Peter J Trainer

Long-term treatment of acromegaly with pegvisomant, a growth hormone receptor antagonist

BACKGROUND Pegvisomant is a new growth hormone receptor antagonist that improves symptoms and normalises insulin-like growth factor-1 (IGF-1) in a high proportion of patients with acromegaly treated for up to 12 weeks. We assessed the effects of pegvisomant in 160 patients with acromegaly treated for an average of 425 days. METHODS Treatment efficacy was assessed by measuring changes in tumour volume by magnetic resonance imaging, and serum growth hormone and IGF-1 concentrations in 152 patients who received pegvisomant by daily subcutaneous injection for up to 18 months. The safety analysis included 160 patients some of whom received weekly injections and are excluded from the efficacy analysis. FINDINGS Mean serum IGF-1 concentrations fell by at least 50%: 467 mg/L (SE 24), 526 mg/L (29), and 523 mg/L (40) in patients treated for 6, 12 and 18 months, respectively (p<0.001), whereas growth hormone increased by 12.5 mg/L (2.1), 12.5 mg/L (3.0), and 14.2 mg/L (5.7) (p<0.001). Of the patients treated for 12 months or more, 87 of 90 (97%) achieved a normal serum IGF-1 concentration. In patients withdrawn from pegvisomant (n=45), serum growth hormone concentrations were 8.0 mg/L (2.5) at baseline, rose to 15.2 mg/L (2.4) on drug, and fell back within 30 days of withdrawal to 8.3 mg/L (2.7). Antibodies to growth hormone were detected in 27 (16.9%) of patients, but no tachyphylaxis was seen. Serum insulin and glucose concentrations were significantly decreased (p<0.05). Two patients experienced progressive growth of their pituitary tumours, and two other patients had increased alanine and asparate aminotransferase concentrations requiring withdrawal from treatment. Mean pituitary tumour volume in 131 patients followed for a mean of 11.46 months (0.70) decreased by 0.033 cm(3) (0.057; p=0.353). INTERPRETATION Pegvisomant is an effective medical treatment for acromegaly.

A consensus on criteria for cure of acromegaly

OBJECTIVE The Acromegaly Consensus Group met in April 2009 to revisit the guidelines on criteria for cure as defined in 2000. PARTICIPANTS Participants included 74 neurosurgeons and endocrinologists with extensive experience of treating acromegaly. EVIDENCE/CONSENSUS PROCESS: Relevant assays, biochemical measures, clinical outcomes, and definition of disease control were discussed, based on the available published evidence, and the strength of consensus statements was rated. CONCLUSIONS Criteria to define active acromegaly and disease control were agreed, and several significant changes were made to the 2000 guidelines. Appropriate methods of measuring and achieving disease control were summarized.

Transsphenoidal resection in Cushing's disease: undetectable serum cortisol as the definition of successfuI treatment

OBJECTIVE We tested the hypothesis that in Cushings disease, ACTH secretion from the normal pituitary surrounding an ACTH‐secreting adenoma is inhibited and hence removal of the entire adenoma should result in an undetectable serum cortisol in the immediate post‐operative period.

A pharmacological guide to medicines which interfere with the biodistribution of radiolabelled meta-iodobenzylguanidine (MIBG)

Radiolabelled meta-iodobenzylguanidine (MIBG) is widely used in the diagnosis, follow-up and treatment of patients with tumours of neural crest origin. Some commonly prescribed and readily available over-the-counter medicines interfere with the uptake and biodistribution of this radiopharmaceutical. This may lead to poor concentration of radiolabelled MIBG within the target organs and tissues. The clinical implications are a potentially inaccurate assessment of tumour burden during diagnostic studies and a suboptimal radiation dose when MIBG is employed for targetted radiotherapy. In order to avoid false negative results a comprehensive list of prescribed and over-the-counter medicines that have the potential to inhibit uptake of MIBG has been compiled. It is hoped that this will help nuclear medicine physicians to avoid this pitfall.

SHORT AND LONG-TERM RESPONSES TO METYRAPONE IN THE MEDICAL MANAGEMENT OF 91 PATIENTS WITH CUSHING'S SYNDROME

Summary. objective To analyse the clinical and biochemical effects of metyrapone in the treatment of Cushings syndrome.

A single sleeping midnight cortisol has 100% sensitivity for the diagnosis of Cushing's syndrome

OBJECTIVE The diagnosis of Cushings syndrome remains a major challenge in clinical endocrinology. Various screening tests are commonly used to support a biochemical diagnosis in the context of clinical suspicion. The aim of this study was to compare the sensitivity in the diagnosis of Cushings syndrome of a single in‐patient sleeping midnight cortisol to a standard 48‐hour in‐patient low‐dose dexamethasone suppression test (LDDST) during the same admission.

