Hypercortisolism

Patients with Cushing disease have an increased risk for new-onset autoimmune disease in the 3 years after surgical remission, according to a new retrospective study published on February 20 in Annals of Internal Medicine.

Outcomes for patients with Cushing disease were compared against those with nonfunctioning pituitary adenomas (NFPAs). New-onset autoimmune disease occurred in 10.4% with Cushing disease and 1.6% among patients with NFPA (hazard ratio, 7.80; 95% CI, 2.88-21.10).

“Understanding and recognizing new and recurrent autoimmune disease in this setting is important to avoid misclassifying such patients with glucocorticoid withdrawal syndrome, which could result in failure to treat underlying autoimmune disease, as well as erroneous diagnosis of steroid withdrawal cases,” wrote Dennis Delasi Nyanyo of Massachusetts General Hospital and Harvard Medical School, Boston, and colleagues.

Given the general population’s annual incidence of major autoimmune diseases, estimated at about 100 cases per 100,000 people, and the 3-year incidence of 10.4% found in this study’s cohort, “our findings suggest that Cushing disease remission may trigger development of autoimmune disease,” the authors wrote.
 

Monitor Patients With Family History of Autoimmune Disease?

The study results were not necessarily surprising to Anthony P. Heaney, MD, PhD, an endocrinologist and professor of medicine at the University of California, Los Angeles, because past research has raised similar questions. The authors’ suggestion that the rapid postsurgical drop in cortisol that occurs as a result of treating Cushing disease becomes some sort of autoimmune trigger is interesting but remains speculative, Dr. Heaney pointed out.

If future evidence supports that possibility, “it would suggest, in terms of managing those patients in the postoperative setting, that there may be some merit to giving them higher concentrations of glucocorticoids for a short period of time,” Dr. Heaney said, thereby bringing their levels down more gradually rather than taking them off a cliff, in a sense. Or, if more evidence bears out the authors’ hypothesis, another approach might be treating patients with medicine to bring down the cortisol before surgery, though there are challenges to that approach, Dr. Heaney said.

At the same time, those who developed new autoimmune disease remain a small subset of patients with Cushing disease, so such approaches may become only potentially appropriate to consider in patients with risk factors, such as a family history of autoimmune disease.

The researchers conducted a retrospective chart review of adult patients who underwent transsphenoidal surgery for either Cushing disease or NFPA at Massachusetts General Hospital between 2005 and 2019.

The study involved 194 patients with Cushing disease who had postsurgical remission and at least one follow-up visit with a pituitary expert and 92 patients with NFPA who were matched to patients with Cushing disease based on age and sex. The authors regarded autoimmune disease diagnosed within 36 months of the surgery to be temporally associated with Cushing disease remission. Among the autoimmune diseases considered were “rheumatoid arthritis, Sjögren syndrome, systemic lupus erythematosus, autoimmune thyroiditis, celiac disease, psoriasis, vitiligo, autoimmune neuropathy, multiple sclerosis, myasthenia gravis, and ulcerative colitis.”

Patients differed in average body mass index and tumor size, but family history of autoimmune disease was similar in both groups. Average BMI was 34.5 in the Cushing group and 29.5 in the NFPA group. Average tumor size was 5.7 mm in the Cushing group and 21.3 mm in the NFPA group.

Before surgery, 2.9% of patients with Cushing disease and 15.4% of patients with NFPA had central hypothyroidism, and 8% in the Cushing group and 56.8% in the NFPA group had hyperprolactinemia. Central adrenal insufficiency occurred in 11% with NFPA and in all with Cushing disease, by definition.

After surgery, 93.8% in the Cushing group and 16.5% in the NFPA group had adrenal insufficiency. In addition, patients with Cushing disease had lower postsurgical nadir serum cortisol levels (63.8 nmol/L) than those with NFPA (282.3 nmol/L).

Of the 17 patients with Cushing disease — all women — who developed autoimmune disease within 3 years, 6 had a personal history of autoimmune disease and 7 had a family history of it. In addition, 41.2% of them had adrenal insufficiency when they developed the new autoimmune disease. Among the diseases were six autoimmune thyroiditis cases, three Sjögren syndrome cases, and two autoimmune seronegative spondyloarthropathy.

Dr. Heaney said he found it interesting that more than half of the new autoimmune diseases in patients with Cushing disease were related to the thyroid. “In this kind of setting, where you have a patient who has been producing too much steroid over a period of time and then you take that away, it’s almost like you release a brake on the TSH [thyroid-stimulating hormone],” Dr. Heaney said. “So, there’s probably some rebound in TSH that occurs, and that could be driving the thyroiditis, to some extent, that we see in these patients.”

Only one patient with NFPA developed new-onset autoimmune disease, a woman who developed Graves disease 22 months after surgery. When the researchers excluded patients in both groups with central hypothyroidism, new-onset autoimmune disease was still significantly higher (11.4%) in the Cushing group than in the NFPA group (1.9%; HR, 7.02; 95% CI, 2.54-19.39).
 

Could Postoperative Adrenal Insufficiency Contribute to Risk?

Within the Cushing cohort, those who developed autoimmune disease had a lower BMI (31.8 vs 34.8) and larger tumor size (7.2 vs 5.6 mm) than those who didn’t develop new autoimmune disease. Patients who developed autoimmune disease also had a lower baseline urine free cortisol ratio (2.7 vs 6.3) before surgery and more family history of autoimmune disease (41.2% vs 20.9%) than those who didn’t develop one.

“The higher prevalence of adrenal insufficiency and the lower nadir serum cortisol levels in the Cushing disease group suggest that the postoperative adrenal insufficiency in the Cushing disease group might have contributed to autoimmune disease pathogenesis,” the authors wrote. “This finding is clinically significant because cortisol plays a pivotal role in modulating the immune system.”

Most postoperative management among patients with Cushing disease was similar, with all but one patient receiving 0.5 or 1 mg daily dexamethasone within the first week after surgery. (The one outlier received 5 mg daily prednisone.) However, fewer patients who developed autoimmune disease (17.6%) received supraphysiologic doses of glucocorticoid — equivalent to at least 25 mg hydrocortisone — compared with patients who didn’t develop autoimmune disease (41.8%).

“Although the daily average hydrocortisone equivalent replacement doses within the first month and during long-term follow-up were within the physiologic range in both subgroups, patients with Cushing disease who had autoimmune disease received slightly lower doses of glucocorticoid replacement within the first month after surgery,” the authors reported. “The immediate postoperative period might be a critical window where supraphysiologic glucocorticoids seem to be protective with regard to development of autoimmune disease,” they wrote, though they acknowledged the study’s retrospective design as a limitation in drawing that conclusion.

At the least, they suggested that new symptoms in patients with Cushing disease, particularly those with a family history of autoimmune disease, should prompt investigation of potential autoimmune disease.

Recordati Rare Diseases funded the study. The research was also conducted with support from Harvard Catalyst (the Harvard Clinical and Translational Science Center) as well as financial contributions from Harvard University and its affiliated academic healthcare centers. One author reported holding stocks in Pfizer and Amgen, and another reported receiving consulting fees from Corcept. Dr. Heaney reported receiving institutional grants for trials from Corcept, Ascendis, Crinetics, and Sparrow Pharm; serving on the advisory board for Xeris, Recordati, Corcept, Novo Nordisk, Lundbeck, and Crinetics; and serving as a speaker for Chiesi, Novo Nordisk, and Corcept.
 

A version of this article appeared on Medscape.com.

Patients with Cushing disease have an increased risk for new-onset autoimmune disease in the 3 years after surgical remission, according to a new retrospective study published on February 20 in Annals of Internal Medicine.

Outcomes for patients with Cushing disease were compared against those with nonfunctioning pituitary adenomas (NFPAs). New-onset autoimmune disease occurred in 10.4% with Cushing disease and 1.6% among patients with NFPA (hazard ratio, 7.80; 95% CI, 2.88-21.10).

“Understanding and recognizing new and recurrent autoimmune disease in this setting is important to avoid misclassifying such patients with glucocorticoid withdrawal syndrome, which could result in failure to treat underlying autoimmune disease, as well as erroneous diagnosis of steroid withdrawal cases,” wrote Dennis Delasi Nyanyo of Massachusetts General Hospital and Harvard Medical School, Boston, and colleagues.

Given the general population’s annual incidence of major autoimmune diseases, estimated at about 100 cases per 100,000 people, and the 3-year incidence of 10.4% found in this study’s cohort, “our findings suggest that Cushing disease remission may trigger development of autoimmune disease,” the authors wrote.
 

Monitor Patients With Family History of Autoimmune Disease?

The study results were not necessarily surprising to Anthony P. Heaney, MD, PhD, an endocrinologist and professor of medicine at the University of California, Los Angeles, because past research has raised similar questions. The authors’ suggestion that the rapid postsurgical drop in cortisol that occurs as a result of treating Cushing disease becomes some sort of autoimmune trigger is interesting but remains speculative, Dr. Heaney pointed out.

If future evidence supports that possibility, “it would suggest, in terms of managing those patients in the postoperative setting, that there may be some merit to giving them higher concentrations of glucocorticoids for a short period of time,” Dr. Heaney said, thereby bringing their levels down more gradually rather than taking them off a cliff, in a sense. Or, if more evidence bears out the authors’ hypothesis, another approach might be treating patients with medicine to bring down the cortisol before surgery, though there are challenges to that approach, Dr. Heaney said.

At the same time, those who developed new autoimmune disease remain a small subset of patients with Cushing disease, so such approaches may become only potentially appropriate to consider in patients with risk factors, such as a family history of autoimmune disease.

The researchers conducted a retrospective chart review of adult patients who underwent transsphenoidal surgery for either Cushing disease or NFPA at Massachusetts General Hospital between 2005 and 2019.

The study involved 194 patients with Cushing disease who had postsurgical remission and at least one follow-up visit with a pituitary expert and 92 patients with NFPA who were matched to patients with Cushing disease based on age and sex. The authors regarded autoimmune disease diagnosed within 36 months of the surgery to be temporally associated with Cushing disease remission. Among the autoimmune diseases considered were “rheumatoid arthritis, Sjögren syndrome, systemic lupus erythematosus, autoimmune thyroiditis, celiac disease, psoriasis, vitiligo, autoimmune neuropathy, multiple sclerosis, myasthenia gravis, and ulcerative colitis.”

Patients differed in average body mass index and tumor size, but family history of autoimmune disease was similar in both groups. Average BMI was 34.5 in the Cushing group and 29.5 in the NFPA group. Average tumor size was 5.7 mm in the Cushing group and 21.3 mm in the NFPA group.

Before surgery, 2.9% of patients with Cushing disease and 15.4% of patients with NFPA had central hypothyroidism, and 8% in the Cushing group and 56.8% in the NFPA group had hyperprolactinemia. Central adrenal insufficiency occurred in 11% with NFPA and in all with Cushing disease, by definition.

After surgery, 93.8% in the Cushing group and 16.5% in the NFPA group had adrenal insufficiency. In addition, patients with Cushing disease had lower postsurgical nadir serum cortisol levels (63.8 nmol/L) than those with NFPA (282.3 nmol/L).

Of the 17 patients with Cushing disease — all women — who developed autoimmune disease within 3 years, 6 had a personal history of autoimmune disease and 7 had a family history of it. In addition, 41.2% of them had adrenal insufficiency when they developed the new autoimmune disease. Among the diseases were six autoimmune thyroiditis cases, three Sjögren syndrome cases, and two autoimmune seronegative spondyloarthropathy.

Dr. Heaney said he found it interesting that more than half of the new autoimmune diseases in patients with Cushing disease were related to the thyroid. “In this kind of setting, where you have a patient who has been producing too much steroid over a period of time and then you take that away, it’s almost like you release a brake on the TSH [thyroid-stimulating hormone],” Dr. Heaney said. “So, there’s probably some rebound in TSH that occurs, and that could be driving the thyroiditis, to some extent, that we see in these patients.”

Only one patient with NFPA developed new-onset autoimmune disease, a woman who developed Graves disease 22 months after surgery. When the researchers excluded patients in both groups with central hypothyroidism, new-onset autoimmune disease was still significantly higher (11.4%) in the Cushing group than in the NFPA group (1.9%; HR, 7.02; 95% CI, 2.54-19.39).
 

Could Postoperative Adrenal Insufficiency Contribute to Risk?

Within the Cushing cohort, those who developed autoimmune disease had a lower BMI (31.8 vs 34.8) and larger tumor size (7.2 vs 5.6 mm) than those who didn’t develop new autoimmune disease. Patients who developed autoimmune disease also had a lower baseline urine free cortisol ratio (2.7 vs 6.3) before surgery and more family history of autoimmune disease (41.2% vs 20.9%) than those who didn’t develop one.

“The higher prevalence of adrenal insufficiency and the lower nadir serum cortisol levels in the Cushing disease group suggest that the postoperative adrenal insufficiency in the Cushing disease group might have contributed to autoimmune disease pathogenesis,” the authors wrote. “This finding is clinically significant because cortisol plays a pivotal role in modulating the immune system.”

Most postoperative management among patients with Cushing disease was similar, with all but one patient receiving 0.5 or 1 mg daily dexamethasone within the first week after surgery. (The one outlier received 5 mg daily prednisone.) However, fewer patients who developed autoimmune disease (17.6%) received supraphysiologic doses of glucocorticoid — equivalent to at least 25 mg hydrocortisone — compared with patients who didn’t develop autoimmune disease (41.8%).

“Although the daily average hydrocortisone equivalent replacement doses within the first month and during long-term follow-up were within the physiologic range in both subgroups, patients with Cushing disease who had autoimmune disease received slightly lower doses of glucocorticoid replacement within the first month after surgery,” the authors reported. “The immediate postoperative period might be a critical window where supraphysiologic glucocorticoids seem to be protective with regard to development of autoimmune disease,” they wrote, though they acknowledged the study’s retrospective design as a limitation in drawing that conclusion.

At the least, they suggested that new symptoms in patients with Cushing disease, particularly those with a family history of autoimmune disease, should prompt investigation of potential autoimmune disease.

Recordati Rare Diseases funded the study. The research was also conducted with support from Harvard Catalyst (the Harvard Clinical and Translational Science Center) as well as financial contributions from Harvard University and its affiliated academic healthcare centers. One author reported holding stocks in Pfizer and Amgen, and another reported receiving consulting fees from Corcept. Dr. Heaney reported receiving institutional grants for trials from Corcept, Ascendis, Crinetics, and Sparrow Pharm; serving on the advisory board for Xeris, Recordati, Corcept, Novo Nordisk, Lundbeck, and Crinetics; and serving as a speaker for Chiesi, Novo Nordisk, and Corcept.
 

A version of this article appeared on Medscape.com.

Patients with Cushing disease have an increased risk for new-onset autoimmune disease in the 3 years after surgical remission, according to a new retrospective study published on February 20 in Annals of Internal Medicine.

Outcomes for patients with Cushing disease were compared against those with nonfunctioning pituitary adenomas (NFPAs). New-onset autoimmune disease occurred in 10.4% with Cushing disease and 1.6% among patients with NFPA (hazard ratio, 7.80; 95% CI, 2.88-21.10).

“Understanding and recognizing new and recurrent autoimmune disease in this setting is important to avoid misclassifying such patients with glucocorticoid withdrawal syndrome, which could result in failure to treat underlying autoimmune disease, as well as erroneous diagnosis of steroid withdrawal cases,” wrote Dennis Delasi Nyanyo of Massachusetts General Hospital and Harvard Medical School, Boston, and colleagues.

Given the general population’s annual incidence of major autoimmune diseases, estimated at about 100 cases per 100,000 people, and the 3-year incidence of 10.4% found in this study’s cohort, “our findings suggest that Cushing disease remission may trigger development of autoimmune disease,” the authors wrote.
 

Monitor Patients With Family History of Autoimmune Disease?

The study results were not necessarily surprising to Anthony P. Heaney, MD, PhD, an endocrinologist and professor of medicine at the University of California, Los Angeles, because past research has raised similar questions. The authors’ suggestion that the rapid postsurgical drop in cortisol that occurs as a result of treating Cushing disease becomes some sort of autoimmune trigger is interesting but remains speculative, Dr. Heaney pointed out.

If future evidence supports that possibility, “it would suggest, in terms of managing those patients in the postoperative setting, that there may be some merit to giving them higher concentrations of glucocorticoids for a short period of time,” Dr. Heaney said, thereby bringing their levels down more gradually rather than taking them off a cliff, in a sense. Or, if more evidence bears out the authors’ hypothesis, another approach might be treating patients with medicine to bring down the cortisol before surgery, though there are challenges to that approach, Dr. Heaney said.

