Robotic versus laparoscopic adrenalectomy in obese patients

Surgical Endoscopy, 10/23/2012 Clinical Article

Aksoy E et al. – The aim of this study is to compare perioperative outcomes of RA versus LA in obese patients. The study did not show any difference in perioperative outcomes between RA and LA in obese patients. These results suggest that the difficulties in maintaining exposure and dissection in obese patients nullify the advantages of robotic articulating versus rigid laparoscopic instruments in adrenal surgery.

Methods

• Between 2003 and 2012, 99 obese (BMI ≥ 30 kg/m2) patients underwent adrenalectomy at a tertiary academic center.
• Of these, 42 patients had RA and 57 had LA. The perioperative outcomes of these patients were compared between the RA and LA groups.
• Data were collected from a prospectively maintained, institutional review board approved database.
• Clinical and perioperative parameters were analyzed using Student t and χ2 tests.
• All data are expressed as mean ± standard error of the mean.

Results

• The groups were similar in terms of age, gender, and tumor side.
• Body mass index was lower in the robotic versus laparoscopic group (35.4 ± 1.0 vs. 38.8 ± 0.8 kg/m2, respectively, p = 0.01).
• Tumor size (4.0 ± 0.4 vs. 4.3 ± 0.3 cm, respectively, p = 0.56), skin–to–skin operative time (186.1 ± 12.1 vs. 187.3 ± 11 min, respectively, p = 0.94), estimated blood loss (50.3 ± 24.3 vs. 76.6 ± 21.3 ml, respectively, p = 0.42), and hospital stay (1.3 ± 0.1 vs. 1.6 ± 0.1 days, respectively, p = 0.06) were similar in both groups.
• The conversion to open rate was zero in the robotic and 5.2 % in the laparoscopic group (p = 0.06).
• The 30–day morbidity was 4.8 % in the robotic and 7 % in the laparoscopic group (p = 0.63).

From MDLinx

Cyclical Cushing's

zhen posted this for us on the message boards

There are many good articles published on cyclical Cushing's. You wouldn't want to restrict your search to NIH.

Dr. Stratakis of NIH published the following paper:
Cyclical Cushing Syndrome Presenting in Infancy: An Early Form of Primary Pigmented Nodular Adrenocortical Disease, or a New Entity?

NIH published the following paper concerning screening tests with author Dr. Nieman and others.

Specificity of Screening Tests for Cushing’s Syndrome in an Overweight and Obese Population

I found the following publications for you using PubMed for the search. BTW, Google is not your friend for starting these medical topic searches. Google will lead you in too many directions and information that hasn't been peer reviewed often has mistakes.
Search on PubMed. If you find an interesting title that only has the abstract, you can often find the full text by pasting the full title into google. Weed through the paid document providers and you'll often find a free full .pdf document later in the list.

Sometimes you can do a search directly on a publisher's web site for even more articles.

Here are some articles for you. I encourage you/your friend to spend s few evenings searching and reading.

The prevalence and characteristic features of cyclicity and variability in Cushing’s disease

A case of cyclical Cushing's disease associated with corticosteroid-binding globulin deficiency: a rare pitfall in the diagnosis of Cushing's disease.

Cyclical Cushing's syndrome: an update.

Cyclical Cushing’s syndrome due to an atypical thymic carcinoid
There's also lots of valuable information on Dr. F.'s (Theodore C. Friedman, M.D., Ph.D.) website.

www.goodhormonehealth.com.

I recommend you spend an entire evening reading on Dr. F.'s web pages. His work integrates clinical experience that's lacking in much of the other work. Then read everything Dr F. published by using www.pubmed.com with an author search. On pubmed you do an author search by typing F. T [au] in the search box.
When you find a useful article on pubmed, click on the authors name in the author list below the title. That will bring up a listing of their other publications. Often these authors have a special interest in the topic you're searching and have published many other papers. If there is a "free text" icon shown to the upper right, you can read the full article by following the link. If the free icon isn't there, copy and paste the article title into google. You may get lucky if you spend some time.

Concerning testing, the endocrine society has published a guideline that represents current practice.

The Diagnosis of Cushing’s Syndrome: An Endocrine Society Clinical Practice Guideline

You have the right approach. An educated patient can get through the diagnostic maze by understanding the limitations of the classical tests. A patient who doesn't know the research is likely to be screened out and never get the necessary care.

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staticnrg added this on the CushieWiki

Cyclic Cushing's is a controversial subject among endocrinologists. Other terms used for it are "episodic" and "intermittent". Tumors which cause Cushing's disease can intermittently secrete hormones which cause increased cortisol.

Pituitary tumors will secrete ACTH intermittently while adrenal tumors secrete cortisol periodically. This leads to a cycle of Cushing's symptoms which may repeat over the period of hours, or days, or weeks, and sometimes even years. Because of this, it is difficult to diagnose for some patients.

To review some articles which include cyclic/episodic/intermittent Cushing's, see the links below:

Staticnrg's Delicious Bookmarks

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

Prevalence of Endocrine Diseases in Morbidly Obese Patients Scheduled for Bariatric Surgery: Beyond Diabetes

Paola Fierabracci, Aldo Pinchera, Silvia Martinelli, Giovanna Scartabelli, Guido Salvetti, Monica Giannetti, Andrea Pucci, Giulia Galli, Ilaria Ricco and Giorgia Querci, et al.