Nitric oxide modulates the release of corticotropin-releasing hormone from the rat hypothalamus in vitro

There is now considerable evidence that nitric oxide (NO) is an important neuroregulatory agent, but there has been very little investigation of the possible role of NO in neuroendocrine mechanisms. We have previously shown that acute rat hypothalamic explants can be used to study the regulation of hypothalamic neuropeptide release, and we have now utilised this experimental approach to investigate the putative involvement of NO in the control of the principal corticotropin-releasing hormone, CRH. We studied the direct effects of the NO precursor L-arginine (L-ARG), as well as the NO donors molsidomine and sodium nitroprusside, on both the basal and stimulated release of CRH; the stimuli used were non-specific depolarisation with potassium chloride (KCl) and the specific cytokine, interleukin-1 beta (IL-1 beta; 100 U/ml). L-ARG was tested in each experimental condition with and without contemporaneous addition of its competitive antagonist NG-monomethyl-L-arginine (L-NMMA). IL-1 beta-induced CRH release was also investigated in the presence of D-arginine (D-ARG), which is not active as a precursor to NO, and ferrous hemoglobin (Hb), a substance which is a potent inactivator of NO. None of the NO precursors (L-ARG, molsidomine, sodium nitroprusside) or antagonists (L-NMMA or Hb) was able to affect basal CRH release. However, L-ARG 10 and 100 microM were found to significantly inhibit the release of CRH induced by 40 mM KCl; CRH fell to 45% of its stimulated level at the higher dose of L-ARG. This effect was attenuated in the presence of L-NMMA at a ten-fold higher dose.(ABSTRACT TRUNCATED AT 250 WORDS)

The diagnosis and differential diagnosis of Cushing's syndrome

Cushings syndrome is defined as the symptoms and signs of glucocorticoid excess, but the precise diagnosis may be difficult to establish and harder to localise. The clinicial, biochemical and imaging features of the syndrome are discussed in the light of our own extensive experience and the published literature. We describe the optimal diagnostic routines currently recommended in major centres, and analyse the sensitivities and specialities of the various tests employed. Only by means of establishing a precise diagnosis can the disorder be successfully treated.

The European Registry on Cushing's syndrome: 2-year experience. Baseline demographic and clinical characteristics

OBJECTIVE The European Registry on Cushings syndrome (ERCUSYN) is designed to collect prospective and follow-up data at EU level on Cushings syndrome (CS). DESIGN AND METHODS Baseline data on 481 CS patients (390 females, 91 males; mean age (±s.d.): 44±14 years) collected from 36 centres in 23 countries, including new patients from 2008 and retrospective cases since 2000. Patients were divided into four major aetiologic groups: pituitary-dependent CS (PIT-CS) (66%), adrenal-dependent CS (ADR-CS) (27%), CS from an ectopic source (ECT-CS) (5%) and CS from other aetiologies (2%). RESULTS Proportion of men in the ECT-CS group was higher than in the other groups (P<0.05). The ADR-CS group was older than the PIT-CS (P<0.05). Prevalence of hirsutism (92%) and diabetes (74%) in ECT-CS was higher than in the other groups (P<0.05 and P<0.01 respectively). PIT-CS had more skin alterations, menstrual irregularities and hirsutism than ADR-CS (P<0.01). Reduced libido was more prevalent in men than women (P<0.01). Prevalence of spine osteoporosis was higher in men than women (P<0.05), and males had more vertebral and rib fractures than females (52 vs 18% for vertebrae; P<0.001 and 34 vs 23% for ribs; P<0.05). ECT-CS consulted a diabetologist more frequently than ADR-CS (P<0.05), while a gynaecologist was consulted more often by women with PIT-CS or ADR-CS than with ECT-CS (P<0.05). Overall, weight gain was more common in women than men (P<0.01). CushingQoL and EuroQoL visual analogue scale scores did not differ between the groups. CONCLUSIONS The ERCUSYN project demonstrates a heterogeneous clinical presentation of CS at a European level, depending on gender and aetiology.

An audit of the insulin tolerance test in adult subjects in an acute investigation unit over one year

OBJECTIVE We audited our practice of insulin tolerance testing (ITT) in terms of safety and technical success. We reviewed the results of those tests performed over a 12‐month period. By relating peak Cortisol response to 0900 h screening Cortisol level, we determined whether we could reduce the number of tests performed.