Objective: Hepatic steatosis may occur in association with insulin resistance and obesity, two features commonly seen in Cushing's syndrome (CS). The aim of this report is to assess the prevalence of hepatic steatosis in patients with active CS using computed tomography (CT) and to identify any associations between hepatic steatosis, endocrine and biochemical variables and body fat distribution. Patients and measurements: We identified 50 patients with active CS in whom appropriate CT was available to allow measurement of liver and spleen attenuation. In 26 patients, abdominal fat measurements were also available. Serum markers of CS and liver function tests were recorded. Results: Ten of 50 patients had a liver-to-spleen CT attenuation ratio (L/S) of less than 1, indicating hepatic steatosis. There was a significant negative correlation between both liver attenuation and L/S ratio with total abdominal fat area, visceral fat area, the percentage of visceral fat and the visceral to subcutaneous fat ratio; the strongest negative correlation was found between visceral fat area and L/S ratio (r ¼ 2 0.638, P , 0.001, n ¼ 26). L/S ratio positively correlated with alkaline phosphatase levels (r ¼ þ0.423, P ¼ 0.044, n ¼ 23) but with no other serum marker of CS activity or liver enzyme. Conclusions: We have demonstrated hepatic steatosis on CT in 20% of patients with active CS. The presence of hepatic steatosis was significantly correlated with total abdominal fat area and visceral fat area.
Objective: Our aims were to describe the abdominal fat distribution in male patients with Cushing's syndrome (CS) on computerised tomography (CT), to compare our findings with non-cushingoid patients, to validate previous reports of increased visceral fat in female patients with CS and to identify any correlations between fat distribution and biochemical findings. Design: Retrospective and observational. Patients: Appropriate CT scans were identified in 31 patients (seven male) with active CS. Measurements: Total, visceral and subcutaneous fat areas were obtained. The percentage of visceral fat and the visceral to subcutaneous fat ratio (V:S ratio) were calculated. Biochemical data were recorded. Control data of fat distribution were obtained from the literature. Results: There was a significant increase in the V:S ratio in male patients with CS when compared with non-cushingoid controls (1.175^0.59 vs 0.77^0.39, 95% confidence interval (CI) 0.0817 -0.728). There was a significant increase in the V:S ratio in female patients with CS (0.845^0.53 vs 0.38^0.19, 95% CI 0.269 -0.661). There was no difference in the V:S ratio between male and female patients with CS (1.175^0.59 vs 0.845^0.53, 95% CI 20.144 -0.804). No significant correlations between fat distribution and glucose levels, circulating cortisol, ACTH or lipids were found. Conclusions: Our data demonstrate an increase in visceral fat distribution in both male and female patients with CS, with the abolition of the normal male to female difference in visceral fat. Increased visceral fat may increase the risk of the metabolic syndrome in this group of patients.
Although growth hormone (GH) replacement therapy is increasingly utilized in the management of adult hypopituitary patients, optimum dosing schedules are poorly defined. The use of weight-based or surface area-based dosing may result in overtreatment, and individual variation in susceptibility on the basis of gender and other factors is now being recognized. To optimize GH replacement and to explore further gender differences in susceptibility, we used a dose titration regimen, starting at the initiation of GH replacement therapy, in 50 consecutive adult-onset hypopituitary patients, and compared the results with those in 21 patients previously treated using a weight-based regimen. Titrated patients commenced GH 0.8 IU/day subcutaneously (0.4 IU/day if hypertensive or glucose tolerance impaired). Serum insulin-like growth factor I (IGF-I) was measured at 0, 2, 4, 6, 8, 10, and 12 weeks in all patients. Serum IGF binding protein 3 and acid labile subunit were measured at the same time points in 17 patients (8 male, 9 female). Patients were reviewed every 4 weeks and the dose of GH increased, if necessary, to achieve a serum IGF-I level between the median and the upper end of the age-related reference range. There was no significant difference between mean serum IGF-I at 2 and 4 weeks, or between 6 and 8 weeks, indicating that the full effects of a change in dose are evident within 2 weeks of that change. Maintenance doses were