What are the side effects of Androgen Deprivation Therapy (ADT)?

Side Effects of Androgen Deprivation Therapy

Androgen deprivation therapy causes a broad spectrum of adverse effects that significantly impact morbidity and quality of life, including sexual dysfunction, metabolic complications, bone loss with increased fracture risk, cardiovascular effects, and vasomotor symptoms—all of which require proactive monitoring and management. 1

Sexual and Reproductive Effects

ADT profoundly affects sexual health through multiple mechanisms:

• Loss of libido and erectile dysfunction occur universally due to testosterone suppression 1, 2
• Shrinkage of penis and testicles develops as a direct consequence of androgen deprivation 1
• Infertility results from suppression of spermatogenesis 2
• These effects are often distressing to patients and may not be reversible even with treatment cessation 3

Vasomotor Symptoms

Hot flashes represent one of the most common and bothersome side effects:

• Hot flashes and flushing occur in approximately 80% of men on ADT 1, 2
• These symptoms may persist throughout the duration of therapy and often do not abate 3
• Evidence-based treatments include venlafaxine, medroxyprogesterone acetate, cyproterone acetate, and gabapentin (with moderate efficacy in a dose-dependent manner) 1, 4, 3

Musculoskeletal and Body Composition Changes

ADT causes significant alterations in body composition with metabolic consequences:

• Loss of muscle mass and strength (sarcopenia) develops progressively 1
• Weight gain and increased body fat occur, particularly subcutaneous rather than visceral fat accumulation 1
• Fatigue is a common complaint that impacts quality of life 1, 2
• Combined resistance and aerobic exercise programs significantly improve fatigue, muscle loss, and metabolic parameters 4

Bone Health Complications

Bone loss represents one of the most serious long-term complications of ADT:

• Osteoporosis develops rapidly, with bone mineral density decreasing by 4% to 13% per year during ADT 1, 5
• Clinical fractures occur at rates of 5% to 8% per year of therapy, representing a 2-fold to 5-fold increased risk compared to men not on ADT 1, 5
• Bone loss is most rapid during the initial year of treatment, with rates as high as 4.6% in the total hip, femoral neck, and lumbar spine 1

Bone Health Management Protocol

All men starting ADT require baseline assessment and preventive therapy:

• Obtain baseline DEXA scan before initiating therapy in men at increased risk 1
• Calculate FRAX score (considering ADT as "secondary osteoporosis" in the algorithm) 1
• Prescribe supplemental calcium (1200 mg daily) and vitamin D3 (800-1000 IU daily) for all men over 50 years 1
• Initiate pharmacologic therapy when 10-year probability of hip fracture is ≥3% or major osteoporosis-related fracture is ≥20% 1

Treatment options for bone protection include:

• Denosumab 60 mg subcutaneously every 6 months (FDA-approved for men on ADT at increased risk of osteoporosis) 1
• Zoledronic acid 5 mg intravenously annually 1
• Alendronate 70 mg orally weekly 1
• Follow-up DEXA scan after 1 year of therapy is recommended 1

Metabolic and Cardiovascular Effects

ADT induces multiple metabolic changes that increase cardiovascular risk:

• Insulin resistance and increased risk for diabetes develop during therapy 1
• Alterations in lipid profiles occur, including changes in high-density lipoprotein levels 1
• Obesity and metabolic syndrome may develop through decreased insulin sensitivity and altered fat distribution 1
• Hypertension requires monitoring as a specific ADT-related risk 1

Cardiovascular Risk Considerations

The cardiovascular impact of ADT remains somewhat controversial:

• Some studies show a 17% increase in cardiovascular-related mortality in men treated with ADT 1
• Short-term ADT use has been associated with shortened time to fatal myocardial infarction in men aged 65 years or older 1
• However, pooled analysis of 4,141 patients from 8 randomized trials showed no significant difference in cardiovascular death between ADT and control groups 1
• Follow USPSTF guidelines for cardiovascular risk factor screening, blood pressure monitoring, lipid profiles, and serum glucose testing 1
• Metformin coupled with lifestyle intervention represents a safe, well-tolerated option for adverse metabolic changes 4

Hematologic Effects

• Anemia develops as a consequence of testosterone suppression 1
• Perform annual complete blood count to monitor hemoglobin levels in men receiving ADT 1

Dermatologic and Other Physical Changes

• Hair loss may occur during ADT 1
• Gynecomastia and breast tenderness are common side effects 5
• Tamoxifen or prophylactic radiation can prevent gynecomastia 6, 4

Neuropsychiatric Effects

ADT affects mental health and cognitive function:

• Depression and mood disturbances occur, particularly in men with a history of depression 1
• Men with preexisting depression are more likely to develop major depressive disorder during ADT 1
• Cognitive function changes may develop, though combined exercise programs can improve cognitive function 4
• PSA anxiety is common among survivors, with symptoms presenting weeks prior to anticipated testing 1
• Assess for distress/depression/PSA anxiety at least annually using screening tools such as the Distress Thermometer 1

QT Interval Prolongation

• ADT may prolong the QT interval, requiring monitoring for signs and symptoms of this cardiac conduction abnormality 2
• Patients should be counseled to immediately report symptoms suggestive of QT prolongation 2

Duration-Dependent Effects

A critical consideration is that many side effects of continuous ADT are cumulative over time:

• Side effects increase with duration of treatment 1
• Intermittent ADT may reduce early side effects such as hot flashes, sexual activity impairment, and fatigue, though effects on long-term complications remain inconclusive 1, 4

Clinical Pitfalls and Monitoring Recommendations

Patients and providers must be counseled about these risks prior to initiating treatment 1. The best prevention strategy is to use ADT only when absolutely indicated 4. However, when ADT is necessary for cancer control, systematic monitoring and proactive management of side effects are essential to minimize treatment-related morbidity and maintain quality of life.