Dynamic tests and basal values for defining active acromegaly

Acromegaly is a rare disease caused by excess secretion of growth hormone (GH), usually from a pituitary somatotrope adenoma. The prevalence of acromegaly is 38-40 cases/1,000,000 subjects, while the annual incidence is 3 new cases/1,000,000 subjects. The increase in morbidity and mortality associated with acromegaly is the result of GH and insulin-like growth factor (IGF)-I oversecretion and the direct mass effect of the pituitary tumor. Once the disease is clinically suspected, laboratory evaluation is mandatory to establish diagnosis. The standard method for the diagnosis of acromegaly has been the measuring of GH nadir (GHn) during an oral glucose tolerance test (OGTT) which in normal individuals is undetectable, while acromegalics failed to suppress GH levels. Determination of IGF-I levels is useful as they correlate with clinical features of acromegaly and with the 24-hour mean GH levels. According to the more recent consensus, a random GH <0.4 microg/l and IGF-I in the age- and gender-matched normal range exclude the diagnosis of acromegaly. If either of these levels are not achieved, an OGTT should be performed, and then GHn <1 microg/l during OGTT excludes acromegaly. The therapeutic goals for acromegaly include the relief of sings and symptoms, the control of the tumor mass, the correction of the biochemical markers to normal levels, and the reduction in morbidity and mortality to the expected rate for the normal population. According to the 2000 consensus criteria, biochemical control of acromegaly is achieved when circulating IGF-I is reduced to an age- and sex-adjusted normal range and GHn during OGTT is <1 microg/l. There is debate in the literature whether GHn or IGF-I levels are more reliable to evaluate treatment of acromegaly. It has been reported that 15% of acromegalics with GHn <1 microg/l after treatment demonstrate abnormal IGF-I levels, while 15% of patients with normal IGF-I fail to suppress GH levels <1 microg/l during the OGTT. Probably, GHn and IGF-I levels represent two different aspects of disease activity in acromegaly. While IGF-I evaluates the secretory function of the somatotropes, GHn provides evidence of the presence or absence of functional autonomy of these cells.     

Current concepts in the biochemical assessment of the patient with acromegaly.

Biochemical assessment of a patient for acromegaly aims to definitively establish or exclude the presence of growth hormone excess. Whether applied to a newly recognized patient or to detect residual disease after therapy, this assessment is best accomplished by measurement of both the degree of GH suppression after oral glucose administration (OGTT) and levels of the GH dependent peptide, insulin-like growth factor I (IGF-I). When measured properly and compared to a well-characterized, age-adjusted normative database, elevation of the serum IGF-I level is a sensitive and specific indicator for the presence of acromegaly or persistent disease after therapy. The diagnosis of acromegaly can be confirmed by documenting an elevated IGF-I level in combination with failure of GH to suppress after oral glucose to below 0.3 microg/l, when GH is measured with a highly sensitive and specific assay. Persistently, normal IGF-I levels along with a nadir GH <0.3 microg/l should exclude the diagnosis. In assessing disease status during or after treatment, normalization of IGF-I is an essential criterion for biochemical control. It is important to recognize that nadir GH levels are >0.3 microg/l in some healthy subjects, so this criterion alone is not diagnostic of acromegaly. Also, because of heterogeneity of clinically available GH assays, this GH criterion, which was developed with a research assay, may not be applicable to use with all other assays. A nadir GH cut off of 1 microg/l has been found to be reliable for use with some standard immunoassays. It is recommended that glucose-suppressed GH levels be interpreted in conjunction with those of IGF-I and with consideration of conditions other than acromegaly that can alter them. With greater assay standardization and the use of IGF-I levels along with new rigorous criteria for interpretation of GH suppression during a OGTT we can improve our identification of patients with acromegaly in earlier stages of the disease as well as better recognize residual disease during therapy.     

