Testosterone replacement therapy in men with prostate cancer: An oncologist’s perspective

“Does testosterone replacement therapy (TRT) increase the risk of my prostate cancer coming back?”

It seems that this question is coming up more often these days among patients who have completed treatment for prostate cancer.

The Background:

Very effective direct to consumer marketing campaigns touting the benefits of TRT and “bio-identical hormone therapy” (i.e. Dr Life’s Cenegenics, BodyLogicMD, etc.) have peeked the interest of many men who are starting to feel the mental and physical effects of ‘aging’. Popular TV news, talk shows and radio programs have spread the word about so the called “male menopause” or “andropause”.

As part of the natural aging process, men after the age of 30 men begin to lose testosterone at a rate of 1-2% per year.  By the time a man reaches 70 years old, his testosterone (T) level can be only 10% of that of a 25 year old.  Although very common among men over 60, andropause can present in men in their 40’s and 50’s (in one recent study, 39% of men >/= 45 years old were considered to be T deficient). The most common cause of andropause is low T, however multiple other hormonal factors can also be responsible. Blood, urine and/or salivary tests are used to help diagnose the and follow the levels of these hormones.

Classic symptoms of andropause (known as ‘hypogonadism‘ in the medical literature) can include the following: increased irritability, depression, memory loss, fatigue, hot flashes, night sweats, weight gain, muscle loss, diminished libido, erectile dysfunction, hair loss, etc.

If you are being told that adding a little T to your life might make you feel and look better, who can blame you for asking more about it? Heck, where do I sign up!?

Unfortunately, simply making a diagnosis of andropause and correcting hormone levels may have minimal-to-little effect on these symptoms. It is important to recognize that the cause of each of these symptoms is typically difficult to pin-down. More often than not, they are attributable to a complex interplay of multiple factors including other medical (i.e. diabetes, heart disease, medication side effects, cancer treatment side effects, etc.) and psychoemotional (i.e. stress, anxiety, depression, etc.) conditions and lifestyle factors (i.e. poor nutritional/dietary habits, lack of physical activity, smoking, excessive alcohol consumption, etc.) that should be addressed.

Risks associated with low T:

Low T is associated with an increased risk of 3 serious medical conditions:

• Cardiovascular disease:
  • Low T is associated with: increased levels of total cholesterol, low-density lipoprotein, increased production of proinflammatory factors, and increased thickness of the arterial wall and contributes to endothelial dysfunction.
  • TRT is associated with: improved arterial vasoreactivity, enodothelial function and reduces proinflammatory cytokines, total cholesterol, and triglyceride levels
• Metabolic syndrome and type 2 diabetes/insulin resistance:
  • Metabolic syndrome is characterized by a cluster of cardiovascular risk factors including increased central abdominal obesity, elevated triglycerides, reduced high-density lipoprotein, high blood pressure, increased fasting glucose, and hyperinsulinemia. These factors increase the risk of cardiovascular disease (CVD) and/or type 2 diabetes. Low T is associated with metabolic syndrome, and with increased deposition of visceral fat, which serves as an endocrine organ, producing inflammatory cytokines and thus promoting endothelial dysfunction and vascular disease.
  • Low T is strongly associated with type 2 diabetes (NIDDM) and insulin resistance. Hypogonadal men are at higher risk for NIDDM. TRT in hypogonadal men improves insulin sensitivity, fasting glucose, and HbA1c levels.

Does TRT increase the risk of developing prostate cancer?

We don’t know.

The data are far from conclusive, as there are no high-quality studies (i.e. placebo-controlled, double-blind randomized trials) that have been reported on the long-term use of TRT.  Short-term (<3 years) use of TRT does not seem to increase the risk of developing prostate cancer among men who were studied during this short time interval. Most studies report that short-term TRT does not lead to a rise in PSA levels or in prostate size, which suggests minimal-to-no effects on stimulating prostate cell growth.

