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PubMed1986

Relationship between somatomedin-C and growth hormone levels in acromegaly: basal and dynamic evaluation.

The relationship between basal and stimulated plasma GH and somatomedin-C (SmC) levels in acromegalic patients was evaluated. The basal plasma SmC levels of 66 patients were significantly correlated (P less than 0.01) with mean daily plasma GH levels, but not with the percent GH increase after GH-releasing hormone or TRH or the GH decrease after acute bromocriptine administration. Bromocriptine (7.5-15 mg/day) administration for 9.2 +/- 0.9 (+/- SD) months in 20 patients significantly (P less than 0.05) decreased GH levels. SmC decreased significantly [from 9.8 +/- 1.9 to 5.1 +/- 0.7 U/ml (mean +/- SE)] only in the 10 patients who had the more marked GH inhibition. The administration of a somatostatin analog, SMS 201-995 (100 micrograms twice daily), to 12 patients for 16 weeks significantly decreased plasma GH and SmC levels beginning on the second day of therapy; normal SmC levels were achieved in 5 of 12 patients. Pituitary adenomectomy resulted in normal GH and SmC levels in 10 of 12 and 8 of 12 patients, respectively. Our data indicate an overall dependency of plasma SmC levels on plasma GH levels in acromegaly, although similar GH levels may have differing somatomedin-stimulating activities. A derangement in the feedback mechanisms controlling GH secretion is indicated by the failure of elevated SmC levels to influence the GH responsiveness to releasing hormones. In evaluating pharmacological or surgical treatments of acromegaly, a single plasma SmC value can reliably replace several plasma GH determinations.

Acromegaly↗
PubMed1987

The response of serum growth hormone levels to the long-acting somatostatin analog SMS 201-995 in acromegaly.

SMS 201-995 (SMS) is a long-acting analog of somatostatin. We studied the effect of SMS (50-100 micrograms, sc, every 8 h) on serum GH in five patients with acromegaly. Serum GH decreased significantly in four of the five patients 4 h after SMS treatment. In two of the four patients, this reduction was not sustained for 7 h, but sustained reduction to normal GH concentrations did occur in the two patients who had basal serum GH levels below 15 ng/ml. In the two patients whose responses were not sustained for 7 h, a higher dose of SMS did not cause sustained reduction in GH. SMS was well tolerated, except for one episode of elevated serum aminotransferase levels. These results indicate that SMS-induced reductions in serum GH in patients with acromegaly are often not sustained despite SMS administration every 8 h and indicate that the insufficient duration of effect may limit its therapeutic efficacy.

Acromegaly↗
PubMed1987

Medical treatment of acromegaly with SMS 201-995, a somatostatin analog: a comparison with bromocriptine.

We studied the effects of acute and chronic sc administration of SMS 201-995 (SMS), a long-acting somatostatin analog, in acromegalic patients. The results were compared with those obtained in the same patients treated with oral bromocriptine (Brc). A single dose of 50 micrograms SMS administered to 28 patients induced a more rapid, greater, and more prolonged reduction in plasma GH levels than did 2.5 mg Brc. Chronic treatment [60-330 days; mean 208 +/- 23 (+/- SEM)] with SMS (100-300 micrograms/day) induced in 16 patients a significantly greater decrease in mean plasma GH and somatomedin-C levels than did 20 mg Brc. Combined treatment with the 2 agents had an additional effect. The clinical and metabolic parameters of acromegaly dramatically improved in all patients whose plasma GH and somatomedin-C levels decreased even if they were not normalized by SMS. Reduction in tumor size occurred in 3 of the 10 patients examined by computed tomography before and during SMS treatment. We conclude that SMS is more effective than Brc and that the 2 drugs may be complementary in the medical treatment of acromegaly.

Acromegaly↗
PubMed1989

Comparison of the effectiveness of 2-hourly versus 8-hourly subcutaneous injections of a somatostatin analog (SMS 201-995) in the treatment of acromegaly.