Insulin-like growth factor-I: marker for diagnosis of acromegaly and monitoring the efficacy of treatment

Acromegaly is caused by chronic excess secretion of growth hormone (GH) and resultant persistent elevation in concentrations of insulin-like growth factor-I (IGF-I), also called somatomedin-C. A number of diagnostic tests are available to support the diagnosis of acromegaly, but those that rely on measurement of serum GH concentrations have important limitations. Concentrations of serum IGF-I, which is produced principally in the liver and mediates the actions of GH, have been shown to correlate with clinical and metabolic markers of disease activity. Additionally, normalisation of IGF-I levels in acromegaly is associated with the resolution of symptoms and normal life expectancy. Thus, serum IGF-I is an important marker of disease activity and a sensitive, practical, and reliable measure of integrated GH concentrations in patients with acromegaly.     

Basal and Glucose-Suppressed GH Levels Less Than 1 μg/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.     

Insulin resistance and pseudoacromegaly: A case report

Patients with acromegaly have soft tissue overgrowth that induced characteristic clinical presentation. A growth hormone-secreting adenoma of the anterior pituitary gland is the most common cause of acromegaly. Metabolic and somatic features of acromegaly caused by high serum concentrations of insulin-like growth factor-I (IGF-I) and excess growth hormone (GH) production. we present a case of ‘pseudoacromegaly’ with an acromegaloid features, suppressed IGF-I levels and marked elevation of serum insulin. Endocrinologists should consider this diagnosis when assessing patients with clinical features of acromegaly and insulin resistance, in the absence of elevated levels of GH and IGF-I.     

Cardiac Abnormalities in Acromegaly

Cardiovascular disease is claimed to be one of the most severe complications of acromegaly, contributing significantly to mortality in this disease. In fact, an excess of growth hormone (GH) and insulin-like growth factor 1 (IGF-I) causes a specific derangement of cardiomyocytes, leading to abnormalities in cardiac muscle structure and function, inducing a specific cardiomyopathy. In the early phase of acromegaly the excess of GH and IGF-I induces a hyperkinetic syndrome, characterized by increased heart rate and increased systolic output. Concentric hypertrophy is the most common feature of cardiac involvement in acromegaly, found in more than two thirds of patients at diagnosis. This abnormality is commonly associated with diastolic dysfunction and eventually with impaired systolic function ending in heart failure, if the GH/IGF-I excess is left untreated. In addition, abnormalities of cardiac rhythm and of heart valves have also been described in acromegaly. The coexistence of other complications, such as arterial hypertension and diabetes mellitus, aggravates acromegalic cardiomyopathy. Successful control of acromegaly induces a decrease in left ventricular mass and an improvement in diastolic function, while the effects of GH/IGF-I suppression on systolic function are more variable. However, since cardiovascular alterations in young patients with short disease duration are milder than in those with longer disease duration, it is likely to be easier to reverse and/or arrest acromegalic cardiomyopathy in young patients with early-onset disease. In conclusion, careful assessments of cardiac function, morphology, and activity are required in patients with acromegaly. An early diagnosis and prompt effective treatment are important in order to reverse acromegalic cardiomyopathy.     

A comparison of different methods for diagnosing acromegaly

OBJECTIVEThe present study was designed to assess the diagnostic value of different single measurements in comparison to the classic time-consuming method, the oral glucose tolerance test (OGTT), in acromegaly. DESIGN, PATIENTS AND MEASUREMENTS IGF-I, free IGF-I, 24-hour-urinary GH (uGH), serum IGFBP-3 and 24-hour-urinary IGFBP-3 (uIGFBP-3) were measured in 12 patients with untreated active acromegaly, in 29 patients who had been treated but were not cured, in 13 patients with cured acromegaly and in 14 healthy control subjects, and compared with the results of the OGTT. RESULTSIn all patients with active acromegaly, whether they had been treated or not, nadir GH in OGTT was >3 mU/I, whereas nadir GH was <1.88 mU/I in the cured patients and the control subjects. In patients with untreated active acromegaly IGF-I, free IGF-I, uGH and IGFBP-3, but not uIGFBP-3, were significantly higher than in healthy individuals (P<0.0001). Only IGF-I values did not overlap with the control group. In those patients with acromegaly who had been treated but not cured these parameters overlapped with the control group. In patients with acromegaly there was a significant correlation between nadir GH levels in OGTT and IGF-I (r=0.71), free IGF-I (r=0.76, IGFBP-3 (t=0.73) and uGH (r=0.81) (P<0.0001), but no correlation with uIGFBP-3. CONCLUSIONSOnly be means of the OGTT could patients with active acromegaly be completely distinguished from the control subjects and from cured patients. IGF-I, free IGF-I, IGFBP-3 and uGH were useful in the diagnosis of acromegaly, but of limited value in the follow-up of acromegalic patients after treatment. The determination of free IGF-I, which has yet not been investigated in acromegaly, offered no advantage over that of total IGF-I and IGFBP-3; uIGFBP-3 was not useful in the diagnosis of acromegaly.     

