Relacorilant Effectively Manages Cortisol Effects in Cushing’s Patients

Posted on May 12, 2018 by MaryO

Relacorilant, an investigational therapy developed by Corcept Therapeutics, may effectively manage the effects of excess cortisol in patients with Cushing’s syndrome, interim data from an ongoing Phase 2 trial show.

In particular, the treatment significantly improved sugar tolerance and the levels of osteocalcin, a bone growth biomarker  commonly suppressed by excess cortisol.

Corcept announced in a press release that the trial (NCT02804750) has completed patient enrollment. Results from the first patients will be presented during the upcoming 27th American Association of Clinical Endocrinologists (AACE) annual meeting, May 16-20 in Boston. Full data is expected by the third quarter of 2018.

Relacorilant, also known as CORT125134, was designed to prevent the effects of excess cortisol by blocking one of its receptors, the glucocorticoid receptor.

In a Phase 1 trial with healthy volunteers, multiple doses of relacorilant had a similar effect as Korlym (mifepristone) — an approved medicine for Cushing’s patients — without its known side effects.

In addition to the early efficacy data, the study showed that the treatment was generally safe and well-tolerated by the patients, with adverse events reportedly mild in severity.

These findings supported the launch of the Phase 2 trial in patients with Cushing’s syndrome. In the trial, roughly 30 patients are receiving escalating doses of relacorilant for a total of 12 weeks.

Patients were divided into two groups. The first group, which includes 17 patients, receives the lowest dose — 100 mg/day of relacorilant for four weeks, followed by 150 mg/day for four weeks, and then 200 mg/day for the last four weeks. The second group, called the high-dose cohort, is treated with a similar regimen but with a starting dose of 250 mg/day and a final dose of 350 mg/day.

Patients in the low-dose group had a significant improvement in their glucose tolerance and a 60% increase in blood osteocalcin.

In addition, the treatment reduced the blood pressure in 45% of patients with uncontrolled high blood pressure from cortisol excess. Importantly, the results after 12 weeks of relacorilant were similar to those seen after six months of Korlym treatment.

Safety data continues to show a positive profile, with no evidence of serious adverse effects and no affinity toward the progesterone receptor, which is a major drawback of Korlym.

“Relacorilant’s clinical results are striking because the doses these patients received were the study’s lowest. We did not expect patients to experience any meaningful clinical benefit, but they clearly did,” Robert S. Fishman, MD, chief medical officer of Corcept, said in the release. “We look forward to presenting data from these low-dose patients at the AACE meeting next week. With the trial’s final, high-dose cohort fully enrolled, we will have final data in the third quarter.”

Supported by these preliminary data, Corcept has accelerated the preparations for a Phase 3 trial on relacorilant in Cushing’s syndrome patients.

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Rare Malignant Tumor of Adrenal Gland Led to Cushing’s, Girl’s Death

Posted on May 5, 2018 by MaryO

While adrenocortical carcinoma — a malignant tumor of the adrenal gland — appears only rarely in children, the tumor may cause secondary Cushing’s syndrome in these patients, a new case report shows.

Early diagnosis of the causes of Cushing’s syndrome could improve the prognosis of these children, researchers say.

The study, “Cushing Syndrome Revealing an Adrenocortical Carcinoma,” was published in the Open Journal of Pediatrics.

Adrenocortical carcinoma is a malignant tumor that develops in the cortex of the adrenal gland. It usually is identified by increased amounts of hormones that are produced by the adrenal glands, like cortisol.

This tumor type is very rare in children, representing fewer than two in every 1,000 pediatric tumors.

Researchers at the University Hospital Center Souro Sanou, in Burquina Faso (West Africa), described the case of a 10-year-old girl who developed this rare cancer.

The patient’s first symptoms were loss of consciousness and recurrent seizures without fever. The patient also had experienced excessive weight gain in the preceding months. At admission she was in a light state of coma and showed obesity in the face and trunk.

An initial analysis of blood, urine, and cerebrospinal fluid failed to detect any alterations, with no diabetes, kidney damage, or infection identified. And, even though no lesions or alteration were seen in the pituitary gland region, brain swelling was detected.

While in the hospital, the patient’s condition continued to deteriorate. She developed fever and difficulty speaking, while showing persistent seizures.

In the absence of a diagnosis, physicians focused on the safeguard of major vital function, control of seizures, and administration of large-spectrum antibiotics. Her condition improved slightly, regaining consciousness and control of seizures.

One month later, however, the patient developed symptoms that are commonly associated with increased levels of cortisol and male sex hormones, including obesity and early development of pubic hair.

After confirming high cortisol levels, physicians examined the patient’s abdominal region,  which revealed a tumor in the left adrenal gland.

The patient received a ketoconazole treatment and a surgery to remove the tumor was planned. But her condition worsened, with development of malignant hypertension and convulsive illness, which led to her death before the tumor was removed.

“The delay in the diagnosis and the insufficiency of the therapeutic means darken the prognosis in our context,” the researchers wrote.

“[Adrenocortical carcinoma] diagnosis should be considered in presence of virilization and early signs of puberty,” the researchers suggested. “Early diagnosis and multidisciplinary management of adrenocortical carcinoma could improve the prognosis in children.”

