cortistatin-14 and Pituitary-Neoplasms

Somatostatin (SRIF) and cortistatin (CST) are two cyclic peptides sharing remarkable structural, pharmacological and functional similarities. Both peptides bind all somatostatin receptors subtypes (sst1-5) with comparable affinities, which may explain the considerable similitude between their actions, particularly on endocrine targets. However, the expression patterns of both peptides do not overlap in human tissues, and they are regulated by different stimuli, suggesting that SRIF and CST can exert unique roles. In fact, CST can bind other receptors, different to ssts (e.g. ghrelin receptor, GHS-R and the MrgX2 receptor), which may be involved in those differential actions. In this review, we have summarized the limited knowledge gathered so far regarding the in vitro actions exerted by CST in different endocrine systems under normal and pathophysiological conditions, and have compared them with the well established functions known for SRIF on these systems. Available data suggests that CST substantially reproduces, but not fully mimics the "in vitro" effects of SRIF on pituitary secretions of human and animal models. Conversely, the functions of CST in the majority of peripheral endocrine (and non-endocrine) tissues are still unknown. Notwithstanding this, the differential tissue expression pattern of SRIF, CST and their receptors suggests that CST may act as a mere natural SRIF analogue in a number of tissues but in some endocrine tissues it may play a predominant, unique regulatory role with potential pathophysiological relevance. The challenge is now to find the genuine differences between these seemingly identical endocrine siblings.

Topics: Animals; Corticotrophs; Gonadotrophs; Growth Hormone; Humans; Lactotrophs; Neuropeptides; Organ Specificity; Pancreas; Pituitary Neoplasms; Prolactin; Receptors, Neuropeptide; Receptors, Somatostatin; Somatostatin; Thyroid Gland; Thyrotrophs

Cortistatin (CST) shares high structural homology with somatostatin (SST) and binds all SST-receptors (SST-R) subtypes with similar affinity. However, CST actions, tissue expression patterns and regulation do not fully overlap with those of SST, and, moreover, CST, but not SST, also binds and activates proadrenomedullin N-terminal peptide receptor (MrgX2) and shows binding affinity to ghrelin receptor (GHS-R1a). Several studies performed to clarify the endocrine actions of CST, compared with SST, showed that, in humans, CST and SST share the same endocrine actions, i.e. inhibition of GH and insulin secretion in physiological conditions and in acromegaly. A similar inhibitory effect on PRL and ACTH secretion was shown in acromegaly, prolactinoma or in Cushing's disease. This identity of endocrine actions by CST and SST suggests that SST-R activation by CST overrides any other independent action of this peptide mediated by other receptors. Thus, in terms of endocrine actions, CST can well be considered a natural alternative to SST.

Topics: Acromegaly; Adrenocorticotropic Hormone; Animals; Endocrine System; Growth Hormone; Humans; Insulin; Insulin Secretion; Nerve Tissue Proteins; Neuropeptides; Pituitary ACTH Hypersecretion; Pituitary Neoplasms; Prolactin; Prolactinoma; Receptors, G-Protein-Coupled; Receptors, Ghrelin; Receptors, Neuropeptide; Receptors, Somatostatin; Somatostatin

Cortistatin (CST) is a neuropeptide that shares high homology with somatostatin and binds with high affinity to all somatostatin receptor (SSTR) subtypes. Many of its endocrine and biological activities overlap with those of somatostatin.. The objective of the study was to assess the direct in vitro effects of CST on human pituitary hormone secretion.. This study was performed in the endocrine laboratory of a tertiary academic medical center.. Primary cell cultures of human fetal (21-25 wk gestation) pituitary tissues and cultured hormone-secreting adenoma cells were used in this study.. Cell cultures were incubated with CST-14 or CST-17, somatostatin, GHRH, SSTR analogs, and ghrelin analogs, and hormone secretion was analyzed.. GH and prolactin (PRL) medium concentrations were tested by hormone assay, and SSTR mRNA was tested by RT-PCR.. CST-14 (10 nm) inhibited GH secretion by up to 65% in all fetal pituitary specimens after 4-h incubation (P < 0.05). CST-14 or CST-17 (10 nm) inhibited basal GH secretion in six of the 13 GH-cell adenomas and two of the three GH-PRL mixed adenomas. CST-17 (100 nm) suppressed the GH response to GHRH and ghrelin analog (10 nm each) by 30-50% in adenomas (P < 0.05). Three PRL-adenomas treated with CST-17 (10 nm) showed a 20-40% inhibition of PRL release (P < 0.05), whereas in three others no suppression or mild response was achieved at this concentration. A comparable inhibition of PRL secretion was obtained with SSTR5-selective analog but significantly less with SSTR2-preferential compounds. RT-PCR revealed the expression of both SSTR2 and SSTR5 in all GH-cell and mixed adenomas studied and all PRL-secreting adenomas studied, except for two of the CST-resistant prolactinomas, in which SSTR5 was absent.. This is the first report of in vitro CST suppression of human GH and PRL in cultured pituitary tissues. The regulation of PRL release from cultured adenomas appears to be primarily mediated by SSTR5.

Topics: Adenoma; Fetus; Human Growth Hormone; Humans; Neuropeptides; Pituitary Gland; Pituitary Neoplasms; Prolactin; Prolactinoma; Tumor Cells, Cultured