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PubMed1998

Gonadal status is an important determinant of bone density in acromegaly.

OBJECTIVE: To measure bone mineral density (BMD) in patients with acromegaly and to look for clinical features which may explain previously reported discrepant results. DESIGN: Prospective case controlled observational study. PATIENTS: 18 patients with acromegaly (seven women, 11 men; mean age 53.2 +/- 3.5 years). Eight patients had active disease and 10 had controlled acromegaly. Growth hormone and insulin-like growth factor-1 (IGF-1) concentrations were measured to assess disease activity. MEASUREMENTS: BMD was measured at four sites on the lumbar spine, three at the femoral neck and at Ward's triangle using a Hologic dexa scanner. Results were compared to a locally determined control population (n = 1800). In eight patients with active acromegaly, urinary free pyridinoline and deoxypyridinoline, and serum osteocalcin, propeptide of type 1 procollagen, vitamin D, 1000 h parathyroid hormone, bone specific alkaline phosphatase, calcium and phosphate concentrations were measured before and after 6 months treatment with octreotide. RESULTS: The mean BMD for all acromegalic patients was not significantly different from the control population except at the femoral neck where it was increased (P = 0.05). At all sites, the BMD of patients who had been hypogonadal (n = 12/18) was significantly lower (P < 0.05-0.01) than that of patients who had been eugonadal (n = 6/18). BMD for hypogonadal patients was lower than the control population at Ward's triangle (P = 0.03). Eugonadal acromegalic patients had BMD greater than non-acromegalic controls at all sites. Patients with controlled acromegaly had a higher BMD than non-acromegalic controls, but there were no differences in BMD between patients with active and controlled acromegaly. Serum IGF-1 concentrations decreased from 64.5 +/- 5.1 nmol/l to 37.5 +/- 6.9 nmol/l (P = 0.02) after 6 months treatment with octreotide, but there was no change in any of the biochemical markers of bone turnover. CONCLUSIONS: Eugonadal acromegalic patients have increased lumbar spine and femoral neck BMD compared to hypogonodal acromegalic patients and the general population, but it is reduced if patients have been hypogonadal.

Acromegaly↗
PubMed2003

The effect of pegvisomant-induced serum IGF-I normalization on serum leptin levels in patients with acromegaly.

BACKGROUND: In humans, serum leptin correlates positively with fat mass. GH is lipolytic and patients with active acromegaly have lowered serum leptin compared to age, sex and body mass index (BMI)-matched controls, but a direct influence of GH on serum leptin remains unclear. In patients with acromegaly, total leptin increases following successful pituitary surgery and during somatostatin (SMS) analogue therapy (despite no change in BMI) but whether this represents changes in soluble leptin receptor, bound or free leptin is unclear. Pegvisomant, a GH receptor antagonist capable of normalizing serum IGF-I in over 97% of patients, represents a novel treatment strategy in acromegaly and its effect on leptin has not previously been reported. PATIENTS: Sixteen patients (nine male (M), seven female (F), median age 52 years, range 27-78 years) with active acromegaly (serum IGF-I at least 30% above the upper limit of an age-related reference range) were studied. Serum IGF-I was normalized in all subjects with pegvisomant [mean duration 7 months (range 3-11 months), median dose 20 mg/day (range 10-40 mg/day)]. A single batch measurement of leptin, bound leptin (BL), soluble leptin receptor (SLR), insulin and glucose were performed on samples from baseline and first occurrence of serum IGF-I normalization. RESULTS: As in normal subjects, females with acromegaly had higher baseline serum leptin [median M = 6.1 (range 1.6-58.7), F = 25.9 (range 3.19-54.1) ng/ml; P = 0.04], which correlated positively with BMI (R = 0.78, P = 0.0004). Forward step-wise regression analysis demonstrated that BMI and gender accounted for 90% of the variance in mean serum log10 leptin. Pegvisomant-induced serum IGF-I normalization was associated with a rise in serum leptin [8.9 (range 1.6-58.3) to 12.7 (range 2.3-90.8) ng/ml, P < 0.0001]. Although the absolute increase was not significantly different, mean percentage increase was greater in men (M = 66.6 +/- 51%, F = 11.8 +/- 16%, P = 0.017) despite similar serum IGF-I and BMI in male and female subjects at baseline. No change in BL or SLR accompanied serum IGF-I normalization [0.27 (range 0.15-1.26) to 0.27 (range 0.14-1.2) nmol/l, P = 0.27 and 3.2 (range 1.2-6.8) to 2.7 (range 1-7.4) nmol/l, P = 0.5, respectively]. After normalization of serum IGF-I, a correlation between BMI and leptin remained (R = 0.86, P < 0.0001) and together BMI and gender accounted for 87% of the variance in mean log10 serum leptin (P = 0.0002). CONCLUSION: Pegvisomant-induced serum IGF-I normalization in patients with active acromegaly is associated with a significant increase in total, and by implication, free leptin.

