Single-dose response study of the somatostatin analogue octreotide in acromegaly

The recommended dosage schedules for intermittent sc therapy with the somatostatin analogue octreotide in acromegaly vary widely, from 100 to 1500 micrograms daily. As acute administration of octreotide has been shown to predict its long-term response, we performed a single-dose response study in 5 patients with active acromegaly using doses of 25, 50, 100, 200 and 400 micrograms octreotide as well as a placebo injection. Plasma GH of 2 patients did not normalize after any of the injections, but nadir plasma GH overall gradually decreased as doses were increased from 25 to 400 micrograms. The 400 micrograms octreotide dose was superior with regard to the duration of plasma GH suppression to below 5 micrograms/l or 25% of the basal GH level, the mean GH as a percentage of the basal level over the first 4 and 8 h, and the integrated reduction of plasma GH during the first 4 and 8 h. The postprandial integrated insulin secretion during the first 3 h after injection of the octapeptide was significantly lower after 50, 100 and 400 micrograms than after the placebo injection. The mean plasma glucose as a percentage of the basal level during the first 8 h was significantly higher after octreotide after the 200 and 400 micrograms injections. Minor adverse events were seen in 2 patients after injection of 200 and 400 micrograms octreotide. Within the limitations of this single-dose response study it was concluded that injection of 400 micrograms octreotide yields the best results with regard to suppression of GH secretion, whereas the 50, 100 and 200 micrograms doses are superior to 25 micrograms, but do not differ from each other.     

Relations between sex hormones, sex hormone binding globulin, insulin-like growth factor-I and insulin-like growth factor binding protein-I in post-menopausal breast cancer patients

OBJECTIVE Oestrogens, androgens and anti-endocrine drugs such as tamoxifen and aminoglutethimide influence plasma Insulin-like growth factor-I (IGF-I). IGF-I, in turn, has been found to stimulate the peripheral aromatase in vitro. The aim of this study was to examine relations between sex hormones, IGF-I and insulin-like growth factor binding protein-1 (IGFBP-1) In post-menopausal women with breast cancer. DESIGN To measure plasma sex steroids, sex hormone binding globulin (SHBG), IGF-I, IGFBP-1, Insulin and urinary oestrogen metabolites In post-menopausal women with breast cancer not receiving any endocrine therapy. PATIENTS Thirty-two patients had fasting blood samples obtained between 0800 and 1000h. A sub-group of 10 patients had 24-hour urine oestrogen metabolites determined. MEASUREMENTS Plasma steroids and proteins were measured by radioImmunoassays. Urinary oestrogens were measured by GC-MS. RESULTS SHBG correlated negatively with plasma androstenedione (P < 0·001), insulin (P < 0·001), IGF-I, height and plasma oestrone sulphate (P < 0·025 for all), but positively with plasma IGFBP-1 (P < 0·025). IGFBP-1 correlated negatively with IGF-I (P < 0·001) and the testosterone/SHBG ratio (P < 0·05). Neither IGF-I nor IGFBP-1 correlated with any of the plasma or urinary sex hormones or with the oestrone/androstenedione and oestradiol/testosterone ratios. Multivariate analysis revealed plasma SHBG to correlate positively with IGFBP-1 (P= 0·029) and negatively with Insulin (P= 0·031). Plasma IGFBP-1 correlated negatively with IGF-I (P < 0·0001) but not with insulin. CONCLUSION Our results do not suggest any influence of plasma sex steroids in physiological concentrations on IGF-I or IGFBP-1 in post-menopausal breast cancer patients, nor do they indicate IGF-I at physiological concentrations Influences the ratios between plasma oestrogens and their androgen precursors.     