At the same time, those who developed new autoimmune disease remain a small subset of patients with Cushing disease, so such approaches may become only potentially appropriate to consider in patients with risk factors, such as a family history of autoimmune disease.

The researchers conducted a retrospective chart review of adult patients who underwent transsphenoidal surgery for either Cushing disease or NFPA at Massachusetts General Hospital between 2005 and 2019.

The study involved 194 patients with Cushing disease who had postsurgical remission and at least one follow-up visit with a pituitary expert and 92 patients with NFPA who were matched to patients with Cushing disease based on age and sex. The authors regarded autoimmune disease diagnosed within 36 months of the surgery to be temporally associated with Cushing disease remission. Among the autoimmune diseases considered were “rheumatoid arthritis, Sjögren syndrome, systemic lupus erythematosus, autoimmune thyroiditis, celiac disease, psoriasis, vitiligo, autoimmune neuropathy, multiple sclerosis, myasthenia gravis, and ulcerative colitis.”

Patients differed in average body mass index and tumor size, but family history of autoimmune disease was similar in both groups. Average BMI was 34.5 in the Cushing group and 29.5 in the NFPA group. Average tumor size was 5.7 mm in the Cushing group and 21.3 mm in the NFPA group.

Before surgery, 2.9% of patients with Cushing disease and 15.4% of patients with NFPA had central hypothyroidism, and 8% in the Cushing group and 56.8% in the NFPA group had hyperprolactinemia. Central adrenal insufficiency occurred in 11% with NFPA and in all with Cushing disease, by definition.

After surgery, 93.8% in the Cushing group and 16.5% in the NFPA group had adrenal insufficiency. In addition, patients with Cushing disease had lower postsurgical nadir serum cortisol levels (63.8 nmol/L) than those with NFPA (282.3 nmol/L).

Of the 17 patients with Cushing disease — all women — who developed autoimmune disease within 3 years, 6 had a personal history of autoimmune disease and 7 had a family history of it. In addition, 41.2% of them had adrenal insufficiency when they developed the new autoimmune disease. Among the diseases were six autoimmune thyroiditis cases, three Sjögren syndrome cases, and two autoimmune seronegative spondyloarthropathy.

Dr. Heaney said he found it interesting that more than half of the new autoimmune diseases in patients with Cushing disease were related to the thyroid. “In this kind of setting, where you have a patient who has been producing too much steroid over a period of time and then you take that away, it’s almost like you release a brake on the TSH [thyroid-stimulating hormone],” Dr. Heaney said. “So, there’s probably some rebound in TSH that occurs, and that could be driving the thyroiditis, to some extent, that we see in these patients.”

Only one patient with NFPA developed new-onset autoimmune disease, a woman who developed Graves disease 22 months after surgery. When the researchers excluded patients in both groups with central hypothyroidism, new-onset autoimmune disease was still significantly higher (11.4%) in the Cushing group than in the NFPA group (1.9%; HR, 7.02; 95% CI, 2.54-19.39).
 

Could Postoperative Adrenal Insufficiency Contribute to Risk?

Within the Cushing cohort, those who developed autoimmune disease had a lower BMI (31.8 vs 34.8) and larger tumor size (7.2 vs 5.6 mm) than those who didn’t develop new autoimmune disease. Patients who developed autoimmune disease also had a lower baseline urine free cortisol ratio (2.7 vs 6.3) before surgery and more family history of autoimmune disease (41.2% vs 20.9%) than those who didn’t develop one.

“The higher prevalence of adrenal insufficiency and the lower nadir serum cortisol levels in the Cushing disease group suggest that the postoperative adrenal insufficiency in the Cushing disease group might have contributed to autoimmune disease pathogenesis,” the authors wrote. “This finding is clinically significant because cortisol plays a pivotal role in modulating the immune system.”

Most postoperative management among patients with Cushing disease was similar, with all but one patient receiving 0.5 or 1 mg daily dexamethasone within the first week after surgery. (The one outlier received 5 mg daily prednisone.) However, fewer patients who developed autoimmune disease (17.6%) received supraphysiologic doses of glucocorticoid — equivalent to at least 25 mg hydrocortisone — compared with patients who didn’t develop autoimmune disease (41.8%).

“Although the daily average hydrocortisone equivalent replacement doses within the first month and during long-term follow-up were within the physiologic range in both subgroups, patients with Cushing disease who had autoimmune disease received slightly lower doses of glucocorticoid replacement within the first month after surgery,” the authors reported. “The immediate postoperative period might be a critical window where supraphysiologic glucocorticoids seem to be protective with regard to development of autoimmune disease,” they wrote, though they acknowledged the study’s retrospective design as a limitation in drawing that conclusion.

At the least, they suggested that new symptoms in patients with Cushing disease, particularly those with a family history of autoimmune disease, should prompt investigation of potential autoimmune disease.

Recordati Rare Diseases funded the study. The research was also conducted with support from Harvard Catalyst (the Harvard Clinical and Translational Science Center) as well as financial contributions from Harvard University and its affiliated academic healthcare centers. One author reported holding stocks in Pfizer and Amgen, and another reported receiving consulting fees from Corcept. Dr. Heaney reported receiving institutional grants for trials from Corcept, Ascendis, Crinetics, and Sparrow Pharm; serving on the advisory board for Xeris, Recordati, Corcept, Novo Nordisk, Lundbeck, and Crinetics; and serving as a speaker for Chiesi, Novo Nordisk, and Corcept.
 

A version of this article appeared on Medscape.com.

More than 50% of obese adolescents met criteria for depression, which also was associated with several components of metabolic syndrome, based on data from 160 individuals.

Previous research shows that the metabolic consequences of obesity are worsened with the coexistence of depression in adults, but a similar relationship in obese adolescents has not been explored, according to Nisha Gupta, a medical student at the University of Texas Health Science Center, Houston, and colleagues.

“This relationship is explained by an overactive stress response and adoption of unhealthy lifestyle habits,” both of which increased during the COVID-19 pandemic, the researchers noted in their abstract.

In a study presented at the Pediatric Academic Societies annual meeting, the researchers reviewed data from 160 obese adolescents seen at a pediatric weight management clinic between July 1, 2018, and Dec. 3, 2021. The data included anthropometric, clinical, and laboratory information. Depression was assessed using the Patient Health Questionnaire–9 (PHQ-9). The goal of the study was to compare the prevalence of metabolic syndrome components in obese youth with and without diagnosed depression.

Overall, 46% of the patients had PHQ-9 scores less than 5, which was defined as no clinically significant depression. A total of 26% had current or prior diagnoses of depression, and 25% met the criteria for moderate to severe depression, with PHQ-9 scores of 10 or higher. Notably, 18% of individuals with no prior history of depression met criteria for moderate to severe depression, the researchers wrote.

Teens who reported daytime fatigue or trouble sleeping, and those who reported eating out seven or more times a week had higher scores than those without these reports.

In laboratory analyses, higher PHQ-9 scores were significantly associated with increasing weight, body mass index, body fat percentage, diastolic blood pressure, and fasting blood insulin (P < .02 for all).

The study findings were limited by the relatively small sample size, the researchers noted. However, the results suggest that depression is common, but often underdiagnosed in obese adolescents, and depression screening should be part of obesity management.
 

Study highlights need to screen

The current study is important because of the overall increase in obesity in the United States, which extends to children and teens, Tim Joos, MD, a Seattle-based clinician with a combination internal medicine/pediatrics practice, said in an interview.

“With skyrocketing rates of obesity among children and teens over the last decades, we are seeing more ‘adult’ diseases seep into the younger ages, including type 2 diabetes, high blood pressure and now, depression,” he said.

“The results are a wake-up call for the need for better system-wide prevention and management of obesity in adolescents and the importance of screening and managing depression in obese teenagers,” he emphasized.

The study received no outside funding. The researchers had no financial conflicts to disclose. Dr. Joos had no financial conflicts to disclose and serves on the editorial advisory board of Pediatric News.

More than 50% of obese adolescents met criteria for depression, which also was associated with several components of metabolic syndrome, based on data from 160 individuals.

Previous research shows that the metabolic consequences of obesity are worsened with the coexistence of depression in adults, but a similar relationship in obese adolescents has not been explored, according to Nisha Gupta, a medical student at the University of Texas Health Science Center, Houston, and colleagues.

“This relationship is explained by an overactive stress response and adoption of unhealthy lifestyle habits,” both of which increased during the COVID-19 pandemic, the researchers noted in their abstract.

In a study presented at the Pediatric Academic Societies annual meeting, the researchers reviewed data from 160 obese adolescents seen at a pediatric weight management clinic between July 1, 2018, and Dec. 3, 2021. The data included anthropometric, clinical, and laboratory information. Depression was assessed using the Patient Health Questionnaire–9 (PHQ-9). The goal of the study was to compare the prevalence of metabolic syndrome components in obese youth with and without diagnosed depression.

Overall, 46% of the patients had PHQ-9 scores less than 5, which was defined as no clinically significant depression. A total of 26% had current or prior diagnoses of depression, and 25% met the criteria for moderate to severe depression, with PHQ-9 scores of 10 or higher. Notably, 18% of individuals with no prior history of depression met criteria for moderate to severe depression, the researchers wrote.

Teens who reported daytime fatigue or trouble sleeping, and those who reported eating out seven or more times a week had higher scores than those without these reports.

In laboratory analyses, higher PHQ-9 scores were significantly associated with increasing weight, body mass index, body fat percentage, diastolic blood pressure, and fasting blood insulin (P < .02 for all).

The study findings were limited by the relatively small sample size, the researchers noted. However, the results suggest that depression is common, but often underdiagnosed in obese adolescents, and depression screening should be part of obesity management.
 

Study highlights need to screen

The current study is important because of the overall increase in obesity in the United States, which extends to children and teens, Tim Joos, MD, a Seattle-based clinician with a combination internal medicine/pediatrics practice, said in an interview.

“With skyrocketing rates of obesity among children and teens over the last decades, we are seeing more ‘adult’ diseases seep into the younger ages, including type 2 diabetes, high blood pressure and now, depression,” he said.

“The results are a wake-up call for the need for better system-wide prevention and management of obesity in adolescents and the importance of screening and managing depression in obese teenagers,” he emphasized.

The study received no outside funding. The researchers had no financial conflicts to disclose. Dr. Joos had no financial conflicts to disclose and serves on the editorial advisory board of Pediatric News.

More than 50% of obese adolescents met criteria for depression, which also was associated with several components of metabolic syndrome, based on data from 160 individuals.

Previous research shows that the metabolic consequences of obesity are worsened with the coexistence of depression in adults, but a similar relationship in obese adolescents has not been explored, according to Nisha Gupta, a medical student at the University of Texas Health Science Center, Houston, and colleagues.

“This relationship is explained by an overactive stress response and adoption of unhealthy lifestyle habits,” both of which increased during the COVID-19 pandemic, the researchers noted in their abstract.

In a study presented at the Pediatric Academic Societies annual meeting, the researchers reviewed data from 160 obese adolescents seen at a pediatric weight management clinic between July 1, 2018, and Dec. 3, 2021. The data included anthropometric, clinical, and laboratory information. Depression was assessed using the Patient Health Questionnaire–9 (PHQ-9). The goal of the study was to compare the prevalence of metabolic syndrome components in obese youth with and without diagnosed depression.

Overall, 46% of the patients had PHQ-9 scores less than 5, which was defined as no clinically significant depression. A total of 26% had current or prior diagnoses of depression, and 25% met the criteria for moderate to severe depression, with PHQ-9 scores of 10 or higher. Notably, 18% of individuals with no prior history of depression met criteria for moderate to severe depression, the researchers wrote.

Teens who reported daytime fatigue or trouble sleeping, and those who reported eating out seven or more times a week had higher scores than those without these reports.

In laboratory analyses, higher PHQ-9 scores were significantly associated with increasing weight, body mass index, body fat percentage, diastolic blood pressure, and fasting blood insulin (P < .02 for all).

The study findings were limited by the relatively small sample size, the researchers noted. However, the results suggest that depression is common, but often underdiagnosed in obese adolescents, and depression screening should be part of obesity management.
 

Study highlights need to screen

The current study is important because of the overall increase in obesity in the United States, which extends to children and teens, Tim Joos, MD, a Seattle-based clinician with a combination internal medicine/pediatrics practice, said in an interview.

“With skyrocketing rates of obesity among children and teens over the last decades, we are seeing more ‘adult’ diseases seep into the younger ages, including type 2 diabetes, high blood pressure and now, depression,” he said.

“The results are a wake-up call for the need for better system-wide prevention and management of obesity in adolescents and the importance of screening and managing depression in obese teenagers,” he emphasized.

The study received no outside funding. The researchers had no financial conflicts to disclose. Dr. Joos had no financial conflicts to disclose and serves on the editorial advisory board of Pediatric News.

The Food and Drug Administration has approved levoketoconazole (Recorlev, Xeris Biopharma) for the treatment of endogenous hypercortisolemia in adults with Cushing syndrome for whom surgery is not possible or was not curative.

Endogenous Cushing syndrome is a relatively rare condition characterized by chronically elevated cortisol levels, typically arising from a benign pituitary tumor. Left untreated, it can lead to reproductive problems and hirsutism in women, as well as serious complications, including diabetes, hypertension, tissue fragility, and mood disorders. Half of patients will die within 5 years if left untreated.

FDA_approved_web.jpg

A version of this article first appeared on Medscape.com.

The Food and Drug Administration has approved levoketoconazole (Recorlev, Xeris Biopharma) for the treatment of endogenous hypercortisolemia in adults with Cushing syndrome for whom surgery is not possible or was not curative.

Endogenous Cushing syndrome is a relatively rare condition characterized by chronically elevated cortisol levels, typically arising from a benign pituitary tumor. Left untreated, it can lead to reproductive problems and hirsutism in women, as well as serious complications, including diabetes, hypertension, tissue fragility, and mood disorders. Half of patients will die within 5 years if left untreated.

FDA_approved_web.jpg

A version of this article first appeared on Medscape.com.

The Food and Drug Administration has approved levoketoconazole (Recorlev, Xeris Biopharma) for the treatment of endogenous hypercortisolemia in adults with Cushing syndrome for whom surgery is not possible or was not curative.

Endogenous Cushing syndrome is a relatively rare condition characterized by chronically elevated cortisol levels, typically arising from a benign pituitary tumor. Left untreated, it can lead to reproductive problems and hirsutism in women, as well as serious complications, including diabetes, hypertension, tissue fragility, and mood disorders. Half of patients will die within 5 years if left untreated.

FDA_approved_web.jpg

A version of this article first appeared on Medscape.com.

A survey of more than 12,000 women of reproductive age found that one in three had experienced changes to their menstrual cycles and symptoms during the COVID-19 pandemic. Noticeably higher stress levels than prepandemic benchmarks could be affecting menstruation.

This has implications for women trying to conceive or struggling with infertility, said Shannon M. Malloy, a research and data associate with Ovia Health, a women’s and family health technology company in Boston. Ms. Malloy presented this study at the American Society of Reproductive Medicine’s 2021 meeting.

COVID-19 has introduced new psychosocial, interpersonal, and environmental stressors. The pandemic is “one of the most stressful, collectively experienced disasters modern society has ever seen,” said Ms. Malloy. Once imagined as an explicit event in time, COVID-19 has ingrained itself into daily life for the foreseeable future.

Research has shown that chronic, long-term stress produces high cortisol levels, which can alter endocrinology and regulation of menstrual cycles. This can make family building even more challenging, said Ms. Malloy. Physicians and other providers have always taken stress into account when managing patients, but never at this level of chronic, episodic stress, she said.
 

Survey examines impact on ART

Ovia Health decided to investigate the relationship between perceived stress and menstrual cycle and symptom changes during the COVID-19 pandemic, to see how it might affect assisted reproductive technology (ART).

From March 2020 to April 2021, users of Ovia Health’s Fertility mobile application in the United States took part in a survey. Items captured changes in menstruation pattern and symptomatology and included the Perceived Stress Scale 4-item version (PSS-4). A paired t-test evaluated differences between groups (menstrual changes versus no menstrual changes). The survey asked participants what changes they noticed in their menstrual cycle and why they thought cycle patterns or symptoms changed.
 

