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PubMed2006

CYP11B2 -344T/C gene polymorphism and blood pressure in patients with acromegaly.

CONTEXT: The pathogenesis of increased blood pressure (BP) in acromegaly is unclear, and the role of IGF-I levels and the renin-angiotensin-aldosterone system (RAAS) in this disease remains controversial. OBJECTIVE AND DESIGN: The aim of this study was to investigate the role of gene polymorphisms of the RAAS and involved in sodium handling on BP in acromegaly. SETTING AND PATIENTS: We conducted a multicentric retrospective study that included 100 consecutive patients with acromegaly referred during the period 2000-2003. INTERVENTION: All patients were genotyped for ACE I/D, AGT M235T, CYP11B2 -344T/C, B2R -58T/C, and alpha-adducin G460W polymorphisms. MAIN OUTCOME MEASURE: We assessed the prevalence of hypertension and BP according to the genotype. RESULTS: Patients with the CYP11B2 -344CC genotype displayed a significant increase in the risk of hypertension compared with patients with CT/TT genotypes (odds ratio = 4.0; 95% confidence interval = 1.4-11.6; P = 0.01). Consistently, a significant proportion of patients with the CYP11B2 -344CC genotypes were under antihypertensive treatment (73.1%) compared with patients with the TT/TC genotypes (38.2%; P = 0.003). Patients with the -344CC genotype displayed a significant increase in systolic BP (10.2 +/- 4.3 mm Hg; P = 0.02) but not a significant increase in diastolic BP (2.6 +/- 2.6 mm Hg; P = 0.32) compared with patients with the CT/TT genotype. CONCLUSIONS: We have shown an association of the -344T/C CYP11B2 gene polymorphism with BP in patients affected by acromegaly. These findings suggest that the RAAS is implicated in the pathogenesis of hypertension in acromegaly.

Acromegaly↗
PubMed2006

McCune-Albright syndrome and acromegaly: effects of hypothalamopituitary radiotherapy and/or pegvisomant in somatostatin analog-resistant patients.

BACKGROUND: Acromegaly, which may be present in patients with McCune-Albright syndrome (MCAS), in association with café-au-lait spots, precocious puberty, and fibrous dysplasia, is often difficult to treat surgically because skull base bone dysplasia prevents the removal of the pituitary adenoma. Somatostatin analogs (SAs) generally give only partial responses. The use of radiotherapy (RT) is controversial because of a possible risk of bone sarcomatous transformation. AIM: This study was a retrospective analysis of the efficacy and adverse effects of different treatment modalities in six patients with both MCAS and acromegaly. PATIENTS AND METHODS: Because surgery was impossible and SA failed to normalize GH/IGF-I hypersecretion, five of the six patients received fractionated RT (45-55 Grays). Three patients (two with previous RT) were also prescribed pegvisomant. We analyzed the clinical features of acromegaly, GH, and IGF-I concentrations and bone radiological features. RESULTS: GH and IGF-I concentrations fell after RT (median follow-up, 5 yr; range, 0.5-9 yr). Symptoms of acromegaly improved in parallel. Bone sarcomatous transformation was only noted in one patient in a region (the mandible) outside the radiation field. RT alone and/or combined with SA failed to normalize GH/IGF-I levels in the five patients concerned. In contrast, IGF-I levels normalized very rapidly (5-9 months) in the three patients receiving pegvisomant (10-20 mg/d). CONCLUSION: RT may be an option for the treatment of acromegaly in patients with MCAS when surgery is impossible and SA therapy is ineffective. However, although no bone sarcomatous transformation was observed within the radiation field in this series, this risk cannot be ruled out. As shown in this small series of severely affected patients, pegvisomant therapy may thus be useful to normalize IGF-I levels rapidly.

Acromegaly↗
PubMed2006

Acromegaly and somatotroph hyperplasia with adenomatous transformation due to pituitary metastasis of a growth hormone-releasing hormone-secreting pulmonary endocrine carcinoma.