Acromegaly↗
PubMed1983

Enteroglucagon and GIP after oral glucose in patients with prolactinoma and acromegaly.

We have performed oral glucose tolerance tests (OGTT) in nine patients with prolactinomas, eight patients with active acromegaly, five patients with acromegaly in remission and nine normal controls, and measured blood glucose, plasma insulin, pancreatic glucagon, enteroglucagon, gastric inhibitory polypeptide (GIP) and GH during the test. Patients with prolactinomas and with active acromegaly were hyperinsulinaemic and five of the nine patients with prolactinomas had impaired glucose tolerance, with blood glucose levels that were significantly higher than the normal controls. Prolactinoma patients had higher GIP levels than those with active acromegaly and both showed a failure of suppression of pancreatic glucagon. Of particular interest was the finding that enteroglucagon, a putative gut growth factor, was low in active acromegaly when compared with acromegaly in remission, but similar to normal in the rest of the patients.

Acromegaly↗
PubMed1990

Familial acromegaly: studies in three families.

Acromegaly is usually regarded as a disease which arises sporadically except on those rare occasions in which it occurs as one component of an inherited pluriglandular syndrome. Familial acromegaly occurring in isolation has been reported only rarely. We have studied three families in each of which two first-degree relatives have developed acromegaly without clinical evidence of other endocrinopathies, in order to clarify the relationship of familial acromegaly to multiple endocrine neoplasia, type 1 (MEN 1). No further subclinical cases of acromegaly have been detected in those first-degree relatives of the index cases who were screened. In two of the families, we have found no evidence of abnormal pancreatic or parathyroid function either in the acromegalic index cases or their asymptomatic relatives: a diagnosis of MEN 1 is therefore effectively excluded. In the third family, the presence of multiple subcutaneous lipomata in several members of the family and elevation of PTH levels in two (normocalcaemic) acromegalic index cases, might indicate a highly atypical presentation of MEN 1. None of the six acromegalic index cases had elevations of circulating growth hormone releasing hormone levels. We conclude that isolated familial acromegaly may be more common than has hitherto been realized and that, in these families at least, ectopic production of growth hormone releasing hormone is not responsible.

Acromegaly↗
PubMed2000

Pituitary surgery for the management of acromegaly.

Active acromegaly is almost always the result of a benign growth hormone (GH)-secreting adenoma of the pituitary gland. Because the same pituitary stem cell can produce both GH and prolactin (PRL), many acromegalic patients also have hyperprolactinemia. The advantages of surgical excision of pituitary adenomas associated with acromegaly include: (1) prompt decrease in GH; (2) reliable and immediate relief of the mass effect from the tumor (decompression of the optic nerves and chiasm), and (3) the opportunity to obtain tumor tissue for characterization and investigative study. Currently, more than 97% of operations for removal of pituitary tumors associated with acromegaly are done using the transsphenoidal approach rather than craniotomy. Technical advances to make the surgery safer continue to evolve, and include endoscopic approaches, computer-guided image-based intraoperative visualization, and intraoperative magnetic resonance imaging. Criteria for satisfactory remission of acromegaly after surgery are the same as those used for medical management. They include normal insulin-like growth factor (IGF)-I and suppression of GH to undetectable levels (<1.0 ng/ml) during an oral glucose tolerance test (OGTT). Data from a recent series of 86 patients operated upon for acromegaly at the University of Virginia and followed for more than 1 year have been reviewed. In patients receiving surgery as the initial procedure, 67% had a normal IGF-I, and 52% suppressed to <1.0 ng/ml in an OGTT. There was one true recurrence of disease diagnosed 81 months after surgery. Results are best in patients with noninvasive microadenomas. Gamma knife radiosurgery has been a valuable adjunct in those patients who fail to achieve postoperative remission. Pathological evaluation of the tumors revealed that 16% expressed GH only, 25% stained for GH and glycoprotein hormones (follicle stimulating hormone, thyroid hormone, thyroid stimulating hormone, alpha-subunit), 21% for GH and PRL, and 33% for GH, PRL and glycoprotein hormones. There was one acidophil stem cell tumor and 10% had the mammosomatotroph subtype. This contemporary series was free of mortality or serious complications. One patient had a transient cerebrospinal fluid leak and 3 developed transient SIADH with hyponatremia. Surgical treatment remains an important aspect of the combined management of patients with acromegaly.