Postoperative evaluation of patients with acromegaly: clinical significance and timing of oral glucose tolerance testing and measurement of (free) insulin-like growth factor I, acid-labile subunit, and growth hormone-binding protein levels

CONTEXT: It is not exactly known when patients with acromegaly should be evaluated for cure after transsphenoidal adenomectomy (TA). OBJECTIVE: The objective of this study was to define the optimal time point of postoperative evaluation by serial measurements of glucose-suppressed GH levels [oral glucose tolerance test (OGTT)] and the GH-dependent parameters IGF-I, free IGF-I, acid labile subunit (ALS), and GH-binding protein (GHBP). DESIGN: We describe a prospective study with 1-yr follow-up. SETTING: The study was conducted at a university hospital. PATIENTS: Seventeen patients with acromegaly were included in the study. MAIN OUTCOME MEASURES: The main outcome measures were OGTT results at 1, 2, 3, 8, and 12 wk after TA; weekly measured GH, (free) IGF-I, ALS, and GHBP levels up to 12 wk; and total IGF-I levels measured at 52 wk. RESULTS: Postoperatively, nine patients were in remission with an OGTT GH nadir of less than 0.5 microg/liter and normalized IGF-I levels, whereas eight patients had persistent acromegaly. In both cured and noncured patients, OGTT results at 1 wk after TA were highly reproducible over time. In contrast, early postoperative IGF-I levels fluctuated and only stabilized at 12 wk. In all cured patients, free IGF-I levels rapidly normalized within 2 wk after TA (specificity, 100%). Preoperative ALS levels were elevated in all patients and normalized only in the cured patients after TA (specificity, 89%). Preoperative GHBP levels were low and increased from 2 wk after surgery. CONCLUSIONS: We show that in the postoperative evaluation of patients with acromegaly, already 1 wk after surgery, an OGTT using 0.5 microg as the GH nadir cutoff value has a high predictive value for cure, whereas early IGF-I levels show varying patterns toward stabilization. Therefore, IGF-I should be measured as a predictive parameter not within 3 months after surgery. Free IGF-I and ALS levels may have an additional value in the postoperative assessment of disease activity.     

Gender and age influence the relationship between serum GH and IGF-I in patients with acromegaly

