Can testosterone shots cause cancer

Older men with high levels of testosterone may have an increased risk of prostate cancer, a new study from Australia says.

In the study, men ages 70 to 88 with higher testosterone levels were 9 percent more likely to develop prostate cancer over a seven-year period than men with lower levels.

Testosterone is needed for the normal growth of the prostate, and it’s possible that high levels of the hormone accelerate the growth of prostate cancer, the researchers said.

However, the new study found only an association, not a cause-effect link. And previous studies on the topic have had conflicting results. A study published last month in the Journal of Sexual Medicine found that men who received testosterone as hormone replacement therapy were not at increased risk for prostate cancer.

Because the new study did not include men receiving testosterone therapy, larger studies are needed to examine the risks and benefits of the treatment, said study researcher Zoë Hyde, of the University of Western Australia’s Centre for Health and Ageing.

Men currently receiving testosterone therapy should not stop treatment because of the new results, but their prostate health should be monitored closely during treatment, Hyde said.

The study was published online yesterday (July 26) in the journal Cancer Epidemiology Biomarkers & Prevention.

Testosterone and prostate cancer

The question of whether testosterone levels are related to prostate cancer is important, given the growing interest in testosterone replacement therapy, the researchers said.

Hyde and colleagues analyzed information from about 3,600 older men living in Perth, who had blood samples collected between 2001 and 2004. Levels of testosterone in the blood were analyzed, and men were followed for an average of 6.7 years.

During the study period, about 300 men developed prostate cancer. The higher the men’s levels of free testosterone, the greater their risk of prostate cancer. (Most testosterone is not “free,” but is bound to a protein. The “free” portion is thought to have the greatest influence on the body.)

The link held even after the researchers took into account factors that could affect prostate cancer risk, such as age, smoking habits, alcohol use and previous diagnosis of cancer.

No link was found between total testosterone (free and bound) and prostate cancer risk.

Criticism

Experts were critical of the findings.

The results show only a weak connection between testosterone levels and prostate cancer risk, and the link might be explained by factors not assessed by the study, said Abraham Morgentaler, founder of Men’s Health Boston, a medical organization that offers care to men, including treatment for low testosterone.

The study did not include information about the men’s frequency of prostate cancer screening, Morgentaler said. Doctors tend not to screen or perform biopsies on men who are predicted to have less than 10 years to live, and therefore they do not pick up prostate cancer in these men. In contrast, doctors tend to screen healthier men with higher testosterone levels, Morgentaler said. (Sicker men tend to have lower testosterone levels.)

“The real interpretation of this study is only healthier men get prostate biopsies,” said Morgentaler, who is also an associate professor of urology at Harvard Medical School.

Morgentaler also said prostate cancer rarely strikes when men’s natural testosterone levels are the highest — in their late teens and early 20s.

No large studies that follow men forward in time have examined the effect of testosterone therapy on prostate cancer risk, Morgentaler said. However, a small study conducted by Morgentaler and colleagues last year and published in the Journal of Urology suggested that testosterone therapy given to men with untreated prostate cancer does not cause progression of the cancer.

However, the Endocrine Society, an international research organization, recommends against testosterone therapy for men with prostate cancer.

Pass it on: High testosterone is linked with a slight increase in the risk of prostate cancer in men in Australia, but more research is needed to confirm the results.

This story was provided by MyHealthNewsDaily, a sister site to LiveScience. Follow Rachael Rettner on Twitter @RachaelRettner,or MyHealthNewsDaily @MyHealth_MHND. We’re also on Facebook & Google+.

This research, carried out by scientists at the University of Oxford, looked at blood samples from around 19,000 men aged between 34 and 76, collected between 1959 and 2004. 6,900 of these men went on to develop prostate cancer. The scientists divided the men into 10 groups, depending on the level of testosterone in their blood, and compared this to prostate cancer risk.

What’s interesting about this research is that while low levels of testosterone were associated with decreased risk of developing prostate cancer, high testosterone levels were not associated with increased risk. This supports the theory that there are only so many androgen receptors (the proteins that bind testosterone to activate it, so that it can do its job) in the body. So once these are all ‘full up’ with testosterone, it doesn’t matter how much more testosterone is circulating in the blood, because it can’t bind to and activate a receptor. This would explain why high levels of testosterone don’t increase risk of developing prostate cancer, but low levels can lower it.

Testosterone levels alone may not hold the key

However, while this research gives some interesting clues about factors involved in causing prostate cancer in the first place – which will undoubtedly prove useful in working out how to one day prevent the disease from occurring – it also raised more difficult questions.

That’s because although men with lower levels of testosterone were less likely to develop prostate cancer, once they did, it was more likely to be an aggressive form of the disease. So far, we don’t have any answers as to why this might be, but it adds yet another layer of complexity to the mystery of prostate cancer development, and opens another avenue of investigation to the scientists set on unravelling these sorts of clues. It also suggests that testosterone levels alone will not hold the key to the causes of prostate cancer development, and that the link between male sex hormones and cancer development may well be more complicated than we previously imagined.

Dr Matthew Hobbs, Deputy Director of Research at Prostate Cancer UK said: “This research gives us some important clues about the role that testosterone might play in triggering prostate cancer. It’s particularly interesting that men in this study with the lowest levels of the hormone were less likely to get prostate cancer, but if they were diagnosed, it was more likely to be aggressive. This is clearly a complex effect and more research is needed to understand it.

“We still know too little about what causes prostate cancer cells to develop. We urgently need this knowledge to understand how we might prevent the disease in the future, which is why this is a key research priority for Prostate Cancer UK. Until we know more about the underlying causes of prostate cancer, it’s important that all men – and particularly black men, men with family history and men over 50 – are aware of their risk of prostate cancer and go to the GP if they have any concerns.”

Researchers have found a number of genes that could help prostate cancer cells to grow and spread in response to testosterone. This could explain some of the benefits of hormone therapy as well as offer a new way to potentially treat prostate cancer.

The researchers, based at the University of Newcastle, and funded by Prostate Cancer UK and the Movember Foundation, wanted to understand what effect the male sex hormone testosterone had on gene activity in prostate cancer cells. They hoped that by finding genes whose activity changed in response to the hormone, it could help suggest new ways to treat the disease.