One-third report changes in cycle, symptoms

Among 12,302 respondents, 1 in 3 (36%) reported changes in cycle or symptoms. Eighty-seven percent said that their cycle started early or late. Twenty-nine percent reported stronger symptoms during menstruation such as low back pain, cramping, or discharge changes, and 27% said bleeding was heavier during periods.

These results are similar to other studies investigating the affect of episodic stress on menstruation, said Ms. Malloy.

Those who reported menstrual cycle or symptom changes scored higher on average on the PSS-4 compared with those who didn’t report any changes (8.5 v. 8.3, respectively, P < .05). PSS-4 scores across the board were notably higher in all respondents, regardless of cycle/symptom irregularity, compared with prepandemic benchmarking in similar populations.

Slightly more than half (55%) thought stress contributed to their menstrual cycle pattern and/or symptom changes, whereas 33% pointed to changes in mental health, such as depression or anxiety. “Interestingly, many users believed the COVID-19 vaccine impacted their menstrual cycle symptom changes,” said Ms. Malloy.
 

No definitive link between vaccine, menstruation

While known side effects of the vaccine include sore arm, fever, fatigue, and myalgia, some women have reported changes in their menstrual cycle, Mark P. Trolice, MD, professor of obstetrics and gynecology at the University of Central Florida and director of the IVF Center in Orlando, said in an interview.

“Vaccination reaction from the immune response rather than the vaccine may be the implicating factor,” said Dr. Trolice, who was not involved in the study.

Currently, there’s no direct link between the vaccine and subsequent effects on menstruation, he continued. “Most women experience resumption of normal intervals 1 month following vaccination. Further, there is no credible evidence that links the vaccine to infertility.

“Nevertheless, research in this area is vital and underway,” he added.
 

Physicians can help with stress

Menstrual cycle disruption is especially frustrating for women trying to build a family, said Ms. Malloy. Providers may be observing more menstrual irregularity in their patient populations, and seeing more patients struggle to conceive on their own, turning to ART.

Providers can’t make COVID-19 go away, but they could help patients by doing a better job of integrating mental health screening, connecting patients to treatments that optimize conception and fertility treatment outcomes, said Ms. Malloy.

The survey was limited in that its questions didn’t consider proper diagnostic criteria for irregularity, versus self-reported changes. But it does highlight the need for more research on the pandemic’s affect on menstruation and the vaccine on menstruation, said Ms. Malloy. “The National Institutes of Health in August committed $1.6 million to explore this connection. We’re looking forward to seeing what their results are.” 

Dr. Trolice and Ms. Malloy had no disclosures.

A survey of more than 12,000 women of reproductive age found that one in three had experienced changes to their menstrual cycles and symptoms during the COVID-19 pandemic. Noticeably higher stress levels than prepandemic benchmarks could be affecting menstruation.

This has implications for women trying to conceive or struggling with infertility, said Shannon M. Malloy, a research and data associate with Ovia Health, a women’s and family health technology company in Boston. Ms. Malloy presented this study at the American Society of Reproductive Medicine’s 2021 meeting.

COVID-19 has introduced new psychosocial, interpersonal, and environmental stressors. The pandemic is “one of the most stressful, collectively experienced disasters modern society has ever seen,” said Ms. Malloy. Once imagined as an explicit event in time, COVID-19 has ingrained itself into daily life for the foreseeable future.

Research has shown that chronic, long-term stress produces high cortisol levels, which can alter endocrinology and regulation of menstrual cycles. This can make family building even more challenging, said Ms. Malloy. Physicians and other providers have always taken stress into account when managing patients, but never at this level of chronic, episodic stress, she said.
 

Survey examines impact on ART

Ovia Health decided to investigate the relationship between perceived stress and menstrual cycle and symptom changes during the COVID-19 pandemic, to see how it might affect assisted reproductive technology (ART).

From March 2020 to April 2021, users of Ovia Health’s Fertility mobile application in the United States took part in a survey. Items captured changes in menstruation pattern and symptomatology and included the Perceived Stress Scale 4-item version (PSS-4). A paired t-test evaluated differences between groups (menstrual changes versus no menstrual changes). The survey asked participants what changes they noticed in their menstrual cycle and why they thought cycle patterns or symptoms changed.
 

One-third report changes in cycle, symptoms

Among 12,302 respondents, 1 in 3 (36%) reported changes in cycle or symptoms. Eighty-seven percent said that their cycle started early or late. Twenty-nine percent reported stronger symptoms during menstruation such as low back pain, cramping, or discharge changes, and 27% said bleeding was heavier during periods.

These results are similar to other studies investigating the affect of episodic stress on menstruation, said Ms. Malloy.

Those who reported menstrual cycle or symptom changes scored higher on average on the PSS-4 compared with those who didn’t report any changes (8.5 v. 8.3, respectively, P < .05). PSS-4 scores across the board were notably higher in all respondents, regardless of cycle/symptom irregularity, compared with prepandemic benchmarking in similar populations.

Slightly more than half (55%) thought stress contributed to their menstrual cycle pattern and/or symptom changes, whereas 33% pointed to changes in mental health, such as depression or anxiety. “Interestingly, many users believed the COVID-19 vaccine impacted their menstrual cycle symptom changes,” said Ms. Malloy.
 

No definitive link between vaccine, menstruation

While known side effects of the vaccine include sore arm, fever, fatigue, and myalgia, some women have reported changes in their menstrual cycle, Mark P. Trolice, MD, professor of obstetrics and gynecology at the University of Central Florida and director of the IVF Center in Orlando, said in an interview.

“Vaccination reaction from the immune response rather than the vaccine may be the implicating factor,” said Dr. Trolice, who was not involved in the study.

Currently, there’s no direct link between the vaccine and subsequent effects on menstruation, he continued. “Most women experience resumption of normal intervals 1 month following vaccination. Further, there is no credible evidence that links the vaccine to infertility.

“Nevertheless, research in this area is vital and underway,” he added.
 

Physicians can help with stress

Menstrual cycle disruption is especially frustrating for women trying to build a family, said Ms. Malloy. Providers may be observing more menstrual irregularity in their patient populations, and seeing more patients struggle to conceive on their own, turning to ART.

Providers can’t make COVID-19 go away, but they could help patients by doing a better job of integrating mental health screening, connecting patients to treatments that optimize conception and fertility treatment outcomes, said Ms. Malloy.

The survey was limited in that its questions didn’t consider proper diagnostic criteria for irregularity, versus self-reported changes. But it does highlight the need for more research on the pandemic’s affect on menstruation and the vaccine on menstruation, said Ms. Malloy. “The National Institutes of Health in August committed $1.6 million to explore this connection. We’re looking forward to seeing what their results are.” 

Dr. Trolice and Ms. Malloy had no disclosures.

A survey of more than 12,000 women of reproductive age found that one in three had experienced changes to their menstrual cycles and symptoms during the COVID-19 pandemic. Noticeably higher stress levels than prepandemic benchmarks could be affecting menstruation.

This has implications for women trying to conceive or struggling with infertility, said Shannon M. Malloy, a research and data associate with Ovia Health, a women’s and family health technology company in Boston. Ms. Malloy presented this study at the American Society of Reproductive Medicine’s 2021 meeting.

COVID-19 has introduced new psychosocial, interpersonal, and environmental stressors. The pandemic is “one of the most stressful, collectively experienced disasters modern society has ever seen,” said Ms. Malloy. Once imagined as an explicit event in time, COVID-19 has ingrained itself into daily life for the foreseeable future.

Research has shown that chronic, long-term stress produces high cortisol levels, which can alter endocrinology and regulation of menstrual cycles. This can make family building even more challenging, said Ms. Malloy. Physicians and other providers have always taken stress into account when managing patients, but never at this level of chronic, episodic stress, she said.
 

Survey examines impact on ART

Ovia Health decided to investigate the relationship between perceived stress and menstrual cycle and symptom changes during the COVID-19 pandemic, to see how it might affect assisted reproductive technology (ART).

From March 2020 to April 2021, users of Ovia Health’s Fertility mobile application in the United States took part in a survey. Items captured changes in menstruation pattern and symptomatology and included the Perceived Stress Scale 4-item version (PSS-4). A paired t-test evaluated differences between groups (menstrual changes versus no menstrual changes). The survey asked participants what changes they noticed in their menstrual cycle and why they thought cycle patterns or symptoms changed.
 

One-third report changes in cycle, symptoms

Among 12,302 respondents, 1 in 3 (36%) reported changes in cycle or symptoms. Eighty-seven percent said that their cycle started early or late. Twenty-nine percent reported stronger symptoms during menstruation such as low back pain, cramping, or discharge changes, and 27% said bleeding was heavier during periods.

These results are similar to other studies investigating the affect of episodic stress on menstruation, said Ms. Malloy.

Those who reported menstrual cycle or symptom changes scored higher on average on the PSS-4 compared with those who didn’t report any changes (8.5 v. 8.3, respectively, P < .05). PSS-4 scores across the board were notably higher in all respondents, regardless of cycle/symptom irregularity, compared with prepandemic benchmarking in similar populations.

Slightly more than half (55%) thought stress contributed to their menstrual cycle pattern and/or symptom changes, whereas 33% pointed to changes in mental health, such as depression or anxiety. “Interestingly, many users believed the COVID-19 vaccine impacted their menstrual cycle symptom changes,” said Ms. Malloy.
 

No definitive link between vaccine, menstruation

While known side effects of the vaccine include sore arm, fever, fatigue, and myalgia, some women have reported changes in their menstrual cycle, Mark P. Trolice, MD, professor of obstetrics and gynecology at the University of Central Florida and director of the IVF Center in Orlando, said in an interview.

“Vaccination reaction from the immune response rather than the vaccine may be the implicating factor,” said Dr. Trolice, who was not involved in the study.

Currently, there’s no direct link between the vaccine and subsequent effects on menstruation, he continued. “Most women experience resumption of normal intervals 1 month following vaccination. Further, there is no credible evidence that links the vaccine to infertility.

“Nevertheless, research in this area is vital and underway,” he added.
 

Physicians can help with stress

Menstrual cycle disruption is especially frustrating for women trying to build a family, said Ms. Malloy. Providers may be observing more menstrual irregularity in their patient populations, and seeing more patients struggle to conceive on their own, turning to ART.

Providers can’t make COVID-19 go away, but they could help patients by doing a better job of integrating mental health screening, connecting patients to treatments that optimize conception and fertility treatment outcomes, said Ms. Malloy.

The survey was limited in that its questions didn’t consider proper diagnostic criteria for irregularity, versus self-reported changes. But it does highlight the need for more research on the pandemic’s affect on menstruation and the vaccine on menstruation, said Ms. Malloy. “The National Institutes of Health in August committed $1.6 million to explore this connection. We’re looking forward to seeing what their results are.” 

Dr. Trolice and Ms. Malloy had no disclosures.

Excess mortality among people with endogenous Cushing’s syndrome (CS) has declined in the past 20 years yet remains three times higher than in the general population, new research finds.

Among more than 90,000 individuals with endogenous CS, the overall proportion of mortality – defined as the ratio of the number of deaths from CS divided by the total number of CS patients – was 0.05, and the standardized mortality rate was an “unacceptable” three times that of the general population, Padiporn Limumpornpetch, MD, reported on March 20 at ENDO 2021: The Endocrine Society Annual Meeting.

Excess deaths were higher among those with adrenal CS, compared with those with Cushing’s disease. The most common causes of death among those with CS were cardiovascular diseases, cerebrovascular accident, infection, and malignancy, noted Dr. Limumpornpetch, of Songkla University, Hat Yai, Thailand, who is also a PhD student at the University of Leeds, United Kingdom.

“While mortality has improved since 2000, it is still significantly compromised compared to the background population ... The causes of death highlight the need for aggressive management of cardiovascular risk, prevention of thromboembolism, infection control, and a normalized cortisol level,” she said.

Asked to comment, Maria Fleseriu, MD, told this news organization that the new data show “we are making improvements in the care of patients with CS and thus outcomes, but we are not there yet ... This meta-analysis highlights the whole spectrum of acute and life-threatening complications in CS and their high prevalence, even before disease diagnosis and after successful surgery.”

She noted that although she wasn’t surprised by the overall results, “the improvement over time was indeed lower than I expected. However, interestingly here, the risk of mortality in adrenal Cushing’s was unexpectedly high despite patients with adrenal cancer being excluded.”

Dr. Fleseriu, who is director of the Pituitary Center at Oregon Health and Science University, Portland, advised, “Management of hyperglycemia and diabetes, hypertension, hypokalemia, hyperlipidemia, and other cardiovascular risk factors is generally undertaken in accordance with standard of clinical care.”

“But we should focus more on optimizing more aggressively this care in addition to the specific Cushing’s treatment,” she stressed.

In addition, she noted, “Medical therapy for CS may be needed even prior to surgery in severe and/or prolonged hypercortisolism to decrease complications ... We definitely need a multidisciplinary approach to address complications and etiologic treatment as well as the reduced long-term quality of life in patients with CS.”

Largest study in scale and scope of Cushing’s syndrome mortality

Endogenous Cushing’s syndrome occurs when the body overproduces cortisol. The most common cause of the latter is a tumor of the pituitary gland (Cushing’s disease), but another cause is a usually benign tumor of the adrenal glands (adrenal Cushing’s syndrome). Surgery is the mainstay of initial treatment of Cushing’s syndrome. If an operation to remove the tumor fails to cause remission, medications are available.

Prior to this new meta-analysis, there had been limited data on mortality among patients with endogenous CS. Research has mostly been limited to single-cohort studies. A previous systematic review/meta-analysis comprised only seven articles with 780 patients. All the studies were conducted prior to 2012, and most were limited to Cushing’s disease.

“In 2021, we lacked a detailed understanding of patient outcomes and mortality because of the rarity of Cushing’s syndrome,” Dr. Limumpornpetch noted.

The current meta-analysis included 91 articles that reported mortality among patients with endogenous CS. There was a total of 19,181 patients from 92 study cohorts, including 49 studies on CD (n = 14,971), 24 studies on adrenal CS (n = 2304), and 19 studies that included both (n = 1906).

Among 21 studies that reported standardized mortality rate (SMR) data, including 13 CD studies (n = 2160) and seven on adrenal CS (n = 1531), the overall increase in mortality compared to the background population was a significant 3.00 (range, 1.15-7.84).

This SMR was higher among patients with adrenal Cushing’s syndrome (3.3) versus Cushing’s disease (2.8) (P = .003) and among patients who had active disease (5.7) versus those whose disease was in remission (2.3) (P < .001).

The SMR was also worse among patients with Cushing’s disease with larger tumors (macroadenomas), at 7.4, than among patients with very small tumors (microadenomas), at 1.9 (P = .004).

The proportion of death was 0.05 for CS overall, with 0.04 for CD and 0.02 for adrenal adenomas.

Compared to studies published prior to the year 2000, more recent studies seem to reflect advances in treatment and care. The overall proportion of death for all CS cohorts dropped from 0.10 to 0.03 (P < .001); for all CD cohorts, it dropped from 0.14 to 0.03; and for adrenal CS cohorts, it dropped from 0.09 to 0.03 (P = .04).

Causes of death were cardiovascular diseases (29.5% of cases), cerebrovascular accident (11.5%), infection (10.5%), and malignancy (10.1%). Less common causes of death were gastrointestinal bleeding and acute pancreatitis (3.7%), active CS (3.5%), adrenal insufficiency (2.5%), suicide (2.5%), and surgery (1.6%).

Overall, in the CS groups, the proportion of deaths within 30 days of surgery dropped from 0.04 prior to 2000 to 0.01 since (P = .07). For CD, the proportion dropped from 0.02 to 0.01 (P = .25).

Preventing perioperative mortality: Consider thromboprophylaxis

Dr. Fleseriu told this news organization that she believes hypercoagulability is “the least recognized complication with a big role in mortality.” Because most of the perioperative mortality is due to venous thromboembolism and infections, “thromboprophylaxis should be considered for CS patients with severe hypercortisolism and/or postoperatively, based on individual risk factors of thromboembolism and bleeding.”

Recently, Dr. Fleseriu’s group showed in a single retrospective study that the risk for arterial and venous thromboembolic events among patients with CS was approximately 20%. Many patients experienced more than one event. Risk was higher 30 to 60 days postoperatively.

The odds ratio of venous thromoboembolism among patients with CS was 18 times higher than in the normal population.

“Due to the additional thrombotic risk of surgery or any invasive procedure, anticoagulation prophylaxis should be at least considered in all patients with Cushing’s syndrome and balanced with individual bleeding risk,” Dr. Fleseriu advised.

