Does Testosterone Replacement Therapy (TRT) cause Prostate Cancer? No.

• Testosterone Replacement Therapy (TRT) and the Prostate

• Low-T is a Risk Factor for Prostate Cancer

• Testosterone and Prostate Health

• Prostate: Testosterone Saturation Model

• FDA Label Warning

• AUA Guidelines

Keywords: Prostate health, BPH, LUTs, Urinary symptoms, TRT, Testosterone and Prostate Health, Prostate Cancer and TRT, Rising PSA, Prostate Specific Antigen, PSA rise on Testosterone Therapy, Saturation Model of Testosterone Therapy, High- Dose Testosterone Therapy for Prostate Cancer Treatment.

BPH

BPH stands for Benign Prostatic Hyperplasia. The prostate is a gland present only in men and serves only to provide fertility. The prostate is located just below the bladder and envelopes the urethra. As a man matures his prostate can grow causing compression of the urethra and abutting the bladder. This can lead to lower urinary tract symptoms, often termed LUTs. Symptoms of an enlarged prostate include straining to urinate, frequency and urgency to void, waking up a night to void and a weak urinary stream. Prostate growth is an androgen dependent process. Testosterone and its derivative DHT (dihydrotestosterone) play an integral role in prostate development and growth.

Testosterone & BPH

It is the concern of clinicians and men that testosterone can increase prostate growth and therefore exacerbate the symptoms of BPH such as frequency of urination, urinary urgency, staining to urinate, waking up at night to urinate or weak urinary stream. In fact, there is evidence to support just the opposite, that testosterone can improve lower urinary tract symptoms (LUTS). As shown in clinic studies men with Low -T who receive testosterone supplementation experience no significant change in urinary symptoms scores or worsening of LUTS. Some clinical studies have shown that testosterone can and may improve symptoms of an enlarged prostate, improve bladder emptying, voided volumes, and improve IPSS (International Prostate Symptom Score) and AUASS (American Urologic Association Symptom Score). IPSS and AUASS are questionnaires developed by physicians to understand the severity of urinary symptoms in men. Testosterone can improve Nitric Oxide (NO) and Nitric Oxide Synthase (NOS) in the bladder and prostate, causing smooth muscle relaxation and easing the passage of urine during voiding. Men with low testosterone may have lower levels of NO and NOS in the tissue of the prostate and bladder, lending to worsening LUTS.

Testosterone Replacement Therapy (TRT) and Prostate Cancer

For years clinicians have been concerned that providing testosterone replacement therapy (TRT) could cause and increase the risk of developing prostate cancer. This idea was born from the current treatment of prostate cancer algorithm. Men with metastatic prostatic cancer are treated by medical castration (medication used to stop testosterone production by the testicles and or by blocking the androgen receptor). That is per say, the treatment for prostate cancer is to lower testosterone levels. So, the opposite has been believed to be true, receiving exogenous testosterone can cause prostate cancer. In addition, it is believed that the use of testosterone in patients with prostate cancer may exacerbate the disease and spread prostate cancer. This theory that exogenous testosterone usage could spread prostate cancer was initially postulated decades ago by Fowler and Whitmore, and by Charles Huggins and Hodges who found that prostate cancer was an androgen provoked condition.

We know today, after years of research and clinical trials there is no evidence that links any increased risk of developing prostate cancer in men undergoing TRT. There is no evidence that normal levels of testosterone have any relationship to prostate cancer. In fact, we know today that men who have low testosterone actually have a higher risk of developing prostate cancer. Having low testosterone level is a significant risk factor for developing prostate cancer. In fact, under clinical investigation at John Hopkins Kimmel Cancer center is the use of high dose testosterone therapy to treat metastatic prostate cancer. There has also been a myriad of studies that have documented treating patients who have or had prostate cancer with TRT and there has not been any association or increased risk of prostate cancer development, prostate cancer spread or continued rise in prostate specific antigen (PSA).

We know today that frequency of prostate cancer development in men on TRT is the same as men not being treated with testosterone. There has been no association between the level of testosterone, free testosterone or DHT levels and risk of developing prostate cancer. A meta-analysis of over 19 clinical studies by Calof et. al in men with Low-T found no increased risk of prostate cancer in men being treated with testosterone compared to a group of men receiving placebo medication. Furthermore, several studies to date have investigated giving testosterone to men with a history of treated prostate cancer and observe any increased risk of recurrence as a result of testosterone supplementation. Several studies have found no increased risk of PSA recurrence in men treated with radiation therapy, brachytherapy or surgical radical prostatectomy.

