What are the side effects and risks of Androgen Deprivation Therapy (ADT) in adult males with prostate cancer, particularly those of older age?

Side Effects and Risks of Androgen Deprivation Therapy

Androgen deprivation therapy causes a broad spectrum of serious adverse effects affecting nearly every organ system, with the most clinically significant being cardiovascular disease, fractures from osteoporosis, metabolic syndrome, sexual dysfunction, and hot flashes—all of which require proactive monitoring and management strategies. 1

Sexual and Reproductive Effects

• Loss of libido and erectile dysfunction occur universally in men receiving ADT due to testosterone suppression 1
• Shrinkage of penis and testicles develops as a direct consequence of androgen deprivation 1
• These sexual side effects are among the most distressing quality-of-life impacts and should be discussed using validated tools such as the Sexual Health Inventory for Men (SHIM) at baseline and monitored at least annually 2

Vasomotor Symptoms

• Hot flashes and flushing affect approximately 80% of men on ADT, representing one of the most common side effects 1
• Evidence-based pharmacologic treatments include venlafaxine, medroxyprogesterone acetate, cyproterone acetate, and gabapentin, all showing moderate efficacy in a dose-dependent manner 1, 3

Bone Health Complications

This represents one of the most serious morbidity risks from ADT:

• Bone mineral density decreases by 4% to 13% per year during ADT, far exceeding the rate of bone loss in normal aging 1
• 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 receiving ADT 1
• Longer treatment duration confers progressively greater fracture risk, with age and comorbidity also associated with higher fracture incidence 2

Bone Health Management Protocol

All men initiating ADT require the following systematic approach:

• 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, 2
• For men determined to be high risk, prescribe weekly oral alendronate 70 mg or annual intravenous zoledronic acid 5 mg to increase bone density; denosumab is also FDA-approved for this indication 2

Cardiovascular and Metabolic Effects

The cardiovascular risks of ADT remain controversial but clinically significant:

• A systematic review found men treated with ADT had a 17% increase in cardiovascular-related mortality compared with men who did not undergo ADT 2
• Some studies demonstrate that even short-term ADT use is associated with a shortened time to fatal myocardial infarction in men aged 65 years or older 2
• However, a pooled analysis of 4141 patients from 8 randomized trials revealed that cardiovascular death in men receiving ADT versus control was not significantly different 2
• The FDA drug label for goserelin explicitly warns of increased risk of myocardial infarction, sudden cardiac death, and stroke associated with GnRH analog use 4

Metabolic Syndrome Components

• Insulin resistance and increased risk for diabetes develop during therapy 1, 5
• Hyperglycemia and an increased risk of developing diabetes have been reported, requiring monitoring of blood glucose and/or HbA1c periodically 5, 4
• Alterations in lipid profiles occur, including increased high-density lipoprotein levels 2
• ADT may result in obesity, decline in lean mass, decreased insulin sensitivity, and subcutaneous rather than visceral fat accumulation 2, 1

Cardiovascular Monitoring Protocol

• Follow USPSTF guidelines for cardiovascular risk factor screening, blood pressure monitoring, lipid profiles, and serum glucose testing 2, 1
• Monitor patients receiving GnRH agonists for symptoms and signs suggestive of cardiovascular disease and manage according to current clinical practice 5

Musculoskeletal and Body Composition Changes

• Loss of muscle mass and strength (sarcopenia) develops progressively, contributing to frailty and increased risk for falls in older men 1, 2
• Weight gain and increased body fat occur, particularly subcutaneous rather than visceral fat accumulation 1
• ADT significantly decreases muscle mass, and treatment-related sarcopenia contributes to functional decline 2

Hematologic Effects

• Anemia is a common complication of ADT, resulting in normochromic normocytic anemia due to the well-known effect of androgens on erythropoiesis 2, 1
• Perform annual complete blood count to monitor hemoglobin levels in men receiving ADT 2, 1
• Anemia should be evaluated with a focus on potential causes other than ADT 2
• There are no convincing data to support routine treatment of asymptomatic anemia in men receiving ADT 2

Cardiac Conduction Effects

• Androgen deprivation therapy may prolong the QT/QTc interval 4, 5
• Providers should consider whether the benefits of ADT outweigh potential risks in patients with congenital long QT syndrome, congestive heart failure, frequent electrolyte abnormalities, and in patients taking drugs known to prolong the QT interval 5
• Electrolyte abnormalities should be corrected, and periodic monitoring of electrocardiograms and electrolytes should be considered 5

Neuropsychiatric Effects

• Depression and mood disturbances occur, particularly in men with a history of depression 1
• Assess for distress/depression/PSA anxiety at least annually using screening tools such as the Distress Thermometer 2, 1
• Manage distress/depression using in-office counseling resources or pharmacotherapy as appropriate, with referral for further evaluation if office-based treatment is insufficient 2

Tumor Flare Phenomenon

• Transient worsening of tumor symptoms may occur during the first few weeks of treatment, which may include ureteral obstruction and spinal cord compression 4
• Testosterone levels increase above baseline during the first week, declining thereafter to baseline levels or below by the end of the second week of treatment 5
• Patients with metastatic vertebral lesions and/or urinary tract obstruction should be closely observed during the first few weeks of therapy 5

Quality of Life Monitoring

• Assessing baseline patient-reported health-related quality of life and tracking it at least annually is an important element of high-quality survivorship care 2
• Validated surveys such as the 5-item Sexual Health Inventory for Men or the Expanded Prostate Cancer Index Composite for Clinical Practice (EPIC-CP) are helpful in identifying and understanding the side effect burden 2
• If brief screening tools are not available, simply starting a conversation around urinary and sexual function may uncover symptom burdens 2