SUN-016 - ACTH/Γ-MSH Ratio as A Mechanism-Based Marker for the Diagnosis of Cushing Disease: A Pilot Study

Background:
Cushing disease (CD) is caused by ACTH-secreting corticotroph tumors, yet current diagnostic tests often lack sufficient accuracy, resulting in repeated evaluations and delayed diagnosis. Proopiomelanocortin (POMC) is processed into multiple peptides, including ACTH and γ-melanocyte–stimulating hormone (γ-MSH). Based on our previous molecular studies, we hypothesized that calculating the peripheral ACTH/γ-MSH ratio may reflect this promoter-biased biology and serve as a practical diagnostic marker.

Methods:
A pilot single center study was conducted. Adults with confirmed CD (n=6) and non-Cushing controls (n=27) underwent measurement of plasma ACTH and γ-MSH using standardized assays, from which the ACTH/γ-MSH ratio was calculated. Logistic regression and ROC analyses assessed diagnostic performance. In two CD patients, bilateral inferior petrosal sinus sampling (BIPSS) with CRH stimulation was used to evaluate dynamic changes in ACTH, γ-MSH, and their ratio.

Results:
γ-MSH levels were comparable between groups, whereas ACTH was elevated in CD, resulting in a significantly higher ACTH/γ-MSH ratio (median 0.070 vs 0.026). Logistic regression demonstrated a significant association between the ACTH/γ-MSH ratio and Cushing’s disease (Exp(B) = 3.07 × 10¹², 95% CI: 1.38–6.86 × 10²⁴, P = 0.047*), whereas ACTH level alone was not predictive (P=0.081). Diagnostic analysis indicated that the ACTH/γ-MSH ratio provided better diagnostic performance than ACTH level alone (0.827 vs. 0.793). The ACTH/γ-MSH ratio was also helpful to differentiate between true CD and mild ACTH elevation seen in hyperprolactinemia non-Cushing subgroup. During BIPSS, CRH triggered sharp ACTH rises with minimal γ-MSH response, producing marked, transient increases in the ratio, suggesting that ACTH is more reactive by CRH stimulation than that of γ-MSH, and these two peptides have different roles.

Conclusion:
Our conceptional promoter-biased POMC peptide calculation of the ACTH/γ-MSH ratio may provide clinically meaningful differentiation between CD and non-Cushing individuals. Larger and multi-site studies are warranted to validate diagnostic thresholds and further define its role in clinical evaluation.

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