Untreated Acromegaly Research Articles

Clinical features and therapeutic outcomes of acromegaly during the recent 10 years in a single institution in Japan

Untreated acromegaly is associated with a twofold to fourfold increased mortality risk compared to the population. Recently, new therapeutic modalities have been developed and may contribute to an improvement in treatment outcomes in patients with acromegaly. In the current study we determined the clinical features and recent therapeutic outcomes in patients with acromegaly. The initial symptoms, selected therapeutic modalities, and outcomes in 125 patients with acromegaly (M/F, 49/76, 19-86years) who were admitted to our institution between 2001 and 2010 were analyzed using medical charts. The basal GH levels and IGF-I SD scores in the patients ranged from 0.17 to 90.21μg/L and 1.9-13.6, respectively. Acral enlargement (face, hands, and feet) without overt complications was essential to the diagnosis in 49% of the patients. In these cases, it required 5years to establish the diagnosis of acromegaly after symptom onset. Twenty (16%) and 13 (10%) patients had diabetes mellitus and hypertension 6years prior to the diagnosis of acromegaly, respectively. In 35 patients with microadenomas, the rate of controlled cases following transsphenoidal surgery was 93%. In 90 patients with macroadenomas, the remission rate was 79% with multidisciplinary treatment. In cases in which the tumor extended beyond the lateral tangent of the internal carotid artery (Knosp grade ≥3), the remission rate was 33-56%. Improvements in surgical techniques and medical therapies may contribute to increased rates of controlled cases in patients with acromegaly, although advanced lateral extension of the tumor remains a critical determinant of the therapeutic outcome.

Effects of previous growth hormone excess and current medical treatment for acromegaly on cognition

In untreated acromegaly patients, decreased cognitive functioning is reported to be associated with the degree of growth hormone (GH) and IGF-1 excess. Whether previous GH excess or current medical treatment for acromegaly specifically affects cognition remains unclear. The aim of this study was to compare cognitive functioning of patients who are treated for acromegaly with patients with non-functioning pituitary adenomas (NFA). In addition, we assessed the influence of prolonged medical treatment after initial transsphenoidal surgery on cognition. In this cross-sectional study, 74 patients participated, who were treated for acromegaly (n = 50; median [interquartile range] age: 53 [45-65] years) or NFA (n = 24; age: 63 [59-70] years). The NFA patients were selected for a high likelihood of normal GH secretion based on an IGF-1 z-score within the normal range (> -2) and zero or one axis substituted. Of the acromegaly patients, 28 had achieved remission, while 22 were biochemically controlled with long-acting somatostatin analogues and/or pegvisomant. Memory and executive functioning were assessed by the 15 Words Test and the Ruff Figural Fluency Test, and reported as z-scores. The total patient group scored significantly poorer than the reference population on memory and executive functioning (P < 0·001). However, cognitive test performance was not significantly different between acromegaly patients with a persistent disease, acromegaly patients in remission and NFA patients. The total patient group scored worse compared with reference populations. We found no association between previous GH excess and cognition. In addition, current medical treatment for GH excess in acromegaly was not related to memory and executive functioning.

Adipocytes as a Source of Increased Circulating Levels of Nicotinamide Phosphoribosyltransferase/Visfatin in Active Acromegaly

Nicotinamide phosphoribosyltransferase (NAMPT)/visfatin is a widely expressed protein with various effects on glucose and lipid metabolism, cell survival, and inflammation. We hypothesized that NAMPT was related to metabolic disturbances in active acromegaly. Body composition, glucose metabolism, and NAMPT levels were measured in 47 patients with active, untreated acromegaly and 24 age-, sex-, and body mass index-matched controls. The in vitro effects of GH/IGF-I on NAMPT expression in human sc adipocytes (SCA), visceral adipocytes, osteoblasts, and hepatocytes were studied. The effects of overnight incubation with the highly specific NAMPT inhibitor FK866 on the GH-stimulated monocyte chemotactic protein-1 and IL-6 expression in mature SCA were evaluated. NAMPT was increased in active acromegaly (P = 0.004) and correlated negatively with limb (arms + legs) fat percentage (% fat, r = -0.32; P = 0.032). After adjusting for age, gender, leptin, and GH, the circulating NAMPT correlated negatively with limb and total body fat percentage (% fat limbs, r = -0.43, P = 0.006; % fat total body, r = -0.36, P = 0.022) and correlated positively with limb and total body lean percentage (% lean limbs, r = 0.31, P = 0.047; % lean total body, r = 0.33, P = 0.034). No correlation between NAMPT and glucose metabolic parameters was found. In vitro studies revealed that GH increased NAMPT expression in adipocytes. The inhibition of NAMPT enzymatic activity attenuated GH-induced monocyte chemotactic protein-1 expression in SCA. NAMPT is increased in active acromegaly and may be an inflammatory mediator that causes monocyte infiltration in adipose tissue.

