Cushing’s Syndrome and Skin Problems

Posted on August 22, 2016 by MaryO

By Afsaneh Khetrapal, BSc (Hons)

Cushing’s Syndrome (sometimes called hypercortisolism) is a hormonal disease caused by an abnormally high level of the hormone cortisol in the body. This may arise because of an endogenous or exogenous source of cortisol. Endogenous causes include the elevated production of cortisol by the adrenal glands, while exogenous causes include the excessive use of cortisol or other similar steroid (glucocorticoid) hormones over a prolonged period of time.

The adrenal glands are situated just above each kidney, and form part of the endocrine system. They have numerous functions such as the production of hormones called catecholamines, which includes epinephrine and norepinephrine. Interestingly, the outer layer (cortex) of the adrenal glands has the distinct responsibility of producing cortisol. This hormone is best known for its crucial role in the bodily response to stress.

At physiologically appropriate levels, cortisol is vital in maintaining normal sleep-wake cycles, and acts to increase blood sugar levels. It suppresses the immune system, regulates the effect of insulin on the metabolism of fats, proteins, and carbohydrates, and help with the homeostasis of water in the body.

Exogenous corticosteroids can also lead to Cushing’s syndrome, when they are used as a form of long-term treatment for various medical conditions. In fact, the long-term use of steroid medication is the most common reason for the development of Cushing’s syndrome.

Prednisolone is the most commonly prescribed steroid medicine. It belongs to a class of medicine that is sometimes used to treat conditions such as certain forms of arthritis and cancer. Other uses include the rapid and effective reduction of inflammation in conditions such as asthma and multiple sclerosis (MS), as well as the treatment of autoimmune conditions such as lupus erythematosus, and rheumatoid arthritis.

Overall, Cushing’s syndrome is quite uncommon and affects approximately 1 in 50,000 people. Most of them are adults between the ages of 20 and 50.  Women are 3 times more commonly affected than men. Additionally, patients who are obese, or those who have type 2 diabetes with poorly controlled blood sugar and blood pressure show a greater predisposition to the disorder.

Symptoms of Cushing’s syndrome

There are numerous symptoms associated with Cushing’s syndrome, which range from muscle weakness, hypertension, curvature of the spine (kyphosis), osteoporosis, and depression, to fatigue Specific symptoms which pertain to the skin are as follows:

  • Thinning of the skin and other mucous membranes: the skin becomes dry and bruises easily. Cortisol causes the breakdown of some dermal proteins along with the weakening of small blood vessels. In fact, the skin may become so weak as to develop a shiny, paper-thin quality which allows it to be torn easily.
  • Increased susceptibility of skin to infections
  • Poor wound healing  of bruises, cuts, and scratches
  • Spots appear on the upper body, that is, on the face, chest or shoulders
  • Darkened skin which is seen on the neck
  • Wide, red-purple streaks (at least half an inch wide) called striae which are most common on the sides of the torso, the lower abdomen, thighs, buttocks, arms, and breasts, or in areas of weight gain. The accumulation of fat caused by Cushing’s syndrome stretches the skin which is already thin and weakened due to cortisol action, causing it to hemorrhage and stretch permanently, healing by fibrosis.
  • Acne: this can develop in patients of all ages.
  • Swollen ankles: this is caused by the accumulation of fluid, called edema.
  • Hyperhidrosis (excessive sweating)

Reviewed by Dr Liji Thomas, MD

From http://www.news-medical.net/health/Cushings-Syndrome-and-Skin-Problems.aspx

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Who’s at Risk for Cushing’s?

Posted on August 16, 2016 by MaryO

by Kristen Monaco
Contributing Writer, MedPage Today

Researchers have developed a new method to assess specific populations for Cushing’s syndrome, based on results from a multicenter study.

The prospective cohort study evaluated at-risk patients for Cushing’s syndrome to create a novel type of scoring system in order to better predict the development of disease, stated lead author Antonio León-Justel, PhD,of the Seville Institute of Biomedicine in Spain, and colleagues.

