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PubMed1977

Pulmonary function in acromegaly.

The lung volumes of 12 female and eight male patients with acromegaly, chosen because of the absence of associated cardiorespiratory disease, were determined physiologically and radiographically. Enlarged lung volumes were found in half the males but in none of the females, due allowance being made for the presence of a significant thoracic kyphosis. Upper airway narrowing was suggested by an increase in the expiratory-inspiratory flow rate ratio in six patients, four of whom were male, and acromegaly of the larynx was confirmed in the three subjects who consented to laryngoscopy. Upper airway obstruction is more likely to account for respiratory death in acromegaly than disordered pulmonary function in enlarged acromegalic lungs. Neither of these respiratory findings could be correlated with the fasting level of growth hormone but there was a suggestion that they were more likely to occur when the duration of the disorder was longer.

Acromegaly↗
PubMed1999

Slow-release lanreotide treatment in acromegaly: effects on quality of life.

BACKGROUND: It is not known whether medical treatment to lower growth hormone (GH) and insulin-like growth factor (IGF)-1 levels may improve the compromised quality of life of patients with acromegaly. METHODS: We studied the effects on quality of life of the slow-release somatostatin analogue lanreotide, 30 mg i.m., every 14 days for 2 months in 10 patients with active acromegaly (8 females/2 males, mean age 57.3 +/- 11.4). Hormone measurements and psychometric evaluation by means of self-rating scales were carried out in baseline conditions and after 1 and 2 months. The Symptom Questionnaire (SQ), the Cognitive Scale of the Screening List for Psychosocial Problems by Kellner and the Social Situation Questionnaire by Marks were employed. RESULTS: Together with a significant decrease in GH and IGF-1, treatment with lanreotide significantly improved SQ psychological distress, SQ well-being and Social Situation Questionnaire social fears. CONCLUSION: Medical treatment with lanreotide may improve the quality of life of patients with acromegaly. Being an open trial, changes could be due to nonspecific effects. However, they did not fade at 2 months. Improvement involved fears of social situations that have been linked to GH abnormalities.

Acromegaly↗
PubMed2004

Modulation of cortisol metabolism during treatment of acromegaly is independent of body composition and insulin sensitivity.

OBJECTIVES: The set point of cortisol-cortisone conversion is shifted in the direction of cortisone by the inhibition of the activity of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) during adult GH replacement and in active acromegaly. Additionally, both fat mass and insulin may modulate 11beta-HSD1 and are both influenced by changes in GH status. This study examined the relative direct contribution of GH/IGF1 in modulating cortisol metabolism. METHODS: Overall cortisol/cortisone conversion (ratio of urine 11-hydroxy-/11-oxo-cortisol metabolites; Fm/Em), insulin sensitivity (homeostatic model assessment; HOMA %S) and fat mass (DXA) were examined in parallel in 6 patients (mean age 53 years, range 42-76; 4 males, 2 females) with previously untreated active acromegaly during 6 months of therapy with Sandostatin LAR (20-30 mg i.m. 4 weekly). All but 1 patient had normal ACTH reserve. RESULTS: At baseline, Pearson correlation demonstrated an inverse relationship between serum GH (mean of a 5-point day curve) and Fm/Em (r = -0.83, p = 0.04) and a trend towards an inverse relationship between HOMA %S and Fm/Em (r = -0.79, p = 0.06) but no other patterns were evident. During the course of treatment, serum GH decreased from 9.9 +/- 6.4 (mean +/- SD) to 3.5 +/- 3.1 ng/ml (p < 0.01) and serum IGF-1 from 785 +/- 268 to 431 +/- 156 ng/ml (p < 0.005). Fm/Em increased from 0.52 +/- 0.1 to 0.75 +/- 0.08 (p < 0.03) consistent with increased 11beta-HSD1 activity. There were no significant changes in truncal fat percentage (33.0 +/- 9.0 vs. 33.0 +/- 8.2) or insulin sensitivity (HOMA %S: 37.1 +/- 8.6 vs. 52.8 +/- 33.7). CONCLUSIONS: Modulation of cortisol metabolism during treatment of active acromegaly is dependent on changes in GH/IGF-1 status and is not influenced by any individual change in body composition or insulin sensitivity.

11-beta-Hydroxysteroid Dehydrogenase Type 1↗
PubMed2004

The challenges of reliance on insulin-like growth factor I in monitoring disease activity in patients with acromegaly.