Acromegaly↗
PubMed2004

Clinical-biochemical correlations in acromegaly at diagnosis and the real prevalence of biochemically discordant disease.

OBJECTIVE: To analyze clinical-biochemical correlations in newly diagnosed acromegaly, focusing in particular on patients with discrepant parameters. DESIGN: Retrospective study. METHODS: Data from 164 patients with acromegaly seen between 1995 and 2003. Patients were reviewed for the presence of headaches, arthralgias, hypertension, menstrual abnormalities, impotence, glucose intolerance or diabetes. Biochemical evaluation consisted of age- and gender-adjusted IGF-I levels and glucose-suppressed GH. RESULTS: Magnetic resonance imaging (MRI) revealed macroadenoma in 127 patients and microadenoma in 37. Patients with macroadenomas were younger than those with microadenomas and the disease was more frequent in females. Excluding acral enlargement, which was present in all the patients, the most commonly reported complaints were headaches (66%) and arthralgias (52%). Hypertension was present in 37% of patients, whereas the prevalence of glucose intolerance and diabetes was 27 and 32%, respectively. Hyperprolactinemia was present in 20% of patients with microadenomas and in 40% of patients with macroadenomas. Hypogonadism was demonstrated in more than half of the patients and was not related to tumor size or prolactin level. Of all the clinical and metabolic abnormalities of acromegaly, only the presence of diabetes correlated with both basal and nadir post-glucose GH levels. Only 4 patients (2.4%) had glucose-suppressed GH values of <1 ng/ml in the presence of clinical evidence of acromegaly, an elevated IGF-I level and a pituitary adenoma on MRI. CONCLUSIONS: Clinical features of acromegaly correlate poorly with indices of biochemical activity. The prevalence of biochemically discordant acromegaly is considerably lower than recently reported.

Acromegaly↗
PubMed2001

Reduction of lung distensibility in acromegaly after suppression of growth hormone hypersecretion.

Whether the growth of the lungs in acromegaly is due to alveolar hypertrophy or alveolar hyperplasia is a subject of debate. To discriminate these hypotheses, we compared pulmonary distensibility and diffusing capacity among 11 patients with active acromegaly and 11 matched control subjects, evaluating the response of pulmonary distensibility and diffusing capacity to suppression of growth hormone (GH) hypersecretion. We performed lineal and exponential analyses of quasistatic pressure-volume curves. Patients with active acromegaly had a greater TLC, lung compliance, and shape constant, K, than did normal subjects. We found no significant differences between the study groups in carbon monoxide diffusing capacity or diffusing capacity per unit of alveolar volume. After treatment, patients with inactive acromegaly showed a reduced TLC (6.95 +/- 1.40 [mean +/- SD] L versus 6.35 +/- 1.23 L), reduced lung compliance (3.61 +/- 0.90 L/kPa versus 2.36 +/- 0.79 L/ kPa), reduced K coefficient (2.62 +/- 0.65 kPa(-)(1) versus 1.35 +/- 0.40 kPa(-)(1)), and increased maximal recoil pressure (1.74 +/- 0.38 kPa versus 2.28 +/- 0.25 kPa). We conclude that the increased lung distensibility with normal diffusion capacity demonstrated in patients with active acromegaly, which was partly reversible after suppression of GH hypersecretion, suggests that lung growth in acromegaly may result from an increase in alveolar size.

Acromegaly↗
PubMed1986

Insulin action in human adipose tissue in acromegaly.