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Abstract

Background 

Bariatric surgery allows stable body weight reduction in morbidly obese patients. In presurgical evaluation, obesity-related co-morbidities must be considered, and a multidisciplinary approach is recommended. Precise guidelines concerning the endocrinological evaluation to be performed before surgery are not available. The aim of this study was to evaluate the prevalence of common endocrine diseases in a series of obese patients scheduled for bariatric surgery.

Methods 

We examined 783 consecutive obese subjects (174 males and 609 females) aged 18–65 years, who turned to the obesity centre of our department from January 2004 to December 2007 for evaluation before bariatric surgery. Thyroid, parathyroid, adrenal and pituitary function was evaluated by measurement of serum hormones. Specific imaging or supplementary diagnostic tests were performed when indicated.

Results 

The overall prevalence of endocrine diseases, not including type 2 diabetes mellitus, was 47.4%. The prevalence of primary hypothyroidism was 18.1%; pituitary disease was observed in 1.9%, Cushing syndrome in 0.8%, while other diseases were found in less than 1% of subjects. Remarkably, the prevalence of newly diagnosed endocrine disorders was 16.3%.

Conclusions 

A careful endocrinological evaluation of obese subjects scheduled for bariatric surgery may reveal undiagnosed dysfunctions that require specific therapy and/or contraindicate the surgical treatment in a substantial proportion of patients. These results may help to define the extent of the endocrinological screening to be performed in obese patients undergoing bariatric surgery.

Keywords  Bariatric surgery - Obese patients - Endocrinological evaluation

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From http://www.springerlink.com/content/nq6hj23286x3k61u/

Pituitary Adenomas In Childhood, Adolescence and Young Adulthood: Presentation, Management, Endocrine and Metabolic Outcomes.

Caroline A Steele, Ian MacFarlane, Jo Blair, Daniel J Cuthbertson, Mohammed Didi, Conor Mallucci, Mohsen Javadpour and Christina Daousi

C Steele, Diabetes & Endocrinology Clinical Research Unit, University Hospital Aintree NHS Foundation Trust, Liverpool, United Kingdom
I MacFarlane, Diabetes & Endocrinology Clinical Research Unit Liverpool,, University Hospital Aintree NHS Foundation Trust, Liverpool, United Kingdom
J Blair, Endocrinology, Alder Hey Children's NHS Trust, Liverpool, United Kingdom
D Cuthbertson, Diabetes & Endocrinology Clinical Research Unit, University Hospital Aintree NHS Foundation Trust, Liverpool, United Kingdom
M Didi, United Kingdom
C Mallucci, Neurosurgery Department, Walton Centre for Neurology and Neurosurgery, Liverpool, Liverpool, L9 7LJ, United Kingdom
M Javadpour, Neurosurgery Department, Walton Centre for Neurology and Neurosurgery, Liverpool, Liverpool, L9 7LJ, United Kingdom
C Daousi, Diabetes & Endocrinology Clinical Research Unit, University Hospital Aintree NHS Foundation Trust, Liverpool, United Kingdom

Correspondence: Caroline Steele, Email: c.steele@nhs.net

Objective: To elucidate the long-term outcomes of pituitary adenomas diagnosed in childhood and adolescence, knowledge of which remains sparse.

Design and methods: A neuroendocrine service in Liverpool, United Kingdom. Retrospective review of patients aged less than 21 years at diagnosis of pituitary adenoma during the period 1984-2009.

Results: There were 41 patients (33 female), mean age at diagnosis 17.3 years (range 11 - 21) and mean follow-up 9.6 years; 29 patients had prolactinomas (15 macroprolactinomas), six non-functioning adenomas (NFPA), five Cushing's disease (CD) and one acromegaly. All prolactinomas received dopamine agonists (DAs) and 3 also pituitary surgery. Ten further patients underwent surgery: all five CD, one acromegaly and four NFPA. Four received radiotherapy after surgery. Ten patients receive hormone replacement: nine hydrocortisone, five thyroxine, seven sex steroids and five growth hormone (GH); another 7 have severe asymptomatic GH deficiency. Three female patients were treated for infertility (two successfully). Thirteen patients gained significant weight (body mass index (BMI) increase >2 kg/m2) since diagnosis and 16 in total are now obese (BMI >30 kg/m2). Five are treated with orlistat and one attends a weight management service. Two receive antihypertensive medications, two have type 2 diabetes and four have treated dyslipidaemia.

Conclusions: This is one of the largest reviews of patients aged 21 or younger at diagnosis of pituitary adenoma followed up by a single service. Two-thirds have prolactinomas, all treated with DAs and three underwent surgery. Increased cardiovascular risk factors (obesity and dyslipidaemia) and infertility are important sequelae and active identification and treatment necessary.

 

From http://www.eje.org/cgi/content/abstract/EJE-10-0519v1

Obesity invites disease

Monday, August 02, 2010
Over 20 million children under the age of five are overweight, indicate latest WHO statistics. Obesity is on the rise and has reached epidemic proportions in the world. About twenty percent of children are either overweight or obese.

The Body Mass Index (BMI) estimates the ideal weight of a person based on his size and weight. It is valid for an adult man or woman (18 to 65 years). Doctors often use it to measure obesity. BMI is equal to a person's weight in kilograms (kg) divided by his height in meters (m) squared. Adults with a BMI of 30 or higher are considered obese. But those having a BMI of 40 or more are extremely obese.

It's a common belief that eating too much and exercising too little is the main cause of gaining weight. But this is not true all the time. It is my personal observation that some people eat a lot but they do not gain weight. They are quite healthy, slim and smart. And there are many who take very little food, but they are overweight. You may also have observed the same.

