A new study reveals an important molecular clue about how inflammation may lead to prostate enlargement or benign prostatic hyperplasia. The researchers believe their discovery may also lead to ways of overcoming resistance to androgen-targeted treatment for the condition.
How BPH happens is still open for debate. Some evidence points to inflammation as a cause, but there is little understanding of the underlying molecular mechanisms.
The new study, led by Baylor College of Medicine in Houston, TX, and published in the journal Molecular Cell, reveals a molecular mechanism involving the androgen receptor in prostate cells that may explain how BPH arises from inflammation.
Role of androgen receptor in homeostasis
At first, the team was investigating the role of the androgen receptor in helping epithelial cells of the prostate gland balance their functions to work properly - a process called homeostasis.
Epithelial cells are the cells that form the lining of cavities and surfaces of blood vessels and organs in the body. The androgen receptor allows the cells to respond to androgens, hormones that influence the development of the male reproductive system.
Other studies have already looked at the role of the androgen receptor in the prostate by deleting in the gland's epithelial cells, but the researchers behind the new study were not happy with those results.
Senior author Li Xin, associate professor of molecular and cellular biology at Baylor, says there are two reasons why they were not happy with the previous animal studies. The first reason is, because they deleted the receptor in the cells before the animals reached puberty, those earlier studies did not clarify whether the results came from the androgen receptor's effect on development or on homeostasis. The second reason was, since the previous studies deleted nearly all the receptors, they made it difficult to determine whether their results came from direct or indirect effects from loss of androgen receptors.
Defective tight junctions leak inflammation molecules
For their study, Prof. Xin and colleagues used genetically engineered mice bred to the adult stage. They also only deleted androgen receptors in a fraction - not all - of the prostate epithelial cells.
When they carried out their experiments in this way, they discovered a chain of events that they believe helps to explain how inflammation and cell proliferation interact to give rise to BPH, as Prof. Xin explains:
"When we deleted the androgen receptor in a fraction of prostate epithelial cells called luminal cells, the cells produced mediators of inflammation called cytokines, which the luminal cells normally don't do. Deletion of the androgen receptor also resulted in defects in tight junctions - connections between two adjacent cells that close the space between them."
He says that in normal cells, the tight junctions are intact and inflammation molecules cannot leak into the surrounding tissue. But in the luminal cells that had deleted androgen receptors, the tight junctions were not intact and the inflammation molecules or cytokines were able to leak through.
The team saw that the inflammation molecules boosted the recruitment of immune cells - especially macrophages and T-cells - into prostate tissue. These then released more cytokines, which summoned more immune cells, and so on. One of the cytokines, IL-1, also triggers release of growth factors that boost cell proliferation in the prostate tissue.
Thus, their work shows that deleting the androgen receptor sets off an inflammation response that boosts cell proliferation, says Prof. Xin, explaining that in the process, "some luminal cells that rely on androgen signaling for their survival will die, but, at the same time, the chain of events creates a signal that promotes luminal cell proliferation."
He says their finding - that disrupting androgen receptor signaling in luminal cells can trigger inflammation - supports observations that find luminal cells of inflamed human prostates have fewer androgen receptors than luminal cells of healthy prostates.
However, Prof. Xin also notes their findings do not rule out that inflammation can influence androgen receptor expression. "It is possible that this is a vicious cycle," he adds. An unexpected benefit of the findings is they may help improve outcomes of androgen-targeting therapy - used in the treatment of BPH and prostate cancer. The goal of the therapy is to deplete androgen and thereby starve cells that need the hormone to survive.
"Our results may explain why some BPH patients respond to androgen-targeting therapies, such as finasteride, while in other patients the disease continues to progress. We suggest that treatment for BPH might be more effective if patients received androgen-targeting therapy together with drugs that target inflammation." Prof. Li Xin
New research suggests a technique that blocks blood flow to the prostate shows promise in the treatment of enlarged prostate. An analysis of men with enlarged prostates and lower urinary tract symptoms who underwent the procedure found many of them experienced a reduction in night visits to the bathroom.
The study on prostatic artery embolization (PAE) and its effectiveness in reducing nocturia - waking in the night because of a need to urinate - featured at the Society of Interventional Radiology meeting (SIR2016) in Vancouver, Canada, April 2-7, 2016.
