What The Researchers Did
Dr. Crawfords team reviewed clinical data from nearly 23,000 men who were given ADT injections between 2007 and 2016. Each mans treatment varied by how their ADT was formulated. Some types of ADT are given once a month, and others are given at three-, four-, or six-month intervals. The researchers wanted to know how many men were late on their ADT treatments, and how that would affect the amounts of testosterone in their blood.
During this research, the investigators defined month in two ways: either as one lasting 28 days, which is how months were defined during the clinical trials that set dosing schedules for ADT, or as a calendar month lasting 31 days. ADT was deemed late if it was given after day 28 by the first definition or after day 32 by the second definition.
What Types Of Hormone Therapy Are Used For Prostate Cancer
Hormone therapy for prostate cancer can block the production or use of androgens . Currently available treatments can do so in several ways:
- reducing androgen production by the testicles
- blocking the action of androgens throughout the body
- block androgen production throughout the body
Treatments that reduce androgen production by the testicles are the most commonly used hormone therapies for prostate cancer and the first type of hormone therapy that most men with prostate cancer receive. This form of hormone therapy includes:
Treatments that block the action of androgens in the body are typically used when ADT stops working. Such treatments include:
Treatments that block the production of androgens throughout the body include:
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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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 .
The Effect Of The Free Testosterone Bath
Now we circle back to the connection between testosterone and prostate cancer. According to Gats publication, when the abnormal valves lead to a concentration of free testosterone in the prostate, this hormone places constant stress on the genes that respond to it. This stress pushes cell mutations, as an increasing number of genetic errors occurs and the cells mechanism for detecting copy errors is increasingly damaged. The authors theorize that rapid proliferation of prostate cells results, leading to the condition known as benign prostatic hyperplasia , and eventually to prostate cancer in many cases. So yes, there is a causal link between testosterone and prostate cancer but its not found on the path decades of research has followed.
Gats work illuminates the problem of two different testosterone effects: total testosterone circulating in the blood vs. a localized saturation of free testosterone affecting the prostate gland. The results of studies showing that testosterone supplementation to treat low T did not affect prostate cancer were puzzling to those who expected the cancer to run wild. However, if Gat is correct, its not serum blood levels that are cancer-causing. Its the pooling and backflow of testicular venous blood saturating the gland thats the source. No wonder the efforts to find a correlation between serum levels of testosterone and prostate cancer ended up with frustration.
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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.
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 .
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About Dr Dan Sperling
Dan Sperling, MD, DABR, is a board certified radiologist who is globally recognized as a leader in multiparametric MRI for the detection and diagnosis of a range of disease conditions. As Medical Director of the Sperling Prostate Center, Sperling Medical Group and Sperling Neurosurgery Associates, he and his team are on the leading edge of significant change in medical practice. He is the co-author of the new patient book Redefining Prostate Cancer, and is a contributing author on over 25 published studies. For more information, contact the Sperling Prostate Center.
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Features Of The Study Population
The study was approved by Institutional Review Board. Informed consent was obtained by all subjects. Data were collected prospectively but evaluated retrospectively. In a period ranging from November 2014 to December 2019, 805 consecutive PCa patients who were not under androgen blockade had ET measured at our lab before surgery and the test was performed at least 1 month after biopsies between 8.00 and 8.30 a.m. by radioimmunoassay. PSA , age , body mass index , PV and percentage of biopsy positive cores were evaluated in each case. PV was calculated by transrectal ultrasound standard method. Biopsies performed elsewhere were assessed for number of cores taken, tumor grade and PV measured by TRUS. In our Institution, the 14-core trans-perineal technique was used . In each case, we also adjusted BPC, PSA and ET as densities related to PV as such BPC density PSAD and ETD were calculated as the ratio of BPC, PSA and ET to PV, respectively. Clinical staging was assessed by the TNM system, accordingly . Finally, patients were classified into risk classes .
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Hormonal Treatments For Prostate Cancer Are Often Given Late
- By Charlie Schmidt, Editor, Harvard Medical School Annual Report on Prostate Diseases
Men with advanced prostate cancer are typically treated with drugs that cause testosterone levels to plummet. Testosterone is a hormone that fuels growing prostate tumors, so ideally this type of treatment, which is called androgen deprivation therapy , or hormonal therapy, will stall the disease in its tracks.
For that to happen, ADT has to be administered correctly. But according to a new study, men frequently dont get ADT at the proper dosing intervals. Too many of them get the treatments later then they should, causing testosterone levels to rise unacceptably. Rapid increases in testosterone following delays in dosing could have implications for cancer progression, cautions Dr. David Crawford, a urologist at the University of California San Diego, who led the study.