They started by adding testosterone to cancer cells grown in the lab to see what happened to gene activity when hormone levels rose. At the same time, they used prostate cancer samples from men who’d had hormone therapy (which reduces testosterone levels) to see what effect lower hormone levels had on gene activity.

The scientists found that changing testosterone levels affected a group of genes linked to a process called glycosylation, where sugar groups are added to the surface of the cancer cells. They noticed that lower testosterone levels in the samples from men on hormone therapy repressed the activity of a number of genes involved in the glycosylation process. However, when they added testosterone to cancer cells, the activity of these genes increased.

Additional benefit to hormone therapy

The scientists believe that the sugar groups (called glycans) added to the cell surface through glycosylation make the cancer cells more likely to survive and spread, making the cancer more aggressive. These results suggest that hormone therapy might benefit men by lowering the production of these glycans, thereby weakening the cancer cells. However, by targeting the genes involved in glycosylation directly, it could offer a new approach to treating prostate cancer.

Although changes in glycosylation are fairly common in cancer, this finding helps us understand what is driving these changes in prostate cancer. This could open new doors to help diagnose more aggressive cancers earlier and identify which men might one day benefit from drugs developed to block the glycosylation process.

“Desperate need”

Dr Jennifer Munkley, who co-led the research project, said: “Our findings are very significant for future treatments as they identify a new group of molecules in prostate cancer, which could be targeted therapeutically.

“Now we have identified these glycans we will be able to develop strategies to inhibit them and help patients with this condition.

“Treatments targeting glycan sugar groups have been developed for other types of illness, such as breast cancer. Our results mean these treatments could also be used for prostate cancer.”

Simon Grieveson, Head of Research Funding at Prostate Cancer UK, said: “There’s a desperate need for more treatments for men with advanced prostate cancer, who currently have too few options available to them. However, in order to develop new, effective treatments, we need to understand more about the genetic make up of aggressive prostate cancers and identify what makes them tick. This promising research has unearthed a new group of genes which could play a part in cancer cell survival and development, and could pave the way for new treatments in the future.

“Although this work is still in its infancy and there is a long way to go before we could have a potential new treatment, we will be watching its progression with great interest.”

Is Testosterone the New Therapy for Prostate Cancer?

Low testosterone (“Low T”), or hypogonadism, is typically encountered by men when they arrive at middle or late stages of life. The symptoms are increased body fat, weight gain, low sex drive, fatigue, anemia, depression, poor memory, osteoporosis, and a higher risk of diabetes. The first step when considering whether testosterone replacement is appropriate is to determine if the cause is primary or secondary. “Primary hypogonadism” is when the testicles themselves fail to produce adequate amounts of testosterone. “Secondary hypogonadism” occurs when the pituitary gland stops producing sufficient amounts of LH (luteinizing hormone), the hormonal factor that stimulates the testicles to produce testosterone.

When a diagnosis of primary hypogonadism is made, direct replacement with testosterone is a reasonable course of action. In secondary hypogonadism, men can take medications, such as Clomid, which work by stimulating the pituitary gland to produce more LH, which in turn stimulates increased production of testosterone from the testicles.

Why do we care about the specific methodology of increasing testosterone? Because long-term testosterone replacement can further suppress any residual testosterone production from the testicles, causing testicular atrophy. By stimulating natural production with Clomid, the functionality of the testicles is maintained in a natural state.

Even though testosterone is a natural hormone, supplementation or replacement is not completely free of potential side effects. Higher testosterone levels can enlarge the prostate, cause balding, acne, fluid retention, breast enlargement, testicular atrophy, emotional liability, decreased sperm count, and an excess of red blood cells. Due to this latter factor of increased red cell production, there is even a potential risk of heart attack and stroke if men who are treated with testosterone fail to be monitored.

For those who have prostate cancer or a history of prostate cancer, the use of testosterone is even more controversial. Historically, more than 99% of physicians would never consider supplementing a patient who has ever been diagnosed with prostate cancer. This is because most doctors believe that testosterone will fuel prostate cancer growth. This association between testosterone and prostate cancer growth was documented back in 1941, by urologist Dr. Charles Huggins.

There is, however, no concrete evidence whatsoever that testosterone causes prostate cancer though it is clear that testosterone can stimulate existing prostate cancer cells to grow. The take home message, therefore, is that men who appear to have been cured of prostate cancer can indeed consider taking testosterone without concern that it will induce new tumors. There is currently a wealth of studies (including randomized controlled trials) in patients who have been treated with surgery or radiation, who went on to use testosterone replacement without any evidence of higher relapse rates. This is, of course, a very different scenario from patients who have existing cancers, especially those who have aggressive, widespread, and castrate-resistant disease. Potentially, such individuals could be harmed by taking testosterone.

Despite historical evidence indicating that testosterone is universally bad for men with active cancers, some avant- garde researchers have been hypothesizing that testosterone administration to castrate-resistant patients may help in restoring hormone-sensitivity and thus aid in transforming bad cancers into a less aggressive phenotype. The emergence of something termed “Bipolar Androgen Therapy” has now surfaced. Bipolar therapy is the concept of rapid cycling between high blood levels of testosterone and low blood levels of testosterone, using hormone blockade and testosterone supplementation in a cyclical fashion. Preliminary studies done on tissue cultures in the lab have demonstrated that, in certain cases, high doses of testosterone do cause suppression of prostate cancer cell growth, whereas normal doses of testosterone stimulate cell growth. This concept that high dose testosterone may suppress cancer growth has been tested in men with prostate cancer in very small, retrospective studies. In one study, for example, that evaluated giving large doses of testosterone on a cyclical basis to 10 men with metastatic castrate- resistant prostate cancer resulted in lower PSA levels and radiologic evidence of tumor shrinkage.

These findings mirror my own experience using high-dose testosterone to treat men with prostate cancer. On a number of occasions, I have certainly used both standard doses of testosterone and high doses of testosterone to treat prostate cancer patients. What I have found is that it is much safer to use testosterone in patients who are in remission after treatment with previous surgery or radiation. Supplementing castrate-resistant men with high doses of testosterone is a much riskier proposition. Even so, I have indeed seen rare cases where men with castrate- resistant prostate cancer have been able to cycle between hormone blockade and testosterone replacement and keep their disease in check for over 10 years without developing radiologic progression of their disease. Unfortunately, for every one of these success stories, I have encountered far more cases where the disease not only failed to respond but the cancer appeared to progress more rapidly due to the high doses of testosterone.

