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C E Higham, J D J Thomas, M Bidlingmaier, W M Drake and P J Trainer

Context

Clinical trials using 80 mg once weekly pegvisomant (pegV) in active acromegaly led to a 30% fall in serum IGF1. Subsequent studies demonstrated that daily administration of up to 40 mg/day achieved an IGF1 within reference range in 97% of patients. PegV has a half-life of >70 h suggesting weekly dosing may be possible but using higher doses than in the initial trials.

Objective

To determine the efficacy of weekly dosing of pegV.

Design

A two center, open-label prospective study in patients with acromegaly converted from a stable daily dose of pegV (median dose 15 mg daily (range 10–20 mg od), IGF1 normal for 3 months prior to inclusion) to twice-weekly (week 0–16) followed by once-weekly (week 16–32) administration.

Results

Seven patients (4M, age 57±7 years, 6/7 prior transsphenoidal surgery, 7/7 prior radiotherapy) were recruited. Six patients completed the twice-weekly and five patients both the twice-weekly and once-weekly administration. Headaches led to two patient withdrawals at 0+24 weeks. Mean pre-dose serum IGF1 levels remained stable with the different administration regimens (IGF1 baseline 145±39 ng/ml, twice-weekly 124±39 ng/ml and once-weekly 127±22 ng/ml) and all values were within age adjusted IGF1 reference range. PegV dose was reduced in two patients and five opted to continue weekly administration at trial termination. Safety and quality of life parameters remained stable.

Conclusions

Twice and once-weekly administration of pegV is effective in controlling serum IGF1 levels in acromegaly and although not formally assessed, continuation of weekly dosing in five patients at study conclusion suggests patient preference for this regimen.

Free access

A N Paisley, K Hayden, A Ellis, J Anderson, G Wieringa and P J Trainer

Introduction: Pegvisomant use in acromegaly negates the use of GH levels to monitor disease activity. To achieve antagonism, plasma concentrations must be ~1000-fold greater than GH which with the high homology between the peptides makes GH measurement a challenge when pegvisomant is present.

Objective: We investigated the effect of pegvisomant on GH measured using commercially available assays.

Methods: Pooled serum samples with GH concentrations <0.38, 3.85 and 7.69 μg/l were spiked with increasing pegvisomant concentrations (9000–494 000μg/l). Samples were analysed by the Nichols Advantage, DPC Immulite 2000, Diasorin IRMA, Beckman Access Dxl, Tosoh AIA and Wallac Delfia assays.

Results: With baseline GH <0.38 μg/l measured levels were <0.38 in all assays except Nichols, Diasorin and Beckman where GH peaked at 1.5, 9.6 and 17.7 μg/l respectively at low pegvisomant concentrations, falling thereafter. With the other two samples, measured GH levels progressively fell with increasing pegvisomant concentrations, except the Beckman assay where an increase (30.8 μg/l) was seen at a pegvisomant concentration of 9000 μg/l; and Diasorin and Tosoh where smaller increases were seen at lower pegvisomant concentrations, levels gradually falling thereafter.

Conclusion: The presence of pegvisomant resulted in artefactually low measured GH in most assays. We speculate this fall is due to assay antibody-binding pegvisomant, reducing the amount of available antibody to bind actual GH thereby producing less sandwich formation: the ‘high-dose hook’ effect. In most assays, this effect is modest and results in lower GH, but the level of interference makes them unsuitable for studies on the influence of pegvisomant on GH neuroregulation.

Free access

W M Drake, R A Loureiro, C Parkinson, J P Monson, G M Besser and P J Trainer

Objective: Pegvisomant, a modified growth hormone (GH) molecule, is a novel medical therapy for acromegaly that functions as a GH receptor antagonist. Serum GH cannot be used as a marker of disease activity in patients taking this form of therapy, partly because GH levels rise on pegvisomant and partly because the drug cross-reacts with many routine GH assays. The purpose of this study was to assess the time for which it is necessary to discontinue pegvisomant prior to biochemical reassessment of acromegaly.

