Desmopressin is Promising Alternative in Diagnosing Cushing’s Disease

Bilateral inferior petrosal sinus sampling (IPSS) — a procedure that uses desmopressin to determine levels of ACTH hormone from veins that drain from the pituitary gland, is a sensitive way to diagnose patients with Cushing’s disease and find tumors, a Chinese study shows.

The study, “Tumour Lateralization in Cushing’s disease by Inferior Petrosal Sinus Sampling with desmopressin,” appeared in the journal Clinical Endocrinology.

Cushing’s disease is characterized by excessive production of the adrenocorticotropin hormone (ACTH) caused by a tumor in the pituitary gland. ACTH is the hormone that causes the adrenal glands to produce cortisol.

Currently, pituitary imaging is insufficient to confirm a Cushing’s diagnosis. This is because 70 percent of pituitary adenomas in Cushing’s are microadenomas, which are physically very small. As a result, 40 percent of Cushing’s patients are reported as being healthy.

This means that a Cushing’s diagnosis requires a combination of techniques including clinical symptoms, imaging methods and endocrinological assays that include measures of serum cortisol and ACTH levels.

IPSS determines ACTH levels from veins that drain from the pituitary gland. ACTH levels are then compared to ACTH levels in blood. Higher levels in the pituitary gland indicate a pituitary tumor.

IPSS can also be used to determine tumor lateralization, which refers to which side of the pituitary gland the tumor is located on. The test is 69 percent accurate.

Doctors administer IPSS along with corticotropin-releasing hormone (CRH) stimulation. IPSS with CRH is considered the gold standard for preoperative diagnosis of Cushing’s, with a diagnostic sensitivity (or true positive rate) of 95 percent and specificity (or true negative rate) of 90 to 95 percent. Unfortunately, the high cost and limited availability of CRH make it impractical for many patients.

Desmopressin has been used to replace CRH to stimulate ACTH secretion for IPSS, and prior studies have shown that desmopressin’s sensitivity is comparable to that of CRH.

Researchers at Peking Union Medical College in Beijing conducted a retrospective analysis of their experience using desmopressin-stimulated IPSS to determine its diagnostic value for Cushing’s and its predictive value for tumor lateralization.

Researchers analyzed 91 Cushing’s patients who either had negative findings on the MRI imaging of the pituitary or negative high-dose dexamethasone suppression tests, which is another method of evaluation. All patients underwent IPSS with desmopressin, followed by pituitary surgery to extract the tumor.

Of the 91 patients tested, 90 patients had confirmed Cushing’s. And of these, 89 had positive IPSS findings, which led to a sensitivity of 98.9 percent for this test. One patient out of 91 who did not have Cushing’s also underwent this test, which led to a negative IPSS result and a specificity of 100 percent.

Researchers also determined tumor lateralization in patients who were ultimately diagnosed with Cushing’s and underwent surgery. Results of the IPSS showed a 72.5 percent concordance between the results from the IPSS and the surgery.

Therefore, IPSS with desmopressin is a comparable approach to IPSS with CRH for the diagnosis of Cushing’s. It also demonstrates moderate accuracy in determining the location of tumors.

“Like many medical centers in China, we currently have no supply of CRH, while desmopressin is readily available,” researchers concluded. “Moreover, desmopressin is cheaper than CRH. As our data and other studies indicate, IPSS with desmopressin yielded comparable outcomes to IPSS with CRH. Therefore, desmopressin-stimulated IPSS might serve as a possible alternative to CRH-stimulated IPSS.”

From https://cushingsdiseasenews.com/2017/11/14/ipss-desmopressin-alternative-method-diagnosis-cushings-disease/

New ACTH Detection Method Improves Cure Rates in Cushing’s Disease Patients

Researchers have identified a new, quick method for detecting ACTH-producing tumors – called Elecsys – that can improve the cure rates of Cushing’s disease patients undergoing surgery.

The study, “Long-term outcomes of tissue-based ACTH-antibody assay–guided transsphenoidal resection of pituitary adenomas in Cushing disease,” was published in the Journal of Neurosurgery.

Transsphenoidal resection (TSR) – a surgical procedure performed through the nose and sphenoid sinus to remove a pituitary tumor – has been the method of choice for treatment for Cushing’s disease.

However, it often fails to localize the tumor with precision, leading to an incomplete resection (removal). This is likely a result of the preoperative methods used to guide surgeons before surgery, which include both magnetic resonance imaging (MRI) and a minimally invasive procedure called bilateral inferior petrosal sinus sampling (BIPSS) that measures ACTH in the veins that drain the pituitary gland.

However, both “suffer from suboptimal sensitivity and thus allow for incomplete resections, specially if pathological frozen sections fail to identify tumor,” researchers wrote.