To determine whether sc injections of a somatostatin analog (SMS 201-995) every 2 h (q2h) is more effective than sc injections every 8 h (q8h) in achieving a constant suppression of GH levels and a more satisfactory clinical response, we studied 10 patients with acromegaly (4 newly diagnosed and 6 previously treated with bromocriptine/pituitary irradiation/transfrontal hypophysectomy). The dose of SMS 201-995 was increased from 300 micrograms/day to a maximum of 600 micrograms/day when the mean serum GH (hourly samples for 12 h) failed to be suppressed to undetectable levels in over 75% of the samples. Five patients received a 200-micrograms sc injection q8h (600 micrograms/day), and the other 5 received sc injections q2h [418 +/- 46 micrograms/day (mean +/- SE); range, 288-504 micrograms/day]. In the group receiving q2h sc SMS 201-995 there was a marked suppression of mean GH from a basal level of 77.3 +/- 24.7 mU/L to less than 5 mU/L in all five subjects. In the group receiving q8h sc SMS 201-995, mean GH was suppressed from a basal level of 82.2 +/- 21.7 to 15.4 +/- 3.3 mU/L after 6 months of therapy, and none of the patients had a mean GH level consistently less than 5 mU/L. Despite the difference in the level of GH suppression, mean serum somatomedin-C levels were decreased promptly in both groups of subjects. Associated with the decrease in somatomedin-C levels there was a marked clinical response in both groups, but improvement in clinical features and decreases in hand volumes and ring size occurred earlier in the group receiving SMS 201-995 q2h. Significant tumor shrinkage (25% to greater than 50% reduction) was observed in two patients receiving q2h injections, while a 25-50% reduction in tumor size was noted in another patient receiving q8h injections. Because of the small doses of SMS 201-995 used side-effects of abdominal discomfort and flatulence were mild and rapidly disappeared. Our results show that increasing the frequency of sc administration of the somatostatin analog from q8h to q2h leads to more marked and consistent suppression of GH levels and more rapid improvement of clinical signs. Increasing the frequency of delivery of SMS 201-995 may be an alternative to increasing the dose in some patients with acromegaly.

Acromegaly↗
PubMed1990

Growth hormone responses to oral glucose loading measured by highly sensitive enzyme immunoassay in normal subjects and patients with glucose intolerance and acromegaly.

Plasma GH levels were determined during a 75-g oral glucose tolerance test using a highly sensitive enzyme immunoassay. Most normal subjects and patients with varying degrees of impaired glucose tolerance showed a decrease in plasma GH levels during the first 60 min. A GH rise within 60 min was observed in 3 of 37 normal subjects. The incidence of the GH rise (8%) was significantly lower than that (40%) in control experiments after water loading. The median minimum GH levels were 0.15 and 0.14 micrograms/L after glucose and water loading, respectively. Plasma GH responses to glucose ingestion were not different between normal subjects and patients with glucose intolerance. After surgery, 12 of 16 patients with acromegaly showed low basal GH levels (less than 5.0 micrograms/L). Six of the 12 patients showed normal GH responses to glucose loading (median minimum GH level, 0.21 micrograms/L) and normal plasma insulin-like growth factor-I levels. Plasma GH levels were not suppressed below 1.0 micrograms/L in the remaining 6 acromegalic patients. Determination of plasma GH levels after glucose loading by the highly sensitive enzyme immunoassay is useful for evaluating the effect of surgical treatment of acromegaly.

Acromegaly↗
PubMed1990

Effective clinical response to long term octreotide treatment, with reduced serum concentrations of growth hormone, insulin-like growth factor-I, and the amino-terminal propeptide of type III procollagen in acromegaly.

Ten patients with active acromegaly, six with a poor response to previous therapies and four newly diagnosed, were treated with the long-acting somatostatin analog octreotide (Sandostatin; 200-500 micrograms/day, sc, twice or three times daily) for 6-15 months. There was rapid clinical improvement in all patients. The mean daily serum GH concentration was reduced by 64% and was normalized (all GH values less than 2 micrograms/L) in three patients. Serum insulin-like growth factor-I (IGF-I) concentrations were lowered by 40% and were normalized in eight patients. Serum concentrations of the amino-terminal propeptide of type III procollagen (PIIINP), an index of tissue collagen metabolism, were reduced by 40% and were normalized in all patients with initially elevated values. There was a statistically significant positive correlation between the mean serum GH and IGF-I levels (r = 0.47; P less than 0.001) as well as between serum GH and PIIINP levels (r = 0.34; P less than 0.05) and between serum IGF-I and PIIINP (r = 0.50; P less than 0.001). The effects of octreotide on pituitary tumor size and pathology were evaluated in one patient. The therapy did not seem to be associated with significant changes in sellar computed tomographic scans or light microscopic findings. The drug was generally well tolerated. However, indications of significant hepato-biliary dysfunction were noted in one patient after 5 months of therapy. This was reversible upon discontinuation of therapy and did not occur later during the rechallenge with a lower dose of the drug. However, there was probably newly formed cholelithiasis in four patients during the therapy. Our study suggests that octreotide is an effective and relatively safe new approach for treating active acromegaly. Further studies are needed to investigate long term effects on the hepatobiliary system.

