Search

The long-term effects of cranial external beam radiotherapy are emerging as survival rates for cerebral tumours improve. Cerebral cavernoma are a recognized consequence of cranial irradiation. Endocrinologists managing the life-long complications of hypopituitarism associated with irradiation need to be aware and vigilant of the risks of cavernoma formation, in particular in the population with a history of childhood irradiation. We present three cases of young patients who were diagnosed with cerebral cavernoma many years after childhood irradiation treatment and review the current literature on this condition. We discuss implications for endocrine practice as rising numbers of patients survive childhood cancer and irradiation and are now attending adult endocrine services for long-term management of secondary hypopituitarism.

11 beta-hydroxysteroid dehydrogenase type 1 (11 beta HSD1) converts inactive cortisone to active cortisol. 11 beta HSD1 activity is increased in GH deficiency and inhibited by GH and IGF-I in acromegaly. However it is not known whether these changes in cortisol metabolism exert significant effects during hydrocortisone therapy, and the effect has not been studied in patients taking cortisone acetate. We have studied the effect of GH induced 11 beta HSD1 inhibition in hypopituitary adults with severe GH deficiency to determine whether this inhibition has a different magnitude of effect when patients are taking different forms of glucocorticoid replacement therapy.We have taken the ratio of 11-hydroxy/11-oxo cortisol metabolites (Fm/Em), an established measure of net 11 beta HSD activity to reflect the likely balance of cortisol to cortisone exposure in tissues expressing 11 beta HSD1, principally the liver and adipose tissue. We recruited 10 hypopituitary adults all on established glucocorticoid replacement therapy, but who were not receiving GH. Patients were treated with their standard hydrocortisone therapy for one week and an equivalent dose of cortisone acetate in its place for one week in random order. Serial serum cortisol assessments and urine steroid profiles were performed on each treatment. All patients were then established on GH therapy for at least three months before the two-week cycle was repeated. Fm/Em was also measured in a control population (20F, 20M).Prior to GH, the ratio Fm/Em was greater with hydrocortisone compared with cortisone acetate replacement (1.17 +/- 0.28 and 0.52 +/- 0.09 respectively, P0.001) or with normal subjects (normal males: 0.81 +/- 0.24, females 0.66 +/- 0.14). Following GH replacement Fm/Em fell in patients on hydrocortisone and cortisone acetate (Pre-GH: 0.84 +/- 0.40, Post-GH: 0.70 +/- 0.34, P0.05) confirming the inhibition of 11 beta HSD1 by GH/IGF-I. Conversely, the ratio of urinary free cortisol/cortisone did not change indicating unchanged 11 beta HSD2 activity. Mean circulating cortisol also fell in all subjects after GH. This effect was greater during cortisone acetate treatment (-18.7%, P0.0001), than during hydrocortisone replacement (-10.9%, P0.05).Our data suggest that tissue exposure to glucocorticoid is supra-physiological in hypopituitary patients with untreated GH deficiency taking hydrocortisone replacement therapy. This situation is ameliorated by GH replacement therapy. However, local and circulating cortisol concentrations are more vulnerable to the inhibitory effect of GH on 11 beta HSD1 in patients taking cortisone acetate, such that serum cortisol assessments should be made in patients taking cortisone acetate after GH therapy to ensure that glucocorticoid replacement remains adequate.