CONTEXT: GHRH excess from extracranial endocrine tumors is known to cause somatotroph hyperplasia and acromegaly. Hypothalamic gangliocytomas producing GHRH are also known to be associated with pituitary adenomas causing acromegaly. OBJECTIVES: The objective of this study was to describe a case of acromegaly due to a pulmonary GHRH-secreting endocrine carcinoma with metastasis to the pituitary gland and to look at the peculiar histological features of this case. SUBJECT: The patient was a 44-yr-old woman who was diagnosed with a biopsy-proven metastatic pulmonary endocrine tumor during pregnancy. After delivery, she underwent radiation and chemotherapy for pulmonary and skeletal metastases. Her disease was clinically stable for 7 yr until she developed bitemporal hemianopia. She had symptoms and signs of acromegaly. METHODS: Imaging, biochemical, and histological studies were performed. RESULTS: Magnetic resonance imaging (MRI) of the brain confirmed the presence of a 2.6-cm lesion within the sella turcica extending above the sella and compressing the optic chiasm. Endocrine studies showed elevated serum levels of GH, prolactin, alpha-subunit of glycoprotein hormones, IGF-I, chromogranin A, and GHRH. The patient underwent uneventful transsphenoidal resection of the sellar tumor. Postoperatively, she noted an improvement in symptoms of acromegaly. Histological examination confirmed metastatic endocrine carcinoma to the pituitary, and immunohistochemistry localized GHRH to the tumor cells. The adjacent pituitary exhibited somatotroph hyperplasia with abundant reactivity for GH and alpha-subunit. In addition, there was focal neoplastic transformation to a sparsely granulated somatotroph phenotype with fibrous bodies. CONCLUSION: This is the first report of a GHRH-producing endocrine tumor metastasizing to the pituitary and causing local hyperstimulation with somatotroph hyperplasia and adenomatous transformation.

Acromegaly↗
PubMed1984

A case for hypothalamic acromegaly: a clinicopathological study of six patients with hypothalamic gangliocytomas producing growth hormone-releasing factor.

We report the histological, ultrastructural, and immunocytochemical features of six hypothalamic gangliocytomas associated with pituitary GH cell adenomas and/or acromegaly. In four patients, the gangliocytoma was intrasellar, and no hypothalamic investigation was performed; in two patients, autopsy confirmed hypothalamic involvement. Four patients had a gangliocytoma associated with pituitary GH cell adenoma and acromegaly; electron microscopy demonstrated an intimate association between neurons and adenomatous GH cells. One patient had a gangliocytoma and a GH cell adenoma but no clinical evidence of acromegaly. In the sixth patient, clinical and biochemical acromegaly was manifest, but no pituitary adenoma was demonstrated. Using immunocytochemistry, human pancreatic tumor GRF (hptGRF-40) was localized in the majority of neurons of all six gangliocytomas. The pituitary adenomas and nontumorous adenohypophyses were negative for hptGRF-40. In addition, somatostatin, glucagon, and GnRH were demonstrated within some neurons of several tumors; insulin and gastrin stains were equivocal. These findings confirm previous proposals of production of a GRF by such gangliocytomas. While the significance of other peptides found in some of the tumors is uncertain, the presence of hptGRF-40 in neurons of these gangliocytomas supports the theory that GRF excess is the mechanism responsible for over-production of GH and provides evidence for a syndrome of hypothalamic acromegaly.

Acromegaly↗
PubMed1989

Increased growth hormone pulse frequency in acromegaly.

To investigate whether GH secretion in acromegaly is subject to regulatory control by the hypothalamic GH-releasing hormone (GHRH) we studied GH secretion in 22 patients with acromegaly. Parameters of pulsatile GH secretion were assessed using frequent blood sampling (every 20 or 10 min for 24 h). Acute GH responses to GHRH-44 (0.1, 0.33, and 1.0 micrograms/kg BW, iv) were measured, and GH secretion during therapy with the long-acting somatostatin analog SMS 201-995 (Sandoz) was assessed. The results were compared to those in normal volunteers. Spontaneous GH pulse frequency was greater in patients with acromegaly than in 6 control subjects (8.6 +/- 0.6 vs. 4.3 +/- 1.1 pulses/24 h), as estimated by the 20-min sampling frequency. The 10-min sampling frequency revealed 12.9 +/- 0.7 pulses/24 h in acromegalics. Spontaneous GH pulse amplitude and acute GH rises in response to GHRH did not differ between control and acromegalic subjects. A similar degree of nocturnal augmentation of GH secretion was observed in both groups, and it persisted during SMS 201-995 therapy in patients with acromegaly. These observations suggest that GH secretion in acromegaly remains under stimulatory control by GHRH, which may be released at an abnormally high rate.

Acromegaly↗
PubMed1992

Basal- and insulin-stimulated substrate metabolism in patients with active acromegaly before and after adenomectomy.

