Updated NIH Clinical Trials of interest to Cushing's patients

• A Study to Confirm Recurrent or Persistent Cushing's Syndrome in Patients With Signs or Symptoms of Hypercortisolemia
• Extension Study to Assess the Safety and Efficacy of Pasireotide in Patients With Cushing's Disease
• Prospective, Open-Label, Multicenter, International Study of Mifepristone for Symptomatic Treatment of Cushing's Syndrome Caused by Ectopic Adrenal Corticotrophin Hormone (ACTH) Secretion
• A Study of the Efficacy and Safety of CORLUX in the Treatment of Endogenous Cushing's Syndrome
• Diagnostic Performance of Screening Tests for Cushing's Syndrome
• Long-term Cardiovascular Risk in Cured Cushing's Patients
• Long Term Post Operative Follow-Up of Cushing Syndrome
• Jugular Vein Sampling for Hormone Levels for the Diagnosis of Cushing Syndrome
• New Imaging Techniques in the Evaluation of Patients With Ectopic Cushing Syndrome
• An Extension Study of CORLUX in the Treatment of Endogenous Cushing's Syndrome
• Study of Hypercortisolism in Cushing's Syndrome and Stress-Induced Pseudo-Cushing's Syndrome
• Preoperative Bexarotene Treatment for Cushing's Disease
• Glucocorticoid Receptor Antagonism in Subclinical Cushings
• Safety and Efficacy of Different Dose Levels of Pasireotide in Patients With de Novo, Persistent or Recurrent Cushing's Disease
• Adrenalectomy Versus Follow-up in Patients With Subclinical Cushings Syndrome
• Insulin Sensitivity and Substrate Metabolism in Patients With Cushing's Syndrome
• A Study to Assess SOM230 in Patients With Pituitary Cushing's Disease
• Study of Cushing's Syndrome Not Related to ACTH Production
• Study of Depression, Peptides, and Steroids in Cushing's Syndrome
• Hippocampal Complex Volume and Memory Dysfunction in Cushing's Syndrome

In Vivo and In Vitro Glucocorticoid Sensitivity in Obese People With Cushingoid Appearance

Obesity (2008) 16 10, 2374–2378. doi:10.1038/oby.2008.346

Akheel A. Syed¹, Christopher P.F. Redfern² and Jolanta U. Weaver^3,4

1. ¹Department of Endocrinology, Newcastle University Teaching Hospitals, Newcastle upon Tyne, UK
2. ²Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK
3. ³School of Clinical Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
4. ⁴Department of Diabetes and Endocrinology, Queen Elizabeth Hospital, Gateshead, UK

Correspondence: Christopher P.F. Redfern (chris.redfern@ncl.ac.uk)

Received 21 September 2007; Accepted 10 March 2008; Published online 24 July 2008.

Abstract:

Clinical similarities between Cushing's syndrome and obesity/metabolic syndrome have led to speculation of a role for glucocorticoids (GCs) in the etiopathogenesis of obesity. People with idiopathic obesity have normal circulating cortisol concentrations. However, there may be considerable interindividual variation in GC sensitivity. The objective of this study was to determine whether enhanced GC sensitivity in the absence of GC excess was a characteristic of obese people with cushingoid features. We studied 12 obese subjects with cushingoid features in the absence of Cushing's syndrome and six slim control participants. Data recorded included BMI, waist-to-hip ratio, blood pressure, glucose and insulin response to 75 g oral glucose challenge, and low-dose (0.25 mg) overnight dexamethasone (DEX) suppression test (ODST-0.25 mg). To study GC-sensitivity in vitro, we performed dose–response studies of DEX-induced suppression of interleukin-6 (IL-6) secretion in skin fibroblast cultures. Seven obese subjects were normosensitive and five subjects hypersensitive to GCs in vitro. ODST-0.25 mg resulted in a median suppression of cortisol from baseline of 32% in normosensitive and 60% in hypersensitive obese subjects (P < 0.004). No other clinical or biochemical measures were discriminatory between these two groups. These data from two independent measures of GC sensitivity suggest that enhanced GC sensitivity may characterize a substantial proportion of obese people with cushingoid appearance.

The role of glucocorticoids (GCs) in promoting and maintaining positive energy balance, a function that is exaggerated in Cushing's syndrome, has been suspected in the etiopathogenesis of simple obesity. People with idiopathic obesity have normal circulating cortisol concentrations that are independent of fat stores but an augmented cortisol turnover rate (1,2) and enhanced hypothalamic–pituitary–adrenal (HPA) axis reactivity (3,4,5,6). There is considerable interindividual variation in GC sensitivity in health (7,8). This is also evident in some patients who develop Cushing's syndrome on low-dose GC therapy for conditions such as asthma, whereas others appear to be resistant to much higher doses. Thus, it has been speculated that obesity with Cushingoid appearance is a state of enhanced responsiveness to GCs. The aim of this study was to test the hypothesis that adiposity was associated with enhanced GC-sensitivity in vitro and in vivo in obese individuals with a cushingoid appearance.

Participants and Methods

We studied 12 obese subjects (10 women) aged 18–53 (median 29.5) years who had cushingoid features such as central obesity and skin striae on clinical assessment, suggestive of enhanced GC activity; none had Cushing's syndrome (at least two normal 24-h urinary free cortisol measurements) or a history of treatment with steroids, hypothyroidism, or any major illness. For comparative analysis, we studied six healthy control participants (four women) aged 33–49 (median 40) years with BMI <25 kg/m². All participants gave informed signed consent and the local research ethics committee approved the study. Data recorded included age, gender, weight, height, BMI, waist circumference, hip circumference, waist-to-hip ratio, blood pressure, and bioimpedance analysis of body composition. A 75-g oral glucose tolerance test was performed after an overnight fast with measurements of fasting and 2-h glucose and insulin levels. Insulin resistance was computed by homeostasis model assessment (9). An overnight dexamethasone (DEX) suppression test (ODST) was performed on a subsequent day with 0.25 mg DEX administered at 2300 hours and serum samples collected at 0900 hours the following morning. Cortisol, corticosteroid-binding globulin, prolactin, adiponectin, resistin, leptin, interleukin-6 (IL-6), testosterone, sex hormone binding globulin, luteinizing hormone, follicle-stimulating hormone, and estradiol concentrations were measured at baseline (0900 hours fasting sample of oral glucose tolerance test); cortisol, prolactin, adiponectin, resistin, leptin, and DEX concentrations were also measured following ODST-0.25 mg. Free cortisol index, calculated as total cortisol (nmol/l)/corticosteroid-binding globulin (mg/l), was used as a surrogate for serum-free cortisol (10). The proportional change in concentrations before and after ODST-0.25 mg was used in analyses. Study participants were not on estrogenic or cytochome P450-metabolized drug therapies and gonadal hormone profiles in menstruating women subjects indicated that they were in the follicular phase of the menstrual cycle when biochemical tests were carried out.