There is another set of people who eat a lot but keep losing weight. It shows there are other factors involved in obesity rather than the eating habit alone.

Genes play a great role in tendencies to gain weight or lose weight. There may be more chances to develop obesity if one or both parents are obese. Some studies have shown that certain drugs, such as steroids, antidepressants, high blood pressure, medications used to lower blood sugar such as insulin may cause excessive weight gain.

For some people, emotions influence their eating habits. Many people eat excessively in response to boredom, sadness, stress or anger. While most overweight people have no more psychological disturbances than normal weight people, about 30 percent of the people who seek treatment for serious weight problems have difficulties with binge eating. Diseases such as hypothyroidism, insulin resistance, polycystic ovary syndrome and Cushing's syndrome also contribute to obesity.

Women tend to be more overweight than men. Men burn more energy at rest than women, so men require more calories to maintain their body weight. The metabolic rate decreases in women when they reach the postmenopausal age. That is partly why many women gain weight after menopause.

Obesity is not just a cosmetic consideration. It is widely known that obesity is the fertile land for disease. Health problems start when someone starts getting overweight, and the likelihood of problems increases as someone becomes more and more overweight. Many of these conditions cause long-term suffering for individuals and families such as cardiovascular disease, type 2 diabetes, osteoarthritis (degenerative arthritis) of the knees, hips, and the lower back.

A very interesting Norwegian study showed that obesity tended to increase blood pressure more significantly in women than in men. The risk of developing high blood pressure is also higher in obese people who are apple shaped (central obesity) than in people who are pear shaped (fat distribution mainly in hips and thighs).

There are a lot of treatments available in the market for obesity. But almost all of them are associated with serious side effects and toxicity except homeopathy. Homeopathy is a time tested, proven method to cure obesity. The writer has also seen amazing results in treating obesity in the patients who were determined and followed the instructions carefully.

International research shows that homeopathic medicines are extremely effective in reducing weight by improving the metabolic system, digestive system and elementary system.

Homeopathy is the fastest growing system of medicine in the world. There is wider acceptance of homeopathy in such countries as France, Germany, Mexico, Argentina, India and Great Britain. The British royal family is patronizing the Royal London Homoeopathic Hospital for the last one hundred years and prefer taking homeopathic treatment when needed.

It is not necessary to achieve an 'ideal weight' to derive health benefits from obesity treatment. Instead, the goal of treatment should be to reach and hold to a 'healthier weight.' The emphasis of treatment should be to commit to the process of life-long healthy living including eating more wisely and increasing physical activity. In sum, the goal in dealing with obesity is to achieve and maintain a 'healthier weight.'

Dr. Asghar Ali Shah

Homeopathic Physician

dr_asghar_shah@yahoo.com

 

From http://www.thenews.com.pk/daily_detail.asp?id=254260

Removing Tumors Through the Nose

Wednesday, February 17, 2010 3:58 PM EST

A brain tumor caused one woman's body to grow uncontrollably.

"It took me from being one person to being a completely different person," Erin Kelley (Cushing’s Help message board member)  said.

Each year, 10 to 15-million Americans are diagnosed with Cushing's Syndrome. It occurs when the body is exposed to high levels of the hormone cortisol, often caused by a benign tumor deep inside the brain.

Now, doctors have been saying that a new kind of tool can make removing these tumors an easier process on the patient.

A year ago, Kelley felt like her body was out of control.

"I gained 120 pounds, went from being an extremely athletic person to not being able to do much at all without getting really sick," Kelley said.

Kelley was diagnosed with Cushing's Syndrome. A tumor on her pituitary gland was throwing off her body's hormonal balance.

Traditionally, removing pituitary tumors means making an incision underneath the lip and going through the nasal cavity to reach the tumor.

Dr. Richard Chole, otolaryngologist at the Washington University School of Medicine in St. Louis, Missouri, invented a new instrument that allows him to do the same surgery with a less-invasive approach through the nose.

"It allows us to do it safely through the nose without any incisions," Chole said.

The blades of his tool expand the sinuses, exposing the pituitary tumor and clearing a path for it to be pulled out through the nose. The device eliminates the need for incisions, avoids any possible nerve damage in the mouth, and there's no swelling or eating issues afterwards.

"This way is more direct. The exposure is just different, and it's proving to be a very successful way of doing it," Chole said.

"I am 900 percent better than I was before," Kelley said.

Less than six months after surgery, Kelley's feeling more like herself every day and has dropped nearly half of her weight. Now that her tumor's history, she's taking her life back.

People who are obese and have type two diabetes and high blood pressure have an increased risk of developing Cushing's Syndrome.

Doctors said the new technology may be useful for other kinds of brain tumors as well.

---

Medical Breakthroughs Research Summary

Topic:       Removing Tumors Through The Nose
Report:      MB #3104

Cushing's Disease: Cushing's Syndrome is a hormonal disorder caused by prolonged exposure to high levels of cortisol. The condition most often affects adults aged 20 to 50, and people who are obese and have type 2 diabetes along with poorly controlled glucose and high blood pressure are at higher risk of developing the condition.

According to the National Institutes of Health, many people develop Cushing's Syndrome because they take glucocorticosteroids like prednisone.

However, pituitary adenomas or tumors that arise in the brain's pituitary gland account for 70 percent of Cushing's cases besides those linked to use of glucocorticosteroids. The benign tumors cause the pituitary gland to secrete extra ACTH, a hormone that stimulates the adrenal glands to release cortisol.

