Long-term treatment of acromegaly with bromocriptine.

Treatment with bromocriptine, 30-55 mg daily, in 13 acromegalics for 1-15 months, resulted in a 60% decrease in growth hormone secretion, as judged from the excretion of growth hormone in 24-h urine. Normal excretion was obtained in 10 patients, while 1 patient showed no response. The plasma growth hormone response to O-GTT was improved, but not normalized, in 4 of 7 patients treated for more than 6 months, and marked glucosuria disappeared in two diabetics. While the secretion of TSH, LH and FSH was unchanged, the prolactin secretion was inhibited. The urine excretion of free cortisol showed a 30% decrease, possibly due to a direct effect of bromocriptine on the ACTH-secretion. Hypercalcaemia was never seen, but the initial hypercalcuria showed a modest decrease without measurable changes in the creatinine clearance. The subjective relief during long-term treatment was marked in 10 of 11 patients and the dominating symptoms disappeared in 40-67%, whereas heal-pad thickness, enlarged sellae, and visual fields remained unchanged. No serious side effects were observed. Treatment with bromocriptine seems effective and should be considered as a remedy amongst others, in suitable cases of acromegaly.     

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.     

Pituitary imaging using a labelled somatostatin analogue in acromegaly

OBJECTIVE: A number of neoplasms are known to express somatostatin receptors, and the use of somatostatin receptor imaging in their localization has recently been described. We have looked at the use of an 123I-labelled Tyr3-octreotide analogue of somatostatin in the visualization and functional characterization of growth hormone-secreting pituitary adenomas. PATIENTS: Fifteen patients with biochemically-proven acromegaly were scanned using this agent. In eight of these we also assessed acute GH responses to octreotide in order to correlate these responses with tumour uptake characteristics. MEASURES: Planar and single-photon-emission computerized tomographic (SPECT) images of the head were obtained using a gamma-camera at 10 minutes, and 4 and 24 hours, after injection of the radiopharmaceutical. Blood for serum GH was sampled for 12 hours after administration of a single dose of 100 micrograms octreotide. RESULTS: Twelve of the acromegalic subjects showed significant uptake of the radiopharmaceutical in the pituitary fossa. Of the eight patients in whom we assessed acute GH responses, five demonstrated a significant fall in GH in response to octreotide. These subjects also showed positive uptake in the pituitary on scanning. The three patients who had no fall in GH had no uptake on scanning. CONCLUSIONS: Uptake of 123I-labelled Tyr3-octreotide in the pituitary fossa appears to correlate closely with the presence of a therapeutic response to octreotide.     

Long-term treatment with 2-Br-alpha-ergocryptine in acromegaly.

Thirty acromegalic subjects underwent chronic CB154 therapy (10-20 mg daily) for periods ranging from 3 months up to 2 years. In 18 out of 21 patients, who exhibited consistent HGH reduction following acute administration of the drug, there was also during chronic treatment, a suppression of the plasma HGH levels exceeding 50% of base line values, e.g. from mean daily values between 14-197 ng/ml (mean +/- SEM = 57.8 +/- 12.4 ng/ml pre-treatment) to 2-19 ng/ml (mean 8.3 +/- 1.2 ng/ml post-treatment). In 12 of the subjects who responsed to chronic CB154 treatment, the mean daily values of HGH were below 10 ng/ml. The suppression of plasma HGH was maintained unaltered throughout the whole course of therapy. In the 9 subjects, in whom no consistent HGH decrease was evidenced with acute CB154 administration, there was accordingly a minor or no suppression of HGH values during the chronic treatment. In 13 subjects, irrespective of the degree of their GH responses, the plasma prolactin levels were constantly inhibited by CB154; instead the drug failed to modify significantly the TRH or insulin-induced GH release. These changes in the hormonal parameters were paralleled by marked clinical amelioration and improvement of some of the metabolic alterations frequently encountered in acromegaly, e.g. reduced carbohydrate tolerance, increased insulin resistance, diminished fall of plasma phosphorus after insulin, decreased urinary excretion of phosphate, hyper-hydroxyprolinuria and hyper-calciuria. Collectively, these data demonstrate that CB154 thrapy is effective in reducing HGH hyper-secretion in many acromegalic patients during long-term treatment.     