The mechanisms underlying insulin resistance in acromegaly were investigated. Adipose tissue was obtained from nine patients with acromegaly who had in vivo insulin resistance and from 14 matched healthy control subjects. Receptor binding and the antilipolytic effect of insulin were determined in isolated fat cells. Insulin-induced glucose oxidation at a physiological hexose concentration was investigated in fat segments. In fat cells obtained from acromegaly patients after an overnight fast, insulin binding at low hormone concentrations was significantly reduced by 20-30%, insulin-induced antilipolysis was unchanged, but glucose oxidation was unresponsive to insulin. Since it has recently been observed that glucose feeding may rapidly modify insulin action in human adipocytes, fat cells were also obtained 60 min after an 100-g oral glucose load. In this situation, insulin binding at low hormone concentrations was further reduced to one-half of that in the control group, and the sensitivity of insulin-induced antilipolysis was markedly decreased in acromegaly. It is concluded that, in the fasting state, the action of insulin on glucose utilization but not on lipolysis is impaired in adipose tissue of acromegalic patients because of a postreceptor defect. After glucose ingestion, the resistance to insulin in acromegaly is further enhanced and antilipolysis is also impaired. Altered coupling between receptor and effector alone or in combination with an additional decrease in receptor binding may explain the enhancement of insulin resistance. These mechanisms may be essential factors in the pathogenesis of insulin resistance in acromegaly.

Acromegaly↗
PubMed1983

Pathophysiology of acromegaly.

This review discusses the pathophysiology of acromegaly. Acromegaly has been classified in this paper into distinct entities based on etiology, ultrastructural features of the pituitary, and cytogenesis. This classification has been proposed based on clinical signs, immunoperoxidase techniques, transmission electromicroscopy and immunoelectron microscopy. Pituitary causes of acromegaly include densely granulated adenomas, sparsely granulated adenomas, mixed growth hormone and prolactin cell adenomas, acidophil stem cell adenomas, mammosomatotroph cell adenomas, and pleurihormonal adenomas. GH cell hyperplasia and GH cell carcinoma are also discussed. Extrapituitary causes of acromegaly include eutopic GH cell adenoma in the sphenoid sinus or parapharyngeal region and excess GHRF secretion which may be eutopic or ectopic. The pathological, clinical, and biochemical evidence in favor of a pituitary or hypothalamic etiology of acromegaly has been reviewed. Finally, a multistage theory of GH cell tumorigenesis has been proposed as a model in an attempt to unify the genetic, environmental and biochemical factors implicated in the pathogenesis of acromegaly.

Acromegaly↗
PubMed2004

Long-term biochemical status and disease-related morbidity in 53 postoperative patients with acromegaly.

UNLABELLED: Assessment of postoperative disease activity of acromegaly is a major challenge. The consensus criteria for cure, which are glucose-suppressed GH less than 1 micro g/liter and normal IGF-I levels, might be discrepant, and their respective relationship to acromegaly-related morbidity is not well known. THE AIMS OF OUR STUDY WERE: firstly, to correlate plasma IGF-I with plasma glucose-suppressed GH concentrations; and secondly, to correlate each of these biochemical parameters with morbidity [impaired glucose tolerance (IGT), diabetes, and hypertension] in postoperative patients with acromegaly. Fifty-three patients with long-term follow-up (mean, 12.7 yr; range, 1-30 yr) after transsphenoidal surgery for acromegaly and 20 healthy subjects matched for age, sex, and body mass index were evaluated for plasma glucose [by 75-g oral glucose tolerance test (OGTT)], GH (by immunoradiometric assay), plasma IGF-I (by immunoradiometric assay), and blood pressure (BP) measurements. Remission was defined by a normal IGF-I. We identified 34 acromegalics in remission and 19 with active disease. There was no statistical difference between all three groups for age, sex, BMI, and for fasting and 2-h post-OGTT plasma glucose. The time elapsed since surgery was similar in both groups of acromegalics. The OGTT-GH nadir was less than 1 micro g/liter in 31 patients in remission (91.2%) and in nine patients with active disease (47.4%). Prevalence of IGT was lower in acromegalics in remission (14.7%) in comparison with patients with active disease (47.4%; P = 0.01). Plasma IGF-I and GH nadir cut-off of 0.25 microg/liter were strong predictors of abnormal glucose tolerance (odds ratio, 13.6; confidence interval, 2.5-73.7; P = 0.003). GH nadir cut-off of 1 microg/liter and basal GH of 2.5 microg/liter failed to predict abnormal glucose tolerance. There was no statistical difference for prevalence of hypertension and systolic BP values, but diastolic BP was significantly lower in patients in remission than in those with active disease (P < 0.05). Our observations indicate that the validity of the GH threshold of 1 microg/liter post OGTT might be inadequate as a criterion of biochemical remission of acromegaly and as a marker of associated comorbidities. However, normalized IGF-I concentrations and a lower GH cut-off value less than 0.25 micro g/liter are strongly associated with a lower prevalence of IGT and lower diastolic BP in long-term postoperative acromegaly.