MRI, for example, detects only 50 percent of Cushing’s adenomas, limiting surgeons’ ability to conduct curative TSR surgeries. Therefore, better diagnostic and tumor localization techniques are needed to increase the likelihood that initial surgeries can remove the entire tumor and cure patients.

A team of researchers at Yale School of Medicine evaluated a new method for guiding tumor localization during TSR. The method – a double-antibody sandwich assay for ACTH – is performed in the operating room in resected pituitary samples from patients. ACTH (adrenocorticotropic hormone) is a hormone produced in the pituitary gland in the brain, that simulated cortisol production in the adrenal glands. In patients with Cushing disease the pituitary gland releases too much ACTH.

In the new method – called Elecsys – samples are squeezed between sandwich-like system composed of two antibodies that recognize two sections of the ACTH protein. The three-step procedure is quick, allowing doctors to analyze samples in the operating room and determine if they have removed the entire tumors.

The performance and outcomes associated with the Elecsys were assessed by reviewing data of tissue samples from 14 patients with ACTH-secreting adenomas, who underwent TSR surgeries between 2009 and 2014.

“The intraoperative TSR protocol was modified with the introduction of the ACTH assay such that if either the assay or the frozen-section pathology returned results positive for tumor, that area of the gland was resected,” the researchers explained.

The new ACTH method detected tumor tissue and was capable of distinguishing it from normal tissue with a 95% sensitivity and 71.3% specificity. These values are comparable to those using the standard method for tumor localization, which requires frozen sections of the tumor. This suggests that the test can be used either in conjunction with or in place of frozen sections.

Also, 85.7% of the patients achieved long-term disease remission, with the remission rate exceeding the rate with previous methods (71.9%).

Overall, “these preliminary findings reflect the promising potential of tissue-based ACTH-antibody-guided assay for improving the cure rates of Cushing’s disease patients undergoing TSR. Further studies with larger sample sizes, further refinements of assay interpretation, and longer-term follow-ups are needed,” the study concluded.

From https://cushingsdiseasenews.com/2017/10/19/acth-detection-method-improved-cure-rates-cushings-disease-study-shows/

Increase in Glucose Uptake by Cushing’s Disease-associated Tumors Could Improve Early Detection

An increase in glucose uptake by Cushing’s disease-associated pituitary tumors could improve their detection, new research shows.

The study, “Corticotropin releasing hormone can selectively stimulate glucose uptake in corticotropinoma via glucose transporter 1,” appeared in the journal Molecular and Cellular Endocrinology.

The study’s senior author was Dr. Prashant Chittiboina, MD, from the Department of Neurosurgery, Wexner Medical Center, The Ohio State University, in Columbus, Ohio.

Microadenomas – tumors in the pituitary gland measuring less than 10 mm in diameter – that release corticotropin, or corticotropinomas, can lead to Cushing’s disease. The presurgical detection of these microadenomas could improve surgical outcomes in patients with Cushing’s.

But current tumor visualization methodologies – magnetic resonance imaging (MRI) and 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) – failed to detect a significant percentage of pituitary microadenomas.

Stimulation with corticotropin-releasing hormone (CRH), which increases glucose uptake, has been suggested as a method of increasing the detection of adenomas with 18F-FDG PET, by augmenting the uptake of 18F-FDG – a glucose analog.

However, previous studies aiming to validate this idea have failed, leading the research team to hypothesize that it may be due to a delayed elevation in glucose uptake in corticotropinomas.

The scientists used clinical data to determine the effectiveness of CRH in improving the detection of corticotropinomas with 18F-FDG PET in Cushing’s disease.

They found that CRH increased glucose uptake in human and mouse tumor cells, but not in healthy mouse or human pituitary cells that produce the adrenocorticotropic hormone (ACTH). Exposure to CRH increased glucose uptake in mouse tumor cells, with a maximal effect at four hours after stimulation.

Similarly, the glucose transporter GLUT1, which is located at the cell membrane, was increased two hours after stimulation, as was GLUT1-mediated glucose transport.

These findings indicate a potential mechanism linking CRH exposure to augmented glucose uptake through GLUT1. Expectedly, the inhibition of glucose transport with fasentin suppressed glucose uptake.

The researchers consistently observed exaggerated evidence of GLUT1 in human corticotropinomas. In addition, human corticotroph tumor cells showed an increased breakdown of glucose, which indicates that, unlike healthy cells, pituitary adenomas use glucose as their primary source of energy.

Overall, the study shows that corticotropin-releasing hormone (CRH) leads to a specific and delayed increase in glucose uptake in tumor corticotrophs.

