The sensitivity of growth hormone secretion to medical treatment in acromegalic patients: influence of age and sex

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: We performed a retrospective study. Correlations were determined between all variables using univariate regression analysis. PATIENTS: 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: 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.     

Inverse correlation between insulin-like growth factor binding protein-I and insulin in patients with acromegaly during treatment with the somatostatin analogue octreotide

OBJECTIVE Previous reports have shown an inverse relation between IGFBP-1 and Insulin levels In healthy men, patients with insulin dependent diabetes mellitus, and insulinoma. We have investigated whether this inverse relation also exists in acromegaly, before and during treatment with octreotide, and whether changes in IGFBP-1 levels relate to OH and IGF-I levels. DESIGN We studied short-term treatment with octreotide in a double-blind placebo-controlled 14-day clinical trial. PATIENTS Eighteen patients with acromegaly were studied. MEASUREMENTS Plasma GH and serum IGFBP-1 levels were measured at hourly intervals from 0700 to 1800h before randomization (day 0) and on days 4, 6, 8,14 and 20. Serum insulin was determined at 0700, 0800 and 0900 h, and serum IGF-I at 0700 h. RESULTS Octreotide increased the daily mean IGFBP-1 level by 43% on day 8 and by 35% on day 14. The IGFBP-1 levels during octreotide were significantly higher (P < 0·05) compared to placebo, 29·9 ± 3·9 vs 19·9 ± 1·7 μg/l (mean ± SEM) on day 8, and 28·3 ± 3·2 vs 19·.9 ± 1·6 μg/l on day 14. Octreotide treatment significantly suppressed the insulin levels on all observation days by 40–48% compared to placebo. There was a significant inverse correlation between IGFBP-1 levels and insulin levels, both before treatment and on the last day of treatment (r= 0·79, P= 0·04; r=?0·90, P= 0·02, respectively). GH and IGF-I were significantly decreased in the octreotide group compared to the placebo group during the entire treatment period. The mean of age related standard deviation scores of IGF-I In the octreotide group decreased from a pretreatment value of 6·47 ± 0·74 to 3·60 ± 1·20 on day 14. There was no significant correlation between IGFBP-1 levels and levels of GH and IGF-I, either before or during treatment. CONCLUSIONS Octreotide treatment, in addition to reducing GH, IGF-I and insulin levels, is associated with an Increase in IGFBP-1 concentrations in patients with acromegaly, and it is suggested that the rise in serum IGFBP-1 Is a consequence of the decrease In insulin secretion.     

The effect of a new slow-release, long-acting somatostatin analogue, lanreotide, in acromegaly

OBJECTIVE Previous studies have shown that somatostatin analogues such as octreotide and lanreotide are effective in suppressing GH and IGF-I levels in acromegaly, but the mode of administration and the frequency of injections were inconvenient for the patients. We have evaluated the effects of a new slow-release (SR), long-acting formulation of lanreotide, a somatostatin analogue, on clinical, biochemical and safety responses in acromegaly. DESIGN We studied the effects of SR-lanreotide 30mg administered intramuscularly twice or three times monthly for 6 months. Ten patients were studied, in whom acromegaly was confirmed by clinical features,mean GH>5 mU/l, and failure to suppress GH to <2 mU/l after a 75-g oral glucose load. MEASUREMENTS Subjective improvement in clinical symptoms of acromegaly was graded and recorded. Any adverse reactions were noted. Plasma GH levels were measured every 10min for one hour from 0830–0930h; fasting IGF-I levels were determined at 0830h; GH, glucose and insulin responses to oral glucose loading were measured at 0,30,60,90 and 120minutes from 0930 to 1130h. Baseline measurements were carried out and repeated at 3 and 6 months. Biliary ultrasonography was performed at baseline and 6 months. RESULTS GH levels in the10 patients decreased from 26.8±12.0 (mean SEM) to 12.7±7.0 mU/l at 3 months (P=0.04) and 9.8±5.0 mU/l at 6 months (P=0.06). Fasting IGF-I levels decreased from 123.2±27.0 to 73.5±13.0nmol/l at 3 months (P=0.01), and increased slightly to 97.4±31.0nmol/l (P=0.05) but remained below baseline levels at 6 months. Five patients achieved good control (GH<5 mU/l) at 3months. In the remaining 5 patients the dose frequency was increased to every 10 days and one achieved good control. IGF-I levels normalized in 3 and 5 patients at 3 and 6 months, respectively. Fasting insulin levels and peak insulin after an oral glucose load did not change significantly at 3 months but decreased from 11.7±2.0 to 7.8±3.3 mU/l (P=0.05) and 106.2±24.6 to 53.3±14.3 mU/l (P=0.04) at 6 months, respectively. There was no significant change in fasting glucose at 3 or 6 months. Most patients reported clinical improvement in acromegalic symptoms. No major adverse events were reported, but mild to moderate gastrointestinal symptoms were recorded after the initial injections. One patient developed asymptomatic gallstones at 6 months. CONCLUSIONS This slow-release formulation of lanreotide given either twice or thrice monthly was well tolerated, more convenient for patients, effective in controlling and alleviating the symptoms of acromegaly, as well as suppressing GH and IGF-I levels, and had no detrimental effects on carbohydrate tolerance in acromegaly.     