A recent Pituitary Society workshop discussed the management of complications of CS at length; proceedings will be published soon, she noted.

Dr. Limumpornpetch commented, “We look forward to the day when our interdisciplinary approach to managing these challenging patients can deliver outcomes similar to the background population.”

Dr. Limumpornpetch has disclosed no relevant financial relationships. Dr. Fleseriu has been a scientific consultant to Recordati, Sparrow, and Strongbridge and has received grants (inst) from Novartis and Strongbridge.

A version of this article first appeared on Medscape.com.

Excess mortality among people with endogenous Cushing’s syndrome (CS) has declined in the past 20 years yet remains three times higher than in the general population, new research finds.

Among more than 90,000 individuals with endogenous CS, the overall proportion of mortality – defined as the ratio of the number of deaths from CS divided by the total number of CS patients – was 0.05, and the standardized mortality rate was an “unacceptable” three times that of the general population, Padiporn Limumpornpetch, MD, reported on March 20 at ENDO 2021: The Endocrine Society Annual Meeting.

Excess deaths were higher among those with adrenal CS, compared with those with Cushing’s disease. The most common causes of death among those with CS were cardiovascular diseases, cerebrovascular accident, infection, and malignancy, noted Dr. Limumpornpetch, of Songkla University, Hat Yai, Thailand, who is also a PhD student at the University of Leeds, United Kingdom.

“While mortality has improved since 2000, it is still significantly compromised compared to the background population ... The causes of death highlight the need for aggressive management of cardiovascular risk, prevention of thromboembolism, infection control, and a normalized cortisol level,” she said.

Asked to comment, Maria Fleseriu, MD, told this news organization that the new data show “we are making improvements in the care of patients with CS and thus outcomes, but we are not there yet ... This meta-analysis highlights the whole spectrum of acute and life-threatening complications in CS and their high prevalence, even before disease diagnosis and after successful surgery.”

She noted that although she wasn’t surprised by the overall results, “the improvement over time was indeed lower than I expected. However, interestingly here, the risk of mortality in adrenal Cushing’s was unexpectedly high despite patients with adrenal cancer being excluded.”

Dr. Fleseriu, who is director of the Pituitary Center at Oregon Health and Science University, Portland, advised, “Management of hyperglycemia and diabetes, hypertension, hypokalemia, hyperlipidemia, and other cardiovascular risk factors is generally undertaken in accordance with standard of clinical care.”

“But we should focus more on optimizing more aggressively this care in addition to the specific Cushing’s treatment,” she stressed.

In addition, she noted, “Medical therapy for CS may be needed even prior to surgery in severe and/or prolonged hypercortisolism to decrease complications ... We definitely need a multidisciplinary approach to address complications and etiologic treatment as well as the reduced long-term quality of life in patients with CS.”

Largest study in scale and scope of Cushing’s syndrome mortality

Endogenous Cushing’s syndrome occurs when the body overproduces cortisol. The most common cause of the latter is a tumor of the pituitary gland (Cushing’s disease), but another cause is a usually benign tumor of the adrenal glands (adrenal Cushing’s syndrome). Surgery is the mainstay of initial treatment of Cushing’s syndrome. If an operation to remove the tumor fails to cause remission, medications are available.

Prior to this new meta-analysis, there had been limited data on mortality among patients with endogenous CS. Research has mostly been limited to single-cohort studies. A previous systematic review/meta-analysis comprised only seven articles with 780 patients. All the studies were conducted prior to 2012, and most were limited to Cushing’s disease.

“In 2021, we lacked a detailed understanding of patient outcomes and mortality because of the rarity of Cushing’s syndrome,” Dr. Limumpornpetch noted.

The current meta-analysis included 91 articles that reported mortality among patients with endogenous CS. There was a total of 19,181 patients from 92 study cohorts, including 49 studies on CD (n = 14,971), 24 studies on adrenal CS (n = 2304), and 19 studies that included both (n = 1906).

Among 21 studies that reported standardized mortality rate (SMR) data, including 13 CD studies (n = 2160) and seven on adrenal CS (n = 1531), the overall increase in mortality compared to the background population was a significant 3.00 (range, 1.15-7.84).

This SMR was higher among patients with adrenal Cushing’s syndrome (3.3) versus Cushing’s disease (2.8) (P = .003) and among patients who had active disease (5.7) versus those whose disease was in remission (2.3) (P < .001).

The SMR was also worse among patients with Cushing’s disease with larger tumors (macroadenomas), at 7.4, than among patients with very small tumors (microadenomas), at 1.9 (P = .004).

The proportion of death was 0.05 for CS overall, with 0.04 for CD and 0.02 for adrenal adenomas.

Compared to studies published prior to the year 2000, more recent studies seem to reflect advances in treatment and care. The overall proportion of death for all CS cohorts dropped from 0.10 to 0.03 (P < .001); for all CD cohorts, it dropped from 0.14 to 0.03; and for adrenal CS cohorts, it dropped from 0.09 to 0.03 (P = .04).

Causes of death were cardiovascular diseases (29.5% of cases), cerebrovascular accident (11.5%), infection (10.5%), and malignancy (10.1%). Less common causes of death were gastrointestinal bleeding and acute pancreatitis (3.7%), active CS (3.5%), adrenal insufficiency (2.5%), suicide (2.5%), and surgery (1.6%).

Overall, in the CS groups, the proportion of deaths within 30 days of surgery dropped from 0.04 prior to 2000 to 0.01 since (P = .07). For CD, the proportion dropped from 0.02 to 0.01 (P = .25).

Preventing perioperative mortality: Consider thromboprophylaxis

Dr. Fleseriu told this news organization that she believes hypercoagulability is “the least recognized complication with a big role in mortality.” Because most of the perioperative mortality is due to venous thromboembolism and infections, “thromboprophylaxis should be considered for CS patients with severe hypercortisolism and/or postoperatively, based on individual risk factors of thromboembolism and bleeding.”

Recently, Dr. Fleseriu’s group showed in a single retrospective study that the risk for arterial and venous thromboembolic events among patients with CS was approximately 20%. Many patients experienced more than one event. Risk was higher 30 to 60 days postoperatively.

The odds ratio of venous thromoboembolism among patients with CS was 18 times higher than in the normal population.

“Due to the additional thrombotic risk of surgery or any invasive procedure, anticoagulation prophylaxis should be at least considered in all patients with Cushing’s syndrome and balanced with individual bleeding risk,” Dr. Fleseriu advised.

A recent Pituitary Society workshop discussed the management of complications of CS at length; proceedings will be published soon, she noted.

Dr. Limumpornpetch commented, “We look forward to the day when our interdisciplinary approach to managing these challenging patients can deliver outcomes similar to the background population.”

Dr. Limumpornpetch has disclosed no relevant financial relationships. Dr. Fleseriu has been a scientific consultant to Recordati, Sparrow, and Strongbridge and has received grants (inst) from Novartis and Strongbridge.

A version of this article first appeared on Medscape.com.

Excess mortality among people with endogenous Cushing’s syndrome (CS) has declined in the past 20 years yet remains three times higher than in the general population, new research finds.

Among more than 90,000 individuals with endogenous CS, the overall proportion of mortality – defined as the ratio of the number of deaths from CS divided by the total number of CS patients – was 0.05, and the standardized mortality rate was an “unacceptable” three times that of the general population, Padiporn Limumpornpetch, MD, reported on March 20 at ENDO 2021: The Endocrine Society Annual Meeting.

Excess deaths were higher among those with adrenal CS, compared with those with Cushing’s disease. The most common causes of death among those with CS were cardiovascular diseases, cerebrovascular accident, infection, and malignancy, noted Dr. Limumpornpetch, of Songkla University, Hat Yai, Thailand, who is also a PhD student at the University of Leeds, United Kingdom.

“While mortality has improved since 2000, it is still significantly compromised compared to the background population ... The causes of death highlight the need for aggressive management of cardiovascular risk, prevention of thromboembolism, infection control, and a normalized cortisol level,” she said.

Asked to comment, Maria Fleseriu, MD, told this news organization that the new data show “we are making improvements in the care of patients with CS and thus outcomes, but we are not there yet ... This meta-analysis highlights the whole spectrum of acute and life-threatening complications in CS and their high prevalence, even before disease diagnosis and after successful surgery.”

She noted that although she wasn’t surprised by the overall results, “the improvement over time was indeed lower than I expected. However, interestingly here, the risk of mortality in adrenal Cushing’s was unexpectedly high despite patients with adrenal cancer being excluded.”

Dr. Fleseriu, who is director of the Pituitary Center at Oregon Health and Science University, Portland, advised, “Management of hyperglycemia and diabetes, hypertension, hypokalemia, hyperlipidemia, and other cardiovascular risk factors is generally undertaken in accordance with standard of clinical care.”

“But we should focus more on optimizing more aggressively this care in addition to the specific Cushing’s treatment,” she stressed.

In addition, she noted, “Medical therapy for CS may be needed even prior to surgery in severe and/or prolonged hypercortisolism to decrease complications ... We definitely need a multidisciplinary approach to address complications and etiologic treatment as well as the reduced long-term quality of life in patients with CS.”

Largest study in scale and scope of Cushing’s syndrome mortality

Endogenous Cushing’s syndrome occurs when the body overproduces cortisol. The most common cause of the latter is a tumor of the pituitary gland (Cushing’s disease), but another cause is a usually benign tumor of the adrenal glands (adrenal Cushing’s syndrome). Surgery is the mainstay of initial treatment of Cushing’s syndrome. If an operation to remove the tumor fails to cause remission, medications are available.

Prior to this new meta-analysis, there had been limited data on mortality among patients with endogenous CS. Research has mostly been limited to single-cohort studies. A previous systematic review/meta-analysis comprised only seven articles with 780 patients. All the studies were conducted prior to 2012, and most were limited to Cushing’s disease.

“In 2021, we lacked a detailed understanding of patient outcomes and mortality because of the rarity of Cushing’s syndrome,” Dr. Limumpornpetch noted.

The current meta-analysis included 91 articles that reported mortality among patients with endogenous CS. There was a total of 19,181 patients from 92 study cohorts, including 49 studies on CD (n = 14,971), 24 studies on adrenal CS (n = 2304), and 19 studies that included both (n = 1906).

Among 21 studies that reported standardized mortality rate (SMR) data, including 13 CD studies (n = 2160) and seven on adrenal CS (n = 1531), the overall increase in mortality compared to the background population was a significant 3.00 (range, 1.15-7.84).

This SMR was higher among patients with adrenal Cushing’s syndrome (3.3) versus Cushing’s disease (2.8) (P = .003) and among patients who had active disease (5.7) versus those whose disease was in remission (2.3) (P < .001).

The SMR was also worse among patients with Cushing’s disease with larger tumors (macroadenomas), at 7.4, than among patients with very small tumors (microadenomas), at 1.9 (P = .004).

The proportion of death was 0.05 for CS overall, with 0.04 for CD and 0.02 for adrenal adenomas.

Compared to studies published prior to the year 2000, more recent studies seem to reflect advances in treatment and care. The overall proportion of death for all CS cohorts dropped from 0.10 to 0.03 (P < .001); for all CD cohorts, it dropped from 0.14 to 0.03; and for adrenal CS cohorts, it dropped from 0.09 to 0.03 (P = .04).

Causes of death were cardiovascular diseases (29.5% of cases), cerebrovascular accident (11.5%), infection (10.5%), and malignancy (10.1%). Less common causes of death were gastrointestinal bleeding and acute pancreatitis (3.7%), active CS (3.5%), adrenal insufficiency (2.5%), suicide (2.5%), and surgery (1.6%).

Overall, in the CS groups, the proportion of deaths within 30 days of surgery dropped from 0.04 prior to 2000 to 0.01 since (P = .07). For CD, the proportion dropped from 0.02 to 0.01 (P = .25).

Preventing perioperative mortality: Consider thromboprophylaxis

Dr. Fleseriu told this news organization that she believes hypercoagulability is “the least recognized complication with a big role in mortality.” Because most of the perioperative mortality is due to venous thromboembolism and infections, “thromboprophylaxis should be considered for CS patients with severe hypercortisolism and/or postoperatively, based on individual risk factors of thromboembolism and bleeding.”

Recently, Dr. Fleseriu’s group showed in a single retrospective study that the risk for arterial and venous thromboembolic events among patients with CS was approximately 20%. Many patients experienced more than one event. Risk was higher 30 to 60 days postoperatively.

The odds ratio of venous thromoboembolism among patients with CS was 18 times higher than in the normal population.

“Due to the additional thrombotic risk of surgery or any invasive procedure, anticoagulation prophylaxis should be at least considered in all patients with Cushing’s syndrome and balanced with individual bleeding risk,” Dr. Fleseriu advised.

A recent Pituitary Society workshop discussed the management of complications of CS at length; proceedings will be published soon, she noted.

Dr. Limumpornpetch commented, “We look forward to the day when our interdisciplinary approach to managing these challenging patients can deliver outcomes similar to the background population.”

Dr. Limumpornpetch has disclosed no relevant financial relationships. Dr. Fleseriu has been a scientific consultant to Recordati, Sparrow, and Strongbridge and has received grants (inst) from Novartis and Strongbridge.

A version of this article first appeared on Medscape.com.

Metyrapone, an inhibitor of endogenous adrenal corticosteroid synthesis currently used in U.S. practice to test adrenocorticotropic hormone (ACTH) function, was safe and effective for treating endogenous Cushing’s syndrome in a multicenter, open-label, single-arm study of 50 patients, the first prospective test of metyrapone (Metopirone) as a therapeutic agent.

Treatment with metyrapone for 12 weeks normalized mean levels of urinary free cortisol (UFC) in 23 of the 49 patients (47%) in the efficacy analysis, and cut pretreatment mean UFC levels by at least 50% in another 16 patients (33%). Treatment also improved clinical signs of hypercortisolism, associated comorbidities, and quality of life, and was well tolerated, Lynnette K. Nieman, MD, said at the annual meeting of the Endocrine Society.

“This prospective study confirms that metyrapone is effective, has a rapid onset of action, and is a safe medical treatment for endogenous Cushing’s syndrome,” declared Dr. Nieman, chief of the endocrinology consultation service of the National Institutes of Health Clinical Center in Bethesda, Md.

The study included a 24-week extension phase of continued metyrapone treatment in patients whose mean UFC level fell to less than two times the upper limit of normal (ULN), but Dr. Nieman did not report results from this extension.
 

Confirmation of off-label and European experience

“This was the first prospective study of metyrapone, albeit a small study and with only short-term data presented. It confirms what we have known from its off label use in the U.S. and retrospective studies in the U.K. and Europe: Metyrapone normalizes mean UFC in approximately half of patients. Probably with more aggressive up titration efficacy will have been even higher, but of course with the trade-off of adrenal insufficiency,” said Maria Fleseriu, MD, professor and director of the pituitary center at Oregon Health & Science University in Portland, who was not involved with the study.

Fleseriu_Maria_OR_web.jpg

“Longer-term data from this prospective study is clearly needed to evaluate for possible loss of response, as well as adverse events related to precursors accumulation. We also need data on tumor size with long-term use in patients with Cushing’s disease, “Dr. Fleseriu added in an interview.

“Metyrapone, an 11-hydroxylase inhibitor, is not [Food and Drug Administration–approved for therapy] and thus it will be hard for it to become a first-line medical therapy,” she continued. “Furthermore, multiple times a day administration is not ideal for most patients; however if metyrapone is readily available and cheaper than other drugs, its use might increase over time. Hirsutism in women (though not all women develop this) and hypertension could be issues with long-term use,” she cautioned.

“We have used metyrapone off label for many years. It has a rapid onset of action, and we also have experience using it in combination therapy with ketoconazole, especially in patients with severe Cushing’s, although ketoconazole is not [FDA] approved for Cushing’s syndrome, and all combination therapies are off-label, too,” Dr. Fleseriu noted.

Metyrapone is approved by the European Medicines Agency for treating Cushing’s syndrome based “on observational, retrospective studies published over more than 50 years,” according to Dr. Nieman. The drug has FDA approval only for diagnostic purposes.

The PROMPT (Effects of Metyrapone in Patients With Endogenous Cushing’s Syndrome) study enrolled patients in eight European countries who were newly diagnosed with endogenous Cushing’s syndrome of any etiology. The study excluded patients with an advanced adrenal carcinoma, as well as patients with recurrent or persistent Cushing’s disease following transsphenoidal surgery. Patients also needed three 24-hour measures of UFC that were at least 50% above the ULN (165 nmol/24 hours).