BACKGROUND: In patients with acromegaly serum IGF-I is increasingly used as a marker of disease activity. As a result, the relationship between serum GH and IGF-I is of profound interest. Healthy females secrete three times more GH than males but have broadly similar serum IGF-I levels, and women with GH deficiency require 30-50% more exogenous GH to maintain the same serum IGF-I as GH-deficient men. In a selected cohort of patients with active acromegaly, studied off medical therapy using a single fasting serum GH and IGF-I measurement, we have reported previously that, for a given GH level, women have significantly lower circulating IGF-I. OBJECTIVE: To evaluate the influence of age and gender on the relationship between serum GH and IGF-I in an unselected cohort of patients with acromegaly independent of disease control and medical therapy. METHODS: Sixty (34 male) unselected patients with acromegaly (median age 51 years (range 24-81 years) attending a colonoscopy screening programme were studied. Forty-five had previously received pituitary radiotherapy. Patients had varying degrees of disease control and received medical therapy where appropriate. Mean serum GH was calculated from an eight-point day profile (n = 45) and values obtained during a 75-g oral glucose tolerance test (n = 15). Serum IGF-I, IGFBP-3 and acid-labile subunit were measured and the dependency of these factors on covariates such as log10 mean serum GH, sex, age and prior radiotherapy was assessed using regression techniques. RESULTS: The median calculated GH value was 4.7 mU/l (range 1-104). A significant linear association was observed between serum IGF-I and log10 mean serum GH for the cohort (R = 0.5, P < 0.0001). After simultaneous adjustment of the above covariates a significant difference in the relationship between mean serum GH and IGF-I was observed for males and females. On average, women had serum IGF-I levels 11.44 nmol/l lower than men with the same mean serum GH (P = 0.03, 95% CI 1.33-21.4 nmol/l). Age significantly influenced the relationship and for a given serum GH, IGF-I was estimated to fall by 0.37 nmol/l per year (P = 0.04, 95% CI 0.015-0.72). CONCLUSIONS: In keeping with previous observations of relative GH resistance in normal and GH-deficient females we have observed lower serum IGF-I levels for equivalent mean serum GH levels in females patients with acromegaly. This gender-dependent difference is independent of disease activity and the use of concomitant medical therapy. Additionally, we have demonstrated that for a given serum GH level, age significantly influences IGF-I concentrations in patients with acromegaly. These data have important implications for the use of serum IGF-I and GH as markers of disease activity in acromegaly.     

Clinically silent somatotropinomas may be biochemically active

The diagnosis of acromegaly is suspected based on the typical clinical presentation and is subsequently confirmed biochemically by elevated GH and IGF-I concentrations. We report three female patients with pituitary tumors who presented without any signs or symptoms of acromegaly but with elevated IGF-I levels. Plasma GH was measured every 10 min for 24 h, and an oral glucose tolerance test was performed. All patients had abnormally elevated mean and trough plasma GH levels as well as post-glucose nadir GH concentrations. All patients had magnetic resonance imaging scans revealing pituitary tumors and underwent transsphenoidal surgery. Histologically, they had GH-producing pituitary tumors. Plasma IGF-I levels returned to normal in two patients after surgery. Some pituitary adenomas are true GH-secreting tumors despite not being accompanied by obvious clinical stigmata of acromegaly. Natural history of this disease is unknown because of the small number of reported patients and inconsistent results of biochemical testing. Based on the results of this and previous reports, we propose that all patients with known pituitary tumors, especially younger women with normal or mildly elevated prolactin level, be evaluated for GH excess.     

New therapeutic options for acromegaly

Acromegaly is a slowly developing disfiguring disease characterized by chronic growth hormone (GH) and insulin-like growth factor-I (IGF-I) excess and caused by a pituitary somatotroph adenoma. It is associated to 2- to 3 fold increased mortality, compared to normal population, mostly due to cardiovascular and cerebro-vascular diseases, and to several co-morbid systemic illnesses, such as diabetes mellitus, hypertension, severe arthropathies, a specific cardio-myopathy, goitre, sleep-apnoea, intractable headache. The morbidity and excess mortality of acromegaly are usually the consequence of the metabolic actions of excess GH and IGF-I secretion, while only in rare patients mortality is due to the mass effects of the pituitary tumour. Since, serum IGF-I concentrations within age-adjusted normal range, and a tight GH control have to be achieved to normalize life-expectancy in these patients, an aggressive, and often multi-modality treatment is required for acromegaly. In recent years, new drugs, and new formulations of old drugs, have been developed that are able to effectively inhibit GH secretion or GH action, and may represent important adjuncts or even alternatives to the traditional approaches of surgery and radiotherapy. This review briefly summarizes the therapeutic options nowadays available for acromegaly. A brief note about innovative drugs under study, is also given.     