The adenomas are five times more common in women than in men.

Treatment of Cushing's Syndrome depends on the cause and may involve surgery, radiation, chemotherapy or the use of cortisol-inhibiting drugs.

Surgery: According to the National Institutes of Health, the cure rate from surgery to remove tumors associated with Cushing's disease is more than 80 percent when performed by a surgeon with extensive experience; and if the first surgery fails, it can be repeated, often with good results.

One type of surgery to remove pituitary tumors involves making an incision underneath the lip to access the sinuses.

"The incision is uncomfortable," Chole said. "It takes time to heal. Some of the nerves are affected by it, and that takes some time to recover."

The surgery also carries risk of damage to tooth roots.

Another approach is endoscopic surgery through the nose. Chole uses a specially designed tool to remove the tumors. The instrument is transferred through an endoscope carrier, and two blades are expanded once inside the operating area.

"The instrument spreads in a certain way to expose the area of the pituitary gland," Chole explained.

"The complexity of the instrument is that it will open and adjust in several different ways, depending on exactly what exposure is needed and the exact anatomy inside that particular person."

Chole also in addition to eliminating the need for incisions, this surgical approach avoids the problem of nerve damage in the mouth and reduces postsurgical complications like swelling and trouble eating.

For More Information, Please Contact:
Judy Martin
Public Affairs
Washington University School Of Medicine, St. Louis

314-286-0105

From http://www.newschannel5.com/global/story.asp?s=12000231

A Reappraisal of Diagnosing GH Deficiency in Adults

Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2009-1134

A Reappraisal of Diagnosing GH Deficiency in Adults: Role of Gender, Age, Waist Circumference, and Body Mass Index

Annamaria Colao*, Carolina Di Somma, Silvia Savastano, Francesca Rota, Maria Cristina Savanelli, Gianluca Aimaretti, and Gaetano Lombardi

Department of Molecular and Clinical Endocrinology and Oncology (A.C., C.D.S., S.S., F.R., M.C.S., G.L.), Section of Endocrinology, University of Naples "Federico II," Italy, 80131 Naples, Italy; and Section of Endocrinology (G.A.), Department of Clinical and Experimental Medicine, University "A. Avogadro" del Piemonte Orientale, 28100 Novara, Italy

* To whom correspondence should be addressed. E-mail: colao@unina.it.

Objective: The objective of the study was to reevaluate the diagnostic accuracy of GH peak after GHRH plus arginine test (GHRH+ARG) according to patients' age, body mass index (BMI), and waist circumference to diagnose GH deficiency (GHD).

Outcome Measures: GH peak after GHRH+ARG and IGF-I levels reported as SD score.

Subjects: Subjects included 408 controls (218 women, 190 men, aged 15–80 yr) and 374 patients with hypopituitarism (167 women, 207 men, aged 16–83 yr).

Results: In the (elderly) healthy subjects 15–25 yr old (young), 26–65 yr old (adults) and older than 65 yr, GH cutoffs were 15.6, 11.7, and 8.5 µg/liter, 11.8, 8.1, and 5.5 µg/liter, and 9.2, 6.1, and 4.0 µg/liter, respectively, in the lean, overweight, and obese subjects. Waist circumference was the best predictor of GH peak (t = -7.6, P < 0.0001) followed by BMI (t = -6.7, P < 0.0001) and age (t = -5.7, P < 0.0001). Based on the old (<9.1 µg/liter) and new GH cutoff, 286 (76.5%) and 276 (73.8%) of 374 hypopituitary patients had severe GHD. The receiving-operator characteristic analysis showed GH cutoffs in line with the third percentile or slightly higher results so that the prevalence of GHD increased to 90.1%.

Conclusions: The results of the current study show that waist circumference and BMI are the strongest predictors of GH peak after GHRH+ARG followed by age. However, the old cutoff value of 9.0 µg/liter was in line with the new cutoffs in 95% of patients.

From http://jcem.endojournals.org/cgi/content/abstract/jc.2009-1134v1

Disordered and Increased Adrenocorticotropin Secretion with Diminished Adrenocorticotropin Potency in Obese in Premenopausal Women

Ferdinand Roelfsema, Petra Kok, Marijke Frolich, Alberto M. Pereira and Hanno Pijl

Department of Endocrinology and Metabolic Diseases, Leiden University Medical Center, 2333ZA Leiden, The Netherlands

Address all correspondence and requests for reprints to: Dr. Ferdinand Roelfsema, Department of Endocrinology and Metabolic Diseases, Leiden University Medical Center, Albinusdreef 2, 2333ZA Leiden, The Netherlands. E-mail: f.roelfsema@lumc.nl.

 

Context: The pituitary-adrenal ensemble of obese humans is marked by increased urinary excretion of cortisol and its metabolites in the face of normal circulating cortisol levels. For better understanding of the (patho) physiological meaning of these changes, the mechanistic underpinnings need to be clarified.

 

Intervention and Methods: We investigated 17 obese women [body mass index (BMI) 30–39.4 kg/m2] and 14 normal women (BMI, 18.3–24.8 kg/m2) who underwent 24-h blood sampling at 10-min intervals, and plasma ACTH and cortisol concentrations were measured with sensitive assays. Data were analyzed with a new deconvolution program, approximate entropy (ApEn) analyses, and cosinor regression.