[embed:render:related:node:218609]

The average age of the patients was 46 years; 69% were women, 90% had Cushing’s disease, and 8% had ectopic ACTH secretion. The average time from initial symptom onset was 4 years. Sixty-one percent had a history of pituitary surgery, 69% were hypertensive, 43% had diabetes or glucose intolerance, and 41% had osteoporosis. The median mean UFC at entry was 570 nmol/24 hours, which is 3.5 times the ULN, and ranged from 291 to 8,476 nmol/24 hours.

Patients began on a metyrapone dosage of 750 mg/day unless their mean UFC exceeded 5 times the ULN, in which case the dosage doubled to 1,500 mg/day. During the 12-week period, clinicians up- or down-titrated the dosage to ideally achieve a UFC less than the ULN while maintaining serum cortisol levels of 7-12 mcg/dL to preclude adrenal insufficiency effects. The median dosage at the end of 12 weeks was 1,500 mg/day, and ranged from 250 to 5,500 mg/day. One of the 50 patients dropped out because of an unrelated acute medical condition, and two patients underwent pituitary surgery despite a response to metyrapone and were included in the efficacy analysis.

After the first week on treatment, patients had a median 49% cut from their baseline UFC level, and after 12 weeks this rose to a median 74% cut from baseline. The study’s primary endpoint was normalization of UFC after 12 weeks, which occurred in 47% of patients, while 22% had a normal level in a late-night salivary cortisol measurement.

Two-thirds of patients had an improvement or resolution of their signs and symptoms, on average quality of life scores improved, median systolic and diastolic blood pressures decreased by 4-5 mm Hg, and average A1c levels were stable, but the mean cholesterol level decreased significantly, and testosterone levels rose significantly in women.

Proper dose titration makes a difference

Adverse events occurred in 26 of the 50 patients (52%) who received any treatment; 1 patient had a serious adverse event, 7 patients required a dosage adjustment because of adverse events, and 6 patients stopped treatment. The most common adverse events were gastrointestinal – nausea in 24% and decreased appetite in 18% – as well as mild symptoms consistent with adrenal insufficiency such as fatigue and headache. Six patients (12%) were identified with reversible adrenal insufficiency, and no patients complained of worsening acne or hirsutism.

“I think the adverse events are a function of [less than optimal] dose titration and variability in UFC levels,” said Dr. Nieman.

This test of metyrapone’s efficacy comes a year after the FDA approved osilodrostat (Isturisa) for treating Cushing’s disease (but not Cushing’s syndrome). Like metyrapone, osilodrostat controls cortisol overproduction by blocking the enzyme 11-beta-hydroxylase and preventing cortisol synthesis, and osilodrostat was the first agent with these properties to receive an FDA label for therapy.

Osilodrostat “is the only adrenal steroidogenesis inhibitor assessed in randomized controlled long-term trials – over 200 patients with Cushing’s disease – and it has been shown to be highly effective at maintaining normal urinary free cortisol in large majority of patients with Cushing’s disease, as well as Cushing’s syndrome in a study in Japan. Adrenal insufficiency was high [with osilodrostat], especially with the high dose in the trial with forced uptitration. In my clinical practice I have noticed less adrenal insufficiency, but I use much slower drug titration,” said Dr. Fleseriu.

“I think these drugs [metyrapone and osilodrostat] are relatively equivalent,” Dr. Nieman said during discussion of her report. “One nonmedical judgment will be cost,” she added. “Everyone is looking forward to what the pricing structure will be for the new drugs.”

Dr. Fleseriu noted that “for most patients, surgery is first-line therapy, and rarely medication is an alternative first option, especially for Cushing’s disease. However, medical therapy is essential in the management of patients with Cushing’s syndrome when curative surgery fails, surgery is not feasible, when a patient is awaiting radiation’s effect, and for recurrent cases of Cushing’s syndrome.”

PROMPT was sponsored by HRA Pharma, the company that markets metyrapone. Dr. Nieman had no disclosures, but several of her associates on the study are HRA employees. Dr. Fleseriu has been a consultant to Novartis, Recordati, Sparrow, and Strongbridge.

mzoler@mdedge.com

Metyrapone, an inhibitor of endogenous adrenal corticosteroid synthesis currently used in U.S. practice to test adrenocorticotropic hormone (ACTH) function, was safe and effective for treating endogenous Cushing’s syndrome in a multicenter, open-label, single-arm study of 50 patients, the first prospective test of metyrapone (Metopirone) as a therapeutic agent.

Treatment with metyrapone for 12 weeks normalized mean levels of urinary free cortisol (UFC) in 23 of the 49 patients (47%) in the efficacy analysis, and cut pretreatment mean UFC levels by at least 50% in another 16 patients (33%). Treatment also improved clinical signs of hypercortisolism, associated comorbidities, and quality of life, and was well tolerated, Lynnette K. Nieman, MD, said at the annual meeting of the Endocrine Society.

“This prospective study confirms that metyrapone is effective, has a rapid onset of action, and is a safe medical treatment for endogenous Cushing’s syndrome,” declared Dr. Nieman, chief of the endocrinology consultation service of the National Institutes of Health Clinical Center in Bethesda, Md.

The study included a 24-week extension phase of continued metyrapone treatment in patients whose mean UFC level fell to less than two times the upper limit of normal (ULN), but Dr. Nieman did not report results from this extension.
 

Confirmation of off-label and European experience

“This was the first prospective study of metyrapone, albeit a small study and with only short-term data presented. It confirms what we have known from its off label use in the U.S. and retrospective studies in the U.K. and Europe: Metyrapone normalizes mean UFC in approximately half of patients. Probably with more aggressive up titration efficacy will have been even higher, but of course with the trade-off of adrenal insufficiency,” said Maria Fleseriu, MD, professor and director of the pituitary center at Oregon Health & Science University in Portland, who was not involved with the study.

Fleseriu_Maria_OR_web.jpg

“Longer-term data from this prospective study is clearly needed to evaluate for possible loss of response, as well as adverse events related to precursors accumulation. We also need data on tumor size with long-term use in patients with Cushing’s disease, “Dr. Fleseriu added in an interview.

“Metyrapone, an 11-hydroxylase inhibitor, is not [Food and Drug Administration–approved for therapy] and thus it will be hard for it to become a first-line medical therapy,” she continued. “Furthermore, multiple times a day administration is not ideal for most patients; however if metyrapone is readily available and cheaper than other drugs, its use might increase over time. Hirsutism in women (though not all women develop this) and hypertension could be issues with long-term use,” she cautioned.

“We have used metyrapone off label for many years. It has a rapid onset of action, and we also have experience using it in combination therapy with ketoconazole, especially in patients with severe Cushing’s, although ketoconazole is not [FDA] approved for Cushing’s syndrome, and all combination therapies are off-label, too,” Dr. Fleseriu noted.

Metyrapone is approved by the European Medicines Agency for treating Cushing’s syndrome based “on observational, retrospective studies published over more than 50 years,” according to Dr. Nieman. The drug has FDA approval only for diagnostic purposes.

The PROMPT (Effects of Metyrapone in Patients With Endogenous Cushing’s Syndrome) study enrolled patients in eight European countries who were newly diagnosed with endogenous Cushing’s syndrome of any etiology. The study excluded patients with an advanced adrenal carcinoma, as well as patients with recurrent or persistent Cushing’s disease following transsphenoidal surgery. Patients also needed three 24-hour measures of UFC that were at least 50% above the ULN (165 nmol/24 hours).

[embed:render:related:node:218609]

The average age of the patients was 46 years; 69% were women, 90% had Cushing’s disease, and 8% had ectopic ACTH secretion. The average time from initial symptom onset was 4 years. Sixty-one percent had a history of pituitary surgery, 69% were hypertensive, 43% had diabetes or glucose intolerance, and 41% had osteoporosis. The median mean UFC at entry was 570 nmol/24 hours, which is 3.5 times the ULN, and ranged from 291 to 8,476 nmol/24 hours.

Patients began on a metyrapone dosage of 750 mg/day unless their mean UFC exceeded 5 times the ULN, in which case the dosage doubled to 1,500 mg/day. During the 12-week period, clinicians up- or down-titrated the dosage to ideally achieve a UFC less than the ULN while maintaining serum cortisol levels of 7-12 mcg/dL to preclude adrenal insufficiency effects. The median dosage at the end of 12 weeks was 1,500 mg/day, and ranged from 250 to 5,500 mg/day. One of the 50 patients dropped out because of an unrelated acute medical condition, and two patients underwent pituitary surgery despite a response to metyrapone and were included in the efficacy analysis.

After the first week on treatment, patients had a median 49% cut from their baseline UFC level, and after 12 weeks this rose to a median 74% cut from baseline. The study’s primary endpoint was normalization of UFC after 12 weeks, which occurred in 47% of patients, while 22% had a normal level in a late-night salivary cortisol measurement.

Two-thirds of patients had an improvement or resolution of their signs and symptoms, on average quality of life scores improved, median systolic and diastolic blood pressures decreased by 4-5 mm Hg, and average A1c levels were stable, but the mean cholesterol level decreased significantly, and testosterone levels rose significantly in women.

Proper dose titration makes a difference

Adverse events occurred in 26 of the 50 patients (52%) who received any treatment; 1 patient had a serious adverse event, 7 patients required a dosage adjustment because of adverse events, and 6 patients stopped treatment. The most common adverse events were gastrointestinal – nausea in 24% and decreased appetite in 18% – as well as mild symptoms consistent with adrenal insufficiency such as fatigue and headache. Six patients (12%) were identified with reversible adrenal insufficiency, and no patients complained of worsening acne or hirsutism.

“I think the adverse events are a function of [less than optimal] dose titration and variability in UFC levels,” said Dr. Nieman.

This test of metyrapone’s efficacy comes a year after the FDA approved osilodrostat (Isturisa) for treating Cushing’s disease (but not Cushing’s syndrome). Like metyrapone, osilodrostat controls cortisol overproduction by blocking the enzyme 11-beta-hydroxylase and preventing cortisol synthesis, and osilodrostat was the first agent with these properties to receive an FDA label for therapy.

Osilodrostat “is the only adrenal steroidogenesis inhibitor assessed in randomized controlled long-term trials – over 200 patients with Cushing’s disease – and it has been shown to be highly effective at maintaining normal urinary free cortisol in large majority of patients with Cushing’s disease, as well as Cushing’s syndrome in a study in Japan. Adrenal insufficiency was high [with osilodrostat], especially with the high dose in the trial with forced uptitration. In my clinical practice I have noticed less adrenal insufficiency, but I use much slower drug titration,” said Dr. Fleseriu.

“I think these drugs [metyrapone and osilodrostat] are relatively equivalent,” Dr. Nieman said during discussion of her report. “One nonmedical judgment will be cost,” she added. “Everyone is looking forward to what the pricing structure will be for the new drugs.”

Dr. Fleseriu noted that “for most patients, surgery is first-line therapy, and rarely medication is an alternative first option, especially for Cushing’s disease. However, medical therapy is essential in the management of patients with Cushing’s syndrome when curative surgery fails, surgery is not feasible, when a patient is awaiting radiation’s effect, and for recurrent cases of Cushing’s syndrome.”

PROMPT was sponsored by HRA Pharma, the company that markets metyrapone. Dr. Nieman had no disclosures, but several of her associates on the study are HRA employees. Dr. Fleseriu has been a consultant to Novartis, Recordati, Sparrow, and Strongbridge.

mzoler@mdedge.com

Metyrapone, an inhibitor of endogenous adrenal corticosteroid synthesis currently used in U.S. practice to test adrenocorticotropic hormone (ACTH) function, was safe and effective for treating endogenous Cushing’s syndrome in a multicenter, open-label, single-arm study of 50 patients, the first prospective test of metyrapone (Metopirone) as a therapeutic agent.

Treatment with metyrapone for 12 weeks normalized mean levels of urinary free cortisol (UFC) in 23 of the 49 patients (47%) in the efficacy analysis, and cut pretreatment mean UFC levels by at least 50% in another 16 patients (33%). Treatment also improved clinical signs of hypercortisolism, associated comorbidities, and quality of life, and was well tolerated, Lynnette K. Nieman, MD, said at the annual meeting of the Endocrine Society.

“This prospective study confirms that metyrapone is effective, has a rapid onset of action, and is a safe medical treatment for endogenous Cushing’s syndrome,” declared Dr. Nieman, chief of the endocrinology consultation service of the National Institutes of Health Clinical Center in Bethesda, Md.

The study included a 24-week extension phase of continued metyrapone treatment in patients whose mean UFC level fell to less than two times the upper limit of normal (ULN), but Dr. Nieman did not report results from this extension.
 

Confirmation of off-label and European experience

“This was the first prospective study of metyrapone, albeit a small study and with only short-term data presented. It confirms what we have known from its off label use in the U.S. and retrospective studies in the U.K. and Europe: Metyrapone normalizes mean UFC in approximately half of patients. Probably with more aggressive up titration efficacy will have been even higher, but of course with the trade-off of adrenal insufficiency,” said Maria Fleseriu, MD, professor and director of the pituitary center at Oregon Health & Science University in Portland, who was not involved with the study.

Fleseriu_Maria_OR_web.jpg

“Longer-term data from this prospective study is clearly needed to evaluate for possible loss of response, as well as adverse events related to precursors accumulation. We also need data on tumor size with long-term use in patients with Cushing’s disease, “Dr. Fleseriu added in an interview.

“Metyrapone, an 11-hydroxylase inhibitor, is not [Food and Drug Administration–approved for therapy] and thus it will be hard for it to become a first-line medical therapy,” she continued. “Furthermore, multiple times a day administration is not ideal for most patients; however if metyrapone is readily available and cheaper than other drugs, its use might increase over time. Hirsutism in women (though not all women develop this) and hypertension could be issues with long-term use,” she cautioned.

“We have used metyrapone off label for many years. It has a rapid onset of action, and we also have experience using it in combination therapy with ketoconazole, especially in patients with severe Cushing’s, although ketoconazole is not [FDA] approved for Cushing’s syndrome, and all combination therapies are off-label, too,” Dr. Fleseriu noted.

Metyrapone is approved by the European Medicines Agency for treating Cushing’s syndrome based “on observational, retrospective studies published over more than 50 years,” according to Dr. Nieman. The drug has FDA approval only for diagnostic purposes.

The PROMPT (Effects of Metyrapone in Patients With Endogenous Cushing’s Syndrome) study enrolled patients in eight European countries who were newly diagnosed with endogenous Cushing’s syndrome of any etiology. The study excluded patients with an advanced adrenal carcinoma, as well as patients with recurrent or persistent Cushing’s disease following transsphenoidal surgery. Patients also needed three 24-hour measures of UFC that were at least 50% above the ULN (165 nmol/24 hours).

[embed:render:related:node:218609]

The average age of the patients was 46 years; 69% were women, 90% had Cushing’s disease, and 8% had ectopic ACTH secretion. The average time from initial symptom onset was 4 years. Sixty-one percent had a history of pituitary surgery, 69% were hypertensive, 43% had diabetes or glucose intolerance, and 41% had osteoporosis. The median mean UFC at entry was 570 nmol/24 hours, which is 3.5 times the ULN, and ranged from 291 to 8,476 nmol/24 hours.

Patients began on a metyrapone dosage of 750 mg/day unless their mean UFC exceeded 5 times the ULN, in which case the dosage doubled to 1,500 mg/day. During the 12-week period, clinicians up- or down-titrated the dosage to ideally achieve a UFC less than the ULN while maintaining serum cortisol levels of 7-12 mcg/dL to preclude adrenal insufficiency effects. The median dosage at the end of 12 weeks was 1,500 mg/day, and ranged from 250 to 5,500 mg/day. One of the 50 patients dropped out because of an unrelated acute medical condition, and two patients underwent pituitary surgery despite a response to metyrapone and were included in the efficacy analysis.

After the first week on treatment, patients had a median 49% cut from their baseline UFC level, and after 12 weeks this rose to a median 74% cut from baseline. The study’s primary endpoint was normalization of UFC after 12 weeks, which occurred in 47% of patients, while 22% had a normal level in a late-night salivary cortisol measurement.

Two-thirds of patients had an improvement or resolution of their signs and symptoms, on average quality of life scores improved, median systolic and diastolic blood pressures decreased by 4-5 mm Hg, and average A1c levels were stable, but the mean cholesterol level decreased significantly, and testosterone levels rose significantly in women.

