Investigators examine effect of statins on LUTS secondary to BPH

Prior studies have shown that statins, drugs typically used to lower cholesterol, are associated with a mild reduction in prostate growth over time. Newer studies are investigating the effect of these drugs on patients with lower urinary tract symptoms (LUTS) and benign prostatic hyperplasia (BPH).

In a recent Journal of Urology study,¹ Jordan J. Kramer, MD, and co-authors examined whether statins impact LUTS incidence in asymptomatic men and progression in symptomatic men with BPH. Kramer is a PGY4 urology resident at Cedars Sinai Medical Center, Los Angeles, California.

Could you discuss the background for this study?

This study looks a lot at BPH and associated LUTS, BPH being benign prostatic hyperplasia, which involves increased proliferation of stromal epithelial cells in the region of the prostate called the transitional zone located around the urethra. Because of that location, this tissue bulges in and can actually decrease the patient's ability to urinate and can lead to lower urinary tract symptoms called LUTS. These LUTS can be very annoying to the patient, and interrupt their day-to-day activities, as well as interrupt their sleep and wake them up multiple times during the night. Not only this, but when those symptoms usually progress, they can lead to urinary retention, catheterization, as well as UTIs and bladder stones, all of these necessitating endoscopic management of some sort in order to get them past these problems. Not only do these symptoms progress, but they’re also seen in a large proportion of patients as well.

There was an autopsy study that looked at men in their 50s and saw that 50% of them had histologic evidence of BPH on the tissue pathology, and that prevalence only increases with age. In addition to any preventative management strategies being widely appreciated on an individual basis, it would also affect a large patient population. So, there needs to be more work looking into preventative strategies.

How does this tie in with cholesterol, and statin use? Picking statins sounds like, “Pick the medication that lots of people are taking, so we can see if it has anything to do with BPH LUTS.” But it's really tied in there pretty well because for sex steroid biosynthesis, one of the starting points is cholesterol. Since statins are HMG coA reductase inhibitors, we thought that if you caught the pathway that early, perhaps fewer cholesterol and its subsequent products will reach the point of becoming testosterone and dihydrotestosterone, which are the fuels for prostatic growth.

There have been some prior studies on this, a few of which came from our group. One of them looked at statin use and its ability to slow down prostate size growth, in which we saw a little bit of an effect. It was about 10 times smaller than the effects seen by dutasteride or finasteride [Proscar]. But still, it was a little bit of effect. We thought, “Maybe that's a possible way into the study of this.” And then another study looked at the effects of cholesterol on the development of LUTS, and that one showed that a higher ratio of cholesterol to HDL was predictive of LUTS progression, and that high HDL was a protective factor for LUTS progression. So, with all of those things combined, we thought, "Hey, maybe there's something here worth looking at for a possible preventative measure."

What were some of the notable findings? Were any of them surprising to you and your co-authors?

We based our study on the data set from the REDUCE trial [NCT00056407], which was done in 2010. This study looked at men in the age range of 50 to 75 who had a prior negative prostate biopsy but an elevated PSA. The REDUCE trial randomized them, testing dutasteride vs placebo to see if that would affect their prostate cancer risk. Now, of course, we didn't look at prostate cancer results in our study, but that age range of 50 to 75 is the perfect range to look at LUTS and BPH, since any man who is going to develop LUTS would develop it within that time frame. Some already have LUTS by the time they enter that time range as well.

We had 2 groups in our study. One was termed "asymptomatic," where they had an International Prostate Symptom Score (IPSS) of less than 8, which is officially in the “mildly symptomatic” category based on the questionnaire. Or, we had “symptomatic” patients who had an IPSS score of greater than 8 already. We looked at whether tatin use, or non-use, was related to a development of new onset of LUTS or a progression of LUTS. We defined those based on an increase in their IPSS score, need for BPH medications, or BPH endoscopic or surgical treatments. We saw that there actually was no difference, unfortunately, in the group where they already had LUTS to begin with, and we didn't see any change in the onset to new LUTS. In the group that already had LUTS, we didn't see any change in the time for progression of their LUTS.

What is the significance of these data for patients with LUTS?

Our results are a little disappointing, but it's still important knowledge to have because these are drugs that are widely taken by elderly people and although there are lots of treatments for BPH and associated LUTS, it'd be great to prevent having those treatments in the first place. Any medication has its own risks and benefits, any surgery has its own risks and benefits, and no intervention is completely innocuous. So, is the result of our study surprising to us? It is a little bit for a few reasons, one of which was that cholesterol fits into that pathway of sex steroid production and you would think that if we're able to cut it off further down the pathway with 5 alpha reductase inhibitors, cutting it off early would maybe have an effect. And the results from prior studies made it seem like it might be possible as well.

What is the take-home message for the practicing urologist?

I'd say there's probably 2 take-home messages, first of which would be that any prescription of statin use for patients should just be left up to the primary care doctor or cardiologist, purely for the cardiovascular benefits. Currently, there is no role for statins in management of LUTS. Any possible benefits seem to be subclinical and would not be appreciated by the patient, so why risk the potential side effects of any drug if they won't even see the benefit?

And then the other take-home message is that more research does need to be put into preventative measures for LUTS and BPH because, currently, there aren't really any good options for that. There's no, at least, pharmaceutical option that's good. The biggest drugs at our disposal right now are alpha blockers and 5 alpha reductase inhibitors. You wouldn't start a patient on alpha blocker preemptively in their 30s or 40s. It's not going to prevent progression, and certainly there's a 15% chance of having retrograde ejaculation and many young men are not going to tolerate that for symptoms that they don't even have yet. So, that wouldn't work.

And then, of course, you wouldn’t want to start a 5 alpha reductase inhibitor preemptively either, also for its potential side effects. There's no pharmaceutical option that's good for us. All we can really offer preemptively is lifestyle changes, which are pretty much the same across the board for almost any disease you're trying to prevent. It's exercise increase, weight loss, eating more fruits and vegetables, and there was even 1 study that looked at small daily alcohol consumption that actually slowed the progression of BPH as well. But you can't really rely on that for this kind of disease.

Is there anything else you feel our audience should know about the findings?

In all likelihood, any future drug that would be used in preventing BPH with LUTS onset and progression would probably have to do with something in the sex steroid biosynthesis pathway. Clearly, intervening too early on that pathway doesn't make a difference. Intervening later in the pathway between the conversion of testosterone into DHT would not be useful preemptively either. Maybe there's something in between there that we just haven't seen yet. So there for sure needs to be more research into possible pharmaceutical intervention, since nothing is taking its place right now.

An interesting proof of the hormone reliance of BPH development, however, is seen in transgender patients. When they are going through their male to female gender-affirming surgery, they undergo bilateral orchiectomy, which drops their testosterone level to run below 20 ng/dL. If these procedures are done early in life, they actually do not go on to develop BPH at all, even though the procedure leaves their prostate intact. The only instances in the literature of BPH with LUTS in a male-to-female transgender patient happened in those who underwent their transition much later in life after having decades of testosterone and DHT affecting their prostate growth. So, I think, ultimately, the next drug that's going to be effective in prevention is going to have to do with that hormone pathway in some respect. We just need to do more research on it.

Reference

1. Kramer JJ, Gu L, Moreira D, et al. Statin use and lower urinary tract symptoms (LUTS) incidence and progression in reduction by dutasteride of prostate cancer events (REDUCE) trial. J Urol. Published online September 21, 2021. doi:10.1097/JU.0000000000002199