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PubMed2005

Outcome of gamma knife radiosurgery in 82 patients with acromegaly: correlation with initial hypersecretion.

CONTEXT: Because surgical and medical therapies of acromegaly all have specific limitations, radiotherapy has been used as an adjunctive strategy. Stereotactic radiosurgery has not yet been widely evaluated. OBJECTIVE: The objective was to perform an analysis of long-term hormonal effects and tolerance of gamma knife radiosurgery. DESIGN: Eighty-two patients were prospectively studied over a decade, with a mean follow-up of 49.5 months. SETTING: All patients were treated at the Department of Functional Neurosurgery of Marseille, France. PATIENTS: The patients included 82 with active acromegaly, of whom 63 had previous transsphenoidal surgery. INTERVENTION: Intervention included radiosurgery using the Leksell Gamma Unit B model. MAIN OUTCOME MEASURES: Remission was diagnosed when mean GH levels were less than 2 ng/ml and IGF-I was normal for age off somatostatin agonists (at least 3 months). RESULTS: Seventeen percent of the patients were in remission without any treatment. Twenty-three percent previously uncontrolled on somatostatin agonists fulfilled the same criteria after gamma knife while maintained on medical treatment. Initial GH and IGF-I levels off somatostatin agonists were significantly higher in uncured than in remission group (P = 0.01 and 0.047, respectively). Withdrawal of somatostatin agonists at the time of radiosurgery had no incidence on the outcome. No significant difference was found in success rate whether patients had previously been treated or not. Long-term side effects included complete (n = 2) or partial (n = 12) hypopituitarism diagnosed 1-7 yr after gamma knife. CONCLUSIONS: Gamma knife radiosurgery may represent a therapeutic approach in patients with moderate initial or residual GH hypersecretion.

Acromegaly↗
PubMed2006

Conventional pituitary irradiation is effective in lowering serum growth hormone and insulin-like growth factor-I in patients with acromegaly.

BACKGROUND: There has been recent controversy as to the effectiveness of conventional pituitary irradiation in reducing circulating GH levels to less than 2.5 ng/ml and/or normalization of serum IGF-I. OBJECTIVES: Our objectives were to determine the effects of conventional pituitary irradiation on 1) lowering of serum GH and IGF-I levels, 2) the proportion of patients who achieve a GH level less than 2.5 ng/ml and a normal age-corrected IGF-I and the time taken to achieve this, and 3) the incidence of hypopituitarism and other adverse effects. DESIGN: We conducted retrospective data collection from 14 centers throughout the United Kingdom. PATIENTS: We studied 1840 patients with acromegaly, of whom 884 had received conventional pituitary irradiation. MEASUREMENTS: We assessed circulating GH and IGF-I levels and pituitary function at intervals after irradiation. RESULTS: Mean GH levels declined from 13.5 to 5.3 ng/ml at 2 yr after irradiation, to 2.0 ng/ml by 10 yr, and to 1.1 ng/ml at 20 yr. Twenty-two percent of patients achieved a level less than 2.5 ng/ml by 2 yr, 60% by 10 yr, and 77% by 20 yr. The interval to achieve this depended on the preirradiation GH level. IGF-I levels fell in parallel to those of GH with 63% of patients having a normal level by 10 yr. The proportions of patients with new pituitary hormone deficiencies 10 yr after irradiation were 18% for LH/FSH, 15% for ACTH, and 27% for TSH. No other side effects were noted. CONCLUSIONS: In this, the largest series reported, conventional pituitary irradiation is shown to be an effective and safe means of reducing both serum GH and IGF-I concentrations in patients with acromegaly.

Acromegaly↗
PubMed2006

Predictors of tumor shrinkage after primary therapy with somatostatin analogs in acromegaly: a prospective study in 99 patients.