significantly higher in females than males [1.2 (0.8-2.0) vs. 0.8 (0.4-1.6) IU/day; median (range); P < 0.0001], and the median time to achieve maintenance dose was significantly shorter in males [4 (2-12) vs. 9 (2-26) weeks; P < 0.0001]. Median maintenance dose was lower overall than in a group of 21 patients initially commenced on GH using a weight-based dosing schedule, with subsequent adjustment of dose during clinical follow-up [1.5 (0.4-3.2) IU/day; P = 0.02]. Reduction in waist measurement and waist to hip ratio at 6 and 12 months was similar in females (P < 0.001) and males (P < 0.01). Well-being improved significantly after 3 months of GH therapy (14.2 +/- 5.9 vs. 7.4 +/- 4.5 SD; P < 0.0001), and there were no gender differences. Adult Growth Hormone Deficiency Assessment (AGHDA) scores at 6 months were similar to maintenance scores in patients commenced on weight-based regimens. Measurements of ALS and IGFBP-3 added no useful extra information to IGF-I in managing the dose titration. The practical scheme outlined for dose titration of GH replacement resulted in rapid achievement of lower maintenance doses than those achieved using conventional weight-based regimens without loss of efficacy. It was particularly important in female patients who demonstrated decreased overall sensitivity to GH and required higher doses to achieve the same effects as males. This constitutes the first report of a uniform titration regimen based on a defined target range of serum IGF-I in a large patient cohort.
Ghrelin is a peptide hormone secreted into the circulation from the stomach but also synthesised in a number of tissues, suggesting both endocrine and paracrine effects. These include: stimulation of GH, prolactin and ACTH secretion; an increase in appetite; a diabetogenic effect on carbohydrate metabolism; positive inotropic effects on heart; vasodilatation; and effects on cell proliferation. The possibility of chronic manipulation of the ghrelin system on body weight, growth and appetite remains an exciting new field of exploration.European Journal of Endocrinology 151 S67-S70
We conclude that not only is leptin stored within the pituitary, but it may also be released from pituitary cells and modulate other pituitary hormone secretion. Pituitary leptin may therefore be a novel paracrine regulator of pituitary function.
The cyclin D1 (CCND1) gene contains a frequent A/G polymorphism within the splice donor region of exon 4/intron 4. CCND1 genotype is associated with clinical outcome in a number of malignancies although prognostic significance varies with tumour type. We examined CCND1 allele frequencies and genotype distribution in 294 patients with sporadic pituitary adenomas of various histologies. CCND1 allele frequencies and distribution of genotypes were similar in the 294 cases compared with previously reported control populations. Analysis according to tumour subtype showed no statistical difference in allele frequencies compared with controls. However, CCND1 genotype distribution in the somatotrophinomas showed a significant difference compared with normal controls (P = 0.008). We next examined CCND1 allele frequencies and genotype distribution across the tumour grades. Within the total tumour cohort the CCND1 allele frequencies showed a significant inverse relationship across the tumour grades (P = 0.005). The CCND1 A allele progressively increased from grade 1 (0.37) through to grade 4 (0.62) tumours, whilst the CCND1 G allele frequency progressively decreased from grade 1 (0.63) through to grade 4 (0.38) tumours. Trend analysis of CCND1 genotypes showed a significant progressive increase in AA frequency from grade 1 (15%) through to grade 4 (46%) tumours (P = 0.005). The CCND1 GG genotype progressively decreased from grade 1 (41%) through to grade 4 (23%) tumours (P = 0.204). No statistical significance was observed between CCND1 AG genotype and tumour grades. While the functional significance of the observed segregation of the CCND1 A/G polymorphism and tumour grade is unclear, our data suggest that CCND1 allele frequencies and genotype distributions show significant differences between tumour grades in sporadic pituitary adenomas. Since CCND1 genotype may be determined by analysis of peripheral blood samples it may provide a useful predictive marker for those tumours likely to show invasive behaviour. This may be clinically useful in indicating which tumours should receive adjunctive treatment (e.g. radiotherapy) immediately after surgical resection.
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