Proper dose titration makes a difference

Adverse events occurred in 26 of the 50 patients (52%) who received any treatment; 1 patient had a serious adverse event, 7 patients required a dosage adjustment because of adverse events, and 6 patients stopped treatment. The most common adverse events were gastrointestinal – nausea in 24% and decreased appetite in 18% – as well as mild symptoms consistent with adrenal insufficiency such as fatigue and headache. Six patients (12%) were identified with reversible adrenal insufficiency, and no patients complained of worsening acne or hirsutism.

“I think the adverse events are a function of [less than optimal] dose titration and variability in UFC levels,” said Dr. Nieman.

This test of metyrapone’s efficacy comes a year after the FDA approved osilodrostat (Isturisa) for treating Cushing’s disease (but not Cushing’s syndrome). Like metyrapone, osilodrostat controls cortisol overproduction by blocking the enzyme 11-beta-hydroxylase and preventing cortisol synthesis, and osilodrostat was the first agent with these properties to receive an FDA label for therapy.

Osilodrostat “is the only adrenal steroidogenesis inhibitor assessed in randomized controlled long-term trials – over 200 patients with Cushing’s disease – and it has been shown to be highly effective at maintaining normal urinary free cortisol in large majority of patients with Cushing’s disease, as well as Cushing’s syndrome in a study in Japan. Adrenal insufficiency was high [with osilodrostat], especially with the high dose in the trial with forced uptitration. In my clinical practice I have noticed less adrenal insufficiency, but I use much slower drug titration,” said Dr. Fleseriu.

“I think these drugs [metyrapone and osilodrostat] are relatively equivalent,” Dr. Nieman said during discussion of her report. “One nonmedical judgment will be cost,” she added. “Everyone is looking forward to what the pricing structure will be for the new drugs.”

Dr. Fleseriu noted that “for most patients, surgery is first-line therapy, and rarely medication is an alternative first option, especially for Cushing’s disease. However, medical therapy is essential in the management of patients with Cushing’s syndrome when curative surgery fails, surgery is not feasible, when a patient is awaiting radiation’s effect, and for recurrent cases of Cushing’s syndrome.”

PROMPT was sponsored by HRA Pharma, the company that markets metyrapone. Dr. Nieman had no disclosures, but several of her associates on the study are HRA employees. Dr. Fleseriu has been a consultant to Novartis, Recordati, Sparrow, and Strongbridge.

mzoler@mdedge.com

Many types of plastics pose an unrecognized threat to human health by leaching endocrine-disrupting chemicals, and a new report from the Endocrine Society and the International Pollutants Elimination Network presents their dangers and risks.

Plastic_waste_web.jpg

Written in a consumer-friendly form designed to guide public interest groups and policy makers, the report also can be used by clinicians to inform discussions with patients about the potential dangers of plastics and how they can reduce their exposure to endocrine-disrupting chemicals.

The report, Plastics, EDCs, & Health, defines endocrine-disrupting chemicals (EDCs) as “an exogenous chemical, or mixture of chemicals, that interferes with any aspect of hormone action.” Hormones in the body must be released at specific times, and therefore interference with their normal activity can have profound effects on health in areas including growth and reproductive development, according to the report.

The available data show “more and more information about the different chemicals and the different effects they are having,” said lead author, Jodi Flaws, PhD, of the University of Illinois at Urbana-Champaign, in a virtual press conference accompanying the release of the report.

Although numerous EDCs have been identified, a recent study suggested that many potentially dangerous chemical additives remain unknown because they are identified as confidential or simply not well described, the report authors said. In addition, creation of more plastic products will likely lead to increased exposure to EDCs and make health problems worse, said report coauthor Pauliina Damdimopoulou, PhD, of the Karolinska Institutet in Stockholm.
 

Lesser-known EDCs populate consumer products

Most consumers are aware of bisphenol A and phthalates as known EDCs, said Dr. Flaws, but the report identifies other lesser-known EDCs including per- and polyfluoroalkyl substances (PFAS), dioxins, flame retardants, and UV stabilizers.

For example, PFAS have been used for decades in a range of consumer products including stain resistant clothes, fast food wrappers, carpet and furniture treatments, cookware, and firefighting foams, according to the report. Consequently, PFAS have become common in many water sources including surface water, drinking water, and ground water because of how they are disposed. “Consumption of fish and other aquatic creatures caught in waterways contaminated with PFAS also poses heightened risks due to bioaccumulation of persistent chemicals in these animals,” the report authors noted. Human exposures to PFAS have been documented in urine, serum, plasma, placenta, umbilical cord, breast milk, and fetal tissues, they added.

Brominated flame retardants are another lesser-known EDC highlighted in the report. These chemical additives are used in plastics such as electronics cases to reduce the spread of fire, as well as in furniture foam and other building materials, the authors wrote. UV stabilizers, which also have been linked to health problems, often are used in manufacturing cars and other machinery.

Microplastics create large risk

Microplastics, defined as plastic particles less than 5 mm in diameter, are another source of exposure to EDCs that is not well publicized, according to the report. Plastic waste disposal often leads to the release of microplastics, which can infiltrate soil and water. Plastic waste is often dumped or burned; outdoor burning of plastic causes emission of dioxins into the air and ground.

“Not only do microplastics contain endogenous chemical additives, which are not bound to the microplastic and can leach out of the microplastic and expose the population, they can also bind and accumulate toxic chemicals from the surrounding environment such as sea water and sediment,” the report authors said.

Recycling is not an easy answer, either. Often more chemicals are created and released during the process of using plastics to make other plastics, according to the report.

Overall, more awareness of the potential for increased exposure to EDCs and support of strategies to seek out alternatives to hazardous chemicals is needed at the global level, the authors wrote. For example, the European Union has proposed a chemicals strategy that includes improved classification of EDCs and banning identified EDCs in consumer products.

New data support ongoing dangers

“It was important to produce the report at this time because several new studies came out on the effects of EDCs from plastics on human health,” Dr. Flaws said in an interview. “Further, there was not previously a single source that brought together all the information in a manner that was targeted towards the public, policy makers, and others,” she said.

Dr. Flaws said that what has surprised her most in the recent research is the fact that plastics contain such a range of chemicals and EDCs.

“A good take-home message [from the report] is that plastics can contain endocrine-disrupting chemicals that can interfere with normal hormones and lead to adverse health outcomes,” she said. “I suggest limiting the use of plastics as much as possible. I know this is very hard to do, so if someone needs to use plastic, they should not heat food or drink in plastic containers,” she emphasized. Individuals also can limit reuse of plastics over and over,” she said. “Heating and repeated use/washing often causes plastics to leach EDCs into food and drink that we then get into our bodies.”

Additional research is needed to understand the mechanisms by which EDCs from plastics cause damage, Dr. Flaws emphasized. “Given that it is not possible to eliminate plastics at this time, if we understood mechanisms of action, we could develop ways to prevent toxicity or treat EDC-induced adverse health outcomes,” she said. “We also need research designed to develop plastics or ‘green materials’ that do not contain endocrine disruptors and do not cause health problems or damage the environment,” she noted.

The report was produced as a joint effort of the Endocrine Society and International Pollutants Elimination Network. The report authors had no financial conflicts to disclose.

Many types of plastics pose an unrecognized threat to human health by leaching endocrine-disrupting chemicals, and a new report from the Endocrine Society and the International Pollutants Elimination Network presents their dangers and risks.

Plastic_waste_web.jpg

Written in a consumer-friendly form designed to guide public interest groups and policy makers, the report also can be used by clinicians to inform discussions with patients about the potential dangers of plastics and how they can reduce their exposure to endocrine-disrupting chemicals.

The report, Plastics, EDCs, & Health, defines endocrine-disrupting chemicals (EDCs) as “an exogenous chemical, or mixture of chemicals, that interferes with any aspect of hormone action.” Hormones in the body must be released at specific times, and therefore interference with their normal activity can have profound effects on health in areas including growth and reproductive development, according to the report.

The available data show “more and more information about the different chemicals and the different effects they are having,” said lead author, Jodi Flaws, PhD, of the University of Illinois at Urbana-Champaign, in a virtual press conference accompanying the release of the report.

Although numerous EDCs have been identified, a recent study suggested that many potentially dangerous chemical additives remain unknown because they are identified as confidential or simply not well described, the report authors said. In addition, creation of more plastic products will likely lead to increased exposure to EDCs and make health problems worse, said report coauthor Pauliina Damdimopoulou, PhD, of the Karolinska Institutet in Stockholm.
 

Lesser-known EDCs populate consumer products

Most consumers are aware of bisphenol A and phthalates as known EDCs, said Dr. Flaws, but the report identifies other lesser-known EDCs including per- and polyfluoroalkyl substances (PFAS), dioxins, flame retardants, and UV stabilizers.

For example, PFAS have been used for decades in a range of consumer products including stain resistant clothes, fast food wrappers, carpet and furniture treatments, cookware, and firefighting foams, according to the report. Consequently, PFAS have become common in many water sources including surface water, drinking water, and ground water because of how they are disposed. “Consumption of fish and other aquatic creatures caught in waterways contaminated with PFAS also poses heightened risks due to bioaccumulation of persistent chemicals in these animals,” the report authors noted. Human exposures to PFAS have been documented in urine, serum, plasma, placenta, umbilical cord, breast milk, and fetal tissues, they added.

Brominated flame retardants are another lesser-known EDC highlighted in the report. These chemical additives are used in plastics such as electronics cases to reduce the spread of fire, as well as in furniture foam and other building materials, the authors wrote. UV stabilizers, which also have been linked to health problems, often are used in manufacturing cars and other machinery.

Microplastics create large risk

Microplastics, defined as plastic particles less than 5 mm in diameter, are another source of exposure to EDCs that is not well publicized, according to the report. Plastic waste disposal often leads to the release of microplastics, which can infiltrate soil and water. Plastic waste is often dumped or burned; outdoor burning of plastic causes emission of dioxins into the air and ground.

“Not only do microplastics contain endogenous chemical additives, which are not bound to the microplastic and can leach out of the microplastic and expose the population, they can also bind and accumulate toxic chemicals from the surrounding environment such as sea water and sediment,” the report authors said.

Recycling is not an easy answer, either. Often more chemicals are created and released during the process of using plastics to make other plastics, according to the report.

Overall, more awareness of the potential for increased exposure to EDCs and support of strategies to seek out alternatives to hazardous chemicals is needed at the global level, the authors wrote. For example, the European Union has proposed a chemicals strategy that includes improved classification of EDCs and banning identified EDCs in consumer products.

New data support ongoing dangers

“It was important to produce the report at this time because several new studies came out on the effects of EDCs from plastics on human health,” Dr. Flaws said in an interview. “Further, there was not previously a single source that brought together all the information in a manner that was targeted towards the public, policy makers, and others,” she said.

Dr. Flaws said that what has surprised her most in the recent research is the fact that plastics contain such a range of chemicals and EDCs.

“A good take-home message [from the report] is that plastics can contain endocrine-disrupting chemicals that can interfere with normal hormones and lead to adverse health outcomes,” she said. “I suggest limiting the use of plastics as much as possible. I know this is very hard to do, so if someone needs to use plastic, they should not heat food or drink in plastic containers,” she emphasized. Individuals also can limit reuse of plastics over and over,” she said. “Heating and repeated use/washing often causes plastics to leach EDCs into food and drink that we then get into our bodies.”

Additional research is needed to understand the mechanisms by which EDCs from plastics cause damage, Dr. Flaws emphasized. “Given that it is not possible to eliminate plastics at this time, if we understood mechanisms of action, we could develop ways to prevent toxicity or treat EDC-induced adverse health outcomes,” she said. “We also need research designed to develop plastics or ‘green materials’ that do not contain endocrine disruptors and do not cause health problems or damage the environment,” she noted.

The report was produced as a joint effort of the Endocrine Society and International Pollutants Elimination Network. The report authors had no financial conflicts to disclose.

Many types of plastics pose an unrecognized threat to human health by leaching endocrine-disrupting chemicals, and a new report from the Endocrine Society and the International Pollutants Elimination Network presents their dangers and risks.

Plastic_waste_web.jpg

Written in a consumer-friendly form designed to guide public interest groups and policy makers, the report also can be used by clinicians to inform discussions with patients about the potential dangers of plastics and how they can reduce their exposure to endocrine-disrupting chemicals.

The report, Plastics, EDCs, & Health, defines endocrine-disrupting chemicals (EDCs) as “an exogenous chemical, or mixture of chemicals, that interferes with any aspect of hormone action.” Hormones in the body must be released at specific times, and therefore interference with their normal activity can have profound effects on health in areas including growth and reproductive development, according to the report.

The available data show “more and more information about the different chemicals and the different effects they are having,” said lead author, Jodi Flaws, PhD, of the University of Illinois at Urbana-Champaign, in a virtual press conference accompanying the release of the report.

Although numerous EDCs have been identified, a recent study suggested that many potentially dangerous chemical additives remain unknown because they are identified as confidential or simply not well described, the report authors said. In addition, creation of more plastic products will likely lead to increased exposure to EDCs and make health problems worse, said report coauthor Pauliina Damdimopoulou, PhD, of the Karolinska Institutet in Stockholm.
 

Lesser-known EDCs populate consumer products

Most consumers are aware of bisphenol A and phthalates as known EDCs, said Dr. Flaws, but the report identifies other lesser-known EDCs including per- and polyfluoroalkyl substances (PFAS), dioxins, flame retardants, and UV stabilizers.

For example, PFAS have been used for decades in a range of consumer products including stain resistant clothes, fast food wrappers, carpet and furniture treatments, cookware, and firefighting foams, according to the report. Consequently, PFAS have become common in many water sources including surface water, drinking water, and ground water because of how they are disposed. “Consumption of fish and other aquatic creatures caught in waterways contaminated with PFAS also poses heightened risks due to bioaccumulation of persistent chemicals in these animals,” the report authors noted. Human exposures to PFAS have been documented in urine, serum, plasma, placenta, umbilical cord, breast milk, and fetal tissues, they added.

Brominated flame retardants are another lesser-known EDC highlighted in the report. These chemical additives are used in plastics such as electronics cases to reduce the spread of fire, as well as in furniture foam and other building materials, the authors wrote. UV stabilizers, which also have been linked to health problems, often are used in manufacturing cars and other machinery.

Microplastics create large risk

Microplastics, defined as plastic particles less than 5 mm in diameter, are another source of exposure to EDCs that is not well publicized, according to the report. Plastic waste disposal often leads to the release of microplastics, which can infiltrate soil and water. Plastic waste is often dumped or burned; outdoor burning of plastic causes emission of dioxins into the air and ground.

“Not only do microplastics contain endogenous chemical additives, which are not bound to the microplastic and can leach out of the microplastic and expose the population, they can also bind and accumulate toxic chemicals from the surrounding environment such as sea water and sediment,” the report authors said.

Recycling is not an easy answer, either. Often more chemicals are created and released during the process of using plastics to make other plastics, according to the report.

Overall, more awareness of the potential for increased exposure to EDCs and support of strategies to seek out alternatives to hazardous chemicals is needed at the global level, the authors wrote. For example, the European Union has proposed a chemicals strategy that includes improved classification of EDCs and banning identified EDCs in consumer products.

New data support ongoing dangers

“It was important to produce the report at this time because several new studies came out on the effects of EDCs from plastics on human health,” Dr. Flaws said in an interview. “Further, there was not previously a single source that brought together all the information in a manner that was targeted towards the public, policy makers, and others,” she said.

Dr. Flaws said that what has surprised her most in the recent research is the fact that plastics contain such a range of chemicals and EDCs.

“A good take-home message [from the report] is that plastics can contain endocrine-disrupting chemicals that can interfere with normal hormones and lead to adverse health outcomes,” she said. “I suggest limiting the use of plastics as much as possible. I know this is very hard to do, so if someone needs to use plastic, they should not heat food or drink in plastic containers,” she emphasized. Individuals also can limit reuse of plastics over and over,” she said. “Heating and repeated use/washing often causes plastics to leach EDCs into food and drink that we then get into our bodies.”

Additional research is needed to understand the mechanisms by which EDCs from plastics cause damage, Dr. Flaws emphasized. “Given that it is not possible to eliminate plastics at this time, if we understood mechanisms of action, we could develop ways to prevent toxicity or treat EDC-induced adverse health outcomes,” she said. “We also need research designed to develop plastics or ‘green materials’ that do not contain endocrine disruptors and do not cause health problems or damage the environment,” she noted.

The report was produced as a joint effort of the Endocrine Society and International Pollutants Elimination Network. The report authors had no financial conflicts to disclose.