CONTEXT: Primary treatment with depot octreotide and lanreotide induces tumor shrinkage in newly diagnosed patients with acromegaly. OBJECTIVE: The objective of the study was to evaluate clinical predictors of tumor shrinkage. DESIGN: This was an analytical, observational, open, prospective study. SUBJECTS: The study included 99 patients: 13 with microadenoma and 86 with macroadenoma (25 enclosed, 32 extrasellar, 29 invasive). MAIN OUTCOME MEASURES: Age, gender, estimated disease duration, body mass index, GH and IGF-I levels, and tumor volume at diagnosis and after 12 months of treatment were measured. Percentage of GH, IGF-I, and tumor size changes from baseline were also analyzed. Tumor changes were scored as absent (+/- 0-25%), mild (+/- 25.1-50%), moderate (+/- 50.1-75%), or notable (75%). INTERVENTIONS: Sixty patients (60.6%) received depot octreotide im (20-30 mg every 28 d), and 39 patients (39.4%) received lanreotide im (60-90 mg every 28 d). RESULTS: Basal tumor volume and maximal tumor diameter correlated with age, disease duration, and GH levels. After 12 months, GH levels were controlled (</=2.5 microg/liter) in 57.6%, IGF-I levels in 45.5%, and both in 42.4%. Shrinkage was absent in 22 patients (22.2%), mild in 31 (31.1%), moderate in 30 (30.3%), and notable in 14 patients (14.1%). Two patients (not responding to treatment) had a mild tumor increase (by 34 and 31.2%, respectively). Basal and posttreatment tumor volumes were highly correlated (r = 0.79, P < 0.0001). At the multistep regression analysis, the percent IGF-I decrease (t = 2.6; P = 0.011) was the best predictor of posttreatment tumor volume, followed by patients' age (t = 2.1; P = 0.042) and percent GH decrease (t = 2.0; P = 0.044). CONCLUSIONS: Most patients with acromegaly (75.5%) had 25% or greater tumor shrinkage after 12 months of primary somatostatin analog therapy: significant increase of tumor mass occurred in only 2.1% of patients (uncontrolled during treatment). Best predictor of tumor shrinkage was posttreatment IGF-I.

Acromegaly↗
PubMed2006

Primary treatment of acromegaly with octreotide LAR: a long-term (up to nine years) prospective study of its efficacy in the control of disease activity and tumor shrinkage.

CONTEXT: Neurosurgery is regarded as the first-line treatment of acromegaly. Because of its low cure rate in macro and invasive adenoma, the role of primary medical treatment is debated. OBJECTIVE: Our objective was to evaluate primary pharmacological treatment in acromegaly. DESIGN AND SETTING: We conducted an open prospective study at two Italian tertiary level centers. PATIENTS: We studied 67 consecutive patients (36 women; age, 54.9 +/- 14.2 yr; 72% bearing macroadenoma). INTERVENTION: Individually tailored octreotide LAR (OCLAR) was administered. MAIN OUTCOME MEASURES: Outcomes included safe GH (<2.5 mug/liter), normal age-matched IGF-I levels, and tumor shrinkage. RESULTS: After a median follow-up of 48 months (range, 6-108 months), safe GH levels and normal age-matched IGF-I values were obtained by 68.7 and 70.1% of patients, respectively. Hormonal endpoints were achieved regardless of basal levels, and early results were predictive of outcome. Tumor shrank in 82.1% of patients by 62 +/- 31% (range, 0-100%), decreasing from 2101 +/- 2912 to 1010 +/- 2196 mm(3) (P < 0.0001). The higher the basal GH values and the greater the GH/IGF-I changes on treatment, the greater the tumor shrinkage. Tumor disappeared in three patients and was progressively reduced to empty sella in five patients; apparent magnetic resonance imaging cavernous sinus invasion disappeared in three. In males, testosterone increased, restoring eugonadism in 64% of hypogonadal patients. CONCLUSIONS: The efficacy on GH/IGF-I levels in unselected patients and the outstanding volumetric control indicate that treatment with OCLAR may be the first therapeutic approach to all acromegalic patients not amenable to surgical cure. Tumor shrinkage might also encourage the evaluation of primary OCLAR adoption in patients with initial visual field defects.