Acute effects of a single administration of dexamethasone on basal and growth hormone-releasing hormone stimulated GH secretion in acromegaly

A single administration of dexamethasone causes both an early stimulatory and a late inhibitory effect on GH secretion in normal subjects. OBJECTIVE We investigated the effects of a single administration of dexamethasone on basal and GH-releasing hormone-stimulated GH secretion in eight patients with active acromegaly. DESIGN On three different days the patients received 4 mg i.v. dexamethasone, 1 μg/kg body weight GH-releasing hormone 1-29, or matched placebos in different order. PATIENTS Eight subjects with active acromegaly, five of whom had not been treated previously, while the other three had received octreotide therapy which was stopped at least 7 days before testing. MEASUREMENTS Serum GH levels were measured in duplicate by a commercially available RIA kit. RESULTS Dexamethasone administration caused a significant decline of mean ± SE GH levels from 51.8 ± 13.8 to 30.0 ± 9.2 mU/l at 180 minutes, that was not influenced by placebo administration at 180 minutes. On the contrary, when GH-releasing hormone substituted placebo administration, GH levels increased from 34.0 ± 9.8 mU/l at 180 minutes to 56.0 ± 15.6 mU/l at 195 minutes. The GH increase was higher when GH-releasing hormone was given without dexamethasone pretreatment (from 52.4 ± 13.0 mU/l at 180 minutes to 86.4 ± 25.4 mU/l at 195 minutes). Analysis of the GH area under the curve confirmed the significant inhibition of GH secretion after dexamethasone administration and the significant reduction of the GH response to GH-releasing hormone in the study with dexamethasone pretreatment. CONCLUSIONS At variance with data in normal subjects, acute i.v. administration of dexamethasone inhibits basal GH secretion and partially suppresses the GH response to GH-releasing hormone in acromegaly. Both alterations in the regulatory mechanism of adenomatous cells and perturbations of hypothalamic regulatory influences, induced by the state of chronic GH hypersecretion, are likely explanations of the different response to dexamethasone.     

A long-term dose-response study of somatostatin analogue (SMS 201-995, octreotide) in resistant acromegaly

Ten acromegalic subjects were studied in a trial designed to ascertain the optimum dosage of the somatostatin analogue SMS 201-995 (octreotide) in active acromegaly. Twenty-four-hour growth hormone (GH) profiles were assessed monthly for 6 months and again after 1 year of continuous therapy. After basal assessment octreotide was administered subcutaneously at a dose of 100 micrograms three times a day throughout the first month. The dose was increased by 300 micrograms/day at monthly intervals to a maximum of 1500 micrograms/day, unless serum GH fell to within set criteria. Eight patients completed the trial. One patient withdrew because of intractable diarrhoea while another died of causes related to his acromegaly and we have no evidence that octreotide played any part in his death. Mean 24-h GH fell from a basal level of 34.3 +/- SEM 7.6 mU/l to 8.0 +/- 1.3 mU/l (P less than 0.05) after 6 months. At 1 month (300 micrograms/day) mean GH was 13.6 +/- 2.2 mU/l and at 2 months (600 micrograms/day) 10.8 +/- 2.2 mU/l (P less than 0.05 vs 300 micrograms/day dose), and at 5 months (1500 micrograms/day) 11.3 +/- 2.0 mU/l (all P less than 0.05 vs basal). Analysis of group means revealed no significant difference between any dose schedules above 600 micrograms/day. After 1 year the mean GH of the group (n = 8) was 7.5 +/- 1.3 mU/l (P less than 0.05 vs basal). Three patients developed a deterioration and one an improvement in their glucose tolerance and three developed asymptomatic gallstones during the year of therapy. In conclusion, octreotide lowered GH levels in acromegaly over a 1-year period. We found no evidence that routinely increasing the dose beyond 600 micrograms/day was helpful.     

