Different mediators signal along the pituitary-adrenal axis to connect hormonal and metabolic systems for the coordination of physiological processes. The systemic interactions were challenging to assess mechanistically furtherly. In this study, we first performed an observational study using PET revealed novel insights into hormonal crosstalk in CD. We found concomitant biochemical activation of the pituitary-adrenal axis in ACTH-producing pituitary microadenoma by 68Ga-pentixafor PET/CT, which potentially determine functional pituitary adenomas. The uptake of 68Ga-pentixafor in pituitary adenoma and adrenal glands were correlated with ACTH and cortisol levels, respectively. However, there was no association between the hormone production and symmetric endogenous glucose metabolism correspondingly.
The ectopic or aberrant expression of GPCRs is crucial in regulating cortisol. It has previously been reported that overexpression of CXCR4 in pituitary adenomas, whose ligand induces autocrine/paracrine proliferation in pituitary tumor cells, and it likely contributes to adenoma development, proliferation and hormone hypersecretion [4]. GPCRs could induce the synthesis and secretion of adrenocortical hormones eg. cortisol and aldosterone [5], which could be detected by 68Ga-pentixafor PET/CT [6–9]. This interactive molecular signaling pituitary-adrenal glands and correlation with hormone level was determined in this study. Hence, 68Ga-pentixafor PET/CT proved to be an extremely powerful analytical methodology that enabled to analyze symmetric molecular and cellular processes in CD disease.
Activation and modulation of hormonal response could also be triggered through glucose metabolic signals. The theoretical underpinnings of 18F-FDG-PET use were established in early studies that showed slight net oxidation of glucose by either the Krebs’cycle or the pentose phosphate pathway in the normal pituitary gland [10, 11]. 18F-FDG PET results hinted at metabolic reprogramming of pituitary adenomas to rely on glycolysis as the primary energy source, similar to the Warburg effect in malignant tumors [12]. However, we did not find an association between pituitary-adrenal 18F-FDG uptake and the serum ACTH/cortisol level. Besides, 18F-FDG showed a limited role in detecting ACTH-producing pituitary microadenomas.
CXCR4 antagonists are potential novel molecules and possible future targets for CD treatment. Further pharmacological perturbations of CXCR4 antagonists on pituitary-adrenal axis might potentially allow a theragnostic approach to inhibit the production of endogenous ligands [13]. In future investigations, a closely entangled framework of in vivo biochemical process and hormonal response in endocrine diseases is required to enable a holistic analysis of pathomechanisms.
The major limitation of our study was the small number of included patients. Besides, the lower spatial resolution and partial volume effect of PET/CT could affect the accuracy of the results, especially in recurrent ACTH-PAs. Therefore, evidence-based outcome evaluation of this symmetric probing or metabolic signaling on a cross-organ level is warranted, especially compared to 18F-FDG.