What is megestrol and how does it stimulate appetite?

Megestrol Acetate: Mechanism and Appetite Stimulation

Megestrol acetate is a synthetic progestational agent that effectively stimulates appetite in patients with cancer-related anorexia and cachexia, with approximately 1 in 4 patients experiencing increased appetite and 1 in 12 achieving measurable weight gain, though it carries risks of thromboembolic events and increased mortality. 1

What is Megestrol Acetate?

• Megestrol acetate is a synthetic derivative of the hormone progesterone that is FDA-approved for the treatment of anorexia, cachexia, or unexplained significant weight loss in patients with AIDS 2
• It is commonly used off-label for cancer-related anorexia and cachexia, as it has demonstrated efficacy in improving appetite and promoting weight gain in these populations 3
• The drug is typically administered as an oral suspension at doses ranging from 400-800 mg/day, with higher doses associated with greater improvement in weight 3, 1

Mechanism of Action for Appetite Stimulation

• The precise mechanism by which megestrol acetate stimulates appetite remains unknown 2
• It is believed to work through both behavioral and metabolic effects related to its progestational properties 4
• Possible mechanisms include:
  • Downregulation of proinflammatory cytokines that contribute to cachexia 3
  • Influence on the hypothalamic appetite regulation center 1
  • Potential glucocorticoid-like effects at higher doses 5

Efficacy in Appetite Stimulation

• Randomized controlled trials have consistently demonstrated that megestrol acetate improves appetite and food intake in patients with anorexia related to cancer and AIDS 6, 7
• A systematic review and meta-analysis showed that patients receiving megestrol acetate were 2.57 times more likely to experience appetite improvement compared to those receiving placebo 3
• Weight gain tends to be modest, with approximately 1 in 12 patients achieving measurable weight gain 3, 8
• In a landmark study, 64.2% of AIDS patients receiving 800 mg/day gained at least 5 pounds compared to 21.4% of those on placebo 7

Clinical Considerations and Risks

• Despite its efficacy, megestrol acetate carries significant risks that must be considered:
  • Approximately 1 in 6 patients will develop thromboembolic phenomena 3, 5
  • Mortality risk is increased, with 1 in 23 patients at risk of death related to treatment 3, 5
  • Other side effects include edema and potential adrenal suppression with long-term use 5, 8
• The weight gain associated with megestrol acetate is primarily adipose tissue rather than skeletal muscle, which may limit its clinical benefit 5
• For patients with months-to-weeks or weeks-to-days life expectancy, the benefits of improved appetite and quality of life may outweigh the risks 3

Alternative and Combination Approaches

• Dexamethasone may be considered as an alternative to megestrol acetate, with similar appetite-stimulating effects but different toxicity profiles 3
• Olanzapine (5 mg/day) can be effective for cancer-related anorexia, particularly in patients with concurrent nausea or anxiety 1
• Combination therapy approaches may yield better outcomes:
  • The addition of olanzapine to megestrol acetate has shown improved weight gain (85% vs 41%) compared to megestrol acetate alone 3
  • Combinations including megestrol acetate plus L-carnitine, celecoxib, and antioxidants have demonstrated improved lean body mass, appetite, and quality of life 3, 1

Monitoring Recommendations

• Regular assessment for thromboembolic phenomena is essential due to the significantly increased risk 5
• Weight should be monitored to assess response, recognizing that weight gain does not necessarily indicate improved muscle mass 5
• For patients on long-term therapy, adrenal function should be assessed 5
• The optimal duration of therapy is not well-established, but benefits should be weighed against risks, particularly for longer-term use 3, 5