GC-sensitivity in vitro

We developed a novel bioassay for determining GC-sensitivity in vitro by quantifying DEX-induced suppression of unstimulated, natural state IL-6 secretion in cultured human skin fibroblasts (HSFs). Forearm skin biopsies were taken with a 3 mm Stiefel disposable punch. Primary cultures were set up on Matrigel (BD Biosciences, Oxford, UK) bathed in MEM-Alpha with Glutamax-I (50%), fetal bovine serum (50%), penicillin (5,000 units), streptomycin (5,000 g), and amphotericin 0.1% (all from Invitrogen, Paisley, UK) at 37 °C in an atmosphere of 5% CO₂. HSFs were propagated in 90% DMEM with Nutrient Mixture F-12 with Glutamax-I (Invitrogen) and 10% fetal bovine serum and passaged by trypsinisation. HSFs harvested at Passage 5–8 were grown to full confluence in 96-well culture plates. The wells were exposed to DEX in doses ranging from 10^–11 to 10^–4 M for 1 h followed by rinsing and incubation in serum-free media overnight for 12 h. Cell supernatants were aspirated and analyzed in duplicate for IL-6 using a human IL-6 ELISA (Bender MedSystems, Vienna, Austria) as per the manufacturer's instructions. Control solutions containing high and low concentrations of IL-6 were used in every batch. A coefficient of variation <20% was accepted for reproducibility of the assay (11), and the overall mean coefficient of variation was 4.58% in this study. Under these conditions, DEX produced a clear dose–response decrement in the IL-6 content of culture supernatants and the IC₅₀ (median inhibitory concentration) was computed by four-parameter nonlinear regression sigmoidal dose–response with variable slope curve fitting. The lower-bound value of the 97% confidence interval of the median IC₅₀ in controls was used as the cutoff for classifying obese subjects as normosensitive (IC₅₀ 4.4 nmol/l) or hypersensitive (IC₅₀ < 4.4 nmol/l) to GCs. Statistical analyses were performed with Prism v4 (GraphPad Software, San Diego, CA), SPSS v11 (SPSS, Chicago, IL), and Systat v10 (Systat Software, San Jose, CA). We used conservative, nonparametric statistics (Mann–Whitney U-test, asymptotic two-tailed significance) for comparative analysis. For testing the association of cortisol response to ODST-0.25 mg and in vitro GC sensitivity, stepwise backward multiple regression analysis was performed with an F-ratio probability of 0.15 as the criterion for removal or inclusion of explanatory variables in the model. Pearson's correlation coefficient was determined as a measure of correlation between variables. Receiver operating characteristic analysis was used for defining sensitivity and specificity of cortisol response to ODST-0.25 mg in relation to GC-sensitivity in vitro. A P value <0.05 was accepted as significant.

Results

GC-sensitivity in vitro

GC-sensitivity in vitro was represented by the IC₅₀ of DEX-induced inhibition of IL-6 secretion in HSFs (Figure 1a). The median IC₅₀ for controls was 9.7 nmol/l (97% confidence interval, 4.4–22.3 nmol/l). Seven obese subjects were normosensitive (obese normosensitive, ONS; Figure 1b) with median IC₅₀ 12.6 nmol/l (compared to controls, P = 0.09). The remaining five obese subjects were hypersensitive (obese hypersensitive, OHS); the median IC₅₀ was 0.5 nmol/l and significantly different from control participants (P < 0.006) and ONS subjects (P < 0.004). There were no significant differences in clinical measures including the degree and distribution of adiposity, blood pressure, fasting and 2-h glucose during oral glucose tolerance test, homeostasis model assessment of insulin resistance, and lipid profiles between ONS and OHS subjects (Table 1).

Figure 1.

Glucocorticoid (GC)-sensitivity in vitro and in vivo. (a) GC- sensitivity in vitro. Dose–response curves showing fall in IL-6 concentration (y-axis; percentage of baseline value) plotted against increasing dexamethasone (DEX) concentrations (x-axis; log scale); thick solid line, median dose–response curve for control participants (CON), flanked by 95% confidence intervals of the curve (gray shaded area) for illustration (97% confidence interval of the median was used for determining the reference range); thin solid lines, dose–response curves for obese-hypersensitive (OHS) subjects; broken lines, dose–response curves for obese-normosensitive (ONS) subjects; IC₅₀ is marked by dotted horizontal line. (b) Median inhibitory concentration. IC₅₀ values for DEX-induced interleukin-6 (IL-6) suppression in vitro (y-axis; log scale), grouped by participant type. (c) GC-sensitivity in vivo. Percent suppression in cortisol concentration from baseline after overnight 0.25 mg DEX suppression test (y-axis), grouped by participant type. (d) Correlation of in vivo and in vitro GC sensitivity. Linear regression of cortisol response to overnight 0.25 mg DEX suppression test (y-axis) against IC₅₀ values of DEX concentration (x-axis; log scale) confirmed significant correlation (Pearson's r = 0.6, P < 0.009). Open circles, female; filled circles, male; horizontal lines, median value.

Full figure and legend (20K)

Table 1 - Clinical measures in participants.

Full table (55K)

Overnight 0.25 mg DEX suppression test (ODST-0.25 mg)

There were no significant differences between the groups in serum DEX concentrations after ODST-0.25 mg (Table 1). Although there were no significant differences in baseline serum total cortisol concentrations or free cortisol index, the median-cortisol response to ODST-0.25 mg was 24.1% in control participants, 32.4% in ONS and 60.0% in OHS subjects (Figure 1c). The cortisol responses in OHS subjects were significantly different compared to ONS subjects (P < 0.004). Stepwise backward multiple regression performed to further test the relationship of cortisol response (dependent variable) to in vitro GC sensitivity in obese subjects with age, BMI, waist-to-hip ratio, baseline cortisol, corticosteroid-binding globulin, and serum DEX concentration after ODST-0.25 mg as additional explanatory variables confirmed a significant association (P < 0.001; Table 2). The IC₅₀ of DEX-induced inhibition of IL-6 secretion in HSFs correlated significantly with cortisol response to ODST-0.25 mg (Pearson's r = 0.6, P < 0.009; Figure 1d). On receiver operating characteristic analysis, a cutoff of 50% suppression in cortisol from baseline in response to ODST-0.25 mg gave a sensitivity of 100% and specificity of 92% for distinguishing OHS from ONS subjects.

Table 2 - Multiple regression of cortisol responses to ODST-0.25 mg.

Full table (27K)

Insulin, prolactin, adipokines, and gonadal hormones

Insulin resistance was greater in obese subjects (1.55) than in controls (0.5; P < 0.04), but there was no significant difference between the ONS (1.8) and OHS (1.1) subgroups (P > 0.51). Median basal concentrations in control participants compared to obese subjects of leptin were 7.68 ng/ml vs. 118.06 ng/ml (P < 0.001), resistin 3.60 ng/ml vs. 7.51 ng/ml (P < 0.025), and IL-6 0.70 pg/ml vs. 1.98 pg/ml (P < 0.002). However, there were no significant differences between ONS and OHS subjects in leptin (99.61 ng/ml vs. 140.24 ng/ml, P > 0.46), resistin (8.24 ng/ml vs. 6.78 ng/ml, P > 0.68), or IL-6 (1.70 pg/ml vs. 2.18 pg/ml, P > 0.93). There were no significant differences in basal concentrations of prolactin and adiponectin between any of the groups and there were no significant differences in the responses of leptin, resistin, adiponectin, IL-6, or prolactin to ODST-0.25 mg across the groups. After taking gender into account, there were no differences in serum concentrations of luteinizing hormone, follicle-stimulating hormone, sex hormone binding globulin, total and calculated bioavailable (free) testosterone, and estradiol between groups.

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Discussion

Obesity with cushingoid appearance, by sharing some clinical features of Cushing's syndrome, raises the possibility of hypersensitivity to normal circulating levels of endogenous GCs. Various bioassays have been described for measuring cellular GC sensitivity (8,12). Most rely on GC-induced suppression of cell proliferation or mitogen-stimulated cytokine release in peripheral blood cells, which may be affected by exposure to circulating GCs in vivo before harvesting, or by the stimulation process itself. We therefore developed a bioassay based on GC-induced suppression of IL-6 secretion in HSFs to measure GC sensitivity. This is unaffected by in vivo circulating GCs and reflects a stable, heritable property of the HSFs derived from each participant. We studied a sample of obese subjects who were preselected on clinical suspicion of GC hypersensitivity (cushingoid appearance with no evidence of GC excess) of which two-fifths manifested evidence of tissue GC hypersensitivity. Furthermore, the hypersensitive obese subjects were indistinguishable from normosensitive obese subjects by routine objective clinical measures such as body weight, BMI, waist circumference, or waist-to-hip ratio in this small sample. Thus, conventional clinical features alone are inadequate at identifying GC-hypersensitive individuals.