Acromegaly↗
PubMed2004

Long-term outcome of patients with acromegaly and congestive heart failure.

Cardiovascular complications are a major cause of morbidity and mortality in patients with acromegaly. Normalization of GH secretion is associated with an improvement in structural and functional cardiac abnormalities. However, the long-term cardiac effects of treatment for acromegaly have not been studied in patients who have already developed chronic congestive heart failure (CHF). We reviewed the charts of 330 consecutive patients with acromegaly treated in two French and Belgian centers since 1985. Ten patients with both acromegaly and CHF (eight men, two women, mean age 49.7 yr) were studied retrospectively. One of them was excluded because CHF was due to severe aortic stenosis.CHF (New York Heart Association stages III-IV and echocardiography showing dilated hypokinetic cardiomyopathy with left ventricular systolic dysfunction and a left ventricular ejection fraction less than 45%) was diagnosed before, concomitantly, or after acromegaly in, respectively, two, five, and two patients. Three patients were referred with terminal heart failure requiring transplantation.One patient had transient CHF associated with a hypertensive crisis. The other eight patients had symptomatic chronic CHF. Control of GH hypersecretion failed, totally or partially, in three patients: one had a long-term survival, and the two others died at 1 and 5 yr. Good GH control was achieved in five patients: four of these are still alive 2-16 yr after diagnosis of CHF, their clinical status is stable or improved, and their quality of life is good. Overall, the 1- and 5-yr mortality (or transplantation) rates for patients with chronic symptomatic CHF were 25% (2 of 8 patients) and 37.5% (3 of 8 patients), respectively. In conclusion, less than 3% of acromegalic patients developed CHF in this study. Although effective treatment of acromegaly improved short-term cardiovascular status, its impact on long-term survival is questionable.

Acromegaly↗
PubMed2005

Effect of active acromegaly and its treatment on parathyroid circadian rhythmicity and parathyroid target-organ sensitivity.

CONTEXT: Patients with active acromegaly have increased bone turnover and skeletal abnormalities. Biochemical cure of acromegaly may represent a functional GH-deficient state and result in cortical bone loss. Reduced PTH target-organ sensitivity occurs in adult GH deficiency and may underlie the associated development of osteoporosis. OBJECTIVE: We examined the effect of active and treated acromegaly on PTH concentration and target-organ sensitivity. PATIENTS: Ten active acromegalic subjects (GH nadir > 0.3 mug/liter after 75-g oral glucose load and IGF-I above age-related reference range) and 10 matched controls participated in the study. DESIGN: Half-hourly blood and 3-h urine samples were collected on patients and controls for 24 h. Samples were analyzed for PTH, calcium (Ca), nephrogenous cAMP (NcAMP, a marker of PTH renal activity), beta C-telopeptide (bone resorption marker), and procollagen type-I amino-terminal propeptide (bone formation marker). Serum calcium was adjusted for albumin (ACa). Eight acromegalic subjects who achieved biochemical cure (GH nadir < 0.3 mug/liter after 75-g oral glucose load and IGF-I within reference range) after standard surgical and/or medical treatment reattended and the protocol repeated. RESULTS: Active acromegalic subjects had higher 24-h mean PTH, NcAMP, ACa, urine Ca, beta C-telopeptide, and procollagen type I amino-terminal propeptide (P < 0.05), compared with controls. Twenty-four-hour mean PTH increased (P < 0.001) in the acromegalic subjects after treatment, whereas NcAMP and ACa decreased (P < 0.05). CONCLUSION: Increased bone turnover associated with active acromegaly may result from increased PTH concentration and action. Biochemical cure of acromegaly results in reduced PTH target-organ sensitivity indicated by increased PTH with decreased NcAMP and ACa concentrations. PTH target-organ sensitivity does not appear to return to normal after successful treatment of acromegaly in the short term and may reflect functional GH deficiency.