Acromegaly↗
PubMed1991

Paradoxical response of growth hormone to peptide histidine methionine in acromegaly: comparison with the effects of thyrotropin-releasing hormone and vasoactive intestinal peptide.

We examined whether peptide histidine methionine (PHM) induces a paradoxical rise in plasma GH in patients with acromegaly. PHM (100 micrograms) was given as an iv bolus to eight patients with active acromegaly, and plasma GH levels were measured before and at intervals up to 120 min after the injection. For comparison, the effects of TRH (500 micrograms) and vasoactive intestinal peptide (VIP, 100 micrograms), peptides known to paradoxically stimulate GH secretion in acromegalics, were assessed in all of the patients. A paradoxical rise (greater than 50% above the basal) in plasma GH was observed in five patients after both TRH and VIP administrations, although TRH responders were not always VIP responders, nor did VIP responders always respond to TRH. In two patients, the GH response to PHM fulfilled the criteria of a paradoxical increase. Both of these patients were also TRH and VIP responders. These results suggest that PHM may be another hypothalamic hormone capable of paradoxically stimulating GH secretion in at least some acromegalics, although PHM appears to be a less potent stimulator of GH release than TRH and VIP. The pathophysiological significance of this phenomenon is yet to be determined.

Acromegaly↗
PubMed1992

Galanin decreases circulating growth hormone levels in acromegaly.

Galanin is able to elicit GH secretion in normal man. In acromegaly, circulating GH levels are elevated, and GH secretory dynamics are usually abnormal. The aim of our study was to investigate the effects of galanin on GH secretion in acromegalic subjects. Six acromegalic patients (four males and two females) and seven healthy adult subjects (five males and two females) underwent in randomized order: 1) iv infusion of 100 mL saline from 0-45 min, and 2) iv infusion of synthetic porcine galanin (0.5 mg in 100 mL saline) from 0-45 min. In normal subjects, peak GH levels after porcine galanin administration (8.2 +/- 1.9 micrograms/L) were significantly higher than after saline infusion (1.3 +/- 0.1 micrograms/L; P less than 0.05). In acromegalic patients, GH values fell from baseline (32.5 +/- 12 micrograms/L) to a mean nadir of 24.5 +/- 12.7 micrograms/L after galanin infusion. The mean change in GH values from baseline after galanin treatment in these subjects significantly differed from that observed after saline infusion from 15-90 min. Serum PRL levels were not significantly affected by galanin in either normal or acromegalic patients. Our results give the first evidence that the same dose of galanin, acting as a GH secretagogue in normal man, is, on the contrary, able to significantly inhibit GH in acromegalic patients. The cause of this paradoxical GH fall after galanin treatment in acromegaly remains to be explained. It can be hypothesized that galanin may interact at the pituitary level with its own receptors expressed by GH-secreting adenomatous cells.

Acromegaly↗
PubMed1994

Enhanced GH responses to combined administration of GHRP and GHRH in patients with acromegaly.

Plasma GH responses to GH-releasing peptide (GHRP) were studied in 11 patients with active acromegaly. Ten of these patients showed plasma GH increases to GHRP (100 micrograms i.v.), whereas every patient showed GH increases to TRH (500 micrograms i.v.) and GHRH (100 micrograms i.v.). When GHRP was administered together with GHRH to the 10 GHRP responders, plasma GH responses were synergistically enhanced. However, combined administration of GHRP and TRH did not enhance the response. The GH response pattern and mean time to the peak value were similar to TRH but were different from GHRH. There was no correlation in the maximum GH increment between GHRP and TRH or GHRP and GHRH. It is concluded that GHRP stimulated GH release in the majority of acromegaly patients. The mode of action of GHRP might be similar to TRH and different from GHRH, although the sites of action of GHRP seemed to be different from those of TRH and GHRH.

Acromegaly↗
PubMed1994

Impaired cardiac performance is a distinct feature of uncomplicated acromegaly.