Long-term safety and efficacy of depot long-acting somatostatin analogs for the treatment of acromegaly

Depot somatostatin analogs are now increasingly being prescribed as adjuvant and primary therapy for the treatment of acromegaly. Previous studies have shown them to be both effective and safe, suppressing GH levels to less than 2 micro g/liter in 50-65% of cases and normalizing serum IGF-I levels in 65%. However, published data on their long-term efficacy and safety is scanty. We analyzed data from 22 patients (16 female and 6 male) treated with Sandostatin LAR or Lanreotide for an average of 41 months (range 12-89). Three patients had previously been treated with surgery, two with radiotherapy, and seven with both. Ten patients had received primary medical therapy. Mean pretreatment GH levels were 13.1 +/- 3.4 micro g/liter, and IGF-I levels were 592.9 +/- 53.9 micro g/liter. Results after 12 months of therapy indicated reduction in GH (3.2 +/- 0.7 micro g/liter; P < 0.0001) and IGF-I (321.9 +/- 33.9 micro g/liter; P < 0.001) concentrations, and this was sustained at latest follow-up. Using GH criteria (serum GH < 2 micro g/liter), 46% of subjects achieved a cure at 12 months, and 36% achieved a cure long-term. Fifty-two percent achieved normal IGF-I values at 12 months, and 67% long-term. Mean fasting and 2-h plasma glucose concentrations were similar at latest follow-up and at 12 months to baseline values. Three patients developed impaired glucose tolerance within 12 months of treatment, one going on to develop frank diabetes mellitus. However, glucose tolerance improved in five patients. Five patients developed gallstones while on treatment. In summary, this study reports the long-term efficacy of the depot somatostatin analogs as either adjuvant or primary therapy. Although overall glucose tolerance did not change, the development of impaired glucose tolerance in three patients at a time when GH levels were not changing highlights the ongoing need to monitor the long-term safety of these preparations.     

The effects of pre-operative somatostatin analogue therapy on treatment cost and remission in acromegaly

Purpose

To investigate the effects of preoperative somatostatin analogue (SSA) treatment on the annual cost of all acromegaly treatment modalities and on remission rates.

Methods

The medical records of 135 patients with acromegaly who were followed at endocrinology clinic of Cerrahpasa Medical Faculty for at least 2 years after surgery between 2009 and 2016 were reviewed.

Results

The mean follow-up time was 50.9?±?25.7 months. Early remission was defined according to 3rd month values in patients who didn’t achieve remission, and 6th month values in patients who achieved remission at the 3rd month after surgery. The early and late remission rates of the entire study population were 40% and 80.7%, respectively. The early remission of the preoperative SSA-treated group (61.5%) was significantly higher than SSA-untreated group (31.2%) (p?=?0.002). The early remission of the preoperative SSA-treated patients with macroadenomas (52.2%) was also significantly higher than the SSA-untreated group (23.5%) (p?=?0.02). In the subgroup analysis; this difference was much more pronounced in invasive macroadenomas (p?=?0.002). There were no differences between the groups in terms of late remission.The median annual cost of all acromegaly treatment modalities in study population was €3788.4; the cost for macroadenomas was significantly higher than for microadenomas (€4125.0 vs. €3226.5, respectively; p?=?0.03). Preoperative SSA use in both microadenomas and macroadenomas didn’t alter the cost of treatment. The increase in the duration of preoperative medical treatment had no effect on early or late remissions (p?=?0.09; p?=?0.8).

Conclusions

Preoperative medical treatment had no effect on the costs of acromegaly treatment. There was a benefical effect of pre-operative SSA use on early remission in patients with macroadenomas; however, this effect didn’t persist long term.

     

Long-term treatment outcome in acromegaly.

A number of groups have developed guidelines to indicate whether an individual with acromegaly has been cured by treatment. However, studies to date do not provide a robust definition of biochemical remission of the disorder based on correlation with long-term outcome. Available data suggest that those with a random serum growth hormone (GH) level of <2.5 microg/l, or a glucose-suppressed GH level of <1 microg/l following treatment have mortality figures indistinguishable from the general population. However, the confidence limits for these mortality estimates are quite wide. It remains possible that growth hormone levels lower than 1 microg/l for random samples, or even lower when using ultrasensitive GH assays, may indicate superior outcome, but this remains to be confirmed. There are limited data relating serum insulin-like growth factor-I (IGF-I) levels to outcome, although normalisation of serum IGF-I clearly improves outcome compared with continued elevation of measurements after treatment. Current evidence suggests that a post-treatment random serum GH <2.5 microg/l and a normal serum IGF-I value defines biochemical cure. Available data suggest that achieving similar growth hormone levels after treatment also reduces the prevalence of chronic complications of the disorder, which is subsequently reflected in improved mortality.     

