Circadian rhythm proteins as potential biomarkers in pituitary adenomas: an immunohistochemical analysis

To investigate the protein expression levels of circadian clock genes in pituitary adenomas (PAs) using the immunohistochemical staining method.

Patients who had regular follow-up at the pituitary center, underwent transsphenoidal surgery (TSS) for PA between 8:00 AM and 2:00 PM, and had sufficient clinical data were enrolled. Patients with a known diagnosis of depression, those receiving psychiatric medication or melatonin agonists that may affect the protein expression of circadian clock genes, or those working night shifts during the preoperative period were excluded. Formalin-fixed paraffin-embedded tissue samples from patients with somatotroph, gonadotroph, lactotroph, and corticotroph adenomas were immunohistochemically stained for BMAL1, CLOCK, CRY1, CRY2, and PER2. Non-neoplastic adenohypophysis tissue adjacent to the adenoma in surgical specimens underwent the same staining procedure and served as the control group. Protein expression levels were then evaluated.

A total of 86 PAs and 17 non-neoplastic adenohypophysis tissue samples were evaluated. Total BMAL1 scores tended to be higher in PAs than in control tissues (170.93 ± 59.81 vs. 142.06 ± 47.40; p = 0.064), whereas total CRY2 scores tended to be lower (12.5 [0-59.25] vs. 35 [10-60]; p = 0.053). Total CLOCK scores were lower in patients with recurrent disease compared to those without recurrence (225 [165-270] vs. 250 [212.5-280]; p = 0.038), and preoperative maximum tumor size was negatively correlated with total CRY2 scores (r=-0.463, p < 0.001). Among PA subtypes, CRY2 was the circadian clock gene showing the most prominent differences.

Alterations in the protein expression levels of circadian clock genes may contribute to the development and behavior of PAs.