The Saturation Model And Its Proposed Mechanisms
A new paradigm gaining momentum to replace the traditional testosterone dependent theory has been termed the saturation model . According to this model, testosterone and its intracellular metabolite 5-DHT are critical for the growth of prostate tissue, but are in excess at physiologic concentrations. The theory maintains that serum testosterone concentration has limited ability to stimulate prostate growth. A hypothesized saturation point occurs at near-castrate levels where the low androgen concentration would be rate-limiting in prostate tissue proliferation . The saturation model is supported by evidence derived from both animal and human studies. In rats, the half-maximal prostate growth occurs at approximately 36 ng/dL, which correlates to near-castrate levels of testosterone . In human prostate tissue, the AR has been reported to become saturated at approximately 120 ng/dL in vitro, and 240 ng/dL in vivo . A 6-month study of TRT in men with LOH revealed that despite administration of exogenous testosterone, which substantially increased serum testosterone, there was no increase in testosterone or DHT within the prostate itself . This has led some to believe that a mechanism of the saturation model could be a lack of prostatic uptake of exogenous testosterone protecting the prostate from large serum androgens changes.
How Long Is Hormone Therapy For Prostate Cancer Effective
Doctors are unable to predict how long hormone therapy will be able to effectively prevent prostate cancer from growing.
Doctors will regularly test PSA levels in people taking hormone therapy longer than a few months. If PSA levels rise despite low androgen levels, it may be a sign that the current hormone therapy is no longer an effective treatment.
Does Low Testosterone Increase The Risk Of Prostate Cancer
While it is a common belief that high testosterone levels increase prostate cancer risk, newer research is showing the opposite. Research that became available over the last 20 years, has shown a correlation between low testosterone and higher prostate cancer risk, according to a recent talk given by Dr. Mohit Khera, a leading researcher at Baylor College of Medicine.
A quote from a 2016 review article, on testosterone and prostate cancer, summarizes our current understanding well: The link between low endogenous testosterone levels and prostate cancer has been extensively studied. Men with low endogenous testosterone levels have increased rates and severity of prostate cancer at diagnosis.
Here are a few of the groundbreaking studies done in this area:
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Systemic Effects Of Testosterone
The systemic effects of TRT may be exacerbated in men with limited cardiovascular reserve. Previous dogma held that androgens could have atherogenic potential. In a randomized, placebo-controlled trial, Basaria et al. reported an increased risk of cardiovascular events in men randomized to TRT however, this small cohort had a high prevalence of chronic disease. Today, current literature suggests that TRT has a neutral to beneficial effect on reported cardiovascular events. Because some men may have a limited cardiovascular capacity, clinicians prescribing TRT must be cautious with respect to its ability to cause edema. Until date, no longitudinal studies examine the impact of TRT on the cardiovascular system, however some studies suggest that TRT may serve as an adjunct rehabilitative therapy in patients with congestive heart failure .
When testosterone reaches supra-therapeutic levels, aggressive behavior and increased rates of suicide among adolescent users have been reported however, no study has documented a negative impact on cognition in men patients receiving TRT. In fact, studies have shown that testosterone replacement to eugonadal levels may improve or stabilize cognitive function. Lower levels of testosterone have a negative impact on spatial and verbal abilities, as well as cognitive function therefore, it is no surprise that normalizing testosterone levels results in cognitive improvements.
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Prostate Cancer The Facts
Cancer is a word nobody likes to hear. A group of diseases that entail abnormal cell growth, where the cells reproduce uncontrollably. Those cells can potentially invade or spread to other parts of the body. We often think of cancer as the end of the road, but thats not true we can fight it.
Based on 2018 estimates, there was well over one million new cases of prostate cancer reported worldwide in 2018. Prostate cancer is the second most frequent cause of cancer in men, with lung cancer being first, and the 5th leading cause of death worldwide 1. Both the incidence and mortality of prostate cancer correlate with an increased age, where the average age at time of diagnosis is 66 years 1.
Prostate cancer may often be asymptomatic during the early stages. Therefore, you are encouraged to get your prostate checked out at your later years of life. Yes, this means a finger in the bum, but its better than having cancer. Generally, the first symptoms noticed may be difficulty with urination, an increased frequency of urination, and nocturia , which often occurs due to prostatic hypertrophy 1. As the cancer develops, one may notice urinary retention and back pain.
On a more positive note, the 5-year survival rate among men in the USA diagnosed with prostate cancer is ~98% 2 and among patients diagnosed between 2003 to 2007 in Europe it was 83%, with a higher survival rate among southern and central European countries at 88% 3.
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Treatment To Lower Androgen Levels From Other Parts Of The Body
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. Some drugs can block the formation of androgens made by these cells.
Abiraterone blocks an enzyme called CYP17, which helps stop these cells from making androgens.