 

Outcome: ACTH and cortisol production rates were higher in obese women than in controls and correlated with BMI. Secretion of ACTH correlated with leptin (R = 0.63; P = 0.0001) and insulin (R = 0.67; P = 0.0001). ACTH ApEn and forward ACTH-cortisol cross-ApEn were diminished in obese women. The half-maximal effective concentration (ED50) of ACTH pulses vs. cortisol pulses was higher in obese women (38.3 ± 4.9 vs. 25.1 ± 3.7 ng/liter; P = 0.03), indicating decreased potency of ACTH. The diurnal properties of ACTH and cortisol secretion were unchanged in obese females.

 

Conclusion: Obese women exhibit enhanced ACTH and cortisol 24-h production compared with lean controls. The amplified ACTH drive is accompanied by decreased secretory regularity and diminished forward coupling between ACTH and cortisol. In addition, the potency of ACTH is decreased in obesity.

From http://jcem.endojournals.org/cgi/content/abstract/94/8/2991

Current Cushing's Newsletter, July 29, 2009

In This Issue

Welcome to the latest Cushing's Newsletter!

Cushie Bloggers

Upcoming Interviews

Upcoming Meetings

Upcoming Cushing's Book

Cushing's on Facebook and Twitter

Addison's Disease

Want to Volunteer?

Help Keep The Cushing's Sites Going

Cushing's Syndrome

Media: Battle goes south of the border

Major Complications of Obesity and Their Causes

Abstract: Two Year Follow-Up Of 32 Nonfunctional Benign Adrenal Incidentalomas

Endo News: Study Provides Documentation That Tumor "Stem-like Cells" Exist In Benign Tumors

Endo News: Hair Analysis Provides a Historical Record of Cortisol Levels in Cushing's Syndrome

Endo News: Specificity of screening tests for Cushing's syndrome in an overweight and obese population

Endo News: Grass-roots voices speak up on health care

Endo News: (Adrenal) UHCG surgeons taught rare surgical procedure

Endo News: Mental illness - it's not all in your head

Patients First: Twitter Transcript

Cushing's or Syndrome X?

New and Updated Helpful Doctors

New and Updated Bios

Abstract: Two Year Follow-Up Of 32 Nonfunctional Benign Adrenal Incidentalomas

Hamiyet Yılmaz, MD, Neslihan Başıl Tütüncü, MD, Mustafa Şhin, MD
Başent University Faculty of Medicine,  Department of Endocrinology

Objective: To evaluate the risk of developing endocrine hyperactivity and carcinoma during a period of up to five years in patients with apparently benign and  nonfunctioning adrenal incidentalomas.

 

Patients and Methods: Thirty two patients (mean age: 57.0 ± 8.3 years) were investigated in a prospective follow-up study for a median time of 24 months. Twenty eight patients had unilateral and four had bilateral masses. Initial avarage mass diameter was 17.47 ± 6.60 mm. All patients were followed-up yearly by physical examination,  metabolic parameters, hormonal evaluation (morning cortisol after 3mg dexamethasone suppression, urinary metanephrines and upright aldosterone/PRA)

 

Results: Among the clinical characteristics, 48% of patients were obese, 20%  were hypertensive, 13 had type 2 diabetes and impaired glucose tolerance.  During follow-up period no significant change in the functional status was observed and no malignant transformation occured. Only one patient developed subclinical Cushing syndrome at the end of the first year and referred to surgery. Change in mass size was correlated with HOMA-IR (p=0.002), upright aldosterone/PRA (p: 0.041), cortisol after dexamethasone suppression (p=0.048) and 24-hour urinary normetanephrine (p=0.005) levels. Gender, body mass index, glucose metabolism and blood pressure were not found to be correlated with change in mass size and functional status.

 

Conclusions: Due to the extremely low risk of developing malignancy during up to five years of follow-up, conservative approach for the management of adrenal incidentalomas is thought to be appropriate. However, possibility of evolution to hormonal hypersecretion makes long-term follow-up of two-to- five years seems to be obligatory.

 

From http://www.kurtis.it/home/en/abstract.cfm?articolo_id=6431&CFID=334394&CFTOKEN=9ad179ca67740edf-B262B722-B2BC-B6B0-ECDC7C6D612F7634&jsessionid=3a30bc945eb3441d4b887a18161839796266

Froedtert, medical college open specialty clinic

Froedtert & The Medical College of Wisconsin have opened a new clinic specializing in endocrine and metabolic conditions such as diabetes, obesity and thyroid disorders.

The clinic, located in the St. Francis Medical Arts Pavilion, 2025 W. Oklahoma Ave., opened in April.

Medical College endocrinologists Dr. Bradley Javorsky and Dr. Ty Carroll practice at the clinic from 1 p.m. to 5 p.m. Wednesdays and 8 a.m. to noon Thursdays.

Both physicians treat medical conditions including adrenal and pituitary gland disorders, cholesterol and lipid issues, Cushing’s disease, diabetes, hypoglycemia, osteoporosis, polycystic ovarian syndrome, obesity, thyroid disorders and thyroid cancer.

“Endocrine and metabolic disorders are usually complex, chronic conditions that should be carefully managed,” said Dr. James Findling, a Medical College endocrinologist and professor who heads the college’s community division of endocrinology. “Our new clinic gives residents of Milwaukee’s southern communities easy access to this specialized expertise.”

From http://www.bizjournals.com/milwaukee/stories/2009/07/06/daily5.html

Diagnosing Cushing’s syndrome

From http://www.onmedica.com/NewsArticle.aspx?id=bed82431-f024-423e-bd4c-7dc0a4fcfbd6

Louise Newson, general practitioner, Solihull. Reviewed by Andrew Krenz, endocrinologist, Southampton.