Serum insulin-like growth factor I (IGF-I) is an important marker of disease activity in patients with acromegaly, and epidemiological data indicate control of circulating IGF-I in patients with acromegaly restores life expectancy to normal. Improvements in the quality of, and access to, IGF-I assays has encouraged monitoring of acromegaly with IGF-I, although circulating growth hormone (GH) and IGF-I values provide different information, so ideally both should be monitored. However, the introduction of the GH receptor antagonist pegvisomant poses new challenges. Pegvisomant binds with high affinity to GH receptors, thereby blocking the action of GH at the tissue level and rendering the hormone biologically inactive. This leaves IGF-I as the principal marker of disease activity. It is conceptually possible to induce a state of functional GH deficiency (GHD) with pegvisomant with IGF-I values within the normal range. With the goal of minimizing the risk of over-treatment and GHD, we have provided preliminary guidance on the target range for IGF-I in patients receiving pegvisomant based on the gender- and decade-based percentile ranges for IGF-I of adult patients with untreated GHD enrolled in the Pfizer International Metabolic Database (KIMS).

Acromegaly↗
PubMed2006

Pathology of acromegaly.

This review summarizes current knowledge on pituitary changes in patients with acromegaly. The histologic, immunohistochemical and electron microscopic study provided conclusive evidence that a marked diversity exists between the tumors which secrete growth hormone (GH) in excess, such as densely and sparsely granulated GH cell adenoma, the mixed GH prolactin cell adenoma and the mammosomatotrope adenoma. The latter two tumors produce GH and prolactin simultaneously. Densely granulated GH cell tumors may produce thyrotropin and alpha subunit as well. Somatotrope carcinomas are extremely rare. GH cell hyperplasia can also be associated with acromegaly in patients with extrapituitary GH-releasing hormone secreting tumors. The medical therapy of acromegaly is reviewed briefly, including long-acting somatostatin analogs and pegvisomant, a GH receptor blocker.

Acromegaly↗
PubMed2006

Medical treatment of acromegaly: comorbidities and their reversibility by somatostatin analogs.

Relief of symptoms can be achieved following surgery for growth hormone (GH)-secreting adenomas, as well as after pharmacological therapy with somatostatin analogs. Recently, long-acting somatostatin analog depot formulations, octreotide LAR and lanreotide SR have become available. Somatostatin analogs control GH/insulin-like growth factor (IGF)-1 excess, induce tumor shrinkage in a high proportion of patients, improve symptoms of acromegaly with relatively limited side effects and are successfully administered in patients not suitable for surgery. Furthermore, preoperative somatostatin analogs have been suggested to improve outcome for tumors with limited invasiveness, while surgical tumor debulking in cases that are, at least partially, somatostatin resistant, increases the achievement of normal IGF-1 levels by postoperative somatostatin analog treatment. Effective control of hypertension, as well as diabetes, is mandatory in order to reduce the increased vascular morbidity/mortality. Control of GH/IGF-1 excess generally improves glucose metabolism. Somatostatin analogs improve insulin sensitivity, exerting, however, a concomitant direct inhibitory effect on insulin secretion, with a net balance leaning towards a deterioration in glucose homeostasis. As a result, oral insulin secretagogues (and/or insulin) should probably be preferred to insulin sensitizers in acromegalic patients developing diabetes while on somatostatin analogs. Nevertheless, glucose tolerance remains normal in most of the nondiabetic acromegalic patients, while diabetic acromegalic patients on insulin are at risk for hypoglycemia during initiation of somatostatin analog therapy. Although successful management of acromegaly has been associated with improvement in morphological and functional parameters of cardiomyopathy, limited and conflicting information is available regarding the effect on blood pressure control. Contradictory results have also been reported regarding sleep hypopnea or apnea in treated acromegalic patients. As acromegalic skeletal abnormalities are rather irreversible, apneic episodes may persist after normalization of hormonal levels. Aggressive therapy, including surgery, pharmacological treatment and, in some cases, pituitary irradiation, aiming at normalization of IGF-1 levels, is required for arthropathy management. Some improvement in pain, crepitus and range of motion has been observed after treatment with somatostatin analogs. Information on the impact of disease control, either by surgery or somatostatin analog treatment, on gonadal function is limited. Finally, the link between the hormonal/biochemical and the psychiatric/psychological features of acromegaly, as well as a potential basis for positive effects of somatostatin analog therapy remain unclear.

Acromegaly↗
PubMed1991

Metabolic effects of hypopituitarism and acromegaly.

