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Background: Previous studies report impaired health-related quality of life (HRQoL) in patients with functional pituitary adenomas (FPA). We assessed HRQoL in FPA patients having undergone surgery at our University Central Hospital between 2000 and 2010, with combined adjuvant treatment given to achieve strict hormonal control., Design: A cross-sectional study including a large control population., Patients and Methods: HRQoL was assessed by the 15D in 100 FPA patients (acromegaly n = 47, Cushing's disease n = 21, prolactinoma n = 26, TSH-adenoma n = 2, gonadotropinoma n = 4), operated on a mean 7·4 (range 2·1-13·0) years earlier. An age- and gender-standardized sample of the general population (n = 4924) served as controls. HRQoL determinants were assessed by independent samples t-test and multiple regression analysis., Results: Hormonal remission rate was 90·9% and 43·9% of the patients received replacement therapy. The mean 15D scores were similar in patients and controls (0·917 vs 0·922, P = 0·568). On single dimensions, patients were worse off regarding speech and sexual activity (both P < 0·05) and better off regarding discomfort and symptoms (P < 0·05). Age (P = 0·001), co-morbidities (P = 0·009), Cushing's disease (P = 0·034), and thyroxine dose (P = 0·002) predicted impaired HRQoL, but not hypopituitarism, hydrocortisone replacement, radiotherapy, or time after surgery., Conclusions: It is possible to achieve near-normal HRQoL in surgically treated FPA patients given adjuvant treatment to achieve strict hormonal remission. However, in addition to age and co-morbidities, Cushing's disease and need for thyroxine replacement therapy predict impaired HRQoL., (© 2014 John Wiley & Sons Ltd.)

Objective: Control of acromegaly may ameliorate blood pressure (BP) in hypertensive (HT) patients. We evaluated the impact of acromegaly control on BP values of normotensive (NT) acromegalics., Design: Retrospective cohort study., Patients: Fifty-eight naïve patients with acromegaly (39 F; age range, 30-69 years), including 28 NT and 30 HT subjects, participated in the study., Measurements: Blood pressure was measured by clinical measurement and 24-h ambulatory monitoring at diagnosis and after 24 months of medical therapy for acromegaly., Results: Acromegaly was controlled by medical therapy in 15 NT and 17 HT patients at 24 months. In the NT group, systolic (SBP) or diastolic (DBP) BP significantly increased (all P < 0·005) when acromegaly was uncontrolled, but did not change when the disease was controlled. Changes in SBP and DBP were also significantly different between uncontrolled and controlled NT patients. At 24 months, clinical hypertension was detected only in uncontrolled NT patients (46% vs 0%, P < 0·001), whereas ambulatory hypertension was found in 38% of uncontrolled and in 7% of controlled NT subjects (P = 0·035). In the HT group, ambulatory SBP increased in patients with uncontrolled acromegaly (24-h SBP P = 0·046, day SBP P = 0·005, night SBP P = 0·005), whereas ambulatory DBP decreased in subjects with controlled disease (24-h DBP P = 0·008, day DBP P = 0·026)., Conclusions: Control of acromegaly has a beneficial effect on BP regulation either in HT or NT subjects; in the latter, it may prevent progression towards hypertension., (© 2014 John Wiley & Sons Ltd.)

Objective: Cardiovascular complications that are probably related to the loss of arterial elasticity, such as secondary hypertension, occur frequently in patients with acromegaly and may persist after the condition has been treated. The aim of the study was to determine arterial compliance in adolescent patients with acromegaly who had undergone surgery to remove the adenoma in the pituitary gland. This is thought to be the first study on such patients., Patients: Sixteen patients (nine male, seven female; mean age at diagnosis, 17·6 ± 1·3 years; mean age at time of study, 23·3 ± 3·7 years) who had undergone surgery for acromegaly that was caused by a pituitary adenoma., Measurements: Arterial stiffness was measured by the standardized noninvasive QKd(100-60) method. In addition, blood pressure at rest was measured, ambulatory blood pressure was monitored over a 24-h period and transthoracic echocardiography was performed., Results: Adolescent patients who had been operated upon for acromegaly showed disadvantageous differences in 24-h ambulatory blood pressure monitoring (systolic blood pressure, P < 0·001; diastolic blood pressure, P < 0·02; mean blood pressure, P < 0·01) and in QKd(100-60) value (194 ± 4 vs 205 ± 5 ms, P < 0·03) compared with controls., Conclusion: Despite successful treatment, the patients showed significantly decreased arterial distensibility as compared with controls, which might explain the observed differences in blood pressure. The findings show that such patients are at increased risk of developing cardiovascular diseases, despite their being youth and the restoration of normal secretion of growth hormone/insulin growth factor., (© 2011 Blackwell Publishing Ltd.)

Context: The impact of acromegaly on the auditory system remains unknown., Objective: This study aimed to examine audiological symptoms and the structure and function of the auditory system in patients with acromegaly. DESIGN/SETTING AND PATIENTS:  The study included 44 patients with acromegaly. Pure tone audiometry, speech audiometry, tympanometry, otoacoustic emissions testing, computerized tomography of the temporal bone and magnetic resonance imaging of the ear were performed in all patients. The study also included 36 age- and sex-matched healthy controls. The patients with acromegaly were divided into three subgroups, as follows: controlled disease (n=13); partially controlled disease (n=16); uncontrolled disease (n = 15)., Results:   In all, 43% of the patients with acromegaly had hearing loss, and 20% had had an episode of otitis in at least one ear. Median pure tone average (PTA) in the patients with acromegaly was 12.5 dB (range: 2-72 dB), vs 8.3 dB (range: 0-20 dB) in the control group (P < 0.001). PTA did not differ significantly between the three patient subgroups. Audiometric tests showed various degrees of hearing loss in at least one ear in 21 patients (48%). Conductive, sensorineural and mixed type hearing loss in at least one ear was noted in 9%, 30% and 18% of the patients, respectively. Auditory imaging showed that 50% of the patients had temporomandibular joint degeneration (TMJD)., Conclusions:   Hearing loss is quite common in patients with acromegaly. Contrary to common belief, in this study, conductive hearing loss did not occur more frequently than other types. Based on PTA findings in the controls and patients with acromegaly, acromegaly caused hearing loss, but the level of disease activity had no effect on hearing. Middle ear pressure problems might be caused by increased perilymph because of growth hormone (GH)-related volume overload., (© 2012 Blackwell Publishing Ltd.)

Background: Acromegaly is associated with increased cardiovascular mortality, and increased aortic root diameter has been recently described in the literature as a possible feature of acromegalic cardiomyopathy., Objective: To assess the aortic root diameter and the prevalence of aortic ectasia in acromegalic patients., Patients and Methods: This paper presents a transversal analysis of 42 acromegalic patients by Doppler echocardiogram and comparison with 42 age, sex, body surface area and hypertension matched controls., Results: The mean aortic root diameter at the level of the aortic leaflets was increased in acromegalic patients when compared to controls (3·4 ± 0·5 vs 2·9 ± 0·4 cm, respectively, P < 0·0001). The aortic root diameter was significantly greater in men than in women (3·6 ± 0·6 cm vs 3·2 ± 0·4 cm, respectively, P = 0·004), and the left ventricular mass index was positively correlated with the diameter of the aorta (r = 0·37, P = 0·01). Using a cut-off point ≥ 3·8 cm, an aortic ectasia prevalence of 26·1 vs 2·3% was found in acromegalic patients and controls, respectively (P = 0·002). Only acromegaly was associated with aortic ectasia (P = 0·01)., Conclusion: The aortic root diameter was higher, and the prevalence of aortic ectasia was more common in acromegalic patients than in controls. In addition, only acromegalic disease was associated with aortic ectasia, suggesting the direct effects of GH and insulin-like growth factor-I excess on the cardiovascular system., (© 2011 Blackwell Publishing Ltd.)

Objective: Data on trabecular bone mass in acromegaly are controversial. All the studies are cross-sectional and bone mineral density (BMD) has been evaluated largely by dual X-ray absorptiometry (DXA), which is influenced by bone enlargement. In this study we assessed in acromegalic patients the effects overtime of GH excess on trabecular bone mass measured by single-energy quantitative computed tomography (QCT) which is not influenced by bone size., Design: Longitudinal retrospective study., Patients: A total of 46 acromegalic patients followed-up for 48 months (median), subdivided into four groups: group A (eugonadal patients with active disease: n = 13), group B (hypogonadal patients with active disease; n = 9), group C (eugonadal patients with controlled disease; n = 10), group D (hypogonadal patients with controlled disease; n = 14)., Measurements: Serum GH and IGF-I levels, spinal trabecular BMD, and vertebral fractures were evaluated in all patients. BMD variations were reported as change (Delta) in Z-values (Z-QCT) measured at baseline and end of follow-up per year (Delta Z-QCT)., Results: Delta Z-QCT was greater in group A vs. group B and D (P =0.002 and P = 0.0001, respectively) and in group C vs. group D (P =0.009). Multivariate regression analysis showed that hypogonadal status (beta = -0.69; P = 0.001) and baseline duration of hypogonadism (beta = 0.44; P = 0.02) but not baseline duration of acromegaly, length of follow-up and disease activity, were significantly associated with Delta Z-QCT., Conclusions: This longitudinal study suggests that the effect of chronic GH excess on spinal trabecular bone mass seems to be anabolic in active eugonadal patients but not in hypogonadal ones.

