Endocrine Abstracts

Background

Corticotroph pituitary adenomas present different degrees of functionality, from silent to whispering and finally to functioning adenomas leading to Cushing’s disease. Compared to their functioning (FCA) counterpart, the silent corticotroph adenomas (SCA) express lower levels of the corticotroph cell lineage marker–TBX19 (TPIT), proopiomelanocortin (POMC), and prohormone converting enzyme 1/3 (PC1/3, PCSK1)–the main enzyme involved in the cleavage of POMC towards a functional ACTH molecule. Our recent data (Eieland, Normann et al. 2020) suggests that SCA may express higher levels of PCSK1N, a specific inhibitor of PC1/3. In vitro studies with AtT-20 cells demonstrated that overproduction of PCSK1N, coding for the protein called Pro-SAAS, reduced the processing of POMC leading to diminished ACTH production.

Aim

To study key molecules involved in the processing of POMC including the regulator proteins PCSK1N/Pro-SAAS and PC1/3 and characterize possible differences between FCA and SCA.

Material and methods

Clinical and imaging characteristics were recorded in a cohort of 30 FCA (18 women, 15 microadenomas) and 18 SCA (7 women, all macroadenomas). Measurement of gene expression by RT-qPCR of POMC, TBX19, PCSK1 and PCSK1N was performed in adenoma tissue from the patients. Data was analyzed with IBM SPPS version 27.0.0.0.

Results

Morning plasma ACTH and cortisol levels, measured preoperatively, were significantly lower (P = 0.032 and P = 0.01) in SCA compared with FCA patients: ACTH median (IQR): SCA 5.6 (1.8–13.2) pmol/l, vs FCA 14.1 (11.6–30.1) pmol/l, P = 0.032; cortisol: mean (SD) SCA 314 (154.6) nmol/l vs FCA 577.6 (230.9) nmol/l, P = 0.01. Tumor size (mm) was significantly larger in SCA (P < 0.001). In SCA as compared to FCA, gene expression of TBX19 (P < 0.001), POMC (P < 0.001) and PCSK1 (P = 0.008) was significantly lower and PCSK1N was higher (P < 0.001). For FCA and SCA combined, POMC gene expression was associated with PCSK1 (r = 0.339, P = 0.018) and PCSK1N (r = -0.678 P < 0.001). TBX19 gene expression likewise correlated strongly with PCSK1 (r = 0.421, P = 0.003) and PCSK1N (r = -0.531, P < 0.001). Plasma cortisol correlated with gene expression of POMC (r = 0.401, P = 0.017) and PCSK1 (r = 0.448, P = 0.007). Tumor size correlated with gene expression of POMC (r=-0.618, P < 0.001), TBX19 (r = -0.385, P = 0.014), PCSK1 (r = -0.340, P = 0.032), PCSK1N (r = 0.739, P = 0.000) and plasma cortisol (r = -0.496, P = 0.003).

Conclusion

We present a strong negative correlation between gene expression of POMC and PCSK1N in human corticotroph pituitary adenomas. In addition to being a new potential differentiation marker distinguishing between SCA and FCA and possibly a marker of tumor growth of corticotroph adenomas, the higher PCSK1N expression in the SCA might explain their diminished ACTH production.