Effective combination treatment with cabergoline and low-dose pegvisomant in active acromegaly: a prospective clinical trial.

CONTEXT: With adequate dose titration, pegvisomant normalizes IGF-I in up to 97% of patients with acromegaly. Pegvisomant is indicated for treatment-resistant disease but is expensive, particularly at a high dose. It has been used successfully in combination with somatostatin analogs. However, there are no therapeutic reports of pegvisomant in combination with dopamine agonists. Cabergoline is orally active, well-tolerated, and relatively inexpensive, and as monotherapy for acromegaly it is reported to normalize IGF-I in up to 30% of patients. OBJECTIVE: The aim of the study was to investigate the efficacy of cabergoline monotherapy and pegvisomant in combination with cabergoline to control serum IGF-I in patients with active acromegaly. Twenty-four patients were recruited into a United Kingdom, multicenter, open-label, prospective clinical trial. MAIN OUTCOME MEASURE: We measured the change in serum IGF-I. RESULTS: After 18 wk of dose titration to a maximum dose of 0.5 mg once daily, cabergoline monotherapy did not significantly reduce IGF-I (454 ± 219 baseline vs. 389 ± 192 ng/ml cabergoline), although two patients did normalize IGF-I. The addition of 10 mg pegvisomant daily for 12 wk significantly reduced IGF-I (389 ± 192 ng/ml cabergoline vs. 229 ± 101 ng/ml combination), and 68% achieved a normal IGF-I. Twelve weeks after cabergoline withdrawal, while continuing to receive pegvisomant 10 mg, only 26% of patients maintained an IGF-I within the reference range (229 ± 101 ng/ml combination vs. 305 ± 177 ng/ml pegvisomant). There were no significant changes in liver transaminases or glucose metabolism throughout the study. CONCLUSION: These data suggest that combination treatment with cabergoline and pegvisomant is more effective at reducing IGF-I levels than either cabergoline or pegvisomant monotherapy.

Clinical Use of Cinacalcet in MEN1 Hyperparathyroidism.

Background. Management of multiple-endocrine neoplasia type 1- (MEN1-) associated hyperparathyroidism is associated with high recurrence rates and high surgical morbidity due to multiple neck explorations. Cinacalcet, a calcimimetic agent licensed for the treatment of secondary hyperparathyroidism and parathyroid carcinoma, may provide a medical alternative for the management of these complex patients. Methods. A prospective audit was performed of eight patients; three males and five females, aged 20-38 at diagnosis. Two patients commenced cinacalcet as primary treatment and six had previous surgery. Six patients had complications of hyperparathyroidism: renal calculi, renal dysfunction, and reduced bone mineral density. All were commenced on cinacalcet 30 mg bd for MEN1 associated hyperparathyroidism; doses were subsequently reduced to 30 mg od in four patients. Results. Significant reductions were observed in serum calcium and PTH measurements. Serum calcium reduced by a median of 0.35 mmol/L (P = .012 Wilcoxon Signed Rank). Serum PTH levels decreased by a median of 5.05 pmol/L (P = .012). There was no change in urine calcium. Duration ranged from 10-35 months with maintenance of control. Cinacalcet was well tolerated by six patients; one experienced nausea and one experienced diarrhoea. Conclusion. Cinacalcet is an effective and well-tolerated medical treatment for the management of complex primary hyperparathyroidism.

d3-GHR genotype does not explain heterogeneity in GH responsiveness in hypopituitary adults.

OBJECTIVE: Heterogeneity in growth hormone (GH) responsiveness in adult hypopituitary patients receiving recombinant human GH (rhGH) is poorly understood; doses vary up to fourfold between individuals. Deletion of exon 3 in the GH receptor (d3-GHR) has been linked to enhanced rhGH responsiveness in children. We investigated the role of the d3-GHR polymorphism in determining adult rhGH responsiveness. METHODS: One hundred and ninety-four patients treated with an identical rhGH dosing protocol in a single centre were genotyped for the d3-GHR, and the results correlated with changes in serum IGF-I and clinical parameters of GH responsiveness after 6 and 12 months of GH replacement therapy. RESULTS: Allele frequencies for homozygous full length (fl/fl), heterozygous d3 (fl/d3) and homozygous d3 (d3/d3) were 52%, 38.7% and 9.3%, respectively, and were in Hardy-Weinberg equilibrium. Baseline IGF-I and DeltaIGF-I at 6 months were comparable between groups. DeltaIGF-I at 12 months was significantly greater in the d3/d3 group (P = 0.028). No difference was detected between fl/d3 and fl/fl groups. Regression analyses of DeltaIGF-I at 12 months and DeltaIGF-I/rhGH dose confirmed a significant relationship of d3/d3 genotype on rhGH response. There was no difference between groups in maintenance rhGH dose between genotypes. CONCLUSION: Homozygosity for d3-GHR confers a marginal increase in GH responsiveness at 12 months but without a detectable change in maintenance rhGH dose required. Both d3 alleles are required to achieve this response; given that only 10% of the population are d3 homozygotes, the d3GHR does not explain the marked heterogeneity of GH responsiveness in hypopituitary adults.

Treatment of Nelson's syndrome with temozolomide.

