Final adult height and body mass index after cure of paediatric Cushing's disease

There is increasing evidence for the existence of a condition consisting of a cluster of metabolic disorders which include insulin resistance, alterations in glucose and lipid metabolism, increased blood pressure and visceral obesity. The metabolic syndrome is now the favoured definition of the cluster. Each single component of the cluster increases the cardiovascular risk, but the combination of factors is much more important. Insulin resistance is the most frequently associated factor to the singular components of the syndrome: most authors believe that it may be the common aetiological factor. However, visceral obesity seems to be the main driving factor by means of the increased production of free fatty acids whose activity, in turn, might interfere with the action of insulin. Some questions exist about the syndrome because of the frequent lack in the cluster of one of the factors. This does not mean that the missing factor does not belong to the syndrome, but only that it is not yet clinically evident. Weight gain has been shown to be a strong predictor of the metabolic syndrome. This aspect gives strength to treatment and prevention because it means that losing weight or stopping weight increase might reduce the risk of a future appearance of a factor that is still not evident. Interventions to treat visceral obesity by means of losing weight seem to be the most efficacious way to treat the metabolic syndrome thus improving the most widespread cardiovascular risk factor in western countries.

Transsphenoidal surgery (TSS) is considered first-line treatment for Cushing's disease (CD). Options for treatment of postoperative persisting hypercortisolemia are pituitary radiotherapy (RT), repeat TSS, or bilateral adrenalectomy. From 1983 to 2001, we treated 18 pediatric patients (age, 6.4-17.8 yr) with CD. All underwent TSS, and 11 were cured (postoperative serum cortisol, <50 nM). Seven (39%) had 0900-h serum cortisol of 269-900 nM during the immediate postoperative period (2-20 d), indicating lack of cure. These patients (6 males and 1 female; mean age, 12.8 yr; range, 6.4-17.8 yr; 4 prepubertal; 3 pubertal) received external beam RT to the pituitary gland, using a 6-MV linear accelerator, with a dose of 45 Gy in 25 fractions over 35 d. Until the RT became effective, hypercortisolemia was controlled with ketoconazole (dose, 200-600 mg/d) (n = 4) and metyrapone (750 mg-3 g/d) +/- aminoglutethimide (1 g/d) or o'p'DDD (mitotane, 3 mg/d) (n = 3). All patients were cured after pituitary RT. The mean interval from RT to cure (mean serum cortisol on 5-point day curve, <150 nM) was 0.94 yr (0.25-2.86 yr). Recovery of pituitary-adrenal function (mean cortisol, 150-300 nM) occurred at mean 1.16 yr (0.40-2.86 yr) post RT. At 2 yr post RT, puberty occurred early in one male patient (age, 9.8 yr) but was normal in the others. GH secretion was assessed at 0.6-2.5 yr post RT in all patients: six had GH deficiency (peak on glucagon/insulin provocation, <1.0-17.9 mU/liter) and received human GH replacement. Follow-up of pituitary function 7.6 and 9.5 yr post RT in two patients showed normal gonadotropin secretion and recovery of GH peak to 29.7 and 19.2 mU/liter. The seven patients were followed for mean 6.9 yr (1.4-12.0 yr), with no evidence of recurrence of CD. In conclusion, pituitary RT is an effective and relatively rapid-onset treatment for pediatric CD after failure of TSS. GH deficiency occurred in 86% patients. Long-term follow-up suggests some recovery of GH secretion and preservation of other anterior pituitary function.