The concern is that long-term administration of TRT may increase a man’s risk of developing prostate cancer. This is a lesson that we learned after long-term administration of estrogen and progestin replacement therapy to help women with post-menopausal symptoms (5+ years of estrogen and progestin therapy increased the risk of developing breast cancer by 25% over placebo). It took over 8 years of follow-up to identify this increased risk.

Recent data suggest that men with low T levels may be more likely to be diagnosed with aggressive prostate cancer pathology (i.e. higher Gleason scores, greater incidence of seminal vesicle invasion, etc.) than men with higher T levels. Regarding these findings, one of the most well-respected researchers on this subject (Abraham Morgentaler, MD, Beth Israel Deaconess Medical Center, Boston MA) states, in a recent editorial, “Finally, after 7 decades of circumstantial evidence pointing us in the wrong direction, perhaps it is time to consider the once unthinkable: a T therapy trial of sufficient size and duration to determine whether normalization of serum T in older men may reduce the risk of PCa, particularly high-risk PCa.”

For the time being, recommending TRT in symptomatic hypogonadal men with no evidence of prostate cancer seems reasonable with the caveat that they completely understand the limitations of the available data.

Read a great review on this topic: “Testosterone Replacement Therapy and Prostate Risks: Where’s The Beef?”

Does TRT fuel the growth or recurrence of prostate cancer?

We don’t know.

Most prostate cancer cells possess receptors that are able to be stimulated by testosterone to grow and divide.  Therefore, giving TRT to a man with active, untreated prostate cancer has been considered analogous to throwing fuel on the fire. Due to this potential concern and the policy of “do no harm”, many physicians do not recommend TRT for men with a history of prostate cancer.  However, the data supporting this policy has been called into question by Dr. Morgentaler and others.

Data regarding men who have been previously treated for prostate cancer:

In a meta-analysis (by Dr. Morgantaler) of 6 uncontrolled studies that included data on the risk of prostate cancer recurrence in men (n=111) who received TRT after treatment for prostate cancer (i.e. radical prostatectomy, external beam radiation therapy or brachytherapy), the author found that the risk of a biochemical recurrence was only 1.8%. (Morgentaler A., J Urol, 2009)

In a separate meta-analysis (by Mohit Khera, M.D., M.B.A., M.P.H., Baylor College of Medicine, Houston, TX), the author reviewed all publications, to date, looking at the effects of TRT on men who were previously treated for prostate cancer. Dr. Khera found that among the 292 men treated with TRT in these studies, their risk of prostate cancer recurrence was less than 1%. (Khera M., Curr Urol Rep, 2010)

Data among men with prostate cancer that has not been treated:

In a small study, Dr. Morgentaler and co-authors examined the effects of TRT in 13 men with untreated prostate cancer undergoing active surveillance. The men had a mean age of 59, mean PSA value of 5.5 ng/mL, mean testosterone concentration of 238 ng/mL, and all but one had a biopsy Gleason score of 6 (one patient with Gleason 7). After a median treatment duration of 2.5 years, the group’s testosterone values averaged 664 ng/dL (P<0.001). Mean PSA level declined to 3.6 ng/mL, which did not differ significantly from baseline. Prostate volume also did not change. The men had an average of two prostate biopsies during follow-up, and 54% of specimens had no evidence of cancer. The limitations of the study included its small size, retrospective design, inclusion of some men who had prostate cancer diagnosed after the start of testosterone therapy, and lack of generalizability to those with higher grade or higher volume disease.