Acromegaly↗
PubMed2006

The role of endogenous growth hormone-releasing hormone in acromegaly.

CONTEXT: Some indirect evidence suggests hypothalamic control of GH secretion in acromegaly. OBJECTIVE: The objective of the study is to examine whether GH secretion in acromegaly is dependent on endogenous GHRH. PATIENTS AND STUDY DESIGN: We studied eight patients with untreated acromegaly due to a GH-producing pituitary tumor. All patients received an iv infusion of normal saline for 24 h and GHRH-antagonist (GHRH-ant) at 50 microg/kg x h for 7 d. GH was measured every 10 min for 24 h during the normal saline infusion and on the last day of the GHRH-ant infusion. A group of nine different patients with untreated acromegaly served as the control group and underwent blood sampling for GH every 10 min for two 24-h periods to assess the day-to-day variability of GH secretion. SETTING: The study was set in a university referral center. MAIN OUTCOME MEASURE: Twenty-four-hour mean GH was the main outcome measured. RESULTS: In six of eight subjects treated with GHRH-ant, 24-h mean GH decreased by 5.8-30.0% during iv GHRH-ant and, in three subjects, the change in the 24-h mean GH was greater than the upper limit of the 95% confidence interval of the spontaneous day-to-day variability of the mean GH in patients with acromegaly. Based on the binomial distribution, the probability of this magnitude of change to occur in three of eight subjects by chance alone is 0.0008. CONCLUSION: In some patients with acromegaly due to a pituitary adenoma, GH secretion is under partial control by endogenous GHRH.

Acromegaly↗
PubMed1988

Supranormal stimulation of deoxyribonucleic acid synthesis in FRTL5 cells by serum from patients with untreated acromegaly.

Insulin-like growth factor I (IGF-I) is one of a number of mitogenic factors in the serum of animals and humans. We demonstrated previously that IGF-I is a potent mitogen for FRTL5 cells, a line of rat thyroid follicular cells. In this study, we assessed the relevance of this finding with respect to the levels of IGF-I found in human serum by comparing the effects of normal serum and serum from patients with untreated acromegaly or hypopituitarism on DNA synthesis in quiescent FRTL5 cells. As expected, when added to cells maintained in Coon's modified Ham's F-12 medium containing 0.1% BSA, but devoid of insulin, transferrin, TSH, or calf serum, normal serum produced a dose-dependent stimulation of [3H]thymidine incorporation into DNA. A similar, but more marked, effect was produced by the addition of serum from patients with untreated acromegaly. In multiple experiments, a standard concentration (0.5%) of acromegaly serum was more stimulatory to DNA synthesis than was normal serum. In a single experiment designed to eliminate interassay variation and define the relationship between the ability of serum to stimulate DNA synthesis and its IGF-I concentration, studies were performed with 0.5% concentrations of serum from 9 normal subjects, 15 patients with untreated acromegaly, and 3 patients with panhypopituitarism. On the average, [3H]thymidine incorporation in the presence of serum from patients with acromegaly was approximately 3 times, and that in the presence of serum from patients with hypopituitarism only one fourth, that in the presence of serum from normal subjects; there was no overlap of individual values in the three groups. For the entire study group, we found a highly significant correlation (r = 0.86) between the serum IGF-I concentration and the ability of that serum to stimulate thymidine incorporation into the DNA of FRTL5 cells. The stimulatory effects of serum from both normal and acromegalic subjects were decreased or abolished by the addition of a monoclonal antibody against IGF-I. In hypophysectomized rats, GH increases the thyroid to body weight ratio and enhances the effect of TSH to promote thyroid growth. Further, an inordinate frequency of nontoxic goiter in patients with acromegaly has been reported. Taken together with these observations, our findings suggest that the effect of IGF-I to promote thyroid cell growth in vitro has a counterpart in the living animal or patient.

Acromegaly↗
PubMed1995

Energy metabolism and substrate oxidation in acromegaly.