Although ODST-1 mg is often used as a screening test in clinical investigation of Cushing's syndrome, in people without Cushing's syndrome, it results in too much suppression of the HPA axis to allow detection of individual differences in feedback sensitivity. However, ODST-0.25 mg results in a broad range of cortisol concentrations, giving a good insight into feedback sensitivity (7) and low-dose DEX can distinguish a finely regulated HPA axis from a poorly regulated one (13). Earlier population studies employing low-dose overnight DEX suppression tests have reported considerable variation in GC sensitivity of the HPA axis, but have been unable to reliably identify enhanced GC sensitivity in obesity. By selecting subjects with morphological features suggestive of GC excess in the absence of true Cushing's syndrome, we have shown that there is a clear difference in regulation of cortisol concentration in vivo between normosensitive and hypersensitive obese people, thus maintaining circulating cortisol levels within normal limits. This autoregulation is also reflected by GC sensitivity at a cellular level. Whereas measurement of serum-free cortisol is technically difficult, expensive, and not widely available, free cortisol index has been shown to correlate strongly with measured free cortisol (10). Moreover, percent-cortisol response (proportional change from baseline) to ODST, as used in this study, is unaffected by whether total cortisol or free cortisol index is used. The results of this study on a small sample of obese individuals suggest that percent-cortisol response to ODST-0.25 mg may be used to identify those who are likely to have underlying enhanced GC sensitivity. However, this conclusion will need independent replication in larger cohorts before warranting incorporation as a test for GC sensitivity into standard clinical practice.

Leptin, an adipokine hormone involved in negative feedback regulation of food intake, is inducible by GCs both in normal weight and obese individuals (14). Conversely, it can directly inhibit GC secretion in the adrenal gland (15). Thus, it has been suggested that feedback loops exist at the tissue level regulating cortisol concentrations within the intraindividual physiological range, resulting in reduced negative feedback tone higher up in the HPA axis (16). Basal leptin, resistin, and IL-6 concentrations were significantly higher overall in obese subjects compared to control participants, but there was no statistical difference between ONS and OHS subjects in our small sample. Similarly, although obese subjects had greater insulin resistance overall, there was no statistical difference between ONS and OHS subjects. This suggests that insulin resistance is more a function of obesity per se rather than GC sensitivity, but study in a larger sample is warranted. A previous study has demonstrated evidence of variation in cortisol response to ODST-0.25 mg depending on the phase of the menstrual cycle in women (17). However, this is unlikely to have influenced the outcome of this study as the women were assessed in the same phase of the menstrual cycle. A reduction in the sensitivity of the HPA axis to GC feedback inhibition has been demonstrated in 70-year-old compared to 26-year-old subjects (18). Although the median age of control participants was 10 years greater than of obese subjects in our study, there was no difference in age between the ONS and OHS subgroups. Moreover, intraindividual GC sensitivity has been shown to be constant with aging (7).

In conclusion, we suggest that enhanced sensitivity to GCs may characterize excess adiposity in a proportion of obese people with cushingoid appearance. As clinical assessment alone may not have sufficient discriminatory value, an ODST-0.25 mg may be used as a screening test to identify people with GC hypersensitivity for future research.

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Disclosure

The authors declared no conflict of interest.

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References

REFERENCES

1. Dunkelman SS, Fairhurst B, Plager J, Waterhouse C. Cortisol metabolism in obesity. J Clin Endocrinol Metab 1964;24: 832–841. | PubMed | ChemPort |
2. Hautanen A, Adlercreutz H. Altered adrenocorticotropin and cortisol secretion in abdominal obesity: implications for the insulin resistance syndrome. J Intern Med 1993;234: 461–469. | PubMed | ChemPort |
3. Marin P, Darin N, Amemiya T et al. Cortisol secretion in relation to body fat distribution in obese premenopausal women. Metabolism 1992;41: 882–886. | Article | PubMed | ChemPort |
4. Weaver JU, Kopelman PG, McLoughlin L, Forsling ML, Grossman A. Hyperactivity of the hypothalamo-pituitary-adrenal axis in obesity: a study of ACTH, AVP, beta-lipotrophin and cortisol responses to insulin-induced hypoglycaemia. Clin Endocrinol (Oxf) 1993;39: 345–350. | Article | PubMed | ChemPort |
5. Rosmond R, Dallman MF, Bjorntorp P. Stress-related cortisol secretion in men: relationships with abdominal obesity and endocrine, metabolic and hemodynamic abnormalities. J Clin Endocrinol Metab 1998;83: 1853–1859. | Article | PubMed | ISI | ChemPort |
6. Pasquali R, Ambrosi B, Armanini D et al. Cortisol and ACTH response to oral dexamethasone in obesity and effects of sex, body fat distribution, and dexamethasone concentrations: a dose-response study. J Clin Endocrinol Metab 2002;87: 166–175. | Article | PubMed | ChemPort |
7. Huizenga NA, Koper JW, de Lange P et al. Interperson variability but intraperson stability of baseline plasma cortisol concentrations, and its relation to feedback sensitivity of the hypothalamo-pituitary-adrenal axis to a low dose of dexamethasone in elderly individuals. J Clin Endocrinol Metab 1998;83: 47–54. | Article | PubMed | ChemPort |
8. Chriguer RS, Elias LL, da Silva IM Jr, Vieira JG, Moreira AC, de Castro M. Glucocorticoid sensitivity in young healthy individuals: in vitro and in vivo studies. J Clin Endocrinol Metab 2005;90: 5978–5984. | Article | PubMed | ChemPort |
9. Levy JC, Matthews DR, Hermans MP. Correct homeostasis model assessment (HOMA) evaluation uses the computer program. Diabetes Care 1998;21: 2191–2192. | Article | PubMed | ISI | ChemPort |
10. le Roux CW, Sivakumaran S, Alaghband-Zadeh J, Dhillo W, Kong WM, Wheeler MJ. Free cortisol index as a surrogate marker for serum free cortisol. Ann Clin Biochem 2002;39: 406–408. | Article | PubMed | ChemPort |
11. Rosner B. Fundamentals of biostatistics. 2006; Thomson-Brooks/Cole: Belmont, CA.
12. Vermeer H, Hendriks-Stegeman BI, Verrijn Stuart AA, van Buul-Offers SC, Jansen M. A comparison of in vitro bioassays to determine cellular glucocorticoid sensitivity. Eur J Endocrinol 2004;150: 41–47. | Article | PubMed | ChemPort |
13. Rosmond R, Bjorntorp P. The hypothalamic-pituitary-adrenal axis activity as a predictor of cardiovascular disease, type 2 diabetes and stroke. J Intern Med 2000;247: 188–197. | Article | PubMed | ChemPort |
14. Dagogo-Jack S, Selke G, Melson AK, Newcomer JW. Robust leptin secretory responses to dexamethasone in obese subjects. J Clin Endocrinol Metab 1997;82: 3230–3233. | Article | PubMed | ChemPort |
15. Bornstein SR, Uhlmann K, Haidan A, Ehrhart-Bornstein M, Scherbaum WA. Evidence for a novel peripheral action of leptin as a metabolic signal to the adrenal gland: leptin inhibits cortisol release directly. Diabetes 1997;46: 1235–1238. | Article | PubMed | ISI | ChemPort |
16. Syed AA, Weaver JU. Glucocorticoid sensitivity: the hypothalamic- pituitary-adrenal-tissue axis. Obes Res 2005;13: 1131–1133. | Article | PubMed | ChemPort |
17. Altemus M, Redwine L, Leong YM et al. Reduced sensitivity to glucocorticoid feedback and reduced glucocorticoid receptor mRNA expression in the luteal phase of the menstrual cycle. Neuropsychopharmacology 1997;17: 100–109. | Article | PubMed | ISI | ChemPort |
18. Wilkinson CW, Peskind ER, Raskind MA. Decreased hypothalamic- pituitary-adrenal axis sensitivity to cortisol feedback inhibition in human aging. Neuroendocrinology 1997;65: 79–90. | Article | PubMed | ChemPort |

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Acknowledgments

Funding for this study was provided by Gateshead NHS Research and Development Fund and the Queen Elizabeth Hospital Diabetes Charitable Fund. We are grateful to Lorna Ingoe (Queen Elizabeth Hospital and Newcastle University) for assisting in the conduct of clinical assessments, John Barker (Queen Elizabeth Hospital) for clinical biochemistry services, and Penny Lovat (Newcastle University) for helpful discussions on tissue culture technique.

