Faculty Bibliography

OBJECTIVE:We investigated the relationship between age, sex, pituitary tumour volume, serum GH, PRL and IGF-I levels with the responsiveness of GH to TRH, bromocriptine and octreotide in patients with acromegaly. DESIGN/METHODS:We performed a retrospective study. Correlations were determined between all variables using univariate regression analysis. PATIENTS/METHODS:One hundred previously untreated acromegalic patients were studied (60 males (age 23-76; mean 49 years) and 40 females (age 25-83; mean 51 years)). MEASUREMENTS/METHODS:We studied tumour volume, fasting morning circulating levels of GH, PRL and IGF-I, mean 24-hour circulating GH levels and the acute GH responses to TRH, bromocriptine and octreotide. RESULTS:Tumour size was related to serum and mean 24-hour GH levels, but not to IGF-I. Circulating IGF-I and GH levels were related only for the group of patients whose fasting and unsuppressed GH level was 80 mU/l (40 micrograms/l) or less. Older patients tended to have lower circulating GH and IGF-I levels. There was a close similarity in the responsiveness of tumorous GH secretion to TRH, bromocriptine and octreotide. An elevated serum PRL level predicted a stronger inhibitory response of bromocriptine on GH. The sensitivity of GH release to octreotide was highest in elderly (especially male) acromegalics, as well as in patients with lower IGF-I levels. CONCLUSIONS:Hormone secretion by GH secreting pituitary tumours, as well as circulating IGF-I levels, tend to be lower in elderly patients. These tumours are more sensitive to octreotide, especially in elderly male patients. This suggests that octreotide might be used especially successfully as a primary medical therapy in elderly, male acromegalics.

Hypertriglyceridemia is the most frequent modification of lipid metabolism observed in acromegaly. The somatostatin analog, octreotide (Sandostatin), widely used in the treatment of acromegaly, is able to produce a decrease in levels of growth hormone (GH), insulin, and Insulin-like Growth Factor 1 (IGF1). We have attempted to evaluate the influence of this treatment on the lipid status of acromegalic patients. Seventeen patients with active acromegaly were treated with octreotide, 100 to 500 micrograms/injection subcutaneously three times daily. The levels of fasting serum triglycerides (TG), total cholesterol, High Density Lipoprotein (HDL) cholesterol and IGF1, as well as mean plasma GH and insulin levels during a diurnal profile, were evaluated before and after three months of octreotide therapy. GH, insulin and IGF1 decreased by 61%, 42% and 36% respectively (p less than 0.05). Mean levels (+/- SEM) of TG and total cholesterol fell from 2.2 +/- 0.4 mmol/l to 1.6 +/- 0.3 mmol/l (p less than 0.05) and 6.4 +/- 0.39 mmol/l to 5.6 +/- 0.27 mmol/l (p greater than 0.05), respectively. There was no correlation between triglyceride decrease and hormonal changes or clinical status (BMI, age, sex). In conclusion, the administration of octreotide over a three month period to acromegalic patients is associated with a decrease in TG levels.

This study evaluates the effect of the long acting somatostatin analogue octreotide on biochemical and clinical parameters of endoscopic retrograde cholangiopancreatography (ERCP) induced pancreatitis. Altogether 245 patients were randomised to receive either octreotide or isotonic saline. Octreotide (100 micrograms) was administered intravenously five minutes before ERCP and subcutaneously 45 minutes after ERCP. There were no significant differences in the median serum amylase and lipase activities at baseline, eight, and 24 hours after ERCP. Five patients (2%) developed clinical pancreatitis--three in the octreotide and two in the placebo groups. Excluding patients who developed pancreatitis, 43 (18%) developed abdominal pain after ERCP--21 in the octreotide and 23 in the placebo groups. There were no significant differences in the median serum amylase and lipase values between the treatment groups. None of the 52 patients who had therapeutic interventions developed pancreatitis. This study suggests that octreotide may not protect against ERCP induced pancreatitis.