Endocrine diseases of any type – not just diabetes – can represent a cardiovascular risk and patients with those disorders should be screened for high cholesterol, according to a new clinical practice guideline from the Endocrine Society.

“The simple recommendation to check a lipid panel in patients with endocrine diseases and calculate cardiovascular risk may be practice changing because that is not done routinely,” Connie Newman, MD, chair of the Endocrine Society committee that developed the guideline, said in an interview.

“Usually the focus is on assessment and treatment of the endocrine disease, rather than on assessment and treatment of atherosclerotic cardiovascular disease risk,” said Newman, an adjunct professor of medicine in the department of medicine, division of endocrinology, diabetes & metabolism, at New York University.

Whereas diabetes, well-known for its increased cardiovascular risk profile, is commonly addressed in other cardiovascular and cholesterol practice management guidelines, the array of other endocrine diseases are not typically included.

“This guideline is the first of its kind,” Dr. Newman said. “The Endocrine Society has not previously issued a guideline on lipid management in endocrine disorders [and] other organizations have not written guidelines on this topic. 

“Rather, guidelines have been written on cholesterol management, but these do not describe cholesterol management in patients with endocrine diseases such as thyroid disease [hypothyroidism and hyperthyroidism], Cushing’s syndrome, acromegaly, growth hormone deficiency, menopause, male hypogonadism, and obesity,” she noted.

But these conditions carry a host of cardiovascular risk factors that may require careful monitoring and management.

“Although endocrine hormones, such as thyroid hormone, cortisol, estrogen, testosterone, growth hormone, and insulin, affect pathways for lipid metabolism, physicians lack guidance on lipid abnormalities, cardiovascular risk, and treatment to reduce lipids and cardiovascular risk in patients with endocrine diseases,” she explained.

Vinaya Simha, MD, an internal medicine specialist at the Mayo Clinic in Rochester, Minn., agrees that the guideline is notable in addressing an unmet need.

Recommendations that stand out to Dr. Simha include the suggestion of adding eicosapentaenoic acid (EPA) ethyl ester to reduce the risk of cardiovascular disease in adults with diabetes or atherosclerotic cardiovascular disease who have elevated triglyceride levels despite statin treatment.

James L. Rosenzweig, MD, an endocrinologist at Hebrew SeniorLife in Boston, agreed that this is an important addition to an area that needs more guidance.

“Many of these clinical situations can exacerbate dyslipidemia and some also increase the cardiovascular risk to a greater extent in combination with elevated cholesterol and/or triglycerides,” he said in an interview. 

“In many cases, treatment of the underlying disorder appropriately can have an important impact in resolving the lipid disorder. In others, more aggressive pharmacological treatment is indicated,” he said.

“I think that this will be a valuable resource, especially for endocrinologists, but it can be used as well by providers in other disciplines.”
 

Key recommendations for different endocrine conditions

The guideline, published in the Journal of Clinical Endocrinology & Metabolism, details those risks and provides evidence-based recommendations on their management and treatment.

Key recommendations include:

• Obtain a lipid panel and evaluate cardiovascular risk factors in all adults with endocrine disorders.
• In patients with  and risk factors for cardiovascular disease, start statin therapy in addition to lifestyle modification to reduce cardiovascular risk. “This could mean earlier treatment because other guidelines recommend consideration of therapy at age 40,” Dr. Newman said.
• Statin therapy is also recommended for adults over 40 with  with a duration of diabetes of more than 20 years and/or microvascular complications, regardless of their cardiovascular risk score. “This means earlier treatment of patients with type 1 diabetes with statins in order to reduce cardiovascular disease risk,” Dr. Newman noted.
• In patients with hyperlipidemia, rule out  as the cause before treating with lipid-lowering medications. And among patients who are found to have hypothyroidism, reevaluate the lipid profile when the patient has thyroid hormone levels in the normal range.
• Adults with persistent endogenous Cushing’s syndrome should have their lipid profile monitored. Statin therapy should be considered in addition to lifestyle modifications, irrespective of the cardiovascular risk score.
• In postmenopausal women, high cholesterol or triglycerides should be treated with statins rather than hormone therapy.
• Evaluate and treat lipids and other cardiovascular risk factors in women who enter menopause early (before the age of 40-45 years).

Nice summary of ‘risk-enhancing’ endocrine disorders

Dr. Simha said in an interview that the new guideline is “probably the first comprehensive statement addressing lipid treatment in patients with a broad range of endocrine disorders besides diabetes.”

“Most of the treatment recommendations are congruent with other current guidelines such as the American College of Cardiology/American Heart Association [guidelines], but there is specific mention of which endocrine disorders represent enhanced cardiovascular risk,” she explained.

The new recommendations are notable for including “a nice summary of how different endocrine disorders affect lipid values, and also which endocrine disorders need to be considered as ‘risk-enhancing factors,’ ” Dr. Simha noted.

“The use of EPA in patients with hypertriglyceridemia is novel, compared to the ACC/AHA recommendation. This reflects new data which is now available,” she added.

The American Association of Clinical Endocrinologists also just issued a new algorithm on lipid management and prevention of cardiovascular disease in which treatment of hypertriglyceridemia is emphasized.

In addition, the new Endocrine Society guideline “also mentions an LDL [cholesterol] treatment threshold of 70 mg/dL, and 55 mg/dL in some patient categories, which previous guidelines have not,” Dr. Simha noted.

Overall, Dr. Newman added that the goal of the guideline is to increase awareness of key issues with endocrine diseases that may not necessarily be on clinicians’ radars.

“We hope that it will make a lipid panel and cardiovascular risk evaluation routine in adults with endocrine diseases and cause a greater focus on therapies to reduce heart disease and stroke,” she said.

Dr. Newman, Dr. Simha, and Dr. Rosenzweig reported no relevant financial relationships.

A version of this article originally appeared on Medscape.com.

Endocrine diseases of any type – not just diabetes – can represent a cardiovascular risk and patients with those disorders should be screened for high cholesterol, according to a new clinical practice guideline from the Endocrine Society.

“The simple recommendation to check a lipid panel in patients with endocrine diseases and calculate cardiovascular risk may be practice changing because that is not done routinely,” Connie Newman, MD, chair of the Endocrine Society committee that developed the guideline, said in an interview.

“Usually the focus is on assessment and treatment of the endocrine disease, rather than on assessment and treatment of atherosclerotic cardiovascular disease risk,” said Newman, an adjunct professor of medicine in the department of medicine, division of endocrinology, diabetes & metabolism, at New York University.

Whereas diabetes, well-known for its increased cardiovascular risk profile, is commonly addressed in other cardiovascular and cholesterol practice management guidelines, the array of other endocrine diseases are not typically included.

“This guideline is the first of its kind,” Dr. Newman said. “The Endocrine Society has not previously issued a guideline on lipid management in endocrine disorders [and] other organizations have not written guidelines on this topic. 

“Rather, guidelines have been written on cholesterol management, but these do not describe cholesterol management in patients with endocrine diseases such as thyroid disease [hypothyroidism and hyperthyroidism], Cushing’s syndrome, acromegaly, growth hormone deficiency, menopause, male hypogonadism, and obesity,” she noted.

But these conditions carry a host of cardiovascular risk factors that may require careful monitoring and management.

“Although endocrine hormones, such as thyroid hormone, cortisol, estrogen, testosterone, growth hormone, and insulin, affect pathways for lipid metabolism, physicians lack guidance on lipid abnormalities, cardiovascular risk, and treatment to reduce lipids and cardiovascular risk in patients with endocrine diseases,” she explained.

Vinaya Simha, MD, an internal medicine specialist at the Mayo Clinic in Rochester, Minn., agrees that the guideline is notable in addressing an unmet need.

Recommendations that stand out to Dr. Simha include the suggestion of adding eicosapentaenoic acid (EPA) ethyl ester to reduce the risk of cardiovascular disease in adults with diabetes or atherosclerotic cardiovascular disease who have elevated triglyceride levels despite statin treatment.

James L. Rosenzweig, MD, an endocrinologist at Hebrew SeniorLife in Boston, agreed that this is an important addition to an area that needs more guidance.

“Many of these clinical situations can exacerbate dyslipidemia and some also increase the cardiovascular risk to a greater extent in combination with elevated cholesterol and/or triglycerides,” he said in an interview. 

“In many cases, treatment of the underlying disorder appropriately can have an important impact in resolving the lipid disorder. In others, more aggressive pharmacological treatment is indicated,” he said.

“I think that this will be a valuable resource, especially for endocrinologists, but it can be used as well by providers in other disciplines.”
 

Key recommendations for different endocrine conditions

The guideline, published in the Journal of Clinical Endocrinology & Metabolism, details those risks and provides evidence-based recommendations on their management and treatment.

Key recommendations include:

• Obtain a lipid panel and evaluate cardiovascular risk factors in all adults with endocrine disorders.
• In patients with  and risk factors for cardiovascular disease, start statin therapy in addition to lifestyle modification to reduce cardiovascular risk. “This could mean earlier treatment because other guidelines recommend consideration of therapy at age 40,” Dr. Newman said.
• Statin therapy is also recommended for adults over 40 with  with a duration of diabetes of more than 20 years and/or microvascular complications, regardless of their cardiovascular risk score. “This means earlier treatment of patients with type 1 diabetes with statins in order to reduce cardiovascular disease risk,” Dr. Newman noted.
• In patients with hyperlipidemia, rule out  as the cause before treating with lipid-lowering medications. And among patients who are found to have hypothyroidism, reevaluate the lipid profile when the patient has thyroid hormone levels in the normal range.
• Adults with persistent endogenous Cushing’s syndrome should have their lipid profile monitored. Statin therapy should be considered in addition to lifestyle modifications, irrespective of the cardiovascular risk score.
• In postmenopausal women, high cholesterol or triglycerides should be treated with statins rather than hormone therapy.
• Evaluate and treat lipids and other cardiovascular risk factors in women who enter menopause early (before the age of 40-45 years).

Nice summary of ‘risk-enhancing’ endocrine disorders

Dr. Simha said in an interview that the new guideline is “probably the first comprehensive statement addressing lipid treatment in patients with a broad range of endocrine disorders besides diabetes.”

“Most of the treatment recommendations are congruent with other current guidelines such as the American College of Cardiology/American Heart Association [guidelines], but there is specific mention of which endocrine disorders represent enhanced cardiovascular risk,” she explained.

The new recommendations are notable for including “a nice summary of how different endocrine disorders affect lipid values, and also which endocrine disorders need to be considered as ‘risk-enhancing factors,’ ” Dr. Simha noted.

“The use of EPA in patients with hypertriglyceridemia is novel, compared to the ACC/AHA recommendation. This reflects new data which is now available,” she added.

The American Association of Clinical Endocrinologists also just issued a new algorithm on lipid management and prevention of cardiovascular disease in which treatment of hypertriglyceridemia is emphasized.

In addition, the new Endocrine Society guideline “also mentions an LDL [cholesterol] treatment threshold of 70 mg/dL, and 55 mg/dL in some patient categories, which previous guidelines have not,” Dr. Simha noted.

Overall, Dr. Newman added that the goal of the guideline is to increase awareness of key issues with endocrine diseases that may not necessarily be on clinicians’ radars.

“We hope that it will make a lipid panel and cardiovascular risk evaluation routine in adults with endocrine diseases and cause a greater focus on therapies to reduce heart disease and stroke,” she said.

Dr. Newman, Dr. Simha, and Dr. Rosenzweig reported no relevant financial relationships.

A version of this article originally appeared on Medscape.com.

Endocrine diseases of any type – not just diabetes – can represent a cardiovascular risk and patients with those disorders should be screened for high cholesterol, according to a new clinical practice guideline from the Endocrine Society.

“The simple recommendation to check a lipid panel in patients with endocrine diseases and calculate cardiovascular risk may be practice changing because that is not done routinely,” Connie Newman, MD, chair of the Endocrine Society committee that developed the guideline, said in an interview.

“Usually the focus is on assessment and treatment of the endocrine disease, rather than on assessment and treatment of atherosclerotic cardiovascular disease risk,” said Newman, an adjunct professor of medicine in the department of medicine, division of endocrinology, diabetes & metabolism, at New York University.

Whereas diabetes, well-known for its increased cardiovascular risk profile, is commonly addressed in other cardiovascular and cholesterol practice management guidelines, the array of other endocrine diseases are not typically included.

“This guideline is the first of its kind,” Dr. Newman said. “The Endocrine Society has not previously issued a guideline on lipid management in endocrine disorders [and] other organizations have not written guidelines on this topic. 

“Rather, guidelines have been written on cholesterol management, but these do not describe cholesterol management in patients with endocrine diseases such as thyroid disease [hypothyroidism and hyperthyroidism], Cushing’s syndrome, acromegaly, growth hormone deficiency, menopause, male hypogonadism, and obesity,” she noted.

But these conditions carry a host of cardiovascular risk factors that may require careful monitoring and management.

“Although endocrine hormones, such as thyroid hormone, cortisol, estrogen, testosterone, growth hormone, and insulin, affect pathways for lipid metabolism, physicians lack guidance on lipid abnormalities, cardiovascular risk, and treatment to reduce lipids and cardiovascular risk in patients with endocrine diseases,” she explained.

Vinaya Simha, MD, an internal medicine specialist at the Mayo Clinic in Rochester, Minn., agrees that the guideline is notable in addressing an unmet need.

Recommendations that stand out to Dr. Simha include the suggestion of adding eicosapentaenoic acid (EPA) ethyl ester to reduce the risk of cardiovascular disease in adults with diabetes or atherosclerotic cardiovascular disease who have elevated triglyceride levels despite statin treatment.

James L. Rosenzweig, MD, an endocrinologist at Hebrew SeniorLife in Boston, agreed that this is an important addition to an area that needs more guidance.

“Many of these clinical situations can exacerbate dyslipidemia and some also increase the cardiovascular risk to a greater extent in combination with elevated cholesterol and/or triglycerides,” he said in an interview. 

“In many cases, treatment of the underlying disorder appropriately can have an important impact in resolving the lipid disorder. In others, more aggressive pharmacological treatment is indicated,” he said.

“I think that this will be a valuable resource, especially for endocrinologists, but it can be used as well by providers in other disciplines.”
 

Key recommendations for different endocrine conditions

The guideline, published in the Journal of Clinical Endocrinology & Metabolism, details those risks and provides evidence-based recommendations on their management and treatment.

Key recommendations include:

• Obtain a lipid panel and evaluate cardiovascular risk factors in all adults with endocrine disorders.
• In patients with  and risk factors for cardiovascular disease, start statin therapy in addition to lifestyle modification to reduce cardiovascular risk. “This could mean earlier treatment because other guidelines recommend consideration of therapy at age 40,” Dr. Newman said.
• Statin therapy is also recommended for adults over 40 with  with a duration of diabetes of more than 20 years and/or microvascular complications, regardless of their cardiovascular risk score. “This means earlier treatment of patients with type 1 diabetes with statins in order to reduce cardiovascular disease risk,” Dr. Newman noted.
• In patients with hyperlipidemia, rule out  as the cause before treating with lipid-lowering medications. And among patients who are found to have hypothyroidism, reevaluate the lipid profile when the patient has thyroid hormone levels in the normal range.
• Adults with persistent endogenous Cushing’s syndrome should have their lipid profile monitored. Statin therapy should be considered in addition to lifestyle modifications, irrespective of the cardiovascular risk score.
• In postmenopausal women, high cholesterol or triglycerides should be treated with statins rather than hormone therapy.
• Evaluate and treat lipids and other cardiovascular risk factors in women who enter menopause early (before the age of 40-45 years).

Nice summary of ‘risk-enhancing’ endocrine disorders

Dr. Simha said in an interview that the new guideline is “probably the first comprehensive statement addressing lipid treatment in patients with a broad range of endocrine disorders besides diabetes.”

“Most of the treatment recommendations are congruent with other current guidelines such as the American College of Cardiology/American Heart Association [guidelines], but there is specific mention of which endocrine disorders represent enhanced cardiovascular risk,” she explained.

The new recommendations are notable for including “a nice summary of how different endocrine disorders affect lipid values, and also which endocrine disorders need to be considered as ‘risk-enhancing factors,’ ” Dr. Simha noted.

“The use of EPA in patients with hypertriglyceridemia is novel, compared to the ACC/AHA recommendation. This reflects new data which is now available,” she added.

The American Association of Clinical Endocrinologists also just issued a new algorithm on lipid management and prevention of cardiovascular disease in which treatment of hypertriglyceridemia is emphasized.