Effect of gender and gonadal status on the long-term response to somatostatin analogue treatment in acromegaly

:GH and IGF-I secretion is related to gender and age. OBJECTIVE: To evaluate the impact of gender and gonadal status on the long-term sensitivity to the somatostatin analogues depot octreotide long-acting release (OCT-LAR) and lanreotide (LAN). PATIENTS: Seventy-three patients with active acromegaly (37 women, median age 34 years; 36 men, median age 38 years) who had not previously been treated with somatostatin analogues were studied: 24 women and 23 men were newly diagnosed; 22 men (61.1%) and 17 women (45.9%) had hypogonadism (P=0.28). Exclusion criteria were age >45 years, follow-up less than 12 months, mixed GH/PRL-secreting adenomas. Study design Observational, analytical, retrospective. Outcome measures (1) Disease control measured as serum GH< 2.5 microg/l and IGF-I normal for age and gender; (2) reduction in tumour volume graded as absent (< 25%), mild (25-50%) and notable (>50%). Results Basal GH, but not IGF-I, levels were higher in women than in men both in the entire series and in 'de novo' patients (97.8+/- 42.2 vs. 71.1+/- 32.6 microg/l, P=0.021). After 12 and 24 months of treatment, respectively, disease control was achieved similarly in men (57.1 and 86.7%) and women (48.6 and 86.7%). Hypogonadal men had longer disease duration than eugonadal men (P=0.022), without any difference in the other parameters. No difference was found between eugonadal and hypogonadal women. Eugonadal men had a smaller tumour volume at baseline than eugonadal women (1396+/- 794 vs. 2896+/- 2871 mm(3), P=0.025). In men undergoing testosterone replacement and withdrawal, there was no change in GH and IGF-I levels after 12 and 24 months of treatment with either LAR or LAN. In the seven women receiving oestro-progestinic replacement, after 24 months of LAR or LAN treatment GH levels were higher during replacement than at withdrawal and IGF-I levels were lower during replacement than withdrawal. Tumour volume decreased significantly in both women and men without any difference between them: the percentage tumour shrinkage in men and women was similar either after 12 (34.4+/-24.4 vs. 40.7+/-22.5%, P=0.38) or 24 months of treatment (58.5+/- 17.4 vs. 56.1+/- 23.6%, P=0.75). Similarly, there was no difference in tumour volume between hypogonadal and eugonadal women and men. CONCLUSIONS: The results of this study demonstrate that long-term responsiveness to OCT-LAR is similar in women and men. Care should be taken in women with acromegaly and hypogonadism treated with somatostatin analogues and oral oestro-progestinic as in this case GH levels are higher while IGF-I levels are lower than after the somatostatin analogues alone.     

Long-term efficacy and safety of combined treatment of somatostatin analogs and pegvisomant in acromegaly

BACKGROUND: We previously reported the efficacy of a combined treatment of active acromegaly with both long-acting somatostatin analogs (SSA) and pegvisomant (PEG-V). OBJECTIVE: Our objective was to assess long-term efficacy and safety in a larger group of acromegalic patients after a period of 138 (35-149) wk [median (range)]. DESIGN: PEG-V was added to high-dose SSA treatment in 32 subjects (13 females) who had not shown a normalization in serum IGF-I concentrations during SSA monotherapy. PEG-V dosage was increased until IGF-I concentration normalized. The maximal dose was 80 mg twice weekly. RESULTS: After dose finding, IGF-I remained within the normal range in all subjects with PEG-V administered once (n = 24) or twice (n = 8) weekly, on a total weekly dose of 60 (40-160) mg. Baseline IGF-I levels were positively correlated with the required dosage of PEG-V (r = 0.48; P = 0.006). PEG-V-dependent liver enzyme disturbances were observed in 11 (6 diabetic) subjects, of which symptomatic gallstones explained two cases. These liver enzyme disturbances were transient in all subjects without discontinuation or dose adaptation of PEG-V. In our series, diabetic patients had a 5.1 times (odds ratio) (confidence interval, 1.02-25.54; P < 0.05) higher risk for developing liver enzyme disturbances. These liver enzyme disturbances seemed to occur earlier. Pituitary adenoma size decreased in four patients. No increase in tumor size was observed in any of the patients. CONCLUSION: Long-term combined treatment with long-acting SSA and (twice) weekly PEG-V for active acromegaly seems to be effective and safe. Patients with acromegaly and diabetes seem to have a higher risk of developing transient liver enzyme disturbances.     