Impact of octreotide, a long-acting somatostatin analogue, on glucose tolerance and insulin sensitivity in acromegaly

OBJECTIVE: We aimed to investigate the impact of a long-acting somatostatin analogue, octreotide, on glucose tolerance and on insulin sensitivity in acromegaly. DESIGN: We performed a non-randomized controlled trial. PATIENTS: Seven patients with active acromegaly were assessed before and during octreotide therapy given in a dose of 500 micrograms three times daily subcutaneously. MEASUREMENTS: The effects of octreotide on carbohydrate metabolism were assessed by performing a glucose tolerance test and a euglycaemic hyperinsulinaemic clamp. These latter tests were undertaken 8 hours after the last dose, allowing GH and glucagon to return to pretreatment levels during the study. RESULTS: Octreotide significantly reduced (P less than 0.05) mean +/- SEM 12-h GH (from 42 +/- 13 to 10 +/- 3 mIU/I) and IGF-I (from 4.2 +/- 0.5 to 2.1 +/- 0.5 U/ml) concentrations. Glucose tolerance was normalized in four of five patients with impaired glucose tolerance without a significant change in mean insulin concentrations. The improvement in fasting and mean blood glucose during glucose tolerance testing was dependent on the pretherapy blood glucose concentrations (r = -0.95, P = 0.002). The glucose infusion rate during the hyperinsulinaemic (5 U/h) clamp was significantly increased (P less than 0.05, 15.3 +/- 1.8 vs 24.2 +/- 5.4 mumol/kg min) following octreotide treatment. Insulin infusion during the glucose clamp completely suppressed hepatic glucose production during but not before octreotide treatment (7.9 +/- 2.4 vs 0.7 +/- 2.2 mumol/kg min, P = 0.02). Insulin-mediated stimulation of peripheral glucose uptake was unaffected by treatment. Mean GH and glucagon levels during both clamp studies were not significantly different. CONCLUSIONS: Octreotide improves whole body insulin sensitivity by an increased ability of insulin to suppress hepatic glucose production without affecting the substantial impairment of peripheral insulin action. Octreotide has beneficial effects on carbohydrate metabolism in acromegalic patients with glucose intolerance.     

Long-term treatment of acromegaly with the somatostatin analogue SR-lanreotide.

OBJECTIVE: To assess the efficacy and tolerability of SR-lanreotide in the treatment of active acromegaly. PATIENTS AND DESIGN: 30 patients (17 men and 13 women) were treated in whom active acromegaly was confirmed by clinical features, a mean GH level of >5 mlU/l and failure to suppress GH to <2 mlU/l after a 75 g glucose load. Patients were treated for a median period of 60 weeks (range 12-168) with im injections of SR-lanreotide 30 mg given every 7-14 days. MEASUREMENTS: Mean GH and IGF-I levels were measured at baseline and every 12-weeks together with symptom score assessment. MRI of the pituitary gland was performed at baseline and if an adenoma was identified at yearly intervals. Gall bladder ultrasound scans were performed at baseline and then every 24-weeks. RESULTS: Twenty-three patients were treated for at least 48-weeks and, in these, GH levels fell from 10.5 mlU/l (7.6-17.6) (median and interquartile range) at baseline to 3.2 mlU/l (2.4-3.9) (p<0.0001) and IGF-I levels ftom 88.9 nmol/L (71.4-137.1) to 56.8 nmol/l (39.3-75.4) (p=0.0002). GH response to treatment was better in elderly patients (age> or =65 years) compared to younger patients but neither sex, pre-treatment GH levels, previous surgery nor previous radiotherapy influenced the response. Treatment resulted in a significant improvement in the symptoms of active acromegaly in the majority of patients. A significant reduction in the size of the pituitary adenoma was documented in 6 of 10 patients who had a repeat MRI scan after one year. Treatment was well-tolerated by the majority of patients; side effects were mainly transient gastrointestinal symptoms. These were severe in only 2 patients necessitating discontinuation of the drug. Two patients developed new gall stones and 4 female patients had temporal hair loss necessitating stopping treatment in one of them. There were minor effects on glucose tolerance which were not of clinical importance. CONCLUSION: Long-term treatment of acromegaly with SR-lanreotide is effective in controlling GH and IGF-I levels and symptoms and is well tolerated in the majority of patients.     

