Angela N Paisley

Treatment of acromegaly improves quality of life, measured by AcroQol

Background   AcroQol is a disease‐generated questionnaire, developed to assess quality of life (QOL) in patients with acromegaly. We have previously demonstrated severely impaired QOL in patients with acromegaly and the value of AcroQol in measuring QOL in a cross‐sectional study compared with the non‐disease‐specific generic tools ‘Psychological general wellbeing schedule’ (PGWBS) and EuroQol (EQ‐5D), and the disease‐specific signs and symptoms score (SSS).

Changes in arterial stiffness but not carotid intimal thickness in acromegaly

CONTEXT Acromegaly increases cardiovascular morbidity. We tested the hypothesis that increased arterial stiffness together with left ventricular hypertrophy may be a contributory factor. PATIENTS AND DESIGN Fifty-six patients (40 males, 54 ± 13 yr; 25 active disease, 31 in remission) and 46 healthy controls (30 males, 52 ± 13 yr) underwent measurements of aortic pulse wave velocity (PWV), carotid Doppler (IMT), echocardiography, and cardiovascular risk factors. RESULTS Mean serum IGF-I was 323 ± 286 ng/ml (sd score 1.8 ± 1.9) in all patients. Age, body mass index, diastolic blood pressure (BP), and lipid levels were similar comparing patients and controls. Systolic BP (130.8 ± 19.9 vs. 122 ± 14 mm Hg controls, P < 0.01) and PWV (11.7 ± 3.8 vs. 9.7 ± 2.8 m/sec, 95% confidence interval -3.4 to -0.7, P <0.01) were higher in patients than controls. Regression analysis revealed age, presence of acromegaly, systolic BP, and body mass index, inversely, as significantly and independently associated with PWV. No difference in carotid IMT was seen (0.8 ± 0.2 patients vs. 0.7 ± 0.2 mm controls, P = 0.5) or between active/controlled disease. In the subset of participants with echocardiography (n = 32), left ventricular mass was higher by a mean of 38.2 g (95% confidence interval -80.9 to +4.6, P = 0.08). CONCLUSION In summary, patients with acromegaly had independently and significantly increased aortic PWV as evidence of arterial stiffening but unaltered carotid IMT compared with controls, also influenced by age and systolic BP. Premature cardiovascular disease in patients with acromegaly is likely related to pressure-related arterial and left ventricular stiffening rather than atherosclerotic disease.

Withdrawal of somatostatin analogue therapy in patients with acromegaly is associated with an increased risk of acute biliary problems.

Background  The prevalence of gallstones (GS) is increased in acromegaly and further increased by somatostatin analogue (SA) therapy. The incidence is reported at 10–63%, but they are often asymptomatic and rarely require definitive management. Evidence suggests discontinuation of SA may precipitate acute biliary problems.

Early diagnosis of acromegaly: computers vs clinicians.

Background  Early diagnosis of a number of endocrine diseases is theoretically possible by the examination of facial photographs. One of these is acromegaly. If acromegaly were found, early in the course of the disease, morbidity would be lessened and cures more likely.

Small Vessel Remodeling and Impaired Endothelial-Dependent Dilatation in Subcutaneous Resistance Arteries from Patients with Acromegaly

CONTEXT Patients with acromegaly have increased morbidity and mortality, predominantly from cardiovascular disease. Hypertension and diabetes are more prevalent, and both cause small vessel remodeling and endothelial dysfunction. OBJECTIVE To understand the structure and function of small arteries in acromegaly, sc blood vessels from gluteal fat biopsies were harvested from 18 patients with active disease (AD; age, 56 +/- 15 yr; 14 males), 23 patients in remission (CD; age, 55 +/- 12 yr; 15 males), and 20 healthy controls (age, 55 +/- 11 yr; 10 males) and examined in vitro using pressure myography. DESIGN Contractile responses to cumulative noradrenaline concentrations were recorded and followed by dose-dependent dilator responses to acetylcholine. The acetylcholine protocol was repeated after incubation with a nitric oxide synthase inhibitor (N-nitro-L-arginine methyl ester) and cyclooxygenase inhibitor (indomethacin). After perfusion with Ca(2+)-free physiological saline solution, structural measurements were recorded at varying intraluminal pressures (3-180 mm Hg). RESULTS Wall thickness and wall:lumen ratio were increased in AD, reduced with treatment but remained greater in CD than controls. Wall cross-sectional area was increased in AD vs. controls (P < 0.001), decreased with treatment (AD vs. CD, P < 0.001), but remained higher than controls (CD vs. controls, P = 0.015). Growth index was increased in AD (20%) compared to controls (CD, 9%). Contractility was similar in all groups. Endothelial-dependent dysfunction was evident in AD compared with CD (P < 0.001) and controls (P < 0.01). Dilation did not change after N-nitro-L-arginine methyl ester but was impaired after indomethacin incubation. CONCLUSION Active acromegaly is associated with hypertrophic remodeling of the vascular wall and embarrassed endothelial function due to reduced nitric oxide and endothelium-derived hyperpolarizing factor bioavailability, both of which may contribute to the early mortality from cardiovascular disease.

