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Background/objective: Pituitary radiotherapy (RT) is an effective second-line treatment for paediatric Cushing’s disease (CD). Although the short-term effects of pituitary RT are well documented, there are less data on possible long-term sequelae. We report the long-term anterior pituitary function in a cohort of paediatric CD patients treated with pituitary RT.

Patients and methods: Between 1983 and 2006, 12 paediatric CD patients (10 males and 2 females) of mean age 11.4 years at diagnosis (range 6.4–17.4) underwent second-line pituitary RT (45 Gy in 25 fractions), following unsuccessful transsphenoidal surgery. Out of 12, 11 patients were cured by RT (cure interval 0.13–2.86 years) defined by mean serum cortisol of <150 nmol/l on 5-point day curve and midnight sleeping cortisol of <50 nmol/l. Long-term data are available for six male patients, who received RT at the age of 7.0–17.6 years. The mean follow-up from the completion of RT was 10.5 years (6.6–16.5).

Results: At a mean of 1.0 year (0.11–2.54) following RT, GH deficiency (peak GH <1–17.9 mU/l) was present in five out of six patients. On retesting at a mean of 9.3 years (7.6–11.3) after RT, three out of four patients were GH sufficient (peak GH 19.2–50.4 mU/l). Other anterior pituitary functions including serum prolactin in five out of six patients were normal on follow-up. All the six patients had testicular volumes of 20–25 ml at the age of 14.5–28.5 years.

Conclusion: This series of patients illustrates the absence of serious long-term pituitary deficiency after RT and emphasises the importance of continued surveillance.

The IGF1 generation test (IGFGT) is often used during the assessment of suspected GH insensitivity (GHI). We report the results of a survey undertaken in 2010 to determine the use of IGFGT amongst members of the European Society for Paediatric Endocrinology to evaluate suspected GHI. The literature surrounding the usefulness and limitations of IGFGT are reviewed, and recommendations provided for its use. Of 112 paediatric endocrinologists from 30 countries who responded to the survey, 91 (81%) reported that they had used the IGFGT in the previous 2 years; >10 IGFGT protocols were used. The IGFGT impacted treatment decisions for 97% of the respondents and was a prerequisite for recombinant human IGF1 treatment for 45% of respondents. From a literature review, sensitivity of the IGFGT was evaluated as 77–91% in molecularly proven cases of GHI; specificity was ≤97%, depending on the protocol. The positive predictive value of the IGFGT is likely to be low, as the frequency of normality is predictably higher than that of abnormality in GH signalling. Given the limitations of the IGFGT in the most severe cases of GHI syndrome (GHIS), the ability of the IGFGT to detect less severe GHIS is doubtful. In a pragmatic approach, the IGFGT may not be useful for the diagnosis of GHIS.

Objective: Early diagnosis and effective treatment of paediatric Cushing’s disease (CD) is necessary to minimise associated morbidity. Accepted first-line treatment is selective transsphenoidal microadenomectomy (TSS), which can be technically difficult, and cure rates vary considerably between centres. In our paediatric CD patient group we have assessed the possible factors which may influence cure by TSS.

Subjects and methods: From 1983–2004, 27 paediatric patients (16 males, 11 females; mean age±s.d., 13.1±3.2 yr; range, 6.4–17.8 yr) with CD were managed in our centre and underwent TSS. Sixteen patients (59%), seven males and nine females (mean age±s.d., 14.2±2.5 yr; range, 8.2–17.8 yr), were cured (post-operative serum cortisol < 50 nM). Eleven patients, nine males and two females (mean age±s.d., 11.5±3.6 yr; range, 6.4–17.8 yr) had post-operative cortisol levels above 50 nM (2–20 days), with mean serum cortisol levels at 09:00 h of 537 nM (range 269–900 nM) indicating a lack of cure. These 11 patients received external beam pituitary radiotherapy (RT). One patient with a pituitary macroadenoma had a post-operative cortisol level of < 50 nM but 0.8 yr later showed an elevated cortisol and residual disease.

