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Rashid Sayyid: Hello, everyone, and thank you for joining us in this UroToday recording. I'm Rashid Sayyid, a urologic oncology fellow at the University of Toronto, and along with Zach Klaassen, associate professor and program director at Wellstar MCG Health. We'll be discussing the recent AUA guidelines that have been modified and published in 2023, discussing the management of lower urinary tract symptoms attributed to BPH. These guidelines were recently published in The Journal of Urology, and this modified version was led by Dr. Jaspreet Sandhu. So this will be a four-part series. In this first recording, we'll be discussing the epidemiologic background of BPH, as well as discussing some nuances of the AUA guidelines.

So before we delve into the guidelines and the epidemiology of BPH, just some terminologies that are worth highlighting for these guidelines. So again, these are evidence-based guidelines, and so the strength of the evidence varies from one particular area to another. So when we talk about grade A, strength of evidence category, this is a high certainty based on high-quality RCT or exceptional observational studies. Typically, those which are large with minimal biases and with long-term follow-up. The grade B, strength of evidence, categories are usually based on a randomized control trial with some weaknesses or moderately strong observational studies with consistent findings. And the grade C, the lowest grade, is a low to very low certainty rating. And this is based on RCTs that are either flawed with serious deficiencies and limitations or observational studies that are of poor quality, meaning small sample size with inconsistent results and a high risk of bias.

And so the AUA gives recommendations based on the certainty of the evidence. And so a strong recommendation is a directive statement that an action should or should not be undertaken because the net benefit or net harm is substantial. And when we talk about a moderate recommendation, it's the statement that an action should or should not be undertaken because the net benefit or harm is moderate, as opposed to substantial. And then the conditional recommendation, essentially, is a committal, non-directive statement when there's really no clear evidence for a net benefit or harm in a certain situation. And with that, let's start with the epidemiologic background for BPH.

So we hear a lot of terminology being thrown around. BPH, meaning benign prostatic hyperplasia. Other terms that we'll hear include benign prostatic hypertrophy, but the correct term is hyperplasia. And if we look at the histology, with this being a histologic diagnosis, BPH is a proliferation of glandular epithelial tissue, smooth muscle, and connective tissue within the prostatic transition zone. So essentially, it's a hyperplasia, as opposed to hypertrophy, or growth of the existing cells. And the exact etiology is unknown; it's slightly multifactorial, but what we do know is that it requires the presence of functioning testes. And we know from eunuchs, men who are castrated before puberty, they have atrophic prostate glands that do not develop BPH. So quite clearly, testosterone is heavily involved in this pathogenic process.

And so, what specifically do testosterone and its metabolite DHT do in this situation? So we know that testosterone is essentially produced mainly by the Leydig cells of the testes, about 90%, and the adrenal glands contribute about 10% of the total testosterone levels. So testosterone diffuses into the prostatic cells from the bloodstream and it's converted to DHT or dihydrotestosterone via the type 2 5-alpha reductase. And then the DHT forms a complex with the androgen receptors, and is transported to the nucleus and undergoes DNA transcription, leading to normal prostate gland development and hyperplasia. And so, histologic BPH starts at about 40 to 45 years, and we know it increases with age. It's about 60% at age 60 and 80% at age 80. This is important information when counseling our patients, and it's easy to correlate the percentage with the age of 60% at 60 years and 80% at age 80.

And BPH itself may lead to benign prostatic enlargement. And that being said, not all men with histologic BPH will develop this benign prostatic enlargement. And then as an additional step to complicate things further, benign prostatic enlargement that may or may not occur may lead to benign prostatic obstruction at the level of the bladder neck. And so this is typically the target of BPH treatment when the BPH leads to benign prostatic enlargement, which leads to benign prostatic obstruction. And so an enlarged prostate in men has been proposed to contribute to the male lower urinary tract symptom complex via at least two routes. So one is the one that comes to mind, the static component, whereby the physical obstruction from the benign prostatic enlargement leads to this blockage. But there's another component, the dynamic component, whereby we see an increased smooth muscle tone and resistance within the enlarged gland, commonly termed the dynamic component of the obstruction. And this may lead to both storage and/or voiding lower urinary tract symptoms.

Storage, meaning patients have to go quite often or have difficulty holding their urine; it's the overactivity and urgency component. And the voiding component is when patients have to strain quite hard to empty their bladders or feel that the stream is quite weak. So, there are two components, and there's often an interplay between those two. In men, specifically, overactive bladder may be the result of primary detrusor overactivity or underactivity, with the meaning that the bladder doesn't empty as often, and so the patient has to go quite often to empty that bladder, leading to the overactivity. Or it could be secondary to the obstruction induced by benign prostatic enlargement, benign prostatic obstruction. And both BPH and LUTS are common in older men. And for the purposes of this guideline, the LUTS among older men, for whom an alternative cause is not apparent after basic evaluation, essentially, refers to the lower urinary tract symptoms, most likely related to a large prostate, or LUTS secondary to BPH.