The effects of somatostatin analogue therapy on pituitary tumor volume in patients with acromegaly

Introduction

In nearly all cases, acromegaly is caused by excess GH from a pituitary adenoma, resulting in elevated circulating levels of GH and, subsequently, IGF-1. Treatment goals are to eliminate morbidity and restore the increased mortality to normal rates. Therapeutic strategies aim to minimize tumor mass and normalize GH and IGF-1 levels. Somatostatin analogues are the medical treatment of choice in acromegaly, as first-line or post-surgical therapy, and have proven efficacy in pituitary tumor volume reduction (TVR).

Methods

Here we review the effects of somatostatin analogue therapy on pituitary tumor volume in patients with acromegaly.

Results

TVR with somatostatin analogues may be mediated by direct anti-proliferative effects via activation of somatostatin receptors, or by indirect effects, such as angiogenesis inhibition, and is more pronounced when they are administered as first-line therapy. Various studies of first-line treatment with octreotide LAR have shown significant TVR in ≥73 % of patients. First-line treatment with lanreotide Autogel has shown evidence of TVR, although more studies are needed. In a recent randomized, double-blind, 12-month trial in 358 medical-treatment-naïve acromegaly patients, significant TVR was achieved by 81 % of patients administered pasireotide LAR and 77 % administered octreotide LAR. Pre-operative somatostatin analogue therapy may also induce TVR and improve post-operative disease control compared with surgery alone. TVR is progressive with prolonged treatment, and decreased IGF-1 levels may be its best predictor, followed by age and degree of GH decrease. However, TVR does not always correlate with degree of biochemical control.

Conclusion

Somatostatin analogues (first- or second-line treatment) are the mainstay of medical therapy and, as first-line medical therapy, are associated with significant pituitary TVR in most patients.

     

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.     

Effective treatment of diabetic diarrhoea with somatostatin analogue, octreotide.

A 22 year old insulin dependent diabetic with high volume, secretory chronic diarrhoea refractory to standard andiarrhoeal drugs was treated with the somatostatin analogue octreotide, 50 micrograms twice daily by subcutaneous injection. She improved markedly with a decrease in mean stool weight from 1170 g/24 h range 440-2900 g) to 440 g/24 h (range 180-800 g) (p < 0.05). Stool frequency also decreased from six (range two to 12) to one (range one to three) bowel movements per day (p < 0.01). Mouth to caecum transit time increased from 45 minutes to > 210 minutes, although total gut transit time was unchanged and remained rapid at nine hours. Thus octreotide can reduce stool volume and frequency in high volume diabetic diarrhoea when conventional antidiarrhoeal agents have failed. Its therapeutic benefit appeared to be predominantly related to a marked increase in mouth to caecum transit time.     

Adenoma granulation pattern correlates with clinical variables and effect of somatostatin analogue treatment in a large series of patients with acromegaly

Context Somatotroph adenomas have been classified into densely granulated (DG) and sparsely granulated (SG) tumours with a transitional, intermediate group. Gsp oncogenes are activating mutations in the Gsα subunit gene, found in approximately 40% of somatotroph adenomas. Objectives To explore granulation pattern and presence of gsp oncogene in acromegaly with correlations to clinical and biochemical variables and to the effect of treatment with somatostatin analogues (SA), as well as to describe granulation pattern in adenomas with and without SA pretreatment. Design/settings/patients Seventy‐eight patients with active acromegaly were included. Long‐term SA efficacy was evaluated in 29 patients treated preoperatively and in ten treated postoperatively. Granulation pattern was examined, as were immunohistochemical analyses for E‐cadherin and SSTR2a. Protein levels of E‐cadherin and SSTR2a were measured (Western blot). Gsp mutation analysis was available for 74 adenomas. Results DG adenomas and the transitional group had higher serum levels of IGF‐1 per tumour volume than SG (P = 0·009; P = 0·005). Acute and long‐term SA responses were lower in SG (P = 0·001; P = 0·043). No correlation between gsp mutation and granulation was found, and no difference in granulation pattern according to preoperative SA treatment was demonstrated. A significant correlation between granulation and E‐cadherin was found, where SG had lowest immunohistochemical expression, substantiated by protein levels, and a highly significant gradient was observed from DG, through the transitional group, to SG. Conclusions Densely granulated adenomas were highly responsive to somatostatin analogues in contrast to SG adenomas. The transitional group behaved clinically more like DG adenomas. However, based on E‐cadherin, a marker of dedifferentiation, the transitional group seemed to be a true intermediate.     

