INTRODUCTION — Somatostatin holds an interesting place in gastrointestinal endocrinology. Originally discovered as an inhibitor of growth hormone release [1], it is now known to inhibit a variety of gastrointestinal processes (table 1) [2]. Somatostatin is produced by paracrine cells that are scattered throughout the gastrointestinal tract and inhibits gastrointestinal endocrine secretion. Somatostatin is also found in various locations in the nervous system and exerts neural control over many physiological functions. Given this vast array of effects, it is not surprising that somatostatin has been the subject of intensive investigation. The development of synthetic analogues has led to treatment of clinical disorders such as acromegaly, hormone-secreting tumors of the gastrointestinal tract, and portal hypertensive bleeding.
MOLECULAR FORMS — Biologically active somatostatin exists in two molecular forms: somatostatin-14 and somatostatin-28. Both are the products of post-translational processing of preprohormone [3] (see "Overview of gastrointestinal peptides in health and disease"). Somatostatin is a cyclic peptide (figure 1) that is remarkably well conserved in evolution. A disulfide bond between cysteine residues maintains the cyclic structure. Somatostatin-14 is identical to the carboxyl terminal 14 amino acids of somatostatin-28. The biological activity of S-14 and S-28 resides in the cyclic region of the mature peptide. The F-W-K-T portion of the ring structure is required for receptor occupancy. This finding made it possible to produce synthetic bioactive peptides such as octreotide acetate (SMS-201-995, Sandostatin) (figure 1).
Cortistatin is a neuropeptide that is structurally similar to somatostatin and binds to all somatostatin receptor subtypes. It can also bind the growth hormone secretagogue receptor (GHS-R, also known as the ghrelin receptor), but as yet its physiological function is unknown [4].
TISSUE DISTRIBUTION — Somatostatin is distributed throughout the entire body, although it is particularly abundant in nervous tissue of the cortex, hypothalamus, brainstem, and spinal cord. It has also been localized in nerves of the heart, thyroid, skin, eye, and thymus. Somatostatin is abundant in the gastrointestinal tract and pancreas where it is produced by paracrine and endocrine-like D cells and by enteric nerves. Both S-14 and S-28 are expressed throughout regions of the gastrointestinal tract.
Somatostatin cells are morphologically diverse. In the gut mucosa, D-cells are flask-shaped and contain long cytoplasmic extensions that end in nerve terminal-like processes poised to participate in endocrine regulation either via release into the systemic circulation or direct secretion onto a neighboring cell (see "Overview of gastrointestinal peptides in health and disease"). These cells appear uniquely suited to sample the luminal contents and influence local cell responses in a paracrine manner. In the central and peripheral nervous systems, nerves release somatostatin where it functions as a peptidergic neurotransmitter.
RECEPTORS — The somatostatin receptor is a typical G protein-coupled receptor (see "Peptide hormone signal transduction and regulation"). At present there are five known subtypes of the somatostatin receptor (designated subtypes 1 to 5). These receptors do not differ appreciably in their binding of somatostatin 14 or 28; however, there is significant variation in binding of synthetic somatostatin peptides [2,5]. All somatostatin receptor subtypes have been found in the brain [6]. In contrast, peripheral tissues vary in the subtype expressed (table 2).
All subtypes of the somatostatin receptor are coupled to adenylate cyclase through an inhibitory G protein (see "Peptide hormone signal transduction and regulation"). Receptor activation results in a reduction of cAMP accumulation. In addition, agonist occupancy of some subtypes couples to activation of ion channels (eg, potassium channels) and mobilization of intracellular calcium [3].
Certain agonists exhibit functional selectivity at individual somatostatin receptors and activate only a portion of the receptor's potential effects. This property is known as selective agonism, and has been described with other G protein-coupled receptors [7]. This may make it possible to develop agonists with various somatostatin-like activities.