So in my judgment, using high-dose testosterone in men who are hormone resistant is a RISKY proposition. What I believe is particularly inappropriate is administering testosterone to men with large tumors in the prostate or who have metastases in the spine. Such men risk catastrophic events such as urinary obstruction, spinal cord compression and paraplegia/quadriplegia due to progression of disease. Most of the men who I have treated with metastatic castrate- resistant disease first underwent aggressive cancer de-bulking with hormone blockade and chemotherapy. But even with this aggressive preparatory protocol, the results were discouraging in the vast majority. Men would typically develop a relatively rapid rise in PSA and manifest radiologic progression quickly, prompting a return to aggressive therapy with chemo and hormone blockade. It is true that a small minority of men with high-risk prostate cancer seemed to have their disease suppressed for a longer duration of time with high doses of testosterone. However, I found it to be impossible to determine in advance who might benefit and who would end up with rapid disease progression.

In conclusion, testosterone replacement is a viable option for prostate cancer patients who are suffering from the symptoms of low testosterone, as long as they are monitored closely. Monitoring should include regular PSA testing, digital rectal examination, and, ideally, prostate imaging such as color Doppler ultrasound or multiparametric MRI. Patients need to be fully informed regarding all the potential risks. In my experience, testosterone replacement is quite safe in low-risk patients who underwent adequate local therapy and are considered to be in remission. Testosterone replacement in men with more advanced cases with metastatic castrate-resistant disease is far more risky. Further studies to evaluate testosterone in this role are ongoing. For the present, I recommend patients exhibit cautious skepticism before embarking on such a treatment outside of a clinical trial as the risks may certainly outweigh the benefits.

SAN FRANCISCO—Testosterone replacement therapy (TRT) for men with a history of prostate cancer (PCa) does not increase recurrence rates following radical treatment or progression rate after placement on active surveillance, investigators reported at the American Urological Association 2018 annual meeting.

In a study examining the outcomes of 190 men with PCa (mean age 68 years) who received TRT after diagnosis and/or treatment for PCa over the previous 5 years, Abraham Morgentaler, MD, Director of Men’s Health Boston and Associate Clinical Professor of Urology at Harvard Medical School in Boston, and colleagues found that biochemical recurrence rates after radical prostatectomy (RP) and radiation therapy, and the progression rate while on active surveillance (AS), were consistent with published rates from other studies.

After a mean follow-up of 47 months, the recurrence rates were 11.6% among the 86 men who underwent RP and 4.1% among the 49 men who had either external beam radiation therapy or brachytherapy. None of the 5 men treated with RP followed by salvage radiation had recurrence. The progression rate among the 47 men on AS was 10.6%.

“This is the largest series to date investigating the safety of testosterone therapy in men with prostate cancer,” Dr Morgentaler told Renal & Urology News. “Recurrence rates following prostate cancer treatment with surgery or radiation were low for men treated with testosterone, and were quite similar to expected recurrence rates based on numerous published studies. This was also true for men on active surveillance.”

He added: “For decades, physicians have feared offering testosterone therapy to men with prostate cancer because we were taught that raising testosterone would be like ‘pouring gasoline on a fire.’ From this study, and smaller studies before it, we know this concept can no longer be correct.”

Dr Morgentaler stated that TRT can make an enormous difference in the lives of men who are testosterone-deficient. “I’ve had quite a few men tell me they wouldn’t mind continuing with testosterone therapy even if it were certain to shorten their lives,” he related.

Eric A. Klein, MD, Chair of the Cleveland Clinic’s Glickman Urological & Kidney Institute, who was not involved in the study, said the investigation by Dr Morgentaler’s team “adds to the existing data that T replacement in men with early stage low-grade prostate cancer or those treated for cancer is safe and does not appear to increase the risk of progression.”

Dr Klein cautioned, however, that testosterone replacement should only be considered for men who have symptoms related to documented low testosterone levels.

Visit Renal and Urology News’ conference section for continuous coverage from AUA 2018.

In a separate study presented at the conference, Unwanaobong Nseyo, MD, and colleagues at the University of California, San Diego, looked at outcomes among 123 men who were on AS for PCa—61 on TRT and a matched group of 62 patients not on TRT. The groups had similar proportions of men with a positive family history of PCa (15.7% vs 16.7%).

Overall, 11 men experienced progression on repeat biopsy during AS (5 in the TRT group and 6 in the non-TRT group). All 5 patients who progressed in the TRT arm and only 1 who progressed in the non-TRT arm underwent definitive treatment due to pathologic progression.

Men in the TRT group were diagnosed at lower PSA values than those in the non-TRT group (3.1 vs 5.3 ng/mL).

Dr Nseyo’s group concluded that their data suggest that aggressive screening or treatment is not indicated for men undergoing TRT, but TRT might alter patient choice of definitive treatment during AS.

Morgentaler A, Magauran D, Neel D, et al. Recurrence rates following testosterone therapy in a large clinical cohort of men with prostate cancer. Data presented in poster format at the American Urological Association 2018 annual meeting in San Francisco, May 18–21. MP17-03.

Nseyo U, Unterberg S, Hsieh M. Testosterone supplementation does not increase the risk of prostate cancer progression but might alter patient choice for definitive treatment during active surveillance. Data presented in poster format at the American Urological Association 2018 annual meeting in San Francisco, May 18–21. MP17-09.

From the June 01, 2018 Issue of Renal and Urology News

Hormone Therapy for Prostate Cancer

Hormone therapy is also called androgen suppression therapy. The goal is to reduce levels of male hormones, called androgens, in the body, to stop them from fueling prostate cancer cells.

Androgens stimulate prostate cancer cells to grow. The main androgens in the body are testosterone and dihydrotestosterone (DHT). Most androgen is made by the testicles, but the adrenal glands (glands that sit above your kidneys) as well as the prostate cancer itself, can also make a fair amount. Lowering androgen levels or stopping them from getting into prostate cancer cells often makes prostate cancers shrink or grow more slowly for a time. But hormone therapy alone does not cure prostate cancer.

