Cushing’s Patient Exhibits Cortisol-Secreting Lesions in Both Adrenal Glands

In rare cases, Cushing’s syndrome may be caused by cortisol-secreting masses in both adrenal glands, a case report shows.

The study with that finding, “ACTH-independent Cushing’s syndrome with bilateral cortisol-secreting adrenal adenomas: a case report and review of literatures” was published in BMC Endocrine Disorders.

Cushing’s syndrome results from the prolonged secretion of excess cortisol. While most cases are caused by tumors in the pituitary gland, up to 20 percent result from tumors in the adrenal glands.

Occasionally, Cushing’s syndrome is caused by masses in both adrenal glands, which may be similar or display different properties. “Determining the nature and function of bilateral adrenal masses is always a challenge in clinical practice,” researchers said.

Now, physicians at Sichuan University in China, reported the case of a 55-year-old woman who complained of difficulty breathing for more than 10 years.

The patient had developed obesity of the trunk and face over the past two years, and had been diagnosed with hypertension 10 years before. She also had high lipid levels for the past five years.

The patient was taking Avapro (irbesartan), Lopressor (metoprolol), Procardia XL (nifedipine), and statins for these disorders. No other health conditions or treatments were reported.

Physical examination showed a moon-shaped face, truncal obesity, and accumulation of fat in the back of the neck and upper back (aka buffalo hump). She also had discoloration of the lower limbs, with slight fluid accumulation and muscle weakness.

Routine blood analysis did not reveal significant changes, but hormone analysis showed high cortisol levels and low adrenocorticotropic hormone (ACTH) was low.

The amount of 24-hour urine-free cortisol was almost five times higher than the upper normal limit. Also, the patients had reduced response to corticosteroids treatment, showing even higher cortisol levels upon treatment with 1 mg dexamethasone. Additional evaluations revealed reduced bone mineral density, indicative of osteoporosis.

Together, the findings led to a diagnosis of ACTH-independent Cushing’s syndrome.

To identify what was causing Cushing’s syndrome, the team looked at the adrenal glands. They detected three lesions, one on the right side measuring 2.5 centimeters, and two on the left side, with 2.3 cm and 0.6 cm respectively. The masses in both sides were actively producing cortisol in similar proportions.

These results confirmed that the patient had Cushing’s syndrome induced by bilateral adrenal excessive cortisol secretion.

Because the patient had poor cardiac function, researchers planned a two-step operation. First, they removed the right adrenal gland laparoscopically, followed by the left adrenal gland two months later. The patient started replacement therapy with hydrocortisone, and her cortisol levels improved significantly, returning to normal levels. She also lost 4 kilograms (8.8 pounds) of body weight in the following year.

“The optimal treatment for patients with bilateral cortisol-secreting adenomas remains uncertain,” the researchers wrote. Although there are no reports of recurrence after surgical treatment, the long-term outcome of these patients remains unclear, and “lifelong follow-up of the patient is required,” they added.

Bilateral cortisol-secreting adrenal adenomas are rare, having been reported in only 15 other studies, the team wrote. Interestingly, some features reported in this study also were identified by other researchers, including the fact that bilateral cortisol-secreting adrenal lesions are more predominantly found in females during adulthood. Also, the size of the lesions commonly range between 1 to 5 centimeters when detected, and appear at approximately the same time in both adrenal glands.

Although there are no treatment guidelines for these cases, surgical removal of the lesions or adrenal glands, plus glucocorticoid replacement therapy, is the mostly used therapeutic approach. Importantly, the researchers noted that patients who underwent partial gland removal were able to withdraw from glucocorticoid replacement therapy during follow-up.

From https://cushingsdiseasenews.com/2018/05/03/cushings-patient-has-cortisol-secreting-lesions-in-both-adrenal-glands/

Unilateral andrenalectomy may be valid first-line treatment for Cushing’s syndrome

Debillon E, et al. J Clin Endocrinol Metab. 2015;doi:10.1210/jc.2015-2662.