The pulsatile GH secretion in acromegaly: Hypothalamic or pituitary origin?*

OBJECTIVE: We studied the effects of different modes of octreotide therapy on the pulsatile pattern of GH release in an attempt to define better its regulation by growth hormone-releasing hormone (GHRH) and somatostatin and its effects on IGF-I plasma levels in acromegaly. DESIGN: In six acromegalic patients not cured by previous treatment we compared the 24-hour GH secretion profiles under basal conditions with subcutaneous (s.c.) bolus injections of 100 micrograms octreotide every 8 hours and with continuous s.c. infusions of the same daily dose. Blood samples were taken every 10 minutes over 24 hours followed by a GHRH test (100 micrograms GHRH i.v.) with blood sampling every 15 minutes for another 2 hours. After a 4-week interval all patients were treated either by the bolus or continuous mode of octreotide application in a randomized cross-over design. On day 4 of treatment blood sampling and GHRH test were repeated. Octreotide treatment was withdrawn for another 4 weeks; all patients then received the alternate application mode and were measured under similar conditions. MEASUREMENTS: Serum GH and plasma IGF-I concentrations were analysed by serial array averaging. IGF-I levels were measured in two different assays with and without previous protein extraction. For GH pulse detection three different algorithms (Cluster, Pulsar, Desade) were applied. RESULTS: With both treatments, the initially elevated basal 24-hour mean serum GH concentrations (58.0 +/- 9.7 mU/l mean +/- SEM) decreased significantly (bolus: 11.5 +/- 4.9 mU/l, P < 0.001 vs basal; continuous infusion: 7.6 +/- 1.9 mU/l, P < 0.001 vs basal) after 4 days. GH suppression was significantly more pronounced following continuous infusion than bolus (P < 0.05). IGF-I plasma concentrations were lowered significantly (P < 0.05) with both forms of treatment which did not differ between themselves. Bolus and continuous infusion treatment significantly inhibited (P < 0.05) the amplitudes of pulsatile GH release, but did not change the pulse frequency. In two of the patients, GHRH stimulation did not increase GH serum levels suggesting a constitutive activation of adenylyl cyclase. CONCLUSION: Continuous subcutaneous octreotide treatment in acromegaly suppresses mean GH levels better than bolus injection. The number of GH pulses remains unaffected by both modes of treatment providing evidence against a somatostatinergic mechanism of pulsatile GH secretion in these patients. The unchanged frequency of pulsatile GH release in the patients unresponsive to exogenous GHRH indicates that this pattern might be independent of hypothalamic GHRH and somatostatin and suggests a pituitary-derived mechanism for GH pulse generation in acromegaly.     

Intravenous octreotide test predicts the long term outcome of treatment with octreotide-long-acting repeatable in active acromegaly.

OBJECTIVE: Depot formulations of somatostatin analogues are increasingly used in the treatment of active acromegaly. A priori knowledge of the efficacy of these drugs in controlling GH excess is clinically relevant, because only approximately 60% of the patients respond with adequate control of GH (GH levels < 5 mU/L) and/or IGF-1 levels upon this treatment. Therefore, we assessed the acute responses of serum GH levels to a new octreotide test (intravenous administration of 50 microg) in 98 consecutive patients with active acromegaly and we measured the predictive value of this test for the efficacy of chronic octreotide-long acting repeatable (octreotide-LAR) treatment in 18 patients. DESIGN: Serum GH concentrations were measured before and at 20, 30, 45, 60, 90, 120, 150 and 180 min following 50 microg i.v. octreotide. The minimal achieved GH was used for analysis. Octreotide-LAR was individually titrated aiming at a normal serum IGF-I for age and a serum GH < 5 mU/L. The mean of 3-6 monthly serum GH and IGF-I measurements after individual dose adjustment was used for evaluating the efficacy of chronic therapy. RESULTS: Octreotide decreased GH levels to values below 5 mU/L in only 49% of unselected consecutive patients and the response was inversely related to basal GH levels. In patients with baseline GH above 50 mU/L, 50 microg i.v. octreotide reduced GH to < 5 mU/L in only 15% of cases (n = 41), whereas in patients with baseline GH levels below 50 mU/L this goal was achieved in 77% of cases. The fractional decrease in GH levels upon octreotide injection was similar in microadenomas and macroadenomas. The minimally achieved serum GH concentration during the intravenous octreotide test was a good predictor for the GH concentrations during long-term octreotide-LAR treatment as assessed in 18 patients. The intravenous octreotide test, using a minimal GH level of < 5 mU/L, had a sensitivity, positive and negative predictive value of 100% for prediction of GH suppression to below 5 mU/L during long term octreotide-LAR treatment. For predicting the response of IGF-I during long-term treatment, the test performed with a sensitivity of 73% and a positive predictive value of 73%. CONCLUSION: Intravenous octreotide reduces GH to concentrations < 5 mU/L in approximately 50% of consecutive patients with active acromegaly, which predicts a good response to chronic octreotide-LAR treatment.     

Bromocriptine treatment over 12 years in acromegaly: effect on growth hormone and prolactin secretion.