Design and methods: This was a retrospective study of 13 patients (seven male, median age 61 years, range 43–77) enrolled in two separate, open-label studies of the efficacy and tolerability of pegvisomant in the treatment of acromegaly. All had been taking a stable dose of pegvisomant (median dose 15 mg daily, range 10–30) as monotherapy for at least 3 months before discontinuing the drug. After discontinuation of pegvisomant, serum IGF-I was measured at 0, 2, 4, 6 and 8 weeks in all patients. Serum GH (single sample) was measured in nine patients at 2, 4, 6 and 8 weeks, but not at baseline on account of the cross-reactivity of pegvisomant with the GH assay.

Results: Mean serum IGF-I rose from 210±105 ng/ml (s.d.) at baseline to 392±175 ng/ml at 2 weeks after discontinuation of pegvisomant (P < 0.0001). Although there was no statistically significant change in mean serum IGF-I beyond 2 weeks (412±181, 392±152 and 399±150 ng/ml at 4, 6 and 8 weeks respectively; P = 0.13 (2 vs 4 weeks), 0.31 (4 vs 6 weeks) and 0.46 (6 vs 8 weeks), serum IGF-I rose by more than twice the interassay coefficient of variation (CV) in two of the 13 patients between weeks 2 and 4. The standard deviation of the difference in serum IGF-I between time points was calculated. The values declined from 118% (weeks 0–2) 17%, 19.7% and 10% (weeks 2–4, 4–6 and 6–8 respectively). The expected measure if there was no systematic change in base would be 15% (1.4 ×interassay CV). Mean serum GH was virtually unchanged at 2–8 weeks after cessation of pegvisomant therapy.

Conclusions: These results suggest that the activity of acromegaly may be assessed by serum IGF-I levels 6 weeks after the discontinuation of pegvisomant.

Free access

E Valassi, I Crespo, B G Keevil, A Aulinas, E Urgell, A Santos, P J Trainer and S M Webb

Objective

Affective alterations and poorer quality of life often persist in patients with Cushing’s syndrome (CS) in remission. Brain-derived neurotrophic factor (BDNF) regulates the hypothalamic–pituitary–adrenal axis (HPA) and is highly expressed in brain areas controlling mood and response to stress. Our aims were to assess affective alterations after long-term remission of CS and evaluate whether they are associated with serum BDNF, salivary cortisol (SalF) and/or cortisone (SalE) concentrations.

Subjects and methods

Thirty-six CS patients in remission (32 females/4 males; mean age (±s.d.), 48.8 ± 11.8 years; median duration of remission, 72 months) and 36 gender-, age- and BMI-matched controls were included. Beck Depression Inventory-II (BDI-II), Center for Epidemiological Studies Depression Scale (CES-D), Positive Affect Negative Affect Scale (PANAS), State-Trait Anxiety Inventory (STAI), Perceived Stress Scale (PSS) and EuroQoL and CushingQoL questionnaires were completed and measured to evaluate anxiety, depression, stress perception and quality of life (QoL) respectively. Salivary cortisol was measured using liquid chromatography/tandem mass spectrometry (LC/TMS). BDNF was measured in serum using an ELISA.

Results

Remitted CS patients showed worse scores in all questionnaires than controls: STAI (P < 0.001), BDI (P < 0.001), CES-D (P < 0.001), PANAS (P < 0.01), PSS (P < 0.01) and EuroQoL (P < 0.01). A decrease in BDNF was observed in CS vs controls (P = 0.038), and low BDNF was associated with more anxiety (r = −0.247, P = 0.037), depression (r = −0.249, P = 0.035), stress (r = −0.277, P = 0.019) and affective balance (r = 0.243, P = 0.04). Morning salivary cortisone was inversely associated with trait anxiety (r = −0.377, P = 0.040) and depressed affect (r = −0.392, P = 0.032) in CS patients. Delay to diagnosis was associated with depressive symptoms (BDI-II: r = 0.398, P = 0.036 and CES-D: r = 0.449, P = 0.017) and CushingQoL scoring (r = −0.460, P < 0.01).

Conclusions

Low BDNF levels are associated with affective alterations in ‘cured’ CS patients, including depression, anxiety and impaired stress perception. Elevated levels of SalE might also be related to poor affective status in these patients.