Cushing’s syndrome is identified by an excess of cortisol and/or glucocorticoids in the blood, which can result in myriad negative health outcomes, including an increased risk of death and morbidity, according to the study in The Journal of Clinical Endocrinology & Metabolism.

Because Cushing’s syndrome (CS) is complex and difficult to diagnose, there is a necessity for new methods to assess at-risk populations in order to mitigate the rising prevalence of the disorder, the authors noted.

“The diagnosis of CS might pose a considerable challenge even for experienced endocrinologists since there are no pathognomonic symptoms or signs of CS and most of the symptoms and signs of CS are common in the general population including obesity, hypertension, bone loss, and diabetes,” the senior author, Alfonso Leal Cerro, MD, toldMedPage Today via email. “Routine screening for CS remains impractical due to the estimated low prevalence of the disease. However this prevalence might be higher in at-risk populations.”

The authors screened a total of 353 at-risk patients from 13 different hospitals across Spain between January 2012 and July 2013 to measure cortisol variability from saliva samples.

At-risk populations, which the authors note have a higher prevalence of Cushing’s syndrome, included individuals with type 2 diabetes, hypertension, and osteoporosis.

The patients screened in the study were each identified as having at least two of the risk factors for Cushing’s syndrome: high blood pressure (defined as taking two or more drugs and having a systolic blood pressure over 140 mmHg and/or a diastolic blood pressure over 90 mmHg), obesity (body mass index >30), uncontrolled diabetes (HbA1c>7.0%), osteoporosis (T-score ≥ -2.5 SD), and virilization syndrome (hirsutism) with menstrual disorders.

The researchers used clinical and biochemical methods of assessment. Clinical methods included inspection of physical characteristics, such as muscle atrophy, purple striae, and/or facial plethora. Biochemical methods included collecting saliva and blood samples from participants to test cortisol levels using a chemiluminescence method. Each individual was identified as either negative for hypercortisolism (late-night salivary cortisol [LNSC] ≤ 7.5 nmol/L and dexamethasone suppression test [DST] ≤ 50 nmol/L) or positive for hypercortisolism (LNSC > 7.5 nmol/L and DST > 50 nmol/L).

Univariate testing indicated the following significant characteristics to be positively correlated with the development of Cushing’s syndrome:

  • Muscular atrophy (15.2, CI 95% 4.48-51.25);
  • Osteoporosis (4.60, 1.66-12.75); and
  • Dorsocervical fat pad (3.32, 1.48-7.5).

A logistic regression analysis of LNSC values also showed significant correlation between Cushing’s syndrome and the following top three characteristics:

  • Muscular atrophy (9.04, CI 95% 2.36-34.65);
  • Osteoporosis (3.62, CI 95% 1.16-11.35); and
  • Dorsocervical fat pad (3.3, CI 95% 1.52-7.17).

Roberto Salvatori, MD, professor and medical director of the Johns Hopkins Pituitary Center, who was not involved with the study, commented to MedPage Today in an email: “Any endocrinologist would proceed with careful Cushing biochemical evaluation in the presence of the clinical features (muscular atrophy, osteoporosis, and dorsocervical fat pad) that are well known to be associated with hypercortisolism. Of notice, the odds ratio is further increased by an abnormal late-night salivary cortisol, which is already a screening test for hypercortisolism.”

The researchers used their results to develop an equation to determine the level of risk a patient has for developing Cushing’s syndrome, taking into account factors for osteoporosis, dorsocervical fat pads, muscular atrophy, and LNSC levels.

Although the study was able to develop a comprehensive risk model for the syndrome, when tested against the prevalence for Cushing’s syndrome in the subject group, the equation generated a total of 56 false-positive and 25 true-positive results. Overall, the researchers wrote, 83% of patients were accurately classified as belonging to the at-risk population when using the equation.

