What are the side effects of Androgen Deprivation Therapy (ADT) in a male patient, likely in his 60s or older, with a diagnosis of prostate cancer?

Side Effects of Androgen Deprivation Therapy for Prostate Cancer

Androgen deprivation therapy causes a broad spectrum of adverse effects across multiple organ systems, including universal sexual dysfunction, vasomotor symptoms in 80% of patients, rapid bone loss with 2-5 fold increased fracture risk, metabolic complications including diabetes and cardiovascular events, anemia, and neuropsychiatric effects—all requiring proactive monitoring and management. 1, 2

Sexual and Reproductive Effects

• Loss of libido and erectile dysfunction occur universally due to testosterone suppression 2
• Shrinkage of penis and testicles develops as a direct consequence of androgen deprivation 2
• These effects are physiologic consequences of decreased testosterone and should be anticipated in all patients 3

Vasomotor Symptoms

• Hot flashes and flushing occur in approximately 80% of men on ADT 2
• Evidence-based treatments with moderate efficacy include venlafaxine, medroxyprogesterone acetate, cyproterone acetate, and gabapentin in a dose-dependent manner 2, 4
• Hot flashes were reported in 55% of patients in comparative trials 3

Bone Health Complications

This represents one of the most serious complications requiring aggressive management:

• Bone mineral density decreases by 4-13% per year during ADT 2
• Clinical fractures occur at rates of 5-8% per year of therapy, representing a 2-5 fold increased risk compared to men not on ADT 2
• Orchiectomy is associated with lower fracture risk compared to LHRH agonists 1

Bone Health Management Protocol

• Obtain baseline DEXA scan before initiating therapy in men at increased risk 2
• Calculate FRAX score, considering ADT as "secondary osteoporosis" in the algorithm 2
• Prescribe supplemental calcium (1200 mg daily) and vitamin D3 (800-1000 IU daily) for all men over 50 years 2
• For high-risk patients, prescribe weekly oral alendronate 70 mg, annual intravenous zoledronic acid 5 mg, or denosumab 1

Musculoskeletal and Body Composition Changes

• Loss of muscle mass and strength (sarcopenia) develops progressively 2
• Weight gain and increased body fat occur, particularly subcutaneous rather than visceral fat accumulation 1, 2
• Fat mass increases significantly while lean body mass decreases 5
• Upper body strength is significantly reduced compared to non-ADT patients 5
• Resistance and aerobic exercise have proven efficacy in mitigating muscle loss 4

Cardiovascular and Metabolic Effects

The evidence on cardiovascular risk is mixed but concerning:

• Men treated with ADT had a 17% increase in cardiovascular-related mortality in systematic reviews 1
• Short-term ADT use is associated with shortened time to fatal myocardial infarction in men aged 65 years or older 1
• However, pooled analysis of 4,141 patients showed cardiovascular death was not significantly different in some trials 1
• Increased risk of myocardial infarction, sudden cardiac death, and stroke has been reported with GnRH agonists 3
• Orchiectomy is associated with lower risk of cardiac-related complications compared to LHRH agonists 1

Metabolic Syndrome Components

• Insulin resistance and increased risk for diabetes develop during therapy 2, 3
• Hyperglycemia may represent new-onset diabetes or worsening glycemic control 3
• Alterations in lipid profiles occur, including changes in high-density lipoprotein levels 1, 2
• Obesity and decreased insulin sensitivity are common 1

Monitoring Protocol

• Follow USPSTF guidelines for cardiovascular risk factor screening, blood pressure monitoring, lipid profiles, and serum glucose testing 1
• Monitor blood glucose and/or HbA1c periodically in patients receiving GnRH agonists 3
• Monitor for symptoms and signs of cardiovascular disease according to current clinical practice 3

Hematologic Effects

• Anemia develops as a normochromic normocytic anemia due to the well-known effect of androgens on erythropoiesis 1, 2
• Perform annual complete blood count to monitor hemoglobin levels 1, 2
• Anemia was reported in 5% of patients in comparative trials 3
• Evaluate anemia with focus on potential causes other than ADT 1
• No convincing data support routine treatment of asymptomatic anemia in men receiving ADT 1

Neuropsychiatric Effects

• Depression and mood disturbances occur, particularly in men with a history of depression 2
• Assess for distress/depression/PSA anxiety at least annually using screening tools such as the Distress Thermometer 1, 2
• Manage distress/depression using in-office counseling resources or pharmacotherapy as appropriate 1
• If office-based counseling is insufficient, refer for further evaluation by appropriate specialists 1
• Anxiety, mood swings, nervousness, and memory disorders have been reported 3
• Overall quality of life scores are lower, with significant limitation of physical function, role limitation, and perception of physical health 5

Cardiac Conduction Effects

• ADT may prolong the QT/QTc interval 3
• Consider whether benefits outweigh risks in patients with congenital long QT syndrome, congestive heart failure, frequent electrolyte abnormalities, and those taking QT-prolonging drugs 3
• Electrolyte abnormalities should be corrected 3
• Consider periodic monitoring of electrocardiograms and electrolytes 3

Additional Common Side Effects

• Gynecomastia/breast tenderness or pain occurs in 7% of patients on leuprolide (63% with DES comparator) 3
• Tamoxifen or prophylactic radiation have proven efficacy for gynecomastia 4
• Peripheral edema occurs in 12% of patients 3
• Asthenia (weakness) occurs in 10% of patients 3
• Decreased testicular size occurs in 7% of patients 3
• Fatigue is common 5

Critical Clinical Caveats

• Patients with metastatic vertebral lesions and/or urinary tract obstruction should be closely observed during the first few weeks of therapy due to risk of tumor flare 3
• Temporary worsening of bone pain, hematuria, and urinary obstruction can occur during the first week due to transient testosterone increase 3
• Temporary weakness and paresthesia of lower limbs have been reported 3
• Patients with known allergies to benzyl alcohol may present with hypersensitivity reactions 3
• Symptoms consistent with anaphylactoid or asthmatic process have been rarely reported (incidence ~0.002%) 3