Treatment of resistant acromegaly with a long-acting somatostatin analogue (SMS 201-995)

Six patients with resistant acromegaly were given a long-acting somatostatin analogue (SMS 201-995) for 5 to 12 months. The clinical response was dramatic; relief of headache occurred within minutes of the injection. The mean 24-hour growth hormone levels fell acutely after the administration of 50 or 100 micrograms every 12 hours, especially in four patients with small tumors (p less than 0.001). Dosages of up to 1500 micrograms/d were necessary to produce maximum lowering of growth hormone secretion in some patients. On long-term treatment, plasma somatomedin-C levels fell in all patients and became normal in four. Plasma immunoreactive levels of SMS 201-995 related inversely to growth hormone concentration: A reproducible threshold for growth hormone inhibition in five of the patients, ranging from 70 to 1200 pg/mL, was maintained for 6 to 8 hours after the injections. This somatostatin analogue is effective in the treatment of acromegaly, has no major side effects, and causes only transient changes in carbohydrate metabolism.     

Optimal dosage interval for depot somatostatin analogue therapy in acromegaly requires individual titration

BACKGROUND: The recent introduction of the depot somatostatin analogues octreotide LAR and lanreotide represent major advances in the medical treatment of acromegaly. However, it is uncertain whether the recommended dose intervals of 4 weeks and 10-14 days, respectively, are applicable to all patients. AIMS: To determine the optimum intervals between depot injections of either octreotide LAR and lanreotide for the suppression of serum GH and IGF-I in patients with acromegaly. Twenty-seven patients with acromegaly were randomly allocated to receive either three injections at 4 week intervals of octreotide LAR (n = 18) or five injections at 14 day intervals of lanreotide (n = 11); two patients participated in both arms. Prior to the first injection, at 4 and 6 weeks after the last injection of LAR, and at 10, 14 and 21 days after the last injection of lanreotide, serum mean GH and IGF-I levels were measured. RESULTS: In the LAR-treated group, at 4 and 6 weeks after the third injection 13 patients (72%) and 12 patients (67%), respectively, had a mean GH < 5 mU/l. IGF-I was normalized in 12 and 11 patients at these times. In the lanreotide-treated group, five (45%), four (36%) and three (27%) patients, respectively, had a GH < 5 mU/l at 10, 14 and 21 days after the last injection and eight, six and five patients had a normal serum IGF-I. CONCLUSION: There is marked variability in individual patient responses to depot somatostatin analogues. The establishment of optimal drug intervals requires careful assessment. For octreotide LAR many patients may be as adequately controlled with 6 weekly injections as with 4 weekly injections. It is important to measure serum GH profiles at intervals after initiating therapy with these drugs to individualize doses for each patient and hence minimize cost.     

Glucose status in patients with acromegaly receiving primary treatment with the somatostatin analog lanreotide

To describe glucose status changes in patients with acromegaly receiving somatostatin analog lanreotide as primary treatment. This retrospective, single-center study conducted during 1996-2008, included acromegalic patients receiving primary lanreotide treatment. Baseline and last follow-up visit assessments included glucose status (according to American Diabetes Association criteria), growth hormone (GH), and insulin-like growth factor-1 (IGF-1) levels. Glucose control was considered improved when fasting plasma glucose or antidiabetic treatments were reduced, and deteriorated if fasting glucose was the same/higher but with increased antidiabetic treatments. 42 patients (median age 50?years; range 29-75?years) were included. At baseline, 26 (62%) were normoglycemic, eight (19%) had impaired glucose tolerance/fasting glycemia, and eight (19%) had diabetes mellitus; family history of diabetes mellitus was significantly associated with abnormal glucose status. At final visit, the mean (SE) lanreotide dose was 108 (21) mg/month. Median treatment duration was 23?months, range 3-138?months, and 74% of patients received the 120-mg dose. Median GH levels decreased significantly (baseline, 12 [5-20] μg/l; final visit, 2.1 [1.0-4.7] μg/l; P?相似文献