Evolving Treatment Paradigms in Hypercortisolism: Integrating Emerging Evidence into Practice - Episode 11
Unmet Needs and Future Research Directions for Hypercortisolism
Panelists discuss how future research should focus on understanding why hypercortisolism is becoming more prevalent, developing more specific treatments with fewer adverse effects, and determining optimal thresholds for circadian rhythm dysfunction and treatment duration.
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The fundamental question driving future research centers on understanding why hypercortisolism appears to be increasingly prevalent in modern society. Researchers propose that chronic stress from contemporary lifestyle factors—including constant connectivity, social media, and persistent stimulation—may be driving autonomous cortisol production. This parallels the historical evolution of subclinical hypothyroidism recognition, which progressed from being considered rare to becoming one of the most common referral reasons to endocrinology clinics. The pathophysiological mechanisms underlying this apparent epidemic require urgent investigation.
Future therapeutic developments focus on more selective and refined treatment options. The development of relacorilant, a more specific glucocorticoid receptor antagonist, promises to reduce adverse effects associated with mifepristone, including vaginal bleeding and endometrial thickening. Early data suggest relacorilant causes less corticotropin elevation and associated mineralocorticoid effects while maintaining efficacy in blood pressure reduction and glucose control. Additional compounds in development include CRH receptor antagonists and 11β-HSD type 1 inhibitors, which could provide tissue-specific cortisol modulation in liver and adipose tissue.
Research priorities include establishing thresholds for clinically significant circadian rhythm dysfunction and developing noninvasive continuous cortisol monitoring technologies. The potential for temporary treatment to reset circadian rhythms represents an intriguing therapeutic possibility that could transform hypercortisolism from a chronic condition to a potentially curable disorder. Understanding the relationship between insulin resistance and circadian disruption may reveal whether insulin sensitizers could help restore normal cortisol rhythms. The field also needs to address long-term management questions, including optimal treatment duration and strategies for preventing disease recurrence.