Acromegaly↗
PubMed2006

Treatment with growth hormone receptor antagonist in acromegaly: effect on cardiac structure and performance.

AIM: The aim of the current study was to evaluate the effect of short-term (6 months) and long-term (18 months) treatment with pegvisomant on cardiac structure and performance in patients with acromegaly. PATIENTS: Seventeen patients (nine women, eight men, 27-61 yr) with active acromegaly entered and 12 completed the long-term study. After a baseline evaluation, including measurement of hemodynamic, biochemical, and hormonal parameters, and a standard Doppler echocardiography, treatment with pegvisomant was started at the initial dose of 10 mg/d, increasing by 5 mg/d every 6 wk on the basis of IGF-I levels until normalization or the achievement of a maximal dose of 40 mg/d. RESULTS: After short-term treatment, IGF-I levels were normalized in 10 of the 17 (59%) patients. Left ventricular mass index (LVMi) was significantly decreased without changes in diastolic and systolic performance. After long-term treatment, IGF-I levels were normalized in 10 of the 12 (83%) patients. Blood glucose and serum insulin levels were decreased compared with baseline. LVMi was further decreased compared with short-term treatment, so that the prevalence of left ventricle hypertrophy decreased from 50% at baseline to 17% after 18 months of treatment. Moreover, ejection fraction as well as early to late (atrial) peak velocity ratio (E/A) were significantly increased, whereas isovolumic relaxation time was significantly decreased compared with baseline, demonstrating an improvement of both diastolic and systolic function. A significant correlation was found between the change in IGF-I levels and that of left ventricular ejection fraction. In general, the prevalence of cardiac insufficiency was present in 13 of the 17 (76%) patients at baseline and in one (8%) patient after 18 months of treatment. CONCLUSIONS: Long-term treatment with the GH receptor antagonist improves acromegalic cardiomyopathy by decreasing cardiac hypertrophy and enhancing diastolic and systolic function, and consequently partially or completely reverting the cardiac insufficiency.

Acromegaly↗
PubMed1975

Recovery from paradoxical growth hormone responses in acromegaly after transphenoidal selective adenomectomy.

A patient with acromegaly was studied before and after treatment by transphenoidal removal of a pituitary adenoma. "Paradoxical" GH responses to the dopamine agonists L-DOPA and ampomorphine disappeared after surgery, with reversion of GH responsiveness to normal. TSH-releasing hormone (TRH)-induced GH release observed pre-operatively did not occur after surgery. The findings suggest that in certain cases, acromegaly is due to pituitary dysfunction alone.

Acromegaly↗
PubMed1977

Failure of growth hormone-suppressing agents to affect TSH-releasing hormone- and LH-releasing hormone-induced growth hormone release in acromegaly.

In patients with acromegaly whose basal plasma GH levels were suppressed with 9 mg/day of dexamethasone for 2 days, TRH-(6 cases) and LHRH-(1 case) induced GH release were unaffected when the responses were compared to the basal levels. Phentolamine infusion, 70 mg in 150 min, or hyperglycemia induced by iv infusion of 700 ml of 50% glucose solution also did not suppress TRH-induced GH release in 2 acromegalic patients whose basal GH levels were lowered with these agents alone. These results seem to indicate that dexamethasone does not affect TRH- or LHRH-induced GH release per se, but affects the basal state which determines the absolute level of response. They also support the concept that TRH and LHRH act directly on pituitary tumor cells to release GH in acromegaly.

Acromegaly↗
PubMed1978

Effect of thyrotropin-releasing hormone and bromoergocriptine on growth hormone and prolactin secretion in perfused pituitary adenoma tissues of acromegaly.