High affinity growth hormone binding protein in plasma of patients with acromegaly and the effect of octreotide treatment

OBJECTIVE: The objective of this study was to investigate the effect of plasma GH-levels on the high affinity growth hormone binding protein (GHBP). PATIENTS: We studied plasma samples of eight patients with acromegaly and eight age and sex matched healthy subjects. DESIGN: Patients with acromegaly were treated with octreotide administered by continuous subcutaneous infusion. Levels of growth hormone binding protein (GHBP) were measured in plasma samples before therapy and 3, 6 and 12 months after starting treatment. During this period, octreotide was administered in doses of 300-800 micrograms/day. The mean dose per patient over the study period ranged from 300 to 575 micrograms/24 h. The GHBP levels of patients with acromegaly were compared with those in the healthy subjects. MEASUREMENTS: Bound and free 125I-GH in plasma were measured using FPLC gel chromatography on a Superose 12 column, after an overnight incubation period. The binding data were used for a Scatchard plot analysis. Wilcoxon's signed rank test was used for statistical analysis. RESULTS: We found lower GHBP levels in acromegalic patients (P = 0.01) than in the control subjects. Octreotide treatment resulted in IGF-I levels < 300 micrograms/l in four patients. In these patients GHBP levels increased. CONCLUSIONS: We conclude that growth hormone binding protein levels are down regulated in acromegaly, indicating an important role for GH in the regulation of this protein.     

Short-term pre-surgical treatment with somatostatin analogues, octreotide and lanreotide, in acromegaly

Eighteen patients with symptoms of active acromegaly were treated with somatostatin analogues for 4 weeks before surgery. Both before and after the treatment, levels of growth hormone (GH), prolactin (PRL), insulin growth factor -I (IGF-I), luteotropin (LH), folliculostimulin (FSH) and subunit alpha of glycoprotein hormones were estimated. Glucose tolerance test, magnetic resonance imaging (MRI) examination, sight acuity and field of vision tests were also performed. The same tests were performed on ten control patients with clinically and biochemically active acromegaly, subjected to surgery but not treated with somatostatin analogues. In six patients treated with somatostatin analogues GH levels decreased significantly to less than 5 ng/ml and in two patients remained elevated while in 10 patients GH level decreased and ranged from 6.1 to 42.9 ng/ml. In 13 patients we observed a decrease in IGF-I to normal levels (<400 ng/dl) and in 3 patients we noted a decrease to levels slightly higher than normal. There was also a slight decrease in alpha subunit concentration. In the glucose inhibition test 4 patients demonstrated normalized GH levels. In patients with elevated PRL and TSH levels, treatment with somatostatin analogues induced their decrease. No changes were observed in levels of LH and FSH. After therapy MRI examination disclosed a decrease in tumor volume in two patients (by 20 and 25%, respectively) and no changes in tumor size in 16 patients. The two patients with a decreased tumor volume also showed normalized glucose tolerance tests. All patients manifested an improved clinical condition. Neurosurgeons disclosed a decreased tumor consistency which greatly facilitated surgical procedure. Our studies documented favourable effects of somatostatin analogues on the assayed hormone levels, and on the general condition of the patients as well as on the course of the surgical procedure itself.     