When is hormone therapy used?

Hormone therapy may be used:

  • If the cancer has spread too far to be cured by surgery or radiation, or if you can’t have these treatments for some other reason
  • If the cancer remains or comes back after treatment with surgery or radiation therapy
  • Along with radiation therapy as the initial treatment, if you are at higher risk of the cancer coming back after treatment (based on a high Gleason score, high PSA level, and/or growth of the cancer outside the prostate)
  • Before radiation to try to shrink the cancer to make treatment more effective

Types of hormone therapy

Several types of hormone therapy can be used to treat prostate cancer.

Treatment to lower testicular androgen levels

Androgen deprivation therapy, also called ADT, uses surgery or medicines to lower the levels of androgens made in the testicles.

Orchiectomy (surgical castration)

Even though this is a type of surgery, its main effect is as a form of hormone therapy. In this operation, the surgeon removes the testicles, where most of the androgens (testosterone and DHT) are made. This causes most prostate cancers to stop growing or shrink for a time.

This is done as an outpatient procedure. It is probably the least expensive and simplest form of hormone therapy. But unlike some of the other treatments, it is permanent, and many men have trouble accepting the removal of their testicles.

Some men having this surgery are concerned about how it will look afterward. If wanted, artificial testicles that look much like normal ones can be inserted into the scrotum.

LHRH agonists

Luteinizing hormone-releasing hormone (LHRH) agonists (also called LHRH analogs or GnRH agonists) are drugs that lower the amount of testosterone made by the testicles. Treatment with these drugs is sometimes called medical castration because they lower androgen levels just as well as orchiectomy.

Even though LHRH agonists cost more than orchiectomy and require more frequent doctor visits, most men choose this method. With these drugs, the testicles stay in place, but they will shrink over time, and they may even become too small to feel.

LHRH agonists are injected or placed as small implants under the skin. Depending on the drug used, they are given anywhere from once a month up to once a year. The LHRH agonists available in the United States include:

  • Leuprolide (Lupron, Eligard)
  • Goserelin (Zoladex)
  • Triptorelin (Trelstar)
  • Histrelin (Vantas)

When LHRH agonists are first given, testosterone levels go up briefly before falling to very low levels. This effect is called a flare and results from the complex way in which these drugs work. Men whose cancer has spread to the bones may have bone pain. Men whose prostate gland has not been removed may have trouble urinating. If the cancer has spread to the spine, even a short-term increase in tumor growth as a result of the flare could press on the spinal cord and cause pain or paralysis. A flare can be avoided by giving drugs called anti-androgens (discussed below) for a few weeks when starting treatment with LHRH agonists.

LHRH antagonists

Degarelix (Firmagon) is an LHRH antagonist. It works like the LHRH agonists, but it lowers testosterone levels more quickly and doesn’t cause tumor flare like the LHRH agonists do. Treatment with this drug can also be considered a form of medical castration.

This drug is used to treat advanced prostate cancer. It is given as a monthly injection under the skin. The most common side effect are problems at the injection site (pain, redness, and swelling).

Possible side effects: Orchiectomy and LHRH agonists and antagonists can all cause similar side effects from lower levels of hormones such as testosterone. These side effects can include:

  • Reduced or absent sexual desire
  • Erectile dysfunction (impotence)
  • Shrinkage of testicles and penis
  • Hot flashes, which may get better or go away with time
  • Breast tenderness and growth of breast tissue (gynecomastia)
  • Osteoporosis (bone thinning), which can lead to broken bones
  • Anemia (low red blood cell counts)
  • Decreased mental sharpness
  • Loss of muscle mass
  • Weight gain
  • Fatigue
  • Increased cholesterol levels
  • Depression

Some research has suggested that the risk of high blood pressure, diabetes, strokes, heart attacks, and even death from heart disease is higher in men treated with hormone therapy, although not all studies have found this.

Many side effects of hormone therapy can be prevented or treated. For example:

  • Hot flashes can often be helped by treatment with certain antidepressants or other drugs.
  • Brief radiation treatment to the breasts can help prevent their enlargement, but this is not effective once breast enlargement has occurred.
  • Several drugs can help prevent and treat osteoporosis.
  • Depression can be treated with antidepressants and/or counseling.
  • Exercise can help reduce many side effects, including fatigue, weight gain, and the loss of bone and muscle mass.

There is growing concern that hormone therapy for prostate cancer may lead to problems thinking, concentrating, and/or with memory, but this has not been studied thoroughly. Still, hormone therapy does seem to lead to memory problems in some men. These problems are rarely severe, and most often affect only some types of memory. More studies are being done to look at this issue.

Treatment to lower androgen levels from the adrenal glands

LHRH agonists and antagonists can stop the testicles from making androgens, but cells in other parts of the body, such as the adrenal glands, and prostate cancer cells themselves, can still make male hormones, which can fuel cancer growth. Drugs are available that block the formation of androgens made by these cells.

Abiraterone (Zytiga) blocks an enzyme (protein) called CYP17, which helps stop these cells from making androgens.

Abiraterone can be used in men with advanced prostate cancer that is either:

  • High risk (cancer with a high Gleason score, spread to several spots in the bones, or spread to other organs)
  • Castrate-resistant (cancer that is still growing despite low testosterone levels from an LHRH agonist, LHRH antagonist, or orchiectomy)

This drug is taken as pills every day. It doesn’t stop the testicles from making testosterone, so men who haven’t had an orchiectomy need to continue treatment with an LHRH agonist or antagonist. Because abiraterone also lowers the level of some other hormones in the body, prednisone (a corticosteroid drug) needs to be taken during treatment as well to avoid certain side effects.

Ketoconazole (Nizoral), first used for treating fungal infections, also blocks production of androgens made in the adrenal glands, much like abiraterone. It’s most often used to treat men just diagnosed with advanced prostate cancer who have a lot of cancer in the body, as it offers a quick way to lower testosterone levels. It can also be tried if other forms of hormone therapy are no longer working.

Ketoconazole also can block the production of cortisol, an important steroid hormone in the body, so men treated with this drug often need to take a corticosteroid (such as prednisone or hydrocortisone).