To determine the site of action of TRH and 2-brom-alpha-ergocriptine (CB154) on pituitary hormone release in acromegalic patients, the effect of these substances on GH and PRL secretion was examined in perfused pituitary adenoma tissues obtained at surgery from subjects with acromegaly. Relatively stable baseline secretion levels of GH and PRL were followed by an abrupt and marked discharge of the hormones after TRH infusion in all of the experiments. The pattern of GH response was essentially the same as that of PRL. Moreover, a dose-response relationship was obtained between the TRH concentrations infused and the magnitude of GH and PRL responses. The infusion of CB154, on the other hand, inhibited both GH and PRL secretion in three experiments performed on different adenoma tissues. This effect of CB154 was prompt and lasted for a long period even after the infusion was discontinued. When TRH was perfused concomitantly with CB154, the stimulatory effect of TRH on GH release was maintained, while TRH-induced PRL secretion was completely blocked. The results suggest that both TRH and CB154 possess a direct action on pituitary adenoma cells of acromegaly and that aberrant GH responses to TRH and dopaminergic agonists in acromegalic patients may be explained by the altered cellular membrane receptors of the adenoma of these subjects.

Acromegaly↗
PubMed1979

Blood pressure response to an angiotensin II antagonist in patients with acromegaly.

The renin-angiotensin-aldosterone system in patients with acromegaly was evaluated by infusing [sarcosine1, isoleucine8]angiotensin II, a competitive angiotensin II antagonist, into five acromegalic patients with hypertension and three normotensive acromegalics. The drug was infused at a rate of 600 ng/kg . min for 30 min, 1 h after iv injection of 40 mg furosemide. In addition, before the infusion, plasma samples were obtained for determination of PRA and plasma aldosterone concentration. A significant pressor response to [sarcosine1, isoleucine8]angiotensin II was observed in all eight patients. Preinfusion PRA and plasma aldosterone concentration were significantly lower than in normal controls. It is concluded that in acromegaly, the renin-angiotensin-aldosterone system is suppressed and that this system is probably not involved in maintenance of the high blood pressure observed in some acromegalic patients.

Acromegaly↗
PubMed1980

Transsphenoidal microsurgery in the treatment of acromegaly and gigantism.

Twenty-five patients with acromegaly and 3 patients with gigantism underwent transsphenoidal microsurgery in an attempt to remove the tumor and preserve normal pituitary function whenever possible. An adenoma was identified and removed in 27 of 28 patients. Evaluation 3--6 months postoperatively revealed a GH level less than 5 ng/ml in 29 patients, 5--10 ng/ml in 4 patients and 11--29 ng/ml in 4 other patients. Dynamics of GH secretion were normal in 11 patients who had normal pituitary function and are considered cured. Two patients with low or undetectable GH levels are also considered cured at the expense of being hypopituitary. Three of 7 patients with normal basal GH levels but abnormal dynamics of GH secretion relapsed within 1 yr. Eleven of the 13 patients considered cured did not have extrasellar extension, while 14 of the 15 patients not cured had extrasellar extension. Five patients who were not cured with surgery received radiation therapy. Three patients were treated with an ergot derivative, Lergotrile mesylate, after surgery and radiation therapy failed to normalize GH levels. Transsphenoidal microsurgery is an optimal form of therapy for patients with acromegaly or gigantism, especially those with no extrasellar extension. Dynamics of GH secretion are very useful in evaluating the completeness of adenoma removal.

Acromegaly↗
PubMed1981

Somatomedin C in treated acromegaly: poor correlation with growth hormone and clinical response.

To determine the usefulness of commercially available somatomedin C levels in the evaluation of the treatment of acromegaly, 15 patients were tested at 0.25-15.4 yr after onset of therapy. Clinical response, as determined by a numerical scoring system, was compared with RIA of GH and somatomedin C. Symptomatic response was poorly correlated with somatomedin C (r = 0.033) as well as with GH (r = 0.24). The correlation of GH and somatomedin C was also poor (r = 0.46, P greater than 0.05). Eighty-three percent of patients with clinical improvement had GH less than or equal to 10 ng/ml, 50% had GH less than or equal to 5 ng/ml, while 42% had somatomedin C less than or equal to 3.0 U/ml. All patients who were evaluated at 1 yr or less after therapy had elevated somatomedin C levels with normal or near normal GH values. In contrast only 2 of 11 patients evaluated at more than 1 yr after therapy had a mild persistence of somatomedin C elevation with normal GH levels. Determination of somatomedin c costs more than GH determinations and appears to offer no apparent advantage over GH in following patients treated for acromegaly.