Short term GH administration increases lipid breakdown and oxidation (lipidox) and reduces glucose uptake and carbohydrate oxidation (CHOox). It is not clear whether similar shifts in substrate oxidation occur in acromegaly, and our aim was to investigate this. Using indirect calorimetry, we compared energy expenditure, CHOox, and lipidox in 20 acromegalic patients and 20 normal subjects pair-matched for sex, age, height, and weight. Investigations were performed in the basal state (12-h fast) and during a 75-g oral glucose tolerance test (OGTT). Acromegalic patients had significantly higher fasting glucose levels and greater glucose and insulin responses during an OGTT than normal subjects. Fasting nonesterified free fatty acid and insulin-like growth factor (IGF)-binding protein-1 levels were similar in the two groups, and both were acutely suppressed by oral glucose to the same degree. Basal energy expenditure was significantly greater in the acromegalic patients (1682 +/- 49 vs. 1540 +/- 45 Cal/24 h; P < 0.05), who showed a trend toward higher basal CHOox. Oral glucose resulted in a significantly higher rise in energy expenditure in the normal compared to the acromegalic subjects. During the OGTT, CHOox significantly increased in both groups, but rose to a higher level in the acromegalic patients (177 +/- 10 vs. 138 +/- 9 mg/min; P = 0.004). Oral glucose significantly reduced lipidox in both groups, but lipidox was reduced to a significantly lower level in the acromegalic patients (32 +/- 4 vs. 46 +/- 3 mg/min; P = 0.004). In acromegaly, basal CHOox (r = 0.56; P = 0.01) and postglucose CHOox (r = 0.79; P = 0.0001) were both positively correlated to IGF-I, but not to insulin and/or glucose. In normal subjects, postglucose CHOox was positively correlated to IGF-I. In summary, hyperinsulinemia in acromegaly was associated with higher glucose levels and a blunted thermogenic response to glucose, and displayed no relationship to the pattern of substrate oxidation. CHOox was increased, and lipidox was reduced in acromegaly, and the extent of IGF-I elevation was related to CHOox in the basal and postglucose states. We conclude that 1) the chronic effects of GH excess on substrate oxidation differ from the short term effects of GH administration; 2) impaired insulin action in acromegaly extends to effects on energy expenditure; and 3) IGF-I may be an important regulator of substrate oxidation in acromegaly.

Acromegaly↗
PubMed2002

Cardiovascular risk factors in acromegaly before and after normalization of serum IGF-I levels with the GH antagonist pegvisomant.

Acromegaly is associated with premature cardiovascular mortality. GH replacement therapy decreases inflammatory markers of cardiovascular risk, but little is known about these markers in patients with acromegaly. The GH receptor antagonist, pegvisomant, reduces IGF-I levels in 98% of patients treated. We investigated the effects of GH receptor blockade on inflammatory and other cardiovascular risk markers in active acromegaly. Forty-eight patients with acromegaly and 47 age- and body mass index-matched controls were included. The study consisted of 3 parts: a cross-sectional study, a prospective randomized 12-wk placebo-controlled study, and a longitudinal open-label study of up to 18 months of pegvisomant treatment. After baseline evaluation, patients with acromegaly were randomized to placebo (n = 14), 10 mg (n = 12), 15 mg (n = 10), or 20 mg (n = 12) daily pegvisomant for 12 wk. Subsequently, all patients received at least 10 mg pegvisomant daily for up to 18 months, with dose adjustments to achieve a normal IGF-I level. Anthropometry, GH, IGF-I, and pegvisomant levels were measured monthly. C-reactive protein (CRP), IL-6, homocysteine, lipoprotein(a), glucose, insulin, triglycerides, total cholesterol, and high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol were determined at baseline, 4 and 12 wk in the placebo-controlled study and at 3-month intervals (during which IGF-I levels were normal) in the longitudinal study. In the cross-sectional study, patients had lower CRP than did controls [median, 0.3 (range, 0.2-0.8) vs. 2.0 (0.6-3.7) mg/liter; P < 0.0001] and had higher insulin [78.6 (55.8-130.2) vs. 54.5 (36.6-77.5) pM, P = 0.0051]. IL-6, homocysteine, triglycerides, lipoprotein(a), LDL cholesterol and HDL cholesterol were not different between groups. In the placebo-controlled study, CRP increased in patients treated with 20 mg pegvisomant, compared with placebo (mean +/- SEM, 13.7 +/- 3.6 vs. 0.5 +/- 3.3 mg/liter; P = 0.010). There were no significant differences in IL-6, homocysteine, glucose, insulin, triglyceride, total cholesterol, LDL cholesterol and HDL cholesterol levels. In the longitudinal open-label study (median duration, 15.6 months), CRP increased by 2.0 +/- 0.5 mg/liter (P = 0.0002). Total cholesterol and triglycerides increased (0.22 +/- 0.11 mM, P = 0.050; and 0.25 +/- 0.09 mM, P = 0.007, respectively), whereas lipoprotein(a) decreased (-70 +/- 33 mg/liter, P = 0.039). Glucose, insulin, homocysteine, HDL cholesterol, and IL-6 did not change. We conclude that patients with active acromegaly have lower CRP and higher insulin levels than healthy controls. Administration of pegvisomant increases CRP levels. We propose that GH secretory status is an important determinant of serum CRP levels, although additional studies are needed to determine the mechanism and significance of this finding.