Role of somatostatin receptor ligands in the treatment of acromegaly – review of literature

Acromegaly is a rare disease with typical clinical manifestations. Untreated acromegaly carries a 2-4-fold increase in mortality in long-term outcome. The goal of treatment is double, including biochemical control of the disease (normalization of serum IGF1 levels compared to age and gender matched controls, GH levels below 1 ng/ml after oral glucose load, or random GH below 2.5 ng/ml) and control of the tumor mass. The therapeutic modalities currently available for the treatment of acromegaly are: surgery, medical therapy, radiation therapy and their combinations. The cornerstones of medical therapy in acromegaly are the somatostatin receptor ligands due to their effectiveness in controlling GH excess in 60-70 % of patients and their beneficial effects on tumor volume. Somatostatin analogues have an established role as adjuvant therapy after non-curative surgery, and evidence suggests their use as primary treatment for selected patients. The long-term use of somatostatin receptor ligands is safe and they are well tolerated. Future medical therapy consists of pasireotide, a novel, universal somatostatin receptor agonist, and a new class of drugs named dopastatins. The latter so-called chimeric molecules have strong affinity for somatostatin receptors and dopamine-2 receptors, resulting in a more effective blocking of GH secretion, according to preliminary data. The authors of this paper review the current medical therapy of acromegaly, focusing on the role of somatostatin receptor ligands. Orv. Hetil., 2011, 152, 715–721.

Limited utility of oral glucose tolerance test in biochemically active acromegaly

Measurement of GH after oral glucose tolerance test (OGTT) is used for the diagnosis and surveillance of acromegaly. However, there are major discrepancies between glucose-suppressed GH and plasma IGF1 as indices of biochemical activity of acromegaly in patients with relatively mild GH oversecretion. This study was aimed to assess the performance of OGTT in patients with acromegaly and variable GH outputs. Forty adults with newly diagnosed, untreated acromegaly (15 with GH >4.3 μg/l and 25 with GH <4.3 μg/l) and elevated IGF1 levels were studied. All underwent Q10 min for 24 h sampling for GH followed by an OGTT. Postglucose nadir GH (GHn) correlated significantly to 24 h GHn, mean 24 h GH, and baseline GH (P<0.001 for all comparisons). GHn correlated significantly to IGF1 z-scores for the 'low' GH group and for the entire group (P<0.0001 for both comparisons), but not for the 'high' GH group. None of the patients with mean GH >4.3 μg/l had GHn below 1 μg/l. In contrast, 13 out of 25 patients (52%) with GH <4.3 μg/l showed GHn lower than 1 μg/l, and 7 of them (28%) had GHn lower than 0.4 μg/l. These groups did not differ significantly either for average or for maximal GH suppression in OGTT. Our data show that suppressibility of GH by glucose in acromegaly is a function of the degree of GH hypersecretion and that OGTT has only limited diagnostic value in patients with biochemically active acromegaly but only mildly increased GH output.