In patients with evident Cushing’s syndrome related to primary bilateral macronodular adrenal hyperplasia, unilateral adrenalectomy of the large gland appears to be a suitable alternative to bilateral adrenalectomy as a first-line treatment, according to recent findings.

Unilateral adrenalectomy yielded normalized urinary free cortisol and improved Cushing’s syndrome, according to the researchers.

Olivier Chabre , MD, PhD, of the Service d’Endocrinologie-Diabétologie-Nutrition in France, and colleagues evaluated all patients (n = 15) with overt Cushing’s syndrome related to primary bilateral macronodular adrenal hyperplasia who underwent unilateral laparoscopic adrenalectomy of the larger gland between 2001 and 2015. Patients were seen for clinical and biological follow-up assessments at 1, 3 and 6 months postoperatively, 5 years after surgery and at the time of the last available urinary free cortisol measurement.

The study’s primary outcome measures were pre- and postoperative levels of urinary free cortisol, plasma cortisol, adrenocorticotropic hormone (ACTH), BMI, blood pressure, plasma glucose and lipids and measurements of these values on follow-up assessments. Patients were followed for a median of 60 months.

The researchers found that in early postoperative measurements, all 15 patients who underwent unilateral adrenalectomy achieved normal or low urinary free cortisol. Between 7 days and 1 month, there was a decrease in median urinary free cortisol from 2.19 times the upper limit of normal (ULN) at baseline to 0.27 ULN (P = .001). At 1 month, only one patient had elevated urinary free cortisol, and this patient went into remission by month 3 and continued to be in remission after 12 years of follow-up.

Forty percent of the patients developed adrenal insufficiency after unilateral adrenalectomy and latent adrenal insufficiency could not be excluded in two of the other patients. No predictors of postoperative adrenal insufficiency were identified.

Six of the patients had diabetes before unilateral adrenalectomy surgery; four of those were treated with antidiabetes drugs. At 12 months, only two of these patients had a continued need for antidiabetes drugs and had reductions in HbA1c despite decreases in their treatment. Recurrence occurred in two patients, demonstrating urinary free cortisol above the ULN at 7 years postoperatively and 8 years postoperatively. Both cases required treatment with mitotane, and in one of the patients, adrenalectomy of the second gland was required 9 years after the initial adrenalectomy.

According to the researchers, postoperative management and vigilant follow-up is needed in order to monitor patients for the risk for adrenal insufficiency.

“Further prospective studies are needed to better evaluate the long-term benefits of [unilateral adrenalectomy], which has one major benefit over [bilateral adrenalectomy]: if needed, [unilateral adrenalectomy] can be transformed in [bilateral adrenalectomy], while the opposite is obviously not true,” the researchers wrote. “One could propose that in further prospective studies [bilateral adrenalectomy] could be performed only if [unilateral adrenalectomy] fails to normalize [urinary free cortisol] at 1 month postoperatively.” – by Jennifer Byrne

Disclosure: The researchers report no relevant financial disclosures.

From Healio

Endocrine Society Releases Guidelines on Treatment of Cushing’s Syndrome

To lessen the risk for comorbidity and death, the Endocrine Society’s newly published guidelines on the treatment of Cushing’s syndrome focus on surgical resection of the causal tumor with the goal of normalizing cortisol levels. Furthermore, there is increased emphasis on individualizing treatment options when choosing a second-line treatment.

In July 2015, the Endocrine Society published treatment guidelines to assist endocrinologists in appropriately initiating treatment or referring patients with Cushing’s syndrome to treatment. A task force of experts compiled evidence from systematic reviews and graded the strength of the recommendations.

“We hope that it will lead to improved treatment of comorbidities both before and after definitive treatment of the syndrome, and to increased individualization of patient treatment,” said chair of the task force Lynnette Nieman, MD, who is chief of the Endocrinology Consultation Service at the National Institutes of Health Clinical Center.