Abiraterone can be used in men with advanced prostate cancer that is either:
- Castration-resistant
This drug is taken as pills every day. It doesnt stop the testicles from making testosterone, so men who havent 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 needs to be taken during treatment as well to avoid certain side effects.
Ketoconazole , 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 .
Confusion About Testosterone Therapy And Prostate Cancer
One of the most commonly cited side effects for hormone replacement therapy as a cure to low testosterone in men is an increased risk of prostate cancer. However, much like with the Million Woman Study that linked HRT and breast cancer, the evidence corroborating this belief is dated and likely false. In fact, according to some modern research, low testosterone is actually a risk factor FOR types of male cancer.
The origins of the theory that testosterone replacement increased the risk of prostate cancer go back to research done at the University of Chicago in the 1940s by a group led by urologist Charles Huggins. Based on experiments performed first on dogs and then on humans, Huggins group concluded that prostate cancer was androgen dependent when testosterone levels were high, the cancer worsened, but when the levels were lowered, the cancer shrank. Huggins theory led to surgical castration removal of the testicles becoming the standard treatment for prostate cancer because of the resultant drop in testosterone. Huggins was awarded a Nobel Prize in 1966 for these contributions to medical research.
So if youre a man who suspects he may have low testosterone, and are considering hormone replacement therapy, you can rest easy. HRT wont give you prostate cancer in fact, it might help prevent it.
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What Are The Advantages And Disadvantages Of Hormone Therapy
What may be important to one person might be less important to someone else. So speak to your doctor or nurse about your own situation.
- Its an effective way to control prostate cancer, even if it has spread to other parts of your body.
- It can be used alongside other treatments to make them more effective.
- It can help to reduce some of the symptoms of advanced prostate cancer, such as urinary symptoms and bone pain.
- It can cause side effects that might have a big impact on your daily life.
- It cant cure your cancer when its used by itself, but it can help to keep the cancer under control, sometimes for many years.
Sex Hormones & Prostate Cancer
First, I need to make it clear that there are different types of prostate cancers. They are as follows:
Develops in gland cells which line the prostate gland, and is the most common.
2. Ductal Adenocarcinoma
Starts in the cells that line the tubes of the prostate gland. Tend to grow and spread more quickly than acinar adenocarcinomas.
3. Transitional Cell Cancer
Starts in the cells that line the tubes which carry urine out of your body . Generally, this starts in the bladder and spreads to the prostate.
4. Squamous Cell Cancer
Develops from flat cells that cover the prostate they tend to grow and spread more quickly than adenocarcinomas.
5. Small Cell Prostate Cancer
Made up of small round cells a neuroendocrine cancer.
Testosterone & Dihydrotestosterone
Well, testosterones metabolite dihydrotestosterone does indeed mediate the development of the prostate, particularly when an adult. Excess DHT can lead to benign prostatic hypertrophy 18. Historically, it was proposed by Huggins and Hodges that prostate cancer growth was specifically drive by androgens, as they observed benefits after castrating prostate cancer patients. This appears to be validated by cell studies, and androgen deprivation therapy does remain a mainstay in prostate cancer treatment. But again, in clinical studies looking at patients, its mostly the contrary. Some studies demonstrate no association, some show low testosterone, some show elevated. Biopsies show conflicting results too 18.
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Testosterone Replacement Linked To Lower Rates Of Aggressive Prostate Cancer
Men who receive testosterone replacement therapy had an increased rate of favorable-risk prostate cancer compared to those who did not use the therapy, and a decreased rate of aggressive prostate cancer.
Men who receive testosterone replacement therapy had an increased rate of favorable-risk prostate cancer compared to those who did not use the therapy, and a decreased rate of aggressive prostate cancer. The favorable risk disease may represent a detection bias in these patients, according to the researchers.
Research into the association between TRT and prostate cancer risk has been somewhat inconclusive in the past. Given the rapid increase in the administration of TRT in recent years, an association with the risk of prostate cancer has important implications, wrote study authors led by Stacy Loeb, MD, MSc, of New York University.
They conducted a nested case-control study based on the National Prostate Cancer Register of Sweden. This included all 38,570 cases diagnosed from 2009 to 2012, along with 192,838 age-matched men without prostate cancer. The results of the analysis were online ahead of print in the Journal of Clinical Oncology.
The study was limited by a lack of data on circulating testosterone levels, which make any connection between changes in hormone levels and prostate cancer risk impossible to evaluate. Still, they concluded that the findings suggest that from a prostate cancer perspective, TRT is safe in hypogonadal men.
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Testosterone Supplementation After Prostate Cancer
Two experts examine the pros and cons of this controversial practice
At some point in their 40s, mens testosterone production begins to slow. By some estimates, levels of this hormone drop by about 1% a year. As men get into their 50s, 60s, and beyond, they may start to have signs and symptoms of low testosterone. These include reduced sex drive and sense of vitality, erectile dysfunction, decreased energy, lower muscle mass and bone density, and anemia. When severe, these signs and symptoms characterize a condition called hypogonadism.
