Corticotroph hyperplasia and Cushing disease: diagnostic features and surgical management

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Abstract

Objective: This study was done to compare corticotroph hyperplasia and histopathologically proven adenomas in patients with Cushing disease by analyzing diagnostic features, surgical management, and clinical outcomes.

Methods: Patients with suspected pituitary Cushing disease were included in a retrospective cohort study and were excluded if results of pathological analysis of the surgical specimen were nondiagnostic or normal. Cases were reviewed by two experienced neuropathologists. Total lesion removal was used as a dichotomized surgical variable; it was defined as an extracapsular resection (including a rim of normal gland) in patients with an adenoma, and for hyperplasia patients it was defined as removal of the presumed lesion plus a rim of surrounding normal gland. Bivariate and multivariate analyses were performed. Recurrence-free survival was compared between the two groups.

Results: The final cohort consisted of 63 patients (15 with hyperplasia and 48 with adenoma). Normal pituitary acinar architecture was highly variable. Corticotroph hyperplasia was diagnosed based on the presence of expanded acini showing retained reticulin architecture and predominant staining for adrenocorticotropic hormone. Crooke’s hyaline change was seen in 46.7% of specimens, and its frequency was equal in nonlesional tissue of both groups. The two groups differed only by MRI findings (equivocal/diffuse lesion in 46% of hyperplasia and 17% of adenoma; p = 0.03). Diagnostic uncertainty in the hyperplasia group resulted in additional confirmatory testing by 24-hour urinary free cortisol. Total lesion removal was infrequent in patients with hyperplasia compared to those with adenoma (33% vs 65%; p = 0.03). Initial biochemical remission was similar (67% in hyperplasia and 85% in adenoma; p = 0.11). There was no difference in hypothalamic-pituitary-adrenal axis recovery or disease recurrence. The median follow-up was 1.9 years (IQR 0.7-7.6 years) for the hyperplasia group and 1.2 years (IQR 0.4-2.4 years) for the adenoma group. Lack of a discrete lesion and diagnostic uncertainty were the only significant predictors of hyperplasia (sensitivity 53.3%, specificity 97.7%, positive predictive value 88.9%, negative predictive value 85.7%). An adjusted Cox proportional hazards model showed similar recurrence-free survival in the two groups.

Conclusions: This study suggests an association between biochemically proven Cushing disease and histopathologically proven corticotroph hyperplasia. Imaging and operative findings can be ambiguous, and, compared to typical adenomas with a pseudocapsule, the surgical approach is more nuanced. Nevertheless, if treated appropriately, biochemical outcomes may be similar.

Keywords: ACTH = adrenocorticotropic hormone; CRH = corticotropin-releasing hormone; Cushing disease; HPA = hypothalamic-pituitary-adrenal; HR = hazard ratio; IPSS = inferior petrosal sinus sampling; ROC = receiver operating characteristic; UFC = urinary free cortisol; corticotroph adenoma; corticotroph hyperplasia; diagnosis; pathology; pituitary surgery; surgical outcomes.

From https://pubmed.ncbi.nlm.nih.gov/32886921/

No Increased COVID-19 Risk With Adequately Treated Adrenal Insufficiency

COVID-19

Adults with adrenal insufficiency who are adequately treated and trained display the same incidence of COVID-19-suggestive symptoms and disease severity as controls, according to a presenter.

“Adrenal insufficiency is supposed to be associated with an increased risk for infections and complications,” Giulia Carosi, a doctoral student in the department of experimental medicine at Sapienza University of Rome, said during a presentation at the virtual European Congress of Endocrinology Annual Meeting. “Our aim was to evaluate the incidence of COVID symptoms and related complications in this group.”

In a retrospective, case-control study, Carosi and colleagues evaluated the incidence of COVID-19 symptoms and complications among 279 adults with primary or secondary adrenal insufficiency (mean age, 57 years; 49.8% women) and 112 adults with benign pituitary nonfunctioning lesions without hormonal alterations, who served as controls (mean age, 58 years; 52.7% women). All participants lived in the Lombardy region of northern Italy. Participants completed a standardized questionnaire by phone on COVID-19-suggestive symptoms, such as fever, cough, myalgia, fatigue, dyspnea, gastrointestinal symptoms, conjunctivitis, loss of smell, loss of taste, upper respiratory tract symptoms, thoracic pain, headaches and ear pain. Patients with primary or secondary adrenal insufficiency were previously trained to modify their glucocorticoid replacement therapy when appropriate.

From February through April, the prevalence of participants reporting at least one symptom of viral infection was similar between the adrenal insufficiency group and controls (24% vs. 22.3%; P = .788).

Researchers observed “highly suggestive” symptoms among 12.5% of participants in both groups.

