteries throughout the body, the concern has been that if they are mixed with alpha-1 blockers, they may cause a precipitous drop in blood pressure.
The common wisdom is that it’s not safe to mix PDE-5 inhibitors with alpha-1 blockers. Is that really the case?
Morgentaler: I would say that, in my experience, the concern about combining alpha-1 blockers and PDE-5 inhibitors has lessened. Even the FDA has softened its cautionary language.
Loughlin: Most urologists today advise patients to take these medications at different times during the day rather than simultaneously. There’s not great compelling evidence that if you take them simultaneously anything terrible would happen, but it’s wise to be cautious.
So do you recommend taking the alpha-1 blocker in the morning and the erectile dysfunction drug in the evening?
Morgentaler: Frankly, I don’t. I’ve been prescribing these medicines since Viagra came out in 1998, and I’ve never seen a single problem of hypotension from the combination. I think this is an issue that really has no substance to it.
Sanda: If a patient who is on an alpha-1 blocker is also using Viagra or another PDE-5 inhibitor, I mention that there have been some reports of interactions, but that I’ve never encountered it in my practice and that I don’t know of any of my colleagues who have. I personally feel that it’s quite safe for people to use both types of drugs at once.
Other concerns about alpha-1 blockers
|In brief: Alpha-1 blockers can cause other types of side effects and interact with other medications and herbal remedies.
Do you believe there is the potential to aggravate BPH symptoms or urinary retention if your patients take over-the-counter medicines such as Sudafed during cold and flu season? And what are your thoughts about herbal and over-the-counter remedies?
Sanda: I’ve certainly encountered many men who have gone into urinary retention while taking over-the-counter cold remedies. I think it’s important for any man with BPH, whether or not he’s being treated, to be aware that medications for nasal congestion can exacerbate urinary problems and could potentially lead to acute urinary retention. To avoid problems, I advise patients to pay attention to any changes in urination while they are taking Sudafed or similar agents.
Loughlin: Another thing men with BPH may want to be aware of is that there are a lot of people out there who still take saw palmetto and swear by it, and I think it’s important to say that the best study done on saw palmetto, which was published in the New England Journal of Medicine, found that it’s no better than placebo [see “How effective is saw palmetto?” below].
Most herbal therapies do appear to be safe. But they are not FDA-regulated. A lot of patients don’t consider herbal remedies to be drugs, and technically they’re not, but sometimes they interact with medications. If you are taking an herbal remedy, it’s important that you mention it to your doctor.
How effective is saw palmetto?
In an effort to determine how well saw palmetto reduces symptoms of BPH, researchers randomly assigned 225 men over age 49 with moderate to severe BPH symptoms to one of two groups. One group took 160 mg of saw palmetto extract twice a day; the other received a placebo. At the end of one year, there was no significant difference in the two groups in symptoms such as prostate size, PSA level, or maximal urinary flow.
Source: Bent S, Kane C, Shinohara K, et al. Saw Palmetto for Benign Prostatic Hyperplasia. New England Journal of Medicine 2006;354:557–66. PMID: 16467543.
Sanda: I probably take an even stronger stance. On the one hand, I certainly tell patients that if they’re on herbal remedies, I can accept that and that’s okay, but I do like to mention the PC-SPES story, and the reality that there are herbal medications that have been used for prostate conditions in the past, but when they were evaluated more rigorously were found to actually be dangerous to patients. [Note: PC-SPES was pulled from the market because of concerns about contamination.] The real issue is that the danger wasn’t evident for many years while those formulations were being used by many people. I think men need to be aware that there is the potential for hidden dangers in those herbal remedies and probably a greater potential among those than there is among the FDA-approved drugs.
|In brief: Two 5–alpha-reductase inhibitors are on the market: dutasteride (Avodart) and finasteride (Proscar, generic). Because both of these drugs work by affecting levels of male hormones in the prostate, they may have sexual side effects. Although uncommon, these can be devastating when they occur.
Do you recommend one 5–alpha-reductase inhibitor more than the other?
Loughlin: At this point, there’s no evidence that one or the other is superior. There are studies ongoing to see whether that may be true, but I think from a patient’s point of view, there’s no evidence that Proscar is better than Avodart or vice versa.
What kind of side effects do you see with the 5–alpha-reductase inhibitors?
Loughlin: Both can cause gynecomastia [enlargement of the breasts in men]. It doesn’t happen in a large percentage of patients, but some men are extremely bothered by it, and I think it’s something that’s important to tell a patient before he starts taking one of these drugs.
Is there any way to identify men who are more likely to develop this problem?
Loughlin: Unfortunately, no. And when you stop taking a 5–alpha-reductase inhibitor, in my experience, the gynecomastia does not always go away. So it happens in a small percentage of men, but when it does happen, it can be bothersome. I can remember at least one man whom we actually had to refer to a plastic surgeon to talk about having breast reduction surgery.
Sanda: It’s not one of the more common problems, but it can happen. What I’ve encountered more often are complaints about reduced ejaculate volume, and physical changes such diminishment in the size of the flaccid penis.
Morgentaler: I do a lot of research on testosterone, and gynecomastia can be a sign of low testosterone. So it may be that the 5–alpha-reductase inhibitors cause gynecomastia because of their effect on testosterone.
But I actually can’t remember ever seeing anybody on Proscar or Avodart in my practice who developed gynecomastia, although clearly it happens. I just don’t remember seeing it. It must be relatively uncommon. This probably develops in men who are somehow predisposed to it. It can be treated by plastic surgery or in some cases, radiation.