From http://www.nature.com/oby/journal/v16/n10/full/oby2008346a.html

Corticotrophin-releasing factor mediates hypophagia after adrenalectomy, increasing meal-related satiety responses

Ernane Torres Uchoa, Lilian Eslaine Costa Mendes da Silva, Margaret de Castro, Jose Antunes-Rodrigues and Lucila Leico K. Elias

a Department of Physiology, School of Medicine of Ribeirao Preto, University of Sao Paulo, Brazil

b Department of Internal Medicine, School of Medicine of Ribeirao Preto, University of Sao Paulo, Brazil

Adrenalectomy-induced hypophagia is associated with increased satiety-related responses, which involve neuronal activation of the nucleus of the solitary tract (NTS). Besides its effects on the pituitary–adrenal axis, corticotrophin-releasing factor (CRF) has been shown to play an important role in feeding behaviour, as it possesses anorexigenic effects. We evaluated feeding-induced CRF mRNA expression in the paraventricular nucleus (PVN) and the effects of pretreatment with CRF₂ receptor antagonist (Antisauvagine-30, AS30) on food intake and activation of NTS neurons in response to feeding in adrenalectomised (ADX) rats. Compared to the sham group, ADX increased CRF mRNA levels in the PVN of fasted animals, which was further augmented by refeeding. AS30 treatment did not affect food intake in the sham and ADX + corticosterone (B) groups; however, it reversed hypophagia in the ADX group. In vehicle-pretreated animals, refeeding increased the number of Fos and Fos/TH-immunoreactive neurons in the NTS in the sham, ADX and ADX + B groups, with the highest number of neurons in the ADX animals. Similarly to its effect on food intake, pretreatment with AS30 in the ADX group also reversed the increased activation of NTS neurons induced by refeeding while having no effect in the sham and ADX + B animals. The present results show that adrenalectomy induces an increase in CRF mRNA expression in the PVN potentiated by feeding and that CRF₂ receptor antagonist abolishes the anorexigenic effect and the increased activation of NTS induced by feeding in the ADX animals. These data indicate that increased activity of PVN CRF neurons modulates brainstem satiety-related responses, contributing to hypophagia after adrenalectomy.

Research Highlights

►Primary adrenal insufficiency increases meal-related satiety responses.

►Adrenalectomy-induced hypophagia is associated with increased CRF mRNA expression in the hypothalamic paraventricular nucleus (PVN) and increased NTS neuron activation in the brainstem. ►The increased activity of PVN CRF neurons modulates brainstem satiety-related responses. ►CRF type 2 receptor mediates CRF suppressing effect on food intake after adrenalectomy.

Keywords: Glucocorticoids; Food intake; Corticotrophin-releasing factor; Paraventricular nucleus of the hypothalamus; Nucleus of the solitary tract

Article Outline

Introduction

Experimental procedures

Animals

Intracerebroventricular (icv) surgery

Perfusion, tissue preparation and immunohistochemistry

Microdissection, total RNA isolation and quantitative real-time PCR

Experimental protocols

Experiment 1: effects of ADX and B replacement on CRF mRNA expression in the PVN in the fasting–refeeding regimen

Experiment 2: effects of pretreatment with CRF₂ receptor antagonist on food intake in sham, ADX and ADX + B animals

Experiment 3: effects of pretreatment with CRF₂ receptor antagonist on NTS neuron activation in sham, ADX and ADX + B animals in the fasting–refeeding regimen

Statistical analysis

Results

Experiment 1: effects of ADX and B replacement on CRF mRNA expression in the PVN in the fasting–refeeding regimen

Experiment 2: effects of pretreatment with CRF₂ receptor antagonist on food intake in sham, ADX and ADX + B animals

Experiment 3: effects of pretreatment with CRF₂ receptor antagonist on NTS neuron activation in sham, ADX and ADX + B animals in the fasting–refeeding regimen

Discussion

Acknowledgements

References

Fig. 1.

Relative CRF mRNA expression in the PVN of fasted and refed sham, ADX and ADX + B animals (n = 5–8 rats/group). Data are shown as mean ± SEM. *P < 0.05.

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Fig. 2.

Food intake (g/100 g) after 4 h of refeeding (n = 5–7 rats/group) for sham, ADX and ADX + B animals pretreated with vehicle or d-Phe¹¹,His¹²-Sauvagine 11–40 (Antisauvagine-30, AS30; 5 μg/5 μL icv). Data are shown as mean ± SEM. *P < 0.05.

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Fig. 3.

Number of Fos-immunoreactive (A) and Fos/TH-immunoreactive (B) neurons in the NTS (n = 4–8 rats/group) of fasted and refed sham, ADX and ADX + B animals pretreated with vehicle or d-Phe¹¹,His¹²-Sauvagine 11–40 (Antisauvagine-30, AS30; 5 μg/5 μL icv). Data are shown as mean ± SEM. ND: not detectable. *P < 0.05 vs. respective fasted group. #P < 0.05 vs. refed sham/vehicle, refed ADX + B/vehicle and refed ADX/AS30 groups.

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Fig. 4.

Representative photomicrographs (40× magnification) of coronal sections showing Fos/TH immunoreactivity in the NTS of refed sham, ADX and ADX + B animals pretreated with vehicle or d-Phe¹¹,His¹²-Sauvagine 11–40 (Antisauvagine-30, AS30; 5 μg/5 μL icv). Each inset depicts at 20× magnification the area where the photomicrograph was taken. Scale bar, 100 μm.

View Within Article

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Table 1. Number (means ± SEM) of TH-immunoreactive neurons and percentage of Fos/TH double labelled neurons in the NTS of fasted and refed sham, ADX, and ADX + B animals, pretreated with vehicle or AS30.

Data are expressed as means ± SEM (n = 4–8 rats/group). NTS, nucleus of the solitary tract; TH, tyrosine hydroxylase.

^a P < 0.05 vs. respective fasted group.
^b P < 0.05 vs. refed sham/vehicle, refed ADX + B/vehicle and refed ADX/AS30 groups.

View Within Article

Corresponding author. Avenida Bandeirantes, 3900, 14049-900 Ribeirao Preto, Sao Paulo, Brazil. Fax: +55 16 3633 0017.

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Hormones and Behavior
Volume 58, Issue 5, November 2010, Pages 714-719

From http://www.sciencedirect.com/science

Regulation of Placental Growth by Aldosterone and Cortisol

Endocrinology, doi:10.1210/en.2010-0525

Carine Gennari-Moser, Eliyahu V. Khankin, Simone Schüller, Geneviève Escher, Brigitte M. Frey, C.-Bettina Portmann, Marc U. Baumann, Andrea D. Lehmann, Daniel Surbek, S. Ananth Karumanchi, Felix J. Frey, and Markus G. Mohaupt*

Departments of Nephrology/Hypertension (C.G.-M., S.S., G.E., B.M.F., F.J.F., M.G.M.) and Obstetrics and Gynecology (C.-B.P., M.U.B., D.S.), University Hospital Bern, Inselspital, 3010 Berne, Switzerland; Division of Vascular and Molecular Medicine (E.V.K., S.A.K.), Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215; and Division of Histology (A.D.L.), Institute of Anatomy, University of Bern, 3000 Berne, Switzerland

* To whom correspondence should be addressed. E-mail: markus.mohaupt@insel.ch.