Hypopituitarism is associated with reduced lean body mass and increased body fat, while in acromegaly the converse is true. Fasting plasma glucose is increased in acromegaly but fasting plasma insulin and C-peptide are increased in both groups. There is a positive association between fat mass and fasting serum insulin in hypopituitarism, suggesting insulin resistance. Hypoglycaemia unresponsiveness, rather than insulin sensitivity, is the feature of growth hormone deficiency. Basal metabolic rate (expressed per kg body weight) is increased in acromegaly and decreased in hypopituitarism but when expressed 'per kg lean body mass', is increased in both groups. There is a close correlation between fat mass and fasting free fatty acid and glycerol levels in obese but not normal weight patients with hypopituitarism; slim patients appear to metabolise and oxidise their fat stores more effectively than those who remain obese. Thus indirect evidence suggests that growth hormone has an important role in maintaining normal body composition and energy stores.

Acromegaly↗
PubMed1992

Growth-hormone-binding protein in patients with acromegaly.

The present study was undertaken to investigate the possible regulatory effect of chronic exposure to human growth hormone (hGH), in patients with acromegaly, on growth-hormone-binding protein (GH-BP). Nineteen patients with active acromegaly, before, during or after treatment, comprised the subjects of this study. Serum GH was measured by radioimmunoassay and GH-BP by a binding assay with dextran-coated charcoal separation. The specific binding of [125I]hGH (1 ng) obtained with 50 microliters serum was expressed as a percentage of total cpm. To evaluate the impact of the lower GH-BP on GH activity, we studied the effect of acromegalic serum on hGH displacement of [125I]hGH binding to GH receptors in rabbit liver membranes. Compared to normal controls (11.43 +/- 0.37%), the acromegalic patients had low serum levels of GH-BP (5.45 +/- 0.40%; p < 0.001), which correlated negatively with serum GH levels (p < 0.01). In 7 patients, GH-BP normalized within 2-3 months of successful therapy. The lower GH-BP was due to a reduction in binding capacity, whereas binding affinity remained unchanged. Acromegalic serum, with its low GH-BP, resulted in a shift to the left of the GH displacement curve when compared with normal human sera: IC50 values were 7.47 +/- 0.29 and 11.19 +/- 0.84 ng (p < 0.02) for acromegalic and normal human sera, respectively. We conclude that acromegaly is characterized by low levels of GH-BP due to a decrease in serum-binding capacity. The decrease in GH-BP may render the acromegalic serum GH relatively more active in the GH receptor assay.

Acromegaly↗
PubMed1992

Acute effects of hydrocortisone on circulating growth hormone levels in patients with acromegaly.

Aim of our study was to investigate the acute effects of intravenous infusion of hydrocortisone on circulating growth hormone (GH) levels in acromegaly. We studied 5 adult patients with active acromegaly, 3 males and 2 females; age 52 +/- 3.6 years, body mass index 27 +/- 1 kg/m2. The patients underwent in randomized order from 0 to 120 min: (1) intravenous infusion of saline, 250 ml; (2) bolus intravenous injection of hydrocortisone succinate, 100 mg at time 0 followed by intravenous infusion of hydrocortisone succinate, 250 mg in 250 ml of saline for 120 min. Blood samples for GH, cortisol and glucose assay were taken at -15, 0 (time of beginning of saline or hydrocortisone infusion), 15, 30, 45, 60, 90, 120, 150 and 180 min. In all the acromegalic patients, during hydrocortisone succinate infusion, GH values clearly fell with respect to saline (nadir range 18.4-50.5% with respect to baseline levels) with nadir between 60 and 180 min after the beginning of the infusion. Our data show that acute and sustained hypercortisolism, decreases circulating GH levels in acromegaly. It seems likely that also in acromegalic patients as well as in normal subjects short-term increases in serum cortisol levels may be able to cause an enhancement of hypothalamic somatostatin secretion, which in turn may be responsible for the glucocorticoid-mediated GH inhibition.

Acromegaly↗
PubMed1994

Effect of hydrocortisone on the growth hormone response to growth hormone-releasing hormone in acromegaly.