Tuesday, 19 May 2009.

Key learning points

• The commonest cause of Cushing’s syndrome is iatrogenic
• 2% of obese, poorly controlled patients with type 2 diabetes diabetes type 2 diabetics may have Cushing’s syndrome
• Various biochemical tests are needed for diagnosis; this is complex and requires specialist expertise.
• The underlying cause of Cushing’s syndrome needs to be determined
• Treatment and prognosis depend on the underlying cause.
• Surgery is the treatment of choice for Cushing’s disease i.e. pituitary-dependent

---

The adrenal cortex produces glucocorticoids including cortisol which affect metabolism of carbohydrate, lipid and protein as well as mineralocorticoids in the form of aldosterone. Both steroid axes are controlled by negative feedback.

Cushing’s syndrome is the term used to describe the clinical state of increased free circulating glucocorticoid concentrations.

Aetiology

Traditionally, the incidence of Cushing’s syndrome is quoted as 1/250,000, with no specific geographical variation. However, more recent data suggest that 3–5% of all obese, hypertensive individuals with type 2 diabetes may have Cushing’s syndrome, and actually experience improve­ment in metabolic control following intervention¹. Thus, clinicians should have a high index of suspicion in this patient group.

Cushing's syndrome due to an adrenal or pituitary tumour is more common in females (ratio 5:1). The peak incidence of Cushing syndrome caused by an adrenal or pituitary adenoma is between the ages of 25 and 40 years.

The commonest cause of Cushing’s syndrome is iatrogenic from administration of high doses of glucocorticoids.

Causes of Cushing’s syndrome

Causes of Cushing’s syndrome are divided into two groups:

ACTH-dependent disease

• Pituitary adenoma (Cushing’s disease) – 65% of cases
• Ectopic ACTH-producing tumours – 10% of cases
• ACTH administration (rarely given now)

Non-ACTH-dependent causes

• Adrenal adenomas or hyperplasia – 25% of cases
• Adrenal carcinomas
• Glucocorticoid administration

Ectopic ACTH production usually arises from malignancy, especially small cell carcinoma of the lung and carcinoid tumours, especially of the lung.

Figure 1: A hyperplastic adrenal gland taken from a patient with Cushing's syndrome.

Figure 2: An adrenocortical adenoma from a patient with Cushing's syndrome.

Clinical features

The predominant clinical features of Cushing’s syndrome are those of glucocorticoid excess as listed in the table below.

Table 1: Symptoms and signs of Cushing’s syndrome.

Symptoms

Signs

Weight gain

Plethora

Depression

Central obesity

Insomnia

Osteoporosis

Amen/oligomenorrhoea

Moon face

Poor libido

“Buffalo hump” / kyphosis

Thin skin / easy bruising

Bruising / striae / thin skin

Hair growth / acne

Hirsuitism / acne

Muscle weakness

Proximal myopathy

Polyuria / polydipsia

Glycosuria

Presentation is common to all aetiologies, although syndromes caused by ectopic ACTH may be a little different. Pigmentation only occurs in patients with ACTH-dependent causes. Pigmentation is most marked with ectopic production of ACTH.

Typical features of ectopic ACTH production include pigmentation (due to melanocyte stimulating hormone production as a byproduct of ACTH synthesis), weight loss, hypokalaemia, metabolic alkalosis and hyperglycaemia. Classical features of Cushing's syndrome, especially weight gain, are often absent. As this tends to occur at a later age than Cushing's disease, if the syndrome develops later in life, a carcinoma should be excluded as an underlying cause.

Note: A cushingoid appearance can be due to alcohol excess (pseudo-Cushing’s syndrome). The pathophysiology of this is poorly understood.

Impaired glucose tolerance or even diabetes mellitus are common, especially in the ectopic ACTH syndrome. Patients also suffer from psychological disturbances where depression and anxiety are common.

Figure 2: A patient with Cushing's syndrome showing signs of acne and hirsuitism.

Figure 3: Striae in a patient with Cushing's syndrome.

Investigations

Confirmation of Cushing’s syndrome needs to be performed using investigations, it is not a clinical diagnosis. Most obese, and/or hypertensive patients do not have Cushing’s syndrome².

It is important to note that random cortisol measurements are of no value in the diagnosis of Cushing’s syndrome.

Oral oestrogens increase cortisol-binding globulin and therefore lead to falsely elevated serum cortisol levels. They should be stopped for six weeks before investigation. It would be prudent to involve a specialist should this situation occur.

The three main investigations to confirm the diagnosis of Cushing’s syndrome include:

• 24-hour urinary free cortisol (can be checked in primary care)
• low-dose dexamethasone suppression test
• midnight plasma or salivary cortisol

The latter two usually require specialist input.

Low-dose dexamethasone suppression test – the two tests commonly used are as follows:

• 1 mg overnight (dexamethasone, 1 mg, is given at 11:00 p.m. and serum cortisol measured at 9:00 a.m. the next day)
• 48-hour test (dexamethasone, 0.5 mg, is given at 9:00 a.m., 3:00 p.m., 9:00 p.m. and 3:00 a.m. and serum cortisol measured at 9:00 a.m. at the start and end of the test).

In healthy people, serum cortisol is less than 50 mmol/litre following either test. The 48-hour test is more accurate.

Midnight plasma cortisol – the normal circadian rhythm of cortisol level is lost in Cushing’s syndrome. Following admission to hospital for 48 hours, a single sleeping midnight plasma cortisol level of more than 50 mmol/litre is the most sensitive indicator of Cushing’s syndrome.