“There are two new drugs that were approved in 2012, and so I think that is what prompted the review. Still, medications are not the first line of treatment, but we have some new therapeutic options, and I think the idea was to help people understand where to use them,” Julie Sharpless, MD, assistant professor and director of the UNC Multidisciplinary Pituitary Adenoma Program, told Endocrinology Advisor.

“The primary treatment is surgical resection of the causal tumor(s). If that cannot be done (because the tumor is occult or metastatic) or is not successful, then the choice of secondary treatment should be individualized to the patient. The comorbidities of Cushing’s syndrome, for example hypertension and diabetes, should be treated separately as well,” Nieman said.

For example, the guidelines recommend surgical removal of the causative lesion, with the exception of cases which are unlikely to cause a drop in glucocorticoids or in patients who are not surgical candidates.

Likewise, in patients with benign unilateral adrenal adenoma, adrenalectomy by an experienced surgeon has a high rate of cure in children and adults. Because of the poor prognosis associated with adrenal carcinoma, the guidelines highlight the need for complete resection and possibly medical treatment to stabilize cortisol levels.

Other first-line treatment options include recommending surgical resection of ectopic ACTH-secreting tumors; referring to an experienced pituitary surgeon for transsphenoidal selective adenomectomy; treatments to block hormone receptors in bilateral micronodular adrenal hyperplasia; and surgical removal in bilateral adrenal disorders.

The elevated mortality rate seen in patients with Cushing’s syndrome is due to infection, venous thrombosis and cardiovascular disease (CVD). Appropriately lowering cortisol levels improves hypertension, insulin resistance, dyslipidemia and obesity in patients with Cushing’s syndrome. Therefore, the guidelines highlight the need for restoring cortisol levels and treating the associated comorbidities.

Nevertheless, the task force specifically recommends against treatment without an established diagnosis or when there are no signs of Cushing’s syndrome and hypothalamic-pituitary-adrenal laboratory studies are borderline.

In patients who are not surgical candidates or in cases of noncurative resection, the decision on whether to consider second-line treatment options such as medical therapy, radiation, bilateral adrenalectomy or repeat transsphenoidal surgery should be based on several factors. For instance, the guidelines recommend taking into consideration location and size of the tumor, patient desires, goals of treatment and level of biochemical control.

The guidelines note medical therapy should be based on cost, efficacy and individualization of treatment. Endocrinologists can approach medical therapy with a goal of establishing normal cortisol levels or reducing cortisol levels to very low levels and replacing to achieve desired levels.

Remission in Cushing’s syndrome is associated with notable improvement; however, long-term follow-up is recommended for osteoporosis, CVD and psychiatric conditions.

After treatment, patients may experience reductions in weight, blood pressure, lipids and glucose levels that may allow reduction or discontinuation of medications. Even so, patients with a history of Cushing’s syndrome tend to have higher rates of hypertension, hyperlipidemia and diabetes. Likewise, rates of myocardial infarction are higher in this population, further emphasizing the need for treatment and management of diabetes and hypertension.

Sharpless highlighted that Cushing’s syndrome is rare.

“There are multiple studies that have shown that patients do better when they are treated in a specialty center where people see a lot of cases of this. So in that sense, treatment is not usually going to fall to the general practitioner,” she said.

She continued that the guidelines are helpful and provide guidance to endocrinologist who “can’t readily refer their patient to a pituitary center.”

Sharpless went on to describe the multidisciplinary care involved in Cushing’s syndrome including endocrinologists, neurosurgeons, radiologists, counselors and radiation oncologist.

“When the care is complicated, you want to ensure all of your providers have reviewed your case together and figured out the best plan.”

The guidelines were co-sponsored by the European Society of Endocrinology. Nieman received salary support for her work on the manuscript from the Intramural Research Program of the Eunice Kennedy Shiver Institute of Child Health and Human Development. Members of the task force reported multiple disclosures.