Our recent data show that acute and sustained hypercortisolism decreases circulating growth hormone (GH) levels in acromegaly with respect to saline infusion. It has been hypothesized that in acromegalic patients, as well as in normal subjects, short-term increases in serum cortisol levels may be able to cause an enhancement of hypothalamic somatostatin secretion, which in turn may be responsible for the glucocorticoid mediated GH inhibition. The aim of our study was to investigate the acute effects of an intravenous infusion of hydrocortisone on the GH response to growth hormone-releasing hormone (GHRH) in acromegaly. We studied 6 adult patients with active acromegaly (3 M, 3 F; mean age 60.5 +/- 4.1 years; mean body mass index 27.1 +/- 0.6 kg/m2). All the patients underwent: (1) a bolus intravenous injection of 100 mg hydrocortisone succinate in 2 ml saline, at time -60 followed by a 120-min intravenous infusion of 250 mg hydrocortisone succinate in 250 ml saline, from -60 to 60 min; (2) a bolus intravenous injection of human GHRH 1-29NH2 100 micrograms in 1 ml saline, 60 min after initiation of a 2-hour hydrocortisone infusion; (3) a bolus intravenous GHRH injection 60 min after initiation of a 2-hour saline infusion. In all of the acromegalic patients during hydrocortisone succinate infusion, GH values clearly decreased with respect to basal levels (mean nadir 47 +/- 8.6%, p < 0.05 with respect to basal levels). After GHRH injection and saline infusion all the patients showed a significant increase in GH levels (mean peak 231.5 +/- 52.8%, p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Acromegaly↗
PubMed1991

Coexistent urticaria pigmentosa, acromegaly and acanthosis nigricans.

We report a case of urticaria pigmentosa, acromegaly and acanthosis nigricans in a 25-year-old male. The patient exhibited multiple pigmented papules on the trunk and the extremities. Histological examinations of the papules revealed infiltrates of mast cells in the upper dermis. Ultrastructurally, the mast cells were fully matured and exhibited no atypical features. A typical appearance of acromegaly, frontal bossing, prominence of the jaw and bony overgrowth and cutaneous changes of acanthosis nigricans on the neck, the axillae and the groins were observed. Growth hormone hypersecretion and insulin resistance were detected in the patient. A pituitary tumor was found and resected surgically. After the operation, endocrinological abnormalities and cutaneous manifestations of acanthosis nigricans improved markedly. As far as we know, this is the first report of the coexistence of urticaria pigmentosa, acromegaly and acanthosis nigricans.

Acanthosis Nigricans↗
PubMed1980

Hypoxemia and pulmonary function in acromegaly.

Pulmonary function was assessed in 11 patients with acromegaly, 8 of whom were previously treated by external pituitary irradiation. None of the patients had any overt respiratory ailment. Ventilatory function tests were normal in all patients and all had normal total lung capacity ranging from 75 to 123% (mean, 98.18 +/- 4.69%). Eight of ten patients (80%) had hypoxemia with a partial pressure of oxygen in arterial blood ranging between 58 and 90 mmHg (mean, 76.0 +/- 4.2). Calculated alveolar-arterial differences for oxygen ranged between 5.25 and 46.0 (mean, 26.0 +/- 4.7). In 4 of 5 patients in whom lung perfusion scans were performed, perfusion defects were found. There was a significant correlations (p < 0.05) between the presence of hypoxemia and the known duration of acromegaly, but not with the present growth hormone levels or previous therapy. The results indicate that pneumomegaly is not common in acromegaly. However, most patients have some degree of hypoxemia present usually as subclinical disease and it is probably due to a ventilation-perfusion derangement, which is probably a direct effect of the prolonged oversecretion of growth hormone.

Acromegaly↗
PubMed1994

Obstructive sleep apnea syndrome and acromegaly.

Obstructive sleep apnea syndrome is a complex disorder that has been associated with a variety of abnormalities of the upper airway, including tonsil and adenoid hypertrophy, nasal obstruction, retrognathia, and macroglossia. The cause of the airway obstruction in acromegaly is believed to be related to osseous and soft-tissue changes surrounding the upper airway, which lead to narrowing and subsequent collapse during sleep. We describe the results of treatment in seven patients with both sleep apnea and acromegaly. Four patients were treated by transsphenoidal hypophysectomy alone with a resolution of sleep apnea syndrome. One underwent hypophysectomy followed by postoperative radiation therapy, which reduced his apnea. Three patients underwent unsuccessful uvulopalatopharyngoplasty. Successful treatment of the primary disorder, in this case acromegaly, resulted in improved breathing during sleep in five patients. This series would suggest that acromegalic patients with sleep apnea should be treated for their pituitary tumor to reduce growth hormone before consideration of surgery to enlarge or bypass the upper airway.

Acromegaly↗
PubMed2004

Systemic complications of acromegaly: epidemiology, pathogenesis, and management.