Evidence of Cognitive and Neurophysiological Impairment in Patients with Untreated Naive Acromegaly

Evidence of Cognitive and Neurophysiological Impairment in Patients with Untreated Naive Acromegaly

Analysis of voice in patients with untreated active acromegaly

Voice changes are common clinical findings of acromegaly, although scanty data are available so far. To analyze features and quantify changes of voice in patients with untreated active acromegaly. This was a pilot case-control study. Voice was analyzed using the Multi Dimensional Voice Program software, which generates 33 parameters related to fundamental frequency (F0), micro-perturbation of F0 and amplitude, noise, tremor, voice breaks and irregularities, and diplophony. Thirteen consecutive patients (8 women, 5 men, mean age 48+/-9 yr) with active acromegaly, at first diagnosis, and 13 sex- and age-matched normal subjects (controls). Patients with untreated active acromegaly had mean values of parameters related to F0 significantly lower than those of controls, although mostly remaining in the normal range. Most acromegalic patients had micro-perturbation of F0, as indicated by higher mean of absolute or percentage jitter values than those of controls; micro-perturbation of amplitude was a common feature of voice in most acromegalic men. Noise-related parameters were also affected by acromegaly, being higher in male acromegalic patients than in controls and acromegalic women. On the contrary, parameters related to tremors, voice breaks, voice irregularities and diplophony did not differ in acromegalic patients and controls. Patients with untreated active acromegaly had low-pitched voice characterized by lowering F0 and increased values related to noise, micro perturbation of frequency, and amplitude.

Comparison of colonoscopy and fecal occult blood testing as a first-line screening of colonic lesions in patients with newly diagnosed acromegaly

Patients with acromegaly have frequently colonic neoplasms; however, how acromegalic patients should be screened for colonic lesions is still unsettled. To compare fecal occult blood testing (FOBT) and colonoscopy in the screening program of patients with acromegaly. Colonoscopy and FOBT were performed at the first diagnosis of acromegaly. Tertiary University center. Eighty-five consecutive patients with untreated active acromegaly submitted to colonoscopy and FOBT. FOBT, which was positive in 16 (18.8%) out of 85 patients, identified 2 patients with colonic adenocarcinoma and 2 with adenoma; the remaining 12 patients had no detectable colonic lesions. Colonoscopy revealed colonic lesions in 29 patients: 3 (3.5%) cancers, 11 (12.9%) adenomas, and 15 (17.6%) hyperplastic polyps. The remaining 56 acromegalic patients had no detectable lesions. A patient with cancer and 9 patients with adenoma were missed if screened only by FOBT. Colonoscopy is superior to FOBT in detecting colonic lesions at the first diagnosis of acromegaly.

Gender differences in serum GH and IGF-I levels and the GH response to dynamic tests in patients with acromegaly

Gender affects the GH secretory pattern both in normal subjects and in patients with acromegaly by an uncertain mechanism. Here, we report the influence of gender on the relationship between serum GH and IGF-I levels and the GH response to dynamic tests in patients with acromegaly. Seventy-four patients with untreated acromegaly (M/F 27/47, age range 22-86 yr.) were studied. The serum GH levels did not differ between male and female (6.1 vs. 8.7 ng/ml; p=0.26), while serum IGF-I levels, IGF-I SDS and the IGF-I/GH ratio were lower in female than those in male (679 vs. 769 ng/ml; p<0.02, 7.3 vs. 9.2 SDS; p<0.02 and 79.6 vs. 141.5; p<0.05). When the subjects were divided into two groups: age <or=50 yr, and age >50 yr, serum IGF-I levels and IGF-I/GH ratios were lower in female than those in male in patients <or=50 yrs (650 vs. 1002 ng/ml; p<0.05 and 59.8 vs. 142.9; p<0.05), but not in patients >50 yrs (684 vs. 680 ng/ml; p=0.39 and 98.7 vs. 118.4; p=0.40). The GH responses to OGTT, TRH, octreotide, and bromocriptine tests were similar in male and female. In conclusion, IGF-I/GH ratio was significantly lower in female than that in male particularly in younger patients with acromegaly. These data suggest that gender, presumably sex steroids in female, may partially modulate the relationship between circulating IGF-I and GH levels in patients with acromegaly.