Tth In Hypogonadal Men Successfully Treated For Pca
A different situation has evolved in relation to patients with a history of successfully treated PCa. Limited but compelling evidence is accumulating showing that following radical prostatectomy, men with symptomatic hypogonadism can safely receive supplemental T. Smaller but equally encouraging evidence has been presented for similar patients treated with either brachytherapy or external beam radiotherapy.28 The timing for initiation of T therapy remains undefined but has been vaguely described as, after a prudent interval. This, of course, is of little help to the clinician. It is our belief that for those who underwent radical prostatectomy, the prudent interval is achieved once the PSA is no longer detectable, unless there is a strong indication for early salvage or adjuvant therapies. This can be reached fairly early, depending on the pre-surgical levels. The situation is less simple for those who received radiotherapy since undetectable levels might not ever be achieved. For these men, we would consider initiation of T treatment after a persistent PSA nadir has been reached.28 It could be argued for a potential advantage of early initiation of T supplementation in that an elevation of the PSA may indicate incomplete ablation of the cancer, in which case, additional curative measures may be considered something akin to a challenge test.
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Testosterone Therapy And Prostate Cancer
Testosterone therapy may increase the risk of prostate cancer recurrence for some people.
Some factors that are particularly associated with a high risk of recurrence:
- Extraprostatic extension
- Positive margins
- Gleason scores of 8 or more on biopsy
- Invasion of the seminal vesicles
There are some situations when testosterone therapy would not be harmful and may be beneficial for people who have had prostate cancer.
- Men who have low-grade or benign tumors
- Men who have completed therapy with surgery or radiation and appear to be cured can use testosterone therapy after an appropriate waiting period between two and five years. The risk of cancer recurrence at this point is generally quite low.
- When a man with known prostate cancer has a low testosterone level and severe physical infirmity or very advanced muscle loss that is associated with notable weakness.
Testosterone Therapy Does Not Increase The Risks Of Prostate Cancer Recurrence Or Death After Definitive Treatment For Localized Disease
- 469 of the RP group received TRT
- 543 of the RT group received TRT
- Median follow-up was 7 years
- There was no difference in biochemical recurrence
- There was no difference in prostate cancer mortality
- There was no difference in overall mortality
Also, see the following articles about the experimental use of high-dose testosterone for metastatic prostate cancer:
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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.
When The Valves Wear Out
If the ISV malfunctions, blood pools in the veins directly above the testicle. The veins begin to bulge with extra blood, and the pressure of the pooled blood is greater than the flow pressure from the prostate. While the majority of ISV blood will still make its way to the rest of the body, some of it is forced upward into the prostate gland. The blood that heads to the rest of the body will carry the majority of testosterone produced by the testicles, since it is bound with blood proteins. However, the majority of free testosterone the kind most readily available for tissue absorption is not traveling with those proteins. Instead, the blood that backflows to the prostate is saturated with free testosterone, reaching concentrations up to 130 times greater than free testosterone in circulating blood! This means the gland is literally bathing in free testosterone. It also means that free testosterone levels will be lower when a testosterone blood draw is taken.
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Hormone Therapy For Prostate Cancer
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Hormone therapy is also called androgen suppression therapy. The goal of this treatment is to reduce levels of male hormones, called androgens, in the body, or to stop them from fueling prostate cancer cell growth.
Androgens stimulate prostate cancer cells to grow. The main androgens in the body are testosterone and dihydrotestosterone . Most androgens are made by the testicles, but the adrenal glands as well as the prostate cancer cells themselves, can also make androgens.
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.
Androgens And Prostate Physiology
Androgens play a critical role in male sexual development and prostate physiology. The two principal androgens in men are testosterone, produced by testicular Leydig cells, and dihydrotestosterone , produced from testosterone in peripheral tissues by 5- reductase. In circulation, testosterone is bound primarily to sex hormone-binding globulin while the unbound, or free testosterone, is the most bioavailable and active form. In the second trimester, fetal testosterone induces development of the epididymis, vas deferens and seminal vesicles, while DHT mediates development of the prostate, urethra and external genitalia . From birth through puberty, the prostate remains small and immature, while in postpubertal males the surge in androgens drives gland development and an increase in prostate volume up to 10 times its prepubertal size . DHT also plays a well-established role in promoting continued growth of the adult prostate, leading to benign prostatic hypertrophy .
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Active Surveillance And Watchful Waiting
If prostate cancer is in an early stage, is growing slowly, and treating the cancer would cause more problems than the disease itself, a doctor may recommend active surveillance or watchful waiting.
Active surveillance. Prostate cancer treatments may seriously affect a person’s quality of life. These treatments can cause side effects, such as erectile dysfunction, which is when someone is unable to get and maintain an erection, and incontinence, which is when a person cannot control their urine flow or bowel function. In addition, many prostate cancers grow slowly and cause no symptoms or problems. For this reason, many people may consider delaying cancer treatment rather than starting treatment right away. This is called active surveillance. During active surveillance, the cancer is closely monitored for signs that it is worsening. If the cancer is found to be worsening, treatment will begin.
ASCO encourages the following testing schedule for active surveillance:
-
A PSA test every 3 to 6 months
-
A DRE at least once every year
-
Another prostate biopsy within 6 to 12 months, then a biopsy at least every 2 to 5 years
Treatment should begin if the results of the tests done during active surveillance show signs of the cancer becoming more aggressive or spreading, if the cancer causes pain, or if the cancer blocks the urinary tract.