From https://cushingsdiseasenews.com/2018/05/04/rare-malignant-tumor-adrenal-gland-caused-cushings-case-report/

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

Posted on May 4, 2018 by MaryO

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/

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Blood Lipid Levels Linked to High Blood Pressure in Cushing’s Disease Patients

Posted on April 25, 2018 by MaryO

High lipid levels in the blood may lead to elevated blood pressure in patients with Cushing’s disease, a Chinese study shows.

The study, “Evaluation of Lipid Profile and Its Relationship with Blood Pressure in Patients with Cushing’s Disease,” appeared in the journal Endocrine Connections.

Patients with Cushing’s disease often have chronic hypertension, or high blood pressure, a condition that puts them at risk for cardiovascular disease. While the mechanisms of Cushing’s-related high blood pressure are not fully understood, researchers believe that high levels of cortisol lead to chronic hypertension through increased cardiac output, vascular resistance, and reactivity to blood vessel constrictors.

In children and adults with Cushing’s syndrome, the relationship between increased cortisol levels and higher blood pressure has also been reported. Patients with Cushing’s syndrome may remain hypertensive even after surgery to lower their cortisol levels, suggesting their hypertension is caused by changes in blood vessels.

Studies have shown that Cushing’s patients have certain changes, such as increased wall thickness, in small arteries. The renin-angiotensin system, which can be activated by glucocorticoids like cortisol, is a possible factor contributing to vascular changes by increasing the uptake of LDL-cholesterol (LDL-C) — the “bad” cholesterol — in vascular cells.

Prior research showed that lowering cholesterol levels could benefit patients with hypertension and normal lipid levels by decreasing the stiffness of large arteries. However, the link between blood lipids and hypertension in Cushing’s disease patients is largely unexplored.

The study included 84 patients (70 women) referred to a hospital in China for evaluation and diagnosis of Cushing’s disease. For each patient, researchers measured body mass index, blood pressure, lipid profile, and several other biomarkers of disease.

Patients with high LDL-cholesterol had higher body mass index, blood pressure, cholesterol, triglycerides, and apolipoproteinB (apoB), a potential indicator of atherosclerosis and cardiovascular disease.

Data further revealed an association between blood pressure and lipid profile, including cholesterol, triglycerides, apoB and LDL-c. “The results strongly suggested that CHO (cholesterol), LDL-c and apoB might predict hypertension more precisely in [Cushing’s disease],” the scientists wrote.

They further add that high cholesterol, LDL-cholesterol, and apoB might be contributing to high blood pressure by increasing vessel stiffness.

Additional analysis showed that patients with higher levels of “bad” cholesterol — 3.37 mmol/L or higher — had higher blood pressure. This finding remained true, even when patients were receiving statins to lower their cholesterol levels.

No association was found between blood pressure and plasma cortisol, UFC, adrenocorticotropic hormone, or glucose levels in Cushing’s disease patients.

These findings raise some questions on whether lipid-lowering treatment for high blood pressure and cardiovascular disease would be beneficial for Cushing’s disease patients. Further studies addressing this question are warranted.

Adapted from https://cushingsdiseasenews.com/2018/04/24/blood-pressure-linked-lipid-levels-cushings-disease-study/

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Rare Nasal Cancer May Have Caused Cushing’s Syndrome

Posted on April 4, 2018 by MaryO

A very rare case of Cushing’s syndrome developing as a result of a large and also rare cancer of the nasal sinuses gives insights into how to screen and treat such an anomaly, of which fewer than 25 cases have been reported in literature.

Paraneoplastic esthesioneuroblastoma (ENB), a very rare type of nasal tumor, may sometimes produce excess adrenocorticotrophic hormone (ACTH), leading to symptoms of Cushing’s syndrome, according to a recent case report that describes a case of ACTH-secreting ENB. The report aims to demonstrate the importance of recognizing its pathophysiology and treatment.

The case report, “A Case of Cushing’s Syndrome due to Ectopic Adrenocorticotropic Hormone Secretion from Esthesioneuroblastoma with Long Term Follow-Up after Resection,” was published in the journal Case Reports in Endocrinology.

It describes a 52-year-old Caucasian male who had a history of high blood pressure, severe weakness, abnormal production of urine, extreme thirstiness, and confusion.

He was scheduled to undergo surgery for a 7-centimeter skull base mass; the surgery was postponed due to severe high serum potassium concentrations and abnormally high pH levels. His plasma ACTH levels also were elevated and Cushing’s syndrome was suspected. Since imaging of the chest, abdomen, and pelvis did not show any ectopic (abnormal) sources of ACTH, the ENB was suspected to be the source.

Surgery was performed to remove the tumor, which was later found to be secreting ACTH. Consequently, following the procedure, his ACTH levels dropped to normal (below detection limit) and he did not need medication to normalize serum potassium levels. He then underwent subsequent chemoradiation and has shown no sign of recurrence 30 months after the operation, which is considered to be one of the longest follow-up periods for such a case.

Researchers declared it “a case of olfactory neuroblastoma with ectopic ACTH secretion that was treated with resection and adjuvant chemoradiation.”

“Given the paucity of this diagnosis, little is known about how best to treat these patients and how best to screen for complications such as adrenal insufficiency and follow-up,” they wrote. “Our case adds more data for better understanding of this disease.”

From https://cushingsdiseasenews.com/2018/04/03/rare-nasal-cancer-caused-cushings-syndrome-case-report-says/

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