Active acromegaly is characterized by inappropriate tissue growth, increased mortality, and perturbations of intermediary metabolism. It is, in general, not well described to which extent these disturbances are normalized after treatment of the disease. To further assess basal and insulin stimulated fuel metabolism in acromegaly six patients with monotropic GH excess were each studied approximately 1 month prior to and 2 months after successful selective pituitary adenomectomy and compared to a control population of seven subjects. The studies consisted of a 3-h basal postabsorptive period and a 2-h hyperinsulinaemic (0.4 mU/kg/min) euglycemic clamp and the methods employed included isotopical measurement of glucose turnover, indirect calorimetry, and the forearm technique. When compared to the control subjects the patients with acromegaly were preoperatively and in the basal state characterized by: 1) increased circulating concentrations of GH, insulin, and C-peptide (P less than 0.05); 2) increased plasma glucose (5.9 +/- 0.2 vs. 5.2 +/- 0.2 mmol/L), blood lactate (710 +/- 90 vs. 580 +/- 70 mumol/L), glucose turnover (2.34 +/- 0.12 vs. 1.93 +/- 0.12 mg/kg/min), and plasma lipid intermediates and a decreased forearm glucose uptake (0.06 +/- 0.02 vs. 0.19 +/- 0.04 mmol/L) (P less than 0.05); and 3) a 20% increase in energy expenditure, a 50% elevation of lipid oxidation rates, and a 130% elevation of nonoxidative glucose turnover (P less than 0.05). During the clamp the patients with active acromegaly were substantially resistant to the actions of insulin on both glucose and lipid metabolism. Following pituitary surgery all of these metabolic abnormalities were abolished. We conclude that active acromegaly is characterized by profound disturbances of not only glucose but also lipid metabolism, which in theory may precipitate the increased mortality in this disease. By showing that these abnormalities and the concomitant overall insulin resistance can be completely reversed our results may also have important implications for other insulin-resistant states and for the potential therapeutic use of GH.

Acromegaly↗
PubMed1994

Body composition and energy expenditure in acromegaly.

To investigate whether GH is a regulator of body composition and energy metabolism in adult life, we have compared body composition and resting energy expenditure (REE) in a cross-sectional study in 20 acromegalic and 20 normal subjects, pair-matched for sex, age, height, and weight. In a longitudinal study, 8 acromegalic patients were also studied before and after 12 weeks of treatment [n = 6 during octreotide (100 micrograms, 3 times/day); n = 2 after pituitary surgery], and 7 patients were studied 12 weeks after withdrawal of octreotide. REE was measured by indirect calorimetry and fat mass and fat-free soft tissue mass (FFSTM) by dual energy x-ray absorptiometry. A subgroup of 12 matched pairs of subjects and 7 treated patients had measurement of extracellular water (ECW) by 24Na dilution, which when subtracted from FFSTM provided an estimate of body cell mass (BCM). Fat mass was significantly reduced (25.4 +/- 2.2 vs. 29.7 +/- 2.7 kg; P = 0.007) and FFSTM increased (53.3 +/- 2.2 vs. 49.2 +/- 2.3 kg; P = 0.003) in acromegaly with ECW (25.6 +/- 1.6 vs. 21.1 +/- 0.9 L; P = 0.0003), but not BCM, significantly elevated. Treatment of acromegaly increased fat mass and reduced FFSTM [change (delta), -1.3 +/- 0.4 kg; P = 0.004]; the latter reflected a significant fall in ECW (delta, -2.2 +/- 0.4 L; P = 0.002), but not BCM. The opposite effect on body composition occurred after treatment withdrawal. REE was increased in acromegaly (1682 +/- 49 vs. 1540 +/- 45 Cal/24 h; P = 0.02) and significantly related to insulin-like growth factor-I (P = 0.02). REE was significantly reduced (delta, -154 +/- 17 Cal/24 h; P = 0.0001) with treatment and increased after treatment withdrawal (P = 0.003). In acromegaly, there is a reversible 1) reduction in fat mass; 2) increase in FFSTM, accounted for by an increase in ECW, but not BCM; and 3) increase in REE, which is dependent on disease activity. We conclude from these observations in acromegaly that GH is a regulator of energy metabolism and body composition.

Absorptiometry, Photon↗
PubMed1995

Effects of acromegaly treatment and growth hormone on adipose tissue lipoprotein lipase.