In addition, the new Endocrine Society guideline “also mentions an LDL [cholesterol] treatment threshold of 70 mg/dL, and 55 mg/dL in some patient categories, which previous guidelines have not,” Dr. Simha noted.

Overall, Dr. Newman added that the goal of the guideline is to increase awareness of key issues with endocrine diseases that may not necessarily be on clinicians’ radars.

“We hope that it will make a lipid panel and cardiovascular risk evaluation routine in adults with endocrine diseases and cause a greater focus on therapies to reduce heart disease and stroke,” she said.

Dr. Newman, Dr. Simha, and Dr. Rosenzweig reported no relevant financial relationships.

A version of this article originally appeared on Medscape.com.

Patients with COVID-19 who have high levels of the steroid hormone cortisol on admission to hospital have a substantially increased risk of dying, U.K. researchers have discovered.

Waljit S. Dhillo, MBBS, PhD, head of the division of diabetes, endocrinology and metabolism at Imperial College London, and colleagues studied 535 patients admitted to major London hospitals. Their article was published online June 18 in Lancet Diabetes & Endocrinology.

“Our analyses show for the first time that patients with COVID-19 mount a marked and appropriate acute cortisol stress response,” said Dr. Dhillo and colleagues.

Moreover, “high cortisol concentrations were associated with increased mortality and a reduced median survival, probably because this is a marker of the severity of illness.”

So measuring cortisol on admission is potentially “another simple marker to use alongside oxygen saturation levels to help us identify which patients need to be admitted immediately, and which may not,” Dr. Dhillo noted in a statement from his institution.

“Having an early indicator of which patients may deteriorate more quickly will help us with providing the best level of care as quickly as possible. In addition, we can also take cortisol levels into account when we are working out how best to treat our patients,” he said.

However, it’s important to note that this means – particularly in the wake of the RECOVERY trial reported last week – that “in the early part of the disease you don’t need steroids,” he said.
 

In contrast to SARS, no adrenal insufficiency with COVID-19

Cortisol levels when healthy and resting are 100-200 nmol/L and nearly zero when sleeping, the researchers explained.

They decided to examine cortisol levels because, although physiological stress from critical illness normally increases levels of the hormone, the prior coronavirus, severe acute respiratory syndrome coronavirus (SARS-CoV), had the opposite effect and induced cortisol insufficiency in some patients.

“We would have said we’re not quite sure” what effect SARS-CoV-2 is having on cortisol levels, “so that’s why we collected the data,” Dr. Dhillo said in an interview.

The researchers studied patients admitted to three large London teaching hospitals between March 9 and April 22 with a clinical suspicion of SARS-CoV-2 infection. All patients had a standard set of blood tests, including full blood count, creatinine, C-reactive protein, D-dimer, and serum cortisol.

[embed:render:related:node:222746]

After exclusions, the team assessed 535 patients admitted over the study period who had baseline cortisol measured within 48 hours of admission.

Of these, 403 patients were diagnosed with COVID-19 based on a positive result on real-time polymerase chain reaction testing (88%) or a strong clinical and radiological suspicion, despite a negative test (12%).

In total, 132 (25%) individuals were not diagnosed with COVID-19.

Patients with COVID-19 were a mean age of 66.3 years, and 59.6% were men.

Mean cortisol concentrations in patients with COVID-19 were significantly higher than those not diagnosed with the virus (619 vs 519 nmol/L; P < .0001).

And by May 8, significantly more patients with COVID-19 died than those without (27.8% vs 6.8%; P < .0001).

Doubling of cortisol levels associated with 40% higher mortality

Multivariate analysis taking into account age, presence of comorbidities, and laboratory tests revealed that a doubling of cortisol concentrations among those with COVID-19 was associated with a significant increase in mortality, at a hazard ratio of 1.42 (P = .014).

And patients with COVID-19 whose baseline cortisol level was >744 nmol/L had a median survival of just 15 days, compared with those with a level ≤744 nmol/L, who had a median survival of 36 days (P < .0001).

The team notes that the cortisol stress responses in their patients with COVID-19 ranged up to 3,241 nmol/L, which is “a marked cortisol stress response, perhaps higher than is observed in patients undergoing major surgery.”

Of interest, there was no interaction between cortisol levels and ethnicity in their study; a subsequent analysis of the data stratified by black, Asian, and other minority ethnicities revealed no significant differences.

The team note that their results will need to be reproduced in other populations.

“Any potential role for cortisol measurement at baseline and later during an inpatient stay with COVID-19 as a prognostic biomarker, either by itself or in combination with other biomarkers, will require validation in a prospective study.”
 

Implications for treatment: Reserve dexamethasone for critically ill

Dr. Dhillo explained that, because their findings indicate that people initially infected with COVID-19 do mount an appropriate stress (cortisol) response, it is important that people properly understand this in the wake of the RECOVERY trial, reported last week.

The trial showed that the widely available steroid dexamethasone significantly reduced mortality among severely ill COVID-19 patients in the intensive care unit when given at a supraphysiologic dose of 6 mg.

But it would be hazardous for anyone to self-medicate with steroids at an early stage of COVID-19 because that would further increase cortisol levels and could suppress the immune system.

“For the average person on the street with COVID-19,” excess steroids will make their symptoms worse, Dr. Dhillo explained, adding this is important to emphasize because dexamethasone, and similar steroids, “are cheap and likely available on the Internet, and so misunderstanding of the RECOVERY trial could have serious implications.”

But once patients are very sick, with “inflammation in their lungs” and are in the intensive care unit, and often on ventilators – which is a very small subgroup of those with COVID-19 – it becomes a very different story, he stressed.

“RECOVERY shows clearly there seems to be a benefit once you need oxygen or are on a ventilator, and that makes sense because [dexamethasone] is going to be an anti-inflammatory,” in this instance when the “lungs are full of water.”

“But in the early days you definitely don’t need it and it could be harmful,” he reiterated.

The study is funded by the U.K. National Institute for Health Research and Medical Research Council. The authors have reported no relevant financial relationships.

This article first appeared on Medscape.com.

Patients with COVID-19 who have high levels of the steroid hormone cortisol on admission to hospital have a substantially increased risk of dying, U.K. researchers have discovered.

Waljit S. Dhillo, MBBS, PhD, head of the division of diabetes, endocrinology and metabolism at Imperial College London, and colleagues studied 535 patients admitted to major London hospitals. Their article was published online June 18 in Lancet Diabetes & Endocrinology.

“Our analyses show for the first time that patients with COVID-19 mount a marked and appropriate acute cortisol stress response,” said Dr. Dhillo and colleagues.

Moreover, “high cortisol concentrations were associated with increased mortality and a reduced median survival, probably because this is a marker of the severity of illness.”

So measuring cortisol on admission is potentially “another simple marker to use alongside oxygen saturation levels to help us identify which patients need to be admitted immediately, and which may not,” Dr. Dhillo noted in a statement from his institution.

“Having an early indicator of which patients may deteriorate more quickly will help us with providing the best level of care as quickly as possible. In addition, we can also take cortisol levels into account when we are working out how best to treat our patients,” he said.

However, it’s important to note that this means – particularly in the wake of the RECOVERY trial reported last week – that “in the early part of the disease you don’t need steroids,” he said.
 

In contrast to SARS, no adrenal insufficiency with COVID-19

Cortisol levels when healthy and resting are 100-200 nmol/L and nearly zero when sleeping, the researchers explained.

They decided to examine cortisol levels because, although physiological stress from critical illness normally increases levels of the hormone, the prior coronavirus, severe acute respiratory syndrome coronavirus (SARS-CoV), had the opposite effect and induced cortisol insufficiency in some patients.

“We would have said we’re not quite sure” what effect SARS-CoV-2 is having on cortisol levels, “so that’s why we collected the data,” Dr. Dhillo said in an interview.

The researchers studied patients admitted to three large London teaching hospitals between March 9 and April 22 with a clinical suspicion of SARS-CoV-2 infection. All patients had a standard set of blood tests, including full blood count, creatinine, C-reactive protein, D-dimer, and serum cortisol.

[embed:render:related:node:222746]

After exclusions, the team assessed 535 patients admitted over the study period who had baseline cortisol measured within 48 hours of admission.

Of these, 403 patients were diagnosed with COVID-19 based on a positive result on real-time polymerase chain reaction testing (88%) or a strong clinical and radiological suspicion, despite a negative test (12%).

In total, 132 (25%) individuals were not diagnosed with COVID-19.

Patients with COVID-19 were a mean age of 66.3 years, and 59.6% were men.

Mean cortisol concentrations in patients with COVID-19 were significantly higher than those not diagnosed with the virus (619 vs 519 nmol/L; P < .0001).

And by May 8, significantly more patients with COVID-19 died than those without (27.8% vs 6.8%; P < .0001).

Doubling of cortisol levels associated with 40% higher mortality

Multivariate analysis taking into account age, presence of comorbidities, and laboratory tests revealed that a doubling of cortisol concentrations among those with COVID-19 was associated with a significant increase in mortality, at a hazard ratio of 1.42 (P = .014).

And patients with COVID-19 whose baseline cortisol level was >744 nmol/L had a median survival of just 15 days, compared with those with a level ≤744 nmol/L, who had a median survival of 36 days (P < .0001).

The team notes that the cortisol stress responses in their patients with COVID-19 ranged up to 3,241 nmol/L, which is “a marked cortisol stress response, perhaps higher than is observed in patients undergoing major surgery.”

Of interest, there was no interaction between cortisol levels and ethnicity in their study; a subsequent analysis of the data stratified by black, Asian, and other minority ethnicities revealed no significant differences.

The team note that their results will need to be reproduced in other populations.

“Any potential role for cortisol measurement at baseline and later during an inpatient stay with COVID-19 as a prognostic biomarker, either by itself or in combination with other biomarkers, will require validation in a prospective study.”
 

Implications for treatment: Reserve dexamethasone for critically ill

Dr. Dhillo explained that, because their findings indicate that people initially infected with COVID-19 do mount an appropriate stress (cortisol) response, it is important that people properly understand this in the wake of the RECOVERY trial, reported last week.

The trial showed that the widely available steroid dexamethasone significantly reduced mortality among severely ill COVID-19 patients in the intensive care unit when given at a supraphysiologic dose of 6 mg.

But it would be hazardous for anyone to self-medicate with steroids at an early stage of COVID-19 because that would further increase cortisol levels and could suppress the immune system.

“For the average person on the street with COVID-19,” excess steroids will make their symptoms worse, Dr. Dhillo explained, adding this is important to emphasize because dexamethasone, and similar steroids, “are cheap and likely available on the Internet, and so misunderstanding of the RECOVERY trial could have serious implications.”

But once patients are very sick, with “inflammation in their lungs” and are in the intensive care unit, and often on ventilators – which is a very small subgroup of those with COVID-19 – it becomes a very different story, he stressed.

“RECOVERY shows clearly there seems to be a benefit once you need oxygen or are on a ventilator, and that makes sense because [dexamethasone] is going to be an anti-inflammatory,” in this instance when the “lungs are full of water.”

“But in the early days you definitely don’t need it and it could be harmful,” he reiterated.

The study is funded by the U.K. National Institute for Health Research and Medical Research Council. The authors have reported no relevant financial relationships.

This article first appeared on Medscape.com.

Patients with COVID-19 who have high levels of the steroid hormone cortisol on admission to hospital have a substantially increased risk of dying, U.K. researchers have discovered.

Waljit S. Dhillo, MBBS, PhD, head of the division of diabetes, endocrinology and metabolism at Imperial College London, and colleagues studied 535 patients admitted to major London hospitals. Their article was published online June 18 in Lancet Diabetes & Endocrinology.

“Our analyses show for the first time that patients with COVID-19 mount a marked and appropriate acute cortisol stress response,” said Dr. Dhillo and colleagues.

Moreover, “high cortisol concentrations were associated with increased mortality and a reduced median survival, probably because this is a marker of the severity of illness.”

So measuring cortisol on admission is potentially “another simple marker to use alongside oxygen saturation levels to help us identify which patients need to be admitted immediately, and which may not,” Dr. Dhillo noted in a statement from his institution.

“Having an early indicator of which patients may deteriorate more quickly will help us with providing the best level of care as quickly as possible. In addition, we can also take cortisol levels into account when we are working out how best to treat our patients,” he said.

However, it’s important to note that this means – particularly in the wake of the RECOVERY trial reported last week – that “in the early part of the disease you don’t need steroids,” he said.
 

In contrast to SARS, no adrenal insufficiency with COVID-19

Cortisol levels when healthy and resting are 100-200 nmol/L and nearly zero when sleeping, the researchers explained.

They decided to examine cortisol levels because, although physiological stress from critical illness normally increases levels of the hormone, the prior coronavirus, severe acute respiratory syndrome coronavirus (SARS-CoV), had the opposite effect and induced cortisol insufficiency in some patients.

“We would have said we’re not quite sure” what effect SARS-CoV-2 is having on cortisol levels, “so that’s why we collected the data,” Dr. Dhillo said in an interview.

The researchers studied patients admitted to three large London teaching hospitals between March 9 and April 22 with a clinical suspicion of SARS-CoV-2 infection. All patients had a standard set of blood tests, including full blood count, creatinine, C-reactive protein, D-dimer, and serum cortisol.

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After exclusions, the team assessed 535 patients admitted over the study period who had baseline cortisol measured within 48 hours of admission.

Of these, 403 patients were diagnosed with COVID-19 based on a positive result on real-time polymerase chain reaction testing (88%) or a strong clinical and radiological suspicion, despite a negative test (12%).

In total, 132 (25%) individuals were not diagnosed with COVID-19.

Patients with COVID-19 were a mean age of 66.3 years, and 59.6% were men.

Mean cortisol concentrations in patients with COVID-19 were significantly higher than those not diagnosed with the virus (619 vs 519 nmol/L; P < .0001).

And by May 8, significantly more patients with COVID-19 died than those without (27.8% vs 6.8%; P < .0001).

Doubling of cortisol levels associated with 40% higher mortality

Multivariate analysis taking into account age, presence of comorbidities, and laboratory tests revealed that a doubling of cortisol concentrations among those with COVID-19 was associated with a significant increase in mortality, at a hazard ratio of 1.42 (P = .014).

And patients with COVID-19 whose baseline cortisol level was >744 nmol/L had a median survival of just 15 days, compared with those with a level ≤744 nmol/L, who had a median survival of 36 days (P < .0001).

The team notes that the cortisol stress responses in their patients with COVID-19 ranged up to 3,241 nmol/L, which is “a marked cortisol stress response, perhaps higher than is observed in patients undergoing major surgery.”

Of interest, there was no interaction between cortisol levels and ethnicity in their study; a subsequent analysis of the data stratified by black, Asian, and other minority ethnicities revealed no significant differences.

The team note that their results will need to be reproduced in other populations.

“Any potential role for cortisol measurement at baseline and later during an inpatient stay with COVID-19 as a prognostic biomarker, either by itself or in combination with other biomarkers, will require validation in a prospective study.”
 

Implications for treatment: Reserve dexamethasone for critically ill

Dr. Dhillo explained that, because their findings indicate that people initially infected with COVID-19 do mount an appropriate stress (cortisol) response, it is important that people properly understand this in the wake of the RECOVERY trial, reported last week.

The trial showed that the widely available steroid dexamethasone significantly reduced mortality among severely ill COVID-19 patients in the intensive care unit when given at a supraphysiologic dose of 6 mg.

But it would be hazardous for anyone to self-medicate with steroids at an early stage of COVID-19 because that would further increase cortisol levels and could suppress the immune system.

“For the average person on the street with COVID-19,” excess steroids will make their symptoms worse, Dr. Dhillo explained, adding this is important to emphasize because dexamethasone, and similar steroids, “are cheap and likely available on the Internet, and so misunderstanding of the RECOVERY trial could have serious implications.”

But once patients are very sick, with “inflammation in their lungs” and are in the intensive care unit, and often on ventilators – which is a very small subgroup of those with COVID-19 – it becomes a very different story, he stressed.

“RECOVERY shows clearly there seems to be a benefit once you need oxygen or are on a ventilator, and that makes sense because [dexamethasone] is going to be an anti-inflammatory,” in this instance when the “lungs are full of water.”

“But in the early days you definitely don’t need it and it could be harmful,” he reiterated.

The study is funded by the U.K. National Institute for Health Research and Medical Research Council. The authors have reported no relevant financial relationships.

This article first appeared on Medscape.com.