It is not known whether bromocriptine treatment in acromegaly can be implemented for a life-long period. To elucidate this problem, the secretory GH and PRL states of 12 patients with acromegaly were determined, before bromocriptine treatment, under therapy (15.0 +/- 6.8 mg/day for 12 +/- 3 years; mean +/- SD) and during two-weeks long drug withdrawal after long-term treatment, respectively. Before therapy, all patients showed a non-sufficient GH suppression after oral glucose load (greater than 2 micrograms/l), whereas under dopaminergic treatment the post-glucose GH levels of three patients fell below 2 micrograms/l; normal IGF-I concentrations were found in five patients. However, under bromocriptine, only two patients showed GH suppressions below 2 micrograms/l following glucose, accompanied with normal IGF-I levels. During bromocriptine withdrawal, GH secretion at 60 min in the oral glucose tolerance test increased significantly (17.0 +/- 15.5 vs 5.7 +/- 5.2 micrograms/l; p less than 0.01); the mean IGF-I level rose from 2.1 +/- 0.8 to 4.9 +/- 2.2 kU/l (p less than 0.01). IGF-I was normal during bromocriptine cessation in only one patient; none of the 12 patients showed a GH suppression below 2 micrograms/l after oral glucose load. Under dopaminergic treatment hyperprolactinemia could not be detected. In conclusion, bromocriptine led to a stable suppression of both GH hypersecretion and--if present--concomitantly elevated PRL levels. Severe side effects or a further tumor growth could not be observed. Thus, the data of the longest follow-up investigation that has so far been published indicate that effective life-long bromocriptine therapy seems to be possible in selected patients with acromegaly.     

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.     

Treatment of Chinese acromegaly with a combination of bromocriptine and octreotide

Background : Good results have been reported with combined use of octreotide and bromocriptine in acromegalic Caucasians. Data concerning the efficacy and tolerability of this combination treatment in Chinese acromegalic patients are scanty.
Aim : The aim of this study was to assess the efficacy and tolerability of combined therapy using bromocriptine and octreotide in the treatment of acromegaly in Chinese patients and to compare the cost-effectiveness of various regimes.
Methods : Sixteen Chinese acromegalic patients with growth hormone (GH) concentration not suppressible to below 5 mU/L (2 μg/L) during an extended OGTT were recruited to undergo four phases of the study. During the study period, the patients were given bromocriptine alone, bromocriptine and low dose octreotide, bromocriptine and medium dose octreotide, and medium dose octreotide alone. Plasma concentrations of GH and insulin-like growth factor-1 (IGF-1) were measured before and after the completion of each phase.
Results : The number of patients reaching target GH concentrations was significantly higher when treated with octreotide compared to baseline ( p <0.05). Bromocriptine alone had a significant effect but not to the extent of octreotide alone. A combination of low dose octreotide and bromocriptine is as efficacious in the treatment of acromegaly as high dose octreotide. None of the patients suffered from serious adverse effects.
Conclusion : The results confirmed the usefulness and tolerability of bromocriptine and octreotide in Chinese acromegalics. The most cost-effective regime in this study was a combination of low dose octreotide and bromocriptine.     

The value of an acute octreotide suppression test in predicting long-term responses to depot somatostatin analogues in patients with active acromegaly

BACKGROUND: The long-acting depot somatostatin analogues [octreotide LAR (LAR) and lanreotide (LAN)] are among the most effective available medical therapies for acromegaly. However, published data on a biochemical test suitable for predicting the responsiveness to these depot agents are lacking. AIM: To investigate the value of an acute octreotide suppression test (OST) in predicting the responses to treatment with long-acting somatostatin analogues in patients with active acromegaly. PATIENTS AND METHODS: Thirty patients with active acromegaly [mean GH in GH day curve (GHDC) > 5 mU/l] were subjected to an OST [hourly GH measurements for 6 h following 100 microg subcutaneous (s.c.) octreotide]. Subsequently, 14 patients were treated with LAR, 10 with LAN and 6 received both drugs at different times. The final response to treatment was evaluated when the subjects had achieved 'safe' GH levels (mean GH < 5 mU/l) or after receiving the maximal dose of each drug (maximum duration of treatment 6 months). RESULTS: The nadir GH values during the OST were 2.6 +/- 2.5 mU/l (mean +/- SD, range 0.2-8.7) with a percentage fall of 84.8 +/- 15.7% (mean +/- SD, range 26-99%) from the baseline levels (26.2 +/- 31.5 mU/l, mean +/- SD). All the patients except one showed a decrease of greater than 50%. The mean time to achieve the nadir GH value was 3.8 +/- 1.6 h (mean +/- SD, range 1-6). The nadir GH levels showed a positive correlation with both pre-treatment (i.e. before commencing LAN or LAR) GH values during the GHDC (r = 0.63, P < 0.01) and IGF-I levels (r = 0.56, P < 0.05). The nadir GH values during the OST showed a positive correlation with the achieved mean GH levels in patients treated with LAR (r = 0.66, P < 0.01) but not in the ones treated with LAN. The criterion of GH < 5.25 mU/l during the OST had sensitivity 100%, specificity 80%, positive predictive value (PPV) 94% and negative predictive value (NPV) 100% in predicting achievement of 'safe' GH levels in patients treated with LAR. A less optimal prognostic profile was obtained for subjects treated with LAN with the criterion of GH < 6.05 mU/l during the OST providing sensitivity 92%, specificity 67%, PPV 92% and NPV 67%. The above cut-off GH levels had a PPV of only 77% and 60% in predicting normalization of IGF-I on treatment with LAR or LAN, respectively. CONCLUSIONS: The OST is a reliable tool for the selection of patients with active acromegaly who will achieve 'safe' GH levels on therapy with LAR. Its prognostic profile is less optimal for patients treated with LAN. If GH values during the test fall < 5.25 mU/l (in case of LAR treatment) or < 6.05 mU/l (in case of LAN treatment), there is a 92-94% chance of subsequently achieving 'safe' GH levels after up to 6 months treatment with either of these agents.     