Acromegaly↗
PubMed1991

[A case of fibrous dysplasia (McCune Albright syndrome) associated with acromegaly].

We report a case of a 47-year-old woman with McCune-Albright syndrome associated with unusual growth-hormone and prolactin hypersecretion. Acromegaly was suspected on clinical examination, and she was referred to us. She had no history of precocious puberty or pathological fracture. She was 154cm tall, weighing 62kg with so-called acromegalic facies. There were two lumps, one of which was on her right lateral forehead. The other on the right lower extremity seemed to be due to a bone deformity. Some brown pigmented macules with irregular borders were present on her lips and oral mucosa. Endocrine examination revealed elevated basal levels of plasma GH (54ng/ml) and PRL (36.2ng/ml), which paradoxically increased after injection of TRH. Plasma levels of these hormones did not change after LHRH test, and plasma GH level increased after GHRH test. A skull X-ray film showed a double floor of the sella turcia and hyperostotic formation of the right sphenoid bone. MRI and CT showed a tumor shadow in the right sella turcica. Bone roentogenography of the right fibula and tibia showed a large centrally expanding lesion with a ground-glass or cystic appearance and a thin cortex. The left fibula showed a similar lesion. We recognized similar findings in other bones which also showed abnormal accumulation in a radionuclide bone scan with 99mTc. On the basis of physical, endocrinological and roentogenographical examination, we diagnosed her as displaying McCune-Albright syndrome. We operated on her by transsphenoidal surgery and confirmed a functioning chromophobe adenoma which was removed during surgery. She has been free of GH and PRL hypersecretion since then. The pathology of the sphenoidal sinus affected with fibrous bone was in accordance with the findings of fibrous dysplasia. McCune-Albright syndrome (MCAS) is known as a syndrome characterized by polyostotic fibrous dysplasia and cutaneous pigmentation and multiple endocrinopathy. Its etiology is unknown. This syndrome with acromegaly is rare, and although 26 cases have been described in literature, pathological examinations have been undertaken in only three cases. This case was very rare and valuable because, by operating on her by the transsphenoidal route in spite of the sphenoidal sinus being affected with fibrous bone, we were able to confirm a chromophobe adenoma secreting both GH and PRL. We recognized that acromegaly with MCAS was endocrinologically, morphologically and immunohistologically the same as acromegaly without MCAS. Therefore, we concluded that acromegaly with MCAS is much the same as acromegaly without MCAS.

Acromegaly↗
PubMed2000

Incidence of malignant tumors in patients with acromegaly.

Neoplasms may be one of the systemic complications to which we attribute high mortality in acromegaly. The present study was designed to investigate the incidence of malignant tumors in patients with acromegaly in the Japanese population. In this report, 44 patients (25 men and 19 women) with biochemically proven acromegaly were studied retrospectively and had a total 670 patient years of the duration of acromegaly. We investigated the incidence of malignant tumors. There were 5 patients with malignant tumors (5 in men) in this study (11%). Male patients with acromegaly had nearly a 3.5 times higher ratio of malignancy than expected and this increased cancer incidence was considered significant (P=0.01). There was no significant increase in cancer incidence of either the total patient population or female patients. The malignant tumors were two thyroid cancers and one colon, one gastric and one bladder cancer. It is of note that the colon cancer of one patient was diagnosed 2 years after transsphenoidal surgery even though the levels of serum GH and insulin-like growth factor (IGF-1) were reduced to normal after operation. This preliminary study has suggested that male patients with acromegaly might have a high risk of malignancy and that careful screening for tumors is needed both before and after surgical and medical treatment, even in patients with normalized serum GH and IGF-1 levels.

Acromegaly↗