Interestingly, somatostatin receptors can interact with each other and form dimers [8]. Agonist-induced receptor dimerization changes ligand binding affinity and receptor internalization [8]. Different receptor types can interact with the somatostatin receptor (receptor heterodimerization), thus, providing a novel pathway for cellular communication. As an example, the dopamine receptor (type 2) and the somatostatin receptor (type 5) can physically associate to diversify receptor signaling [9]. Cross-talk between somatostatin receptors and growth factor receptors of the receptor tyrosine kinase (RTK) family may be important in cancer [10].
The effects of somatostatin on protein tyrosine phosphatases including the Src homology phosphatases, SHP-1 and SHP-2, appear to counteract growth factor stimulated tyrosine kinase activity and thereby inhibit mitogenic signaling pathways and contribute to the antiproliferative effects of somatostatin and analogues on tumor growth [11]. Somatostatin treatment causes desensitization and internalization of somatostatin receptors within minutes [12]. This process may contribute to refractoriness to chronic somatostatin administration.
SOMATOSTATIN RELEASE — Somatostatin is a key regulatory peptide that functions primarily as a paracrine mediator (see "Peptide hormone signal transduction and regulation"). It is released from neural, endocrine, and enteroendocrine cells and has a short half-life in tissue and in blood. Its concentration in the blood is low, generally in sub-picomolar amounts. After intravenous administration, 50 percent of the peptide is removed from the circulation in less than three minutes. Somatostatin secretion occurs in response to a variety of stimuli. Meal ingestion and gastric acid secretion increase somatostatin output from gastric D-cells [3]. Gut somatostatin production is regulated by the autonomic nervous system with catecholamines inhibiting and cholinergic mediators stimulating peptide release [9].
SOMATOSTATIN PHYSIOLOGY — The physiological effects of somatostatin are largely inhibitory (table 1). In the peripheral organs, somatostatin decreases endocrine and exocrine secretion and blood flow, reduces gastrointestinal motility and gallbladder contraction, and inhibits secretion of most gastrointestinal hormones (table 3 and table 4). In pancreatic islets, somatostatin inhibits both alpha and beta cells and finely tunes glucagon and insulin secretion through paracrine regulation [13]. Somatostatin also inhibits neurotransmission in the brain, but depending on the neural pathways affected, somatostatin in the central nervous system may stimulate endocrine secretion. For example, somatostatin inhibits ghrelin release from X/A-like cells of the gastric mucosa, but in the brain, somatostatin receptor activation increases plasma ghrelin levels [14]. In the hypothalamus, somatostatin inhibits growth hormone and thyroid-stimulating hormone release from the anterior pituitary gland. In the brain and peripheral nervous system, somatostatin can function as a neurotransmitter and modulates neurotransmission. It typically co-localizes in GABAergic neurons and potentiates inhibitory neuronal signaling [15]. Somatostatin is also expressed in immune cells including macrophages, lymphocytes, and monocytes and exerts anti-inflammatory and antinociceptive effects [16].
Excess somatostatin secretion is rare and occurs with somatostatinomas. The clinical syndrome is manifest by the triad of (i) diabetes mellitus, (ii) diarrhea secondary to malabsorption, and (iii) gallstone disease. These pathophysiologic processes are the direct result of the inhibitory effects of somatostatin on insulin secretion, pancreatic exocrine secretion, and gallbladder contraction, respectively (see "Somatostatinoma: Clinical manifestations, diagnosis, and management"). Somatostatin deficiency occurs with persistent Helicobacter pylori infection in the setting of chronic gastritis [17].
CLINICAL IMPLICATIONS OF SOMATOSTATIN — The clinical utility of somatostatin is hampered by its short half-life in the circulation (less than three minutes). As a result, octreotide acetate, a synthetic peptide that maintained the biological activity of somatostatin yet remained active for over 90 minutes, was developed as a drug that could be administered parenterally (figure 1). Octreotide is much more stable in the circulation and is more potent in many of the inhibitory actions than native somatostatin [18]. The clinical use of octreotide has been established for a number of indications (table 4) [2,19].