This study was designed to assess right and left ventricular function in patients with active acromegaly. To this end, 26 acromegalic patients (9 of whom had arterial hypertension) and 15 normal subjects of comparable age and sex distribution were studied by radionuclide angiography at rest and during supine bicycle-ergometer exercise and echocardiography. At rest, the filling rates of left (-19%; P < 0.005) and right ventricle (-32%; P < 0.001) were significantly reduced in acromegalic patients, whereas right and left ventricle ejection fractions (EFs) were normal. During physical exercise, EF was considerably lower in the acromegalic patients than in controls. This was true for both left (61 +/- 11% vs. 75 +/- 8%; P < 0.001) and right ventricle (45 +/- 13 vs. 58 +/- 11%; P < 0.002). In as many as 73% of patients, EF increased less than 5%, thus fulfilling the criteria for impaired cardiac performance. Left ventricular mass index was 60% greater in acromegalics than in controls (P < 0.001). A significant difference in left ventricular mass index was also present when normotensive acromegalic patients were compared with controls (P < 0.001). No significant difference in the indices of systolic and diastolic function was observed between the subgroups of normotensive and hypertensive acromegalics, either at rest or during exercise. The data demonstrate that in uncomplicated acromegaly, besides cardiac hypertrophy, there are also important alterations of systolic and diastolic function of both ventricles, leading to a significant impairment of cardiac performance.

Acromegaly↗
PubMed1996

Development of acromegaly during treatment of hyperprolactinemia with bromocriptine: an unusual acidophil stem cell adenoma.

We present clinical details of a patient with a 20-yr history of amennorhea, a pituitary tumor, elevated PRL levels, and initially undetectable GH. Bromocriptine failed to fully suppress PRL, and there was no tumor shrinkage. Within 7 months of starting bromocriptine treatment, the patient developed clinical and biochemical signs of acromegaly. At surgery, a stem cell adenoma was excised. The mechanisms by which bromocriptine may have resulted in the development of acromegaly in this patient are discussed.

Acromegaly↗
PubMed1996

Effectiveness and tolerability of slow release lanreotide treatment in active acromegaly: six-month report on an Italian multicenter study. Italian Multicenter Slow Release Lanreotide Study Group.

The objective of the study was to determine the tolerability and effectiveness of the slow release (SR) somatostatin analog lanreotide in active acromegaly. Fifty-seven patients, unselected in terms of their previous responsiveness to octreotide therapy, were included in a prospective, open label study carried out at 6 Italian endocrinological centers. The effects of 6 months of SR lanreotide, given at first every 14 days at a dosage of 30 mg, im, were recorded. In some patients (33%), drug dosage was adjusted by increasing the dose (to 60 mg, im) and/or shortening the time interval (every 10 days) of SR lanreotide administration. Fifty patients completed the 6-month period of therapy; 2 subjects dropped out because of adverse events, and 5 dropped out because of ineffectiveness after changes in drug administration. The first SR lanreotide injection produced more than 50% suppression of GH levels from the basal value in 93% of patients. Thirteen days later, baseline GH levels were reduced by over 50% in 25% of patients. Mean GH values were normalized in 85% of patients after 6 months, whereas insulin-like growth factor I (IGF-I) levels were normalized in 38% of patients. No correlation was found between pretreatment GH levels and GH response to SR lanreotide or between changes in GH and IGF-I during therapy. During treatment, there was a significant reduction in the percentage of patients complaining of joint pain, hyperhydrosis, and paresthesias. Changes in soft tissue swelling were documented by significant decreases in finger measurements. Diarrhea and abdominal pain were the most frequent side-effects when therapy was started; these progressively decreased. After the first month of therapy, moderate, mild, and no side-effects were reported by 3%, 40%, and 53% of patients. A nonsignificant increase occurred in asymptomatic gallstones and amylase levels. Minimal changes were noted in carbohydrate tolerance, consisting of a slight increase in glycosylated hemoglobin, a rise in glucose and a decrease in pre- and postprandial insulin levels. No effects on PRL, free cortisol, TSH, or free thyroid hormone levels were noted. No significant change in the percentage of visual field abnormalities was noted. Decreases in pituitary tumor size occurred in 3 of 17 patients reevaluated after 6 months of therapy. The 6-month period of SR lanreotide therapy was compared, on an anamnestic basis, with a 6-month or longer period of sc octreotide therapy (median, 300 micrograms/day) in 34 patients. There were no differences in effectiveness or tolerability between the 2 somatostatin analogs. These data indicate that SR lanreotide at a dose of 30 mg, im, every 14 days is an effective treatment in most unselected acromegalic patients. When administered to a group of poorly responsive patients, an increase in drug dose (60 mg im) and/or a shortening of the drug interval (10 days) seem to improve the GH/IGF-I response. Tolerability to SR lanreotide therapy is high. The use of a new sustained release formulation of somatostatin analog is clearly advantageous in improving patient compliance with medical treatment for acromegaly.

