Expression of target receptors CRHR1 and SSTR5 in pituitary corticotroph tumours varies according to tumour secretory function — ASN Events
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Expression of target receptors CRHR1 and SSTR5 in pituitary corticotroph tumours varies according to tumour secretory function (#340)

Prishila Fookeerah 1 2 3 , Winny Varikatt 4 , Mark Dexter 5 , Sue Lynn Lau 1 2 , Mark McLean 1 2
  1. Diabetes and Endocrinology, Westmead Hospital, Sydney, NSW, Australia
  2. School of Medicine, Western Sydney University, Sydney, NSW, Australia
  3. Prince of Wales Hospital, Randwick, NSW, Australia
  4. Tissue Pathology and Diagnostic Oncology, Westmead Hospital, Sydney, NSW, Australia
  5. Department of Neurosurgery, Westmead Hospital, Sydney, New South Wales, Australia

 

Corticotroph tumours have been shown to overexpress corticotropin-releasing hormone receptor 1 (CRHR1), a target in functional pituitary imaging and dynamic testing. Somatostatin receptor 5 (SSTR5), also overexpressed in corticotroph tumours, may have a role in the downregulation of CRHR1 to control ACTH secretion. The relationship between tumour function, SSTR5 and CRHR1 expression in human corticotroph tumours has not been studied. This work evaluates the association between corticotroph tumour secretory status and immunoexpression of CRHR1 and SSTR5.

 

We conducted a retrospective study of consecutive corticotroph tumours resected between 2011 and 2018 at Westmead Hospital. Tumour sections were stained for pituitary hormones, proliferative markers, transcription factors, SSTR2 and SSTR5. Available tissue was further analysed using a commercial CRHR1 antibody. We compared CRHR1 and SSTR5 expression in functioning corticotroph tumours (FCT) and silent corticotroph tumours (SCT).

 

The final cohort consisted of 44 corticotroph tumours (14 FCT and 30 SCT). Compared to SCT, FCT were smaller (maximum diameter 11 vs 23 mm, p<0.001), less frequently invasive (0% vs 40%, p=0.008) and were associated with higher morning cortisol (530 vs 281nmol/L, p<0.01) and ACTH (12.5 vs 6.5 pmol/L, p<0.001) at diagnosis. Positive CRHR1 immunoexpression was observed in the majority of corticotroph tumours (71.4% FCT and 96.7% SCT). However, staining intensity was significantly lower in FCT with a median immunoreactivity score (IRS) of 6 vs 12 in SCT, p<0.00001. CRHR1 IRS was also significantly negatively correlated with serum cortisol (r = -0.556, p<0.001) and plasma ACTH (r=-0.440, p=0.006). In contrast, positive SSTR5 expression was common in FCT but absent in SCT (64.3% vs 0%, p<0.001).

 

CRHR1 expression is reduced when cortisol level is higher, potentially reflecting cortisol negative feedback and/or SSTR5-mediated CRHR1 downregulation in FCT. These findings may be useful in understanding variability in responses to diagnostic and therapeutic interventions

  1. Dieterich KD, Gundelfinger ED, Lüdecke DK, Lehnert H. Mutation and expression analysis of corticotropin-releasing factor 1 receptor in adrenocorticotropin-secreting pituitary adenomas. J Clin Endocrinol Metab. 1998;83(9):3327-3331.
  2. Fehm HL, Voigt KH, Lang R, Beinert KE, Raptis S, Pfeiffer EF. Somatostatin: a potent inhibitor of ACTH-hypersecretion in adrenal insufficiency. Klin Wochenschr. 1976;54(4):173-175.
  3. Van der Hoek J, Waaijers M, van Koetsveld PM, et al. Distinct functional properties of native somatostatin receptor subtype 5 compared with subtype 2 in the regulation of ACTH release by corticotroph tumor cells. Am J Physiol Endocrinol Metab. 2005;289(2):E278-287.