Because the newly developed equation for identifying at-risk individuals involved factors that are relatively easy to test for, the authors noted that clinical application is broad and cost-effective in a primary care setting.

“We would like to test the scoring system in different clinical settings such as primary care or hypertension clinics,” Leal Cerro said. “Primary care would be a particularly interesting setting since it might significantly decrease the time to diagnosis, something critical to avoid an excessive exposure to glucocorticoid excess and consequent deleterious effects.”

Salvatori said that while the study was a good start at shedding light on some of the unknowns about Cushing’s syndrome, more research is required. “The real question in my mind is when does a non-endocrinologist need to suspect Cushing in a general medicine, orthopedic, or other clinic? When the internal medicine residents ask me about guidelines for ‘who to screen for hypercortisolism in my clinic,’ I am unable to provide an evidence-based answer.”

The study was funded by a grant from Novartis Oncology, Spain.

León-Justel and Leal Cerro disclosed financial relationships with Novartis Oncology, Spain.

  • Reviewed by F. Perry Wilson, MD, MSCEAssistant Professor, Section of Nephrology, Yale School of Medicine and Dorothy Caputo, MA, BSN, RN, Nurse Planner

LAST UPDATED 08.15.2016

From http://www.medpagetoday.com/endocrinology/generalendocrinology/59688

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Improvement of cardiovascular risk factors after adrenalectomy in patients with adrenal tumors and Subclinical Cushing Syndrome

Posted on August 16, 2016 by MaryO

Eur J Endocrinol. 2016 Jul 22. pii: EJE-16-0465. [Epub ahead of print]

Bancos I1, Alahdab F2, Crowley RK3, Chortis V4, Delivanis D5, Erickson D6, Natt N7, Terzolo M8, Arlt W9, Young W10, Murad MH11.

Author information

Abstract

OBJECTIVE:

Beneficial effects of adrenalectomy on cardiovascular risk factors in patients with Subclinical Cushing Syndrome (SCS) are uncertain. We sought to conduct a systematic review and meta-analysis with the following objectives: 1) determine the effect of adrenalectomy compared to conservative management on cardiovascular risk factors in patients with SCS and 2) compare the effect of adrenalectomy on cardiovascular risk factors in patients with SCS versus those with a non-functioning (NF) adrenal tumor.

METHODS:

Medline In-Process & Other Non-Indexed Citations, MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trial were searched on November 17th, 2015. Reviewers extracted data and assessed methodological quality in duplicate.

RESULTS:

We included 26 studies reporting on 584 patients with SCS and 457 patients with NF adrenal tumors. Studies used different definitions of SCS. Patients with SCS undergoing adrenalectomy demonstrated an overall improvement in cardiovascular risk factors (61% for hypertension, 52% for diabetes mellitus, 45% for obesity and 24% for dyslipidemia). When compared to conservative management, patients with SCS undergoing adrenalectomy experienced improvement in hypertension (RR 11, 95% CI 4.3 – 27.8) and diabetes mellitus (RR 3.9, 95%CI 1.5- 9.9), but not dyslipidemia (RR 2.6, 95%CI 0.97 -7.2) or obesity (RR 3.4 (95%CI 0.95-12)). Patients with NF adrenal tumors experienced improvement in hypertension (21/54 patients), however, insufficient data exist for comparison to patients with SCS.

CONCLUSIONS:

Available low to moderate quality evidence from heterogeneous studies suggests a beneficial effect of adrenalectomy on cardiovascular risk factors in patients with SCS overall and as compared to conservative management.

PMID:
27450696
DOI:
10.1530/EJE-16-0465
[PubMed – as supplied by publisher]

From http://www.ncbi.nlm.nih.gov/pubmed/27450696

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Experimental Drug Improves Cushing’s Disease

Posted on August 12, 2016 by MaryO

International phase 3 trial is largest study ever of rare endocrine disorder

A new investigational drug significantly reduced urinary cortisol levels and improved symptoms of Cushing’s disease in the largest clinical study of this endocrine disorder ever conducted.