Fifteen acromegalic patients received four single doses of octreotide in random order (500 micrograms, 1000 micrograms, and 2000 micrograms applied intranasally and 100 micrograms given sc). Serum octreotide and GH data were subjected to pharmacokinetic analyses, and local nasal effects were evaluated by acoustic rhinometry. Average areas (+/- SEM) under the serum octreotide curves were: 2000 micrograms: 4597 +/- 536; 1000 micrograms: 1923 +/- 439; 500 micrograms: 957 +/- 168; and 100 micrograms sc: 896 +/- 81 micrograms.L-1.min (n = 13). The calculated relative availability was 27% +/- 0.03; 22% +/- 0.05; 22% +/- 0.03, respectively, for the three nasal doses. The rate of absorption after intranasally administered octreotide was greater than after sc application: t1/2 ka: 7.1 +/- 1.6; 7.9 +/- 1.6; 11.3 +/- 1.9, respectively, vs. 24.1 +/- 2.5 min, whereas the rates of disappearance were similar. GH suppression started immediately after application and reached minimum levels 1-2 h later. The average intervals during which serum GH was below 50% of preadministration values were: 2000 micrograms: 544 +/- 47; 1000 micrograms: 423 +/- 56; 500 micrograms: 289 +/- 52 vs. 351 +/- 34 min after sc injection of 100 micrograms. With 2000 micrograms intranasally all but one of the 15 patients attained constant suppression of serum GH below 5 micrograms/L for 273 to 680 min. Pharmacokinetic analysis demonstrated that 100 micrograms sc and 1000 micrograms intranasally induced the same GH suppressive effect and that 2000 micrograms intranasally approximately doubled the duration of action. Acoustic rhinometry was performed after nasal application of the largest dose of 2000 micrograms and after carrier (n = 9). A highly significant tumescence of the nasal mucosa was maximal after 10 min and gradually receded over the next 2 h. However, this was felt by the patients to be acceptable. The effect was caused by octreotide per se and was probably due to vasodilation.

The frequency of gallstones during long-term treatment with the somatostatin analogue octreotide reported in different studies varies from 0% to 50%, the reason for this variation being unknown. Therefore, we examined 58 acromegalic patients undergoing different treatment regimens for the frequency of gallstones. Thirteen were treated with octreotide, 20 with bromocriptine, and 25 had no medical treatment after successful neurosurgery. Also, 58 patients without known gallbladder disease served as controls. The postprandial gallbladder contraction was also investigated in 27 acromegalic patients (10 with octreotide, 10 with bromocriptine, and 7 with no medical therapy). Ten of the 58 acromegalic patients were found to have gallstones, 4 of 25 receiving no medical treatment, 4 of 20 treated with dopamine agonists, and 2 of 13 treated with octreotide. In 9 of the 58 control patients, gallstones were detected. Although in the octreotide group the gallstones were newly formed under therapy, there was no difference in gallstone prevalence between the different treatment regimens and the control group. However, the postprandial gallbladder contraction was significantly more often inhibited during octreotide therapy, and this effect was most pronounced during the first hours following injection. Differences in the timing of injections therefore may be an explanation of the variable incidence of cholelithiasis in the different studies.

The effect of the long-acting somatostatin analog octreotide on the sphincter of Oddi was investigated in seven subjects referred for endoscopic sphincter of Oddi manometry. Six patients had unexplained right upper quadrant pain and one had bile duct dilatation without evidence of fixed obstruction on endoscopic retrograde cholangiopancreatography. A triple-lumen low-compliance system was used to record the sphincter of Oddi basal pressure, phasic contraction frequency, amplitude, duration, and direction of wave propagation before and after intravenous administration of octreotide in a dose of 50 micrograms. After a mean latency period of 1 min, significant changes included increased basal pressure in all seven patients, increased frequency of wave contractions in six patients, and decreased wave amplitude in six patients. The median duration of wave contraction and wave propagation sequence were not significantly influenced. Thus, octreotide has a significant stimulatory affect on the sphincter of Oddi activity, which may impair biliary and pancreatic flow.

The acute (TRH-stimulation test), intermediate (0-6 days administration), and long-term (0-30 months administration) effects of SMS 201-995 (octreotide) treatment on thyroid function were studied. Subcutaneous injection of 100 micrograms SMS 201-995 one hour before 200 micrograms TRH intravenously reduced serum TSH response area by more than 50% in 8 healthy volunteers. After 3 days of continuous subcutaneous infusion (CSI) of SMS 201-995 in 9 acromegalic patients (100 micrograms/24 h) a slight but significant decrease in serum total triiodothyronine (TT3) and a concomitant increase in serum TSH were demonstrated, indicating an initial inhibitory effect on peripheral deiodination of thyroxine. After a further 3 days treatment serum T3 and TSH had returned to prevalues. Six of the nine acromegalics were treated with SMS 201-995 (100-1500 micrograms/24 h) and admitted for diurnal hormone profiles on 13 occasions over 30 months. Apart from a barely significant increase in serum TSH, no changes in thyroid function were noted. The study was especially designed to detect minute changes over time in thyroid hormones. The only long-term effect of SMS 201-995 was the barely significant clinically irrelevant increase in serum TSH, possibly caused by a slight inhibition of peripheral deiodination of thyroxine.