The efficacy and safety of lanreotide Autogel in patients with acromegaly previously treated with octreotide LAR

OBJECTIVE: Lanreotide Autogel is a sustained-release aqueous gel formulation supplied in a prefilled syringe, with injection volume <0.5 ml. The aim of this study was to establish the efficacy and safety of Autogel in patients with acromegaly previously treated with octreotide LAR. DESIGN: A 28-week, open, multicentre study. PATIENTS: Twelve patients with acromegaly, treated with 20 mg octreotide LAR for >4 months, with serum GH levels <10.0 mU/l. METHODS: Autogel (90 mg) was given every 28 days during weeks 0-12. At week 16 the dose was titrated based on GH levels at weeks 8 and 12. If GH levels were <2.0, 2.0-5.0, or >5.0 mU/l, Autogel was reduced to 60 mg, maintained at 90 mg, or increased to 120 mg respectively, for the next three injections. GH and IGF-I levels were reassessed at weeks 24 and 28. RESULTS: Ten patients completed the study. Five remained on 90 mg Autogel throughout the study; in two patients the dose was reduced to 60 mg from week 16; in three patients it was increased to 120 mg. Mean GH levels were: baseline, 3.0+/-1.7 mU/l; week 12, 3.5+/-1.8 mU/l; week 28, 3.3+/-1.6 mU/l (NS). Mean IGF-I levels were: baseline, 212+/-70 microg/l; week 12, 185+/-91 microg/l; week 28: 154+/-61 microg/l (P=0.027). Six patients at baseline and eight at week 28 had normalised GH and IGF-I levels. Three patients reported adverse events: musculoskeletal pain (n=2) and injection-site symptoms (n=1). CONCLUSIONS: Lanreotide Autogel is effective and well tolerated in patients with acromegaly. This study in a small group of patients with well-controlled acromegaly suggests that the majority of patients switched from 20 mg LAR to 90 mg Autogel will have equivalent or better disease control.     

Retrospective analysis of long-term surgical results in acromegaly: preoperative and postoperative factors predicting outcome

OBJECTIVE Sixty-one of 83 patients with acromegaly treated between 1969 and 1993 were analysed retrospectively to clarify which early postoperative factors were significant predictors of a successful long-term outcome and which preoperative factors significantly influenced the early postoperative results. PATIENTS Of the 61 patients, 30 were operated on before 1987 and 31 afterwards. A successful long-term surgical outcome was defined as a long-term mean basal GH level <6 mU/l (comparable to <3 μg/l), a normal IGF-I level, and normal GH dynamics. RESULTS Overall, 59% of patients (37% before 1987 and 81% after) had an early postoperative mean basal GH level <6 mU/l, and 56% (29% before 1987 and 77% after) met all three of the specified criteria for a successful long-term surgical outcome. Statistical analysis confirmed that GH dynamics and postoperative mean basal GH level <6 mU/l were significant predictors of the long-term surgical outcome, whereas the postoperative IGF-I level alone was not. On the other hand, abnormal preoperative GH dynamics were normalized in all patients with a postoperative mean basal level <6 mU/l. In addition, there were no patients showing an unsuccessful long-term outcome in those associated with both the early postoperative mean basal GH level <6 mU/l and normalization of the IGF-I level. Therefore, measurement of the early postoperative mean basal GH level and the IGF-I level may be an economical and simple guide to predict the long-term surgical outcome. Moreover, multivariate analysis indicated that cavernous sinus invasion was an independent significant factor influencing the early postoperative outcome. CONCLUSIONS Successful long-term surgical outcome may be predicted if early postoperative mean basal GH level is reduced to <6 mU/l (<3 μg/l) and IGF-I level becomes normal. This study also confirms that early diagnosis and treatment by an experienced endocrinologist and neurosurgeon can improve the operative results in patients with acromegaly.     