Context: Approximately one-third of patients with acromegaly have concomitant hypertension. The outcome of hypertension after treatment of acromegaly is unknown., Objective: To evaluate the role of GH and IGF-I control on systolic (SBP) and diastolic blood pressure (DBP) levels., Patients: One hundred and five hypertensive patients (60 women, 45 men) with active disease receiving treatment for hypertension at their diagnosis of acromegaly., Design: Observational, retrospective, multicentre., Measurements: At diagnosis and after 24 months (median) of treatment we measured serum GH and IGF-I levels, blood pressure levels, left ventricular (LV) mass index (LVMi), early-to-late mitral flow velocity (E/A, as a measure of diastolic function) and LV ejection fraction (LVEF, as a measure of systolic function)., Results: At the diagnosis of acromegaly, hypertension was mild in 41.1% and severe in 58.9%. Serum GH and IGF-I levels did not differ in patients with mild or severe hypertension. After 24 months of treatment, all patients had a notable decrease in both GH and IGF-I levels, and achieved significantly lower levels of DBP, heart rate and LVMi; 76 patients (71%) had achieved control of GH and IGF-I levels. Only the patients with controlled acromegaly achieved significantly lower SBP levels and significantly improved cardiac systolic and diastolic function. A higher dose of antihypertensive drugs and/or an increased number of drugs to control hypertension were significantly greater in patients with uncontrolled (32.3%) than in those with controlled acromegaly (7.8%; P = 0.004)., Conclusion: Hypertensive patients with controlled acromegaly achieved improved control of hypertension and of cardiac diastolic and systolic function. The use of antihypertensive drugs was significantly less in patients achieving control of acromegaly.

Objective: Long-term effects of trans-naso-sphenoidal surgery (TNS) or long-acting somatostatin analogs (SSA) on the function of hypothalamic-pituitary-adrenal (HPA) axis have been poorly investigated. Aim of this study was to evaluate HPA axis integrity during the follow-up in patients with GH-secreting pituitary adenomas and preserved HPA function post-TNS or prior SSA., Design and Patients: This retrospective study investigated 36 acromegalic patients (16M and 20F, age: 47 +/- 13 years), 20 of whom cured by TNS and 16 controlled by SSA therapy (12 previously operated and 4 in primary medical therapy), before and after long-term follow-up (median: 72 months, range: 12-240). No patient previously underwent radiotherapy., Measurements: HPA function was studied by morning circulating cortisol and ACTH levels, 24-h urinary free cortisol (UFC) and cortisol response to low-dose short Synacthen test (LDSST, 1 microg) with a peak > 500 nmol/l as cut-off for normal function., Results: Serum basal cortisol, ACTH and UFC levels were in the normal range and did not significantly change over time. As far as the cortisol peak after LDSST is concerned, 12 patients (32%, 8 TNS and 4 SSA) developed biochemical hypoadrenalism. None of the patients in primary medical therapy showed cortisol peak < 500 nmol/l. No significant correlations between HPA axis deterioration and follow-up duration, serum GH/IGF-I levels, occurrence of other pituitary deficiencies, presence of secondary empty sella, changes in tumour or residual volume were observed., Conclusions: The HPA axis function must be carefully monitored over the time by dynamic testing in all acromegalic patients, independently from the type of treatment.

Background: GH and IGF-I affect cardiac structure and performance. In the general population, low IGF-I has been associated with higher prevalence of ischaemic heart disease and mortality. Both in GH deficiency (GHD) and excess life expectancy has been reported to be reduced because of cardiovascular disease., Objective: To review the role of the GH-IGF-I system on the cardiovascular system., Results: Recent epidemiological evidence suggests that serum IGF-I levels in the low-normal range are associated with increased risk of acute myocardial infarction, ischaemic heart disease, coronary and carotid artery atherosclerosis and stroke. This confirms previous findings in patients with acromegaly or with GH-deficiency showing cardiovascular impairment. Patients with either childhood- or adulthood-onset GHD have cardiovascular abnormalities such as reduced cardiac mass, diastolic filling and left ventricular response at peak exercise, increased intima-media thickness and endothelial dysfunction. These abnormalities can be reversed, at least partially, after GH replacement therapy. In contrast, in acromegaly chronic GH and IGF-I excess causes a specific cardiomyopathy: concentric cardiac hypertrophy (in more than two-thirds of the patients at diagnosis) associated to diastolic dysfunction is the most common finding. In later stages, impaired systolic function ending in heart failure can occur, if GH/IGF-I excess is not controlled. Abnormalities of cardiac rhythm and of cardiac valves can also occur. Successful control of acromegaly is accompanied by decrease of the left ventricular mass and improvement of cardiac function., Conclusion: The cardiovascular system is a target organ for GH and IGF-I. Subtle dysfunction in the GH-IGF-I axis are correlated with increased prevalence of ischaemic heart disease. Acromegaly and GHD are associated with several abnormalities of the cardiovascular system and control of GH/IGF-I secretion reverses (or at least stops) cardiovascular abnormalities.

Background: Radiation induces time-dependent loss of anterior pituitary function, attributed to damage of the pituitary gland and hypothalamic centres. The development of growth hormone deficiency (GHD) in irradiated acromegaly patients is not well defined., Objective: Detailed analysis of spontaneous 24-h GH and prolactin (PRL) secretion in relation to other pituitary functions and serum IGF-I concentrations in an attempt to find criteria for GHD in acromegalic patients with a GH response < 3 microg/l during the insulin tolerance test (ITT)., Design: Plasma hormone profiles obtained by 10 min sampling for 24 h in postoperatively irradiated acromegalic patients, compared with patients cured by surgery only and matched healthy controls., Setting/participants: University setting. Fifteen subjects in each group., Outcome Measures: GH and PRL secretory parameters quantified by deconvolution, cluster, cosinor and approximate entropy (ApEn) analyses, IGF-I concentrations., Results: Irradiation attenuated pulsatile secretion of GH and PRL, but total PRL secretion was unchanged. GH and PRL secretory regularity were diminished. Circadian timing remained intact. Pulsatile GH secretion and IGF-I were correlated (R = 0.30, P = 0.04). Criteria of pulsatile GH secretion = 12 microg/l/24 h and ApEn = 0.800 separated 12 of 15 irradiated patients from all others., Conclusion: Irradiated acromegaly patients with a subnormal GH response to ITT have very limited spontaneous GH secretion, with specific attenuation of the size of GH bursts and a highly irregular pattern, but with retained diurnal properties. These patients are thus likely GH-deficient and might benefit from GH replacement.

Objective: Cardiovascular disease is a major contributor to the increased mortality of acromegalic patients. Prolongation of the QT interval is considered an established risk factor for potentially fatal cardiac arrhythmias, an event frequently observed in acromegaly. Changes in ventricular repolarization have been observed with the use of octreotide, one of the somatostatin analogues (SSA) currently used for the medical treatment of this disease. Furthermore, octreotide is listed among the drugs able to prolong the QT interval. Thus, we elected to study the effects of long-term SSA administration on QT duration and left ventricular mass (LVM) in a group of acromegalic patients., Design and Patients: In a retrospective study, 30 acromegalic patients (19 women and 11 men, aged 25-77 years) were studied under basal conditions; 24 of them (15 women and nine men, aged 25-77 years) were studied again after 3-63 months of treatment (median 18 months) with SSA. Twenty-four healthy volunteers served as controls., Measurements: Patients and controls underwent electrocardiographic (ECG) analysis, and QT interval duration corrected for heart rate (QTc) was established according to the Bazett formula. In 17 of the SSA-treated patients, M- and B-mode echocardiography for the assessment of LVM index (LVMi) was performed., Results: Baseline QTc was significantly longer in patients than in controls. SSA administration was followed by a significant decrease in QTc, which reached a mean value similar to that measured in the controls. In particular, treatment with SSA normalized QTc in three out of the six patients with abnormally elevated values at baseline. After treatment, a significant reduction in heart rate was recorded, while LVMi displayed a slight but not significant decrease., Conclusions: Acromegalic patients frequently display an abnormally prolonged QT interval, a known risk factor for potentially fatal arrhythmias. Treatment of these patients with SSA is able to improve and even normalize this alteration, probably contributing to the beneficial effects of these drugs on cardiac rhythm in this endocrine disorder. The inclusion of octreotide in the list of drugs that may increase QTc should be reconsidered as regards its indication in acromegaly.