Results: The patients cured by TSS alone were significantly older than those not cured (P = 0.038; Student’s t test). All patients had CT/MRI pituitary imaging: 14 were reported to have microadenomas and one macroadenoma, while 12 were reported as normal. Bilateral simultaneous inferior petrosal sinus sampling (BSIPSS) with i.v. corticotropin-releasing hormone (CRH) administration was introduced as a pre-operative investigation in 1986 and was performed in 21 patients (78%), on BSIPSS, 16 (76%) had evidence suggesting pituitary adrenocorticotropic hormone (ACTH) secretion (central to peripheral (IPS:P) ACTH ratio after CRH of ≥ 3.0) and 16 (76%) showed lateralisation of ACTH secretion (IPSG of ≥ 1.4). There was concordance between the BSIPSS finding and the position of the microadenoma at surgery in 17/21 (81%) patients. Of the 16 patients showing lateralisation of ACTH secretion, 12 (75%) were cured by TSS. Of the four without lateralisation of ACTH, suggesting a midline lesion, 3 (75%) were cured by TSS. Post-operative pituitary hormone deficiencies in the patients cured by TSS were: pan-hypopituitarism 1/16, isolated growth hormone deficiency (GHD) (peak GH on glucagon/ITT < 1–17.9 mU/l) 9/16 and diabetes insipidus 3/16.

Conclusion: Over a 21-year period selective adenomectomy by TSS cured 59% of all paediatric CD patients, with higher age favouring cure. Introduction of BSIPSS resulted in the demonstration of a high rate of lateralisation of ACTH secretion consistent with the surgical identification of the adenoma, and therefore appears likely to have contributed to the higher surgical cure rate.

Cushing's syndrome (CS) patients have increased mortality primarily due to cardiovascular events induced by glucocorticoid (GC) excess-related severe metabolic changes. Glucose metabolism abnormalities are common in CS due to increased gluconeogenesis, disruption of insulin signalling with reduced glucose uptake and disposal of glucose and altered insulin secretion, consequent to the combination of GCs effects on liver, muscle, adipose tissue and pancreas. Dyslipidaemia is a frequent feature in CS as a result of GC-induced increased lipolysis, lipid mobilisation, liponeogenesis and adipogenesis. Protein metabolism is severely affected by GC excess via complex direct and indirect stimulation of protein breakdown and inhibition of protein synthesis, which can lead to muscle loss. CS patients show changes in body composition, with fat redistribution resulting in accumulation of central adipose tissue. Metabolic changes, altered adipokine release, GC-induced heart and vasculature abnormalities, hypertension and atherosclerosis contribute to the increased cardiovascular morbidity and mortality. In paediatric CS patients, the interplay between GC and the GH/IGF1 axis affects growth and body composition, while in adults it further contributes to the metabolic derangement. GC excess has a myriad of deleterious effects and here we attempt to summarise the metabolic comorbidities related to CS and their management in the perspective of reducing the cardiovascular risk and mortality overall.

Objective: The use of a growth hormone (GH) receptor antagonist, pegvisomant has shown great promise in adults with acromegaly, but experience in paediatric patients is lacking. We aimed to describe the results of pegvisomant therapy in a 12-year-old girl with an aggressive GH-secreting pituitary tumour.

Design: To evaluate the ability of pegvisomant therapy to control the effects of peripheral GH excess in a case of pituitary gigantism.

Methods: Pegvisomant was introduced at 10 mg/day, given subcutaneously, and gradually increased to 20 mg/day until serum IGF-I was normal for age.

Results: A large pituitary adenoma with suprasellar extension was diagnosed in a 12-year-old girl with progressive tall stature (178 cm), GH hypersecretion without suppression during oral glucose loading (nadir serum GH, 90 mU/l), high serum IGF-I and serum prolactin levels. Surgical extirpation was not possible because tumour tissue was fibrous and adherent to the optical nerves. Histological examination showed a mixed GH- and prolactin-secreting adenoma with lymphocytic infiltration of B and T cells. Treatment with a dopamine agonist, cabergoline, normalized serum prolactin, but GH secretion was resistant to both somatostatin analogue, octreotide and cabergoline. Radiation followed by pegvisomant therapy titrated up in dose to 20 mg/day led to a marked reduction in GH secretion and normalization of IGF-I, and to growth arrest and improvement of well-being.

Conclusions: We suggest that treatment in pituitary gigantism with pegvisomant is safe and may normalize IGF-I levels and effectively stop growing.