ACTH test after adenomectomy may accurately predict Cushing’s disease remission

A plasma adrenocorticotropic hormone suppression test performed shortly after surgical adenomectomy may accurately predict both short- and long-term remission of Cushing’s disease, according to research published in Pituitary.

“Cushing’s disease is caused by hypersecretion of adrenocorticotropic hormone (ACTH) by a pituitary adenoma, resulting in hypercortisolism,” Erik Uvelius, MD, of the department of clinical sciences, Skåne University Hospital, Lund University, Sweden, and colleagues wrote in the study background. “Surgical adenomectomy is the first line of treatment. Postoperative remission is reported in 43% to 95% of cases depending on factors such as adenoma size, finding of pituitary adenoma on preoperative MRI and surgeons’ experience. However, there is no consensus on what laboratory assays and biochemical thresholds should be used in determining or predicting remission over time.”

In the study, the researchers retrospectively gathered data from medical records of 28 patients who presented with Cushing’s disease to Skåne University Hospital between November 1998 and December 2011, undergoing 45 transsphenoidal adenomectomies.

On postoperative days 2 and 3, oral betamethasone was administered (1 mg at 8 a.m., 0.5 mg at 2 p.m., and 0.5 mg at 8 p.m.). Researchers assessed plasma cortisol and plasma ACTH before betamethasone administration and again at 24 and 48 hours, and measured 24-urinary free cortisol on postoperative day 3.

At 3 months postoperatively and then annually, plasma concentrations of morning cortisol and ACTH along with urinary-free cortisol and/or a low-dose dexamethasone suppression test were evaluated at the endocrinologists’ discretion. The researchers defined remission as lessening of clinical signs and symptoms of hypercortisolism, as well as laboratory confirmation through the various tests.

The researchers used Youden’s index to establish the cutoff with the highest sensitivity and specificity in predicting remission over the short term (3 months) and long term (5 years or more). Clinical accuracy of the different tests was illustrated through the area under curve.

The study population consisted of mainly women (71%), with a median age of 49.5 years. No significant disparities were seen in age, sex or surgical technique between patients who underwent a primary procedure and those who underwent reoperation. Two of the patients were diagnosed with pituitary carcinoma and 11 had a macroadenoma. ACTH positivity was identified in all adenomas and pathologists confirmed two cases of ACTH-producing carcinomas.

Of the 28 patients, 12 (43%) demonstrated long-term remission at last follow-up. Three patients were not deemed in remission after primary surgery but were not considered eligible for additional surgical intervention, whereas 13 patients underwent 17 reoperations to address remaining disease or recurrence. Four patients demonstrated long-term remission after a second or third procedure, equaling 16 patients (57%) achieving long-term remission, according to the researchers.

The researchers found that both short- and long-term remission were most effectively predicted through plasma cortisol after 24 and 48 hours with betamethasone. A short-term remission cutoff of 107 nmol/L was predicted with a sensitivity of 0.85, specificity of 0.94 and a positive predictive value of 0.96 and AUC of 0.92 (95% CI, 0.85-1). A long-term remission cutoff of 49 nmol/L was predicted with a sensitivity of 0.94, specificity of 0.93, positive predictive value of 0.88 and AUC of 0.98 (95% CI, 0.95-1). This cutoff was close to the suppression cutoff for the diagnosis of Cushing’s disease, 50 nmol/L. The cutoff of 25 nmol/L showed that the use of such a strict suppression cutoff would cause a low level of true positives and a higher occurrence of false negatives, according to the researchers.

“A 48 h 2 mg/day betamethasone suppression test day 2 and 3 after transsphenoidal surgery of Cushing’s disease could safely predict short- and long-term remission with high accuracy,” the researchers wrote. “Plasma cortisol after 24 hours of suppression showed the best accuracy in predicting 5 years’ remission. Until consensus on remission criteria, it is still the endocrinologists’ combined assessment that defines remission.” – by Jennifer Byrne

DisclosuresThe authors report no relevant financial disclosures.

From https://www.healio.com/endocrinology/neuroendocrinology/news/in-the-journals/%7B0fdfb7b0-e418-4b53-b59d-1ffa3f7b8cd3%7D/acth-test-after-adenomectomy-may-accurately-predict-cushings-disease-remission

Cushing Syndrome Results in Poor Quality of Life Even After Remission

Functional remission did not occur in most patients with Cushing syndrome who were considered to be in biochemical and clinical remission, according to a study published in Endocrine. This was evidenced by their quality of life, which remained impaired in all domains.

The term “functional remission” is a psychiatric concept that is defined as an “association of clinical remission and a recovery of social, professional, and personal levels of functioning.” In this observational study, investigators sought to determine the specific weight of psychological (anxiety and mood, coping, self-esteem) determinants of quality of life in patients with Cushing syndrome who were considered to be in clinical remission.