The ability of GH, via its mediator peptide IGF-1, to influence regulation of cellular growth has been the focus of much interest in recent years. In this review, we will explore the association between GH and cancer. Available experimental data support the suggestion that GH/IGF-1 status may influence neoplastic tissue growth. Extensive epidemiological data exist that also support a link between GH/IGF-1 status and cancer risk. Epidemiological studies of patients with acromegaly indicate an increased risk of colorectal cancer, although risk of other cancers is unproven, and a long-term follow-up study of children deficient in GH treated with pituitary-derived GH has indicated an increased risk of colorectal cancer. Conversely, extensive studies of the outcome of GH replacement in childhood cancer survivors show no evidence of an excess of de novo cancers, and more recent surveillance of children and adults treated with GH has revealed no increase in observed cancer risk. However, given the experimental evidence that indicates GH/IGF-1 provides an anti-apoptotic environment that may favour survival of genetically damaged cells, longer-term surveillance is necessary; over many years, even a subtle alteration in the environmental milieu in this direction, although not inducing cancer, could result in acceleration of carcinogenesis. Finally, even if GH/IGF-1 therapy does result in a small increase in cancer risk compared to untreated patients with GH deficiency, it is likely that the eventual risk will be the same as the general population. Such a restoration to normality will need to be balanced against the known morbidity of untreated GH deficiency.

Objectives: Three major therapeutic modalities (transsphenoidal surgery, radiotherapy and medical therapy) are currently available for acromegaly. Although surgery is regarded as the primary option, 50--60% of macroadenomas require further treatment in the form of radiotherapy and/or medical therapy. Recent studies have suggested that radiotherapy might damage the normal hypothalamic-pituitary axis and also rarely leads to IGF-I normalization. The aims of this study were: (1) to examine the effect of different therapeutic modalities (transsphenoidal surgery, TSS; radiotherapy, RT; medical treatment with somatostatin analogues, SSA) on the daily spontaneous GH secretory pattern (day curve); and (2) to determine the relationship between the characteristics of the GH secretory pattern and the circulating concentration of IGF-I, acid-labile subunit (ALS) and IGFBP-3., Design and Measurements: Spontaneous GH secretion was evaluated at hourly intervals from 0800 to 1800 h. IGF-I, IGFBP-3 and ALS were measured in basal conditions. The mean and the minimum values obtained from the day curve profile and the coefficient of variation (CV) of single values, which are expressions of the magnitude of the spontaneous secretory pulses, were used for statistical analysis., Patients: In a group of 45 acromegalic patients (28 women, mean age 51 years, range 26--83 years, and 17 men, mean age 57 years, range 37--78 years) treated with different protocols, including TSS, RT and SSA therapy, we evaluated GH secretion to determine the effect of single treatment options on the spontaneous secretory profile. Subjects were grouped on the basis of different therapeutic modalities: TSS+RT+SSA (group 1), TSS+SSA (group 2), SSA (group 3), TSS (group 4), TSS+RT (group 5). In patients treated with somatostatin analogues (SSA), tests were performed about midway between two injections., Results: The number of deficiencies of the other pituitary functions (PD) was significantly higher in the groups that underwent RT (groups 1 and 5) than in the other groups; in both cases, P<0.01. No significant differences were observed with regard to the mean GH, IGF-I, ALS or IGFBP-3 among the different treatment groups. A significant difference in the GH nadir was found between groups 2 and 4 (P=0.042) and between groups 3 and 4 (P=0.015). GH CV showed lower values in subjects who underwent RT (groups 1 and 5) than in the other groups. The difference was statistically significant between group 5 and groups 2, 3 and 4 (P<0.05), between group 1 and groups 3 and 4 (P<0.05), and between groups 2 and 4 (P=0.007)., Conclusions: Our data confirm that radiation therapy decreases GH variability, and that this effect is probably due to hypothalamic damage, as already reported by others. In irradiated patients, a single random sample should therefore be sufficient to evaluate spontaneous GH secretion.

Background: Vascular growth factors are important not only in angiogenesis but also for the maintenance of normal endothelial integrity and function. Elevated levels of vascular endothelial growth factor (VEGF), angiopoietin-2, hepatocyte growth factor (HGF), endostatin and angiogenin have been associated with endothelial dysfunction and atherosclerosis. Both acromegaly and growth hormone deficiency (GHD) are associated with endothelial dysfunction and changes in blood vessel morphology., Aim: To investigate the effect of GH status on the circulating levels of angiogenic factors., Design: We measured the levels of six endothelial growth modulators, four angiogenic growth factors and two inhibitors of angiogenesis in 35 untreated acromegalics, 36 untreated GH-deficient subjects and 101 normal control subjects. Fifteen GH-deficient subjects were also studied before and 1 year after treatment with GH., Results: Mean angiogenin concentrations were increased in acromegaly and decreased in GH-deficient subjects compared to control subjects. Endostatin levels showed a similar pattern although the elevated levels in acromegalic subjects did not achieve statistical significance. Angiogenin and endostatin levels both correlated significantly with IGF-I levels (R = 0.61, P < 0.001 and R = 0.22, P < 0.01, respectively). The relationship between angiogenin and IGF-I levels remained significant even after correction for gender, age, body mass index (BMI) and insulin resistance. There were no significant differences in the levels of HGF, VEGF, VEGF-C or angiopoietin-2 between the three groups. VEGF-D levels were elevated in both acromegalic and GH-deficient male subjects. A similar pattern was apparent in female subjects. After GH treatment, a significant reduction in VEGF-D levels and a significant rise in endostatin levels were observed in GH-deficient subjects. A nonsignificant increase in angiogenin levels was also observed., Conclusion: These data indicate that significant perturbations in the levels of vascular growth modulators are present in both acromegaly and GHD. While changes in endostatin and angiogenin levels appear to correlate with IGF-I levels, VEGF-D levels show similar perturbations in both acromegaly and GHD. Further studies are required to determine the relationship of the perturbations to endothelial dysfunction in these conditions.

Objective: Data on bone mineral density (BMD) in acromegaly are conflicting as most previous studies collectively evaluated eugonadal and hypogonadal patients of both sexes, with or without active disease. We have evaluated BMD in 152 acromegalic patients of both sexes with varying disease activity and gonadal status., Design: Cross-sectional, retrospective., Patients: We studied 152 acromegalic patients (99 women aged 26-72 years, and 53 men aged 21-75 years), 107 with active and 45 with controlled disease. Eighty-five patients had normal gonadal status and 67 were hypogonadal., Measurements: In all patients we measured serum GH levels by immunoenzimometric assay, and serum IGF-I levels by radioimmunoassay. BMD was assessed at spine L2-L4 (LS) and at femoral neck (FN) by dual energy X-ray absorptiometry; results are expressed as Z-values., Results: We evaluated the effect of GH excess on bone at different sites in relation to gonadal status, disease activity and gender. At LS, in respect to the reference population, BMD (mean +/- SE) values were higher in eugonadal patients (active: 0.71 +/- 0.29, P < 0.02; controlled: 0.65 +/- 0.28, P < 0.05) and lower in hypogonadal ones (active: -0.64 +/- 0.35, 0.1 < P < 0.05; controlled: -1.05 +/- 0.36, P < 0.01), regardless of disease activity. On the contrary, at FN, BMD was higher than in the reference population, both in eugonadal (1.01 +/- 0.22, P < 0.001) and hypogonadal (0.63 +/- 0.17, P < 0.001) patients only in subjects with active disease, but not in those in which the disease was controlled (eugonadal: 0.31 +/- 0.23, P = ns; hypogonadal 0.04 +/- 0.28, P = ns). We did not observe any difference in BMD values according to gender both at LS (males vs. females -0.02 +/- 0.30 vs. 0.01 +/- 0.24, P = ns) or at FN (0.77 +/- 0.19 vs. 0.63 +/- 0.15, P = ns)., Conclusions: The anabolic effect of GH excess on bone in acromegalic patients is: (i) gender-independent; (ii) evident at the spine only in eugonadal regardless of disease activity; (iii) evident at femoral neck only in the presence of active disease regardless of gonadal status.

