What is the role of LHRH (Luteinizing Hormone-Releasing Hormone) agonists in the treatment of hormone-sensitive prostate cancer in a male patient over 50?

LHRH Agonists in Prostate Cancer

LHRH agonists (leuprolide, goserelin) are a cornerstone of treatment for hormone-sensitive prostate cancer and should be initiated with concurrent antiandrogen therapy for at least 7 days to prevent testosterone flare in metastatic disease. 1

Primary Treatment Indications

For metastatic hormone-sensitive prostate cancer:

• LHRH agonists or bilateral orchiectomy are equally effective first-line options for achieving medical castration 1, 2
• Castrate testosterone levels (<50 ng/dL) are typically achieved within 2-4 weeks and maintained throughout treatment 1
• In metastatic disease, always co-administer an antiandrogen for at least 7 days (preferably 3-4 weeks) when initiating LHRH agonist therapy to prevent disease flare 1, 3

Critical warning: During the first several weeks after LHRH agonist initiation, serum LH and testosterone levels surge, which can worsen existing metastatic disease, cause ureteral obstruction, or precipitate spinal cord compression 1, 4

Locally Advanced or High-Risk Disease

For patients receiving definitive radiotherapy:

• Neoadjuvant LHRH agonist therapy for 4-6 months before and during radiotherapy is recommended for high-risk disease 1
• This approach improves prostate cancer-specific survival (HR 0.56; 95% CI 0.32-0.98; P=0.04) compared to radiotherapy alone 1
• Adjuvant hormonal therapy should continue for 2-3 years after radiotherapy in high-risk patients 1
• For Gleason score 8-10 disease, extended adjuvant therapy (2 years) improves overall survival (81.0% vs 70.7%; P=0.044) 1

Combined Androgen Blockade (CAB)

The addition of nonsteroidal antiandrogens to LHRH agonists provides minimal survival benefit:

• Meta-analysis shows 5-year survival of 25.4% with CAB vs 23.6% with castration alone (P=0.11) 1
• Nonsteroidal antiandrogens combined with castration show small survival advantage (27.6% vs 24.7%; P=0.005) 1
• CAB should only be offered to patients willing to accept increased toxicity for a small survival benefit (number needed to treat: 20-100) 2
• Steroidal antiandrogens should not be used as monotherapy 1

Biochemical Recurrence After Definitive Treatment

Hormonal therapy is NOT routinely recommended for biochemical relapse unless:

• Symptomatic local disease progression is present 1
• Proven metastases are documented 1
• PSA doubling time is <3 months 1

For patients meeting these criteria, intermittent androgen deprivation (IAD) is non-inferior to continuous therapy and provides quality-of-life benefits 1

Cardiovascular and Metabolic Monitoring

LHRH agonists carry significant cardiovascular risks that must be monitored:

• Increased risk of myocardial infarction, sudden cardiac death, and stroke has been reported 2, 5, 4
• Monitor for hyperglycemia and diabetes development; check blood glucose and HbA1c periodically 5, 4
• LHRH agonists may prolong QT/QTc interval—consider periodic ECG monitoring in high-risk patients 5, 4
• Electrolyte abnormalities should be corrected before and during treatment 5, 4

Practical Administration Considerations

Compliance is critical for LHRH agonist efficacy:

• Injections must be administered every 4 weeks (for monthly formulations) 6
• Delays >2 weeks are associated with risk of disease flare 6
• Establish a tracking system (dedicated nurse registry) to ensure appointment adherence 6
• If compliance cannot be assured, consider bilateral orchiectomy as alternative 6

LHRH Antagonists as Alternative

GnRH antagonists (degarelix) offer advantages over agonists in specific situations:

• Produce rapid testosterone suppression without initial surge or flare 7, 8, 9
• No need for concurrent antiandrogen therapy 7, 8
• 72% of patients achieve castrate levels by day 8 vs 0% with leuprolide alone 8
• Consider in patients with high metastatic burden where testosterone flare poses significant risk 7, 9

Monitoring During Treatment

Laboratory surveillance requirements:

• Measure serum testosterone to confirm castrate levels (goal: <50 ng/dL) 1
• Monitor PSA levels regularly to assess treatment response 1, 5
• Castrate levels should be reached within 2-4 weeks and maintained throughout therapy 1

Common Pitfalls to Avoid

• Never start LHRH agonist monotherapy in metastatic disease without antiandrogen coverage—this can cause catastrophic disease flare with spinal cord compression or ureteral obstruction 1, 3
• Do not use LHRH agonists for biochemical recurrence alone without evidence of metastases or rapid PSA doubling time 1
• Do not assume CAB is superior—the survival benefit is minimal and toxicity is increased 1, 2
• Screen for pre-existing cardiovascular disease before initiating therapy, as LHRH agonists increase cardiac risk 2, 5, 4