The cohort included 63 patients with hypercortisolism currently in remission who completed self-administered questionnaires that included quality of life (WHOQoL-BREF and Cushing QoL), depression, anxiety, self-esteem, body image, and coping scales. At a median of 3 years since remission, participants had a significantly lower quality of life and body satisfaction score compared with the general population and patients with chronic diseases. Of the cohort, 39 patients (61.9%) reported having low or very low self-esteem, while 16 (25.4%) had high or very high self-esteem. Depression and anxiety were seen in nearly half of the patients and they were more depressed than the general population. In addition, 42.9% of patients still needed working arrangements, while 19% had a disability or cessation of work.

Investigators wrote, “This impaired quality of life is strongly correlated to neurocognitive damage, and especially depression, a condition that is frequently confounded with the poor general condition owing to the decreased levels of cortisol. A psychiatric consultation should thus be systematically advised, and [selective serotonin reuptake inhibitor] therapy should be discussed.”

Reference

Vermalle M, Alessandrini M, Graillon T, et al.  Lack of functional remission in Cushing’s Syndrome [published online July 17, 2018]. Endocrine. doi:10.1007/s12020-018-1664-7

From https://www.endocrinologyadvisor.com/general-endocrinology/functional-remission-quality-of-life-cushings-syndrome/article/788501/

Metyrapone Reduced Urinary-Free Cortisol Levels in Cushing Syndrome

Metyrapone treatments helped patients with Cushing syndrome reach normal, urinary-free cortisol levels in the short-term and also had long-term benefits, according to a study published in Endocrine.

This observational, longitudinal study evaluated the effects of the 11β -hydroxylase inhibitor metyrapone on adult patients with Cushing syndrome. Urinary-free cortisol and late-night salivary cortisol levels were evaluated in 31 patients who were already treated with metyrapone to monitor cortisol normalization and rhythm.

The average length of metyrapone treatment was 9 months, and 6 patients had 24 months of treatment. After 1 month of treatment, the mean urinary-free cortisol was reduced from baseline by 67% and mean late-night salivary cortisol level decreased by 57%.

Analyzing only patients with severe hypercortisolism, after 1 month of treatment, the mean urinary-free cortisol decreased by 86% and the mean late-night salivary cortisol level decreased 80%. After 3 months, normalization of the mean urinary-free cortisol was established in 68% of patients. Mean late-night salivary cortisol levels took longer to decrease, especially in severe and very severe hypercortisolism, which could take 6 months to drop. Treatment was more successful at normalizing cortisol excretion (70%) than cortisol rhythm (37%). Nausea, abdominal pain, and dizziness were the most common adverse events, but no severe adverse event was reported.

Future research is needed to evaluate a larger cohort with randomized dosages and stricter inclusion criteria to evaluate metyrapone’s effects on cortisol further.

Study researchers conclude that metyrapone was successful and safe in lowering urinary-free cortisol after just 1 month of treatment and controlling long-term levels in patients with Cushing syndrome.

This study was supported by Novartis.

Reference

Ceccato F, Zilio M, Barbot M, et al. Metyrapone treatment in Cushing’s syndrome: a real-life study [published online July 16, 2018]. Endocrine. doi: 10.1007/s12020-018-1675-4

From https://www.endocrinologyadvisor.com/general-endocrinology/metyrapone-cushing-syndrome/article/786716/

Night Cortisol Levels for Diagnosing Cushing’s Syndrome Less Accurate in Clinical Practice

Salivary cortisol levels can be used to diagnose Cushing’s syndrome with relatively high reliability, but each test center should establish its own measurement limits depending on the exact method used for the test, a study from Turkey shows.

Researchers, however, caution that late-night salivary cortisol measurements in clinical practice is likely to be less accurate than that seen in controlled studies, and some patients might require additional tests for a correct diagnosis.

The study, “Diagnostic value of the late-night salivary cortisol in the diagnosis of clinical and subclinical Cushing’s syndrome: results of a single-center 7-year experience,” was published in the Journal of Investigative Medicine

In healthy individuals, the levels of cortisol — a steroid hormone secreted by the adrenal glands — go through changes over a 24-hour period, with the lowest levels normally detected at night.

But this circadian rhythm is disrupted in certain diseases such as Cushing’s syndrome, where night cortisol levels can be used as a diagnostic tool.

Among the tests that can be used to detect these levels are late-night serum cortisol (LNSeC) and late-night salivary cortisol (LNSaC) tests. Since it uses saliva samples, LNSaC is more practical and does not require hospitalization, so it is often recommended for the diagnosis of Cushing’s syndrome.

So far, though, there has been no consensus regarding cutoff values and the sensitivity of the test.

Mustafa Kemal Balci, MD, and his team at the Akdeniz University in Turkey aimed to evaluate the diagnostic use of LNSaC in patients with clinical Cushing’s syndrome and in those with subclinical Cushing’s syndrome — people with excess cortisol but without signs of the disease.

