Testosterone: Friend or Foe?

MICHAEL DATTOLI, MD & GINYA CARNAHAN, APR, CRPC

Perhaps one of the most controversial subjects in the prostate cancer world is the role of testosterone – its influence on the development of prostate cancer, its impact on current tumor growth, and more recently its possible ability to slow the growth of prostate cancer. As a clinic that specializes in, and has treated thousands of prostate cancer patients in our 26 years of operation (Tampa & Sarasota), Dattoli Cancer Center has seen this issue more times than we can count.

For decades within the oncology field, the generally held belief has been that testosterone can be a food source for prostate cancer and as such, it should be avoided using exogenous (via pills, injections or gels) methods. When body-builder type athletes have been found to have prostate cancer, one of the first questions asked is, “Have you been taking testosterone supplements?” There is almost an accusatory undertone if the answer is “yes.” But the testosterone-prostate cancer relationship is more complicated than that.

There is an indisputable understanding about the relationship between prostate cancer and testosterone dating back nearly 75 years. Dr. Charles Huggins identified in the 1940’s, and Dr. Edward Messing in the 1960’s, that removing a man’s testicles, thereby lowering his testosterone (surgical castration) often put advanced prostate cancer into remission and almost immediately reduced bone pain.

There are now at least two landmark studies using randomized, double blind, placebo controlled trials looking at testosterone replacement in men. The first was published nearly a decade ago in the Journal of the American Medical Association (JAMA; January 2008, 39-52 “Effect of Testosterone Supplementation on Functional Mobility, Cognition, and Other Parameters in Older Men.”), and more recently a second one in the New England Journal of Medicine (NEJM; February 2016, 611-624 “Effects of Testosterone Treatment in Older Men”). To date, these were the only trials that used well designed, randomized double blind, placebo controlled methods. Eligibility criteria included age 65 or greater and average testosterone levels of <275 ng/dL. Exclusion criteria included a history of prostate cancer and history of high cardiovascular risk. None of these studies demonstrated statistically significant benefits to numerous parameters. Only “small gains” were appreciated and these benefits waned over months to a few years. All agreed these non-significant gains must be weighed against negative side effects of testosterone such as potential development of prostate cancer and the well documented negative impact on cardiovascular health (myocardial infarction, thrombo-embolitic events, strokes, etc.).

A small study published in the New England Journal of Medicine in 2010 comparing testosterone gel vs. placebo gel, reported no benefit to the patient with respect to vitality or walking status, but slightly better mood and increased libido. The conclusion: too few participants to draw conclusions. In fact, all studies aside from the aforementioned two (JAMA, NEJM) were retrospective studies comprised of very small patient populations.

It should, however, be noted that patients often do benefit from placebo with the percentage varying tremendously depending on the process being studied and psychological conditioning. A Harvard study published in the New England Journal of Medicine in 2011 reported that the placebo effect appears to be most pronounced when treatment success depends largely on the subjective (vs. objective) experience of patients with positive responses up to 40%. So while placebos may provide positive effects, they typically don’t cause untoward side effects.

As recently as 2013, publications were full of articles warning against the use of testosterone therapy based on “new” research confirming the dangers of it increasing prostate cancer risk, and including the potential for development of myocardial infarction (heart attack), congestive heart failure, strokes and death.

The original and longstanding belief that testosterone causes detrimental effects on prostate cancer stems from the “androgen hypothesis.” Based on historical and current observations men having prostate cancer experience a rapid decline in PSA while ceasing prostate cancer progression when reducing testosterone with oral and injectable hormonal agents or surgical castration. Meanwhile, PSA and cancer progression accelerates once testosterone reducing methods are stopped. Moreover, even when men no longer respond to hormones (“castrate resistant”) they often still benefit from even further lowering of testosterone using Zytiga® and Xtandi®.

An article from Brink-zone.com, published in August 2014, stands to turn the old thinking on its head. It is entitled “Testosterone and Prostate Cancer – Bye Androgen Hypothesis, Welcome Saturation Model – Time for a Paradigm Shift.”

This new “saturation model” attempts to explain the paradoxical observations that prostate tissue is highly sensitive to changes in serum testosterone at low concentrations but becomes less reactive to higher concentrations of testosterone. A “threshold effect” occurs when increasing androgen concentrations reach a limit beyond which it no longer affects androgen-driven changes in prostate tissue growth.

Contributing to the saturation model is the finite ability of androgens to bind to the androgen receptor (AR). This model suggests that maximal androgen-AR binding (“saturation”) occurs at fairly low androgen levels. This “saturation point,” subject to individual variation, is believed to be around 230 ng/dL in clinical practice.

