Faculty Bibliography

The SRIH analog octreotide is a potent GH-inhibiting agent that has been used to effectively treat patients with acromegaly. To investigate the morphological changes induced by octreotide on GH-producing pituitary tumors, we examined 86 adenomas from acromegalic patients who participated in a multicenter study. GH- producing pituitary adenomas removed from 43 patients treated preoperatively with octreotide for 4 months were compared to those obtained from 43 untreated acromegalic patients. Tissue samples were studied by histology, immunohistochemistry, and transmission electron microscopy as well as light microscopic and ultrastructural morphometry. The morphological appearance of some tumors was unaltered by octreotide treatment. Necrotic changes were not apparent in any. Acidophilia and GH immunoreactivity were more pronounced in the octreotide-treated tumors. Perivascular and interstitial fibrosis was more prevalent in the octreotide group (72% vs. 42%). An increase in hormone granularity was obvious in 4 of 15 densely granulated and 2 of 9 sparsely granulated (SG) tumors from treated patients. A decrease in cell size was conspicuous in 4 of 15 densely granulated and 2 of 10 SG adenomas. There was a slight downward trend in the cell and cytoplasmic size in all treated tumors and a slight upward trend in secretory granule size in treated SG adenomas. Only 2 of 9 SG adenomas in the octreotide group, however, demonstrated a statistically significant reduction in cell and cytoplasmic size. There was no statistically significant change in the size of nuclei, secretory granules, or lysosomes between the 2 groups. Decreased cell size and increased granularity were not linked, however. We conclude that there are no striking morphological alterations in GH pituitary adenomas that can be consistently associated with octreotide treatment.

To determine the effect of the somatostatin analog octreotide on glucose tolerance in acromegaly, we examined glucose profiles, oral glucose tolerance and the insulinogenic index in patients treated with this analog. Ninety patients participated in a long-term, prospective, open-label study. There was no significant change between mean daily blood glucose profiles at baseline or during octreotide treatment. Using glucose tolerance test criteria, 61% of 90 patients had normal baseline glucose tolerance. While on octreotide, 20% and 29% of these patients, respectively, developed impaired glucose tolerance or became frankly diabetic. Conversely, three of the patients who were diabetic at baseline (N = 11) became normal (18%) or developed impaired glucose tolerance (9%) during octreotide therapy. There was no relationship between the dose of octreotide and change in glycemic state. The insulinogenic index (insulin/glucose) response to a glucose challenge decreased uniformly in octreotide-treated patients. Female patients and those with elevated baseline insulin levels were more likely to develop diabetes mellitus during octreotide therapy. In conclusion, octreotide significantly alters glucose tolerance in patients with acromegaly, mandating glucose monitoring during this form of therapy.

Preliminary data of the use of the long-acting somatostatin analog octreotide (Sandostatin) in pediatrics are reported. In nesidioblastosis and other hyperinsulinemic conditions, timely treatment with octreotide can protect cerebral function and may reduce mortality. The acute use of octreotide produces prompt elevation of blood glucose, even in patients who fail to respond to diazoxide. In addition, it may be possible to avoid the need for partial or subtotal pancreatectomy by the long-term use of octreotide. As in adults, octreotide should find a place in the symptomatic treatment of secretory diarrhea, notably the watery diarrhea hypokalemia-achlorhydria complex and pancreatic cholera syndrome. Octreotide has been shown to be effective in the treatment of familial tall stature by reducing height velocity and final height. Responses to octreotide therapy vary and the individual responsiveness must be extensively studied.

We used [99mTc]EHIDA hepatobiliary scintigraphy to determine whether both hepatic bile secretion and gallbladder contractility are suppressed in acromegalic patients receiving long-term treatment with the somatostatin analogue octreotide. We studied three groups of patients: group 1, untreated patients; group 2, average dose of octreotide 500 +/- 100 micrograms/day for 33 +/- 4 months; and group 3, 1000 +/- 200 micrograms/day for 33 +/- 4 months. Images were taken at specified time intervals during the 120-min period following injection of EHIDA. After a single injection of octreotide, group 1 patients demonstrated delayed visualization of the radioisotope in the liver, gallbladder, and duodenum. At the end of long-term treatment, group 2 patients showed a delay in appearance of maximal radioactivity in the gallbladder. Two weeks following discontinuation of octreotide, this parameter had decreased significantly (P < 0.001). In group 3, visualization of the liver, gallbladder, and duodenum were prolonged, with delayed visualization of the gallbladder persisting two weeks after withdrawal (P < 0.005). These results indicate that gallbladder contractility is decreased after a single injection of octreotide and that during chronic octreotide therapy the rate of bile secretion is reduced. Impaired gallbladder contractility normalizes more rapidly after discontinuation of octreotide in patients receiving low doses of the analog.