Possible side effects: Abiraterone can cause joint or muscle pain, high blood pressure, fluid buildup in the body, hot flashes, upset stomach, and diarrhea. Ketoconazole can cause elevated liver blood tests, nausea, vomiting, gynecomastia (enlargement of breast tissue in men) and a skin rash.

Drugs that stop androgens from working

Anti-androgens

For most prostate cancer cells to grow, androgens have to attach to a protein in the prostate cancer cell called an androgen receptor. Anti-androgens are drugs that also connect to these receptors, keeping the androgens from causing tumor growth. Anti-androgens are also sometimes called androgen receptor antagonists.

Drugs of this type include:

  • Flutamide (Eulexin)
  • Bicalutamide (Casodex)
  • Nilutamide (Nilandron)

They are taken daily as pills.

In the United States, anti-androgens are not often used by themselves:

  • An anti-androgen may be added to treatment if orchiectomy or an LHRH agonist or antagonist is no longer working by itself.
  • An anti-androgen is also sometimes given for a few weeks when an LHRH agonist is first started to prevent a tumor flare.
  • An anti-androgen can also be combined with orchiectomy or an LHRH agonist as first-line hormone therapy. This is called combined androgen blockade (CAB). There is still some debate as to whether CAB is more effective in this setting than using orchiectomy or an LHRH agonist alone. If there is a benefit, it appears to be small.
  • In some men, if an anti-androgen is no longer working, simply stopping the anti-androgen can cause the cancer to stop growing for a short time. This is called the anti-androgen withdrawal effect, although they are not sure why it happens.

Possible side effects: Anti-androgens have similar side effects to LHRH agonists, LHRH antagonists and orchiectomy but may have fewer sexual side effects. When these drugs are used alone, sexual desire and erections can often be maintained. When these drugs are given to men already being treated with LHRH agonists, diarrhea is the major side effect. Nausea, liver problems, and tiredness can also occur.

Newer anti-androgens

Enzalutamide (Xtandi), apalutamide (Erleada) and darolutamide (Nubeqa) are newer types of anti-androgens.

  • All of these drugs can be helpful in men with cancer that has not spread but is no longer responding to other forms of hormone therapy (known as non-metastatic castrate-resistant prostate cancer (CRPC), described below).
  • Enzalutamide can also be used for metastatic prostate cancer (cancer that has spread), whether it is castrate-resistant or castrate-sensitive (still responding to other forms of hormone therapy).
  • Apalutamide can also be used for metastatic castrate-sensitive prostate cancer.

These drugs are taken as pills each day.

Side effects can include diarrhea, fatigue, rash, and worsening of hot flashes. These drugs can also cause some nervous system side effects, including dizziness and, rarely, seizures. Men taking one of these drugs are more likely to fall, which may lead to injuries. Some men also had heart problems related to these newer types of anti-androgens.

Other androgen-suppressing drugs

Estrogens (female hormones) were once the main alternative to removing the testicles (orchiectomy) for men with advanced prostate cancer. Because of their possible side effects (including blood clots and breast enlargement), estrogens have been replaced by other types of hormone therapy. Still, estrogens may be tried if other hormone treatments are no longer working.

Current issues in hormone therapy

There are many issues around hormone therapy that not all doctors agree on, such as the best time to start and stop it and the best way to give it. Studies are now looking at these issues. A few of them are discussed here.

Treating early-stage cancer

Some doctors have used hormone therapy instead of observation or active surveillance in men with early-stage prostate cancer who do not want surgery or radiation. Studies have not found that these men live any longer than those who don’t get any treatment until the cancer progresses or symptoms develop. Because of this, hormone treatment is not usually advised for early-stage prostate cancer.

Early versus delayed treatment

For men who need (or will eventually need) hormone therapy, such as men whose PSA levels are rising after surgery or radiation or men with advanced prostate cancer who don’t yet have symptoms, it’s not always clear when it is best to start hormone treatment. Some doctors think that hormone therapy works better if it’s started as soon as possible, even if a man feels well and is not having any symptoms. Some studies have shown that hormone treatment may slow the disease down and perhaps even help men live longer.

But not all doctors agree with this approach. Some are waiting for more evidence of benefit. They feel that because of the side effects of hormone therapy and the chance that the cancer could become resistant to therapy sooner, treatment shouldn’t be started until a man has symptoms from the cancer. This issue is being studied.

Intermittent versus continuous hormone therapy

Most prostate cancers treated with hormone therapy become resistant to this treatment over a period of months or years. Some doctors believe that constant androgen suppression might not be needed, so they advise intermittent (on-again, off-again) treatment. The hope is that giving men a break from androgen suppression will also give them a break from side effects like decreased energy, sexual problems, and hot flashes.

In one form of intermittent hormone therapy, treatment is stopped once the PSA drops to a very low level. If the PSA level begins to rise, the drugs are started again. Another form of intermittent therapy uses hormone therapy for fixed periods of time – for example, 6 months on followed by 6 months off.

At this time, it isn’t clear how this approach compares to continuous hormone therapy. Some studies have found that continuous therapy might help men live longer, but other studies have not found such a difference.

Combined androgen blockade (CAB)

Some doctors treat patients with both androgen deprivation (orchiectomy or an LHRH agonist or antagonist) plus an anti-androgen. Some studies have suggested this may be more helpful than androgen deprivation alone, but others have not. Most doctors are not convinced there’s enough evidence that this combined therapy is better than starting with one drug alone when treating prostate cancer that has spread to other parts of the body.

Triple androgen blockade (TAB)

Some doctors have suggested taking combined therapy one step further, by adding a drug called a 5-alpha reductase inhibitor – either finasteride (Proscar) or dutasteride (Avodart) – to the combined androgen blockade. There is very little evidence to support the use of this triple androgen blockade at this time.

Castrate-sensitive, castrate-resistant, and hormone-refractory prostate cancer

These terms are sometimes used to describe how well a man’s prostate cancer is responding to hormone therapy.