Objective: Excess GH secretion, as occurs in acromegaly, is associated with abnormalities in bone turnover markers and bone mineral density (BMD). GH administration in GH deficient patients causes an increase in bone turnover. IGF-I mediates many of the metabolic actions of GH, although GH may have direct effects upon bone. In patients with acromegaly who are treated with a GH receptor antagonist, selective blockade of the GH receptor results in a decrease in circulating IGF-I levels in the majority of cases. We hypothesized that, in acromegaly, antagonism of GH receptors would result in a decrease in serum markers of bone turnover, including serum procollagen I carboxy-terminal propeptide (PICP), osteocalcin and N-telopeptide (NTx)., Design and Subjects: Twenty-seven patients with acromegaly were enrolled as part of a multicentre 12-week trial of a GH receptor antagonist and were randomized to placebo (n = 7) or 10, 15 or 20 mg of pegvisomant (n = 20)., Measurements: Serum markers of bone turnover were determined at baseline and 12 weeks., Results: Baseline bone turnover markers were above the upper limit of normal in 23%, 19% and 32% of subjects for osteocalcin, PICP and NTx, respectively. During the 12-week placebo-controlled period, there were significant decreases in serum markers of bone formation, osteocalcin (-2.2 +/- 0.44 vs. placebo +0.01 +/- 0.39 nmol/l, P = 0.009) and PICP (-23.6 +/- 9.6 vs. placebo +18.1 +/- 12.8 micro g/l, P = 0.022) and a serum marker of bone resorption, NTx (-4.4 +/- 1.4, placebo +1.0 +/- 0.3 nm, P = 0.024)., Conclusions: Using a specific GH receptor antagonist, we found that normalization of IGF-I is associated with rapid reductions in markers of both bone formation and resorption, and that these processes remain coupled. These data confirm the highly significant effects of GH and IGF-I in modulating bone turnover. The independent contributions of GH and IGF-I to these effects and the long-term effects on BMD in this population remain to be determined.

Objective: To determine whether acromegalic patients have increased thyroidal vascularity and blood flow on colour flow Doppler sonography (CFDS)., Design: Prospective study of consecutive patients., Patients: Twenty-four acromegalic patients (11 men, 13 women, age 49 +/- 9 years); 38 patients with nontoxic goitre (NTG; 12 men, 26 women, age 50 +/- 7 years); 36 normal subjects (controls; 16 men, 20 women, age 46 +/- 9 years). Among acromegalic patients, 10 had active, untreated disease (Acro-U), seven were in remission after surgery (Acro-R), seven had active disease under treatment with somatostatin analogues (SMSa) (Acro-SA) (Sandostatin LAR, 20 mg, every 28 days)., Measurements: CFDS pattern and intrathyroidal peak systolic velocity (PSV) were determined by a colour Doppler system with a 7.5-MHz linear transducer. PSV measurements were made at the level of the intrathyroidal arteries (normal values 3.8 +/- 1.0 cm/s). Thyroid volume was calculated by the ellipsoidal model. Assays included measurements of serum GH, IGF-I, free T4, free T3, TSH, antithyroglobulin (anti-Tg) and antithyroperoxidase (anti-TPO) antibodies, TSH-receptor antibodies (TRAb)., Results: Serum GH (+/- SD) and IGF-I (+/- SD) levels were: Acro-U: GH 26 +/- 31 microg/l, IGF-I 783 +/- 299 microg/l; Acro-SA: GH 15 +/- 25 microg/l, IGF-I 366 +/- 212 microg/l; Acro-R: GH 1.3 +/- 1.0 microg/l, IGF-I 241 +/- 99 microg/l. To convert values for serum GH to mU/l multiply by 2.6; to convert values for serum IGF-I to nmol/l multiply by 0.13075. All controls had CFDS pattern 0 (absent vascularity or minimal spots); among NTG patients, 36 had pattern 0 and two had pattern I (parenchymal blood flow with patchy uneven distribution). Five patients with acromegaly had pattern 0, 12 had pattern I and seven pattern II (mild increase of colour flow Doppler signal with patchy distribution). Among the five acromegalic patients with pattern 0, three were Acro-R and two were Acro-SA. Among patients with pattern I, six were Acro-U, two were Acro-SA and four were Acro-R. Among patients with pattern II, four were Acro-U and three Acro-SA; two patients of the latter group had elevated serum IGF-I under SMSa treatment. Intrathyroidal PSV was 3.8 +/- 1.0 cm/s in controls, 4.0 +/- 1.1 cm/s in NTG, 7.4 +/- 0.8 cm/s in Acro-U, 4.9 +/- 1.3 cm/s in Acro-SA treatment and 4.5 +/- 1.0 in Acro-R. (Acro-U vs. Acro-SA, P = 0.0003; vs. Acro-R, Controls, or NTG, P < 0.0001). PSV values in Acro-SA were higher than those observed in NTG or controls (P = 0.05, P = 0.01, respectively); PSV values in Acro-R did not differ from those in NTG or controls. Intrathyroidal PSV values were correlated with serum IGF-I (r = 0.73, P < 0.0001) and, although less strongly, GH levels (r = 0.54, P = 0.01). Goitre was present in 19 of 24 patients; diffuse in three and nodular in 16. Thyroid function was normal in all subgroups of acromegalic patients. Anti-Tg, anti-TPO antibodies and TRAb were negative in all subjects., Conclusions: Patients with active acromegaly have increased intrathyroidal blood flow (colour flow Doppler sonography pattern II, increased peak systolic velocity values); this was not observed in the large majority of patients under treatment with somatostatin analogues and in any patient in remission. Accordingly, colour flow Doppler sonography and peak systolic velocity measurements may be considered an additional useful peripheral parameter for rapid assessment of the activity of acromegaly.

Objective: Fatigue is a prominent symptom among patients with GH excess and acromegaly. Identifying the physiological basis of such complaints and obtaining objective measures to quantify their severity remains an ongoing challenge. We investigated whether submaximal measures of aerobic performance can be used to assess GH excess-associated fatigue objectively., Design and Patients: To investigate this possibility we examined the relation between physical function and physical capacity in 12 patients with active acromegaly and persistent fatigue before and after 3 and 6 months of treatment with the long-acting somatostatin analogue octreotide (LAR(R))., Measurements: Heart rate (HR) and rating of perceived exertion (RPE using Borg's 10-point scale) were measured during a 160-metre self-paced walk test (SPW). Maximum oxygen uptake (VO2max) and ventilation threshold (VeT: a measure of work rate when breathlessness develops) were measured during a progressive treadmill test to fatigue or symptom-limited maximum. The Profile Of Mood States questionnaire (POMS) was used to quantify subjective feelings of fatigue and vigour. Morning fasting levels of GH and IGF-I were measured using immunoassay of serum samples., Results: SPW speed at a fast pace of 1.69 +/- 0.18 m/s was achieved with higher than normal HR (112 +/- 15/min; normal = 102) and RPE (2.4 +/- 1.2). Similar to GH-deficient adults, VO2max (22.6 +/- 6.4 ml.kg-1.min-1; normal approximately 30 ml.kg-1.min-1) and VeT (13.1 +/- 2.9 ml.kg-1.min-1; predicted normal approximately 16 ml.kg-1(min-1) were low. However, VeT occurred at a normal fraction of VO2max (VeT/VO2max = 0.58). VeT was significantly increased and plasma IGF-I levels reduced following 3 and 6 months of octreotide LAR(R) treatment. Reduction in circulating IGF-I levels was correlated with improvement in reported vigour (r = 0.85) and VeT (r = 0.65) (P < 0.05)., Conclusions: Our findings demonstrate impairment in physical function and physical capacity consistent with the perception of increased fatigue among acromegalic patients. These objective measures of compromised physical function are similar to the changes that we have reported previously in adults with GH deficiency. Taken together, these data suggest that a narrow window for GH/IGF-I levels is required to maintain optimal physical function.

Objective: Transsphenoidal surgery results in biochemical remission of acromegaly in 45-80% of patients; however, few studies have addressed the impact of transsphenoidal surgery on cardiovascular function in acromegalic patients. The aim of this prospective study was to investigate the effects of postoperative GH/IGF-I normalization on echocardiographic parameters and blood pressure (BP) in a series of patients with active acromegaly., Design: An open prospective study., Patients: Thirty newly diagnosed acromegalic patients undergoing transsphenoidal surgery., Measurements: Doppler echocardiography and 24-h ambulatory blood pressure monitoring were performed before and 6 months after transsphenoidal surgery., Results: Fifteen patients were considered to be well controlled postoperatively (group A), as defined by normal age-corrected IGF-I levels and glucose-suppressed GH levels less than 2 mU/l, the remaining 15 patients being considered as poorly controlled (group B). In group A, a postoperative decrease of left ventricular mass index was observed (104.4 +/- 6.6 vs. 127.1 +/- 7.7 g/m2; P < 0.001), associated with an improvement of some indices of diastolic function, such as an increase of the early/late transmitral peak flow velocity (P < 0.05) and a decrease of isovolumic relaxation time (P < 0.01). No significant change was observed in group B. A significant decrease of 24-h systolic BP was also observed in group A (P < 0.05) and five of six patients normalized their BP circadian rythm. In contrast, a nonsignificant increase in BP values, with a persistent blunted BP profile where present, was observed in group B., Conclusions: We conclude that successful transsphenoidal surgery is able to induce a significant improvement in some cardiac parameters and a slight reduction in systolic blood pressure in acromegalic patients.