Thyroid volume and serum thyroglobulin levels in patients with acromegaly: correlation with plasma insulin-like growth factor I levels

The pathogenesis of the goiter that is frequently found in patients with acromegaly is not known. Using ultrasonic scanning, we measured thyroid volume in 17 euthyroid patients with acromegaly and examined the relationships among thyroid size, plasma GH and insulin-like growth factor (IGF-I) levels, and serum thyroglobulin (TG) levels. The mean estimated thyroid volume in these 17 patients was 32.8 +/- 15.5 (+/- SD) mL, significantly larger than that in normal subjects (15.4 +/- 3.1 mL), and 64.7% of the patients had multinodular goiter, as identified by ultrasonography. Thyroid volume was positively correlated with plasma GH and IGF-I levels and heel-pad thickness, but not with the serum TSH level. In 7 patients, thyroid volume decreased in association with a decline in plasma GH and IGF-I levels after surgical treatment. The serum TG level was elevated in 7 of the 15 patients in whom it was measured, and the mean value was 51.7 +/- 62.7 (+/- SD) micrograms/L (normal, 12.6 +/- 6.4 micrograms/L). We found no correlations among the serum TG and TSH levels, plasma GH and IGF-I concentrations, and/or thyroid volume. However, serum TG decreased after surgical treatment, just as did plasma IGF-I. These observations together with the results of recent in vitro studies by others suggest that IGF-I is one of the factors involved in goiter formation, but the elevated serum TG levels in acromegaly are controlled not only by IGF-I but also by other factors.     

The nadir growth hormone after an octreotide test dose predicts the long-term efficacy of somatostatin analogue therapy in acromegaly

OBJECTIVE: In the treatment of acromegaly, a 'test dose' of octreotide is recommended prior to the use of depot somatostatin analogue (SSA) therapy. However, there remains no consensus regarding the criteria that predict a response to treatment. The ability to select patients who may benefit most from medical therapy is potentially of great value in clinical practice. The aim of the study was to determine the predictive value of both the nadir GH and the mean GH following an octreotide test dose in identifying patients who subsequently achieved disease remission with depot SSA therapy. Remission was defined as a mean GH < 5 mU/l (< 2 microg/l). DESIGN: Retrospective case-control study. PATIENTS: A group of 41 patients with acromegaly underwent an octreotide test dose where GH was measured hourly for a total of 6 h following an injection of octreotide 50 microg subcutaneously. Nadir GH and mean GH following the octreotide test dose were determined. Thirty-three patients were subsequently treated with depot SSA therapy and mean GH and IGF-I levels were determined at follow-up. RESULTS: The nadir GH demonstrated superior predictive power to that of mean GH across a range of GH cut-off values. A nadir GH < 5 mU/l demonstrated 80% sensitivity and 83% specificity in predicting remission with depot SSA therapy. A nadir GH < 10 mU/l demonstrated 100% sensitivity and 56% specificity. CONCLUSIONS: The nadir GH following an octreotide test dose is a useful predictive marker of achieving disease remission with depot SSA therapy used as either a primary or an adjuvant agent.     

No effect of the long-acting somatostatin analogue octreotide in patients with insulinoma

The efficacy of subchronic (3 weeks) treatment with the long-acting somatostatin analogue octreotide was studied in four patients with symptomatic benign insulinoma. No clinical or biochemical effect on serum glucose, insulin, C-peptide or glucagon was observed in all four patients despite clearly detectable serum levels of octreotide. The resistance to octreotide therapy in these patients might be explained by the absence of somatostatin analogue receptors on their tumours.     

Monitoring of treatment success in patients with acromegaly: the value of serum insulin-like growth factor binding protein-3 and serum leptin measurements in comparison to plasma insulin-like growth factor I determination