A 64-year-old woman was previously treated for Cushing's disease with trans-sphenoidal surgery, external beam radiotherapy and bilateral adrenalectomy. Progression of an aggressive corticotroph adenoma was evident 3 years post-adrenalectomy; involvement of the clivus was treated with surgery and gamma knife radiosurgery. Tumour spread through the skull base, occiput and left ear with persistent facial pain and left ear discharge; progression continued despite second gamma knife treatment. ACTH levels peaked at 2472 and 2265 pmol/l pre- and post-hydrocortisone respectively. Treatment with temozolomide resulted in a significant improvement in symptoms, a reduction of plasma ACTH to 389 pmol/l and regression of tumour on magnetic resonance imaging scan after four cycles of treatment. We propose that temozolomide is an effective and well-tolerated therapeutic tool for the treatment of Nelson's syndrome and a useful addition to the range of therapies available to treat this condition.

The appearance of the adrenal glands on computed tomography in multiple endocrine neoplasia type 1.

AIMS: To review the morphology of the adrenal glands in multiple endocrine neoplasia type 1 (MEN1) on computed tomography (CT) to compare the results with established normal values for adrenal size and nodularity and to correlate adrenal size with serum cortisol secretory dynamics. MATERIALS AND METHODS: Two observers independently reviewed the adrenal CT in 28 patients with MEN1, measuring the maximum width of the body of the gland and the medial and lateral limbs. Incidence and location of nodules >5 mm within the gland were recorded. Following exclusion of known cases of Cushing's syndrome, adrenal gland size was compared with previously documented normative data. Adrenal gland size was compared between patients with normal and abnormal cortisol dynamics. RESULTS: Comparison of mean adrenal size in MEN1 patients with normative data showed that the adrenal limbs were significantly larger in MEN1 than normal (P<0.0001 in all four limbs). Adrenal body was also significantly larger (P<0.05). Nodules were demonstrated in 17 (60%) of patients (versus 0.4-2% in the normal population). No statistically significant correlation was demonstrated between adrenal limb hyperplasia and abnormal cortisol dynamics. CONCLUSIONS: In patients with MEN1, adrenal limb hyperplasia and adrenal nodules are significantly more common than in the normal population, a phenomenon not previously documented in a quantitative manner. There was no significant correlation between adrenal limb hyperplasia and abnormal cortisol dynamics.

Clinical use of cabergoline as primary and adjunctive treatment for acromegaly.

BACKGROUND: Cabergoline is a dopamine agonist that may be used as primary or adjunctive therapy for acromegaly. Although one study suggested biochemical control may be achieved in a substantial proportion of patients, it is still commonly perceived to be a relatively ineffective treatment. DESIGN AND METHOD: A prospective audit was performed of 15 consecutive acromegalic patients (eight males, seven females, median age 55, range 31-92 at presentation) treated with cabergoline to determine the effective dose and tolerability. All had normal anterior pituitary function; two patients had hyperprolactinaemia. Magnetic resonance imaging revealed nine adenomata, two partially empty sellae and four structurally normal pituitary glands. Nine patients had undergone transsphenoidal surgery 1-12 months, and one patient had received pituitary radiotherapy 18 years, prior to commencement of cabergoline. All patients had biochemical GH excess; median serum IGF1 471 ng/ml, range 239-746 ng/ml. The calculated mean of a series of GH measurements ranged from 2.7-45.8 mIU/l, median 9.7 mIU/l. RESULTS: On a median weekly dose of cabergoline of 1.75 mg (range 0.5-7 mg) normalisation of both IGF1 and GH occurred in 4 out of the 15 patients (27%). Out of the 15 patients (33%), 5 achieved a serum IGF1 within the reference range with notable reductions seen in a further five patients. Nine patients (60%) achieved a mean serum GH level of less than 5 mIU/l. Duration of treatment was 2-52 months and was well tolerated in 14 patients. CONCLUSION: Cabergoline can be an effective and well tolerated primary or adjunctive therapy for acromegaly and useful clinical responses are noted even with modest doses.

Insulin allergy in a patient with Type 2 diabetes successfully treated with continuous subcutaneous insulin infusion.

BACKGROUND: Patients with poor control of Type 2 diabetes on maximum oral hypoglycaemic therapy invariably need insulin therapy. Insulin allergy is uncommon, particularly in patients with Type 2 diabetes. Management of the condition can be difficult, and here we report the case of a patient with Type 2 diabetes and insulin allergy successfully managed with a continuous subcutaneous insulin infusion (CSII). CASE REPORT: A 60-year-old man was referred with insulin allergy. He had poorly controlled Type 2 diabetes (glycated haemoglobin 10.4%), on maximum doses of sulphonylurea and metformin, with osmotic symptoms. He was compliant with diet and tablets. His diabetes was complicated by retinopathy, nephropathy, coronary heart disease, obstructive sleep apnoea, obesity, depression and hypertension. He commenced on twice daily mixed insulin and, shortly after, developed pain, itching and erythema at the injection sites. The sites became indurated and tender, and he had constitutional symptoms. The insulin was changed to other preparations, including short- and long-acting analogues, with similar responses. Triple therapy with rosiglitazone was tried, with no improvement in control. Skin-prick testing confirmed allergy to insulin rather than additives. The patient was reluctant to undergo desensitization. He was commenced on an insulin pump in addition to his oral hypoglycaemics, and achieved fair control (glycated haemoglobin 8.3%) on 88 units of lispro per day, with little or no skin or systemic reaction. CONCLUSION: This is the first case report of insulin allergy in Type 2 diabetes being successfully managed by CSII.