Acromegaly↗
PubMed1997

Effect of octreotide pretreatment on surgical outcome in acromegaly.

Pretreatment with octreotide (OCT) in acromegaly has been reported to improve surgical outcome. The objective of this study was to analyze retrospectively the effects of a 3- to 6-month presurgical treatment with OCT in acromegalics focusing on electrocardiographic (ECG) records, blood pressure levels, glucose and lipid profile, tumor size and consistency, easy tumor removal at surgery, and morphological findings at pathology. Fifty-nine patients with acromegaly who were undergoing surgical treatment were studied randomly before surgery; 37 patients were untreated, and 22 were treated with OCT at doses ranging 150-600 micrograms/day for 3-6 months. At study entry, untreated and OCT-treated patients had similar circulating GH and insulin-like growth factor I (IGF-I), glucose, and cholesterol levels as well as prevalence of overt diabetes mellitus, hypertension, and ECG abnormalities. In untreated and OCT-treated patients, respectively, radiological imaging documented microadenoma in 0 and 1, intrasellar macroadenoma in 10 and 6, intra- and suprasellar macroadenoma in 18 and 11, invasive macroadenoma in 9 and 4 patients. Before surgery, serum GH and IGF-I levels significantly decreased in the 22 OCT-treated acromegalics, and in 5 of them, a significant shrinkage was documented. ECG abnormalities disappeared in 7 of 11 (63.6%) OCT-treated patients. In 3 of the 7 patients with diabetes mellitus, treatment with OCT together with low carbohydrate intake normalized blood glucose levels, whereas in 2 patients, insulin could be replaced by oral antidiabetics, and in 2 patients, the insulin dose was reduced. Presurgical blood glucose, total cholesterol and triglyceride levels, as well as systolic (145.2 +/- 3.4 vs. 132.9 +/- 2.5 mm Hg; P < 0.01) and diastolic (94.3 +/- 1.7 vs. 84.3 +/- 1.6 mm Hg; P < 0.001) blood pressure levels were significantly higher in untreated than in OCT-treated patients. Two weeks after surgery, circulating GH and IGF-I levels were normalized in 11 untreated (29.7%) and 12 OCT-treated (54.5%) patients (P < 0.005, by chi 2 test). Macroscopically, no difference was found between untreated and OCT-treated adenomas, whereas at pathology, a significant increases in cellular atypia (31.6% vs. 19.2%; P < 0.05) was found in OCT-treated adenomas. One patients in the untreated group died from cardiorespiratory arrest during the early postoperative period. Finally, the average duration of hospitalization after operation was longer in untreated than in OCT-treated patients (8.6 +/- 0.7 vs. 5.6 +/- 0.5 days). We conclude that a 3- to 6-month treatment with OCT before surgery for GH-secreting adenoma improved clinical conditions and surgical outcome and reduced the duration of hospitalization after operation.

Acromegaly↗
PubMed1998

Long-term mortality after transsphenoidal surgery and adjunctive therapy for acromegaly.

