Study Resolves Testosterone Paradox in Prostate Cancer

A treatment paradox has recently emerged for prostate cancer: Blocking testosterone production halts tumor growth in the early stages of the disease, while increasing the hormone can delay disease progression in patients with advanced disease. The inability to understand how different levels of the same hormone can have different effects on prostate tumors has been an obstacle to the development of new therapeutics that exploit this biology.

How Testosterone Levels and Prostate Cancer Are Linked

A Duke Cancer Institute-led study conducted in the laboratory of Dr. Donald McDonnell and appearing in Nature Communications now provides the necessary answers to this puzzle. The researchers found that prostate cancer cells are equipped with a system that allows them to proliferate when testosterone levels are very low. However, when the hormone level is increased to resemble that present in the normal prostate, the cancer cells differentiate. “For decades, the goal of endocrine therapy for prostate cancer has been to achieve absolute inhibition of androgen receptor function, the protein that senses testosterone levels,” said lead researcher Dr. Rachid Safi, assistant professor in the Department of Pharmacology and Cancer Biology at Duke University School of Medicine. “It was an extremely effective strategy that led to a significant improvement in overall survival,” he said. Unfortunately, most patients with advanced, metastatic disease who are treated with drugs that inhibit androgen signaling develop an aggressive form of the disease for which there are limited therapeutic options.

Using a combination of genetic, biochemical, and chemical approaches, the research team defined the mechanisms by which prostate cancer cells detect and respond differently to varying levels of testosterone, the most prevalent androgen hormone. It turns out to be fairly simple. At low androgen levels, the androgen receptor is encouraged to “act alone” within the cell. In doing so, it activates the signaling pathways that cause cancer cells to grow and spread. However, when androgens increase, the androgen receptors are forced to “act as a pair,” creating a form of the receptor that stops tumor growth.

Nature has devised a system in which low doses of the hormone stimulate cancer cell proliferation and high doses cause differentiation and growth suppression, allowing the same hormone to serve different functions. In recent years, doctors have begun treating patients with late-stage prostate cancer that has stopped responding to therapy with a monthly high-dose testosterone injection using a technique called bipolar androgen therapy (BAT). A lack of understanding of how this intervention works has prevented it from becoming a mainstream treatment for prostate cancer patients. According to the researchers, this study describes how BAT and similar approaches work and could help doctors select patients who are most likely to respond to this intervention. The scientists have already developed new drugs that utilize this new mechanism and are bringing them into the clinic for evaluation as prostate cancer therapeutics.

How Long Does it Take for Testosterone Levels to Return to Normal After Prostate Cancer Treatment?

A study led by researchers at UCLA Health Jonsson Comprehensive Cancer Center sheds light on testosterone recovery after androgen deprivation therapy (ADT) in men undergoing radiation therapy for prostate cancer, and provides important insights for optimizing patient care. Researchers found that baseline testosterone levels, age, and duration of androgen deprivation therapy are important predictors of testosterone recovery. The study, which analyzed data from five large randomized controlled trials involving 1,444 patients, shows that testosterone recovery can vary widely from person to person. The study also introduces a nomogram, a prediction tool that allows clinicians to estimate recovery times based on patient-specific characteristics.

ADT, often used in combination with radiotherapy to treat prostate cancer, significantly lowers testosterone levels, leading to side effects such as fatigue, loss of libido and mood swings that can impact patients’ quality of life. Understanding testosterone recovery after ADT is essential to improving treatment outcomes, as it allows clinicians to balance the anti-cancer benefits of testosterone suppression with its debilitating side effects. This study provides a much-needed framework for helping patients anticipate the time frame for their recovery and manage these side effects more effectively. The researchers found that recovery time is influenced by the duration of ADT treatment, with older age and lower testosterone baseline levels associated with slower recovery. They also found that for men receiving six months of ADT, maintaining low testosterone levels for approximately 11 months may lead to improved metastasis-free survival, suggesting that a longer period of suppression may be beneficial even with shorter ADT regimens.

The findings have important implications for clinical practice, particularly as newer therapies that allow for rapid testosterone recovery are increasingly being utilized. For men undergoing shorter ADT therapies, the results suggest that slower testosterone recovery, as seen with conventional therapies, may provide better cancer control.