Androgen Deprivation Therapy (ADT) treats prostate cancer by suppressing male hormones, known as androgens, that fuel cancer growth. Prostate cancer cells frequently depend on androgens, primarily testosterone, to survive and proliferate. By drastically reducing these hormone levels, ADT aims to shrink the tumor or slow its progression. This systemic treatment is utilized across various stages of prostate cancer management. The goal is to achieve “castration,” meaning testosterone levels are lowered to a minimal threshold, typically below 50 ng/dL.
The Biological Mechanism of ADT
Prostate cancer cells possess androgen receptors, proteins that bind to circulating androgens like testosterone and dihydrotestosterone (DHT). Once bound, the androgen-receptor complex moves into the cell’s nucleus, activating genes that promote cell growth and survival. This hormone dependence makes ADT an effective strategy for controlling the disease.
The core principle of ADT is to disrupt this signaling pathway by blocking the supply of androgens. The testes are the main source, producing approximately 95% of the body’s total androgens. ADT suppresses the production of testicular androgens, drastically lowering circulating testosterone levels.
When androgen levels fall to castrate levels, cancer cells are deprived of their necessary fuel. This deprivation leads to the death or dormancy of the cancer cells, resulting in tumor shrinkage or slowed growth. However, cancer cells can eventually evolve to survive and multiply even in the low-androgen environment, a condition known as castration-resistant prostate cancer.
Methods Used to Achieve Androgen Deprivation
Androgen deprivation is achieved through chemical and physical methods targeting the hormone production axis. The most common pharmacological options modulate the Luteinizing Hormone-Releasing Hormone (LHRH), also known as Gonadotropin-Releasing Hormone (GnRH). These agents have largely replaced surgical castration.
LHRH agonists initially stimulate the pituitary gland, causing a temporary surge in Luteinizing Hormone (LH) and a brief spike in testosterone, known as a “flare.” Continuous exposure to the agonist desensitizes pituitary receptors, leading to profound suppression of LH and a sustained drop in testosterone. To prevent the temporary flare from worsening symptoms, an antiandrogen drug is often given concurrently for the first few weeks.
LHRH antagonists operate differently by immediately blocking LHRH receptors on the pituitary gland. This direct blockade prevents the release of LH and Follicle-Stimulating Hormone (FSH), achieving a rapid reduction in testosterone without the initial hormone flare. This rapid reduction is advantageous for patients with advanced symptoms, such as spinal cord compression, where a testosterone surge is risky.
Other Methods
Antiandrogens, such as bicalutamide, do not stop testosterone production but block androgen receptors on cancer cells, preventing androgens from binding. These are often used in combination with LHRH agents for a more complete blockade of the androgen signaling pathway. Surgical orchiectomy, the removal of the testes, is a permanent physical method that achieves an immediate and sustained reduction in testosterone levels.
Clinical Scenarios for ADT Use
ADT is used in various clinical situations, with goals depending on the stage of prostate cancer. For men with advanced or metastatic disease, ADT serves as the primary systemic treatment to control widespread cancer and alleviate complications like bone pain. In this setting, the goal is long-term disease control and prolonged life.
ADT is also utilized in conjunction with radiation therapy for men with localized, high-risk, or intermediate-risk disease. When given before, during, or after radiation, hormonal therapy enhances the effectiveness of the radiation by shrinking the tumor and making cancer cells more susceptible to damage. This is termed neoadjuvant or adjuvant use, depending on the timing relative to the primary local treatment.
In cases of biochemical recurrence, where Prostate-Specific Antigen (PSA) levels begin to rise after initial treatment, ADT suppresses the hormone-dependent microscopic disease. PSA level is a measurable marker used to track the effectiveness of ADT. For some patients, doctors may recommend intermittent ADT, cycling the treatment on and off based on PSA levels, to provide periods of relief without compromising long-term control.
Managing Common Treatment Effects
The reduction in male hormones leads to a predictable range of treatment effects, as androgens influence many bodily systems.
Hot Flashes
One frequently reported effect is vasomotor flushing, commonly known as hot flashes, affecting up to 80% of men on ADT. These sudden feelings of intense warmth are caused by the disruption of the hypothalamic thermoregulatory center due to low testosterone. Management includes simple behavioral modifications like using a fan or drinking cold beverages. If symptoms are persistent, medical interventions like gabapentin or hormonal agents may be prescribed to reduce frequency and severity.
Fatigue and Muscle Loss
Fatigue is a pervasive symptom, often compounded by associated anemia and loss of muscle mass. A management strategy for fatigue is the implementation of a supervised exercise program, as physical activity improves ADT-related fatigue and cognitive function. Regular weight-bearing and resistance exercise is also important for combating the loss of lean body mass and strength.
Metabolic Changes
The body’s metabolic profile shifts dramatically with ADT, often leading to weight gain, increased body fat, and a higher risk for insulin resistance and cardiovascular issues. Patients should be monitored for changes in cholesterol and triglyceride levels. Dietary counseling is important for managing weight and reducing cardiovascular risk, and medications like metformin and statins can mitigate these metabolic changes.
Bone Health
Bone health is a serious concern, as the loss of androgens accelerates the thinning of bones, increasing the risk of osteoporosis and fractures. Men on ADT are more likely to develop a significant bone deficiency compared to those not on the therapy. Maintaining bone density requires adequate supplementation with calcium and Vitamin D, along with regular bone density monitoring via DEXA scans. Bone-targeted therapies, such as bisphosphonates or denosumab, may be prescribed to prevent bone loss and reduce fracture risk.
Neuropsychological Effects
ADT can also have neuropsychological effects, including mood swings, depression, and changes in cognitive function. The reduction in testosterone affects mood regulation. Patients should report any persistent changes in emotional well-being to their care team, as addressing these changes may require formal psychological support or antidepressant medications.