The short and long-term effects of octreotide on calcium homeostasis in patients with acromegaly

OBJECTIVE The somatostatin analogue octreotide (Sandostatin, Sandoz) is effective in reducing growth hormone levels in patients with acromegaly. Early and transient gastrointestinal side-effects are frequent. The aim was to evaluate whether gastrointestinal side-effects during the initial phase of octreotide treatment affect calcium homeostasis, and whether effects on calcium homeostasis are seen during long-term treatment with octreotide in patients with optimal effect on GH and subjectively normal gastrointestinal function. DESIGN We first studied short-term treatment with octreotide during 14 days. From day 15 of the study medication was withdrawn, and on day 20 follow-up measurements were made. We then observed the effects of long-term treatment with octreotide. Mean duration of treatment until the day of blood sampling was 32 months (range 9–48 months). PATIENTS Sixteen patients with acromegaly were studied, ten in the short-term study and ten in the long-term study; four were included in both. MEASUREMENTS Serum levels of calcium, phosphate, PTH, alkaline phosphatase, 1,25(OH)₂ Vit D, vitamin D-binding protein and sex hormone-binding globulin (SHBG) were measured before treatment (day 0) and on days 4, 6, 8,14 and 20 during the short-term study and, except SHBG, before treatment and during therapy in the long-term study. RESULTS During the short-term treatment mean (± SEM) serum calcium decreased significantly (on days 6 and 8, 2.21 ±0.08 and 2.15 ± 0.09 mmol/l, respectively vs basal level, 2.38 ± 0.08 mmol/l), whereas significant increments were seen in mean serum PTH (on day 14, 36 ± 4 vs basal, 24 ± 3 ng/l; ng/l ± 9.425 = pmol/l), mean serum 1,25(OH)2 Vit D (on day 8, 112 ± 7 vs basal 96 ± 8 pmol/l), and ‘free 1,25(OH)2 Vit D-index', i.e. molar ratio of 1,25(OH)2 Vit D and vitamin D-binding protein (on days 8 and 14, 1.72 ± 0.09 ± 105 and 1 66 ± 0.11 ± 10–5, respectively vs basal, 1.33 ± 0.09 ± 10–5). The changes were within the normal range. No changes were seen in serum phosphate, alkaline phosphatase, or vitamin D-binding protein. During the long-term study mean serum calcium and phosphate decreased significantly, 2.32 ± 0.04 vs basal 2.42 ± 0.04 mmol/l and 1.24 ± 0.07 vs basal 1.40 ± 0.09 mmol/l, respectively, whereas mean serum PTH increased significantly, 40 ± 8 vs basal 21 ± 5 ng/l. The changes were within the normal range. No changes were seen in serum alkaline phosphatase, 1,25(OH)₂ Vit D, free 1,25(OH)₂ Vit D-index, or vitamin D-binding protein. CONCLUSION Altered calcium homeostasis during octreotide treatment in acromegaly is not only initial and temporary, but can also be seen after several years of treatment. The clinical relevance of these long-standing effects needs to be further investigated.     

Comparison of octreotide acetate LAR and lanreotide SR in patients with acromegaly

BACKGROUND AND OBJECTIVE: The most effective option for the medical treatment of patients with acromegaly is the use of somatostatin analogues. Long-acting depot formulations for intramuscular injection of two somatostatin analogues have recently become available: octreotide acetate LAR (Sandostatin LAR, Novartis Pharma AG) and lanreotide SR (Somatuline, Ipsen Biotech). We wished to compare efficacy of octreotide LAR and lanreotide SR in acromegalic patients. PATIENTS AND METHODS: A group of 125 patients with acromegaly (67 females; mean age, 47 years; 59 patients had previous pituitary irradiation) from 26 medical centres in France, Spain and Germany were studied. Before the study, all patients had been treated with intramuscular injections of lanreotide SR (mean duration, 26 months) at a dose of 30 mg which was injected every 10 days in 64 and every 14 days in 61 patients, respectively. All patients were switched from lanreotide SR to intramuscular injections of 20 mg of octreotide LAR once monthly for three months. In order to obtain efficacy and safety data of lanreotide SR under study conditions, it was decided to randomly assign at day 1, in a 3 : 1 ratio, the time point of the treatment switch; 27 of the patients were randomly assigned to continue the lanreotide SR treatment for the first 3 months of the study (group A); they were on octreotide LAR 20 mg from month 4-6. The other 98 patients were assigned to be switched to treatment with octreotide LAR 20 mg at day 1 (group B). In group B patients, octreotide LAR treatment was continued until month 6, with an adjustment of the dose based on GH levels obtained at month 3. RESULTS: The mean GH concentration decreased from 9.6 +/- 1.3 mU/l at the last evaluation on lanreotide SR to 6.8 +/- 1.0 mU/l after three injections of octreotide LAR (P < 0.001). The percentages of patients with mean GH values < or = 6.5 mU/l (2.5 microg/l) and < or = 2.6 mU/l (1.0 microg/l) at the last evaluation on lanreotide SR were 54% and 14%, and these values increased after 3 months treatment with octreotide LAR to 68% and 35% (P < 0.001), respectively. IGF-I levels were normal in 48% at the last evaluation on lanreotide SR and in 65% after 3 months on octreotide LAR (P < 0.001). Patients with pre-study pituitary irradiation had lower mean GH and IGF-I concentrations. But the effects of the treatment change did not differ between the irradiated and the nonirradiated patients. In general both drugs were well tolerated. CONCLUSION: Octreotide LAR 20 mg administered once monthly was more effective than lanreotide SR 30 mg administered 2 or 3 times monthly in reducing GH and IGF-I in patients with acromegaly.     