So, essentially, it's patients in whom we could find no other cause for the obstruction or the lower urinary tract symptoms they're having. And we equate that to the underlying cause being a benign prostatic enlargement, BPH. And so there's some evidence for supplements and pharmaceuticals in this space, and I'll turn it over to Zach to go over the evidence in this space.

Zach Klaassen: Thanks so much, Rashid. So, with regards to supplements and pharmaceuticals, we hear about this quite commonly in the clinic. And so far, there's weak evidence for these supplements in pharmaceuticals. And this includes saw palmetto, stinging nettles, zinc, selenium, etc. And these studies are limited by their single-center nature, small sample size, short follow-up, lack of/poorly chosen or undefined placebo, and lack of medication washout period, responder bias, etc. What I'm particularly interested in is saw palmetto, which we do commonly hear about in the clinic, and this is a berry extract of the American dwarf palm tree. And so, focusing a little bit further on saw palmetto, there have actually been two double-blind, placebo-controlled, parallel-group studies in the last two decades. This includes the STEP and the CAMUS trial, that compared saw palmetto to placebo. And these two trials showed that there was no significant difference in lower urinary tract symptoms, max flow urinary rate, prostate size, PVR, quality of life, serum PSA, or safety outcomes between these two trials.

What's the population burden of lower urinary tract symptoms? So, we know that up to 90% of men between 45 and 80 years of age suffer from some type of lower urinary tract symptoms. Moderate to severe lower urinary tract symptoms are defined as an AUA symptom index of greater than or equal to seven. And this certainly progresses with increasing age, maybe as high as 50% by the eighth decade of life. And we know that acute urinary retention episodes increased from about 6.8 per 1000 patient-years in the overall population to more than 34.7 episodes in men, 70 years or older, with moderate to severe lower urinary tract symptoms.

This is a snapshot of the IPSS/AUA symptom index, and this is a commonly used validated tool for assessing scores as well as bladder health. And so, if we look on the left, this tool asks patients over the past month questions about incomplete emptying, frequency, intermittency, urgency, weak stream, straining, and nocturia. And most importantly, at the bottom, is the quality of life due to urinary symptoms. And I think this is the most important metric at the bottom, where we really see how the above symptoms may be actually affecting their quality of life. And this is rated from zero, as delighted, to six, which is a terrible quality of life.

So with regards to BPH and surgical treatment, we see that there's several categories. So the first is transurethral surgery. This is the classic monopolar transurethral resection of the prostate, otherwise known as TURP, which is the historical gold standard to which novel procedures are usually compared to. Important modifications over the last several decades have included bipolar TURP as well as laser-based therapies, as well as requiring importantly regional or general anesthesia. This is a procedure that's performed typically in an operating room. Additionally, there's simple prostatectomy. This was historically done open, but laparoscopic and robotic-assisted approaches have been described. And this is important when the prostate is so big, the transurethral surgery is likely not feasible or not likely to work, secondary to the prostate size.

What's really important is a whole host of minimally invasive surgical techniques, and these are office-based treatments that are new, that obviate the need for regional or general anesthesia. They don't have a hospital stay. There's no need for discontinuation of anticoagulation therapy for many of these. And so, I think the last probably 10 to 15 years has really seen an increase in these minimally invasive techniques that do not require the resources or the time and anesthesia that TURP does. So, as we go through these guidelines over the next several discussions, the AUA guidelines have selected an index patient and prostate size cutoffs. And so, for the future discussions, the guideline index patient is a male, who is 45 years or older, who's consulting a qualified clinician for his lower urinary tract symptoms. This individual does not have a history suggesting non-BPH causes of LUTS, and his LUTS may or may not be associated with an enlarged prostate gland, bladder outlet obstruction, or histological BPH.

When we think about size categories, the panel recommends four different breakdowns. So, small prostates, are less than 30 grams. An average-sized prostate, 30 to 80 grams. Large prostate, 80 to 150 grams, and very large is defined as greater than 150 grams. So, in conclusion, BPH is a histological diagnosis. We know that lower urinary tract symptoms are common, especially with increasing prevalence with age, up to 90% in elderly men. The IPSS-AUA symptom index is a common and an established tool for evaluating symptoms. And TURP is the gold standard treatment, but there are many new minimally invasive procedures that have been established over the last several years. We thank you very much for your attention. We hope you enjoyed this UroToday AUA guidelines discussion looking at BPH epidemiology.