The aim of the present study was to determine the value of serum insulin-like growth factor binding protein-3 (IGFBP-3) and serum leptin measurements in comparison with plasma insulin-like growth factor I (IGF-I) measurements as indicators of treatment success in patients with acromegaly. Thirty-five acromegaly patients, 25 female and 10 male, divided into groups of patients with postadenomectomy "active" acromegaly (n = 20) and patients with postadenomectomy "controlled" acromegaly (n = 15), and 44 healthy volunteers sex- and age-matched with the acromegaly patients were included in the present study. We comparatively analyzed plasma IGF-I, serum IGFBP-3, and serum leptin levels in the aforementioned groups. Because serum leptin has sex dimorphism, the groups were divided into sexes when leptin was evaluated. As expected, the patients with active acromegaly had significantly higher mean values of plasma IGF-I and serum IGFBP-3 and lower mean values of serum leptin (only in women) than the control group. However, individual evaluation showed that 1 of 20, 9 of 20, and many patients with postadenomectomy active acromegaly patients had values that overlapped values of control subjects for plasma standard deviation score (SDS)-IGF-I, serum SDS-IGFBP-3, and sex-adjusted serum leptin, respectively. Application of the receiver operating characteristic (ROC) curves method shows that plasma IGF-I measurement has the best discriminatory power to differentiate patients with postsurgical active acromegaly from healthy people. Its area under the curve (AUC) was 0.95, with a sensitivity and specificity of 86% and 94%, respectively. Its positive and negative likelihood ratios were 14 and 0.15. Serum IGFBP-3 has certain discriminatory power, its AUC being 0.89, with a sensitivity and specificity of 83% and 77%. Its positive and negative likelihood ratios were 3.6 and 0.22. Serum leptin, both in women and in men, has a poor performance with sensitivity and specificity of 53% and 50% for women and 55% and 56% for men and positive and negative likelihood ratios of 1.06 and 0.94 for women and 1.26 and 0.8 for men. Application of the ROC curves method and the determination of positive and negative likelihood ratios in comparative evaluation of serum IGFBP-3 and serum leptin with plasma IGF-I as indicators of treatment success in acromegalic patients showed that neither serum IGFBP-3 nor serum leptin determinations have accuracy better than or similar to that of plasma IGF-I for monitoring treatment success in acromegaly patients. Serum IGFBP-3 is accurate but does not increase accuracy for age-adjusted plasma IGF-I, whereas determination of serum leptin level has no value in monitoring these patients.     

Prevalence of gastritis in patients with acromegaly: untreated and during treatment with octreotide

OBJECTIVE: It has previously been suggested that acromegalic patients treated with the somatostatin analogue octreotide invariably have chronic gastritis. We have examined the prevalence of gastritis in a large group of acromegalic patients, untreated and during treatment with octreotide. DESIGN: We studied three groups of acromegalic patients: (A) untreated; (B) octreotide-treated; (C) a subgroup of these studied both before and during octreotide therapy. PATIENTS: Forty-eight patients, grouped as above, with active acromegaly were examined for the presence of gastritis. MEASUREMENTS: Gastroscopy and histological examination of gastric biopsies for the presence of gastritis and Helicobacter organisms were undertaken. The principal outcome was quantification of the prevalence of gastritis in the various study groups. RESULTS: Group A: 10 of the 33 patients (30%) had gastritis before any therapy with octreotide. Group B: 17 of 36 patients (47%) on octreotide treatment for 6-59 months (mean 20.5) had gastritis, and this was present in five out of the sub-group of eight patients (62%) treated for over 3 years. Group C: three of 21 patients (14%) developed gastritis during treatment with octreotide for between 6 and 23 months (mean 12.4). There was a highly significant association between the presence of gastritis and the presence of Helicobacter pylori organisms. CONCLUSIONS: Octreotide therapy of acromegaly may predispose to the development of gastritis, but this remains statistically unproven. Certainly, gastritis is not an invariable consequence of octreotide therapy, even after prolonged periods of treatment. The presence of gastritis is associated with H. pylori infection.     

