Testosterone Therapy In Men With Prostate Cancer
Recently, several groups have reported the use of testosterone replacement therapy in men after a diagnosis of prostate cancer. Investigators have reported favorable outcomes with testosterone supplementation after radical prostatectomy. In the largest study to date, Pastuszak et al report the outcome of 103 men treated with testosterone after radical prostatectomy including 26 patients with high risk disease. With an average follow-up of 27.5 months, the authors noted 4 recurrences, which was similar to their comparison group. Sarosdy reported the treatment of 31 men with testosterone supplementation after brachytherapy. After a median follow-up of 5 years, no prostate cancer recurrences were reported. Favorable outcomes have also been reported after external beam radiotherapy .
In contrast, Leibowitz et al reported data on 96 men after prostate cancer treatment who were on testosterone supplementation. They reported 41 men who had biochemical progression.
Prostate Cancer Information: Prostate Cancer Hormone Therapy
Prostate cancer hormone therapy is the systemic ablation of the bodys testosterone which, for a period of time, will slow or stop the growth and spread of prostate cancer. Hormone therapy may also be called androgen deprivation or androgen ablation.
The Role of Hormones in Prostate Cancer The male sex hormone, testosterone, causes the growth of the prostate gland and other sex organs in the developing male. Even as men pass through the age of puberty, testosterone continues to contribute to the growth of the organ. Testosterone will fuel the growth of any prostatic cell: the chemical cannot discriminate between the receptors of healthy tissue and cancerous tissue. Prostate cancer hormone therapy removes the chemical that feeds cells and can stop or slow the growth and spread of the tumor.
Where does Testosterone Come From? A chemical sequence in the brain signals the testicles, which make 90% of the bodys hormones, to begin production. A structure in the brain called the hypothalamus continually monitors the blood stream for adequate levels of testosterone. If these levels drop, the hypothalamus releases a chemical called GnRH or LHRH . GnRH acts as a messenger and travels to the pituitary gland where it plugs into designated receptors.
How is Hormone Therapy Administered? There are four basic methods androgen deprivation: castration, estrogen, anti androgens, and combine androgen blockade.
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Treatment To Lower Testicular Androgen Levels
Androgen deprivation therapy, also called ADT, uses surgery or medicines to lower the levels of androgens made by the testicles.
Orchiectomy
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 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. Because of this, they may choose treatment with drugs that lower hormone levels instead.
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 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.
With these drugs, the testicles stay in place, but they will shrink over time, and they may even become too small to feel.
- Leuprolide mesylate
LHRH antagonists
Possible side effects
Many side effects of hormone therapy can be prevented or treated. For example:
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Obesity & Physical Activity
I think it comes as no surprise that obesity is very well linked to advanced and aggressive prostate cancer 14,15. One possible reason for this is due to altered hormone and metabolic profiles. Elevated insulin, due to the insulin resistance associated with obesity can promote prostate cancer growth. Furthermore, in obesity we note an elevation in oestradiol levels, which can encourage prostate cancer growth 16. Exercise can naturally decrease the risk of prostate and other cancers 1.
Lets expand on the point regarding Oestradiol What role do your sex hormones play?
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The Truth About Testosterone Replacement Therapy And Prostate Cancer
Many men with low testosterone find themselves apprehensive about undergoing testosterone replacement therapy . The commonly held theory is that high levels of testosterone stimulate the growth of prostate cancer.
New findings show that TRT has very little impact on the growth of prostate cancer or the elevation of PSA levels and may change the way you think about the efficacy of testosterone in cancer treatment.
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Take A Cautious Approach
A large, definitive trial for hormone treatment of men is still to come. Until then, here is how to take a cautious approach to testosterone therapy.
Take stock of your health first
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Have you considered other reasons why you may be experiencing fatigue, low sex drive, and other symptoms attributable to low testosterone? For example, do you eat a balanced, nutritious diet? Do you exercise regularly? Do you sleep well? Address these factors before turning to hormone replacement therapy for men.
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If your sex life is not what it used to be, have you ruled out relationship or psychological issues that could be contributing?
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If erectile dysfunction has caused you to suspect “low T” as the culprit, consider that cardiovascular disease can also cause erectile dysfunction.
Get an accurate assessment
Be mindful of unknown risks of testosterone replacement therapy
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Approach testosterone therapy with caution if you are at high risk for prostate cancer have severe urinary symptoms from prostate enlargement or have diagnosed heart disease, a previous heart attack, or multiple risk factors for heart problems.