Open access

Fabrice Bonneville, Louis-David Rivière, Stephan Petersenn, John S Bevan, Aude Houchard, Caroline Sert, Philippe J Caron and the PRIMARYS Study Group

Objective

Pituitary adenoma MRI T2 signal intensity associates with tumor characteristics including responsiveness to somatostatin analogs (SSAs). These analyses determined whether baseline T2 signal intensity predicts response to primary medical treatment with long-acting SSA.

Design

Post hoc analyses of the prospective multicenter, open-label, single-arm PRIMARYS study in which patients with treatment-naïve GH-secreting pituitary macroadenomas received fixed-dose lanreotide autogel (120 mg) every 4 weeks for 48 weeks.

Methods

Associations were investigated between adenoma T2-signal hypo/iso/hyperintensity and treatment responses at week 48/last visit: hormonal control (GH ≤2.5 μg/L and IGF-1 normalization); tumor response (tumor volume reduction (TVR) ≥20%); separate GH/IGF-1 control and change from baseline in GH/IGF-1 and tumor volume.

Results

Adenomas were hypointense at baseline in 50/85 (59%) patients using visual assessment. Of these, 40% achieved hormonal control and 76% achieved a tumor response. Significant univariate associations arose for hypo- vs isointensity with tumor response and achievement of GH ≤2.5 μg/L, but not IGF-1 normalization or overall hormonal control. In multivariate analysis, tumor response was six times more likely for hypo- vs iso-intense tumors (= 6.15; 95% CI: 1.36–27.88). In univariate change-from-baseline analyses, hypo- vs isointensity was associated with greater TVR and IGF-1 reduction but not change in GH. In multivariate analysis, IGF-1 decreased by an estimated additional 65 μg/L (P = 0.0026)) for hypo- vs isointense.

Conclusions

Patients with hypointense vs isointense GH-secreting macroadenomas had greater reductions in IGF-1 following primary treatment with lanreotide autogel and were more likely to achieve tumor response. Assessment of T2 signal intensity at baseline may help to predict long-term responses to primary treatment with SSAs.

Free access

Elena Valassi, Holger Franz, Thierry Brue, Richard A Feelders, Romana Netea-Maier, Stylianos Tsagarakis, Susan M Webb, Maria Yaneva, Martin Reincke, Michael Droste, Irina Komerdus, Dominique Maiter, Darko Kastelan, Philippe Chanson, Marija Pfeifer, Christian J Strasburger, Miklós Tóth, Olivier Chabre, Michal Krsek, Carmen Fajardo, Marek Bolanowski, Alicia Santos, Peter J Trainer, John A H Wass, Antoine Tabarin and for the ERCUSYN Study Group

Background

Surgery is the definitive treatment of Cushing’s syndrome (CS) but medications may also be used as a first-line therapy. Whether preoperative medical treatment (PMT) affects postoperative outcome remains controversial.

Objective

(1) Evaluate how frequently PMT is given to CS patients across Europe; (2) examine differences in preoperative characteristics of patients who receive PMT and those who undergo primary surgery and (3) determine if PMT influences postoperative outcome in pituitary-dependent CS (PIT-CS).

Patients and methods

1143 CS patients entered into the ERCUSYN database from 57 centers in 26 countries. Sixty-nine percent had PIT-CS, 25% adrenal-dependent CS (ADR-CS), 5% CS from an ectopic source (ECT-CS) and 1% were classified as having CS from other causes (OTH-CS).

Results

Twenty per cent of patients took PMT. ECT-CS and PIT-CS were more likely to receive PMT compared to ADR-CS (P < 0.001). Most commonly used drugs were ketoconazole (62%), metyrapone (16%) and a combination of both (12%). Median (interquartile range) duration of PMT was 109 (98) days. PIT-CS patients treated with PMT had more severe clinical features at diagnosis and poorer quality of life compared to those undergoing primary surgery (SX) (P < 0.05). Within 7 days of surgery, PIT-CS patients treated with PMT were more likely to have normal cortisol (P < 0.01) and a lower remission rate (P < 0.01). Within 6 months of surgery, no differences in morbidity or remission rates were observed between SX and PMT groups.

Conclusions

PMT may confound the interpretation of immediate postoperative outcome. Follow-up is recommended to definitely evaluate surgical results.