Treatment of pituitary tumors: pegvisomant.

Pegvisomant is a pegylated analog of growth that functions as a growth hormone receptor antagonist. The drug is capable of normalizing serum IGF-I concentrations (the chief mediator of disease activity in acromegaly) in 97% of patients, and therapy is associated with significant improvements in the symptoms and signs of GH excess. Biochemical control may be achieved with pegvisomant in patients wholly or partially resistant to somatostatin analogs, and there are emerging data to suggest that the drug may be particularly suitable for patients with acromegaly and co-existent diabetes mellitus.

Pegvisomant: a novel pharmacotherapy for the treatment of acromegaly

Pegvisomant is a pegylated analogue of growth hormone (GH) that functions as a growth hormone receptor antagonist. Clinical trials of its use in acromegaly commenced in 1997; the drug was approved in the US in March 2003 and in Europe in November 2003. In the same year, it was made available on prescription in several European countries, with further launches due in 2004. Pegvisomant is capable of normalising serum insulin-like growth factor-I concentrations (the chief mediator of disease activity in acromegaly) in 97% of patients with active acromegaly, and therapy is associated with a significant improvement in the symptoms and signs of GH excess. Disease control is achievable with pegvisomant in patients who are wholly or partially resistant or do not tolerate somatostatin analogues; preliminary data suggest that the drug may be particularly suitable for patients with acromegaly and co-existent diabetes mellitus.

A Subnormal Peak Cortisol Response to Stimulation Testing Does Not Predict a Subnormal Cortisol Production Rate

INTRODUCTION The decision to commence lifelong glucocorticoid replacement therapy is often based on a cortisol stimulation test. We investigated the relationship between the peak cortisol response to insulin-induced hypoglycemia and daily cortisol production rate (CPR) to ascertain whether provocative tests are accurate in indicating the need to initiate lifelong glucocorticoid replacement. PATIENTS AND METHODS Ten patients (five male; mean age, 44 +/- 13 yr) with pituitary disease and with demonstrably suboptimal peak cortisol response (350-500 nmol/liter) to insulin-induced hypoglycemia, underwent CPR measurement by isotope dilution using gas chromatography-mass spectrometry and 24-h urinary free cortisol (UFC). RESULTS The median baseline and peak cortisol attained with hypoglycemia were 284 (164-323) and 473.5 (366-494) nmol/liter, respectively. A strong positive correlation was seen between peak stimulated cortisol and CPR (adjusted for body surface area) (r = 0.75; P = 0.02), and in all patients CPR [4.6 (2.9-15.1) mg/d x m(2)] was within the reference range (2.1-12 mg/d x m(2)) or elevated (one patient). A wide range was found for 24-h UFC [116.5 (20.5-265.9) nmol/liter] in this group of patients, and this parameter lacked significant correlation with either serum cortisol concentration or CPR. CONCLUSION This is the first study to demonstrate a significant correlation between CPR and peak cortisol values during hypoglycemic challenge. An inadequate cortisol response to hypoglycemia suggests the need for glucocorticoid cover at times of stress, but these data indicate that a suboptimal peak cortisol does not equate to a low CPR and should not be an automatic indication for lifelong glucocorticoid replacement therapy. UFC bears no relation to serum cortisol or CPR and is therefore unhelpful in assessment of such patients.

Recent developments in the therapy of acromegaly

Acromegaly, a condition due to growth hormone hypersecretion usually from a benign pituitary tumour, is associated with significant morbidity and mortality. Disease control leads to normalisation of life expectancy with a reduction in signs and symptoms. Treatment modalities include surgery, radiotherapy and medical management. Surgery is the primary treatment in most of the patients, with success rates of 61 – 91% reported for those with microadenomas who are operated on by a specialist pituitary surgeon; however, most patients have macroadenomas and, although benefiting from surgery, are not cured and require additional medical therapy. This review will focus on emerging concepts in the medical treatment of acromegaly.

The Challenges of Reliance on Insulin-Like Growth Factor I in Monitoring Disease Activity in Patients with Acromegaly

Serum insulin-like growth factor I (IGF-I) is an important marker of disease activity in patients with acromegaly, and epidemiological data indicate control of circulating IGF-I in patients with acromegaly restores life expectancy to normal. Improvements in the quality of, and access to, IGF-I assays has encouraged monitoring of acromegaly with IGF-I, although circulating growth hormone (GH) and IGF-I values provide different information, so ideally both should be monitored. However, the introduction of the GH receptor antagonist pegvisomant poses new challenges. Pegvisomant binds with high affinity to GH receptors, thereby blocking the action of GH at the tissue level and rendering the hormone biologically inactive. This leaves IGF-I as the principal marker of disease activity. It is conceptually possible to induce a state of functional GH deficiency (GHD) with pegvisomant with IGF-I values within the normal range. With the goal of minimizing the risk of over-treatment and GHD, we have provided preliminary guidance on the target range for IGF-I in patients receiving pegvisomant based on the gender- and decade-based percentile ranges for IGF-I of adult patients with untreated GHD enrolled in the Pfizer International Metabolic Database (KIMS).