During pregnancy, trophoblasts grow to adapt the feto-maternal unit to fetal requirements. Aldosterone and cortisol levels increase, the latter being inactivated by a healthy placenta. By contrast, preeclamptic placental growth is reduced while aldosterone levels are low and placental cortisol tissue levels are high due to improper deactivation. Aldosterone acts as a growth factor in many tissues, whereas cortisol inhibits growth.

We hypothesized that in preeclampsia low aldosterone and enhanced cortisol availability might mutually affect placental growth and function. Proliferation of cultured human trophoblasts was time- and dose-dependently increased with aldosterone (P < 0.04 to P < 0.0001) and inhibited by spironolactone and glucocorticoids (P < 0.01). Mineralo- and glucocorticoid receptor expression and activation upon agonist stimulation was verified by visualization of nuclear translocation of the receptors.

Functional aldosterone deficiency simulated in pregnant mice by spironolactone treatment (15 ?g/g body weight/day) led to a reduced fetal umbilical blood flow (P < 0.05). In rat (P < 0.05; R2 = 0.2055) and human (X2 = 3.85; P = 0.0249) pregnancy, placental size was positively related to plasma aldosterone.

Autocrine production of these steroid hormones was excluded functionally and via the absence of specific enzymatic transcripts for CYP11B2 and CYP11B1. In conclusion, activation of mineralocorticoid receptors by maternal aldosterone appears to be required for trophoblast growth and a normal feto-placental function.

Thus, low aldosterone levels and enhanced cortisol availability may be one explanation for the reduced placental size in preeclampsia and related disorders.

 

From http://endo.endojournals.org/cgi/content/abstract/en.2010-0525v1

Are Guidelines for Glucocorticoid Coverage in Adrenal Insufficiency Currently Followed?

Coralie Leblicq, MD, Diane Rottembourg, MD, Johnny Deladoëy, MD, PhD, Guy Van Vliet, MD, Cheri Deal, PhD, MD Corresponding Author

Received 11 January 2010; received in revised form 14 July 2010; accepted 17 August 2010. published online 01 November 2010.

 

Objectives

To search for evidence of acute adrenal failure linked to inappropriate use of stress management protocols.

Study design

Patients followed up for primary adrenal insufficiency (n = 102) or secondary adrenal insufficiency (n = 34) between 1973 and 2007 were included. All hospitalizations, both urgent (n = 157) and elective (n = 90), were examined. We recorded clinical evidence of acute adrenal failure, parental management before admission, and details of glucocorticoid prescription and administration in the hospital setting.

Results

For urgent hospitalizations, subgroup and time period did not influence the percentage of patients hospitalized (primary adrenal insufficiency 45%; secondary adrenal insufficiency 38%; P = .55). The use of stress glucocorticoid doses by parents increased significantly after 1997 (P < .05), although still only 47% increased glucocorticoids before hospitalization. Stress doses were more frequently administered on arrival in our emergency department after 1990 (P < .05); patients with signs or symptoms of acute adrenal failure decreased to 27% after 1997 (P < .01). Twenty-four percent of all hospitalizations were marked by suboptimal adherence to glucocorticoid stress protocols, with rare but significant clinical consequences.

Conclusions

In spite of an increased use of glucocorticoid stress dose protocols by parents and physicians, patients remain at risk of morbidity and death from acute adrenal failure. This risk may be minimized with conscientious application of stress protocols, but other patient-specific risk factors may also be implicated.

 

Keywords

21OH, 21-hydroxylase, 3?HSD, 3-?-hydroxysteroid dehydrogenase, ACTH, Adrenocorticotropic hormone, AI, Adrenal insufficiency, CAH, Congenital adrenal hyperplasia, ED, Emergency department, EH, Elective hospitalization, HPA, Hypothalamic-pituitary-adrenal, PAI, Primary adrenal insufficiency, UH, Urgent hospitalization

 

Endocrinology Service and Research Center, CHU Sainte-Justine and Department of Pediatrics, University of Montreal, Montreal, Quebec, Canada

Reprint requests: Cheri Deal, PhD, MD, FRCPC, Endocrinology Service, CHU Sainte-Justine Hospital, Research Center, 3175 Côte Sainte-Catherine, Montréal (Québec), Canada, H3T 1C5.

Supported by scholarships from the Belgian Study Group of Pediatric Endocrinology (C.L.), the Fonds de Recherche en Santé du Québec (C.D.), and a donation from Group Cossette Communications (C.D.). The authors declare no conflicts of interest.

PII: S0022-3476(10)00690-6

doi:10.1016/j.jpeds.2010.08.021

 

From http://www.jpeds.com/article/PIIS0022347610006906/abstract?rss=yes

Treatment of Cushing disease: overview and recent findings

Authors: Tatiana Mancini, Teresa Porcelli, Andrea Giustina

Published Date October 2010 , Volume 2010:6 Pages 505 - 516 DOI 10.2147/TCRM.S12952

Tatiana Mancini¹, Teresa Porcelli², Andrea Giustina^2
1Department of Internal Medicine and Medical Specialties, San Marino Hospital, San Marino, Republic of San Marino, ²Department of Medical and Surgical Sciences, University of Brescia, Brescia, Italy

Abstract:

Endogenous Cushing syndrome is an endocrine disease caused by excessive secretion of adrenocorticotropin hormone in approximately 80% of cases, usually by a pituitary corticotroph adenoma (Cushing disease [CD]). It is a heterogeneous disorder requiring a multidisciplinary and individualized approach to patient management.

The goals of treatment of CD include the reversal of clinical features, the normalization of biochemical changes with minimal morbidity, and long-term control without recurrence. Generally, the treatment of choice is the surgical removal of the pituitary tumor by transsphenoidal approach, performed by an experienced surgeon. Considering the high recurrence rate, other treatments should be considered.

Second-line treatments include more radical surgery, radiation therapy, medical therapy, and bilateral adrenalectomy. Drug treatment has been targeted at the hypothalamic or pituitary level, at the adrenal gland, and also at the glucocorticoid receptor level. Frequently, medical therapy is performed before surgery to reduce the complications of the procedure, reducing the effects of severe hypercortisolism.

Commonly, in patients in whom surgery has failed, medical management is often essential to reduce or normalize the hypercortisolemia, and should be attempted before bilateral adrenalectomy is considered. Medical therapy can be also useful in patients with CD while waiting for pituitary radiotherapy to take effect, which can take up to 10 years or more.

So far, results of medical treatment of CD have not been particularly relevant; however, newer tools promise to change this scenario. The aim of this review is to analyze the results and experiences with old and new medical treatments of CD and to reevaluate medical therapies for complications of CD and hypopituitarism in patients with cured CD.

Keywords: ketoconazole, somatostatin analogs, dopamine agonists, rosiglitazone, Cushing disease, glucocorticoids, hypopituitarism

From http://www.dovepress.com/treatment-of-cushing-disease-overview-and-recent-findings-peer-reviewed-article-TCRM

Back Ache And Hypercortisolism

Hypercortisolism is an extended medical time period that defines Cushing’s syndrome. Cushing’s syndrome is a hyperactive disorder that affects the adrenal cortex and leads to extreme secretion of cortisol, which is handed from Glucocorticoids. Cushing’s syndrome can increase sex hormones and mineralocorticoids.

The pituitary glands are stimulated by hypothalamic. The pituitary glands are additionally affected by carcinoma and/or adenoma. As nicely, the adrenal glands are affected by hyperplasia when Cushing’s syndrome is present. When Cushing’s syndrome is current, exogenous secretes into the ACTH through the neoplasm, which is malignant. It continues onto the gallbladder and lungs. You will need to read the anatomy of the skeleton system to see the way it affects the spinal column, which in turn causes back pain.