  • Castrate-sensitive prostate cancer (CSPC) means the cancer is being controlled by keeping the testosterone level as low as what would be expected if the testicles were removed (called the castrate level). Levels can be kept this low with an orchiectomy, or by taking an LHRH agonist or an LHRH antagonist.
  • Castrate-resistant prostate cancer (CRPC) means the cancer is still growing even when the testosterone levels are at or below the castrate level. Some of these cancers might still be helped by other forms of hormone therapy, such as abiraterone or one of the newer anti-androgens.
  • Hormone-refractory prostate cancer (HRPC) refers to prostate cancer that is no longer helped by any type of hormone therapy, including the newer medicines.

Graph created with raw data from St. Sauver et al and Muller et al.
Finally, to date there are multiple studies that have shown there to be no relationship between TRT and worsening LUTS/BPH. On the contrary, some studies have suggested improvements of LUTS with TRT, likely through the mechanisms mentioned above. It is the authors’ opinion that TRT is not a risk factor for LUTS/BPH and the warning set forth by the FDA likely needs reevaluation.
Written by: Wesley Baas and Tobias S. Köhler, Division of Urology, Southern Illinois University School of Medicine, Springfield, IL, USA.
Read the Abstract

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What is the role of hormones in the pathophysiology of benign prostatic hyperplasia (BPH)?

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Testosterone therapy does not raise risk of aggressive prostate cancer

This is the finding of an analysis of more than a quarter-million medical records of mostly white men in Sweden, research led by investigators at NYU Langone Medical Center and its Laura and Isaac Perlmutter Cancer Center. The international team of study authors will present these results on May 9 at the annual meeting of the American Urological Association in San Diego, Calif.

In the study, researchers found that, as a group, men prescribed testosterone for longer than a year had no overall increase in risk of prostate cancer and, in fact, had their risk of aggressive disease reduced by 50 percent.

“Based on our findings, physicians should still be watching for prostate cancer risk factors — such as being over the age of 40, having African-American ancestry, or having a family history of the disease — in men taking testosterone therapy, but should not hesitate to prescribe it to appropriate patients for fear of increasing prostate cancer risk,” says lead study investigator and NYU Langone urologist Stacy Loeb, MD, MSc.

Loeb points out that much of the concern over cancer risk is that, as part of standard therapy for advanced prostate cancer, tumor growth is decreased by drugs that drastically reduce rather than increase male hormones. “But when used appropriately by men with age-related low testosterone who are otherwise healthy, testosterone replacement has been shown to improve sexual function and mood.”

The researchers say use of testosterone therapy — taken by mouth, gel patch, or injection to treat “low T” — has skyrocketed in the past decade. Its popularity is a consequence, experts say, of an aging “boomer” population and heavy drug industry marketing, and has come about despite its unknown, long-term health risks. According to some surveys, use of testosterone therapy has more than tripled since 2001, with more than 2 percent of American men in their 40s and nearly 4 percent of men in their 60s taking it. Testosterone levels drop naturally by about 1 percent per year in men past their 30s.

Specifically, the current study found that 38,570 of the men whose records were examined developed prostate cancer between 2009 and 2012. Of these men, 284 had prescriptions for testosterone replacement therapy before they were diagnosed with prostate cancer. Their records were compared with 192,838 men who did not develop prostate cancer, of whom 1,378 had used testosterone therapy.

Researchers noted that while their initial analysis showed an uptick (of 35 percent) in prostate cancer in men shortly after starting therapy, the increase was only in prostate cancers that were at low risk of spreading and was likely a result from more doctor visits and biopsies performed early on. The authors stressed that the long-term reduction in aggressive disease was observed only in men after more than a year of testosterone use, and the risk of prostate cancer did not differ between gels and other types of preparations.

“Overall, our study suggests that what is best for men’s health is to keep testosterone levels balanced and within a normal range,” says Loeb, who suggests that men with testosterone levels below 350 nanograms per deciliter and symptoms should seek medical advice about whether they should consider testosterone therapy.

For the study, researchers matched and analyzed data from the National Prostate Cancer Register and the Prescribed Drug Register in Sweden. The country is one of the few in the world that collects detailed information on cancer and medication prescriptions for its entire population, and for which no comparable North American data source exists.

Loeb says the team next plans further studies to determine why low testosterone levels might trigger aggressive prostate cancer and why maintaining normal levels may protect against aggressive disease.

Signs You Shouldn’t Take Testosterone Therapy

Testosterone therapy is not appropriate for all men.

Easy ways to get low T therapy, like patches and gels, make treating low testosterone seem deceptively simple. Yet it’s far from risk-free.

“There is big money pushing men to use testosterone as an energy boost,” said Bruce Gilbert, MD, an adjunct clinical professor of urology and reproductive medicine at Weill Cornell Medical College in New York City. “Some men can benefit and will feel better on testosterone, but the risks of testosterone therapy can outweigh the benefits if you are not careful about who gets treated.” Dr. Gilbert is also a professor of urology at the North Shore-LIJ School of Medicine and director of reproductive and sexual medicine at the Smith Institute for Urology at the North Shore-LIJ Health System in Great Neck, N.Y.

In fact, a 2013 study published in the American Medical Association’s journal JAMA added to concerns about the risks of testosterone therapy for men. The study followed more than 1,000 men who had low testosterone, went through coronary angiography (a test to evaluate coronary heart disease), and were treated with testosterone therapy. The researchers found that, subsequently, the men had a significantly higher rate of stroke and heart attack than a similar group of men with low testosterone and coronary angiography who were not treated with testosterone.

“Men may think that testosterone replacement therapy is the answer to feeling tired or having a tired sex life,” said Richard Harris, MD, chief of urology at Gottlieb Memorial Hospital in Melrose Park, Ill. “In most cases, those symptoms are a normal part of aging and a normal part of life. Testosterone therapy is not the fountain of youth.”

When Testosterone Is Not the Answer

Testosterone therapy comes with risks, and it’s not appropriate for all men. Certain situations and certain health conditions make testosterone therapy less than a good idea and worthy of a talk with your doctor. These include:

If you have low T only. A man’s testosterone level starts to fall naturally after age 40. There’s a difference between a natural decline, which often accelerates after age 60, and actual low T. “We measure testosterone with a blood test,” said Dr. Gilbert. Still, having a low number without symptoms is not enough reason to treat low testosterone, he added.