Objective: Patients with acromegaly have an increased risk of ventricular dysrhythmias and sudden death. Late potentials in a signal-averaged electrocardiogram (SAECG), a predictor of ventricular dysrhythmias, are frequently seen in patients after previous myocardial infarction, but little is known about the prevalence of late potentials in acromegaly. The aim of our study was to investigate the prevalence of late potentials in patients with acromegaly and their relation to the activity of the disease and to myocardial hypertrophy., Patients: The study included 48 patients with acromegaly [27 males, 21 females, mean age 52.3 +/- 14.2 years, 16 active disease, 32 cured or 'well controlled', under treatment with sandostatin analogues (12/32)] and 38 healthy volunteers as a control group., Results: Late potentials were detected in 9/16 (56%) patients with active acromegaly vs. 2/32 (6%) with cured/well controlled acromegaly (P = 0.001), defined as normal age-related IGF-1 levels and GH levels suppressible below 1 microg/l after an oral glucose load (75 g). Late potentials were not related to muscle mass index (127 +/- 35 active vs. 123 +/- 34 g/m2 cured/well controlled). The association of disease activity with the detection of late potentials was independent of age, gender, duration of the disease and body mass index. In comparison to the control group, the prevalence of late potentials was significantly higher in patients with acromegaly (23%) than in the control group (0%; P < 0.001)., Conclusions: Late potentials in the SAECG are frequently seen in active acromegaly and may represent an early and sensitive parameter to detect myocardial injury in acromegaly.

Impaired cardiovascular function has recently been demonstrated to potentially reduce life expectancy both in GH deficiency and excess. Experimental and clinical studies have supported the evidence that GH and IGF-I are implicated in cardiac development. In most patients with acromegaly a specific cardiomyopathy, characterized by myocardial hypertrophy with interstitial fibrosis, lympho-mononuclear infiltration and areas of monocyte necrosis, results in biventricular concentric hypertrophy. In contrast, patients with childhood or adulthood-onset GH deficiency (GHD) may suffer both from structural cardiac abnormalities, such as narrowing of cardiac walls, and functional impairment, that combine to reduce diastolic filling and impair left ventricular response to peak exercise. In addition, GHD patients may have an increase in vascular intima-media thickness and a higher occurrence of atheromatous plaques, that can further aggravate the haemodynamic conditions and contribute to increased cardiovascular and cerebrovascular risk. However, several lines of evidence have suggested that the cardiovascular abnormalities can be partially reversed by suppressing GH and IGF-I levels in acromegaly or after GH replacement therapy in GHD patients. Recently, much attention has been focussed on the ability of GH to increase cardiac mass suggesting its possible use in the treatment of chronic nonendocrine heart failure. In fact, GH administration can induce an improvement in haemodynamic and clinical status in some patients. Although these data need to be confirmed in more extensive studies, such promising results seem to open new perspectives for GH treatment in humans.

Background and Objectives: Hypertension is found in one-third of acromegalic patients. An heterogenous distribution of cardiac output has been recently demonstrated in acromegalic patients with an increased blood flow at the level of the upper limb, suggesting that acromegalic patients may have some degree of endothelial dysfunction. Elsewhere, studies involving hypopituitary GH-deficient adults have shown that GH and/or IGF-I may have direct effect on endothelial function., Subjects and Methods: We thus compared cutaneous vasoreactivity responses in 10 normotensive patients with active acromegaly (A) (six women and four men) aged 25-59 (mean, 43.2 years), whose basal GH and IGF-I levels ranged from 7.4 to 158 mU/l and from 401 to 1690 microg/l, respectively, and in 10 normal age- and sex-matched controls (NC) by means of Laser Doppler flowmetry at the levels of the palm and the dorsum of the right hand. Circulatory skin velocities were studied basally and after increasing skin temperature to 44 degrees C (in order to study direct nonspecific vasodilatation response which is independent of endothelial or autonomous nervous system and reflects normal vascular muscle function), after shear-stress (known to produce flow-dependent vasodilatation, mediated by nitric oxyde (NO) originating from endothelial cells) and after cold-stress applied on the opposite hand (known to produce vaso-constriction mediated by the sympathetic nervous system)., Results: The warm test induced a significant (P<0.001) and similar increase in both dorsal and palmar skin perfusion in A (mean +/- SD) (240+/-96 and 238+/-134%, respectively) and NC (232+/-137 and 233+/-73, respectively). Ischaemia release induced a significant increase in both dorsal and palmar skin blood flows in the two groups (P<0.001), but reactivities in acromegalic patients were about one half of those measured in controls (22.9+/-16.2% (A) vs. 46.9 25% (NC), 2P<0.02, at the level of the dorsum; and 45.0+/-43.6% (A) vs. 104.7+/-40.1 (NC), 2P<0.01, at the level of the palm). Cold pressor test resulted in significant decreases in both cutaneous flows (P<0.01) in the two groups, with a larger vasoconstriction (that did not reach statistical significance) in acromegalic patients as compared with controls (P< 0.10)., Conclusion: Vascular smooth cell ability to produce skin vasodilatation is normal but endothelium-dependent vasodilatation appears to be impaired while sympathetic-mediated vasoconstrictive response might be increased in acromegaly. This endothelial dysfunction may contribute to hypertension and represent a risk factor for cardiovascular complications in acromegaly.

Background: A number of surgical series have been reported on the treatment of acromegaly and their results vary widely. The acceptable definition of remission has changed in recent years and it is known, though in a small series, that growth hormone levels of > 5 mU/l are still associated with an increased mortality from the condition. We have analysed data at this centre and examined the outcome of transphenoidal surgery for acromegaly, compared our results with recently published series from other centres and also assessed factors which might effect outcome including whether there is any demonstrable effect of the experience of the surgeon on outcome., Patients and Methods: We have analysed data from all of our 139 patients in whom follow up data are available who have undergone initial transphenoidal surgery for acromegaly by one surgeon at this centre, between 1974 and 1995. Follow up was for a median of 5 years (range 1 month to 17 years)., Results: 67% of patients achieved the criterion for remission (mean GH < 5 mU/l). Success was related to tumour size and preoperative growth hormone values. Thus 91% of patients with microadenomas were in remission postoperatively compared to 46% of patients with macroadenomas. Analysis of the results according to the year of operation showed an improvement in success rates with time. More than 15 years ago, the success rate according to the growth hormone criteria set was 48% and the failure rate 52%. In contrast in the last 5 years analysed, the overall success rate was 74% with a failure rate of 26% (P < 0.04). The success rate for microadenomas was 50% initially, then remained 100%. The case mix was analysed and no change was found. We have also demonstrated an improvement in pituitary function (including normalization of preoperative elevated prolactin) with time so that pre 1981 16% of patients' pituitary function improved perioperatively but 10 years later this figure had risen to 34% (P < 0.03). There was no change over time in the development of pituitary hypofunction, complication rate or recurrence rate., Conclusion: Surgical treatment is a safe and effective treatment for acromegaly and remains the first choice of treatment for most acromegalic patients. The results of this centre compare favourably with series from other centres. We have demonstrated improved results, both in terms of post operative growth hormone values and pituitary function tests with time and increasing neurosurgical experience. We conclude that outcome for the surgical treatment for acromegaly is best achieved with one surgeon specialising in pituitary surgery. Improved operative outcome thus achieved has major cost implications and avoids the necessity for consideration of postoperative radiotherapy and the use of expensive growth hormone suppressing drugs in the postoperative period.

Background and Aims: One-third of acromegalic patients have hypertension. Acromegaly is also associated with intrinsic cardiac abnormalities known collectively as a hyperkinetic heart syndrome, which is characterized by an increased cardiac index and decreased systemic vascular resistance. As a result, blood flow should be increased in the regional vascular beds of acromegalic patients. The aim of the study was to measure, using direct methods, blood flow and vascular resistance at the level of the brachial artery in acromegalic patients with a confirmed hyperkinetic heart syndrome., Patients and Controls: Twelve patients with active acromegaly (five females, seven males; mean (+/- SD) age, 43 +/- 10 years) were studied. Twelve age- and sex-matched normal subjects served as controls., Methods: Right heart catheterization was used to measure the cardiac index and stroke volume and to calculate systemic vascular resistance in the acromegalic patients. Brachial haemodynamics were evaluated with a two-dimensional pulsed Doppler system (double transducer probe and range-gated time system of reception). The mean diameter of the brachial artery and mean blood velocity were measured and used to calculate mean blood flow. Vascular resistance was calculated in the brachial artery as the mean arterial pressure/blood flow ratio., Results: Age, body weight, height, body surface area and heart rate were similar in the acromegalic patients and controls, while mean arterial pressure was higher in patients. The cardiac index and stroke volume were increased in the acromegalic patients, at 4.08 +/- 0.47 (mean +/- SD) l/min/m2 body surface area and 116.7 +/- 19.4 ml, respectively, while systemic vascular resistance was low (12.5 +/- 2.1 U). Brachial artery diameter was similar in the patients and controls. Brachial artery mean blood velocity (P < 0.01) and mean blood flow (P < 0.05) were lower in the patients than in the controls (3.35 +/- 1.26 vs. 5.12 +/- 1.74 cm/s, and 16.4 +/- 9.4 vs. 25.6 +/- 11.6 ml/min/m2, respectively). The higher mean arterial pressure and lower mean blood flow resulted in higher forearm vascular resistance in the patients than in the controls (132 +/- 61 vs. 83.8 +/- 47 mmHg/ml/s/m2, respectively, P < 0.01)., Conclusion: While cardiac output is increased and systemic vascular resistance is decreased in active acromegaly, direct measurement of brachial artery haemodynamics showed lower regional blood flow and increased local resistance relative to healthy controls. These results suggest a heterogeneous distribution of cardiac output in acromegaly.

