The Double-Edged Sword of Androgen Deprivation Therapy
Patients living with advanced prostate cancer suffer from losses in muscle mass, physical function, and overall quality of life. Androgen deprivation therapy is the most effective treatment for advanced disease. By lowering testosterone levels, it slows disease progression and prolongs survival. Yet for many patients, this benefit comes with a substantial toll on the body. Fatigue increases, exercise tolerance declines, daily activities become harder, and patients lose muscle, gain fat mass, and experience a marked reduction in physical function and quality of life.
The biological reason behind these changes is still not fully understood. We know patients lose muscle and feel more fatigued, but the deeper story inside the muscle has remained largely unexplored. We focused on the mitochondria, the “powerhouse” that give muscles their ability to produce energy. Despite their central role in muscle health, they have scarcely been examined in men with prostate cancer undergoing ADT. We wanted to move beyond simply measuring how much muscle patients lose and instead understand how healthy the muscle was. We followed men through their first six months of ADT, measuring how their muscle mass, strength, endurance, mitochondrial health, and quality of life shift over time. Our hope was to elucidate why some patients decline more than others and to identify the biological signals that might help guide therapeutic intervention development and choose adequate clinical trial endpoints.
Beyond Muscle Mass
Muscle mass has been thought to reflect muscle health and overall function. Yet studies show that gains in mass don’t necessarily lead to improvements in function or patient reported quality of life. This mismatch is important, especially because regulatory agencies prioritize outcomes that reflect how a patient feels or functions, or survives, not just changes in mass. To better reveal what truly drives decline during ADT, we examined how muscle biology, physical performance, and quality of life are related, with a particular focus on the mitochondrial function.
One of the first surprises emerged prior to starting ADT. Muscle mass was related to measures of strength, but it had no relationship with endurance. And those with more muscle mass reported worse symptoms and lower quality of life. In contrast, those with better endurance, and healthier mitochondria, consistently felt and functioned better.
Predicting The Decline
Following patients through six months of ADT revealed that muscle mass declined and many measures of physical function and quality of life worsened with this treatment. But not everyone declined to the same degree. What separated those who remained resilient from those who lost the most muscle mass and function and had their QOL worsened?
Baseline mitochondrial function and muscle endurance stood out. Patients who began therapy with higher mitochondrial function and better aerobic capacity experienced smaller declines in endurance, muscle mass, and patient‑reported outcomes. In other words, mitochondrial health appeared to predict vulnerability to treatment related decline.
A Molecular Signature of Dysfunction
To further comprehend the biology behind these changes, we analyzed skeletal muscle proteomics before and after ADT. The muscle proteome showed widespread remodeling. Pathways related to mitochondrial function and oxidative metabolism were among the most strongly downregulated after ADT. Pathways involved in extracellular matrix remodeling, inflammation, immune signaling, and coagulation became increasingly activated. Moreover, the patients who declined the most clinically were the same individuals who showed the greatest suppression of mitochondrial pathways and the strongest activation of inflammatory and remodeling programs. ADT wasn’t just reducing the muscle, it was remodeling it.
Why it Matters
These findings are deeply relevant to patients because they reflect how they feel and function each day. Fatigue, reduced endurance, and loss of physical capacity influence their independence, mobility, and overall well‑being, and while ADT is essential for treating their cancer, it can also intensify the symptoms that make daily life more challenging.
Looking Forward
Many questions remain. Can interventions that target mitochondria preserve physical function and quality of life during ADT? Could mitochondrial measurements help identify high‑risk patients before the decline occurs? Future studies will be needed to answer these questions. But collectively, our findings suggest that mitochondrial function relates to better endurance and patient reported outcomes and may help identify those who are most vulnerable.