Results of the clinical trial conducted at centers on four continents appear in the March 8 issue of the New England Journal of Medicine and show that treatment with pasireotide cut cortisol secretion an average of 50 percent and returned some patients’ levels to normal.

“Cushing’s disease is a rare disorder, with three to five cases per million people. It can affect all ages and both genders but is most common in otherwise healthy young women,” says Harvard Medical School Professor of Medicine Beverly M.K. Biller of the Massachusetts General Hospital (MGH) Neuroendocrine Unit, senior author of the study.

“Often misdiagnosed, Cushing’s is associated with a broad range of health problems – causing physical changes, metabolic abnormalities, and emotional difficulties – and if not controlled, significantly increases patients’ risk of dying much younger than expected,” Biller says.

Cushing’s disease, one of several conditions that lead to Cushing’s syndrome, is characterized by chronically elevated secretion of the hormone cortisol. The disease is caused by a benign pituitary tumor that oversecretes the hormone ACTH, which in turn induces increased cortisol secretion by the adrenal glands.

Symptoms of Cushing’s syndrome include weight gain, hypertension, mood swings, irregular or absent periods, abnormalities of glucose processing (insulin resistance, glucose intolerance, and type 2 diabetes), and cardiovascular disease. Because those symptoms are associated with many health problems, physicians may not consider the rare possibility of Cushing’s. The diagnosis can be difficult to make and usually requires the expertise of an endocrinologist. Because cortisol levels normally fluctuate during the day, a single blood test is unlikely to identify chronic elevation, and thus the most common diagnostic test measures a patient’s 24-hour urinary output.

First-line treatment for Cushing’s disease is surgical removal of the ACTH-secreting tumor, which leads to remission in 65 to 90 percent of patients. But symptoms return in 10 to 30 percent of those patients, requiring repeat surgery, radiation therapy, or treatment with drugs that interfere with part of the cortisol control system. Until last month, there was no specific FDA-approved medical treatment for Cushing’s syndrome; the newly approved drug mifepristone should benefit some patients, but it does not affect the pituitary source of the condition or reduce cortisol levels.

The current phase 3 trial of pasireotide — the first drug that blocks ACTH secretion by binding to somatostatin receptors on the pituitary tumor — was sponsored by Novartis Pharma. The trial enrolled 162 patients at 62 sites in 18 countries. Nearly 85 percent of participants had either persistent disease that had not responded to surgery or had recurrent disease; the other 15 percent were recently diagnosed but not appropriate candidates for surgery.

Participants were randomly assigned to two groups, one starting at two daily 600-microgram injections of pasireotide and the other receiving 900-microgram doses. Three months into the 12-month trial, participants whose urinary cortisol levels remained more than twice the normal range had their dosage levels increased. During the rest of the trial, dosage could be further increased, if necessary, or reduced if side effects occurred.

At the end of the study period, many patients had a significant decrease in their urinary cortisol levels, with 33 achieving levels within normal range at their original dosage by month six of the trial. Participants whose baseline levels were less than five times the upper limit of normal were more likely to achieve normal levels than those with higher baseline levels, and the average urinary cortisol decrease across all participants was approximately 50 percent. Many Cushing’s disease symptoms decreased, and it became apparent within the first two months whether or not an individual was going to respond to pasireotide.

Transient gastrointestinal discomfort, known to be associated with medications in the same family as pasireotide, was an expected side effect. Another side effect was elevated glucose levels in 73 percent of participants, something not seen to the same extent with other medications in this family. These elevated levels will require close attention, because many Cushing’s patients already have trouble metabolizing glucose. Biller explains, “Those patients who already were diabetic had the greatest increases in blood sugar, and those who were pre-diabetic were more likely to become diabetic than those who began with normal blood sugar. However, elevations were even seen in those who started at normal glucose levels, so this is real and needs to be monitored carefully.”