Thus, major organization guidelines began to state: “there is no conclusive evidence that testosterone therapy increases the risk of prostate cancer or benign prostatic hyperplasia. There is also no clinical evidence that testosterone treatment will convert subclinical prostate cancer into clinically detectable prostate cancer.”

Now the opposite end of the spectrum is being promulgated. A 2015 article on the Cancer Network website asks this question: Can Testosterone Treat Prostate Cancer?
It references a very small sample of men (16) with asymptomatic (no pain) metastatic prostate cancer, who had rising PSA levels and evidence of resistance to androgen deprivation therapy. The men were treated with three 28-day cycles of testosterone and two weeks of the VP-16 chemotherapy. The men who had declining PSA levels after three cycles continued to receive testosterone injections alone.

Seven of the men had 30% to 99% decreases in PSA levels. Four of these men stayed on testosterone therapy for 1 to 2 years and had steady low PSA levels. Of the remaining nine men, seven had no changes in their PSA levels, one died due to pneumonia and sepsis from the chemotherapy, while one did not complete the study due to unwanted side-effects from testosterone.

Ten men underwent imaging scans to measure their disease – five of the men had tumor shrinkage of more than 50%, including one whose cancer was no longer detectable by imaging. All ten men experienced reductions in PSA including four whose PSA did not change during the trial, and who were given testosterone-blocking drugs after the testosterone treatment.

This study came from the Sidney Kimel Comprehensive Cancer Center at the Johns Hopkins University Medical School and the study group was extremely small. Meanwhile, it must be emphasized that both testosterone and chemotherapy were used (vs. testosterone alone).

A caveat stresses that timing in giving the testosterone therapy is extremely important and not easy to determine. This researcher warns against self-medication with over–the-counter testosterone supplements.

We can’t ignore the exploitation of testosterone supplements in the marketplace. Testosterone products are among the top ten grossing items from GNC, the giant national vitamin and supplement house. They are touted as miracle “drugs” to skyrocket the libido, boost energy levels, enhance “performance,” and create muscle mass! The ads proclaim, “If you are 80 years old and want to feel like 20 again, you need a Testosterone Boost.” Whether they increase prostate cancer risk, or can actually assist in treating the disease remains to be seen. Of concern, across the country prescription forms of testosterone are currently being ordered not only by Endocrinologists, but also Internists, Family Practitioners, Orthopedists, Physical Rehabilitation Physicians and, of course, Oncologists and Urologists.

My partner, Dr. Joseph Kaminski, citing his recent experience at the Food and Drug Administration, is quick to point out that there are stringent FDA required warnings on all testosterone products about the potential of cardiac complications from the use of these products.

Here is an example of the warnings statement from one product:

• Men with carcinoma of the breast or known or suspected carcinoma of the prostate should not take products containing testosterone.
• Exposure to testosterone may cause fetal harm to pregnant or breast feeding women.

The package insert goes on to warn about numerous other effects: worsening of BPH; sleep apnea; azoospermia (absence of sperm); venous thromboembolism (VTE) including deep vein thrombosis (DVT) or pulmonary embolism (PE); increased risk of myocardial infarction and stroke; edema with or without congestive heart failure; many resulting in death.

To sum it up, in 2015, Laurence Klotz, MD (Sunnybrook Health Sciences Centre, Toronto) published this opinion piece in the Nature Review Urology journal: “Testosterone is a potent hormone with a variety of physiological effects. The diagnosis of androgen deficiency has increased dramatically over the past decade, along with widespread use of testosterone supplementation therapy. The long-term effects of testosterone supplementation therapy are uncertain, and the risk of over-diagnosis and overtreatment of men who have a normal age-related decline in testosterone is substantial. The biology of the androgen receptor (AR) pathway is complex, and the saturation model does not take the heterogeneity of human prostate cancer into account. Large-scale trials to confirm the safety of testosterone with respect to the risk of prostate cancer and cardiovascular disease with reasonable confidence limits have not been done, and existing data are insufficient to exclude these adverse events. Instead, evidence suggests that prostate cancer could, in fact, be stimulated by testosterone supplementation therapy, and that the risk of cardiovascular events is increased. Overall, testosterone supplementation therapy seems to impose significant risks and should be used with extreme caution.”