Growth hormone and pituitary radiotherapy, but not serum insulin-like growth factor-I concentrations, predict excess mortality in patients with acromegaly

Increased mortality in patients with acromegaly has been confirmed in a number of retrospective studies, but causative factors and relationship to serum IGF-I remain uncertain. The West Midlands Pituitary database contains details of 419 patients (241 female) with acromegaly. Serum IGF-I data from the Regional Endocrine Laboratory were available for 360 patients (86%). At diagnosis, mean age was 47 yr (range, 12-84) and mean duration of follow-up was 13 yr (0.5-48). Sixty-one percent were treated by surgery and 39% by nonsurgical means. Radiotherapy was used alone or as adjuvant therapy in 50%. All patients were registered with the Office of National Statistics to obtain information on deaths. At the date of analysis (31 December 2001), 95 of the 419 patients had died (43 males), giving a standardized mortality ratio of 1.26 [confidence interval (CI), 1.03-1.54; P = 0.046]. After controlling for age and sex, data indicated that mortality was increased in subjects with posttreatment GH levels more than 2 micro g/liter, compared with those with levels less than 2 micro g/liter [ratio of mortality rates (RR), 1.55 (range, 0.97-2.50); P = 0.068]. By contrast, a much smaller increase was observed for subjects with elevated posttreatment IGF-I levels compared with those with normal levels [RR, 1.20 (range, 0.71-2.03); P = 0.50]. Treatment with radiotherapy was associated with increased mortality [RR, 1.67 (range, 1.09-2.56); P = 0.018], with cerebrovascular disease the predominant cause of death [standardized mortality ratio, 4.42 (range, 2.71-7.22); P = 0.005]. These results confirm the increased mortality in acromegaly and suggest that reduction of GH levels to less than 2 micro g/liter is beneficial in terms of improving long-term outcome. The sole use of IGF-I as a marker for effective treatment of acromegaly is not justified by this data. This study also highlights the potential deleterious effect of radiotherapy.     

Pathogenesis and Prevalence of Hypertension in Acromegaly

Hypertension is an important complication of acromegaly, contributing to the increased morbidity and mortality of this condition. Prevalence of hypertension in acromegalic patients is about 35%, ranging from 18 to 60% in different clinical series, and the incidence is higher than in the general population. The lowering of blood pressure observed concomitantly with the reduction in GH levels after successful therapy for acromegaly suggests a relationship between GH and/or IGF-I excess and hypertension. The exact mechanisms underlying the development of hypertension in acromegaly are still not clear but may include several factors depending on the chronic exposure to GH and/or IGF-I excess. Experimental and clinical studies suggest that the anti-natriuretic action of GH (due to direct renal action of GH or IGF-I and/or to indirect, systemic GH or IGF-I-mediated mechanisms) may play a role in the pathogenesis of hypertension. Acromegaly is frequently associated with insulin resistance and hyperinsulinaemia which may induce hypertension by stimulating renal sodium absorption and sympathetic nervous activity. Whether sympathetic tone is altered in acromegalic hypertensive patients remains a matter of debate. Recent studies indicate that an increased sympathetic tone and/or abnormalities in the circadian activity of sympathetic system could play an important role in development and/or maintenance of elevated blood pressure in acromegaly, and may partially account for the increased risk of cardiovascular complications. Acromegalic cardiomiopathy may also concur to elevate blood pressure and can be aggravated by the coexistence of hypertension. Finally, a role of GH and IGF-I as vascular growth factors cannot be excluded. In conclusion, acromegaly is associated with hypertension, but there is still no real consensus in the literature on the mechanisms behind the development of the high blood pressure.     

Characterization of 24-hour growth hormone secretion in acromegaly: implications for diagnosis and therapy