The study involved 58 patients with clinical Cushing’s syndrome (CCS), 53 with subclinical Cushing’s syndrome (SCS), and 213 patients without Cushing’s syndrome who were used as controls.

Saliva and serum cortisol levels were measured in all patients, and statistical tests were used to study differences in these levels among the three groups of patients.

In CSC patients, the median cortisol levels were 0.724 micrograms per deciliter of blood (µg/dL), which dropped to 0.398 and 0.18 in patients with subclinical disease and controls.

The optimal cutoff point to distinguish patients with clinical Cushing’s was set at 0.288 µg/dL, where 89.6% of patients identified as positive actually have the disease (sensitivity), and 81.6% of patients deemed as negative were without the disease (specificity).

With a lower cutoff point — 0.273 µg/dL — researchers were also able to identify patients with subclinical disease with high sensitivity and specificity.

While the test showed high sensitivity and specificity values for clinical Cushing’s syndrome, its diagnostic performance was lower than expected in daily clinical practice, researchers said.

“The diagnostic performance of late-night salivary cortisol in patients with subclinical Cushing’s syndrome was close to its diagnostic performance in patients with clinical Cushing’s syndrome,” researchers wrote.

However, regarding the application of this test in other centers, they emphasize that “each center should determine its own cut-off value based on the method adopted for late-night salivary cortisol measurement, and apply that cut-off value in the diagnosis of Cushing’s syndrome.”

From https://cushingsdiseasenews.com/2018/07/31/late-night-salivary-cortisol-levels-questioned-diagnosis-cushings-syndrome/

MEKT1 Could Be a Potential New Therapy for Treating Cushing’s Disease

MEKT1, a type of therapy called a PPAR-γ agonist, acts to reduce levels of the adrenocorticotropic hormone and could be a potential new therapy for Cushing’s disease, according to researchers.

Their study, “Inhibitory Effects of a Novel PPAR-γ Agonist MEKT1 on Pomc Expression/ACTH Secretion in AtT20 Cells,” was published in the journal PPAR Research.

Cushing’s disease is caused by a tumor in the pituitary gland — generally a type of tumor called an adenoma that produces high levels of adrenocorticotropic hormone (ACTH).

ACTH causes the adrenal glands to make too much cortisol, leading to the classic symptoms associated with Cushing’s disease.

PPAR-gamma (PPAR-γ) is a transcription factor protein (meaning it regulates the levels of certain genes by acting through other proteins), and is seen in high levels in the normal human pituitary and in ACTH-secreting pituitary adenomas.

The Pomc gene is a precursor molecule to ACTH. While it is known that PPAR-γ plays a role in regulating Pomc levels, its mechanism has not yet been clarified in pituitary cells.

PPAR-γ agonists — agents that activate PPAR-γ — include the medications rosiglitazone and pioglitazone, both of which are used to treat type 2 diabetes. Some studies have shown that rosiglitazone and pioglitazone have an effect on Pomc suppression, which would lead to lower levels of ACTH and help treat patients with Cushing’s disease.

However, the benefits of PPAR-γ agonists in the treatment of Cushing’s disease are still controversial.

Researchers examined the effects of a new PPAR-γ agonist, MEKT1, on Pomc levels and ACTH secretion using a mouse pituitary tumor-derived cell line called AtT20 cells. They also compared its effects with the well-established PPAR-γ agonists rosiglitazone and pioglitazone.

AtT20 cells were treated with either MEKT1, rosiglitazone, or pioglitazone at various concentrations ranging from 1 nM to 10 μM (micrometers) for 24 hours.

Results showed that 10 μM of MEKT1 significantly inhibited Pomc gene levels compared to rosiglitazone and pioglitazone. Additionally, ACTH secretion from AtT20 cells was also significantly inhibited by the agonist.

To see if it worked to decrease Pomc levels by acting specifically on PPAR-γ, researchers eliminated the PPAR-γ protein using a technique called siRNA knockdown. In this case, the effects of MEKT1 on Pomc levels were significantly halted.

It is known that other proteins, such as Nur77, Nurr1, and Tpit activate Pomc levels by binding to the promoter region of Pomc — the area of the gene responsible for activating gene levels.

To determine whether these proteins could be targeted by MEKT1, researchers also looked at levels of Nur77, Nurr1, and Tpit. The PPAR-γ agonist was found to significantly suppress the levels of the three genes that encode these proteins.

“Although clinical trials of MEKT1 are needed to determine its drug efficacy in the future, it can be speculated that MEKT1 is much more effective than the previously recognized PPAR-γ agonists rosiglitazone, and pioglitazone for the suppression of Pomc expression/ACTH secretion from our in vitro [laboratory] research,” they added.

Results from this study suggest MEKT1 could be a potential new therapy for the treatment of Cushing’s disease.

From https://cushingsdiseasenews.com/2018/06/12/mekt1-could-be-potential-therapy-treatment-cushings-disease/

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