To analyze the long term outcome after multimodality therapy for acromegaly, a retrospective review was performed on 162 patients who underwent transsphenoidal surgery at Massachusetts General Hospital between 1978 and 1996. The surgical cure rate for microadenomas was 91%, that for macroadenomas was 48%, and it was 57% overall. The surgical cure rate was significantly dependent on tumor size, but was not dependent on age or sex. An improvement in the surgical cure rate was noted over the course of the review, from 45% before 1987 to 73% since 1991. Long term follow-up was obtained in 99% of U.S. residents (149 of 151), with a mean follow-up period of 7.8 yr. Adjuvant radiation and/or pharmacological therapy was given to 61 patients. Of the entire group, 83% (124 of 149) were in biochemical remission as determined by normalization of serum insulin-like growth factor I levels or by GH suppression after oral glucose tolerance testing at last contact or at death. The recurrence rate was 6% at 10 yr and 10% at 15 yr after surgery in those patients who initially met the criteria for surgical cure. The 10-yr survival rate was 88%, and there were 12 deaths at postoperative intervals of 2-12 yr, with the most common cause of death being cardiovascular disease. A Cox proportional hazards model showed that patient-years with persistent disease carried a 3.5-fold [95% confidence interval (CI), 1.0-12; P = 0.02] relative mortality risk compared to those patient-years in remission. A Poisson person-years regression analysis showed no significant difference in survival between those 86 patients cured at operation and an age- and sex-matched sample from the U.S. population [standardized mortality ratio (SMR), 0.84; 95% CI, 0.3-2.2; P = 0.35]. A similar analysis on the entire group of 149 patients showed no significant difference in survival from that in a control sample (SMR, 1.16; 95% CI, 0.66-2.0; P = 0.3). Mortality risk for patient-years with persistent active disease after unsuccessful treatment vs. that in the U.S. population sample remained increased (SMR, 1.8; 95% CI, 0.9-3.6; P = .05). This analysis suggests that the decreased survival previously reported to be associated with acromegaly can be normalized by successful surgical and adjunctive therapy.

Acromegaly↗
PubMed1998

Cabergoline in the treatment of acromegaly: a study in 64 patients.

Cabergoline is a new, long acting, dopamine agonist that is more effective and better tolerated than bromocriptine in patients with hyperprolactinemia. Because dopamine agonists still have a place in the medical management of acromegaly, cabergoline might be a useful treatment. We, therefore, evaluated the effect of long term administration of cabergoline in a large group of unselected acromegalic patients. Sixty-four patients were included in a multicenter, prospective, open labeled study. A subgroup of 16 patients had GH-/PRL-cosecreting pituitary adenomas. Cabergoline was started at a dose of 1.0 mg/week and was gradually increased until normalization of plasma insulin-like growth factor I (IGF-I) levels, occurrence of unacceptable side-effects, or a maximal weekly dose of 3.5 mg (7.0 mg in 1 case) was reached. Treatment with cabergoline suppressed plasma IGF-I below 300 micrograms/L in 39% of cases and between 300-450 micrograms/L in another 28%. With pretreatment plasma IGF-I concentrations less than 750 micrograms/L, a suppression of IGF-I below 300 micrograms/L was obtained in 53% of cases, and a suppression between 300-450 micrograms/L was obtained in another 32%. By contrast, with pretreatment plasma IGF-I concentrations above 750 micrograms/L, only 17% of cases showed a suppression of IGF-I below 300 micrograms/L, and there was IGF-I suppression between 300-450 micrograms/L in another 21%. In GH-/PRL-cosecreting adenomas, 50% of cases suppressed plasma IGF-I levels below 300 micrograms/L, and another 31% did so between 300-450 micrograms/L, in contrast to only 35% and 27%, respectively in GH-secreting adenomas. Similar results were obtained concerning the secretion of GH. Tumor shrinkage was demonstrated in 13 of 21 patients, with a mass reduction by more than half in 5 GH-/PRL-cosecreting adenomas. Except for slight gastrointestinal discomfort and orthostatic hypotension in a few patients at the beginning of therapy, cabergoline treatment was well tolerated. Only 2 patients stopped medication because of nausea. The weekly dose of cabergoline ranged between 1.0-1.75 mg. A further increase in the dose was only effective in 1 GH-/PRL-cosecreting adenoma. The results of this study suggest that cabergoline is an effective, well tolerated therapy that should be considered in the management of acromegaly, especially if the pituitary adenoma cosecretes GH and PRL or if pretreatment plasma IGF-I levels are below 750 micrograms/L.

Acromegaly↗
PubMed1998

Hypothalamic dysfunction in "cured" acromegaly is treatment modality dependent.