Objective: To assess the outpatient investigations, overnight urinary growth hormone (uGH) excretion, random serum GH and insulin like growth factor 1 (IGF-1), and GH indices from the oral glucose tolerance test (OGTT) (fasting, nadir and mean GH), as measures of mean GH secretion in treated acromegaly, in comparison with a GH day series, which served as a gold standard., Design: Prospective cross-sectional study, with patients admitted to a metabolic ward for the following investigations: random GH, IGF-1, 6 point GH day series (day 1), 9 h timed overnight uGH excretion, OGTT with GH response (day 2). Agreements between the mean GH during the day series and the other outcome measures, and the diagnostic performance of the latter, for the presence or absence of active acromegaly (mean GH during day series > or = 5 or < 5 mU/l, respectively) were determined., Patients: 26 patients with treated acromegaly (11 with inactive acromegaly off drug therapy)., Measurements: Serum GH and uGH were measured by immunoradiometric assays and IGF-1 by radioimmunoassay., Results: Agreements with the mean GH during the day series were perfect for the nadir GH during the OGTT with a 2 mU/l cutoff (Cohen's kappa (kappa) = 1, P < 0.00001), almost perfect for the fasting and mean GH throughout the OGTT (both kappa = 0.92, P < 0.0001) and random GH (kappa = 0.85, P < 0.0001), and substantial for the nadir GH with a 5 mU/l cutoff (kappa = 0.77, P < 0.0001), IGF-1 (kappa = 0.62, P < 0.001) and overnight uGH excretion (kappa = 0.61, P = 0.002). Nadir GH with a 2 mU/l cutoff was completely accurate for diagnosing the presence or absence of active acromegaly (positive and negative predictive values (% +/- standard error percentage) 100 +/- 8% and 100 +/- 10%). None of the outpatient tests used alone was an adequate diagnostic test (positive and negative predictive values: overnight uGH excretion -86 +/- 10% and 75 +/- 13%; random GH -100 +/- 11% and 85 +/- 11%; IGF-1 -92 +/- 10% and 71 +/- 13%) and so combinations of tests were assessed. The best was overnight uGH excretion plus random GH (positive and negative predictive values 88 +/- 9% and 100 +/- 12%). Using all three outpatient investigations, the positive predictive value of three raised results was 100 +/- 13%., Conclusions: In treated acromegaly, residual GH secretion can be reliably assessed with the OGTT, using standard diagnostic criteria. It can also be assessed on an outpatient basis with overnight uGH excretion and random GH, as direct measures, and IGF-1. If these are all normal, active acromegaly is excluded. Three raised results denote active acromegaly, and one or two raised results would need further investigation with a GH day series.

Objective: The interpretation of echocardiographic abnormalities in acromegalic patients is complicated by non-specific age-related diseases, many of which are commoner in acromegaly. We have therefore investigated the cause-effect relationship between GH/IGF-I hypersecretion and precocious cardiovascular abnormalities in a series of young acromegalic patients., Design: An open prospective study., Patients: 20 acromegalic patients aged under 30 years, with normal blood pressure and glucose tolerance, and 20 age-matched control subjects., Measurements: Cardiac morphological parameters and indices of systolic and diastolic function at rest were studied by Doppler echocardiography., Results: Left ventricular mass (LVM) and LVM index (LVMi) were higher in acromegalics than in control subjects (215.0 +/- 15.4 g vs 140.8 +/- 8.5 g, P = 0.0002 and 109.8 +/- 5.9 g/m2 vs 82.1 +/- 3.7 g/m2, P = 0.0008, respectively), reaching values of left ventricular hypertrophy in 4 patients (20%). Both ejection fraction and fractional shortening were normal (66.4 +/- 2.1% vs 62.2 +/- 1.9% and 37.5 +/- 1.5% vs 35.8 +/- 1.3%, respectively), indicating normal left ventricular systolic function. Abnormalities of left and right diastolic ventricular filling were found, which consisted of an increased isovolumic relaxation time (99.2 +/- 2.7 ms vs 89.0 +/- 2.7 ms, P = 0.01) and impaired mitral and tricuspidal flow velocity curves., Conclusions: An increase in cardiac mass and subclinical biventricular diastolic dysfunction were observed in young acromegalic patients. These findings argue for a direct cause-effect relationship between GH/IGF-I hypersecretion and myocardial abnormalities, and indicate that careful cardiological evaluation is mandatory in all acromegalics, whatever their age.

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

Objective: Previous studies of surgical treatment for acromegaly have used varied criteria for 'cure', but elevated GH levels are considered to be associated with continuing disease activity. We wished to analyse the results of transsphenoidal pituitary surgery for acromegaly and assess the longer-term outcome for patients not offered further treatment when post-operative levels of GH < 5 mU/l were achieved., Design: We studied a retrospective group of patients who underwent transsphenoidal surgery for acromegaly at St Bartholomew's Hospital between 1985 and 1993., Patients: One hundred consecutive patients (53 male, mean age 46 years, range 18-68 years) undergoing transsphenoidal surgery for acromegaly were assessed. The patients were followed for a mean of 3.8 years (range 0.5-8 years) after operation., Measurements: GH levels are represented as a mean value from a four-point day curve taken at 0830, 1300, 1700 and 1900 h. ACTH reserve was assessed basally and, if this was normal, with the insulin tolerance or glucagon tests. TSH, T4, PRL, LH, FSH, testosterone or oestradiol and plasma and urine osmolality were also measured., Results: Post-operatively, 42% of patients achieved a mean GH level of < 5 mU/l. The success of surgery was related to the preoperative GH level; 65% of the patients with preoperative GH levels < 20 mU/l but only 18% of the patients with GH levels > 100 mU/l achieved post-operative GH values < 5 mU/l. In addition, tumour size influenced the outcome of surgery with 61% of patients with a microadenoma but only 23% of patients with a macroadenoma achieving post-operative GH levels of < 5 mU/l. Of the 42 patients considered in remission post-operatively (mean GH < 5 mU/l), 32 were available for long-term follow-up and were not offered any further treatment: only one of these has shown evidence of mild biochemical recurrence after a mean follow-up of 3.8 years (range 0.5-8). There were no peri-operative deaths. Two patients required surgical repair for CSF leaks and there were eight documented cases of meningitis. Permanent diabetes insipidus was noted in eight patients post-operatively. New anterior pituitary deficiency occurred in 21% of patients following surgery; 73% had unaltered pituitary function and in 6% recovery of partial hypopituitarism was noted., Conclusions: The stated outcome of surgery depends on the criteria adopted. Safe GH levels (mean levels < 5 mU/l) can be achieved in 42% of an unselected series of patients with acromegaly and if the tumour is a microadenoma this figure rises to 61%. Based on the current evidence it is safe not to offer further treatment to those patients in whom post-operative GH < 5 mU/l are achieved.

Objective: In active acromegaly body composition is characteristically altered by an increase in lean body mass and a corresponding reduction in fat mass. These changes are induced by an excessive secretion of GH and insulin-like growth factor I (IGF-I). Growth hormone is an anabolic hormone and leads to stimulation of protein synthesis and an increased lipolysis in adipose tissue. Treatment with the somatostatin analogue, octreotide, has been shown to reduce GH levels causing reduced hormonal effects on target tissues. We have studied changes in body composition during short-term reduction in GH level by octreotide in active acromegaly., Design: Octreotide was compared to placebo in a double-blind, cross-over trial. Dual-energy X-ray absorptiometry scanning was employed to calculate body composition. Relations between body composition parameters and clinical signs of acromegaly (finger circumference and foot volume) were studied., Patients: Twelve patients with active acromegaly, confirmed by lack of GH suppression during oral glucose loading, were included. All had pituitary adenomas diagnosed by computed tomography., Measurements: Serum GH and IGF-I. Lean body mass, fat mass and total weight, foot volume and finger circumference., Results: Four weeks of octreotide treatment caused a 75% decrease in GH levels (n = 10), a reduction in IGF-I from 476 +/- 51.9 (mean +/- SEM) to 233 micrograms/l +/- 46.3 (P < 0.005) and a corresponding decrease in both body weight (2.51 kg +/- 0.41) (P < 0.005) and lean body mass (2.44 kg +/- 0.48) (P < 0.005). No significant changes in fat mass were observed. These findings were paralleled by significant reductions in foot volume (44.50 ml +/- 17) (P < 0.05) and finger circumference (1.3 mm +/- 0.3) (P < 0.05)., Conclusions: Short-term octreotide therapy reduces growth hormone levels leading to a significant reduction in lean body mass as assessed by dual-energy X-ray absorptiometry. Alterations in lean body mass were positively correlated with reductions in foot volume. Thus, simple clinical tests may be valuable in judging the effects of treatment in active acromegaly.