If you have symptoms only. Symptoms of low testosterone may include low energy, low mood, loss of your sex drive, and poor erections. “About 25 percent of men take testosterone without ever having a blood test,” Dr. Harris said. “Symptoms alone tell you nothing. You need to have low testosterone proved by blood tests along with symptoms to benefit from treatment.”

If you have prostate cancer. “Testosterone therapy does not cause prostate cancer, but it can make prostate cancer grow,” said Gilbert. “It might be like adding flame to the fire.” According to guidelines from the Endocrine Society, you should not take testosterone if you have prostate cancer. If you have been successfully treated, you may be able to take testosterone, but you need to talk with your doctor. Although rare in men, breast cancer is another reason not to take testosterone.

If you have benign prostate disease. The Endocrine Society also warns against taking testosterone if you have severe urinary tract symptoms caused by an enlarged prostate or if your doctor finds a lump on your prostate gland during a digital rectal exam. Testosterone makes your prostate grow, which can increase symptoms of benign prostate disease. This is not an absolute red light for testosterone therapy, but you need discuss this risk with your doctor.

If you want to have children. “A younger man who may want to have children needs to know that taking testosterone can lower his sperm count and decrease his fertility,” Gilbert warned. “When you take testosterone, your brain shuts down natural testosterone production by your testicles. You may get bigger muscles but smaller testicles.” Loss of sperm occurs after about 10 weeks of testosterone therapy.

If you have polycythemia. This is a condition in which you have too many red blood cells. Testosterone therapy can make polycythemia worse because testosterone stimulates the production of red blood cells. Polycythemia can also be a side effect of testosterone therapy. And, it makes your blood thicker, which increases your risk for a heart attack or stroke. If you’ve been diagnosed with this condition, you should not take testosterone.

If you have sleep apnea. “Untreated sleep apnea may get worse with testosterone therapy,” Gilbert said. Sleep apnea involves brief but frequent periods of interrupted breathing while sleeping, often accompanied by loud snoring. If you have symptoms of sleep apnea, you should have a sleep study done to get formally diagnosed and try treatment with continuous positive airway pressure (CPAP). If this treatment doesn’t work, you should not take testosterone.

If you’re seriously overweight. “Men who are 30 to 40 pounds overweight often have low testosterone,” Harris said. “But this is not a reason to take testosterone therapy. Losing weight is a much healthier and effective solution.”

Side Effects of Testosterone Therapy

Risks and side effects of testosterone therapy may be reasons not to have the treatment or be reasons to stop if you’ve started. Make sure to ask your doctor about them. They include breast enlargement, acne, and skin reactions related to the testosterone gels, patches, and injections.

If you can get by the risks and side effects of testosterone therapy, your doctor will still need to make sure you are safe on testosterone. “Most men can tolerate treatment well, and many men do get benefits, but you need to keep watch,” Gilbert said.

Monitoring and screening should include periodic blood tests to monitor your testosterone levels, digital rectal exams to check your prostate, testing your blood for prostate-specific antigen to check for prostate cancer, and blood tests to check your red blood cell level, called a hemoglobin and hematocrit.

“Finally, even if you do everything right, testosterone just does not work for some men,” Harris said. “If you don’t feel any better after a trial of testosterone therapy, that’s another reason not to take it.”

Testosterone Strokes and Blood Clots

Testosterone replacement therapy is approved to treat low testosterone levels in cases where the body is not making enough hormone due to a medical condition known as hypogonadism. Men may have used it for symptoms of “Low-T”, a term coined by the pharmaceutical industry which is not an approved diagnosis.

Testosterone replacement therapy has been linked to serious side effects including blood clot formation which can cause:

  • Cerebrovascular accident (CVA) or Stroke
  • Deep vein thrombosis (DVT)
  • Venous thromboembolism (VTE)
  • Myocardial infarction (MI) or Heart Attack
  • Pulmonary embolism (PE)

Any of these events can be debilitating or life-threatening and may lead to death.

Testosterone and Blood Clots

Testosterone increases the chance of clot formation in two ways. A common side effect of testosterone therapy is polycythemia which increases the body’s supply of hemoglobin and hematocrit, affecting the blood cells. This can increase the blood pressure and thicken the blood slightly.

Thicker and slower moving blood causes the blood cells to “bump” into each other more often and clump together as a blood clot. Testosterone is also known to increase production of thromboxane, a blood vessel constrictor which also may increase the risk of clot formation.

Testosterone also changes the body’s metabolism of cholesterol and may lead to the formation of plaques in the arteries and veins. As the blood is restricted in moving past the plaques, it can create blood clots and in some cases, the plaque may become loose. In either case, a solid or semi-solid particle can travel to the brain and cause a stroke.

In most cases, clots are formed in the legs in a condition known as deep-vein thrombosis (DVT). When a clot has formed and breaks loose, it can become known as a venous thromboembolism (VTE). These clots can travel to the brain, heart or lungs and can be fatal as a stroke, heart attack or pulmonary embolism.

A 2013 study published in Clinical and Applied Thrombosis/Hemostasis showed a link between DVT hospitalization and testosterone use. The risks may be particularly high in the first six months of treatment but overall, may increase the risk of a clotting event by about 60%.

Many of the men who are using testosterone replacement products have never been tested for low testosterone levels. A large percentage of testosterone products may be in use for naturally occurring symptoms of aging, by men who have not been made aware of the serious risks.

Testosterone and Stroke

Taking testosterone may increase the risk of cerebrovascular accident (CVA) or stroke because of an increased chance of clotting. In addition, changes in the body’s cholesterol metabolism may increase the risk of atherosclerosis.

A stroke or CVA is the occurrence of a sudden blockage of the arteries that supply blood and oxygen to the brain. When the supply of blood and oxygen to the brain is blocked, the brain tissue cannot survive. CVAs are most often caused by blood clots that have developed elsewhere in the body but may also be caused by arterial or venous plaques from atherosclerosis that have broken off, producing a piece that may lodge in an artery.

Strokes occur suddenly and are not always treatable. In some cases, a CVA will cause permanent damage to the brain and may even result in death. Damage to the brain can result in physical disability which is permanent.