- Ask your doctor to explain the various side effects for the different formulations of testosterone. The different treatments include testosterone injections, gels and patches. Know what to look for if something goes wrong.
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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Complications Of Hormonal Therapy
E. David Crawford, MD, Professor of Surgery and Radiation Oncology, Head of the Section of Urologic Oncology at the University of Colorado, and Chairman of the 16th International Prostate Cancer Update, provided an excellent overview of complications of hormonal therapy and their treatment. He began this discussion by outlining not only the benefits but also the complications of androgen deprivation, the latter including osteoporosis, hot flushes, gastrointestinal side effects, anemia, gynecomastia, sarcopenia, central nervous system effects, change in body weight, sexual dysfunction, loss of bone density, and increased risk of bone fracture and hot flushes .
How May Changing Prostate Cancer Screening Guidelines Impact Use Of Adt
PSA is the most utilized biomarker for diagnosing prostate cancer. It is a serine protease inhibitor that was discovered and purified in 1979. Thirteen years later, two large studies reported the utility of using PSA screening for prostate cancer., In one study, approximately 15% of men of 1249 over the age of 50 years were found to have an elevated PSA, defined by a serum level > 4.0 ng/mL. Prostate cancer was diagnosed in slightly more than 30% of men with an elevated PSA. Soon thereafter, PSA screening gained widespread acceptance in the United States. According to Zeliadt and colleagues, it has been estimated that approximately 50% of the male US population between the ages of 55 and 74 years undergo PSA screening over a 6- to 7-month period.
The European Randomized Study of Screening for Prostate Cancer had less contamination than the PLCO study because a smaller proportion of men in the unscreened cohort underwent screening prior to randomization or during the study. The median follow-up was 9 years. Overall, prostate cancer mortality was reduced by 20%. Upon correcting for contamination, PSA screening decreased prostate cancer mortality by 31% in actually screened patients.
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What Are Male Sex Hormones
Hormones are substances that are made by glands in the body. Hormones circulate in the bloodstream and control the actions of certain cells or organs.
Androgens are a class of hormones that control the development and maintenance of male characteristics. The most abundant androgens in men are testosterone and dihydrotestosterone .
Androgens are required for normal growth and function of the prostate, a gland in the male reproductive system that helps make . Androgens are also necessary for prostate cancers to grow. Androgens promote the growth of both normal and cancerous prostate cells by binding to and activating the androgen receptor, a protein that is expressed in prostate cells . Once activated, the androgen receptor stimulates the expression of specific genes that cause prostate cells to grow .
Almost all testosterone is produced in the testicles a small amount is produced by the adrenal glands. Although prostate cells do not normally make testosterone, some prostate cancer cells acquire the ability to do so .
Testosterone Replacement Therapy And Voiding Dysfunction
Wesley Baas, Tobias S. Köhler
Division of Urology, Southern Illinois University School of Medicine, Springfield, IL, USA
Contributions: Conception and design: TS Köhler Administrative support: TS Köhler Provision of study materials or patients: None Collection and assembly of data: All authors Data analysis and interpretation: All authors Manuscript writing: All authors Final approval of manuscript: All authors.
Correspondence to:
Abstract: Testosterone replacement therapy represents an increasing popular treatment option for men with late-onset hypogonadism . Because of unsubstantiated beliefs of testosterones effect on the prostate, the FDA has recently placed a warning on testosterone products, stating that TRT may worsen benign prostatic hyperplasia . Within this review article we have demonstrated the current understanding of the physiology of testosterone and its relationship with prostatic and lower urinary tract physiology. The current evidence suggests that not only does TRT not worsen lower urinary tract symptoms , but that hypogonadism itself is an important risk factor for LUTS/BPH.
Keywords: Benign prostatic hyperplasia lower urinary tract symptoms testosterone replacement therapy hypogonadism
Submitted Jun 07, 2016. Accepted for publication Jun 20, 2016.
doi: 10.21037/tau.2016.08.11
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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:
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. This can help 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 . 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 it is not clear why it happens.
Newer anti-androgens
Enzalutamide , apalutamide and darolutamide are newer types of anti-androgens. They can sometimes be helpful even when older anti-androgens are not.
These drugs are taken as pills each day.
Testosterone And Prostate Cancer What You Should Know
What is the relationship between testosterone and prostate cancer? Does testosterone stimulate the growth of prostate cancer? Lets answer the many questions surrounding the association between mens hormones and prostate cancer.