Acromegaly↗
PubMed1983

Insulin receptor on monocytes from patients with acromegaly and fasting hyperglycemia.

[125I]Insulin binding to insulin receptors on circulating monocytes was studied in 9 patients with acromegaly associated with fasting hyperglycemia and was compared to previously reported studies of 11 patients with acromegaly who had normal or nearly normal glucose tolerance and 29 normal volunteers. In the hyperglycemic acromegalic, as had been found in the normoglycemic acromegalic, the total receptor concentration per cell was decreased in proportion to the hyperinsulinemia, i.e. the receptor concentration was inversely related to the basal level of insulin, similar to what is found in patients with obesity, diabetes, and insulin-secreting tumors. However, the acromegalic patients with hyperglycemia failed to show the increase in affinity of the empty receptor that had previously been found in their normoglycemic counterparts. The failure to increase receptor affinity causes the cells of the hyperglycemic acromegalic patients to bind less insulin at each insulin concentration than do the cells of normoglycemic patients. Again, the abnormalities in the patients correlates very closely with abnormalities at the level of the insulin receptor, though the sequence of the molecular events that produce these changes remains to be determined.

Acromegaly↗
PubMed1984

Acromegaly and Zollinger-Ellison syndrome secondary to an islet cell tumor: characterization and quantification of plasma and tumor human growth hormone-releasing factor.

A young woman with acromegaly and Zollinger-Ellison syndrome associated with a GH-releasing factor (GRF)- and gastrin-secreting metastatic islet cell carcinoma was studied by means of specific antisera which recognize various regions of the GRF molecule. Using specific immunohistochemical techniques, the tumor cells were shown to contain GRF, gastrin, and gastrin-releasing peptide, but not GH. During a 4-h period, plasma GRF levels averaged 5.6 +/- 1.4 ng/ml (+/- SD), while GH levels averaged 148 +/- 71 ng/ml. GH secretion was pulsatile and increased after TRH administration. GRF RIAs may be useful in establishing the diagnosis of acromegaly secondary to the ectopic secretion of GRF.

Acromegaly↗
PubMed1985

Effect of dexamethasone on growth hormone (GH) response to growth hormone releasing hormone in acromegaly.

The effect of dexamethasone on the GH response to GH-releasing hormone (GHRH) was studied in vivo in six patients with acromegaly as well as in vitro in monolayer cultures of GH-secreting pituitary tumor cells obtained from three of these patients. Oral administration of 9 mg/day dexamethasone for 2 days decreased plasma GH responses to iv injection of 100 micrograms GHRH-(1-44 amide) in all six patients. Blood glucose levels were significantly increased, while plasma somatomedin-C levels were significantly decreased by this regimen of dexamethasone treatment. On the other hand, 2-day pretreatment with 50 nM dexamethasone of monolayer cultures of pituitary adenoma cells potentiated GH release basally and/or in response to 100 pM to 1 nM GHRH in vitro. These results indicate that the potentiating action of 2-day treatment of dexamethasone in vitro is overwhelmed in vivo by some extra-pituitary action, probably on the central nervous system, of glucocorticoids in patients with acromegaly.

Acromegaly↗
PubMed1985

Resolution of acromegaly, amenorrhea-galactorrhea syndrome, and hypergastrinemia after resection of jejunal carcinoid.

A young woman presented with acromegaly and amenorrhea-galactorrhea with hypersomatotropinemia and hyperprolactinemia. In addition, she had hypergastrinemia with abnormal secretory dynamics and evidence of a large pituitary tumor with suprasellar extension and erosion of the floor of the sella turcica. Evaluation of secretory diarrhea revealed a large abdominal tumor, which on removal was found to be a carcinoid of the jejunum. Postoperatively, the acromegaly, amenorrhea-galactorrhea, and hypergastrinemia resolved, and the pituitary returned to normal size, with regrowth of the sella floor. The carcinoid tumor was shown by immunoperoxidase staining to contain GH-releasing hormone.