Symptoms of stroke include:

  • Sudden numbness or weakness of face or limbs (arm or leg), often on only one side of the body
  • Sudden confusion or difficulty speaking
  • Sudden dizziness, loss of balance or coordination
  • Sudden headache

Symptoms of stroke should be treated as a medical emergency. In some cases, though not always effective, immediate treatment will help to reverse some of the effects of a stroke.

The FDA announced an investigation in January of 2014 regarding severe adverse events caused by testosterone, particularly heart attack and in June of 2014 the FDA began requiring a warning regarding the risk of clot formation on all testosterone products. In 2015, a warning about heart attack risks was added to all testosterone product labelling.

Severe Side Effects of Testosterone Replacement Treatment

All medications carry some side effects. Most of the side effects caused by testosterone are hormonal type side effects and are mild to moderate, however some of the side effects of testosterone can be life-threatening.

Life-threatening events caused by testosterone treatment can include:

  • Stroke
  • Deep vein thrombosis
  • Venous thromboembolism
  • Heart attack
  • Pulmonary Embolism
  • Death

Read more about testosterone side effects.

Testosterone Blood Clot or Stroke Lawsuits

Many men who have used testosterone replacement therapy have experience serious adverse events such as heart attack, pulmonary embolism and stroke which may have been caused by blood clots and some of which resulted in death. Up to half of all men taking testosterone have never been tested for “Low-T”, but took the medication without understanding the risks.

Many of these men or their loved ones have filed testosterone lawsuits for injuries caused by replacement therapy. Some testosterone settlements have been offered but more lawsuits remain in federal, state and local courts and more may be expected.

Read more about Testosterone Lawsuits.

Thicker blood and testosterone

It’s difficult for men to be treated for low testosterone levels for a number of reasons. This is true even for men with clinically proven low testosterone levels. The reasons for the reluctance of physicians to treat low testosterone levels in men has to do with the notion that testosterone levels are related to both the onset of prostate cancer, as well as adverse cardiovascular effects. I covered in depth the misinformation concerning the relationship of testosterone to prostate cancer in a recent article in Ironman, and interested readers should refer to that article for the truth about testosterone and prostate cancer onset. In relation to cardiovascular disease, a recent article published in the New England Journal of Medicine suggested that providing testosterone therapy to older men (average age, 74) could rapidly result in adverse cardiovascular outcomes, including increased incidence of both heart attacks and strokes. I also discuss this study and the actual effects of testosterone on heart function in an upcoming edition of my Bodybuilding Pharmacology column, also in Ironman.

While the relationship between testosterone replacement therapy (TRT) and cardiovascular disease (CVD) is specious at best, there is one effect of testosterone that could cause problems in this area. This relates to a thickening of the blood, also known as polycythemia, that can occur when testosterone is provided, particularly in injectable form. For some reason, this side effect is more likely to happen in older men, who are the prime candidates for TRT. It usually occurs when the weekly dose of injectable testosterone exceeds 150 milligrams. The effect is evident by blood tests that reveal an increased hematocrit of the blood. Hematocrit is a measure of the viscosity, or thickness of the blood. Interestingly, one of the primary side effects of blood doping, which involves drug-based increases in the red blood cell content of the blood, is polycythemia. Ironically, when this happens, any athletic edge induced by the increased red blood cell count (which results in increased oxygen delivery to muscle, and therefore, increased endurance) is negated because the blood has now become too thick, which lowers oxygen delivery to tissues, inducing a relative hypoxic (lacking oxygen) state. Testosterone causes a type of natural blood doping because it stimulates the kidneys to produce increased levels of erythropoietin (EPO), which in synthetic form, is used for athletic blood doping. Since EPO works by boosting the synthesis of new red blood cells, it would appear that the higher levels of EPO released by testosterone adminstration could account for the increased blood thickness shown by older men who use injectable forms of testosterone. This is a problem because higher hematocrit levels are linked to increased onset of strokes and heart attacks due to increased clotting activity in the blood.

But a new study found the root cause of higher hematocrit levels in men who use injectable testosterone. The study included both younger (ages 19 to 35) and older (ages 59 to 75) men. These men were provided weekly injections of testosterone enanthate (a long-acting ester of testosterone) in varying doses of 25, 50, 125,300, and 600 milligrams over a course of 20 weeks. The men’s own testosterone production was purposely supressed by providing them with a drug that blocks the secretion of gonadatrophic releasing hormone (GRH), which controls testosterone production in the body. This was done to more precisely determine the effects of the testosterone injections. The men underwent blood tests 5 times over the course of the 20-week study. The study results showed that within one week of getting the testosterone injections at higher doses, a substance called hepcidin was markedly suppressed in the men. The effect was related to the dose of testosterone, and was more likely to occur with the higher doses, above 125 milligrams a week. It also was more pronounced in the older, compared to the younger men in the study, and corresponded to a rise in hemoglobin, or the oxygen-carrying protein in red blood cells. The study concluded that the rise in hematocrit or blood thickness, is related to the supression of hepcidin caused by high dose injectable testosterone. This is probably the most common side effect seen when older men use higher doses of injectable testosterone.

Hepcidin is a 25-amino acid peptide that is produced in the liver. It was discovered in 2000, and is now known to be the master regulator of iron metabolism in the body. It works by directly inhibiting another protein called ferroportin, which works to transport iron out of cells that store the mineral. Ferroportin is present mainly in the cells that line the small intestine, and in immune cells called macrophages. By interfering with the actions of ferroportin, hepcidin reduces iron absorption. When larger doses of injectable testosterone block hepcidin, more iron is released and absorbed into the body. This increased iron, in turn, leads to a greater production of red blood cells, and it is that greater amount of red blood cells that results in the thicker blood or polycythemia that can occur with the testosterone injections. One unanswered question is why this effect of thicker blood with higher dose testosterone injections is more prevalent in older men. One possibility is that older men have lower iron stores than younger men, and this changes when high dose testosterone is used. But that is strictly speculation on my part. The elevated hematocrit effect can be eliminated through either using alternative forms of TRT, such as testosterone creams or gels, or by injecting doses of testosterone that are 125 milligrams or less each week.

Bachman, E, et al. Testosterone suppresses hepcidin in men: A potential mechanism for testosterone-induced erythrocytosis. J Clin Endocrin Metab 2010: in press.

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