Our best advice is to seek advice only from a prostate oncologist who is well researched on testosterone replacement in men having prostate cancer, as this topic is so controversial that even general oncologists (and some “informed” prostate oncologists) may be unaware of the potential benefits and/or detriments associated with testosterone. I am of the position that the “jury is still out” and continue to not use testosterone replacement until better studies have matured, with rare exceptions. To date, only retrospective data based on extremely small patient populations have suggested that replacement testosterone may be safe in patients with prostate cancer. For replacement testosterone my exceptions, with reservations and great trepidation, are:

• in patients who suffer from primary or secondary hypogonadism (and not including aging in the latter, as testosterone commonly diminishes naturally with age), and following 3 years of having undetectable PSA’s may initiate low doses of testosterone gel and titrated to moderately low to mid-normal range. These conditions may be caused by an inherited (congenital) trait or something that may occur later in life (acquired), such as an injury or infection. According to the American Association of Clinical Endocrinologists (AACE), 30% of men older than 75 years have a testosterone level below the normal range of young men. Even the AACE has determined it to be highly controversial to supplement testosterone and these are men without a history of prostate cancer; and
• in men who suffer from persistent hypogonadism (primary or secondary) and have had 5 consecutive years of undetectable PSA’s and with initial presentation not containing a single high-risk feature (PSA ≥ 20, Gleason 8-10, clinical stage > T2c and elevated PAP. Refer to AJCC Cancer Staging Manual, eighth edition and my PAP studies published in the Journal of Urology in 2008).

Don’t risk your health on outrageous claims of this widely available but potentially dangerous product. Prostate cancer survivors should exercise extreme caution while prescribers should beware. Numerous law firms are lining up to do battle with the testosterone “industry” and two class-action law suits have already been filed.

References:

1. Journal of Urology, 71 (1) 2008, 146-150 “Pap Adversely impacts Cause-specific Survival in Patients having Prostate Cancer having Intermediate and High- Risk Features.”
2. JAMA; January 2008, 39-52 “Effect of Testosterone Supplementation on Functional Mobility, Cognition, and Other Parameters in Older Men.”
3. NEJM, 2010, 374: 611-624 “Testosterone Gel vs Placebo.”
4. NEJM, 2011, 365: 119-126. “Active albuterol or placebo, sham acupuncture, or no intervention in asthma.”
5. Live Science; July 27, 2012, “High Testosterone Linked to PCA Risk.”
6. Brink-zone.com; August 9, 2014, “Testosterone and Prostate Cancer – Bye Androgen Hypothesis, Welcome Saturation Model – Time for a Paradigm Shift.”
7. CANCER; January 9, 2015, “Can Testosterone Treat Prostate Cancer.”
8. 8) Nature Reviews Urology; January 2015, 48-54 “Testosterone therapy and prostate cancer – safety concerns are well founded.”
9. NEJM, February 18, 2016, “Effects of Testosterone Treatment in Older Men

INTERESTING TRIALS IN IMMUNOTHERAPY

for Prostate Cancer

JAN MANARITE, VP OF ADVOCACY & EDUCATION

Dr. Charles Drake of Johns Hopkins is a medical oncologist and immunologist who specializes in prostate cancer. He is well known in his field for explaining the concept of immunotherapy in simple terms. On his “Find an Expert” profile page on the Johns Hopkins website, you will find a video where he explains immunotherapy in prostate cancer this way:

“Prostate cancer is an excellent target for immunotherapy because…prostate cancer is usually a slow-growing cancer. For immunotherapy this is important…because it takes time for the patient’s immune system to wake up and mount a response to the cancer…We think what’s happening in these patients is a new balance where the immune system is adapting to the changes in the cancer, effectively slowing down progression of the disease…”

Look carefully at the following trials below if this is something that interests you. Do your research, contact the trial site, then talk to your physicians and nurses if there is a trial that you appear to qualify for.

1. Prostvac® in Patients With Biochemically Recurrent Prostate Cancer

   Phase 2, NO Placebo. Half of men receive Prostvac right away, Half receive Prostvac 6 months after starting trial.

   Basic Eligibility Criteria:

   • Prior surgery, radiation, or other local treatment for prostate cancer
   • Rising PSA which includes the following:
     • 3 consecutive PSA rises, taken 1 week to 1 month apart
     • PSA doubling time between 5 mos and 15 mos
     • For patients who had prostatectomy (surgery), a PSA of 0.8 or highe
     • For patients who had radiation or other local treatment, a PSA that has risen 2.0 above PSA nadir
   • No metastases
   • No prior chemo
     (For full eligibility criteria, check with contact below)

Location: Bethesda, MD (NIH)

Contact: Anna Couvillon, CRNP, (301) 443-6211, couvilla@mail.nih.gov

Source: Prostate Cancer Communication / Summer 2016