Dr. Morgentaler writes: “The prohibition against the use of testosterone therapy in men with a history of prostate cancer is based on a model that assumes the androgen sensitivity of prostate cancer extends throughout the range of testosterone concentrations. Although it is clear that prostate cancer is exquisitely sensitive to changes in serum testosterone at low concentrations, there is considerable evidence that prostate cancer growth becomes androgen indifferent at higher concentrations. The most likely mechanism for this loss of androgen sensitivity at higher testosterone concentrations is the finite capacity of the androgen receptor to bind androgen. This saturation model explains why serum testosterone appears unrelated to prostate cancer risk in the general population and why testosterone administration in men with metastatic prostate cancer causes rapid progression in castrated but not hormonally intact men. Worrisome features of prostate cancer such as high Gleason score, extracapsular disease and biochemical recurrence after surgery have been reported in association with low but not high testosterone…Anecdotal evidence suggests that testosterone therapy does not necessarily cause increased prostate specific antigen even in men with untreated prostate cancer. In terms of giving TRT to men with a history of prostate cancer, the main impediment at this point is that there still are no large, long-term studies that can give us the bounds of safety data on this.”

Dr. Khera writes: “Historically, testosterone supplementation has been avoided in men with a history of prostate cancer because of concern about prostate cancer progression or recurrence. However, recently published data suggest that this concern may not be well founded. The recurring presence of prostate-specific antigen in men with hypogonadism being treated with testosterone after prostatectomy is far less than the expected natural recurrence rate of the disease. There are many theories (including the prostate saturation theory) that may help us understand why testosterone may be safely administered in men with hypogonadism after surgical treatment of prostate cancer. Finally, because patients with hypogonadism already may be at a significant disadvantage in recovering their erectile function after prostatectomy, they perhaps should receive special consideration as candidates for androgen replacement therapy.”

Pre-TRT assessments and monitoring during TRT:

Experts recommend:

• A baseline digital rectal examination (DRE) and PSA should be checked before starting a patient on TRT, and a PSA should be checked again within 3-6 months. The PSA and DRE should then be monitored every 6 months while on TRT.
• The American Society of Andrology recommends periodic monitoring of men receiving testosterone replacement therapy. Subject to individual clinical response, evaluation is recommended at 3-6 months after initiation of therapy, and then yearly. A physical examination, including DRE, a prostate- related symptom assessment, PSA level and hematocrit should be performed at 3,6, and 12 months and then annually. TRT should be altered or ended if the hematocrit exceeds 52%.
• Read an evidence-based review: December 2010,The Journal of Family Practice, “How should we monitor men receiving testosterone replacement therapy?”
• Typically, a PSA velocity > 0.75 ng/ml/year (regardless of the baseline PSA) or a nodule on DRE during testosterone replacement therapy should prompt further evaluation by a urologist and possible prostate biopsy. However, the optimal frequency of monitoring and cutoff points, both for referral to urology and prostate biopsy, remain somewhat controversial. This ambiguity is reflected in the various PSA cutoff points that have been suggested, ranging from > 0.4 to > 1.5 ng/ml/year, depending on how many years of observation are considered.

How is TRT administered?

Risks and side effects of TRT:

In general, hormone replacement therapy is safe. It is occasionally associated with the following side effects:

• acne or oily skin
• mild fluid retention
• prostate enlargement
• breast enlargement
• worsening of sleep apnea
• decreased testicular size

Laboratory abnormalities that can occur with hormone replacement include:

• changes in cholesterol concentrations
• increase in red cell count
• decrease in sperm count, producing infertility (especially in younger men)

If you are taking TRT, regular follow-up appointments with your physician are important.

Contraindications to therapy include active prostate cancer, breast cancer, untreated sleep apnea, and untreated and/or severe congestive heart failure.

The bottomline:

For some patients, the quality of life improvement on TRT is worth more to them than the likely small risk of prostate cancer progression. I feel that it is very reasonable to offer patients, who are symptomatic from their hypogonadal state (with or without a prior history of prostate cancer), TRT as long as:

1. they are not actively receiving androgen deprivation therapy for prostate cancer
2. they do not have advanced or progressing prostate cancer
3. they do not have a history of breast cancer
4. their post-treatment PSA has been stable for at 6 months after treatment of their prostate cancer
5. they understand the limitations of the available data (i.e. short-term TRT administration, limited follow-up, lack of randomized controlled trials)
6. they recognize that there are potential risks of TRT stimulating prostate cancer growth and progression
7. they agree to close follow-up