Late-night salivary cortisol is an alternative to midnight plasma cortisol, with a slightly lower sensitivity. These samples are easier to obtain as do not require a hospital admission.

Urinary free cortisol – although this test is in widespread use it has a low sensitivity; at least three or four collections are required to avoid missing mild disease. The specificity is also poor as the cortisol levels obtained overlap those found in patients with depression or polycystic ovary syndrome.

Tests to diagnose the cause of Cushing’s syndrome

This can be very difficult as all causes can results in clinically identical Cushing’s syndrome. Differentiation can be difficult even by experts.

Following confirmation of Cushing’s syndrome, the next step is measurement of plasma ACTH.

If plasma ACTH levels are less than 5 pg/ml then a primary adrenal cause is likely. Imaging of the adrenals with CT or MRI is then the appropriate next step³.

If levels of ACTH are persistently more than 15 pg/ml then an ACTH-dependent pathology is likely and the patient will require further investigations as discussed below.

Levels of 5–15 pg/ml require cautious interpretation, because individuals with Cushing’s disease may have plasma ACTH of less than 10 pg/ml. At least two or three estimations are made, to avoid inappropriate classification.

ACTH-dependent Cushing’s syndrome – further tests

Biochemical evaluation, rather than imaging, should be relied on to differentiate pituitary from non-pituitary sources of ACTH with the following tests:

High-dose dexamethasone suppression test

Tumours caus­ing Cushing’s disease (pituitary pathology) typically retain some responsiveness to the suppressive effects of glucocorticoids, whereas tumours causing ectopic ACTH secretion usually do not.

This is the rationale for the high-dose dexamethasone suppression test. In about 80% of patients with Cushing’s disease, cortisol is reduced to less that 50% of the basal level.

Corticotrophin-releasing hormone (CRH) test

CRH stimu­lates release of ACTH from the corticotrophs of the anterior pitui­tary. Patients with Cushing’s disease typically exhibit an excessive increase in plasma cortisol, whereas those with ectopic ACTH secretion usually do not.

Imaging in ectopic ACTH secretion – the most common sites of ectopic ACTH secretion are small cell lung cancers and bronchial carcinoid tumours. High-definition, multi-slice CT of the chest is required. Carcinoid tumours often express somatostatin receptors and may be visualized on radiolabelled octreotide or lanreotide scintigraphy.

Pituitary imaging

If a pituitary source is likely, CT or MRI of the pituitary is the next investigation but sensitivity is not high.

However, around 40% of corticotroph microadenomas are not visualized with a MRI scan and ‘incidentalomas’ are found in 10% of the healthy population. Therefore biochemical assessment of patients is extremely important.

Bilateral inferior petrosal sinus sampling is a highly spe­cialised, invasive investigation, but is the most reliable test for differentiating pituitary and non-pituitary sources of ACTH.
Management

The cause must be addressed.

Iatrogenic

If the cause is iatrogenic, the prescription must be reviewed. There will be a medical need for the steroids but it may be possible to use "steroid sparing" drugs to reduce the dose. More than 7.5 - 10 mg/day (or equivalent in other steroids) may produce Cushings. It is dose-response.

Pituitary Adenoma (Cushing’s disease)

Surgery

Trans-sphenoidal selective microadenomectomy by an experienced surgeon is the treatment of choice in most patients with Cushing’s disease. Long-lasting remission without other pituitary hormonal deficiency is achieved in 50–60% of cases.

Following the operation, ACTH levels fall below normal. This is temporary, but hydrocortisone or prednisolone replacement must be given to avoid acute hypoadrenalism. Most patients can stop this replacement therapy in less than a year. A steroid card including education about intercurrent illness should be given to the patient.

Medical treatment

Medical therapy to lower cortisol may be used in preparation for surgery or after unsuccessful surgery. It may also be used with pituitary radiotherapy. It is only rarely given long-term.

Metyrapone and ketoconazole are often used to inhibit cortisol synthesis. Metyrapone causes an increase in steroid androgenic precursors, and hirsutism is a major adverse effect in women; this does not occur with ketoconazole.

Radiotherapy

Where transphenoidal surgery has failed or in patients who are unsuitable candidates for surgery, radiotherapy is another possible treatment.

Progressive anterior pituitary failure is the major side-effect; growth hormone deficiency is present in almost all patients 10 years after treatment and gonadotrophin deficiency in about 15%. About four years after treatment, 80% of patients are in remission with respect to circulating plasma cortisol levels. Patients must be evaluated by specialist with regular follow up to identify deficiences early.

Adrenal tumours

Surgery for adrenal adenomas is usually curative but carcinomas have a much worse prognosis. Adrenal adenomas are usually removed by a laparoscopic unilateral adrenalectomy⁴.

Micronodular or macronodular hyperplasia is usually treated by bilateral total adrenalectomy as leaving any gland will often lead to recurrence.

Ectopic ACTH production

This may be treated by surgery if the tumour can be located and has not metasasized

Prognosis

Untreated Cushing’s syndrome has a very poor prognosis. Patients with incompletely controlled Cushing's syndrome have a five-fold excess mortality⁵.

However, with treatment the results are very good unless there is underlying malignancy.

As many studies have shown that a relatively high number of diabetic patients may have unsuspected Cushing's syndrome, one study has even suggested that it may be worthwhile actually screening for Cushing’s syndrome may be feasible at the clinical onset of diabetes⁶. Clearly this would only be reserved for cases with a high level of suspicion.