Patients with type 1 diabetes are at increased risk of cardiovascular disease, which may be related to abnormal lipid metabolism. Secretion and clearance of VLDL apolipoprotein B100 (apoB) are important determinants of plasma lipid concentrations and are known to be influenced by hormones, including insulin and growth hormone.This study examined overnight VLDL apoB metabolism and VLDL composition in six lean patients with type 1 diabetes during euglycaemia (controlled by a varying insulin infusion) and in six age-, sex- and BMI-matched control subjects.VLDL apoB kinetics were determined using a primed constant 1-13C leucine infusion, and VLDL apoB enrichment was measured by gas-chromatography mass-spectrometry. Fasting lipid profile, IGF-I, IGFBP-3, overnight GH profiles and free insulin concentrations were also assessed.Fasting concentrations of triglycerides (TG), total cholesterol (TC), HDL-cholesterol (HDL-C) and LDL-cholesterol (LDL-C) were similar in both groups. The VLDL apoB secretion and metabolic clearance rates were not significantly different between the two groups, but the VLDL-TGNLDL apoB and the VLDL-CNLDL apoB ratios were significantly increased in those with diabetes (P0.02 and P0.03, respectively). Total IGF-I concentrations were similar between the two groups; however, the GH area under the curve and free insulin concentrations were increased in patients with type 1 diabetes (GH: diabetes: 94.8 +/- 15.1 vs. controls: 45.6 +/- 10-6, mU/L/h, P0.04; free insulin: diabetes: 78.4 +/- 5.0 vs. controls: 28.3 +/- 3.26, pmol/l, P0.001). IGFBP-3 concentrations were lower in diabetic patients (diabetes: 2,454.2 +/- 68.7 vs. controls: 3,219.4 +/- 76.4, ng/ml, P0.001). In the control group overnight GH secretion correlated negatively with fasting TC (P0.01) and LDL-C (P0.03) concentrations, whereas free insulin concentrations correlated positively with fasting TG concentrations (P0.009). No significant correlations were found in the patients with diabetes.This study suggests that in euglycaemic conditions patients with type 1 diabetes mellitus have normal VLDL apoB kinetics but altered VLDL composition. The altered VLDL composition may be associated with accelerated atherogenesis. We speculate that the disrupted hormonal balance and, in particular, the increased GH secretion might be responsible for the compositional changes of VLDL particles in type 1 diabetes mellitus.

Insulin-like growth factor-I (IGF-I) has both insulin-like and anabolic actions but unlike insulin, IGF-I circulates bound to a number of specific binding proteins that regulate its availability and activity. Patients with type 1 diabetes mellitus have low levels of circulating IGF-I despite increased growth hormone (GH) secretion, and are a group that may benefit from rhIGF-I therapy. Understanding the relationship between IGF-I and its binding proteins is necessary to appreciate the actions of exogenously administered rhIGF-I. Therefore, we examined the effects of 19 days' subcutaneous administration of rhIGF-I (50 micrograms/kg BID) on the levels of IGF-I, IGF-II and the IGF-binding proteins (IGFBPs), as well as the daily dose of insulin necessary to maintain glycaemic control in patients with type 1 diabetes mellitus.This was an open study, and the patients were studied initially while resident (days 1-5) in the hospital and thereafter (days 6-24) as outpatients. Serum was collected at baseline and at intervals throughout the study for the measurement of total IGF-I, IGF-II, IGFBP-1, -2, -3, free insulin and growth hormone (GH). Daily insulin doses and glucometer readings were recorded throughout the study. The changes in each of these variables were examined. The subjects were six adults (35.3 +/- 4.0 years, mean +/- SE), with type 1 diabetes, and all had reasonable glycaemic control (HbA1c 7.2 +/- 0.5%).rhIGF-I administration increased circulating total IGF-I over two-fold (15.3 +/- 1.9 vs. 33.7 +/- 5.4 nmol/l, mean +/- SEM, P0.01, day 1 vs. day 20) and decreased plasma IGF-II concentration (85.0 +/- 4.7 vs. 50.6 +/- 4.7 nmol/l, P0.01, day 1 vs. day 20). The dose of insulin required for adequate glycaemic control decreased significantly during rhIGF-I therapy (46 +/- 7 vs. 31 +/- 8 U/day, P0.05, day -1 vs. day 19), as did the fasting free insulin concentration (8.4 +/- 1.5 vs. 5.0 +/- 0.8 mU/l, P0.05, baseline vs. day 5). IGFBP-2 concentration increased (388 +/- 115 vs. 758 +/- 219 micrograms/l, P0.05, day 1 vs. day 20), but IGFBP-1 and IGFBP-3 were unchanged during rhIGF-I treatment. Mean nocturnal GH concentration decreased (12.7 +/- 3.3 vs. 3.8 +/- 0.9 mU/l, P = 0.05) after 4 days' rhIGF-I therapy.Twice daily rhIGF-I therapy in adults with type 1 diabetes resulted in an increase in circulating IGF-I with a reciprocal decrease in IGF-II, and a marked elevation of IGFBP-2 concentration. The levels of IGFBP-1 and -3 were not dramatically changed despite a reduction in the concentration of serum free insulin, and a large decrease in the requirement for insulin. The mechanisms behind these changes remains unclear but alterations in circulating levels of of IGFBPs may alter IGF-I bioactivity. If rhIGF-I is to have an application in the management of adults with type 1 diabetes, further work is necessary to determine the metabolic consequences of the alterations seen in the IGFs and their binding proteins following rhIGF-I administration.