Lipoprotein lipase (LPL) hydrolyzes lipoprotein triglyceride into nonesterified fatty acids, which are then reesterified and stored in adipose tissue. Previous studies have demonstrated increases in LPL in response to insulin-like growth factor I and GH when added in vitro. This study examined the effects of acromegaly treatment on adipose tissue LPL. Ten patients with clinically active acromegaly were recruited. A fasting adipose tissue biopsy was performed both before and 3 months after treatment with octreotide (8 patients) or surgery plus octreotide (2 patients). With treatment, mean baseline insulin-like growth factor I levels fell from 6.41 to 3.98 U/mL (normal, < 2.2 U/mL; P < 0.05), and serum glycohemoglobin fell from 8.6 to 7.2 (normal, < 6.8). Adipose LPL was measured in the heparin-released fraction as well as the cellular fraction extracted with nonionic detergent (EXT). After treatment of acromegaly, there was no change in heparin-released fraction LPL activity or immunoreactive mass. However, there was an increase in EXT activity from 0.73 +/- 0.33 to 1.83 +/- 0.58 nEq/min.10(6) cells (mean +/- SEM; P < 0.05) and an increase in EXT mass from 4.1 +/- 0.89 to 11.4 +/- 2.0 ng/10(6) cells (P < 0.05). There was no change in LPL messenger ribonucleic acid levels with treatment, determined using both quantitative polymerase chain reaction and Northern blotting. Thus, treatment of acromegaly resulted in an increase in the intracellular level of the LPL protein, with no change in messenger ribonucleic acid levels, suggesting posttranscriptional regulation of LPL. These changes in LPL may be due to improved insulin sensitivity, or to other changes associated with acromegaly treatment.

Acromegaly↗
PubMed1995

Serum insulin-like growth factor-binding protein-3 levels in the diagnosis of acromegaly.

Insulin-like growth factor-binding protein-3 (IGFBP-3) is a GH-dependent protein that binds insulin-like growth factor-I (IGF-I) in the circulation and modulates its action at the tissue level. Because IGFBP-3 is a stable and specific marker of somatotroph function, we hypothesized that it would be a useful biochemical marker in the diagnosis of patients with acromegaly and the assessment of surgical cure. We, therefore, investigated the sensitivity of serum IGFBP-3 levels to detect GH excess in 44 patients with clinical acromegaly and pathologically confirmed somatotroph adenomas, including a cohort of 18 patients with untreated disease evaluated before transsphenoidal surgery and medical therapy. IGFBP-3 levels were compared to IGF-I and random GH levels before and after transsphenoidal surgery. Concordance among IGFBP-3, IGF-I, and GH suppressibility by glucose was also determined. In addition, the response of IGFBP-3 to glucose suppression was investigated. All 18 patients with untreated acromegaly had elevated serum IGFBP-3 levels, ranging from 4,186-10,026 micrograms/L (mean +/- SD, 6566 [plusm] 1800 micrograms/L). There was no overlap with the age-adjusted normative ranges (P = 0.0001 in patients 18-55 yr old and P = 0.0176 in patients > 55 yr old) or with the levels obtained in age-comparable controls (P = 0.0001). In 11% of untreated patients with clinical findings of acromegaly and a pathologically confirmed adenoma, IG-FBP-3 levels were elevated, although GH was suppressed to less than 2 micrograms/L with glucose. In these patients, IGF-I levels were either normal or minimally elevated and considered nondiagnostic. IGFBP-3 and IGF-I levels were correlated in patients with untreated acromegaly (r = 0.650; P = 0.0162) and after transsphenoidal surgery (r = 0.644; P = 0.0001). Neither IGF-I nor IGFBP-3 correlated with random GH levels before surgery. However, both IGF-I (r = 0.471; P = 0.0001) and IGFBP-3 (r = 0.259; P = 0.041) correlated with random GH levels in patients studied more than 1 month after transsphenoidal surgery. IGFBP-3 and IGF-I levels were concordant with GH suppressibility by glucose (P = 0.0039) and IGFBP-3 decreased with glucose suppression in 7 of 10 patients. These data indicate that IGFBP-3 is a sensitive physiological marker of somatotroph function and is concordant with glucose suppression and IGF-I levels before and after transsphenoidal surgery.(ABSTRACT TRUNCATED AT 250 WORDS)

Acromegaly↗
PubMed1997

Pituitary irradiation is ineffective in normalizing plasma insulin-like growth factor I in patients with acromegaly.