5–alpha-reductase inhibitors, prostate cancer, and PSA
|In brief: The PCPT found that men who took one of the 5–alpha-reductase inhibitors — finasteride (Proscar) — reduced their risk of developing prostate cancer by nearly 25%. However, if they did develop prostate cancer, it tended to be the more aggressive kind.
What did you think of the Prostate Cancer Prevention Trial (PCPT) and what it means for patients taking one of the 5–alpha-reductase inhibitors?
Loughlin: The study is interesting, certainly, but we don’t have the final answer yet about whether Proscar really does decrease the risk of cancer. I think the honest assessment at this point is that the study has raised the possibility of this effect, and it’s being actively investigated, but we don’t have a resolution of that question yet. So, that’s something that readers need to be aware of and they need to talk about with their urologist.
Morgentaler: You know, it’s a fascinating study. On the one hand, taking Proscar caused a remarkable reduction in prostate cancer, a 25% reduction. I mean, we would hope for treatments for other kinds of conditions that would have the success rate as good as that. And yet at the same time it looks as if taking Proscar increased the cancers that probably are the most worrisome in terms of mortality and morbidity, so it’s really hard to know what to make of that.
I personally don’t use finasteride or 5–alpha-reductase inhibitors for prevention. I don’t know too many doctors who do.
Sanda: It clearly hasn’t caught on, precisely because of the concerns about the downside — of whether increasing the risk of developing an aggressive cancer outweighs the possible benefit of reducing overall risk of cancer.
Loughlin: Although if we’re talking about monitoring risk, anyone taking a 5–alpha-reductase inhibitor should be aware that it will change their PSA level. Generally speaking, after a man has been on a 5–alpha-reductase inhibitor for several months, his PSA should decrease by half. And then you can interpret that PSA as you would any other PSA by doubling it. Alpha-1 blockers don’t affect PSA levels.
Morgentaler: And even though the common wisdom is that you double the PSA once a man is on a 5–alpha-reductase inhibitor, it’s important to point out that that’s actually an average, and that not everybody is going to have his PSA reduced by half while on one of these medications. There are always differences with individuals, and when somebody’s had a PSA level increase from 3 to 3.5, and then up to 4, and then we’ve put them on a 5–alpha-reductase inhibitor, some of those guys don’t see their PSA levels go from 4 to 2. Some of them may go from 4 to 3, and some may go from 4 to 1. So it’s important to establish a baseline PSA before you begin taking a 5–alpha-reductase inhibitor, and then get tested again after taking the medication for six months or so.
Acute urinary retention
|In brief: Acute urinary retention occurs when someone is unable to urinate normally even though he has a strong urge. This is a medical emergency, because if the bladder is unable to excrete urine, over time it may cause pressure on the kidneys, possibly leading to kidney failure — which is life-threatening. A man who develops acute urinary retention usually has to go to the emergency room to have a catheter inserted so urine can exit the body.
When you counsel patients, what do you tell them about avoiding problems with acute urinary retention? Is there any way for a man taking a BPH medication to avoid developing this problem while taking a plane trip or at a sporting event — where he may not have easy access to a toilet and need to hold in his urine?
Loughlin: Well, unfortunately, I don’t think there’s a clearly identifiable prodrome that says Mr. Jones is likely to go into retention during a plane trip while Mr. Smith isn’t. We sometimes see this problem develop during a non-urologic surgical procedure, where they go into retention as a consequence of anesthesia.
Sanda: Usually there are no warning signs of who is going to go into retention. Of course, if the symptoms are increasing in severity, then it may well be a sign that the bladder is being damaged because of the obstruction. And you may be able to avoid problems by increasing the dose of your medication or changing your medication. So if the symptoms get worse, definitely contact your doctor. Make an adjustment.
Morgentaler: As a rule, I do not speak to my patients about urinary retention if I’m treating them for BPH, unless there is something about their situation that sort of raises a red flag. If a man has an enormous prostate, if I have objective data like urine flows that are very weak or post-void residuals that are substantial, or I think that maybe a small additional insult may tip him over into retention, then I might discuss some options with him. But I think it’s important to recognize that urinary retention can happen even in the absence of a prostate: It happens to women. And it sometimes happens after people receive certain anesthetics, if they’re on narcotics, if they’re older, or if they become constipated.
Combination medical therapy
|In brief: The MTOPS study, reported in the New England Journal of Medicine in 2003, provided evidence that taking a combination of an alpha-1 blocker and a 5–alpha-reductase inhibitor reduced the chance of BPH symptoms worsening more significantly than taking either medication alone. But questions remain about which patients are best served by combination therapy.
When do you recommend combination therapy for someone with BPH?
Loughlin: The Medical Therapy of Prostatic Symptoms (MTOPS) study showed that combination therapy clearly has a role. Obviously, these two classes of drugs have different mechanisms of action, so if you use both drugs simultaneously, chances are you’ll have a higher response rate. The downside is that the cost is increased when you’re using two drugs, and each type of drug has its own side effect profile, so you may increase the likelihood of experiencing side effects.
We usually don’t start off with combination therapy. But if one of my patients has a large prostate gland and yet is eager to see results soon, then sometimes I simultaneously prescribe both an alpha-1 blocker and a 5–alpha-reductase inhibitor, with the plan to drop the alpha-1 blocker in six months or so, once the other medication has begun to show results. That’s a reasonable strategy for some men.
Originally published Jan. 1, 2007; last reviewed April 26, 2011.
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