Poor Responses to a Test Dose of Subcutaneous Octreotide Predict the Need for Adjuvant Therapy to Achieve 'Safe' Growth Hormone Levels

Objective: Somatostatin analogues are an established treatment in acromegaly. This study was designed to evaluate whether the acute serum growth hormone (GH) response to a test dose of octreotide in acromegaly predicts longer-term response to the drug at 3 years. Design and methods: In 23 patients, GH responses across 8 h to a subcutaneous test dose (50 μg) of octreotide were compared with GH levels after 3 years of therapy. The majority had pituitary surgery as primary therapy and at 3 years were receiving at least 600 μg octreotide daily subcutaneously or 20 mg LAR monthly intramuscularly. Results: Seven had a test day GH Nadir of 5 mU/l or less of whom 4 achieved GH < 5 mU/l at 3 years. Sixteen had a test day nadir GH of 10 mU/l or less and of these 8 achieved GH < 5 mU/l at 3 years. Seven of the 23 had a GH Nadir >10 mU/l and of these 3 had achieved GH <5 mU/l at 3 years. However all of these 3 had received external pituitary irradiation within 4 years of the 3 year assessment, as compared with 3 of the <5 mU/l nadir group and 5 of the <10 mU/l nadir group. Conclusions: In patients on optimal long-term doses of octreotide for acromegaly, absence of a nadir GH <10 mU/l in the 8 h after a test dose was associated with failure to achieve GH levels associated with a normal life expectancy (5 mU/l or less) unless adjunctive external pituitary irradiation was given. As well as testing tolerability a test dose of octreotide may help in determining which patients should be offered early external pituitary irradiation or therapy with a GH receptor antagonist if surgery has failed to achieve ‘safe' GH levels.     

A comparison of lanreotide and octreotide LAR for treatment of acromegaly

BACKGROUND AND OBJECTIVE: Two long-acting depot somatostatin analogues have recently been licensed for the treatment of acromegaly. We wished to assess the effectiveness of both these drugs in suppressing mean GH to a target of < 5 mU/l in patients with acromegaly unselected for responsiveness to octreotide, and also to compare the effects of both drugs METHODS: We prospectively studied 10 unselected patients with acromegaly who were treated first with lanreotide (LAN) and then octreotide LAR (LAR) following a washout period. The target for therapy was to achieve mean GH less than 5 mU/l. RESULTS: Five (50%) patients achieved mean GH < 5 mU/l on lanreotide 30 mg every 10 days, and 7 out of 9 (77.8%) achieved this level when the dose frequency was increased to every 7 days. On 20 mg octreotide LAR, 6 (60%) patients achieved the target mean GH and a further 2 (80%) when the dose was increased to 30 mg. Normalization of IGF-1 occurred in 5/9 (55.6%) patients who received lanreotide and 7/10 (70%) of those who received octreotide LAR. There was a significant difference in mean GH attained on the 2 drugs. The patients' mean GH was significantly lower when treated with octreotide LAR 20 mg every 4 weeks compared with lanreotide 30 mg every 10 days (P = 0.037). Maximal suppression of mean GH with 30 mg octreotide LAR or 7 day dosing of lanreotide was significantly greater on octreotide LAR (P < 0.02). CONCLUSIONS: At current dose recommendations, lanreotide and octreotide LAR are both effective in lowering mean GH to 'safe' (< 5 mU/l) levels in 80% patients but octreotide LAR treatment leads to significantly lower mean GH.     

Bioactive GH-like immunoglobulins G in active acromegaly: response to long-term treatment with bromocriptine*