The octreotide test dose is not a reliable predictor of the subsequent response to somatostatin analogue therapy in patients with acromegaly

In many centres, a test dose (TD) of octreotide is administered before commencing somatostatin analogue therapy (SAT), although the merits of this procedure are uncertain. We have analysed the value of the GH response to a TD in predicting the efficacy of subsequent SAT in 47 patients with acromegaly (25 male, median age 51 years, range 20-82). The primary goal of SAT was a mean GH of < 5 mU/l. Median baseline GH was 19.3 mU/l (2.2-233 mU/l) and with the TD fell by 78% (35-98%) to a nadir of 4.2 mU/l (< 0.3-85 mU/l). Optimal predictive power was observed when GH fell to < 5 mU/l after the TD. With this criterion, the TD had a positive predictive value (PPV) of achieving the primary goal on SAT of 82% and a negative predictive value (NPV) of 50%. However, baseline GH was also highly predictive of the likelihood of successful SAT (GH < 5 mU/l). The GH response to the TD had PPV of 83% and NPV of 61% of normalising IGF-I on SAT. In summary, baseline GH and nadir after a TD are highly predictive of a good response to SAT; however, a poor response to a TD does not exclude an optimal response to SAT. Furthermore, failure to achieve biochemical control does not equate to no benefit, as biochemical improvement was seen in every patient; therefore, no patient should be deprived of octreotide therapy because of the result of a TD. In conclusion, our data indicate that the octreotide TD has no place in selecting patients for SAT.     

The growth hormone responses to octreotide in acromegaly correlate with adenoma somatostatin receptor status

We studied the correlation between the presence of somatostatin (SRIH) receptors in GH secreting tumors and the in vivo GH responsiveness to the SRIH analog octreotide in 11 acromegalic patients. To test in vivo octreotide (SMS 201-995) responsiveness, the patients were given a single dose (100 micrograms, sc) and their plasma GH levels were measured for several hours. Somatostatin receptor content was measured by receptor autoradiography on frozen tumor tissue sections using either a somatostatin-28 analog or a SRIH octapeptide analog (Tyr3-octreotide) as iodinated radioligands. In eight acromegalic patients, who had complete and long lasting GH inhibition after octreotide administration, SRIH receptors with high affinity for octreotide were distributed homogeneously in the tumor tissue. Two patients had moderate, short duration, and incomplete inhibition of GH secretion after octreotide administration, and their tumors had very low capacity and/or affinity SRIH receptors. A further patient who had a moderate response to octreotide had SRIH receptors that were nonhomogeneously distributed throughout the tumor. These data suggest that the therapeutic efficacy of octreotide may be related to tumor SRIH receptor levels; the best in vivo responses to octreotide occurred in patients whose tumors contained a high density of homogeneously distributed receptors which had a high affinity for octreotide.     

Total and free insulin-like growth factor I, insulin-like growth factor binding protein 3 and acid-labile subunit reflect clinical activity in acromegaly

The aim was to evaluate, markers of disease activity in acromegaly in relation to perceived disease activity. Thirty-seven consecutively treated, acromegalic patients, classified by clinical symptoms as inactive (n=16), slightly active (n=10) and active (n=11), entered the study. When evaluating the inactive and the active groups, we found that positive and negative predictive values (PV(pos), PV(neg)) for clinical disease activity of total and free insulin-like growth factor-I (IGF-I) were 0.59, 0.90 and 1.00, 0.82 respectively. Acid-labile subunit (ALS) showed diagnostic merit similar to insulin-like growth factor binding protein-3 (IGFBP-3) with PV(pos) of 0.69 and 0.71 and PV(neg) of 0.91 and 0.92 respectively. We conclude that free IGF-I is more closely related than total IGF-I to perceived disease activity and is as such useful when evaluating previously treated acromegaly for disease activity. Total IGF-I, IGFBP-3 and ALS possess a higher PV(neg) for the clinical disease activity. None of the parameters can at present be claimed to be superior to the others and thus all the measured parameters are recommended to be part of the evaluation of acromegalic patients.     

The insulin-like growth factor binding protein-1 in low and high insulin responders before and during dexamethasone treatment.