Effect of presurgical long-acting octreotide treatment in acromegaly patients with invasive pituitary macroadenomas: a prospective randomized study

Therapeutic effects of presurgical long-acting octreotide treatment on tumor shrinkage, and short- and long-term postoperative GH and IGF-1 levels of acromegaly patients with invasive pituitary macroadenomas were investigated prospectively in Huashan Hospital, Shanghai, China. Thirty-nine untreated acromegaly patients, all with invasive pituitary macroadenomas, were randomly divided into two groups: experimental group (n=19), and control group (n=20). Patients in the experimental group received a three-month course of long-acting octreotide treatment before transsphenoidal surgery; the control group underwent surgery directly. Tumor shrinkage after drug treatment and short- and long-term postoperative GH and IGF-1 levels were analyzed in the two groups. Long-acting octreotide treatment reduced tumor size from 7893 ± 6450 to 4794 ± 4682 mm(3). Mean shrinkage rate was 37.4 ± 30.9%. GH and IGF-1 levels of the experimental group were lower than the control group at 3 months, 6 months after surgery, and after long-term follow-up. Remission rate (both GH and IGF-1 normal) of the experimental group was higher at 3 and 6 months follow-up, but exhibited no advantage in long-term follow-up. In the experimental group, the total resection rate was higher in patients whose Hardy-Knosp grading decreased to ≤ 2 than those whose Hardy-Knosp grading is still ≥ 3 after drug pretreatment. In conclusion, presurgical long-acting octreotide treatment effectively reduces tumor size and invasion, which helps enhance early remission rates of invasive macroadenomas by transsphenoidal surgery, but does not appear to improve the long-term cure rate.

D3 GH receptor polymorphism is not associated with IGF1 levels in untreated acromegaly

A discrepancy between serum GH and IGF1 concentrations is frequent in patients with acromegaly. Here, we examined whether the exon 3-deleted (d3) GH receptor (GHR) variant, which has been linked to increased responsiveness to GH treatment in short children, influences the GH/IGF1 relationship in patients with acromegaly. To study the possible influence of the GHR genotype on the GH/IGF1 relationship in untreated acromegalic patients. GHR genotype analysis with retrospective clinical and biochemical data collection performed in a single third-reference medical center. Clinical data were obtained from the medical records of 105 acromegalic patients who had GH and IGF1 assays in the same laboratory and who were genotyped for the full-length (fl) or d3-GHR alleles. The distribution of GHR genotypes was 51% fl/fl, 30% fl/d3, and 19% d3/d3. Patients with d3/d3 genotype were younger than the patients in the other two groups (P<0.05). Baseline GH and IGF1 concentrations did not differ among the three groups. The linear correlation between GH and IGF1 concentrations was similar in the three genotypic groups. The exon 3 GHR genotype does not affect the GH/IGF1 relationship in untreated acromegalic patients with high circulating GH and IGF1 levels.

Diminished and Irregular Thyrotropin Secretion with Preserved Diurnal Rhythm in Patients with Active Acromegaly

The hypothalamo-pituitary-thyroid axis in acromegaly may be altered. Previous studies report diminished serum TSH concentrations in patients with active acromegaly and decreased response to TRH. On the other hand, most patients have normal thyroid hormone concentrations. Our aim was to analyze serum TSH profiles in relation to GH profiles in patients with untreated acromegaly, in order to delineate aberrations in the hypothalamo-pituitary-thyroid system. Twenty-one patients with active acromegaly and matched controls underwent a 24-h, 10-min blood sampling study. GH and TSH data were analyzed with a newly developed automated deconvolution program, approximate entropy, and cosinor regression. Basal (10.4 +/- 2.0 vs. 13.8 +/- 1.4 mU/liter . 24 h; P = 0.02) and pulsatile (11.4 +/- 1.7 vs. 18.6 +/- 1.6 mU/liter . 24 h; P = 0.002) TSH secretion was decreased in patients. TSH secretory regularity was diminished with loss of pattern synchrony between TSH and GH. Total TSH secretion correlated with TSH increase after TRH (R = 0.75; P = 0.0001), negatively with the log-transformed GH secretion rate (R = -0.52; P = 0.001), but not with adenoma size. The diurnal TSH rhythm was preserved. Total and free T4 concentrations were similar in patients and controls. Basal and pulsatile TSH secretion is decreased in active acromegaly, although T4 levels are unaffected. Diminished TSH secretion is compatible with enhanced restraint by tumoral GH feedback-driven somatostatin outflow, explaining also the reduced regularity of TSH secretion. Unchanged T4 concentrations might reflect decreased sympathetic function in GH excess states, heightening responsiveness of the thyroid gland to TSH.