This review focuses on the systemic complications of acromegaly. Mortality in this disease is increased mostly because of cardiovascular and respiratory diseases, although currently neoplastic complications have been questioned as a relevant cause of increased risk of death. Biventricular hypertrophy, occurring independently of hypertension and metabolic complications, is the most frequent cardiac complication. Diastolic and systolic dysfunction develops along with disease duration; and other cardiac disorders, such as arrhythmias, valve disease, hypertension, atherosclerosis, and endothelial dysfunction, are also common in acromegaly. Control of acromegaly by surgery or pharmacotherapy, especially somatostatin analogs, improves cardiovascular morbidity. Respiratory disorders, sleep apnea, and ventilatory dysfunction are also important contributors in increasing mortality and are advantageously benefitted by controlling GH and IGF-I hypersecretion. An increased risk of colonic polyps, which more frequently recur in patients not controlled after treatment, has been reported by several independent investigations, although malignancies in other organs have also been described, but less convincingly than at the gastrointestinal level. Finally, the most important cause of morbidity and functional disability of the disease is arthropathy, which can be reversed at an initial stage, but not if the disease is left untreated for several years.

Acromegaly↗
PubMed2003

Lanreotide 60 mg, a new long-acting formulation: effectiveness in the chronic treatment of acromegaly.

Lanreotide (LAN) 60 mg (LAN60), a new long-acting formulation of LAN alleged to suppress GH/IGF-I hypersecretion for 28 d in acromegalic patients, was administered in a prospective open multicenter study to 92 patients with active acromegaly (61 women and 31 men, aged 20-79 yr). LAN60 was given as adjuvant treatment (AT) in 62 patients; the other 30 patients [primary treatment (PT)] were de novo (n = 20) or previously treated only by pharmacotherapy (n = 10). After wash-out from previous treatments, LAN60 was started im every 28 d for 3 injections; the dose was then individually tailored, aiming at lowering GH to less than 2.5 micro g/liter and IGF-I to the normal range. After a median follow-up of 24 months (range, 6-48 months), IGF-I normalized in 65% of patients, decreasing from 199 +/- 8% (expressed as a percentage of the upper limit of normal range; mean +/- SE) to 87 +/- 4% (P < 0.0001). GH fell to less than 2.5 microg/liter in 63% of patients and to less than 1 microg/liter in 25%, decreasing from 20 +/- 3 to 3 +/- 0.4 microg/liter (P < 0.0001). A progressive increase in the rate of IGF-I normalization was observed (from 49% at 1 yr to 77% at 3 yr). The rate of GH/IGF-I normalization was 72% at 36 months by Kaplan-Meier analysis. No tachyphylaxis was observed throughout the study. Shortening the interval between injections to 21 d improved GH/IGF-I suppression. PT and AT patients achieved similar final GH/IGF-I levels and rates of normalization. Tumor shrank in 39% of assessable patients and in 50% of PT. Plasma glucose levels did not change, and high density lipoprotein cholesterol increased (by 19.3 +/- 5.1%; P = 0.0215). Gallstones appeared or worsened in 13% of patients. LAN60 is a new, very effective and long-lasting formulation for the treatment of acromegaly. The persistence of a powerful suppression of GH/IGF-I levels, the progressive increase in the rate of IGF-I normalization, and the similarity in the efficacy achieved in PT and AT patients point to a role for LAN60 in the primary treatment of acromegaly.

Acromegaly↗
PubMed2003

Left ventricular diastolic function and cardiac performance during exercise in patients with acromegaly.

Exercise-induced impairment of left ventricular (LV) ejection fraction is common in patients with acromegaly and normal resting systolic function. This study aimed to clarify whether diastolic dysfunction plays a role in the abnormal adaptation to exercise in these patients. Forty-eight patients with active acromegaly underwent LV radionuclide angiography at rest and during exercise. Doppler echocardiography was also performed to assess LV mass index and diastolic function by combined analysis of mitral and pulmonary flow velocity curves. LV ejection fraction at peak exercise was related to rest ejection fraction (r = 0.78; P < 0.001), peak filling rate (r = 0.55; P < 0.01), LV mass index (r = -0.56; P < 0.001), and the difference between duration of diastolic reverse pulmonary vein flow and mitral flow at atrial contraction (Delta duration) (r = -0.54; P < 0.01). At stepwise regression analysis, rest ejection fraction and Delta duration were the only variables that independently influenced (P < 0.001) ejection fraction at peak exercise. Diastolic dysfunction is important in determining cardiac performance during exercise in patients with acromegaly and normal resting systolic function. Combined analysis of pulmonary vein and mitral flow velocity curves allows the identification of impaired LV diastolic function in such patients.