No participant required hospitalization and no adrenal crisis was reported. Replacement therapy was correctly increased for about 30% of symptomatic participants with adrenal insufficiency.

Carosi noted that few nasopharyngeal swabs were performed (n = 12), limiting conclusions on the exact infection rate (positive result in 0.7% among participants with adrenal insufficiency and 0% of controls; P = .515).

“We can conclude that hypoadrenal patients who have regular follow-up and trained about risks for infection and sick day rules seem to present the same incidence of COVID-19 symptoms and the same disease severity as controls,” Carosi said.

As Healio previously reported, there is no evidence that COVID-19 has a more severe course among individuals with primary and secondary adrenal insufficiency; however, those with adrenal insufficiency are at increased risk for respiratory and viral infections, and patients experiencing major inflammation and fever are at risk for life-threatening adrenal crisis. In a position statement issued by the American Association of Clinical Endocrinologists in March, researchers wrote that people with adrenal insufficiency or uncontrolled Cushing’s syndrome should continue to take their medications as prescribed and ensure they have appropriate supplies for oral and injectable steroids at home, with a 90-day preparation recommended. In the event of acute illness, those with adrenal insufficiency are instructed to increase their hydrocortisone dose per instructions and call their health care provider for more details. Standard “sick day” rules for increasing oral glucocorticoids or injectables would also apply, according to the statement.

From https://www.healio.com/news/endocrinology/20200910/no-increased-covid19-risk-with-adequately-treated-adrenal-insufficiency

LOGICS Trial Supports Recorlev’s Efficacy in Lowering Cortisol Levels

Patients with endogenous Cushing’s syndrome who stopped using Recorlev (levoketoconazole) and moved to a placebo in a study started having their urine cortisol levels rise in response to lack of treatment, compared with those who remained on Recorlev, according to top-line data from the Phase 3 LOGICS trial.

Based on these findings and data from a previous Phase 3 trial of Recorlev called SONICS (NCT01838551), the therapy’s developer, Strongbridge Biopharma, is planning to submit a new drug application requesting its approval to the U.S. Food and Drug Administration (FDA) early next year.

If approved, Recorlev could be available to patients in the U.S. in 2022.

“We are delighted to announce the positive and statistically significant top-line results of the LOGICS study, which add to the growing body of evidence supporting the potential of Recorlev (levoketoconazole) as an effective and well tolerated cortisol synthesis inhibitor to treat Cushing’s syndrome,” Fredric Cohen, MD, chief medical officer of Strongbridge Biopharma, said in a press release.

Recorlev, also known as COR-003, is an investigational oral treatment for endogenous Cushing’s syndrome that inhibits the production of cortisol, the glucocorticoid hormone that is overly produced in patients with the disorder.

The safety, tolerability, effectiveness, and pharmacological properties of Recorlev in people with endogenous Cushing’s syndrome are currently being assessed in the LOGICS trial (NCT03277690).

LOGICS enrolled patients who had never been treated with Recorlev, as well as those given the medication in SONICS.

The study included an initial withdrawal phase, in which patients were assigned randomly to either Recorlev (up to a dose of 1,200 mg), or to a placebo for about 8 weeks. This was followed by a restoration phase, lasting approximately the same time, in which all patients received Recorlev in combination with a placebo. With this design, patients initially assigned to Recorlev continued treatment in the study’s second phase, while those originally assigned to a placebo switched to Recorlev.

Before enrolling in the study’s initial randomized-withdrawal phase, patients completed an open-label titration and maintenance phase lasting 14 to 19 weeks, which determined the best dose of Recorlev they should receive later.

Of the 79 patients who entered the open-label titration and maintenance phase, 44 enrolled in the randomized-withdrawal phase, and 43 completed this initial portion of the trial.

Top-line data now announced by the company showed the proportion of patients having their urine cortisol levels rise by the end of the randomized-withdrawal phase was 54.5% higher among those on a placebo than among those treated with Recorlev (95.5% vs. 40.9%).

All 21 patients who lost their initial treatment response in the open-label portion of the study, and saw their cortisol levels rise after moving to a placebo (withdrawal phase) were given early rescue treatment. Their cortisol levels started to drop after a median of 22 days.

The percentage of patients whose urine cortisol levels were within normal range by the end of the withdrawal phase was 45.5% higher among those treated with Recorlev, compared with those given a placebo (50.0% vs. 4.5%).

In addition to losing benefits related to cortisol control, patients receiving a withdrawal-phase placebo also lost the therapy’s positive cholesterol-lowering effects.