In acromegaly, certain forms of circulating immuno reactlve hGH are not true 6H but IgGs which possess G H biological activity (bioactive G H-like IgGs). In this study, we tested the effect of bromocriptine on circulating bioactive G H-like IgGs In an acromegalic woman. Increasing doses of oral bromocriptine (2.5, 5.0 and 7.5mg/day) were administered (for 2, 8 and 6 months respectively). TRH tests were performed before treatment and at the end of treatment with each dose. The patient was without detectable pituitary or extra-pituitary tumour by magnetic resonance imaging. Her serum contained bioactive G H-like IgGs equivalent to 240mU/l of hGH and elevated insulin-like growth factor I (IGF-I; 9500 U/l). Basal hGH was 12.8 μ/l and Increased to 220mU/l 15 min after TRH (200 μg, l.v.). In addition, in the basal samples of each test we measured total IgGs (radial immunodiffusion), bioactive GH-like IgGs (isolated by Sephadex and protein A affinity chromatography and assayed using the Nb2 cell assay) and IGF-I(RIA). Bromocriptine treatment gradually reduced serum levels of bioactive GH-like IgGs and IGF-I, with significant falls observed first at 10 months of treatment. Bioactive GH-like IgGs were 240, 240, 36-0 and <0.124mU/l and IGF-I levels were 9500,8700,4000 and 3100 U/l at 0,2,10 and 16 months of treatment, respectively. In contrast, IR-hGH response to TRH decreased after 2 months of treatment to 89 mU/l and to 49.2 mU/l at the end of the study while basal IR-hGH remained between 13 and 8-4 mU/l. Basal PRL fell to almost undetectable levels. Bromocriptine treatment decreased the G H response to TRH and the serum concentration of bioactive G H-like IgGs and IGF-I. The striking similarity between the pattern of decrease of serum bioactive GH-like IgGs and IGF-I supports the presence of an immuno component in our patient's acromegaly     

Short term treatment of acromegaly with the somatostatin analog octreotide: the first double-blind randomized placebo-controlled study on its effects

Several studies suggest that the somatostatin analog octreotide, or SMS 201-995, may effectively reduce GH hypersecretion. However, no double blind, placebo-controlled study has substantiated these findings. We present the results of a randomized double blind 14-day clinical trial with octreotide in 20 patients with acromegaly. The drug was given sc every 8 h and to the initial dose (50 micrograms) was added another 50 micrograms every other day up to 200 micrograms. GH levels, calculated as the mean values of 12 observations at hourly intervals during 0700-1800 h, and insulin-like growth factor-I (IGF-I) levels were significantly reduced during octreotide treatment. Responses varied from a reduction of 97% of the basal mean GH level to no significant reduction in 2 of 10 patients. There was a good correlation between the reduction of GH and IGF-I levels. The main side-effects were gastrointestinal and well tolerated. We found a spontaneous variation of daily mean GH and IGF-I levels (at 0700 h) in the placebo group, ranging from approximately 150% to 50% of the GH and 120% to 80% of the IGF-I levels noted on day 0. In patients treated with octreotide, the occurrence of GH rises between administration times suggests that it may be desirable to give octreotide every 6 h in some patients.     

Gender and age influence the relationship between serum GH and IGF-I in patients with acromegaly

BACKGROUND: In patients with acromegaly serum IGF-I is increasingly used as a marker of disease activity. As a result, the relationship between serum GH and IGF-I is of profound interest. Healthy females secrete three times more GH than males but have broadly similar serum IGF-I levels, and women with GH deficiency require 30-50% more exogenous GH to maintain the same serum IGF-I as GH-deficient men. In a selected cohort of patients with active acromegaly, studied off medical therapy using a single fasting serum GH and IGF-I measurement, we have reported previously that, for a given GH level, women have significantly lower circulating IGF-I. OBJECTIVE: To evaluate the influence of age and gender on the relationship between serum GH and IGF-I in an unselected cohort of patients with acromegaly independent of disease control and medical therapy. METHODS: Sixty (34 male) unselected patients with acromegaly (median age 51 years (range 24-81 years) attending a colonoscopy screening programme were studied. Forty-five had previously received pituitary radiotherapy. Patients had varying degrees of disease control and received medical therapy where appropriate. Mean serum GH was calculated from an eight-point day profile (n = 45) and values obtained during a 75-g oral glucose tolerance test (n = 15). Serum IGF-I, IGFBP-3 and acid-labile subunit were measured and the dependency of these factors on covariates such as log10 mean serum GH, sex, age and prior radiotherapy was assessed using regression techniques. RESULTS: The median calculated GH value was 4.7 mU/l (range 1-104). A significant linear association was observed between serum IGF-I and log10 mean serum GH for the cohort (R = 0.5, P < 0.0001). After simultaneous adjustment of the above covariates a significant difference in the relationship between mean serum GH and IGF-I was observed for males and females. On average, women had serum IGF-I levels 11.44 nmol/l lower than men with the same mean serum GH (P = 0.03, 95% CI 1.33-21.4 nmol/l). Age significantly influenced the relationship and for a given serum GH, IGF-I was estimated to fall by 0.37 nmol/l per year (P = 0.04, 95% CI 0.015-0.72). CONCLUSIONS: In keeping with previous observations of relative GH resistance in normal and GH-deficient females we have observed lower serum IGF-I levels for equivalent mean serum GH levels in females patients with acromegaly. This gender-dependent difference is independent of disease activity and the use of concomitant medical therapy. Additionally, we have demonstrated that for a given serum GH level, age significantly influences IGF-I concentrations in patients with acromegaly. These data have important implications for the use of serum IGF-I and GH as markers of disease activity in acromegaly.