NMR spectroscopy is a useful tool for monitoring multiple intermediate metabolic pathways in different organs in intact animals and humans. We report the effect of the somatostatin analogue octreotide on the fate of 13C-labeled glucose administered to fasted and well-fed rats as determined by NMR spectroscopy. The production of 13C-labeled glycogen and its subsequent breakdown after the end of infusion was identified with a time resolution of 7 min. Hepatic glycogen synthesis was not different between control and octreotide-treated animals but persisted for 15 min after the end of the infusion only in control animals. Glycogenolysis, however, was initiated immediately after the end of infusion in octreotide-treated animals where the half-life of glycogen was 40 min compared with 68 min in control animals. However, once initiated, the rate of glycogenolysis was not significantly altered by octreotide. Although octreotide had no effect on glucose signal intensities in fasted animals, 13C glucose signals were more intense in octreotide compared with control well-fed animals. In conclusion, octreotide alters rat hepatic metabolism by accelerating the onset of glycogenolysis and stimulating glucose accumulation without significantly interfering with glycogen synthesis.

Somatostatin is a 14 amino acid peptide that inhibits pancreatic exocrine and endocrine secretion. Its clinical application has been limited by its very short half life, necessitating continuous intravenous infusion. Octreotide is an 8 amino acid synthetic analogue of somatostatin that possesses similar pharmacological effects. It has a much longer duration of action, however, and can be given subcutaneously. Both the intravenous and subcutaneous routes of injection of octreotide are well tolerated. Peak serum concentrations occur within 30 minutes after subcutaneous administration and within four minutes of a three minute intravenous infusion. Serum concentration increases linearly with dose. Octreotide is distributed rapidly, mainly in the plasma, where it is 65% protein bound. The elimination half life is about 1.5 hours and about 32% of a subcutaneous dose is excreted in the urine as unchanged octreotide. Octreotide inhibits gastroenteropancreatic secretion, especially of insulin, glucagon, pancreatic polypeptide, gastric inhibitory polypeptide, and gastrin. It also inhibits both release of thyroid stimulating hormone and growth hormone secretion in response to exercise, insulin induced hypoglycaemia, and argenine stimulation. Octreotide reduces splanchnic blood flow in healthy volunteers and hepatic venous pressure in cirrhotic patients. It can accelerate or delay gastric emptying, prolong transit time at moderate to high doses, stimulate motility at low doses, and inhibit gall bladder emptying. Octreotide considerably inhibits pentagastrin stimulated gastric acid secretion and significantly diminishes exocrine pancreatic function (amylase, trypsin, lipase). Octreotide increases intestinal transit time and decreases endogenous fluid secretion in the jejunum and ileum, thus increasing the absorption of water and electrolytes. These pharmacological effects of the analogue point to its therapeutic role in a variety of endocrine and gastrointestinal disorders.

Octreotide, the first somatostatin analogue developed, has pharmacological properties (it inhibits pituitary GH and TSH secretion, pancreatic and digestive tract endocrine secretion and various gastrointestinal functions) which are qualitatively similar to those of the natural 14 amino acids peptide. Enzymatic structural modification had resulted in a peptide which is very resistant to degradation and has a 90-110 min half-life permitting subcutaneous administration. Following a subcutaneous injection of 50 to 100 micrograms, absorption is rapid and complete. The peak plasma concentration is obtained within 20 to 30 minutes. The drug is degraded mostly in the liver. Among pituitary tumours, GH- and TSH-secreting adenomas constitute the primary indication. Octreotide has been widely tested in the treatment of acromegaly; 50 to 80 percent of patients with that disease respond to a discontinuous administration (usually 3 subcutaneous injections per day), and the IGF1 level is normalized in 50 percent of the cases. No long-term desensitization and no rebound phenomenon after drug withdrawal have been observed. Clinical improvement is obvious, even in cases with partial response to treatment. The dose required to obtain maximum response may vary from one patient to another, and resistance to the peptide has been observed in a few patients. This resistance does not seem to be related solely to the absence of somatostatin receptors on the tumours. The principal side-effect of octreotide treatment is the occurrence of gallstones. In some patients, continuous subcutaneous injection gives a better result with a lower dose. Other ways of administration (nasal or oral) have been tested or are being evaluated.

Endoscopic sphincterotomy (ES) was performed in 25 patients for common bile duct (CBD) calculi in the absence of stones in the gallbladder. Eighteen of these patients were considered unfit for surgery because of age or concomitant disease. All ES procedures were technically successful with complete evacuation of the CBD in all cases. Early complications occurred in only one patient, a 91-year-old female who died from nonbiliary tract disease. Long-term follow up over a period of 42 months was available in 19 of the 24 patients. Late complications occurred in two patients (10%), both of whom developed cholecystitis; they underwent surgery without subsequent morbidity or mortality. This 10% incidence of long-term complications is similar to that of other series that did not differentiate between patients with isolated CBD calculi and those with stones also present in the gallbladder. The observed complication rate does not justify routine prophylactic cholecystectomy after ES for isolated CBD stones.