Pituitary irradiation suppresses GH hypersecretion in patients with acromegaly. Within 10 yr after radiotherapy, up to 80% of patients achieve plasma GH levels below 5 micrograms/L. Whether this is sufficient to normalize plasma insulin-like growth factor I (IGF-I) levels, is unknown. We examined the effect of radiotherapy on plasma IGF-I concentrations in patients with acromegaly. We reviewed hospital charts of 140 patients with acromegaly seen in our institution between 1975 and 1996. Data on plasma GH and IGF-I were extracted and tabulated longitudinally together with the information about the concomitant medical therapy. We included data from the patients who received radiotherapy as a part of their treatment and whose IGF-I was monitored for more than 1 yr afterward. To avoid the potential bias, the data for patients who were referred to us for medical therapy, having failed radiation elsewhere, were excluded. A total of 38 datasets were submitted for the final analysis. The average follow-up was 6.8 +/- 0.8 yr (range, 1-19). Only 2 patients achieved age- and sex-adjusted normal IGF-I levels while off medical therapy. Noncured patients had a mean plasma GH level of 4.6 +/- 1.1 micrograms/L but still elevated plasma IGF-I levels (219 +/- 26% of the upper normal limit) at the last follow-up visit. A random GH concentration below 1.5 micrograms/L was associated with a pathologically high plasma IGF-I concentration in 43% of instances. Radiotherapy appears to be ineffective in normalizing plasma IGF-I levels in acromegaly. A multicenter study to reevaluate the future use of this modality in patients with acromegaly is warranted.

Acromegaly↗
PubMed1999

Menstrual irregularity in women with acromegaly.

Menstrual irregularity is common in women with acromegaly, occurring in 40-84%. Although it has been attributed to gonadotropin deficiency and/or PRL excess, it has not been evaluated in detail, and its pathogenesis is not well understood. To explore the various possible pathogenic mechanisms, we have analyzed the clinical, endocrinological, and radiological characteristics of 47 women with active acromegaly within the reproductive age range (15-41 yr) with respect to their menstrual pattern; 9 patients (19%) had normal cycles, 7 (15%) had oligomenorrhea, 29 (62%) had amenorrhea, and 2 (4%) had polymenorrhea. Compared to patients with normal cycles (n = 9), patients with menstrual irregularity (oligo/polymenorrhea or amenorrhea; n = 38) were more hirsute, had lower serum estradiol (normal: median, 76.5 pmol/L; range, 20-570; menstrual irregularity: median, 283; range, 140-431; P < 0.01), and sex hormone-binding globulin (SHBG; normal: median, 19.6 nmol/L; range, 5-52; menstrual irregularity: median, 48; range, 18-60; P < 0.01), but similar testosterone levels; in addition, patients with amenorrhea had higher serum GH (normal: median, 100 mU/L; range, 8.8-400; amenorrhea: median, 30; range, 10.7-120; P < 0.05). PRL levels in excess of 1000 mU/L were found in 16 of the 38 patients with menstrual irregularity compared to only 1 of the 9 patients with normal cycles. Patients with menstrual irregularity had a greater impairment of anterior pituitary function than patients with normal cycles. Acromegalic patients who were defined as estrogen sufficient (estradiol, >140 pmol/L) had clinical baseline endocrine profiles and LH responses to GnRH stimulation similar to those in patients with polycystic ovarian disease. There was a positive correlation between GH levels and tumor size (r = 0.35; P < 0.05) and an independent inverse correlation between GH and SHBG levels (r = -0.6; P < 0.01), which persisted even in patients who were estrogen sufficient, but there was no correlation between GH and estradiol levels; in addition, there was a negative correlation between estradiol levels and tumor size (r = -0.42; P < 0.05). Thirty-five of the patients with menstrual irregularity had meso- or macroadenomas and 3 had microadenoma, whereas 6 of the 9 patients with normal cycles had microadenomas. In conclusion, menstrual irregularity is common in women with acromegaly (81% of our patients). Amenorrheic patients have higher GH levels, are mainly estrogen deficient, and tend to have larger tumors than patients with normal cycles. However, the independent negative correlation between GH and SHBG levels suggests that GH may, directly or indirectly, lead to a fall in SHBG, possibly determined by the hyperinsulinemia known to occur in acromegaly. Low SHBG levels may contribute to the menstrual disturbance seen in acromegaly in addition to any gonadotropin deficiency or hyperprolactinemia and may account for hirsutism in the presence of normal testosterone levels.