Researchers estimate that hypogonadism affects two to six million men in the United States. Yet it is an underdiagnosed problem, with only about 5% of those affected receiving treatment, according to the FDA. Deciding which patients should receive testosterone supplementation has proved tricky, however. For example, little consensus exists on what constitutes low testosterone. In addition, some men may have low blood levels of testosterone but not experience any symptoms. And few large, randomized studies on the long-term risks or benefits of testosterone supplementation have been completed.
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What Is Intermittent Adt
Researchers have investigated whether a technique called intermittent androgen deprivation can delay the development of hormone resistance. With intermittent androgen deprivation, hormone therapy is given in cycles with breaks between drug administrations, rather than continuously. An additional potential benefit of this approach is that the temporary break from the side effects of hormone therapy may improve a mans quality of life.
Randomized clinical trials have shown similar overall survival with continuous ADT or intermittent ADT among men with metastatic or recurrent prostate cancer, with a reduction in some side effects for intermittent ADT .
Why Testosterone Replacement Therapy May Not Affect Enlarged Prostate
Researchers are still studying the link between testosterone and the prostate. However, there are a few reasons why TRT may have no effect on prostate size or enlarged prostate symptoms. While its true that the prostate increases in size during puberty, serum testosterone in your blood as you get older may not have much influence on your prostate. Several researchers believe that blood testosterone has little effect on the prostate, only the testosterone inside the prostate, which doesnt seem to change easily with testosterone administration.
Also, for those who noticed improvements, there may be an explanation for that as well. Its not entirely clear what causes an enlarged prostate. However, some believe low nitric oxide levels in the body may be partially to blame. Nitric oxide may help with the process of relaxing smooth muscles. How does this relate to testosterone? Many believe testosterone affects nitric oxide production in your body.
So, while research continues for testosterone and enlarged prostate, there may be several explanations to why testosterone replacement therapy later in life does not seem to cause or worsen enlarged prostate.
If youre experiencing symptoms of low testosterone, our treatment providers may be able to help. Our team can help find underlying causes of your symptoms and work with you to create customized treatment plans to help you feel great again.
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Does High Testosterone Protect Against Prostate Cancer
As for evidence that men who have higher levels of testosterone are protected against prostate cancer, the jury is still out. However, a European Urology report noted that numerous reports have shown that men who receive testosterone therapy after treatment for localized prostate cancer have shown no or low recurrence rates. Some men with untreated cancer who have taken T therapy also have not had any progression of their disease.
Study: Testosterone Therapy Does Not Raise Prostate Cancer Risk
Review of nearly 150,000 patient cases provides strong evidence, says UW Medicine urologist who led research.
In the past 30 years, millions of men globally have been diagnosed with low testosterone levels and been prescribed supplemental testosterone as therapy even as oncologists have confirmed testosterone as an agent that fuels prostate cancer and have treated the disease by reducing patients levels of the hormone.
With this backdrop comes research today showing that, among nearly 150,000 men over age 40 with low testosterone levels, treatment with testosterone was not associated with increased risk for aggressive prostate cancer.
The study, published in PLOS ONE, was jointly led by Drs. Thomas Walsh, Alvin Matsumoto and Molly Shores, all of UW Medicine and the VA Puget Sound Health Care System in Seattle.
This finding doesnt change the guidelines for how we recommend testosterone therapy, said Walsh, an associate professor of urology at the University of Washington School of Medicine and clinician at VA Puget Sound. Men should still have their testosterone diagnosed appropriately, with multiple readings, and be counseled about risks and benefits of treatment. But this large foundation of evidence allows us to look patients in the eye and say testosterone therapy does not appear to increase risk of prostate cancer over a moderate duration.
The researchers focused on the development of aggressive prostate cancer, Walsh said.
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The Original Huggins Article
The basement of Countway Library is where the old volumes of medical journals are kept. Some of these, from august journals such as The Lancet, go back to the 1800s. It is an amazing collection, open to any member of the Harvard community.
I found the original article by Huggins from 1941. It was in the very first published volume of what is now a highly respected journal called Cancer Research. I read how Dr. Huggins and his coinvestigator, Clarence Hodges, used the new blood test called acid phosphatase to show that lowering testosterone by castration or estrogen treatment caused prostate cancer to regress, and how T injections had caused enhanced growth of prostate cancer in these men. And then I noticed something that made my heart race.
Huggins and Hodges had written that three men had received T injections. But results were given for only two men. And one of these men had already been castrated. This meant that there were results for only a single man who had received T injections without prior hormonal manipulation. Dr. Huggins had based his enhanced growth conclusion on a single patient, using a testacid phosphatasethat has since been abandoned because it provides such erratic results!