What are the potential side effects of hormone therapy, such as leuprolide (Lupron) or goserelin (Zoladex), in older adult males with prostate cancer?

Side Effects of Hormone Therapy for Prostate Cancer

Hormone therapy for prostate cancer causes a broad spectrum of adverse effects that significantly impact morbidity and quality of life, with the most concerning being cardiovascular disease, metabolic complications, bone loss, and sexual dysfunction—all stemming from androgen deprivation. 1

Common and Expected Side Effects

Sexual and Vasomotor Effects

• Hot flashes occur in approximately 46% of patients and represent the most frequently reported symptom 1
• Sexual dysfunction including diminished libido and erectile dysfunction affects the majority of patients 1
• These effects are direct consequences of testosterone suppression and occur regardless of the specific GnRH agonist used 2

Metabolic and Cardiovascular Complications

• Weight gain, obesity, and diabetes risk increases substantially with androgen deprivation therapy 1
• Insulin sensitivity decreases by 12.9% within just 12 weeks of treatment with leuprolide and bicalutamide 3
• Cardiovascular disease risk is elevated, though newer agents like relugolix show significantly lower risk of major cardiovascular events (HR 0.46) compared to leuprolide 1
• Fasting insulin levels increase by 25.9% and glycosylated hemoglobin rises significantly within 12 weeks 3

Musculoskeletal Effects

• Osteoporosis develops due to androgen deprivation, increasing fracture risk 1
• Loss of muscle strength and mass (sarcopenia) occurs and contributes to frailty 1
• This muscle loss specifically increases fall risk in older men, compounding fracture risk 1
• Fat body mass increases by 4.3% within 12 weeks of treatment 3

Hematologic Effects

• Anemia develops and contributes to overall fatigue 1

Breast Changes

• Breast enlargement and/or tenderness (gynecomastia) occurs commonly 1

Neuropsychiatric and Cognitive Effects

Emotional and Psychological Changes

• Emotional changes including anger, sadness, and generalized fatigue are common 1
• Clinical depression may occur or worsen during treatment, particularly in women with a history of depression 2
• Psychotic disorders, mood swings, suicidal ideation and attempt have been reported, especially in women 2

Cognitive Impairment

• Cognitive changes including impaired thought processes and memory loss occur 1
• These effects are more subtle than sexual dysfunction but can significantly impact quality of life 1

Serious and Life-Threatening Complications

Tumor Flare Phenomenon

• Initial testosterone surge occurs with GnRH agonists like goserelin and leuprolide 2
• A small percentage of patients experience temporary worsening of symptoms, manifested by increased cancer-related pain 2
• Ureteral obstruction or spinal cord compression can occur, though at similar rates to orchiectomy 2

Cardiovascular Events

• Arrhythmia, cerebrovascular accident, hypertension, myocardial infarction, and peripheral vascular disorder occur in 1-5% of patients 2
• Ischemic heart disease occurs more frequently with apalutamide (4.4% vs 1.5% with placebo) 1
• QT/QTc interval prolongation may occur, requiring consideration of risk-benefit ratio in patients with congenital long QT syndrome, congestive heart failure, or frequent electrolyte abnormalities 2

Injection Site Complications

• Injection site injury and vascular injury including pain, hematoma, hemorrhage, and hemorrhagic shock requiring blood transfusions and surgical intervention have been reported with goserelin 2
• Extra care is needed in patients with low BMI or those receiving full-dose anticoagulation 2

Less Common but Notable Side Effects

Gastrointestinal Effects

• Diarrhea occurs in 36-40% of patients receiving combination therapy with radiation 1, 2
• Nausea affects approximately 9% of patients 1
• Constipation, ulcer, and vomiting occur in 1-5% of patients 2

Genitourinary Effects

• Renal insufficiency, urinary obstruction, and urinary tract infection occur in 1-5% of patients 2

Other Reported Effects

• Skin rash affects approximately 8% of patients 1
• Sweating occurs in 6% of patients 2
• Insomnia and dizziness each affect 5% of patients 2
• Unusual lipodystrophy with abnormal fat deposition has been reported in at least one case, potentially compromising upper limb mobility 4

Monitoring and Management Considerations

Required Monitoring

• Serial PSA every 3-6 months and conventional imaging every 6-12 months during therapy 5
• Baseline and periodic monitoring of testosterone, LDH, hemoglobin, alkaline phosphatase, and thyroid function 5
• Blood pressure monitoring for hypertension 5
• Electrocardiogram and electrolyte monitoring should be considered periodically, especially in high-risk patients 2

Critical Management Points

• Bone health attention is warranted given the increased fracture risk 1
• Growth factor support should be considered in patients ≥65 years receiving docetaxel to decrease neutropenic complications 1
• Electrolyte abnormalities should be corrected before and during treatment 2
• Concurrent ADT must be maintained during treatment with newer hormonal agents 5

Comparative Considerations Between Agents

• Goserelin and leuprolide show similar efficacy and tolerability profiles, though there are significant differences in endocrine response patterns in the first 4 weeks 6, 7
• Relugolix demonstrates reduced cardiovascular toxicity compared to leuprolide (HR 0.46 for major CV events) 1
• The side effect profiles are largely class effects related to androgen deprivation rather than agent-specific differences 1