Acromegaly↗
PubMed2000

Cardiac effect of thyrotoxicosis in acromegaly.

Cardiac structure and function are affected both by acromegaly and hyperthyroidism. Whereas the former is mainly characterized by ventricular hypertrophy as well as diastolic and systolic impairment, the latter frequently leads to increased heart rate and enhancement of contractility and cardiac output. To further investigate this issue, we designed this two-arm study. In the first cross-sectional study, we compared echocardiography and radionuclide angiography results obtained in eight hyperthyroid acromegalic patients, eight hyperthyroid nonacromegalic patients, and eight healthy subjects. All acromegalic patients were receiving treatment for acromegaly at the onset of hyperthyroidism. In the second longitudinal study, performed in the group of acromegalic patients, we compared the cardiovascular results obtained during hyperthyroidism with the retrospective data obtained at the initial diagnosis of acromegaly and after 1-yr treatment for this disease and those prospective data obtained during the remission of hyperthyroidism. In the cross-sectional study, hyperthyroid acromegalic patients showed an increase in the left ventricular (LV) mass index (LVMi) compared to healthy and hyperthyroid controls (P < 0.05), with evidence of LVMi hypertrophy in five of them (62.5%). A significant correlation was found between LVMi and GH levels (r = 0.785; P < 0.05). The LV ejection fraction (LVEF) at rest was higher in the control hyperthyroid population than in healthy controls (P < 0.05), whereas the LVEF response to exercise was reduced in acromegalic patients (P < 0.05 vs. healthy controls). In acromegalics, the exercise-induced change in LVEF was significantly reduced compared to that in healthy controls (P < 0.001), but not to that in hyperthyroid controls (P < 0.07), being abnormal (<5% increase vs. baseline values) in six patients. Four of these six patients (66%) had elevated GH and insulin-like growth factor I levels during the treatment of acromegaly. An inverse correlation between GH and LVEF at rest (r = -0.896;P < 0.05) and at peak exercise (r = -0.950; P < 0.001) was recorded. The peak filling rate was reduced in hyperthyroid acromegalic patients compared to those in both control populations (P < 0.05). In the longitudinal study, acromegalic patients showed an increased LVMi during hyperthyroidism compared to that observed after successful treatment of acromegaly (P < 0.05); resting LVEF was increased compared to both basal (P < 0.001) and posttreatment values (P < 0.05). However, the exercise-induced change in LVEF was reduced (P < 0.05 vs. previous follow-up values). Remission of hyperthyroidism led to significant reduction of LVMi (P < 0.05) and resting LVEF (P < 0.05) and an increase in exercise-induced LVEF (P < 0.05). In light of these findings, hyperthyroidism produces a detrimental effect on the cardiovascular system of acromegalic patients, particularly in those with uncontrolled disease. Thus, control of GH and insulin-like growth factor I should be a major objective, as cardiovascular risk persists in patients with ineffective hormonal suppression, and constant endocrine and cardiovascular surveillance remain crucial steps in patient follow-up.

Acromegaly↗
PubMed2000

Insulin-like growth factor I and the development of colorectal neoplasia in acromegaly.

Patients with acromegaly are at increased risk of colorectal neoplasia and, by analogy with high-risk nonacromegalic patients, may require regular colonoscopic screening. However, it is unknown whether the risk is equal in all patients or whether some should be regarded as carrying a particularly high risk. The aims of this study were: 1) to establish the natural history of colorectal neoplasia in acromegaly; 2) to establish which patients are at increased risk of developing neoplasia; and 3) to elucidate the influence of insulin-like growth factor I (IGF-I) in adenoma formation. A prospective colonoscopic evaluation of the development of new premalignant adenomas in the colon was performed in 66 patients with biochemically proven acromegaly who had previously undergone colonoscopic screening and removal of all visible polyps. Twenty-five patients (38%) had a total of 37 polyps detected at the second colonoscopy: nine (14%) had at least one adenoma, and 18 (27%) had one or more hyperplastic polyps (2 patients had both). The development of new adenomas, but not hyperplastic polyps, was associated both with elevated serum IGF-I (P < 0.005) and, to a lesser extent, with a previous adenoma at the original colonoscopy (P < 0.07). In summary, patients with acromegaly and in whom serum IGF-I remains elevated and/or who have had a previous adenoma should be regarded as having an especially high risk for the development of subsequent colorectal neoplasia. Serum IGF-I seems to be implicated in the development of colorectal neoplasia in acromegaly, although the exact mechanisms remain uncertain.