The current definition of cure after treatment for acromegaly stipulates a reduction in GH levels to less than 2 ng/mL (< 5 mU/L), as such GH concentrations are believed to be associated with normalization of long term survival. We sought to further define the nature of the cure in such patients, when cure has been achieved by alternative therapeutic modalities, in the expectation that hypothalamic neuroregulatory control of GH secretion might be affected differently by radiotherapy or surgery. In particular we wished to determine the effect of therapy modality on endogenous somatostatin (SMS) tone, using the GH response to i.v. arginine as a paradigm. We studied 20 patients with cured acromegaly (mean 24-h GH concentration, < 2 ng/mL). Eight patients had been cured by surgery only (S; 4 women and 4 men; mean +/- SEM age, 52 +/- 5 yr), and 12 patients had been cured by radiotherapy (R; 4 women and 8 men; age, 52 +/- 3 yr). Sixteen healthy subjects were studied as a control group (C; 6 women and 10 men; age 53 +/- 3]. The median (range) GH during 24-h profiles was similar in each group: S, 1.3 (0.7-1.8) ng/mL; R, 0.6 (0.4-1.8) ng/mL; and C, 0.7 (0.4-3.2) ng/mL (P = 0.57). The median incremental GH responses to arginine were significantly lower in the R group compared with those in the S and C groups: S, 6.4 (2.1-16.6) ng/mL; R, 0.1 (0-1.7) ng/mL; and C, 9.2 (0-16.1) ng/mL (P = 0.0002; S vs. R, P < 0.01; S vs. C, P > 0.05; R vs. C, P < 0.001). We conclude that in acromegalic patients deemed to be cured (GH, < 2 ng/mL), the mode of therapy has considerable influence on the remaining hypothalamic-somatotroph function. In view of the putative mechanism by which arginine releases GH, we suggest that radiotherapy leads to a reduction or complete loss of endogenous SMS tone. This may have implications for the treatment of those acromegalic patients who are not cured (GH, > 2 ng/mL) and who require SMS analog therapy.

Acromegaly↗
PubMed1998

Current treatment guidelines for acromegaly.

Acromegaly, an indolent disorder of growth hormone (GH) hypersecretion is most typically caused by a somatotroph cell adenoma and may be treated by several modalities. Transsphenoidal surgical resection of micro-adenomas by experienced neurosurgeons results in biochemical normalization (postglucose GH <2 ng/mL, assay-dependent, age- and sex-matched IGF-I levels) in 70% of patients. However, over 65% of GH-secreting adenomas are invasive or macroadenomas, and over 50% of these patients have persistent postoperative GH hypersecretion. Irradiation of adenomas results in attenuation of GH secretion to more than 5 ng/mL in 50% of subjects after 12 yr. However, the percent of parents who normalize IGF-I levels is less certain. Most of these patients develop associated pituitary failure and rarely develop other local adverse effects. About 60% of patients receiving somatostatin analogs achieve normalized IGF-I levels. Efficacy of medical management with somatostatin analogs may be improved by increasing injection frequency, changing delivery modes to depot preparations, and in the future, development of novel SRIF receptor subtype-specific analogs. An integrated approach to acromegaly management based upon relative risks and benefits of the currently available therapeutic modes is presented that allows for a national individualized strategy designed to achieve maximal biochemical control of GH hypersecretion and elevated IGF-I levels.

Acromegaly↗
PubMed1998

Long-acting lanreotide induces clinical and biochemical remission of acromegaly caused by disseminated growth hormone-releasing hormone-secreting carcinoid.

Ectopic GHRH-secreting tumors, such as carcinoid, rarely cause acromegaly. As protracted exposure to high levels of GH is associated with considerable morbidity and mortality, these patients require early and effective medical therapy to control hormonal hypersecretion. We employed a prolonged release somatostatin analog, lanreotide, to treat a patient with disseminated GHRH-producing carcinoid. Before treatment, the patient had a biochemical profile characteristic of active acromegaly. Plasma GHRH levels were markedly elevated (200-fold), and urinary 5-hydroxyindolacetic acid (5-HIAA) levels were increased (4-fold). Magnetic resonance imaging revealed a large asymmetrical pituitary mass consistent with somatotroph hyperplasia. Somatostatin receptor scintigraphy revealed multiple bony and soft tissue lesions as well as striking pituitary uptake. Lanreotide (30 mg) was administered weekly by im injection for 12 weeks. Rapid and sustained symptomatic clinical improvement with diminished soft tissue swelling and hyperhidrosis was observed. GHRH levels decreased by 70%; glucose-suppressed GH and insulin-like growth factor I levels were reduced by 90% and 75%, respectively, to near normal values; urinary 5-HIAA levels normalized; and the pituitary mass remained unchanged. Unfortunately, the patient died due to complications of osteogenic sarcoma. In conclusion, prolonged release lanreotide induced clinical and biochemical remission in this patient with diffusely metastatic GHRH-producing carcinoid. This long-acting drug thus offers an effective, well tolerated, and convenient medical therapy for control of hormonal hypersecretion induced by excess GHRH.

Acromegaly↗