“The Phase 3 LOGICS results complement the long-term efficacy and safety data supplied by the Phase 3 SONICS study, which was published in The Lancet Diabetes & Endocrinology, by confirming that the effects of Recorlev (levoketoconazole) were responsible for the therapeutic response when treatment was continued compared to withdrawing patients to placebo,” said Maria Fleseriu, MD, FACE, professor of Medicine and Neurological Surgery and director of the Oregon Health Sciences University Pituitary Center, and principal investigator of the study. 

 “The LOGICS findings — which build upon the long-term benefit shown during open-label treatment in SONICS — provide robust evidence to support the use of RECORLEV as an important treatment option for this life-threatening rare endocrine disease,” Fleseriu added.

Recorlev was found to be safe and well-tolerated in LOGICS. Of the 79 patients who entered in the study’s open-label titration and maintenance phase, 19% discontinued due to side effects in this phase, and none of the 44 who proceeded to the withdrawal phase stopped treatment for these reasons.

The most common side effects observed during the first two parts of LOGICS included nausea (29%), low blood potassium levels (28%), headache (21%), high blood pressure (19%), and diarrhea (15%).

Some patients saw the levels of their liver enzymes rise above normal levels — a sign of liver inflammation and damage — during the study. However, this and other side effects of special interest, including those associated with adrenal insufficiency, resolved by either lowering the dose or stopping treatment with Recorlev. The proportion of patients experiencing these side effects was similar to that seen in SONICS.

These findings are part of a subset of data from a planned interim analysis of LOGICS. Final study data requires analyses of additional datasets.

Adapted from https://www.globenewswire.com/news-release/2020/09/08/2089872/0/en/Strongbridge-Biopharma-plc-Announces-Positive-and-Statistically-Significant-Top-Line-Results-from-the-Pivotal-Phase-3-LOGICS-Study-of-RECORLEV-levoketoconazole-for-the-Treatment-of.html

Study Shows Metyrapone Effective for Treating Rare Cushing’s Syndrome

The first ever prospective study to test the safety and efficacy of metyrapone in patients with Cushing’s Syndrome in a real-life setting has shown successful results.

HRA Pharma Rare Diseases SAS, of Paris, has presented data from PROMPT, the first ever prospective study designed to confirm metyrapone efficacy and good tolerance in patients with endogenous Cushing’s Syndrome, with results confirming that metyrapone controlled 80% of the patients at week 12 with either normalisation or at least 50% decrease of urinary free cortisol. These initial results are being published to coincide with HRA Pharma Rare Diseases’ participation in the e-ECE conference 2020.

Cushing’s Syndrome is a rare condition where patients have too much cortisol in their blood. Endogenous Cushing’s Syndrome is most often caused by hormone-releasing tumours of the adrenal or the pituitary glands. To manage this condition, controlling high cortisol levels in patients is important.

Successful results with metyrapone

Metyrapone is an inhibitor of the 11-beta-hydroxylase enzyme, which majorly contributes to cortisol synthesis and is approved in Europe for the treatment of endogenous Cushing’s Syndrome based on observational retrospective studies published over more than 50 years. As this prospective study took place over five years from April 2015 to April 2020, the longitudinal format reduced potential sources of bias and helped determine the risk factors of metyrapone when compared to the previous retrospective studies.

The first results of this study showed that at the end of the 12 weeks, metyrapone therapy is a rapid-onset, effective and safe medical treatment in patients living with the syndrome.

Evelina Paberze, COO of HRA Pharma Rare Diseases, said: “At HRA Pharma Rare Diseases, we are dedicated to building comprehensive evidence of our products. The first results of this prospective study clearly demonstrate the effectiveness of metyrapone in treating Cushing’s Syndrome.”

The next set of data on the six-month optional extension is awaiting confirmation and the full study with the final results will be published next year.

Frederique Welgryn, Managing Director of HRA Pharma Rare Diseases, added: “Cushing’s Syndrome is a chronic disease that can lead to deterioration in patients’ conditions if not treated appropriately. We are thrilled to announce that this first prospective study verifies that metyrapone is both an effective and safe way to treat endogenous Cushing’s Syndrome. This is a big step given the high unmet medical need for patients with endogenous Cushing’s Syndrome.”

From https://www.healtheuropa.eu/study-shows-metyrapone-effective-for-treating-rare-cushings-syndrome/102584/

High Cortisol Levels in Urine May Be Linked to Changes in Blood Sugar Metabolism

Abnormally high levels of cortisol in the urine — one of the hallmarks of Cushing’s syndrome — seem to be associated with alterations in blood sugar metabolism in obese patients, a study found.

The study, “Hypercortisolism and altered glucose homeostasis in obese patients in the pre-bariatric surgery assessment,” was published in the journal Diabetes/Metabolism Research and Reviews.

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