“Taken together, these novel findings support the potential use of delayed 18F-FDG PET imaging following CRH stimulation to improve microadenoma detection in [Cushing’s disease],” researchers wrote. The scientists are now conducting a clinical trial to further explore this promising finding.

From https://cushingsdiseasenews.com/2017/10/12/glucose-uptake-in-cushings-disease-could-improve-presurgical-tumor-detection/

An unusual case of Cushing’s syndrome due to bihormonal ACTH–prolactin secreting pituitary macroadenoma with rapid response to cabergoline

  1. Shalini Kunasegaran1,2,
  2. Michael S Croxson1,
  3. Ian Holdaway1,
  4. Rinki Murphy1

+Author Affiliations


  1. 1Department of EndocrinologyAuckland District Health BoardAuckland, New Zealand

  2. 2Department of EndocrinologyWaitemata District Health BoardTakapuna, New Zealand
  1. Correspondence to Dr Shalini Kunasegaran, shal84@gmail.com
  • Accepted 13 July 2017
  • Published 7 August 2017

Summary

A 23-year-old man presenting with florid Cushing’s syndrome was found to have high plasma ACTH and very high serum prolactin. Pituitary MRI showed a large invasive macroadenoma.

Low-dose cabergoline promptly suppressed both ACTH and prolactin levels within 2 weeks, with unexpected clinical and biochemical hypocortisolism requiring hydrocortisone replacement. Secondary hypogonadism was reversed. Clinical and biochemical remission of his Cushing’s syndrome together with significant shrinkage of his macroadenoma has been maintained for 1 year on cabergoline 0.5 mg twice weekly. Reduction in pituitary

Reduction in pituitary tumour volume and brisk fall in serum prolactin in response to low-dose cabergoline is regularly observed in patients with macroprolactinomas, but the concurrent fall in the plasma ACTH level and hypocortisolism was a pleasant surprise.

We assume that he most likely has a single bihormonal adenoma that is enriched with dopamine-2 receptors.

From http://casereports.bmj.com/content/2017/bcr-2017-219921.short?rss=1

Topical Steroid Use in Psoriasis Patient Leads to Severe Adrenal Insufficiency

This article is written live from the American Association of Clinical Endocrinologists (AACE) 2017 Annual Meeting in Austin, TX. MPR will be reporting news on the latest findings from leading experts in endocrinology. Check back for more news from AACE 2017.

 

At the AACE 2017 Annual Meeting, lead study author Kaitlyn Steffensmeier, MS III, of the Dayton Veterans Affairs (VA) Medical Center, Dayton, OH, presented a case study describing a patient “who developed secondary adrenal insufficiency secondary to long-term topical steroid use and who with decreased topical steroid use recovered.”

The patient was a 63-year-old white male with a 23-year history of psoriasis. For 18 years, the patient had been applying Clobetasol Propionate 0.05% topically on several areas of his body every day. Upon presentation to the endocrine clinic for evaluation of his low serum cortisol, the patient complained of a 24-pound weight gain over a 2-year period, feeling fatigued, as well as facial puffiness.

Laboratory analysis found that the patient’s random serum cortisol and ACTH levels were low (0.2µg/dL and <1.1pg/mL, respectively). According to the study authors, “the labs were indicative of secondary adrenal insufficiency.” Additionally, a pituitary MRI “showed a 2mm hypoenhancing lesion within the midline of the pituitary gland consistent with Rathke’s cleft cyst versus pituitary microadenoma.”

The patient was initiated on 10mg of hydrocortisone in the morning and 5mg in the evening and was instructed to decrease the use of his topical steroid to one time per month. For the treatment of his psoriasis, the patient was started on apremilast, a phosphodiesterase-4 enzyme (PDE4) inhibitor, and phototherapy.

After 2.5 years, the patient had a subnormal response to the cosyntropin stimulation test. However, after 3 years, a normal response with an increase in serum cortisol to 18.7µg/dL at 60 minutes was obtained; the patient was then discontinued on hydrocortisone. Additionally, a stable pituitary tumor was shown via a repeat pituitary MRI.

The study authors explained that, although secondary adrenal insufficiency is not commonly reported, “one study showed 40% of patients with abnormal cortisol response to exogenous ACTH after two weeks of topical glucocorticoids usage.” Another meta-analysis of 15 studies (n=320) revealed 4.7% of patients developing adrenal insufficiency after using topical steroids. Because of this, “clinicians need to be aware of potential side effects of prolong topical steroid use,” added the study authors.

For continuous endocrine news coverage from the AACE 2017 Annual Meeting, check back to MPR’s AACE page for the latest updates.

From http://www.empr.com/aace-2017/topical-steroid-psoriasis-clobestasol-propionate/article/654335/

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