Objective: We wished, by means of power spectrum EEG analysis, to examine REM and delta sleep energy in adults with high and normal plasma growth hormone (GH) concentration., Design: After a 3-day regular sleep/wake schedule, all-night polysomnographic recordings were performed on two consecutive nights before as well as one year after treatment for acromegaly by adenomectomy. The sleep energy was calculated by power spectrum analysis., Patients: We studied nine patients aged 24-45 years with untreated active acromegaly. The same patients were reexamined one year after adenomectomy when plasma GH concentrations were normal., Measurements: The acromegaly was verified biochemically by measuring basal plasma GH concentration and plasma GH during hyperglycaemia as well as insulin-like growth factor. Cerebral computer tomography (CT) and magnetic resonance (MR) scans revealed an intrasellar adenoma in all patients. The resulting sleep records obtained before and after adenomectomy were subjected to power spectrum analysis and a manually blinded sleep scoring., Results: The power spectrum analysis showed that when circulating GH was elevated the energy in the REM sleep per minute was significantly higher compared to the REM energy/min after surgery when GH concentration had normalized. A similar relation was found for delta sleep (stage 3 + 4, deep sleep) where the energy per minute was higher before treatment than after., Conclusions: The study demonstrates that plasma GH concentration was correlated to sleep energy. During high GH concentration the REM and delta sleep energy were high and normalization of plasma GH was followed by normalization of REM and delta sleep energy per time unit.

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

We have investigated the relationship between the plasma PRL concentrations of 98 untreated acromegalic patients and the GH levels during basal and dynamic conditions. Hyperprolactinaemia was present in 27 patients. In patients with marked hyperprolactinaemia (PRL greater than 80 ng/ml or greater than 1600 mU/l), basal plasma PRL and the TRH-induced response correlated with basal plasma GH (correlation coefficients of 0.9, P less than 0.001 and 0.74, P less than 0.02, respectively). The PRL response to TRH also correlated with GH response to TRH (r = 0.38, P less than 0.01). In contrast, in patients with moderately elevated PRL (20 to 80 ng/ml), and in those with normal plasma PRL (less than 20 ng/ml or less than 400 mU/l), no such correlations were found. Immunostaining for PRL was positive in 24 out of 25 adenomas of patients with hyperprolactinaemia, while no PRL was found in the tumour tissue of 10 normoprolactinaemic patients. In conclusion, our data suggest the existence of two populations of acromegalic patients with hyperprolactinaemia, one group with correlations between GH and PRL secretion, and the other without.

Total body water (TBW) and total potassium (TBK) were measured in patients participating in a follow-up investigation of all acromegalic patients seen between 1956 and 1984. The results were compared with population-based estimates of TBK and TBW calculated from height (BH), weight (BW) age and sex, using data from a large number of healthy subjects (n = 476). The findings were compared with values obtained at diagnosis and were also related to growth hormone (GH) and IGF-I/SmC concentrations at follow-up. BW at follow-up was unchanged compared to BW at diagnosis and was 9.7 and 10.0 kg higher in males and females, respectively, than in healthy subjects of the same BH (BWnorm). Growth hormone concentration at follow-up correlated directly with excess extracellular fluid volume (ECW%) (P less than 0.001) and inversely with the ratio observed/predicted body fat (BF%) (P less than 0.001) as well as with BW/BWnorm (P less than 0.05). On the other hand, GH concentration did not correlate with excess body cell mass (BCM%) estimated from TBK. IGF-I/SmC concentration correlated with GH concentration at follow-up (P less than 0.001) and with ECW% (P less than 0.01) but not with BCM% or BF%. In 39 patients, data on body composition were also available at diagnosis. Of these, three males had developed gonadal insufficiency and their BCM had decreased markedly. One patient had suffered from hemiplegia. Five patients had not received any treatment. In the remaining 30 treated patients, those with a post-treatment GH concentration below 5 mU/l were normalized with respect to ECW and BF. BCM, however, was unchanged. In contrast, patients with GH concentration greater than or equal to mU/l displayed unchanged body composition. Furthermore, BH decreased significantly in successfully treated patients.

In ninety-nine patients with pituitary adenomas, forty-six with acromegaly, the serum level of the glycoprotein hormone alpha subunit was elevated in eighteen cases. Thirteen of these were acromegalic and one had an FSH-producing tumour. Alpha levels varied little during the day, from one day to the next and over a 6 month period. In twenty-five patients with a variety of other hypothalamic-pituitary disorders examined, one patient with a craniopharyngioma had a mildly elevated alpha level. External pituitary irradiation was followed by an acute and often transient fall in alpha level in several of these patients. Of the fifty-four patients with pituitary adenomas who had received external irradiation before testing, only five had elevated alpha subunit levels compared with thirteen patients of the forty-five who had not been irradiated. This difference in incidence of elevated alpha level was statistically significant (P less than 0.025). We conclude that external irradiation may reduce alpha subunit level chronically in many patients with pituitary adenoma.

Human pancreatic growth hormone releasing factor 1-44 (hpGRF), 100 micrograms was administered as an i.v. bolus injection to eleven patients with acromegaly. The mean serum growth hormone (GH) levels rose (P less than 0.001) from 54 +/- 20 ng/ml to 215 +/- 126 ng/ml (+/- SEM) 20 min after the injection. Although the maximum response of GH levels was highly variable it correlated positively with the individual GH levels (P less than 0.01, Rs = +0.80). Thus the higher the GH levels, the greater the responsiveness to hpGRF. Administration of somatostatin (SRIF), 300 micrograms/h, lowered basal GH levels from 76 +/- 38 ng/ml to 13 +/- 5 ng/ml (P less than 0.01) after 1 h. hpGRF administration during concomitant SRIF infusion also led to highly variable growth hormone responses. The maximum GH responses again correlated positively with the GH level before hpGRF after 1 h of SRIF administration (P less than 0.05, Rs = +0.79). GH responses to hpGRF were completely blocked by SRIF in three out of four patients whose GH levels decreased to normal levels during SRIF infusion. Our data illustrate that the pituitary in acromegaly is normally responsive to both SRIF and hpGRF but at a higher setting of basal GH levels.

The oral administration of bromocriptine 5 mg 6-hourly to twelve patients with acromegaly for a mean period of 12 (range 3-27) months significantly reduced whole blood glucose, plasma insulin and plasma growth hormone (GH) concentrations during a 50 g oral glucose tolerance test (OGTT). After this period of treatment, bromocriptine was withdrawn for 48 h resulting in a significant rise in whole blood glucose, plasma insulin and plasma GH concentrations during a repeat OGTT. It is concluded that bromocriptine therapy improves glucose tolerance in acromegaly by suppressing GH secretion and consequently GH-mediated antagonism of insulin.

Human pancreatic growth hormone releasing factor (hpGRF1-44) was given intravenously as a 100 micrograms bolus to 20 patients with active acromegaly. The GH-responses were variable, ranging from an increase of 8 to 2813% from the basal level (mean +/- SE, 428 +/- 136%). Sixteen GRF-responders (delta% greater than or equal to 100%) were arbitrarily distinguished from four GRF non-responders, whose GH-levels increased less than 100% from basal level after GRF-administration. The outcome of the GRF-test did not correlate with the results of other dynamic tests of GH-secretion in acromegaly (oral glucose tolerance test, insulin hypoglycaemia, TRH-, LHRH-, CRF-stimulation). In 10 patients who had not been treated before, the GH-increments after GRF were higher than those in seven patients who had previously been subjected to transsphenoidal surgery, though they still had clinically and biochemically active acromegaly. Ten acromegalics, who were tested with GRF, were later treated surgically by the transsphenoidal route and were reevaluated with GRF-stimulation 2 months after surgery. Eight patients appeared clinically cured of whom four had complete normalization and four had significantly lower basal and conventionally stimulated GH-levels postoperatively. These patients also had normal postoperative GH-responses to GRF, which had been significantly higher before surgery compared with normal controls. It is concluded that the GRF-test in acromegaly does not help in establishing the diagnosis. The normalization of the GH-response to GRF after transsphenoidal surgery seems to represent additional evidence for normalization of GH-secretion, though the latter is not proven by the normal outcome of this test.