OBJECTIVE Early studies of acromegaly undertaken before the general availability of insulin-like growth factor I (IGF-I) assays have used arbitrary and varying growth hormone (GH) threshold levels for diagnosing and assessing outcome of treatment for this disease. We have undertaken a detailed study of GH secretion and its relationship to IGF-I levels to assess the usefulness of GH and IGF-I measurements in the assessment of acromegaly. PATIENTS Thirty acromegalic subjects (12 untreated and 16 previously treated) and 30 age and sex-matched normal subjects were studied. MEASUREMENTS Twenty-four-hour GH secretion was obtained from 20-minute sampling and serum IGF-I was measured. Comparisons were made of IGF-I, mean 24-hour GH concentration, and of the pulsatile and diurnal characteristics of GH secretion between the two groups. RESULTS IGF-I levels In untreated acromegaly were elevated and clearly separated from the normal range. Mean 24-hour GH concentrations in untreated and treated acromegalic subjects with elevated IGF-I (>40 nmol/l) were greater than (P < 0.01), and showed good separation from, those of normal subjects only after age-matching. From the 24-hour prollfes, nadir GH levels In normal subjects fell below the level of detectability while those in untreated acromegalic subjects did not. Pulse amplitude (P<0.01), ratio of pulsatile to non-pulsatile GH release and the night to daytime GH ratio (P<0 05) were significantly reduced in acromegaly. In the six patients who attained normal IGF-I levels after surgery, pulsatile characteristics remained abnormal in four. Mean 24-hour GH was significant related (r = 0.57) to IGF-I. A random GH concentration >2.5 μg/l (5 mlU/l) has a sensitivity of 77% and specificity of 95% In identifying acromegalic patients who have biochemically active disease (elevated IGF-I) after treatment. CONCLUSIONS Patients with active acromegaly secrete more GH than age-matched normal controls. GH secretion in acromegaly is characterized by marked blunting of pulsatile secretion and, in contrast to normal subjects, the failure of GH to fall to undetectable levels at any time during the 24-hour day. IGF-I measurement is a more practical alternative in the diagnosis of acromegaly and in the assessment of therapeutic outcome. Since abnormalities of GH regulation may persist despite normalization of IGF-I, a distinction between remission and cure should be made. Detailed post-treatment evaluation of GH secretion is necessary to define the nature of underlying GH regulation and to evaluate the risk of disease recurrence.     

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

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 and end-stage renal disease: a diagnostic challenge

Chronic renal failure is associated with an impairment of the GH/IGF-I axis. We report the diagnostic challenges in a 72-yr-old female suffering from end-stage renal disease and presenting with clinical findings suggestive of acromegaly. GH was not suppressed during an oral glucose tolerance test, but rose paradoxically. However, serum IGF-I levels were within the normal range. IGF-binding proteins (IGFBP)-2 and -3 were markedly elevated and GH-binding protein (GHBP) was diminished. Clinical findings suspicious of acromegaly could be ascribed to pre-existing characteristics and consequences of end-stage renal disease. This suggested that the disturbances of the GH/IGF-I axis in our patient were due to chronic renal disease, rather than acromegaly. In the work-up for acromegaly, clinicians should be alerted to GH resistance in chronic renal failure.     

Cardiovascular complications in acromegaly

Cardiovascular morbidity and mortality are increased in acromegaly. In fact, GH and IGF-I excess induces a specific cardiomyopathy. The early stage of acromegaly is characterized by the hyperkinetic syndrome (high heart rate and increased systolic output). Frequently, concentric biventricular hypertrophy and diastolic dysfunction occur in acromegaly, leading to an impaired systolic function ending in heart failure if the disease is untreated or unsuccessfully untreated. Besides, abnormalities of cardiac rhythm and of valves have been also described in acromegaly. The coexistence of other complications, such as arterial hypertension and diabetes, aggravates the acromegalic cardiomyopathy. The suppression of GH/IGF-I following an efficacious therapy could decrease left ventricular mass and improve cardiac function. In conclusion, a careful evaluation of cardiac function, morphology and activity seems to be mandatory in acromegaly.     

Lower visceral and subcutaneous but higher intermuscular adipose tissue depots in patients with growth hormone and insulin-like growth factor I excess due to acromegaly

