When it comes to men and women, the French declare “Vive la difference!” Long live the difference, which is heavily based in our body’s biochemistry, especially hormones. The primary androgen (male hormone) that makes men MEN is testosterone, and healthy masculinity is certainly worth celebrating. However, when it comes to prostate cancer (PCa), there’s a down side to testosterone. The normal prostate cells that mutate into cancer capitalize on testosterone to fuel their own selfish purposes.

This is especially dangerous if PCa recurs beyond the prostate capsule after localized treatment, or a man is diagnosed with PCa after disease extension. The PCa is then poised to spread in the near vicinity of the prostate capsule (the surrounding tissue and nearby lymph nodes) and eventually develop remote spread (metastasis) into the bone and other organs.

Hormone therapy

When PCa is detected beyond the gland, it is considered incurable, but it can be halted for a period of time. The conventional treatment involves depriving the marauding cells of testosterone, which initially stops PCa in its tracks. This is a systemic therapy that washes through a man’s body instead of (or in addition to) performing a tumor-focused procedure. There are several pharmaceuticals that accomplish this by either switching off the supply of testosterone (e.g. Lupron, Zoladex), and/or blocking cell receptors from taking it up even when it’s present (e.g. Casodex, Eulexin). Collectively, this is called androgen deprivation therapy or ADT; it is often simply called hormone therapy.

The side effects of ADT and their negative impact on quality of life are well documented—but there is no doubt that ADT can extend life until the cancer eventually “outsmarts” it. During ADT, patients experience physical problems: loss of libido, hot flashes, breast tenderness, loss of muscle tone/weakness, loss of bone density, erectile dysfunction, changes in blood lipids, insulin resistance, etc. Emotionally, men may undergo mood swings, suffer from depression, cry easily, etc. Also documented, but less well understood, is a correlation between ADT and cognitive dysfunction.

ADT and dementia risk

During the most recent five years, there have been a number of studies trying to answer the question, can being on ADT lead to dementia, even Alzheimer’s? The data points to a relationship, but is it causal? After all, many PCa patients are already at an age where cognitive function may be on the decline simply from getting older. Or they may have co-existing conditions such as poor cardiovascular function or stroke risk, so it’s a knotty problem to sort out the cause of diminished memory, declining judgement and decision-making, fuzzy thinking, and other hallmarks of age-related mental failing. A majority of experts believe that PCa patients should be advised of this risk before going on ADT, and some even suggest that for patients who already have diagnosed dementia or Alzheimer’s, ADT may not be advised.

New antiandrogens

Newer drugs called novel antiandrogens target androgen receptors on PCa cells have been able to add months or even years to patient lives, even when remote metastasis exists. The main ones are

• Xtandi (enzalutamide)
• Zytiga (abiraterone)
• Erleada (apalutamide)
• Nubeqa (darolutamide)

Each of them can affect the central nervous system (CNS), with sporadic reported adverse events such as falls (Zytiga, Xtandi), and in clinical trials Nubeqa had a comparable rate of cognitive problems to ADT alone.[i] A December, 2019 article reported a meta-analysis of 33 papers published between 2000-08 that explored the relationship between ADT (especially the novel antiandrogens) and mental function.[ii] It was a challenge. According to the authors, “Some studies suggested a clear association between ADT and CNS effects in men with [PCa}, whereas others did not. Accurate assessment is limited by test instrument variability, inadequate sample sizes, short follow-up duration, and limited prospective longitudinal studies.” In other words, there were no standardized universal testing measures of cognition, study enrollment was too small to power conclusions, follow-up was too short, and many of them were based on existing records instead of a new study designed from scratch.

Nonetheless, what the authors did find concerned them. In an interview, lead author Charles Ryan, MD remarked, “Novel AR-targeted drugs may be an issue. We think only a fraction of the men who experience cognitive impairment report it.”[iii] The human mind is at the core of what we experience as quality of life. Our attitudes, beliefs, thoughts, philosophy of life, values, preferences—all these aspects of mental function and more—are precious. Losing even a fraction of one’s mind diminishes quality of life as much as physical discomforts and emotional seesaws. Their paper reminds us that medicines designed to extend life may come at a price. Patients need to know the possible trade-offs of ADT so they and their doctors can make informed decisions on how best to help them keep their minds.

NOTE: This content is solely for purposes of information and does not substitute for diagnostic or medical advice. Talk to your doctor if you have health concerns or questions of a personal medical nature.

References

[i] Schieszer, J. “Novel Antiandrogens and Cognitive Function.” Prostate Cancer Advisor/Renal & Urology News, Jan. 28, 2020. https://www.renalandurologynews.com/home/news/urology/prostate-cancer/enzalutamide-abiraterone-cognition/
[ii] Ryan, C, Wefel, JS, Morgans, AK et al. A review of prostate cancer treatment impact on the CNS and cognitive function [published online December 16, 2019]. Prostate Cancer Prostatic Dis. doi: 10.1038/s41391-019-0195-5
[iii] Schieszer, Ibid.