The dysfunction prolongs or submits excessive administration of ACTH and/or Glucocorticoids into the system, which transmits to the cortex. Since ACTH is secreted excessively into the system, it causes joint ache, edema, fragile pores and skin, weight achieve, hypertension, ecchymosis, fatigue, weak spot, hirsutism, temper swings, and so on. The signs carry onto create acne, stomach striae, slow healing, moon face, muscle waste, recurrent infections, buffalo humps, gynecomastia, truncal weight problems, and so on. We see that weight problems, joint pain, weight acquire, edema, and other components of the dysfunction causes back ache as well.

The signs are thought of earlier than diagnostics is conducted. Medical doctors will use a wide range of assessments to find Hypercortisolism or Cushing’s syndrome. In brief, Cushing’s syndrome is a condition set up by weak muscles and obesity, or irregular situations of the physique’s functions. The exams performed to show Cushing’s syndrome include blood chemistry, dexamethasone suppression, X-rays, GTT, CT scans, angiography, ultrasonography, and so on. Throughout testing docs will search for decreases in “17-OHCS,” osteoporosis, tumors, particularly in the pituitary glands and adrenal glands, decreases in potassium, will increase in cortisol, sodium, Aldosterone, ACTH, etc. Doctors will also search for decreases in eosinophilis, pink blood cells, and white blood cells.

When the situation is noted, docs suggest management. Diets are instructed, which include low-calorie, sodium, carbohydrates, etc. The patient is ordered to take excessive-protein and potassium regimens as well. Activity is ordered, but solely as tolerated by the patient.

Once management begins, the doctor will monitor the patient. During monitoring your physician will perform extra checks, which include UO, I/O, VS, glucose, ketones, and so on. Radiation remedy is prescribed within the worst conditions.

Cushing’s syndrome can lead to additional problems, together with nephrosclerosis, inadequate adrenal, fractures, arteriosclerosis, infections, diabetes mellitus, hypertension, CHF, arrhythmias, psychosis, and so on.

If you are diagnosed with Cushing’s syndrome, it is important to maintain your weight loss plan, steadiness fluids, relaxation, and restrict intake of water. Your physician will arrange a routine and/or management scheme, which you need to comply with accordingly to avoid additional complications. Since this dysfunction affects the whole body and puts you liable to fractures, peptic ulcers, and many others, you will need to observe precise orders.

Fractures can result in critical back pain. Fractures are outlined in medical terms as permanence breaks of the bones. Cushing’s syndrome places you susceptible to fractures, which may embody greenstick, avulsions, pathologic, melancholy, indirect, spiral, compound, compressed, etc. In addition to fractures, weight problems will cause back pain. If attainable, attempt to scale back your weight. You may ask your medical doctors about exercises suited for your condition, which you can act on to reduce weight. Your physician might counsel some steps you may take to scale back weight as well.

Cushing’s syndrome can cause back pain, but numerous other illnesses could cause pain to the again as well, together with cholecystitis. Learn extra concerning the inflammatory illness to see the way it causes again pain.

 

From http://www.relievechronicbackpains.com/474

ENEA 2010: Potential new options for the treatment of Cushing's disease: the dawn of a new era?

24/09/2010
Posted by Jo Armstrong, ecancer

Beverly Biller, Massachusetts General Hospital, USA

The goal of treatment of Cushing's disease is to normalise cortisol levels. However, current treatment options are limited and are associated with a variety of drug related adverse events and relapse. There are no approved medical therapies for Cushing's disease, and the efficacy of medical treatments that are used is limited, highlighting the unmet need in these patients.

Of great benefit would be a pituitary-directed medical treatment which targets the underlying cause of ACTH hypersecretion. There are a number of agents under investigation for the treatment of Cushing's disease, including pituitary targeted drugs and drugs targeting blockade of the glucocorticoid receptor.

Pasireotide, a new investigational drug with multi-serotonin subtype receptor affinity, is a pituitary targeted medical therapy that has been associated with rapid normalisation of UFC levels in a small number of patients in a Phase II study of patients with Cushing's disease. This has led to a Phase III, randomised, double-blind, multicentre study, the initial results of which were presented at ENEA 2010. This ongoing clinical trial is the largest study to evaluate a medical therapy in this patient population. After 6 months of treatment with pasireotide 600 or 900 µg sc bid, 14.6% and 26.3% of patients with moderate to severe hypercortisolism achieved UFC ≤ULN. At 12 months, 13.4% and 25.0% patients achieved UFC ≤ULN. Overall, there was a rapid and sustained improvement in clinical signs and symptoms from baseline, as well as improvements in patient health related quality of life. Around 50% of patients at ≥1.5 to <2 ULN achieved UFC ≤ULN with 900 at 6 months. In addition, systolic and diastolic blood pressure and weight improved in line with the decline in cortisol levels. Non-responding patients, based on UFC levels, were identified early after treatment initiation, which may be clinically useful for identifying patients inappropriate for this therapy.

With the exception of hyperglycaemia, the safety profile of pasireotide was similar to that of other somatostatin analogues. As expected with an active agent in Cushing's disease, some patients experienced symptoms of hypocortisolism, which was adequately managed in patients by decreasing the dose of pasireotide.

 

From http://www.ecancermedicalscience.com/blog.asp?postId=113

Cushing's Disease and Idiopathic Intracranial Hypertension: Case Report and Review of Underlying Pathophysiological Mechanisms

Gabriel Zada*, Amir Tirosh, Ursula B. Kaiser, Edward R. Laws, and Whitney W. Woodmansee

Department of Neurosurgery (G.Z., E.R.L.) and Division of Endocrinology, Diabetes, and Hypertension (A.T., U.B.K., W.W.W.), Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115

* To whom correspondence should be addressed. E-mail: gzada@usc.edu.

Context: Several studies have reported an association between idiopathic intracranial hypertension (IIH) and deficits of the hypothalamic-pituitary-adrenal (HPA) axis.

Case Illustration: A 33-yr-old woman with Cushing's disease underwent successful surgical resection of a pituitary adenoma and developed IIH 11 months later after inadvertent withdrawal of oral glucocorticoids.

Methods: A review of the literature was conducted to identify previous studies pertaining to IIH in association with neuroendocrine disease, focusing on reports related to HPA axis dysfunction.

Results: A number of patients developing IIH due to a relative deficiency in glucocorticoids, after surgical or medical management for Cushing's disease, withdrawal from glucocorticoid replacement, or as an initial presentation of Addison's disease, have been reported. Hypotheses regarding the underlying pathophysiology of IIH in this context and, in particular, the role of cortisol and its relationship to other neuroendocrine and inflammatory mediators that may regulate the homeostasis of cerebrospinal fluid production and absorption are reviewed.

Conclusion: In a subset of patients, dysfunction of the HPA axis appears to play a role in the development of IIH. Hormonal control of cerebrospinal fluid production and absorption may be regulated by inflammatory mediators and the enzyme 11ß-hydroxysteroid dehydrogenase type 1. Further study of neuroendocrine markers in the serum and cerebrospinal fluid may be an avenue for further research in IIH.

From http://jcem.endojournals.org/cgi/content/abstract/jc.2010-0896v1

Iatrogenic Cushing's Syndrome due to Coadministration of Ritonavir and Inhaled Budesonide in an Asthmatic Human Immunodeficiency Virus Infected Patient.

J Asthma. 2010 Jul 26. [Epub ahead of print]

Kedem E, Shahar E, Hassoun G, Pollack S.

Institute of Clinical Immunology, Allergy and AIDS, Rambam Health Care Campus, Haifa, Israel.

