Androgen deprivation therapy (ADT) is a treatment for prostate cancer that works by drastically reducing levels of testosterone and other male hormones (androgens) in the body. Because prostate cancer cells rely on androgens to grow, cutting off that fuel supply can slow or shrink tumors. ADT is a cornerstone of treatment for advanced prostate cancer, and it’s also used alongside radiation or surgery in earlier stages to improve outcomes.
How ADT Stops Cancer Growth
Prostate cells, both healthy and cancerous, have androgen receptors on their surface. When testosterone binds to these receptors, it activates genes that tell the cells to multiply. ADT interrupts this process in one of three ways: stopping the body from making testosterone, blocking testosterone from reaching cancer cells, or both.
The testicles produce the vast majority of testosterone, so most forms of ADT target them directly or shut down the brain signals that tell them to work. A smaller amount of androgens comes from the adrenal glands and even from prostate tumor tissue itself. Some newer treatments block production at all three sources by disabling an enzyme the body needs to manufacture testosterone.
Types of ADT
There are several ways to achieve androgen deprivation, and they differ in how they’re administered, how quickly they work, and what side effects they carry.
Surgical Removal of the Testicles
Orchiectomy is the most direct approach. Removing both testicles drops blood testosterone levels by 90% to 95%. It’s permanent, works immediately, and doesn’t require ongoing medication. For some patients, the permanence is a drawback; for others, it’s the simplicity that appeals.
LHRH Agonists
These are the most commonly used medications for ADT. They work by overstimulating the pituitary gland (which normally signals the testicles to produce testosterone) until it essentially burns out and stops sending that signal. They’re given as injections, typically in depot formulations that last one, three, or six months.
One important caveat: LHRH agonists cause a temporary spike in testosterone before levels crash. This initial “flare” can briefly worsen symptoms, particularly bone pain in men with metastatic disease. To prevent this, doctors often prescribe a short course of an antiandrogen medication for the first few weeks.
LHRH Antagonists
These drugs block the pituitary signal directly, without the initial testosterone surge. Testosterone drops rapidly from the first dose. They’re a better option for men whose cancer has spread and who can’t afford any temporary worsening of symptoms. Antagonists have historically been available only as monthly injections, though newer oral formulations have expanded the options.
Antiandrogens
Rather than reducing testosterone production, antiandrogens block the hormone from attaching to receptors on cancer cells. They’re often used in combination with other forms of ADT rather than alone. Second-generation antiandrogens are significantly more potent than older versions and have become central to modern treatment regimens.
Androgen Synthesis Inhibitors
These medications shut down testosterone production throughout the body, not just in the testicles. They block an enzyme called CYP17 that’s active in testicular, adrenal, and tumor tissue. This makes them useful when cancer continues to progress despite standard ADT, because they eliminate the small but meaningful androgen production that happens outside the testicles.
When ADT Is Recommended
ADT plays different roles depending on how advanced the cancer is. For men with metastatic hormone-sensitive prostate cancer (cancer that has spread but still responds to hormone manipulation), ADT is a strong recommendation from major guidelines. It’s rarely used alone in this setting. Instead, it’s typically combined with a second-generation antiandrogen or chemotherapy, because combination therapy significantly improves survival. Clinical trials have shown that adding potent antiandrogens to standard ADT reduces the risk of death by roughly a third compared to ADT alone.
For men whose PSA is rising after surgery or radiation but who have no visible metastases on imaging, the situation is less clear-cut. Guidelines generally favor observation over rushing into ADT, because the side effects are substantial and the cancer may take years to become clinically significant. If ADT is started in this scenario, intermittent therapy (cycling on and off) is a reasonable alternative to continuous treatment.
Men whose cancer has become castration-resistant, meaning it progresses despite low testosterone levels, still continue ADT as a backbone while adding more targeted agents. For those without metastases but with a rapidly rising PSA (doubling time of 10 months or less), adding a second-generation antiandrogen to ongoing ADT is strongly recommended.
Continuous vs. Intermittent ADT
Intermittent ADT involves cycling between periods of treatment and treatment breaks. During the off periods, testosterone partially recovers, which can relieve some side effects and improve quality of life. The concept came from lab research showing that cycling androgens on and off actually delayed the cancer’s ability to become resistant to hormone therapy.
Meta-analyses comparing the two approaches have found no meaningful difference in prostate cancer deaths between intermittent and continuous ADT. There’s a slight trend toward fewer non-cancer deaths with intermittent therapy, likely because of reduced long-term side effects, though the difference hasn’t reached statistical significance. For many men, intermittent ADT offers a better quality of life with similar cancer control.
Side Effects of ADT
Because testosterone affects nearly every organ system, suppressing it comes with wide-ranging side effects. These aren’t rare complications; they’re expected consequences of the treatment.
Hot flashes are among the most common, affecting roughly a quarter of patients. Fatigue is even more prevalent, reported by about 36% of men in clinical studies. Many men also experience loss of libido, erectile dysfunction, and mood changes including depression and difficulty concentrating.
Bone Loss
ADT accelerates bone thinning rapidly. Bone mineral density drops by 2% to 8% in the first year alone, which is a faster rate of loss than what most postmenopausal women experience. This raises fracture risk substantially over time. Guidelines recommend a bone density scan (DEXA) at the start of ADT, with follow-up scans every two years for men who continue treatment or who already have osteoporosis. Medications that strengthen bone are often prescribed alongside ADT to counteract this effect.
Metabolic Changes
ADT shifts body composition toward more fat and less muscle, even without changes in diet or activity. It raises blood sugar levels, with hyperglycemia affecting about 15% of patients in clinical studies. Cholesterol levels often climb as well. These metabolic shifts collectively increase the risk of diabetes and cardiovascular disease over time.
Cardiovascular Risks
The link between ADT and heart disease deserves particular attention, because it’s one of the more serious long-term consequences. Large meta-analyses have found that LHRH agonists increase the risk of cardiovascular death by 36% to 38% compared to men not receiving ADT. The risk of heart attack rises by 20% to 51%, depending on the study, and stroke risk increases as well.
Not all forms of ADT carry equal cardiovascular risk. LHRH antagonists appear to be significantly safer for the heart, with one analysis finding a 56% lower risk of heart attack compared to LHRH agonists. This difference is large enough that men with pre-existing heart disease may benefit from choosing an antagonist over an agonist. Orchiectomy, somewhat counterintuitively, carries its own cardiovascular concerns, with some data suggesting a near-doubling of heart attack risk compared to combined drug approaches.
Certain add-on medications also affect heart health. Androgen synthesis inhibitors paired with steroids have been associated with higher rates of cardiac events and a roughly twofold increase in significant hypertension. For men with existing cardiovascular risk factors, these tradeoffs should factor into treatment decisions.
Exercise as a Counterbalance
Resistance training is one of the most effective tools for managing ADT’s physical side effects. A well-studied program involved supervised strength training three times per week for 12 weeks, using nine exercises targeting the major muscle groups: legs, chest, back, shoulders, and arms. Patients started at a moderate intensity (about 60% of the maximum weight they could lift once) and gradually increased the load as they got stronger.
The results were clear: resistance exercise reduced fatigue, improved muscular fitness, and boosted overall quality of life. This isn’t a marginal benefit. For men dealing with the muscle loss, tiredness, and body composition changes that ADT brings, a structured strength program directly counteracts several of the treatment’s most burdensome effects. Walking and aerobic exercise help with cardiovascular and metabolic health, but the muscle-preserving benefits of lifting weights are harder to replace with other activities.