Growth hormone after oral glucose overload: revision of reference values in normal subjects

The evaluation of growth hormone (GH) secretion continues to be important in acromegaly and the nadir GH (n-GH) level in the oral glucose tolerance test (OGTT) is the gold standard for the demonstration of secretory autonomy of this hormone. n-GH levels < 1 microg/L are defined as normal suppression but, using current assays, n-GH < 1 microg/L is detected in patients with untreated acromegaly and this value seems to be much lower in normal subjects. The objective of the present study was to evaluate n-GH levels in the OGTT in normal subjects using three different assays (GH ICMA Immulite; GH IRMA DSL and GH IFMA AutoDelfia). Two-hundred apparently healthy subjects (120 women) ranging in age from 18 to 70 years and with a BMI > 18.5 and < 27 kg/m(2), who used no medications and presented normal glycemia, blood count, albumin, creatinine, TSH, SGOT, SGPT and bilirubin were studied. Serum samples were obtained before and 30,60,90 and 120 min after oral administration of 75 g glucose. The test was repeated after 4 weeks in 157 participants, with the same protocol being used in 79 and 78 receiving an overload of 100 g glucose. n-GH cut-off values (97.5th percentile) were higher in women than in men (GH-IFMA: 0.30 versus 0.11 microg/L; GH-ICMA: 0.60 versus 0.25 microg/L; GH-IRMA: 0.20 versus 0.10 microg/L, respectively). No correlation was observed between n-GH and age or BMI. A difference was only observed when comparing women < 35 years (n = 40) versus > 35 years (n = 80), with higher values in the former (n-GH cut-off in this subgroup: GH-IFMA 0.40 versus 0.26 microg/L, GH-ICMA 0.74 versus 0.50 microg/L, GH-IRMA 0.25 versus 0.15 microg/L). A good correlation was observed between the assays (r = 0.9-0.96), however, the highest values were always obtained with the Immulite assay. Test repetition with 75 g oral glucose showed a variation in n-GH < 10.2% (GH-IFMA), < 13.4% (GH-ICMA) and < 11% (GH-IRMA) in 95% of the subjects. This variation was similar when the test was repeated with 100 g glucose. A good correlation was observed between n-GH in the first and second test (r = 0.83-0.92). We suggest the following n-GH reference values: for men, 0.14 microg/L for the GH IRMA DSL and GH IFMA AutoDelfia kits and 0.25 microg/L for the GH ICMA Immulite kit; for women, 0.25 microg/L, 0.40 microg/L and 0.70 microg/L, respectively.

Diagnosis in acromegaly. Insulin-like growth factor as a parameter of activity

The peripheral actions of growth hormone (STH) are mediated by somatomedins or "insulin-like growth factors" (IGF I and II). In untreated acromegaly (n = 24) IGF I was always found increased, IGF II, however, was unchanged. The mean IGF-I-level (+/- SEM) was 553 +/- 75 (range 319-1066) ng/ml in active acromegaly and 193 +/- 10 (range 120-300) ng/ml in control persons. The corresponding IGF-II-values were 533 +/- 38 (range 187-720) and 647 +/- 21 (range 400-900) ng/ml. After treatment of acromegaly IGF I followed changes of the basal STH level with a delay of 4-8 weeks independent of the mode of treatment. This was in contrast to behaviour of IGF II. When STH was suppressible below 1 ng/ml after oral administration of 100 g glucose IGF I was never increased. STH after glucose of more than 5 ng/ml was always associated with increased IGF I. STH values between 1 and 5 ng/ml after glucose were combined with IGF-I-increases in 3 out of 6 cases. Thus, IGF I represents a valuable diagnostic criterion for assessment of activity of acromegaly, particularly in borderline cases, in contrast to IGF II. The criterion of normal somatotrophic function is suggested to be suppressibility of STH level below 1 ng/ml after oral administration of 100 g glucose.

Pegvisomant increases intra-abdominal fat in patients with acromegaly: a pilot study.