Abstract

Introduction. Iatrogenic Cushing's syndrome (CS) is caused by exposure to glucocorticoids and may be promoted by interaction with additional drugs. It is well known in asthmatic human immunodeficiency virus (HIV)-infected patients treated with inhaled fluticasone with ritonavir-containing antiretroviral regimen (cART).

Case Report. The authors present an asthmatic HIV-infected Ethiopian woman, treated with fluticasone/salmeterol, commencing cART with tenofovir, emtricitabine, and lopinavir/ritonavir. During 7 months she gained 9 kg and hyperpigmentation, mild edema, marked abdominal striae, and increase in blood pressure were noted. Plasma am and urine free cortisol levels confirmed CS diagnosis and fluticasone was discontinued. Complete resolution of CS occurred within 2 months. However, frequent asthma symptoms required resumption of inhaled corticosteroid (ICS) treatment, and budesonide/formeterol was prescribed. Soon reemergence of symptomatic CS was noted. Ritonavir dose was halved, but CS symptoms continued to develop. Budesonide was stopped and montelukast initiated. Resolution of cushingoid symptoms was observed within weeks.

Discussion. Corticosteroids are metabolized by cytochrome P450 3A4 (CYP3A4). Fluticasone has the longest glucocorticoid receptor-binding half-life and is 300 times more lipophilic than budesonide. Inhaled fluticasone possesses a high suppression rate of hypothalamic-pituitary-adrenal axis. Ritonavir, a potent CYP3A4 inhibitor, may inhibit corticosteroid degradation and increase its accumulation. Inhaled budesonide is less likely to cause adrenal suppression.

Diagnosing Cushing's syndrome presents a clinical challenge due to similarities with clinical manifestations and side effects related to cART.

In patients treated with inhaled or intranasal corticosteroids together with cART there may be a higher incidence of iatrogenic CS. CS should be looked for, and management considered carefully.

PMID: 20653496 [PubMed - as supplied by publisher]

LinkOut - more resources

From http://www.ncbi.nlm.nih.gov/pubmed/20653496

Active Cushing's Disease Is Associated With Subtle Cognitive Impairment: Presented at ECE

By Karen Dente

PRAGUE, Czech Republic -- April 29, 2010 -- Researchers have found a correlation between Cushing's disease and cognitive impairments long after Cushing's was cured.

Results of a study were presented here during an oral session at the 12th European Congress of Endocrinology (ECE).

"We hypothesised that previous hypercortisolism in patients with Cushing's disease results in irreversible impairments in cognitive functioning," said Jitske Tiemensma, Leiden University Medical Center, Leiden, Netherlands, on April 25.

The study was designed to assess cognitive functioning using 11 tests looking at memory, global cognitive functioning, and executive functioning.

A total of 74 patients cured of Cushing's disease were matched with 74 controls. More than 80% of the patients were female and the mean age was 52 years.

Another 54 patients who were previously treated for non-functioning pituitary macroadenomas (NFMA) along with 54 matched controls were included as well.

In contrast to the NFMA patients, those cured from Cushing's disease had lower scores on the Mini-Mental State Examination (P = .001) and on the Wechsler Memory Scale (P = .050).

Patients with previous Cushing's also tended to recall fewer words on the imprinting trial (P = .013), the immediate recall trial (P = .012), and the delayed recall trial (P = .003) of the Verbal Learning Test of Rey. They also recalled more intrusions on all trials of this test (P = .002, P = .003, and P = .003, respectively).

"The results from our study indicated that irreversible effects from previous hypercortisolism remain on cognitive function, and, thus on the central nervous system," said Dr. Tiemensma.

These observations may also be of relevance for patients treated with high doses of exogenous glucocorticoids.

[Presentation title: Subtle Cognitive Impairments in Patients With Long-Term Cure of Cushing's Disease. Abstract H2.3]

From http://www.docguide.com/news/content.nsf/news/852576140048867C85257714007D13FB

(Adrenal Cushing’s) Hormone May Ward Off Osteonecrosis

By Crystal Phend, Senior Staff Writer, MedPage Today
Published: April 29, 2010
Reviewed by Zalman S. Agus, MD; Emeritus Professor
University of Pennsylvania School of Medicine and
Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner

 

Action Points  

---

• Explain to interested patients that long-term glucocorticoid treatment may be part of the therapy for asthma, ulcerative colitis, kidney diseases, and rheumatologic disorders.

 

Patients on chronic glucocorticoid therapy often develop osteonecrosis of the hip, but injections of adrenocorticotropic hormone (ACTH) might prevent that devastating complication, a preclinical study showed.

Rabbits treated with depot methylprednisolone acetate (Depo Medrol) showed half as much necrotic surface area on the femoral head when also given the synthetic cosyntropin (Cortrosyn) form of ACTH (P<0.05), Mone Zaidi, MD, PhD, of the Mount Sinai School of Medicine in New York City, and colleagues found.

The protective effect weakened for deeper bone, with all rabbits in both groups showing focal necrotic spots.

But these deeper areas of necrosis were smaller and generally not consolidated in ACTH-treated rabbits compared with prominent consolidated areas of necrosis in those that got only the glucocorticoid, Zaidi's group reported online in the Proceedings of the National Academy of Sciences.

 

These results provide a rationale for extended use of cosyntropin to decrease the risk of osteonecrosis for human patients who have to be on long-term glucocorticoid treatment, they suggested.

 

"The results are very promising because this is the first proof-of-concept of any medical therapy" in this setting, Zaidi said in an interview.

 

The only treatment for this debilitating, painful condition has been surgical debridement, the researchers explained.

 

The rate of osteonecrosis of the hip induced by long-term glucocorticoid use isn't clear, but it is thought to account for about 10% of hip replacements in the U.S. each year, Zaidi noted.

The mechanism appears to be different than with osteoporosis from long-term glucocorticoid treatment, which occurs largely due to osteocyte apoptosis, his group wrote.

 

The researchers started looking into the the role of ACTH after noting that ACTH-producing adenomas result in a profound glucocorticoid excess but not osteonecrosis.

 

They gave rabbits 10 mg/kg depot methylprednisolone acetate, which consistently produced damage to bone in the femoral head within 28 days.

 

Half the rabbits also received 0.2 μg/kg ACTH in the form of subcutaneous cosyntropin injections daily, which normalized ACTH serum levels for about three hours.

 

Bone scans showed a small effect of ACTH on density of the femoral head: it was 10% greater with the hormone.

 

There was a highly significant approximately 50% reduction in the necrotic surface area in femora from the rabbits treated with MPA plus ACTH compared with those given the glucocorticoid alone.

 

The explanation for this and the other morphological results appeared to be that ACTH supported osteoblast activity, the researchers wrote.

 

Quantitative PCR indicated significantly greater vascular endothelial growth factor (VEGF) mRNA expression in bone marrow of rabbits that got ACTH compared with those on methylprednisolone alone.

 

VEGF might maintain viability of components of the bone matrix given its central role in bone development and homeostasis, Zaidi's group noted.

 

"The femoral head is a site of high bone turnover, with formation and resorption occurring continuously over a large fraction of the total surface area," they explained in the paper. "This surface area is also embedded with an extensive capillary network; this means that the maintenance and regeneration of capillaries requires support by molecules such as VEGF."

 

Further testing suggested that ACTH stimulated production of VEGF in osteoblasts, not monocytes, and that the glucocorticoid dexamethasone profoundly inhibited monocyte-induced VEGF production, "probably as one of several mechanisms that initiate osteonecrosis," the researchers wrote.

 

The effect of ACTH appeared VEGF-dependent in cell line experiments with ACTH-stimulated VEGF production apparently through the ACTH receptor MC2R.

 

The investigators didn't look at whether this mechanism is a normal feature of bone mass regulation in the absence of glucocorticoid treatment. They noted, though, that results from patients with familial glucocorticoid deficiency and adrenal Cushing's syndrome support "at least a small anabolic effect of ACTH, which seemingly counteracts the bone loss due to cortisol."

