Is Relugolix Connected to Adrenal Insufficiency?
Relugolix is not associated with adrenal insufficiency in men with prostate cancer. This GnRH receptor antagonist specifically targets testicular testosterone production without directly affecting adrenal gland function or cortisol production.
Mechanism of Action and Adrenal Function
Relugolix works by competitively blocking GnRH receptors in the pituitary gland, leading to rapid suppression of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), which subsequently reduces testicular testosterone production without causing an initial testosterone surge 1, 2.
The adrenal glands remain functionally intact during relugolix therapy because the drug does not inhibit adrenal steroidogenesis pathways or suppress ACTH production 1.
Unlike CYP17 inhibitors (such as abiraterone acetate), which block both testicular and adrenal androgen synthesis and require concomitant corticosteroid supplementation, relugolix does not interfere with adrenal hormone production 3.
Clinical Evidence
Phase III HERO trial data demonstrate no increased risk of adrenal insufficiency with relugolix compared to leuprolide acetate in over 900 patients with advanced prostate cancer 1, 2.
Relugolix has been safely combined with cardiovascular medications (antihypertensives, antithrombotics, lipid-lowering agents) without evidence of adrenal dysfunction 4.
The drug's safety profile focuses on cardiovascular events, not endocrine dysfunction, with relugolix showing a 54% lower incidence of major adverse cardiovascular events compared to LHRH agonists 2.
Important Clinical Distinctions
Drugs That DO Cause Adrenal Suppression in Prostate Cancer:
Abiraterone acetate requires mandatory prednisone co-administration because it inhibits CYP17, blocking adrenal androgen and cortisol synthesis 3.
Corticosteroids used as second-line therapy (dexamethasone, prednisone) decrease adrenal function including androgen production, and can lead to adrenal suppression with prolonged use 3.
Relugolix-Specific Considerations:
Patients with pre-existing adrenal dysfunction can safely receive relugolix as it does not further compromise adrenal function 1.
No baseline cortisol testing or adrenal function monitoring is required when initiating relugolix, unlike with abiraterone 3.
Rapid testosterone recovery upon discontinuation occurs without adrenal involvement, demonstrating the drug's selective action on the hypothalamic-pituitary-gonadal axis 1, 2.
Clinical Pitfalls to Avoid
Do not confuse relugolix with abiraterone: Only abiraterone requires corticosteroid supplementation due to adrenal suppression 3.
Prior steroid use does not contraindicate relugolix therapy, as the drug does not interact with or suppress the hypothalamic-pituitary-adrenal axis 4.
Patients on chronic corticosteroids for other conditions can receive relugolix without dose adjustments, as there is no pharmacologic interaction affecting adrenal function 4.