Prostate: Testosterone Saturation Model

The Prostate: Testosterone saturation model provides a reasonable scientific explanation why exogenous testosterone supplementation does not result in a rising PSA or prostate enlargement. If we consider that the body has a finite amount of androgen receptors in the body, then we can also conclude that there is testosterone level in which all these androgen receptors are saturated. Any rise in testosterone above this level in which all androgen receptor are saturated would not exert any further effect on prostate growth or rise in PSA. The prostate: testosterone saturation model theory predicts that PSA and prostate tissue are stimulated and sensitive to exogenous testosterone at low testosterone levels. Several studies have revealed that testosterone is maximally bound to all receptors at testosterone concentrations of 60-90ng/dL. This means that men with low testosterone levels who receive testosterone supplementation may experience a slight rise in their PSA or prostate growth until this threshold is met. Any testosterone level above this level does not stimulate the prostate any further. This theory has been supported by several studies, but of note some prostate cancers that may not adhere to such principles.

Low Testosterone is an Independent risk factor for Prostate Cancer.

It is a common practice in urology when screening a man for prostate cancer with a digital rectal examination and PSA level to also include a testosterone level. There is a significant association between a low testosterone level and an increased detection of prostate cancer and unfavorable pathology on prostate biopsy. As thus men who present for TRT and are above the age of 40, a PSA level should be coordinated with the testosterone level to ascertain any increased risk of prostate cancer.

A study by Pichon et. al. revealed that a low serum testosterone level was an independent risk factor for upgrading prostate cancer stage after radical prostatectomy. From the San Francisco et. al. study, men on active surveillance (active monitoring of diagnosed low grade prostate cancer) with low serum testosterone levels at a higher risk (x4) of being upstaged.

Testosterone Replacement Therapy (TRT) is safe even with a History of Prostate

As reported the American Urologic Association 2018 annual meeting, men with a history of prostate cancer who undergo testosterone supplementation do not have an increased risk of prostate cancer recurrence. Several studies have looked at men with a history of prostate cancer treated by radical prostatectomy, and found no significant rise in PSA or recurrence of prostate cancer when these men underwent testosterone replacement therapy post operatively. This also holds true for men who underwent radiation or brachytherapy for prostate cancer, no increased risk of recurrence or significant rise in PSA when undergoing testosterone injections.

Urologist have long been giving patients testosterone therapy even after being diagnosed and treated for prostate cancer. To date, there are approximately a total of 9 published studies on TRT in men after treatment for prostate cancer. Only 10 men or 2.8% of men, were noted to have biochemical recurrence. Furthermore, a study by Moregentaler et. al published in the 2011 Journal of Urology looked at men with untreated prostate cancer who were given testosterone therapy found

- No significant changes in PSA

- No change in prostate volume

- No prostate cancer progression

- No cancer identified in 54% of follow up biopsies.

There is now basic science data that testosterone may even be protective against prostate cancer.

FDA Label

Worsening of Benign Prostate Hyperplasia (BPH) and Potential Risk of Prostate Caner

o Patients with BPH treated with androgens are an increased risk for worsening of signs and symptoms of BPH. Monitor patients with BPH for worsening signs and symptoms.

o Patients treated with androgens may be at increased risk for prostate cancer. Evaluate patients for prostate cancer prior to initiating and during treatment with androgens.

o Androgen 1% is contraindicated in men with carcinoma of the breast or known or suspected carcinoma of the prostate.

Of note: There is not a single study that shows that men on T therapy have a worsening of their BPH symptoms. On the contrary there are studies that show improvement in urinary flow and symptoms of BPH of men on androgen therapy.

AUA Guidelines

Clinicians should inform patients of the absence of evidence linking testosterone therapy to development of prostate cancer.

Patients with testosterone deficiency and a history of prostate cancer should be informed that there is inadequate evidence to quantify the risk-benefit ratio of testosterone therapy.

According to the American Urologic Association guidelines, “while the FDA retains a warning regarding the potential risk of prostate cancer in patients who are prescribed testosterone products, there is accumulating evidence against the link between testosterone therapy and prostate cancer development.”

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Sources

Ronny et. al. Testosterone and the Prostate. Journal of Sexual Medicine. Vol. 2, Issues 3-4, P112-120. Pub. October 2014

Khera et al. Testosterone Replacement in Men Treated and Untreated Prostate Cancer. Journal of Sexual Medicine. Vol. 1. Pages 143-149. Pub. 2013

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Yasmin AA et al. World J Urology. 2008; 26(4): 359-364

Huggins C. Effect of orchiectomy and irradiation on cancer of the prostate. Ann Surg 1942; 115: 1192–200

Yano M, Imamoto T, Suzuki H et al. The clinical potential of pretreatment serum testosterone level to improve the efficiency of prostate cancer screening. Eur Urol 2007; 51: 375–80

Pichon A, Neuzillet Y, Botto H, Raynaud JP, Radulescu C, Molinie V, Herve JM and Lebret T. Preoperative low serum testosterone is associated with high-grade prostate cancer and an increased Gleason score upgrading. Prostate Cancer Prostatic Dis. 2015; 18:382-387.