 

Zaidi said that because synthetic ACTH would be dosed to restore the naturally occurring hormone levels and is already in clinical use for testing adrenal sufficiency there shouldn't be any safety concerns with long-term use in patients on glucocorticoids.

 

However, the protective effect wouldn't extend to patients who already have developed osteonecrosis, he told MedPage Today.

 

"The idea is to prevent," he said in the interview. "Once that part of the bone is dead, I can't see any logical way to bring it back to life again."

 

The study was supported by grants from the National Institutes of Health and by the American Federation for Aging Research.

 

Primary source: Proceedings of the National Academy of Sciences
Source reference:
Zaidi M, et al "ACTH protects against glucocorticoid-induced osteonecrosis of bone" Proc Natl Acad Sci 2010; DOI:10.1073/pnas.0912176107

 

From http://www.medpagetoday.com/Orthopedics/Orthopedics/19823

Subtle Cognitive Impairments in Patients with Long-Term Cure of Cushing's Disease

Jitske Tiemensma*, Nieke E. Kokshoorn, Nienke R. Biermasz, Bart-Jan S. A. Keijser, Moniek J. E. Wassenaar, Huub A. M. Middelkoop, Alberto M. Pereira,  and Johannes A. Romijn

Departments of Endocrinology and Metabolism (J.T., N.E.K., N.R.B., B.-J.S.A.K., M.J.E.W., A.M.P., J.A.R.) and Neurology (H.A.M.M.), Leiden University Medical Center, 2300 RC Leiden, The Netherlands

* To whom correspondence should be addressed. E-mail: J.Tiemensma@lumc.nl.

Context and Objective: Active Cushing's disease is associated with cognitive impairments. We hypothesized that previous hypercortisolism in patients with Cushing's disease results in irreversible impairments in cognitive functioning. Therefore, our aim was to assess cognitive functioning after long-term cure of Cushing's disease.

Design: Cognitive assessment consisted of 11 tests, which evaluated global cognitive functioning, memory, and executive functioning.

Patients and Control Subjects: We included 74 patients cured of Cushing's disease and 74 controls matched for age, gender, and education. Furthermore, we included 54 patients previously treated for nonfunctioning pituitary macroadenomas (NFMA) and 54 controls matched for age, gender, and education.

Results: Compared with NFMA patients, patients cured from Cushing's disease had lower scores on the Mini Mental State Examination (P = 0.001), and on the memory quotient of the Wechsler Memory Scale (P = 0.050). Furthermore, patients cured from Cushing's disease tended to recall fewer words on the imprinting (P = 0.013), immediate recall (P = 0.012), and delayed recall (P = 0.003) trials of the Verbal Learning Test of Rey. On the Rey Complex Figure Test, patients cured from Cushing's disease had lower scores on both trials (P = 0.002 and P = 0.007) compared with NFMA patients. Patients cured from Cushing's disease also made fewer correct substitutions on the Letter-Digit Substitution Test (P = 0.039) and came up with fewer correct patterns on the Figure Fluency Test (P = 0.003) compared with treated NFMA patients.

Conclusions: Cognitive function, reflecting memory and executive functions, is impaired in patients despite long-term cure of Cushing's disease. These observations indicate irreversible effects of previous hypercortisolism on cognitive function and, thus, on the central nervous system. These observations may also be of relevance for patients treated with high-dose exogenous glucocorticoids.

 

From http://jcem.endojournals.org/cgi/content/abstract/jc.2009-2032v1

Addison's disease presenting with idiopathic intracranial hypertension in a 24-year-old woman: a case report

Dushyant Sharma , Rohini Mukherjee , Peter Moore and Daniel J Cuthbertson

Journal of Medical Case Reports 2010, 4:60doi:10.1186/1752-1947-4-60

Published:
19 February 2010

Abstract (provisional)

Introduction

Idiopathic intracranial hypertension can rarely be associated with an underlying endocrine disorder such as Cushing's syndrome, hyperthyroidism, or with administration of thyroxine or growth hormone. Though cases of idiopathic intracranial hypertension associated with Addison's disease in children have been reported, there is only one documented case report of this association in adults. We describe a case of an acute adrenal insufficiency precipitated by idiopathic intracranial hypertension in a Caucasian female.

Case presentation

A 24-year-old Caucasian woman was acutely unwell with a background of several months of generalised fatigue and intermittent headaches. She had unremarkable neurological and systemic examination with a normal computerised tomography and magnetic resonance imaging of the brain. Normal cerebrospinal fluid but increased opening pressure at lumbar puncture suggested intracranial hypertension. A flat short synacthen test and raised level of adrenocorticotrophic hormone were consistent with primary adrenal failure.

Conclusion

Addison's disease can remain unrecognised until precipitated by acute stress. This case suggests that idiopathic intracranial hypertension can rarely be associated with Addison's disease and present as an acute illness. Idiopathic intracranial hypertension is possibly related to an increase in the levels of arginine vasopressin peptide in serum and cerebrospinal fluid secondary to a glucocorticoid deficient state.

The complete article is available as a provisional PDF. The fully formatted PDF and HTML versions are in production.

Influence of hydrocortisone dosage scheme on health-related quality of life in patients with adrenal insufficiency

Authors: Bleicken, Benjamin; Hahner, Stefanie¹; Loeffler, Melanie¹; Ventz, Manfred²; Decker, Oliver³; Allolio, Bruno¹; Quinkler, Marcus²

Source: Clinical Endocrinology, Volume 72, Number 3, March 2010 , pp. 297-304(8)

Publisher: Blackwell Publishing

 

Abstract:

Summary Context

Recent studies suggest that current glucocorticoid replacement therapies fail to completely restore well-being in patients with adrenal insufficiency (AI).

 

Objective

The objective of this study was to investigate health-related quality of life (QoL) in patients with AI depending on dose and frequency of daily intake of hydrocortisone (HC).

 

Design and patients

In a cross-sectional study, primary and secondary AI patients were contacted and asked to complete three validated self-assessment questionnaires [Short Form-36 (SF-36), Giessen Complaint List (GBB-24), Hospital Anxiety and Depression Scale (HADS)]. HC doses were corrected for body surface area. Results were compared with sex- and age-matched controls drawn from the questionnaire-specific reference cohort.

 

Results

Completed questionnaire sets were available from 334 patients on HC (primary AI n = 194; secondary AI n = 140). Patients on higher doses of HC (>30 mg/day) showed significantly impaired subjective health status in two of eight SF-36 dimensions, and three of five GBB-24 scales compared with those on lower HC doses. No significant differences in QoL were found between lower HC doses (15-30 mg/day) or between primary or secondary AI. Patients on HC with thrice daily intake showed significantly impaired QoL in one of eight SF-36 dimensions (15-20 mg/day, 20-25 mg/day), in one of five GBB-24 scales (15-20 mg/day), as well as higher anxiety scores.

 

Conclusions

Health-related QoL was impaired in patients with primary and secondary AI. HC doses above 30 mg/day were associated with a worse health status. Thrice daily intake of HC was not superior to twice daily intake. Our data support the perception that current replacement strategies are still insufficient to fully restore well-being and daily performance.

 

Document Type: Research article

DOI: 10.1111/j.1365-2265.2009.03596.x

Affiliations: 1: Endocrinology & Diabetes Unit, Department of Medicine I, University Hospital, University of Wuerzburg, Wuerzburg, Germany 2: Clinical Endocrinology, Charité Campus Mitte, Charité University Medicine Berlin, Berlin, Germany 3: Department of Psychotherapy and Psychosomatic Medicine, University Hospital Leipzig, Leipzig, Germany

 

From http://www.ingentaconnect.com/content/bsc/cend/2010/00000072/00000003/art00004