Initial renal hypertrophy in experimental diabetes is prevented by administration of a long-acting somatostatin analogue octreotide (SMS). To investigate the long-term effects of SMS on renal hypertrophy and urinary albumin excretion (UAE), streptozotocin-diabetic and non-diabetic rats were treated with two daily subcutaneous injections of SMS (100 micrograms x 2) for six months. Untreated diabetic and non-diabetic animals were used as reference groups. No differences were seen between the two diabetic groups in respect to body weight, food intake, blood glucose levels, urinary glucose output, hemoglobin A1C(HbA1C), fructosamine, serum growth hormone (rGH) or creatinine clearance, but kidney weight (896 +/- 36 vs. 1000 +/- 24 mg, P less than 0.02), UAE (417 +/- 131 vs. 1098 +/- 187 micrograms/24 hr, P less than 0.02), kidney insulin-like growth factor I (IGF-I) (167 +/- 16 vs. 239 +/- 17 ng/g, P less than 0.01) and serum IGF-I (301 +/- 26 vs. 407 +/- 17 micrograms/liter, P less than 0.01) were all reduced in the SMS-treated diabetic animals when compared to the untreated diabetic group. In non-diabetic rats SMS reduced body weight (274 +/- 3 vs. 293 +/- 5 g, P less than 0.01), kidney weight (695 +/- 9 vs. 764 +/- 17 mg, P less than 0.01), UAE (83 +/- 29 vs. 364 +/- 114 micrograms/24 hr, P less than 0.02), kidney IGF-I (202 +/- 12 vs. 280 +/- 12 ng/g, P less than 0.01), serum IGF-I (428 +/- 21 vs. 601 +/- 54 micrograms/liter, P less than 0.01) and serum rGH (67 +/- 6 vs. 126 +/- 27 micrograms/liter, P less than 0.05) when compared to untreated controls. When kidney weights were expressed in relation to body weight no difference was found between SMS-treated and untreated controls, while the difference between SMS-treated and untreated diabetic animals was still present (P less than 0.01). In conclusion, chronic administration of SMS has abating effects on diabetic renal hypertrophy and UAE, and thus indicates that SMS may reduce development of diabetic kidney lesions in experimental diabetes. The long-term suppressive effects of SMS on renal enlargement and UAE may in part be mediated through reduction in circulating and kidney IGF-I levels.

Octreotide is a long acting synthetic analogue of native somatostatin that exerts a potent inhibitory effect on the release of a wide variety of peptide hormones from the gastroenteropancreatic endocrine system. It represents a new dimension to traditional therapies in the treatment of various conditions characterised by excessive peptide production and secretion, particularly when conventional therapeutic approaches have either been exhausted or have provided suboptimal symptomatic control. While emergency sclerotherapy remains the definitive treatment for both the arrest of acute variceal bleeding episodes and the prevention of further bleeding, its effective use depends on the patients being admitted to a hospital well versed in the procedure. There remains, therefore, a need for an easily administered and effective treatment for acute variceal bleeding emergencies. Although not all investigators agree, it appears that somatostatin is effective, at least for the duration of its administration. Given its evident advantages over somatostatin, octreotide is likely to make a major contribution towards the treatment of variceal bleeding, at least as an emergency treatment during the bleeding crisis. The potential for octreotide in the management of gastrointestinal and pancreatic fistulae is considerable. While sharing the inhibitory actions of native somatostatin on gastrointestinal motility and secretion, it can be administered at home by suitably motivated patients. Suppression of gastrointestinal peptides from the gastrointestinal tract by octreotide appears to parallel symptomatic improvements in patients with dumping syndrome, with normalisation of plasma glucagon and insulin profiles as well as suppression of vasoactive intestinal polypeptide (VIP), motilin, neurotensin, pancreatic polypeptide and C peptide being reported. Release of polypeptide hormones, such as VIP and gastrin, by tumour cells in the gastroenteropancreatic system results in profuse diarrhoea. While the nature of the diarrhoea depends on the specific peptide secreted by the tumour, all possess a common secretory mechanism which makes them sensitive to treatment with octreotide. Octreotide is suitable for the treatment of VIPoma since it inhibits released VIP. Although the available data are derived primarily from small studies and case reports, initial responses are encouraging. By reducing the circulating levels of VIP, octreotide improves diarrhoea in these patients. Octreotide has also been evaluated in several trials in patients with the carcinoid syndrome, with symptomatic improvement being observed in over 75% of cases. Clinically significant improvements in diarrhoea (elimination, or reduction of > 50%) have been observed in the great majority (up to 83%) of treated patients. Slowed tumour growth, as well as an improvement in diarrhoea, has been observed during long term treatment. A number of miscellaneous conditions can give rise to severe secretory diarrhoea, and include long standing neuropathic diabetes mellitus, short bowel syndrome after intestinal resection, intestinal graft-versus-host disease and coeliac plexus block. Idiopathic hypersecretory diarrhoea may also occur, particularly in infants. A number of studies and patient reports have shown octreotide to be a valuable adjunct in the management of patients with such conditions, and to be worthy of further investigation. Now that case report data have been confirmed by clinical trials, it is becoming evident that octreotide is a valuable treatment in the management of otherwise treatment-refractory severe diarrhoea in AIDS patients. © 1992, Adis International Limited. All rights reserved.