Acromegaly↗
PubMed2001

Modulation of cortisol metabolism by the growth hormone receptor antagonist pegvisomant in patients with acromegaly.

Pegvisomant is a GH receptor antagonist and highly efficacious new treatment for acromegaly. The two isoenzymes of 11beta-hydroxysteroid dehydrogenase are responsible for the interconversion of cortisol and its inactive metabolite cortisone. We demonstrated previously that the type I isoform, which is principally responsible for conversion of cortisone to cortisol, is partially inhibited by GH. The net activity of the enzyme can be measured by analysis of the urinary ratio of 11-hydroxy/11-oxo cortisol metabolites or of the urinary ratio of tetrahydrocortisol/tetrahydrocortisone [(tetrahydrocortisol + 5alpha-tetrahydrocortisol)/tetrahydrocortisone]. We studied the influence of pegvisomant on cortisol metabolism in patients with active acromegaly. Seven patients (four women and three men; median age, 58 yr; range, 39-72) were studied at baseline and again after a mean of 46 weeks of treatment. The mean insulin-like growth factor I (IGF-I) level at baseline fell from 939.7 +/- 271.1 to 346.9 +/- 379.0 ng/mL on 20 mg/day pegvisomant. The 11-hydroxy/11-oxo ratio increased from a pretreatment mean value of 0.61 +/- 0.18 to 0.88 +/- 0.20 (P < 0.02) and when the six patients in whom serum IGF-I normalized were considered separately, the change was from 0.62 +/- 0.19 to 0.90 +/- 0.21 (P < 0.04). The tetrahydrocortisols/tetrahydrocortisone ratio increased from a pretreatment mean value of 0.64 +/- 0.21 to 0.98 +/- 0.26 (P < 0.02) and in the six patients in whom serum IGF-I normalized, the ratio rose from 0.66 +/- 0.23 to 1.01 +/- 0.26 (P < 0.04). These data 1) indicate that blockade of GH action with pegvisomant in patients with acromegaly is associated with reversal of the inhibition of 11beta-hydroxysteroid dehydrogenase and correction of cortisol metabolism, and 2) suggest that in active acromegaly, cortisol clearance is accelerated and that this is reversed by successful treatment. This is further evidence of the efficacy of pegvisomant in the management of acromegaly and has important implications for determining optimum glucocorticoid replacement.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed2002

Early vascular alterations in acromegaly.

Acromegaly is associated with increased cardiovascular mortality; however, little is known about the early atherosclerotic changes occurring in such patients. Endothelial function, in the form of flow-mediated dilation (FMD) of the brachial artery, and intima-media thickness (IMT) of the carotid artery were measured by B-Mode ultrasound in: 1) 18 patients with active acromegaly; 2) 12 subjects cured from acromegaly; 3) 18 subjects without acromegaly, each of them matched to an acromegalic patients for age, sex, risk factors and treatments; and 4) 10 healthy subjects. Results are expressed as median plus (25th, 75th) percentile. In active acromegalic patients, FMD was 5.7 (3.9, 7.7)%, significantly lower than in both healthy subjects (P < 0.01) and matched controls (P < 0.01). No difference between groups was observed for endothelium-independent vasodilation. Acromegalic patients had also higher IMT than healthy controls (P < 0.05), whereas no difference was observed with matched controls. In cured acromegalic patients, FMD was 9.2 (7.7, 10.5)%, significantly lower (P < 0.01) than in healthy controls but higher (P < 0.01) than in active patients. No difference in IMT was observed between active and cured patients. In conclusion, patients with acromegaly have functional and morphological vascular alteration that seems, at least in part, dependent on the GH excess itself.

Acromegaly↗
PubMed2005

Type 1 diabetes associated with asymptomatic acromegaly successfully treated with surgery after pregnancy: a case report.