Acromegaly↗
PubMed1986

Growth hormone-releasing hormone infusion in patients with active acromegaly.

To determine GH-releasing hormone (GHRH)-stimulated GH secretion in patients with active acromegaly, nine patients received a 50-microgram GHRH-(1-44) bolus dose followed by a 2-h infusion with 100 micrograms GHRH/h, after which a second 50-microgram GHRH bolus dose was given. Serum GH, PRL, and immunoreactive GHRH levels were measured from 2 h before to 1 h after the end of the infusion and compared with hormone levels in six normal subjects subjected to the same protocol. In addition, seven of the nine acromegalic patients received 100 micrograms GHRH as an iv bolus dose, followed by a 2-h saline infusion on a different day. After the 100-micrograms GHRH bolus dose, the mean GH level increased from 55.9 +/- 18.0 (+/- SE) to 148.5 +/- 40.0 ng/ml within 15 min. Thereafter, GH levels decreased and were significantly lower at 90 and 120 min compared to the peak level 15 min after GHRH injection. After the 50-micrograms GHRH bolus dose, all acromegalic patients except two also had a clear-cut rise of GH levels, with the mean GH level increasing from 37.5 +/- 13.2 to 108.4 +/- 55.0 ng/ml at 60 min. Thereafter, elevated GH levels were sustained in the acromegalic patients throughout the GHRH infusion. In contrast, normal subjects had a significant decrease in the initially elevated GH levels, despite continuous GHRH infusion. There were no significant differences between PRL secretion and immunoreactive GHRH levels in either group. These findings suggest that patients with active acromegaly not only have elevated basal GH levels, but also have a greater ready releasable GH pool and/or accelerated GH turnover compared to those of normal subjects, which cannot be exhausted by a 2-h GHRH infusion.

Acromegaly↗
PubMed1986

Growth hormone (GH) and prolactin responses to repetitive administration of GH-releasing hormone in acromegaly.

We investigated the pattern of GH secretion in response to repetitive GH-releasing hormone (GHRH) administration in patients with active acromegaly and in normal subjects. Twelve acromegalic patients (nine women and 3 men; aged 21-76 yr) were studied. Eight had never been treated, whereas four had undergone neurosurgery but still had active disease. All patients and eight normal subjects received three doses of 50 micrograms GHRH, iv, at 2-h intervals. Seven patients were retested 6-8 weeks after transsphenoidal removal of a pituitary adenoma. There was a marked serum GH rise in acromegalic patients and normal subjects after the first GHRH dose [area under the curve, 2070 +/- 532 (+/- SE) vs. 1558 +/- 612 ng/min X ml, respectively; P = NS]. Successive GHRH doses stimulated GH release only in acromegalic patients (second dose, 1123 +/- 421 ng/min X ml; third dose, 2293 +/- 1049 ng/min X ml). In normal subjects, the GH response to the second and third GHRH doses was blunted (second dose, 86 +/- 32 ng/min X ml; third dose, 210 +/- 63 ng/min X ml; P less than 0.01). PRL secretion did not change in normal subjects, whereas 6 of 12 acromegalic patients had PRL release after each GHRH dose (PRL responders to GHRH). Transsphenoidal surgery led to normalization (less than 5 ng/ml) of the preoperatively elevated GH levels in all but 2 patients, who, however, had reduction of somatomedin-C levels. The amount of GH released in the postoperative test was significantly lower than that released preoperatively (first dose, 722 +/- 209 vs. 2945 +/- 743 ng/min X ml; second dose, 358 +/- 117 vs. 1737 +/- 633 ng/min X ml; third dose, 320 +/- 144 vs. 1776 +/- 676 ng/min X ml, respectively; P less than 0.05 in all instances). Thus, patients with active acromegaly, but not normal subjects, respond to repetitive GHRH administration at 2-h intervals with an increase in GH levels. This increase may be due to a larger releasable GH pool and/or faster GH turnover in the adenomatous cell.

Acromegaly↗