Starting with probably the single most common question that has been weighing on the minds of many scientists and medical professionals for decades:
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What Are The Side Effects Of Hormone Therapy For Prostate Cancer
Because androgens affect many other organs besides the prostate, ADT can have a wide range of side effects , including:
- loss of interest in sex
Studer UE, Whelan P, Albrecht W, et al. Immediate or deferred androgen deprivation for patients with prostate cancer not suitable for local treatment with curative intent: European Organisation for Research and Treatment of Cancer Trial 30891. Journal of Clinical Oncology 2006 24:18681876.
Zelefsky MJ, Eastham JA, Sartor AO. Castration-Resistant Prostate Cancer. In: Vincent T. DeVita J, Lawrence TS, Rosenberg SA, eds. DeVita, Hellman, and Rosenberg’s Cancer: Principles & Practice of Oncology, 9e. Philadelphia, PA: Lippincott Williams & Wilkins 2011.
Smith MR, Saad F, Chowdhury S, et al. Apalutamide and overall survival in prostate cancer. European Urology 2021 79:150158.
How Is Hormone Therapy Used To Treat Hormone
Hormone therapy may be used in several ways to treat hormone-sensitive prostate cancer, including:
Early-stage prostate cancer with an intermediate or high risk of recurrence. Men with early-stage prostate cancer that has an intermediate or high risk of recurrence often receive hormone therapy before, during, and/or after radiation therapy, or after prostatectomy . Factors that are used to determine the risk of prostate cancer recurrence include the grade of the tumor , the extent to which the tumor has spread into surrounding tissue, and whether tumor cells are found in nearby lymph nodes during surgery.
The use of hormone therapy before prostatectomy has not been shown to be of benefit and is not a standard treatment. More intensive androgen blockade prior to prostatectomy is being studied in clinical trials.
Relapsed/recurrent prostate cancer. Hormone therapy used alone is the standard treatment for men who have a prostate cancer recurrence as documented by CT, MRI, or bone scan after treatment with radiation therapy or prostatectomy.
Hormone therapy is sometimes recommended for men who have a “biochemical” recurrencea rise in prostate-specific antigen level following primary local treatment with surgery or radiationespecially if the PSA level doubles in fewer than 3 months.
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Benefits Of Testosterone Replacement
Hypogonadism is a major cause of secondary osteoporosis in men. Up to 20% of men with symptomatic, pathologic vertebral fractures and 50% of men with hip fractures are found to be hypogonadal. In a study of 72 hypogonadal men, testosterone replacement was associated with an average 39% increase in bone density in the first year. Bone density eventually increased into the normal range and was maintained there throughout the study.
Previous guidelines have suggested there is too little evidence in the literature regarding the safety of TRT in the setting of prostatic diseases including prostate cancer to make a definitive recommendation. The 2008 European Association of Urology guidelines indicate that testosterone replacement can be used in men with symptomatic hypogonadism after successful treatment of prostate cancer provided that a prudent interval has passed with no evidence of recurrent disease. The duration of a prudent interval is not specifically defined in the guidelines. Additionally, the guideline advises that a high risk of developing prostate cancer should be considered a contraindication for TRT. High risk for developing prostate cancer is not defined. As more information regarding the effects of TRT on the prostate and prostate cancer becomes available the risks and benefits of TRT can be more accurately assessed.
Prostate Cancer In Men Receiving Exogenous Testosterone
To date no study or review has documented any direct evidence that testosterone therapy increases incident prostate cancer risk. However, it is still difficult to argue that androgen replacement is safe since no long-term studies have been completed in large populations receiving exogenous androgens over many years. The question of whether androgen replacement increases prostate cancer incidence in an aging population has yet to be answered. The Institute of Medicine, recognizing the need for additional clinical trials to clarify the risks and benefits of testosterone replacement therapy , formed a committee to evaluate the present status of TRT in 2003. This was the most recent statement on the issue of TRT from the Institute of Medicine.
Even studies of TRT in men with high risk for incident prostate cancer because of preexisting prostatic intraepithelial neoplasia did not show an increased risk of prostate cancer. There has been one small study examining the risk of TRT in men with high-grade PIN. These men should presumably be at higher risk for prostate cancer development. After a year of TRT, only one patient with previous high-grade PIN had a detected prostate cancer. The study included 70 men overall 20 with high-grade PIN and 50 controls. This study suggests that TRT does not significantly increase the risk of incident cancer even in an already high-risk population.
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