Long-acting somatostatin analogues, somatostatin LAR (Sandostatin LAR), lanreotide-PR (Somatuline PR), and pasireotide (Signifor) have also simplified treatment with somatostatin analogues [20]. These agents are slow-release formulations that require only monthly injection and supply high-dose, stable blood levels of octreotide. These agents provide for improved patient compliance since they are administered on a weekly to monthly schedule depending upon the indication. An oral form of octreotide has been developed [21].
Acromegaly — Acromegaly is caused by excessive growth hormone secretion, usually from a pituitary tumor. Medical therapy is important for reducing growth hormone secretion and may be used as an adjunct to neurosurgery or radiotherapy [22] (see "Treatment of acromegaly"). Acromegaly and other pituitary tumors, including Cushing's disease, have been treated with somatostatin analogues [23].
Secretory diarrhea — Secretory diarrhea is a manifestation of a variety of disorders. Human immunodeficiency virus (HIV) infection, for example, can cause serious volume-depleting diarrhea that may respond to octreotide [24]. Given the clinical improvement some patients with profound secretory diarrhea have demonstrated with octreotide treatment, it has been tried in a number of other diseases with variable results (table 4).
One of the approved indications is for patients with vasoactive intestinal polypeptide secreting tumor (VIPoma), also called pancreatic cholera or watery diarrhea/hypokalemic/achlorhydria (WDHA) [25]. These individuals have high serum VIP levels and respond to therapy with octreotide (see "VIPoma: Clinical manifestations, diagnosis, and management", section on 'Clinical features' and "VIPoma: Clinical manifestations, diagnosis, and management", section on 'Somatostatin analogs'). Octreotide is also effective in carcinoid syndrome in which it reduces serotonin release and improves symptoms of flushing and diarrhea [26,27]. (See "Clinical features of carcinoid syndrome".)
Gastrointestinal bleeding — Somatostatin has an important role in regulating intestinal blood flow. Octreotide reduces splanchnic blood flow and, therefore, has been used to treat gastrointestinal bleeding [28,29]. Octreotide may be useful in gastrointestinal angiodysplasia, which is often difficult to manage [30,31]. (See "Overview of the treatment of bleeding peptic ulcers" and "Methods to achieve hemostasis in patients with acute variceal hemorrhage" and "Angiodysplasia of the gastrointestinal tract", section on 'Octreotide'.)
Pancreatic disorders — Somatostatin inhibits pancreatic exocrine and endocrine secretion. Although somatostatin/octreotide has been studied, it is not routinely used to prevent post-ERCP pancreatitis [32,33]. (See "Post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis".)
Somatostatin receptor agonists have been investigated in a number of disorders of the pancreas, including acute pancreatitis and pancreatic fistulae. However, the results of many studies of acute pancreatitis indicate no clear benefit on the clinical utility of either somatostatin or octreotide [34] in improving pancreatic fistulae drainage [35], or enterocutaneous fistulae [36,37] (see "Management of acute pancreatitis"). A meta-analysis suggested that somatostatin analogues may reduce complications following pancreatic surgery but did not reduce overall mortality [38].
Diagnostic imaging — Most neuroendocrine tumors express somatostatin receptors on their cell surface, providing a rationale for the use of radiolabeled octreotide to image these tumors. Conventional imaging techniques, including computed tomography, ultrasound, angiography, and magnetic resonance imaging, are the mainstay of tumor localization. However, because neuroendocrine tumors are frequently small they are often difficult to localize accurately by these methods. Somatostatin receptor scintigraphy appears to be more sensitive for detecting such tumors [39]. 111In-DTPA-octreotide was initially the most common radiolabeled ligand; however, somatostatin analogues with higher affinity and different specificities for somatostatin receptor subtypes have been labeled with other radioelements such as technetium-99, gallium-68, fluorine-18, and copper-64 and used to image gastro-entero-pancreatic neuroendocrine tumors (GEP-NETs) and other solid tumors [40,41]. (See "Classification, epidemiology, clinical presentation, localization, and staging of pancreatic neuroendocrine neoplasms".)