We report a rare case of type 1 diabetes in a woman associated with acromegaly who was treated with surgery after pregnancy. An 18-year-old woman came to our hospital in April, 1998, complaining of thirst, polydipsia, polyuria, appetite loss, body weight loss of 8 kg in a month, and amenorrhea beginning 2 months earlier. Based on laboratory data, she was diagnosed as having type 1 diabetes mellitus. Although we suspected her of having acromegaly because of high growth hormone (GH) levels (6.9 or 8.5 ng/ml), blood levels of insulin-like growth factor 1 (IGF-1) and IGF-binding protein-3 (IGFBP-3) were within normal range and the circadian rhythm of her blood GH levels was normally maintained. Her blood GH level was elevated to 12.6 ng/ml 15 minutes after a TRH administration. Blood GH levels were suppressed from 49 ng/ml to 1.5 ng/ml 4 hours after an oral administration of 2.5 mg of bromocriptine. A magnetic resonance images (MRIs) showed pituitary swelling, but no nodules were found in the pituitary. Therefore, we diagnosed her as having acromegaly and observed her without surgery, while prescribing diet therapy and intensive insulin therapy for diabetes. We started a treatment of oral administration of 7.5 mg of bromocriptine per day for the acromegaly from April 28, 2000, because her elevated GH was suspected of causing her diabetes to be poorly controlled. During a pregnancy from October, 2000 to September, 2001, diabetic control was improved with increased administration of insulin under a constant dose of bromocriptine. She delivered a normal full-term infant. After the bromocriptine therapy was stopped as she hoped to breastfeed, blood levels of GH and IGF-1 became elevated and her diabetic control deteriorated. As her pituitary tumor observed in pituitary MRIs became larger during the course, a transsphenoidal surgery was performed on March 8, 2002. After the surgery, blood levels of GH and IGF-1 lowered and diabetic control improved again. We concluded as follows: to rule out acromegaly in patients with poorly controlled diabetes, 1) measurements of serum GH and IGF-1 should be performed, and 2) pituitary MRIs should be performed if blood levels of GH or IGF-1 are high.

Acromegaly↗
PubMed2006

Manifestation of rheumatoid arthritis after transsphenoidal surgery in a patient with acromegaly.

Acromegalic arthropathy is one of the most frequent manifestations occurring in acromegaly patients. In contrast, rheumatoid arthritis (RA) is a rare clinical complication in acromegaly patients. Here, we report a 70-year-old Japanese woman with acromegaly, who complained of bilateral finger stiffness and polyarthralgia two months after transsphenoidal surgery of a growth hormone (GH)-secreting pituitary adenoma. Postoperative levels of serum GH and insulin-like growth factor-1 (IGF-1) were markedly decreased without any secretory deficiency of other anterior pituitary hormones. Hand X-ray did not show typical RA changes; however, erosive changes in carpal bones were clearly detected by magnetic resonance imaging with gadolinium enhancement. Based on the levels of serological markers in the patient following surgery including C-reactive protein, rheumatoid factor and matrix metalloproteinase-3, anti-rheumatic therapy was subsequently commenced. Regardless of the levels of GH and IGF-1, acromegaly patients frequently complain about joint-related symptoms even after remission. Therefore, careful observation of bone erosive changes and immunological activity in acromegaly patients is required when joint-related symptoms persist.

Acromegaly↗
PubMed2001

The place of pegvisomant in the management of acromegaly.

Conventional treatments for acromegaly include surgery, radiotherapy, dopamine agonists and somatostatin (SMS) analogues, which effect disease control by lowering circulating growth hormone (GH). Due to variability in tumour characteristics, combinations of these treatment modalities leave a significant number of patients with sub-optimal serum GH and insulin-like growth factor-I (IGF-I) levels, which have been linked to increased morbidity and mortality. The GH receptor antagonist pegvisomant is a genetically engineered analogue of GH that prevents functional dimerisation of the growth hormone receptor (GHR); a process that is critical to GH action at the cellular level. A crucial amino acid substitution at Gly(120) to Arg(120) within the third alpha helix of the antagonist prevents functional GHR dimerisation. Pegvisomant represents a novel treatment for acromegaly as, unlike existing treatment modalities, the effectiveness of pegvisomant is independent of pituitary tumour characteristics. Initial clinical studies in patients with active acromegaly have demonstrated serum IGF-I normalisation in over 90% of patients receiving 20 mg per day, such that, in terms of serum IGF-I normalisation, pegvisomant now represents the most effective medical treatment for acromegaly. Although there are limited long-term data on the use of pegvisomant and questions regarding pituitary tumour growth and altered liver function remain, this therapy offers the prospect of serum IGF-I normalisation in the vast majority of patients with active acromegaly.

Acromegaly↗