Acromegalic patients have increased lipolysis and decreased fat mass as well as reduced insulin sensitivity and glucose intolerance. During somatostatin analog therapy, these changes persist despite GH suppression, but they are now due to drug-induced suppression of insulin secretion. By contrast, during pegvisomant (PEG) therapy, GH no longer stimulates lipolysis due to the blockade of its receptor, while insulin action is unabated. Hence, both insulin sensitivity and fat mass, including intra-abdominal fat, should increase. We therefore studied intra-abdominal fat and insulin resistance in acromegalic patients after a 3-month octreotide-washout period, i.e., during untreated acromegaly, and during PEG treatment. Five acromegalic patients, not controlled on octreotide (OCT) therapy, were studied after 3-month OCT washout and 6-month PEG therapy. Insulin sensitivity was determined by homeostatic model assessment value and hyperinsulinemic, normoglycemic clamp. Subcutaneous and intra-abdominal fat were measured by electron beam computed tomography. During PEG therapy, all the patients had normal, age-adjusted IGF-I concentrations. Compared with washout, insulin sensitivity (HOMA and M value) was not significantly different. However, intra-abdominal fat mass increased significantly during therapy (median (range) cm(2): 112 (84-480) and 172 (112-524) respectively, P<0.05), while subcutaneous fat was not significantly different. Low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides remained unchanged. During PEG therapy of acromegalic patients, intra-abdominal fat increases. Visceral obesity is a risk factor for cardiovascular disease. Hence, confirmation and further studies in a larger cohort of acromegalic patients on PEG treatment are warranted.

The Role of Endogenous Growth Hormone-Releasing Hormone in Acromegaly

Some indirect evidence suggests hypothalamic control of GH secretion in acromegaly. The objective of the study is to examine whether GH secretion in acromegaly is dependent on endogenous GHRH. 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. The study was set in a university referral center. Twenty-four-hour mean GH was the main outcome measured. 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. In some patients with acromegaly due to a pituitary adenoma, GH secretion is under partial control by endogenous GHRH.

Effect of Sex and Assay Method on Serum Concentrations of Growth Hormone in Patients with Acromegaly and in Healthy Controls

Diagnosis and follow-up of acromegaly is based on measurements of serum growth hormone (GH) concentrations during an oral glucose tolerance test (OGTT). A nadir value <1 microg/L is commonly used to define a normal response, but some authors suggest lower cutoff values. To compare the results and subsequent patient classification obtained with 3 GH assays, we obtained basal serum samples from 78 apparently healthy adult controls (43 women and 35 men; median age, 32.5 years) and from 71 treated (44 women and 27 men; median age, 55.2 years) and 7 untreated acromegaly patients (4 women and 3 men; median age, 54.6 years), and OGTT was performed on all patients and on 72 of the 78 controls. GH was determined by 2 immunometric assays-a double monoclonal (AutoDELFIA; Wallac) and a monopolyclonal (Immulite 2000; DPC) assay-and in a limited set of samples by an RIA (Spectria RIA; Orion). There was a strong correlation (r = 0.995; P < 0.001) between the 2 immunometric methods, but the results obtained with the Immulite 2000 were, on average, 1.4-fold higher than those obtained with the AutoDELFIA. At concentrations around the cutoff (1 microg/L), however, the difference was approximately 2-fold. Overall, the Orion RIA method also showed a good correlation (r = 0.951-0.959) with the other methods, but it did not measure concentrations <2 microg/L. Women had higher basal and OGTT nadir GH concentrations than men. Reference intervals should be determined separately for each method, and the need for establishing sex-specific reference values should be investigated.