Lead researcher Dr. Sandeep Bagla, an interventional radiologist at the Vascular Institute of Virginia, says that the lack of a full night's sleep due to waking in the night with an urgent need to visit the bathroom can significantly affect quality of life, and explains:
"For many men, the cause of their discomfort is an enlarged prostate and these results show men can live a more normal life once they've undergone PAE to address this condition."
Over half of men over the age of 50 have benign prostatic hyperplasia (BPH), or an enlarged prostate gland. Excess cell growth causes the gland to swell and squeeze the urethra that it surrounds. This interferes with urine flow. In very severe cases, affected men cannot pass urine at all.
BPH is not life-threatening, but it causes unpleasant and sometimes aggravating symptoms, such as weak urine flow, inability to empty the bladder completely and frequent urination at night. If untreated, the condition can lead to bladder stones, poor kidney function and infection.
What is PAE?
PAE is a relatively new interventional radiology treatment for BPH. It is not as invasive as other treatments that use surgery; it is usually performed on an outpatient basis, allowing many men to go home the same day.
The treatment involves inserting a catheter into the femoral artery and guiding it to the prostate artery on both sides of the enlarged gland. The catheter delivers tiny plastic beads into the artery to block blood flow, causing the prostate to shrink.
Dr. Bagla says interventional radiologists are probably the best specialists for carrying out PAE because they know all about arteries, how to use microcatheters and have experience of carrying out other types of embolization.
PAE is not yet approved by the Food and Drug Administration (FDA), but the agency is working with interventional radiologists, and it is thought the technique could become part of standard care for treating BPH within the next 5 years or so.
PAE reduced urinary symptoms and improved quality of life
For the retrospective study, the team analyzed data on 68 men with BHP and lower urinary tract symptoms who underwent PAE. Before treatment, the men filled in a symptom index about the severity of their urinary symptoms, with scores ranging from 0 for no symptoms to 35 for very severe symptoms. They also completed quality-of-life surveys and were asked how often they had to urinate at night.
Before undergoing PAE, the patients' average symptom index score was 23.9, their average quality-of-life score was 4.8 and the average number of times they woke at night to urinate was 3.3. Forty-six of the men were caught up with 1 month after treatment, and 38 of the men after 3 months, at which points they filled in the questionnaires again.
The results at 1 month after treatment showed reductions in nighttime waking to urinate, with 25 of the 46 (54.4%) reporting an absolute reduction of 0.85 episodes per night. Also, the 46 patients showed an average 10-point reduction in their symptom severity index, and their quality-of-life score went up by 2.1, suggesting their urinary symptoms were less bothersome and they were experiencing a better quality of life.
The results at 3 months after treatment showed further reductions in nighttime waking to urinate, with an average reduction of 1.4 episodes per night. And there was a 13.4 reduction in the symptom severity scores and a 2.8 improvement in the quality-of-life scores.
The researchers conclude that these improvements put PAE on a par with surgical procedures such as TURP and PVP, both of which have higher reported complications than PAE.
TURP (transurethral resection of the prostate) involves going through the urethra to cut away sections of the prostate. PVP (photoselective vaporization of the prostate) also goes through the urethra and uses a laser to burn away prostate tissue.
Dr. Bagla says that many of his PAE patients tell him that sleep deprivation takes a toll and not having to go to the bathroom so often in the night has improved their daily lives in many ways, including work performance. He adds: "Anecdotally, patients who show signs of a better quality of life 3 months after the treatment appear to continue their progress 2 or 3 years after undergoing PAE."
However, he warns that while this study shows PAE reduces nighttime waking to urinate for men with BPH and lower urinary tract symptoms, it may not completely eliminate the symptom. He urges patients to speak to their health care professionals to establish what else they may need.
Other studies have also suggested PAE shows promise for the treatment of enlarged prostate. What is now needed, say the researchers, are more high-quality clinical studies that follow larger groups over a longer period and compare PAE with surgical techniques.
Meanwhile, Medical News Today learned how another study presented at a recent urology meeting suggests testing for non-coding RNA molecules in a man's urine may be a more accurate and reliable way to detect prostate cancer than using current biomarkers like PSA and PCA3.
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