Inhibition of tumor growth — Somatostatin and analogues can slow the growth of some gastrointestinal cancers, particularly neuroendocrine tumors. This antitumor activity appears to be related to both direct and indirect effects. Directly, activation of somatostatin receptors in tumor cells induces cell cycle arrest or apoptosis primarily through regulation of MAP kinase and phosphotyrosine phosphatase activities. Somatostatin receptors are also expressed on some tumor blood vessels, providing an indirect mechanism for inhibiting tumor angiogenesis and secretion of growth factors [42,43].
Non-endocrine solid tumors may express multiple somatostatin receptor subtypes and it has been proposed that other somatostatin analogues with a broader range of binding activity may actually be more effective than octreotide or lanreotide in inhibiting tumor growth [44].
Radiolabeled somatostatin analogues can be used to deliver isotopes to tumors that contain somatostatin receptors through somatostatin receptors on tumor cells [45-49]. Low-grade neuroendocrine tumors with high somatostatin receptor expression are particularly susceptible to radiolabeled somatostatin analogue therapy with reported response rates of up to approximately 30 percent [50,51]. Loss of somatostatin receptors has been described in pancreatic cancer and may lead to lack of somatostatin inhibitory growth responses [52].
Other uses — As mentioned above, somatostatin exerts some anti-angiogenic effects and induces apoptosis in endothelial cells. These actions have stimulated interest in evaluation of somatostatin analogues in the treatment of proliferative diabetic retinopathy [53].
Neuropathic pain following nerve injury is accompanied by an increase in spinal G protein-coupled receptors and ion channels that reinforce pain pathways. However, there is often a compensatory increase in inhibitory receptors on nerves that include somatostatin receptors. These inhibitory influences are becoming recognized for their ability to restrain allodynia and hyperalgesia [54]. For these reasons, somatostatin also has antinociceptive effects and in some circumstances may be useful in treating pain [55,56]. Due to their antinociceptive effects and the wide distribution of somatostatin receptors in the brain, somatostatin analogues may be used to treat migraine and cluster headaches [57].
By virtue of its generalized anti-secretory effects, octreotide has been used to manage the diarrhea and vasomotor symptoms associated with dumping syndrome following gastric or bariatric surgery [58]. (See "Postgastrectomy complications", section on 'Dumping syndrome'.)
The ability of somatostatin to inhibit intracellular adenosine 3’, 5’-cyclic monophosphate (cAMP) renders it effective in reducing cell proliferation and fluid secretion in autosomal dominant polycystic disease [59,60] and polycystic liver disease [61,62].
SUMMARY
●Somatostatin is produced by paracrine cells that are scattered throughout the gastrointestinal tract and inhibits gastrointestinal endocrine secretion. In the central and peripheral nervous systems, somatostatin functions as a peptidergic neurotransmitter. (See 'Tissue distribution' above.)
●The somatostatin receptor is a typical G protein-coupled receptor. Somatostatin receptors can interact with each other and form dimers. Different receptor types can also interact with the somatostatin receptor (receptor heterodimerization), thereby providing a novel pathway for cellular communication. (See 'Receptors' above.)
●Meal ingestion and gastric acid secretion increase somatostatin output from gastric D-cells. In the peripheral nervous systems and peripheral organs, somatostatin decreases endocrine and exocrine secretion and blood flow, reduces gastrointestinal motility and gallbladder contraction, and inhibits secretion of most gastrointestinal hormones (table 3). (See 'Somatostatin release' above and 'Somatostatin physiology' above.)
●Somatostatinomas are characterized by somatostatin excess and the triad of diabetes mellitus, diarrhea secondary to malabsorption, and gallstone disease. Somatostatin deficiency occurs with persistent Helicobacter pylori infection in the setting of chronic gastritis. (See 'Somatostatin physiology' above.)
●Octreotide and other long acting analogues of somatostatin, have a number of established clinical indications including the treatment of secretory diarrhea, gastrointestinal bleeding, inhibition of tumor growth, and imaging neuroendocrine and other solid tumors (table 4). (See 'Clinical implications of somatostatin' above.)
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