Additional trials of pasireotide are in the works, and a phase 3 study of a long-acting version of the drug was recently announced. Biller notes that the potential addition of pasireotide to available medical treatments for Cushing’s disease would have a number of advantages. “It’s very important to have medications that work at different parts of the cortisol control system – which is the case for the currently used medications that work at the adrenal gland level; pasireotide, which works at the pituitary gland; and mifepristone, which blocks the action of cortisol at receptors in the body. Having more options that work in different ways is valuable because not all patients respond to one medicine and some may be unable to tolerate a specific drug’s side effects.

“As we have more drugs available to treat Cushing’s,” Biller adds, “I think in the long run we may start using combinations of drugs, which is the approach we use in some patients with acromegaly, another disorder in which a pituitary tumor causes excess hormone secretion. Ultimately, we hope to be able to give lower doses leading to fewer overall side effects, but that remains to be determined by future studies.”

Annamaria Colao, University of Naples, Italy, is the lead author of the report. Additional co-authors are Stephan Petersenn, University of Duisberg-Essen, Germany; John Newell-Price, University of Sheffield, U.K.; James Findling, Medical College of Wisconsin, Milwaukee; Feng Gu, Peking Union Medical College Hospital, Beijing; Mario Maldonado, Ulrike Schoenherr, and David Mills, Novartis Pharma; and Luiz Roberto Salgado, University of São Paulo Medical School, Brazil.

From http://dailyrecords.us/experimental-drug-improves-cushings-disease/

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New Diagnostic Criteria for Subclinical Hypercortisolism using Postsurgical Hypocortisolism

Posted on August 12, 2016 by MaryO

Clin Endocrinol (Oxf). 2016 Jun 24. doi: 10.1111/cen.13145. [Epub ahead of print]

 

Abstract

OBJECTIVE:

There is no consensus on the biochemical diagnostic criteria for subclinical hypercortisolism (SH). Using parameters related to the hypothalamic-pituitary-adrenal axis, we aimed to develop a diagnostic model of SH for predicting postsurgical hypocortisolism and metabolic complications.

DESIGN:

Prospective and cross-sectional, observational, multicentre study in Korea.

METHODS:

After exclusion of overt Cushing’s syndrome, adrenal incidentaloma (AI) patients who underwent unilateral adrenalectomy (n = 99) and AI patients (n = 843) were included. Primary outcome was defined as the presence of postsurgical hypocortisolism; secondary outcome was the presence of ≥4 complications (components of the metabolic syndrome and low bone mass). Postsurgical hypocortisolism was determined on the fifth postsurgery day using the ACTH stimulation test.

RESULTS:

Thirty-three of the 99 patients developed postsurgical hypocortisolism. Analysis of the presurgery overnight 1-mg dexamethasone suppression test (1-mg DST) showed that all patients with cortisol levels of >138 nmol/l experienced postsurgical hypocortisolism, whereas those with levels of ≤61 nmol/l did not. The models of (i) 1-mg DST >138 nmol/l or (ii) >61 nmol/l with the presence of one among low levels of ACTH and dehydroepiandrosterone-sulphate had the highest accuracy (89·9%, P < 0·001) and odds ratio [OR 111·62, 95% confidence interval (CI) 21·98-566·74, P < 0·001] for predicting postsurgical hypocortisolism. Finally, patients with the same criteria in the 843 AI patients showed the highest risk for having ≥4 complications (OR 3·51, 95% CI 1·84-6·69, P < 0·001), regardless of gender, age, body mass index and bilaterality.

CONCLUSIONS:

Our proposed model is able to accurately predict subtle cortisol excess and its chronic manifestations in AI patients.

© 2016 John Wiley & Sons Ltd.

PMID:
27341314
DOI:
10.1111/cen.13145

From http://www.ncbi.nlm.nih.gov/pubmed/27341314

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