CONTEXT: GH and IGF-I are important regulators of metabolism and body composition. In acromegaly, a state of GH and IGF-I excess, the lipolytic and insulin antagonistic effects of GH may alter adipose tissue (AT) distribution. OBJECTIVES: Our objective was to test the hypothesis that in acromegaly whole-body AT mass is less and to examine for the first time the relationship between GH/IGF-I excess and intermuscular AT (IMAT), an AT depot associated with insulin resistance in other populations. DESIGN, SETTING, AND PATIENTS: We conducted a cross-sectional study in 24 adults with active acromegaly compared with predicted models developed in 315 healthy non-acromegaly subjects. OUTCOME MEASURES: Mass of AT in the visceral AT (VAT), sc AT (SAT), and IMAT compartments from whole-body magnetic resonance imaging and serum levels of GH, IGF-I, insulin, and glucose were measured. RESULTS: VAT and SAT were less in active acromegaly (P < 0.0001); these were 68.2 +/- 27% and 79.5 +/- 15% of predicted values, respectively. By contrast, IMAT was greater (P = 0.0052) by 185.6 +/- 84% of predicted. VAT/trunk AT ratios were inversely related to IGF-I levels (r = 0.544; P = 0.0054). Acromegaly subjects were insulin resistant. CONCLUSIONS: VAT and SAT, most markedly VAT, are less in acromegaly. The proportion of trunk AT that is VAT is less with greater disease activity. IMAT is greater in acromegaly, a novel finding, which suggests that increased AT in muscle could be associated with GH-induced insulin resistance. These findings have implications for understanding the role of GH in body composition and metabolic risk in acromegaly and other clinical settings of GH use.     

Effects of GH assay standardization on evaluation of treatment outcomes for acromegaly in Japan

In Japan, the growth hormone (GH) assay has been standardized since April 2005 through use of a uniform recombinant human GH (rhGH) standard. Since then, GH values measured using the rhGH standard have been approximately 40% lower than previous values measured using kit standards based on the WHO standards for hGH of pituitary origin. However, the Japanese criteria for evaluating treatment outcomes for acromegaly have remained the same: a nadir GH during a 75 g OGTT <1 μg/L is considered cured, 1≤GH<2.5μg/L is considered inadequately controlled, and ≥2.5 μg/L is considered poorly controlled, instead of these levels were lowered to 60%, i.e. from 1 to 0.6 μg/L for cured and from 2.5 to 1.5μg/L for inadequately controlled (termed as "newly proposed criteria" in this study). We investigated the effects of standardization of the GH assay on the evaluation of post-surgical disease activity in 50 patients with acromegaly (M/F 19/31, 21-72 yr.). Post-surgical nadir GH levels during OGTT were positively correlated with the IGF-I SD score 3 months after TSS. Five of 6 patients whose post-surgical nadir GH levels ranged between 0.6 and 1 μg/L had normal serum IGF-I levels 3 months after TSS. Rates of improvement in glucose metabolism did not differ when patients were classified based on the present criteria vs. the newly proposed criteria. In conclusion, the current Japanese remission criteria for acromegaly still accurately reflect post-surgical disease activity in most patients, though long-term observation is still required.     

Pitfalls in the Biochemical Assessment of Acromegaly

The biochemical assessment for newly recognized acromegaly is in most, but not all patients straightforward. Although significant improvements in the methods of biochemical testing for acromegaly have recently been made, major pitfalls to the assessment of this disease still exist. A number of different schemes have been employed for the assessment of GH secretion in clinical practice. Random GH levels have been often used, but remain unreliable for the assessment of acromegaly. Mean GH levels are also frequently used to assess GH status, but are not specific for the diagnosis of acromegaly. Measurement of glucose suppressed GH levels is the preferred method for assessing GH secretion in acromegaly. However, it is essential to recognize that when using highly sensitive and specific GH assays, nadir GH levels can be < 1 microg/L after oral glucose in some patients with newly diagnosed acromegaly and postoperative patients with active disease. On the other hand, when using most clinically available commercial GH assays which are less sensitive and specific than those used in research studies, failure of GH suppression into the normal range set in these studies is not alone diagnostic of active acromegaly. In order to diagnose acromegaly, documentation of GH excess should be accompanied by elevation in levels of the GH dependent peptide, insulin-like growth factor I (IGF-I). Consideration also needs to be given to the clinical context in which GH and IGF-I are being measured as both can be altered in a number of clinical settings other than acromegaly. Both IGF-I and GH evaluations are important and complimentary parts of the biochemical assessment of acromegaly.