The serum TSH and prolactin responses to dopamine receptor blockade (domperidone 10 mg i.v.) were measured in eight acromegalic subjects and seven normal controls. The serum TSH response was exaggerated in acromegalics when compared to controls (sum of the increments 12.2 +/- 2.8 mU/l and 4.0 +/- 1.2 mU/l respectively P less than 0.05), whereas the serum prolactin response was blunted (sum of the increments 5029 +/- 1377 mU/l and 14 673 +/- 2889 mU/l respectively P less than 0.01). Dopamine receptor blockade did not significantly alter basal growth hormone levels in either group. To ascertain whether this response was merely a reflection of high circulating growth hormone levels six normal controls were pretreated for 24 h with either intramuscular growth hormone (three injections of 4 IU) or an equivalent volume of saline before the administration of domperidone (10 mg i.v.). The serum TSH and prolactin responses were not affected by prior growth hormone treatment. The opposite TSH and prolactin responses to dopamine blockade do not allow any firm conclusions to be made about the level of hypothalamic dopamine activity in acromegaly.

Eighteen acromegalic patients GH-responsive to TRH were reinvestigated following trans-sphenoidal surgery and radiotherapy. Basal serum GH decreased below 10 microgram/1 in thirteen cases; nine of them became GH-unresponsive to TRH 1 month after operation, and another one following conventional pituitary irradiation. Four of these ten patients also showed a normal GH response to L-Dopa after treatment, and five responded normally to insulin-induced hypoglycaemia; two patients had a normal GH secretory pattern after both these stimuli. No recurrences were observed over a follow-up period of 15-80 months among the ten patients who became GH-unresponsive to TRH following operation, while one of the three subjects still responsive to TRH in spite of normalized basal serum GH concentration relapsed 10 months after surgery. Three patients with normalized TRH test following operation were repeatedly reinvestigated over a 3-6 years period and always found unresponsive. The present study shows that the 'paradoxical' GH responses to TRH and L-Dopa frequently disappear after surgery, that complete normalization of GH secretory pattern may rarely be attained, and that the disappearance of GH response to TRH probably indicates satisfactory treatment of acromegaly. These data suggest that the 'paradoxical' GH responses frequently found in acromegaly are dependent on the adenoma per se and not on hypothalamic dysfunction.

The 24-h PRL and LH hormone profiles were analysed of 16 cured male acromegalic patients who had undergone selective transsphenoidal surgery 4-9 years previously. Eight of these patients also underwent pituitary irradiation. Blood samples were taken at 20-min intervals; the PRL and LH data were analysed with the cluster program. ARIMA modelling, cross-correlation techniques, Fourier analysis, and cosinor analysis. About 10-11 PRL and LH peaks were demonstrated for both non-irradiated and irradiated patients. The absolute heights of PRL pulses and the mean valley levels were significantly greater for irradiated patients than for non-irradiated patients, but the increment in amplitude did not differ. A significant diurnal rhythm for PRL was found for all non-irradiated patients but for only one irradiated patient. LH pulse area and amplitude were lower in the group of irradiated patients. The incremental responses of LH and PRL to GnRH and TRH, respectively, were lower in irradiated patients than in non-irradiated patients. During the night (0200-0800 h) the number of PRL pulses decreased in non-irradiated patients but not in irradiated patients. Pulse nadirs and amplitudes increased during the evening and night in non-irradiated patients but were constant in irradiated subjects. Bivariate modelling of the data for 14 patients revealed significant cross-correlations between LH and PRL pulses in nine subjects. This study demonstrates that the pulsatile secretion of PRL and LH in treated acromegalics is basically normal. Additional radiation therapy, however, may lead to damage of the hypothalamus, as reflected by the absence of a circadian PRL rhythm. A direct influence on the pituitary by radiation is indicated by the decreased magnitude of LH pulses and the diminished response of LH and PRL after injection of GnRH and TRH, respectively.

Nine acromegalic patients were treated by the somatostatin analogue SMS 201-995 octreotide (Sandostatin (octreotide), Sandoz, Basle, Switzerland] 250 micrograms/day in 4 divided s.c. injections (50 + 50 + 50 + 100 micrograms) for 1 month, 250 micrograms/24 has continuous s.c. infusions for another month and thereafter 200 micrograms three times daily as s.c. injections. Echocardiography was performed before the treatment, following 1 month of octreotide s.c. infusion/injection and after 6 and 12 months of octreotide treatment. No differences in serum growth hormone, heart rate, blood pressure, cardiac contractility or left ventricular wall mass or wall thickness were found between the infusion and the injection periods. As compared to the pretreatment levels serum growth hormone decreased by 62 and 66% respectively following 6 and 12 months octreotide treatment. The heart rate per minute (+/- SD) decreased from the pretreatment level of 75 +/- 12 to 63 +/- 13 (P less than 0.007) at month 12. The systolic and the diastolic blood pressure decreased from the pretreatment level of 121 +/- 8 and 79 +/- 5 mmHg respectively to 108 +/- 7 (P less than 0.0007) and 71 +/- 7 mmHg (P less than 0.0001) respectively at month 12.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of TRH (200 micrograms) on blood pressure, pulse rate, TSH and GH release was investigated in 10 acromegalics, four patients with non-GH secreting pituitary tumours, and seven normal controls. TRH produced a rapid-onset, short-lived pressor response in the acromegalic group (delta mean blood pressure 33 mmHg) compared to the two control groups (P less than 0.001). There was no response to the same volume of saline. The pressor response in the acromegalic group was not different in those who did or did not release GH. The pressor response to TRH was linearly related over the range 50-200 micrograms. Measurement of plasma noradrenaline and plasma renin activity during TRH testing in six acromegalics indicated that the pressor effect was neither mediated by adrenergic mechanisms, nor the renin-angiotensin system. Echocardiographic monitoring in five of these six patients showed that there was a significant increase in directly measured end systolic, end diastolic dimensions and heart rate (all P less than 0.02), and calculated stroke volume (P less than 0.001) and cardiac output (P less than 0.01) without changes in systemic vascular resistance. These data suggest that increase in preload, probably via venoconstriction, is the most likely factor producing the pressor response to TRH in acromegalics.

In 44 patients with acromegaly treated by transsphenoidal pituitary microsurgery, the relationship between changes in pre- and post-operative GH dynamics and postoperative fasting plasma GH levels was examined to clarify which is the optimal approach for evaluating postoperative removal of the tumour. TRH, LHRH and bromocriptine tests, which act directly on the pituitary somatotroph, and the oral glucose tolerance test (oGTT) and insulin tolerance test (ITT), which act via hypothalamus, were carried out pre- and post-operatively. Abnormal responses postoperatively were found in most patients with fasting postoperative plasma GH over 5 ng/ml. In 24 patients with postoperative fasting plasma GH level of 5 ng/ml or below, 7 of 17 (41%) showed abnormal responses in the TRH test, 2 of 5 (40%) in the LHRH test and 3 of 13 (23%) patients in the bromocriptine test. All patients with a fasting plasma GH level less than 10 ng/ml, except for those with panhypopituitarism, showed normal responses to ITT and the paradoxical increases with the oGTT were absent. These results indicate that abnormal responses caused by a direct action on adenoma cells do not necessarily disappear even when the fasting plasma GH level is below 5 ng/ml. Abnormal responses caused by indirect actions, through the hypothalamus, disappear when the level is less than 10 ng/ml.

Sixty patients with clinically and biochemically active acromegaly were treated by transsphenoidal surgery. All patients underwent a full assessment of pituitary function both preoperatively and postoperatively; these studies were repeated 6 months after surgery and every year, when possible. The mean follow-up period was 3.3 years (range 0.5-7 years). The GH level normalized in 62% of patients after surgery. A paradoxical reaction of GH to TRH was present in 35 patients before surgery and had normalized in 17 after surgery. Large tumours were associated with higher GH levels than smaller tumours. A prognostic factor in terms of normalization of both the GH level and an eventual paradoxical reaction to TRH or a glucose challenge was a low preoperative GH level. Three out of seven patients with either a positive postoperative TRH test but a normal GH level, or a slightly elevated GH level suffered a biochemical and clinical recurrence and two of them underwent reoperation. In contrast, when the TRH test had normalized (always in association with normal GH levels) no recurrence was found. The impact of surgery on the other pituitary functions was generally slight and the numbers of patients with preoperative and postoperative impairment were about equal. Postsurgical radiation therapy was administered to patients with an elevated GH level, a non-normalized TRH test irrespective of whether the GH level had normalized, or local invasion of the tumour. In 11 out of 17 patients with elevated GH levels after surgery, normalization was achieved by radiation therapy after a mean period of 2.7 years. The incidence of pituitary failure after irradiation appeared to be high; gonadal function in men and the GH reserve function were especially vulnerable. From this study we conclude that in many cases the adenoma can be removed effectively, without compromising the other pituitary functions. However, a substantial number of the patients require additional radiation therapy, leading to an inevitable loss of other pituitary functions.