Acromegaly↗
PubMed2003

Optimizing control of acromegaly: integrating a growth hormone receptor antagonist into the treatment algorithm.

Acromegaly is associated with significant morbidities and a 2- to 3-fold increase in mortality because of the excessive metabolic action of GH and IGF-I, a marker of GH output. Reductions in morbidity correspond with decreases in IGF-I, and mortality is lowered following normalization of IGF-I or GH levels. Therefore, this has become an important end point. Current guidelines for the treatment of acromegaly have not considered recent advances in medical therapy, in particular, the place of pegvisomant, a GH receptor antagonist. Treatment goals include normalizing biochemical markers, controlling tumor mass, preserving pituitary function, and relieving signs and symptoms. Surgery reduces tumor volume and is considered first-line therapy. Radiation reduces tumor volume and GH and IGF-I levels, but the onset of action is slow and hypopituitarism typically develops. Therefore, pharmacotherapy is often used following surgery or as first-line therapy for nonresectable tumors. Dopamine agonists can be considered in patients exhibiting minimal disease or those with GH-prolactin-cosecreting tumors but will not achieve hormone normalization in most patients. Somatostatin analogs effectively suppress GH and IGF-I in most patients, but intolerance (e.g. diarrhea, cramping, gallstones) can occur. Pegvisomant, the newest therapeutic option, blocks GH action at peripheral receptors, normalizes IGF-I levels, reduces signs and symptoms, and corrects metabolic defects. Pegvisomant does not appear to affect tumor size and has few adverse effects. Pegvisomant is the most effective drug treatment for acromegaly in normalizing IGF-I and producing a clinical response; it is the preferred agent in patients resistant to or intolerant of somatostatin analogs.

Acromegaly↗
PubMed2003

Pegvisomant-induced serum insulin-like growth factor-I normalization in patients with acromegaly returns elevated markers of bone turnover to normal.

Active acromegaly is associated with increased biochemical markers of bone turnover. Pegvisomant is a GH receptor antagonist that normalizes serum IGF-I in 97% of patients with active acromegaly. We evaluated the effects of pegvisomant-induced serum IGF-I normalization on biochemical markers of bone and soft tissue turnover, as well as levels of PTH and vitamin D metabolites, in 16 patients (nine males; median age, 52 yr; range, 28-78 yr) with active acromegaly (serum IGF-I at least 30% above upper limit of an age-related reference range). Serum procollagen III amino-terminal propeptide (PIIINP) and type I procollagen amino-terminal propeptide, osteocalcin (OC), bone-related alkaline phosphatase, C-terminal cross-linked telopeptide of type I collagen (CTx), albumin-corrected calcium, intact PTH, 25-hydroxy vitamin D, 1,25-dihydroxy vitamin D [1,25-(OH)(2) vit D], urinary type 1 collagen cross-linked N-telopeptide/creatinine ratio, and urinary calcium (24 h collection) were measured (single-batch analysis) at study entry and after IGF-I normalization, along with sera from 32 age- and sex-matched controls. Compared with controls, PIIINP, OC, and CTx were significantly elevated in patients at baseline. Pegvisomant-induced serum IGF-I normalization (699 +/- 76 to 242 +/- 28 micro g/liter, P < 0.001) was associated with a significant decrease in PIIINP, markers of bone formation (type I procollagen amino-terminal propeptide, OC, and bone-related alkaline phosphatase), and resorption (CTx and urinary type 1 collagen cross-linked N-telopeptide/creatinine ratio). 1,25-(OH)(2) vit D decreased and intact PTH increased significantly, but 25-hydroxy vitamin D was unaffected. A significant decline in calculated calcium clearance was observed. The decrease in serum IGF-I correlated positively with the decrease of serum PIIINP (r = 0.7, P < 0.01). After normalization of serum IGF-I, there was no statistical difference between patients and controls for any parameters for which control data were available. In conclusion, GH excess is associated with increased bone and soft tissue turnover. Pegvisomant-induced normalization of serum IGF-I results in a decrease in markers of bone and soft tissue turnover to levels observed in age-matched controls, and these changes are accompanied by an increase in PTH and a decrease in 1,25-(OH)(2) vit D. These data provide further evidence of the effectiveness of pegvisomant in normalizing the altered biological effects of GH hypersecretion.

Acromegaly↗