Video 1: A summary of Cushing's syndrome occuring in children with discussion about the aetiology.

Video 2: A US based case history illustrating a patients journey through diagnosis of Cushing's disease to surgical treatment on her pituitary gland.

References

1. Catargi B, Rigalleau V, Poussin A et al. Cushing’s syndrome in type-2 diabetes. J Clin Endocrinol Metab 2003; 88: 5808–13.

2. Newell-Price J, Bertagna X, Grossman AB, et al; Cushing's syndrome. Lancet. 2006 May 13;367(9522):1605-17.

3. Rockall AG, Babar SA, Sohaib SA, et al; CT and MR imaging of the adrenal glands in ACTH-independent cushing syndrome. Radiographics. 2004 Mar-Apr;24(2):435-52.

4. Chow JT, Thompson GB, Grant CS, Farley DR et al. Bilateral laparoscopic adrenalectomy for corticotrophin-dependent Cushing's syndrome: a review of the Mayo Clinic experience. Clin Endocrinol 2008;68(4):513-9.

5. Newell-Price J, Bertagna X, Grossman AB, et al; Cushing's syndrome. Lancet 2006;367(9522):1605-17.

6. Reimondo G, Pia A, Allasino B, Tassone F, et al. Screening of Cushing's syndrome in adult patients with newly diagnosed diabetes mellitus. Clin Endocrinol 2007;67(2):225-9.

Further reading

Association for Cushing's Treatment and Help: A support group for people suffering from all forms of Cushing's syndrome.

Pituitary Foundation - Supports pituitary patients and their carers.

Author and reviewers competing interests: none.

Images: Wellcome.

Childhood Obesity: Why Parents Are to Blame

It’s one of the most troubling trends in the current state of the health of our nation: childhood obesity.  A particularly troubling condition because the extra pounds they put on now, often put children on the path to health problems that were once confined to adults, such as diabetes, high blood pressure and high cholesterol.

In certain rare cases, genetic diseases and hormonal disorders can predispose a child to obesity. These diseases, such as Prader-Willi syndrome and Cushing's syndrome, affect a very small proportion of children. In the general population, however, eating and exercise habits play a much greater role as the root cause of childhood obesity....

From http://singlemindedwomen.com/womensfamily/758/childhood-obesity-why-parents-are-to-blame.html

I missed it!

With all the hubbub over the weekend, and finding out yesterday morning that my best friend was in the hospital, I completely forgot that yesterday was the 21st anniversary of my pituitary surgery at NIH.

I even had a reminder on my calendar, a notice on the calendar section of the message boards, all kinds of places.  But it just slipped my mind.

Maybe this is a sign that I should somehow forget that I had Cushing's, that I should move on with my life as a "cured" Cushie.

My new life, in addition the the panhypopituitarism, involves kidney cancer and, for me anyway, that's a zebra disease.

I consider this a zebra disease because it's one that I shouldn't have had.

For one thing, I "should" have had colon cancer because both parents and an aunt had it twice each.  Of course, there's no guarantee that I won't get that, too.

Anyway, other "zebra" reasons are the risk factors for kidney cancer aka renal cell carcinoma.
The majority of kidney cancers are renal cell carcinomas. Risk factors for renal cell carcinoma include:

• Age. Your risk of renal cell carcinoma increases as you age. Renal cell carcinoma occurs most commonly in people 60 and older.

I was younger than this.

• Sex. Men are more likely to develop renal cell carcinoma than women are.

I am female

• Smoking. Smokers have a greater risk of renal cell carcinoma than nonsmokers do. The risk increases the longer you smoke and decreases after you quit.

Not me!

• Obesity. People who are obese have a higher risk of renal cell carcinoma than do people who are considered average weight.

A Cushing's gift

• High blood pressure (hypertension). High blood pressure increases your risk of renal cell carcinoma, but it isn't clear why. Some research in animals has linked high blood pressure medications to an increased risk of kidney cancer, but studies in people have had conflicting results.

Never had this until the kidney cancer.  It went away immediately post-op.

• Chemicals in your workplace. Workers who are exposed to certain chemicals on the job may have a higher risk of renal cell carcinoma. People who work with chemicals such as asbestos, cadmium and trichloroethylene may have an increased risk of kidney cancer.

What?  Me work?.

• Treatment for kidney failure. People who receive long-term dialysis to treat chronic kidney failure have a greater risk of developing kidney cancer. People who have a kidney transplant and receive immunosuppressant drugs also are more likely to develop kidney cancer.

Nope.  Some sites also list polycystic  kidney disease.  I don't have that but half my husband's family does.  Hmmm - wonder if that's contagious

• Von Hippel-Lindau disease. People with this inherited disorder are likely to develop several kinds of tumors, including, in some cases, renal cell carcinoma.

I've wondered about this but, you know, it's too "rare".

• Hereditary papillary renal cell carcinoma. Having this inherited condition makes it more likely you'll develop one or more renal cell carcinomas.

Not that I know of. 

So, yesterday after I went with DH to his doctor, I went to see my new zebra doctor - my kidney surgeon - for pain I've been having.  Over the summer he said if I "wanted" my CT scan earlier than my next visit, just let him know.  I've been having pain in my abdomen and he is sending me for the CT I requested.  Plus, he suggested I call my gastroenterologist just in case there's something happening in my colon. 

Oh no!  What if I finally get the disease I always felt I was destined to get?

But, like Scarlett O'Hara, I'll think about that another day and head off with DH to see his new surgeon...