Reference

  1. Nieman LK et al. J Clin Endocrinol Metab. 2015;100(8):2807-2831.

From http://www.endocrinologyadvisor.com/adrenal/cushings-syndrome-endocrine-society-guidelines/article/434307/

Hypercortisolism Is Associated With Increased Coronary Arterial Atherosclerosis

Hypercortisolism Is Associated With Increased Coronary Arterial Atherosclerosis: Analysis of Noninvasive Coronary Angiography Using Multidetector Computerized Tomography

Journal of Clinical Endocrinology and Metabolism, 05/21/2013  Clinical Article

  1. Nicola M. Neary*,
  2. O. Julian Booker*,
  3. Brent S. Abel,
  4. Jatin R. Matta,
  5. Nancy Muldoon,
  6. Ninet Sinaii,
  7. Roderic I. Pettigrew,
  8. Lynnette K. Nieman and
  9. Ahmed M. Gharib

Author Affiliations


  1. Program in Reproductive and Adult Endocrinology (N.M.N., L.K.N., B.S.A.), Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892; Laboratory of Cardiac Energetics (O.J.B.), National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892; Integrative Cardiovascular Imaging Laboratory (J.R.M., R.I.P., A.M.G.), National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892; Critical Care Medicine (N.M.), Clinical Center, National Institutes of Health, Bethesda, Maryland 20892; and Biostatistics and Clinical Epidemiology Service (N.S.), Clinical Center, National Institutes of Health, Bethesda, Maryland 20892
  1. Address all correspondence and requests for reprints to: Ahmed M. Gharib, MB, ChB, National Institutes of Health, Building 10, Room 3-5340, Mail Stop Code 1263, 10 Center Drive, Bethesda, MD 20892. E-mail: agharib@mail.nih.gov.
  1. * N.M.N. and O.J.B. contributed equally to this work.

Abstract

Background: Observational studies show that glucocorticoid therapy and the endogenous hypercortisolism of Cushing’s syndrome (CS) are associated with increased rates of cardiovascular morbidity and mortality. However, the causes of these findings remain largely unknown.

Objective: To determine whether CS patients have increased coronary atherosclerosis.

Design: A prospective case-control study was performed.

Setting: Subjects were evaulated in a clinical research center.

Subjects: Fifteen consecutive patients with ACTH-dependent CS, 14 due to an ectopic source and 1 due to pituitary Cushing’s disease were recruited. Eleven patients were studied when hypercortisolemic; 4 patients were eucortisolemic due to medication (3) or cyclic hypercortisolism (1). Fifteen control subjects with at least one risk factor for cardiac disease were matched 1:1 for age, sex, and body mass index.

Primary outcome variables: Agatston score a measure of calcified plaque and non-calcified coronary plaque volume were quantified using a multidetector CT (MDCT) coronary angiogram scan. Additional variables included fasting lipids, blood pressure, history of hypertension or diabetes, and 24-hour urine free cortisol excretion.

Results: CS patients had significantly greater noncalcified plaque volume and Agatston score (noncalcified plaque volume [mm3] median [interquartile ranges]: CS 49.5 [31.4, 102.5], controls 17.9 [2.6, 25.3], P < .001; Agatston score: CS 70.6 [0, 253.1], controls 0 [0, 7.6]; P < .05). CS patients had higher systolic and diastolic blood pressures than controls (systolic: CS 143 mm Hg [135, 173]; controls, 134 [123, 136], P < .02; diastolic CS: 86 [80, 99], controls, 76 [72, 84], P < .05).

Conclusions: Increased coronary calcifications and noncalcified coronary plaque volumes are present in patients with active or previous hypercortisolism. Increased atherosclerosis may contribute to the increased rates of cardiovascular morbidity and mortality in patients with glucocorticoid excess.

  • Received October 29, 2012.
  • Accepted March 7, 2013.

From JCEM

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