To investigate the influence of normal insulin levels on levels of the insulin-like growth factor binding protein-1 (IGFBP-1) we measured this peptide postabsorptively and during hyperglycemic clamp in 17 healthy subjects, nine with low insulin response (LIR) and eight with high insulin response (HIR). The study was performed before and after 60 hours of treatment with dexamethasone 6 mg/d. The fasting levels of IGFBP-1 were significantly higher in LIR, 36 +/- 2.5 micrograms/L, than in HIR, 22 +/- 2.6 micrograms/L (P less than .01), while no differences in glucose, insulin, and C-peptide concentrations were found. Dexamethasone induced an increase in basal concentrations of insulin, while IGFBP-1 levels decreased to 18.8 +/- 2 micrograms/L in LIR (P less than .01) and to 14.0 +/- 0.9 micrograms/L in HIR (P less than .05). There was no correlation between the individual basal IGFBP-1 concentrations and basal insulin levels. In contrast, basal levels of IGFBP-1 were inversely correlated to the integrated insulin or C-peptide concentrations during the hyperglycemic clamp both before (r = -.67, P less than .01) and during dexamethasone (r = -.79, P less than .001). Dexamethasone, which increased the insulin resistance, did not change the relationship between basal IGFBP-1 and the glucose-induced insulin release. In conclusion, the morning levels of IGFBP-1 in healthy subjects reflect the acute beta-cell responsiveness to glucose, which may correspond to integrated diurnal insulin levels. The inhibitory effects of dexamethasone on the morning levels of IGFBP-1 can be explained by attendant hyperinsulinemia.     

Dose-response study and long term effect of the somatostatin analog octreotide in patients with therapy-resistant acromegaly

Twelve acromegalic patients in whom standard therapy was unsuccessful were evaluated with 24-h serum GH profiles (hourly sampling) and oral glucose tests (oGTT) while being treated with octreotide, a long-acting somatostatin analog. During a dose-response study (300, 600, and 1500 micrograms/day sc, for 4 weeks), serum GH decreased significantly after 300 micrograms/day in 8 of 12 patients [from 14.5 +/- 6.2 (+/- SE) to 4.9 +/- 1.9 micrograms/L]. Higher doses further reduced serum GH concentrations in 3 (600 micrograms/day) and 1 (1500 micrograms/day) patients, respectively. Four patients did not respond to any dose. Serum GH concentrations declined normally (GH nadir, less than 2 micrograms/L) after glucose ingestion in 4 of the 10 nondiabetic acromegalic patients. In 4 patients, including 2 of the initial nonresponders, serum GH further declined during long term treatment (12 and 18 months). In the latter 2 patients, serum insulin-like growth factor I (IGF-I) concentrations had decreased during the dose-response study despite the absence of measurable GH suppression. Eight patients attained normal serum IGF-I concentrations during treatment. Serum IGF-I and GH correlated significantly before, but not during, treatment. Retrospective comparison suggested that in 5 of 6 patients, serum GH was more effectively suppressed by octreotide than by bromocriptine. The 24-h serum octreotide concentration varied greatly among the patients. Although the 24-h serum octreotide and GH concentrations did not correlate with one another, the serum octreotide and IGF-I concentrations when the patients were receiving 300 micrograms/day tended to be negatively correlated (r = -0.496; P = 0.118). The 24-h serum insulin values decreased and those of glucose increased during treatment; after oral glucose, serum insulin was lower and glucose was higher. However, after 12 months of treatment, the 8-h serum insulin profile and peak serum insulin after oral glucose administration had returned to pretreatment values, while serum glucose remained abnormal. We conclude that 1) octreotide lowers serum GH in many, but not all, acromegalic patients resistant to other forms of treatment; 2) doses in excess of 300 micrograms/day should be tested in those patients in whom lower doses are ineffective; 3) serum IGF-I measurement may be a better indicator of treatment success than GH measurement; 4) octreotide concentrations do not correlate with GH suppression; and 5) deterioration of carbohydrate tolerance does occur but tends to improve during chronic treatment.