Apoptosis is reduced in the colonic mucosa of patients with acromegaly

Patients with acromegaly have an increased risk of developing colonic tumours; reduced apoptosis is considered a leading mechanism in tumorigenesis. GH and IGF-1 decrease apoptosis in several cell lines including human colonic adenocarcinoma, but it is unknown whether epithelial cells of colonic mucosa of patients with acromegaly have reduced apoptosis. The aim of the study was to evaluate the degree of apoptosis in a cross-sectional study, in biopsy samples of colonic mucosa obtained from patients with acromegaly. Eleven patients with active, untreated acromegaly (AcroUntr), 16 patients with acromegaly in remission (AcroRem) and 23 controls were enrolled in the study. Samples of colonic mucosa were obtained during colonoscopy; apoptosis was evaluated by either DNA fragmentation or terminal deoxynucleotidyl transferase assay. Apoptotic cells were 60.0 +/- 2.5% in samples of colonic mucosa of controls, 62.0 +/- 3.4% in those from patients with AcroRem (P = ns vs. controls), and 39.0 +/- 4.1% in those from patients with AcroUntr (P < 0.0001 vs. the other groups). Apoptosis was inversely related to serum IGF-I (r = 0.771, P < 0.001) or GH (r = 0.404, P = 0.05) levels and less to the estimated duration of disease (r = 0.384, P = 0.07). PPARgamma is considered to be a tumour suppressor gene the expression of which might be involved in colonic tumorigenesis. The expression of PPARgamma was lower in the colonic mucosa of patients with AcroUntr (2845 +/- 947 transcripts) than in that of controls (35 200 +/- 2450 transcripts) or AcroRem (29 547 +/- 3650 transcripts) (P < 0.005). The recovery of PPARgamma expression was associated with apoptosis in most cells. The lower degree of apoptosis in patients with AcroUntr was associated with a reduced expression of the antiapoptotic Bax protein. In conclusion, patients with AcroUntr have reduced apoptosis in colonic mucosa that is apparently reversed after acromegaly is cured. It is conceivable that reduced apoptosis may represent an early event in colonic tumorigenesis of patients with acromegaly.

Basal and glucose-suppressed GH levels less than 1 microg/L in newly diagnosed acromegaly.

The development of highly sensitive and specific GH assays has necessitated a critical re-evaluation of the biochemical criteria needed for the diagnosis of acromegaly. Use of these assays has revealed that GH levels after oral glucose in healthy subjects and postoperative patients with active acromegaly can be significantly less than previously recognized with older GH assays. In order to assess GH criteria for newly diagnosed acromegaly with a modern assay we have evaluated GH levels in 25 patients referred to our Neuroendocrine Unit for evaluation of untreated acromegaly. All patients underwent measurement of basal GH and IGF-I levels and 15 of these patients also underwent oral glucose tolerance testing for GH suppression (OGTT). Basal GH levels were < 1.0 microg/L at diagnosis in 5 of these 25 patients. Nadir GH levels were less than 1 microg/L also in 5 of 15 patients, and as low as 0.42 microg/L. All patients had elevated IGF-I levels preoperatively and pathological confirmation of a GH secreting pituitary tumor at the time of transsphenoidal surgery. The clinical presentations of these patients was variable. Most patients presented with classical manifestations of acromegaly, but 3 of the 5 patients with low nadir GH values had only very subtle signs of acromegaly. Although most newly diagnosed patients have classically elevated GH levels and obvious clinical features of acromegaly, early recognition of disease may uncover patients with milder biochemical and clinical abnormalities. The diagnosis should not be discounted in patients who have elevated IGF-I levels, but have basal or nadir GH levels less than 1 microg/L. Conventional GH criteria for the diagnosis of acromegaly cannot be applied to the use of modern sensitive and specific GH assays.

Risk factors for glucose intolerance in active acromegaly.

In the present retrospective study we determined the frequency of glucose intolerance in active untreated acromegaly, and searched for risk factors possibly supporting the emergence of the diabetic condition. Among 43 patients, 8 (19%; 95% CI: 8-33%) had diabetes mellitus and 2 (5%; 1-16%) impaired glucose tolerance. No impaired fasting glycemia was demonstrable. The frequency of diabetes was on average 4.5 times higher than in the general Slovak population. Ten factors suspected to support progression to glucose intolerance were studied by comparing the frequency of glucose intolerance between patients with present and absent risk factors. A family history of diabetes and arterial hypertension proved to have a significant promoting effect (P<0.05, chi-square test). A significant association with female gender was demonstrated only after pooling our data with literature data. Concomitant prolactin hypersecretion had a nonsignificant promoting effect. In conclusion, the association of active untreated acromegaly with each of the three categories of glucose intolerance (including impaired fasting glycemia, not yet studied in this connection) was defined as a confidence interval, thus permitting a sound comparison with the findings of future studies. Besides a family history of diabetes, female gender and arterial hypertension were defined as additional, not yet described risk factors.