Objective: Endogenous Cushing's syndrome (CS) is associated with bone loss and an increased risk of fractures. However, the long-term outcome of treatment on bone health has not been adequately clarified. Design: We followed 33 patients with active CS prospectively before and twice after treatment (mean follow-up 33 (n ¼ 25) and 71 months (n ¼ 18), respectively). The patients were compared to age-, sex-and body mass index (BMI)-matched controls, also followed longitudinally. Methods: Bone mineral indices (bone mineral density (BMD), bone mineral content (BMC) and bone area) were evaluated in the lumbar spine (LS), femoral neck (FN), and total body (TB) by dual-energy X-ray absorptiometry (DXA). Biochemical markers of bone turnover were assessed by serum levels of osteocalcin and C-terminal telopeptides of Type-1 collagen (CTX-1). Results: Mann -Whitney rank sum tests showed that BMD of the LS, FN and TB was reduced by 14.8% (P , 0.001), 15.7% (P , 0.001), and 9.2% (P , 0.001) in CS vs. controls at baseline, with markedly reduced serum osteocalcin (P ¼ 0.014) and increased CTX-1 (P ¼ 0.012) levels, but no correlation between markers. At first follow-up, BMD was increased in LS (7.9%, P , 0.001) and FN (3.5%, P ¼ 0.003) compared to baseline. The time-dependent rise in BMD (LS (r ¼ 0.59; P ¼ 0.002) and FN (r ¼ 0.52; P ¼ 0.007); Spearman's rank correlation), in CS was paralleled by increased osteocalcin (275%, P , 0.001) and correlation between biochemical markers (r ¼ 0.92, P , 0.001; Pearson's correlation). TB BMD did not increase significantly before the second follow-up, when BMD Z-scores were normalized in all three compartments. Conclusion: Our observations demonstrate restoration of coupled bone remodeling and normalization of bone mineral density in all measured skeletal compartments of treated CS patients after prolonged recovery, first significant in predominantly trabecular bone (i.e. lumbar spine).

Objective: It is well known that patients with endogenous Cushing's syndrome (CS) have decreased bone mass and enhanced risk for osteoporotic fractures, secondary to decreased bone formation and increased bone resorption. Immunological mediators, such as cytokines, have recently been shown to influence bone metabolism, and in the present study we examined serum levels of several cytokines, with known or potential effects on bone homeostasis, in 33 consecutive recruited untreated CS patients and 33 age-, sex-and body mass index-matched healthy controls. Methods: Cytokine levels were measured by enzyme immunoassay and bone mass by dual-energy X-ray absorptiometry. Results: Our main findings were (i) interleukin (IL)-8 and IL-18 levels were significantly increased in CS patients compared with controls. (ii) Levels of both IL-8 and IL-18 were positively correlated to serum cortisol. (iii) For serum levels of the 'classical' resorptive cytokines, i.e. IL-6 and tumor necrosis factor a, no significant differences were found between CS patients and controls. (iv) Raised IL-18 levels were correlated with decreased osteocalcin levels in CS patients. Conclusions: Our results demonstrated that CS patients have markedly elevated levels of the proinflammatory cytokines IL-8 and IL-18 in spite of high levels of the immunosuppressive hormone cortisol. These cytokines may be involved in the pathogenesis of disturbed bone homeostasis in CS.

The weight gain and visceral obesity associated with Cushing's syndrome (CS) has been linked to elevated plasma leptin levels, although the mechanism behind a central leptin resistance in these patients is unknown. Several studies describe interactions among the hypothalamic-pituitary-adrenal axis, leptin, and the IL-1 system. To investigate these interactions, we have evaluated changes in regional fat distribution, by DEXA, and the role of circulating cortisol, leptin, IL-1beta, and IL-1 receptor antagonist (IL-1Ra), in relation to these changes, in 27 (19 DEXA; 27 serum measurements) patients with CS, before and after surgical treatment (mean follow-up, 31 months; range, 5-80), and compared them with measurements of age-, sex-, and body mass index-matched healthy controls (also obtained longitudinally). We found that surgical treatment caused a decrease in all fat parameters, without changing lean body mass, and these changes were significantly larger than the so-called natural changes occurring in control subjects. These changes in CS patients were paralleled by decreases in cortisol, leptin, and IL-1Ra, whereas IL-1beta increased. Stepwise linear regression showed that serum IL-1Ra was strongly associated with regional fat distribution, and especially truncal fat mass, both at baseline and during treatment. In conclusion, the present study shows that treatment significantly changes body composition in CS patients by decreasing fat mass, especially in the truncal region, without major effects on lean body mass. We also show that circulating IL-1Ra is strongly associated with these changes, signifying a relationship among the hypothalamic-pituitary-adrenal axis, IL-1 system, and regional fat distribution in these patients.

Fifty-five patients with adult-onset GH deficiency (mean age, 49 years) were enrolled in a placebocontrolled, crossover study to investigate the effects of GH therapy on exercise capacity, body composition, and quality of life (QOL). GH and placebo were administered for 9 months each, separated by a 4-month washout period. GH therapy was individually dosed to obtain an IGF-I concentration within the normal range for age and sex. The final mean daily dose of GH was 1.2 IU/day for men and 1.8 IU/day for women. Mean IGF-I concentration at baseline was higher in men than in women (95^33 vs 68^41 mg/l respectively; P , 0.04) and increased to a similar level on GH therapy. Body fat mass was reduced by 1.9^2.9 kg and lean body mass was increased by 1.8^2.8 kg (P ¼ 0.0001 for each) with GH treatment. Total and low-density cholesterol levels decreased. Absolute maximal oxygen uptake increased by 6% (P ¼ 0.01), relative to body weight by 9% (P ¼ 0.004), and there was a trend toward increased endurance performance by 7% (P ¼ 0.07). There were no significant effects on QOL. In conclusion, treatment with a low, physiologic dose of GH produced positive effects on body composition and lipids and improved exercise capacity, likely to be of clinical relevance. No changes in QOL were seen, possibly because of a good QOL at baseline.

Taken together, these results implicate the transcription factor GILZ in the pathophysiology of GIO by regulating osteoblast maturation and bone turnover.

Our findings suggest a complex interaction between CS and inflammation. In particular, the raised levels of IL-8 and OPG in CS patients, despite glucocorticoid excess, may represent an inflammatory and pro-atherogenic phenotype. However, the clinical relevance of these findings will have to be clarified.

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