Thyroid dysfunction highly prevalent in Cushing’s syndrome

Central hypothyroidism is prevalent in about 1 in 2 adults with Cushing’s syndrome, and thyroid function can be restored after curative surgery for most patients, according to study findings.

“Our study findings have confirmed and greatly extended previous smaller studies that suggested a link between hypercortisolism and thyroid dysfunction but were inconclusive due to smaller sample size and short follow-up,” Skand Shekhar, MD, an endocrinologist and clinical investigator in the reproductive physiology and pathophysiology group at the National Institute of Environmental Health Sciences, NIH, told Healio. “Due to our large sample and longer follow-up, we firmly established a significant negative correlation between hypercortisolemia measures — serum and urinary cortisol, serum adrenocorticotropic hormone — and thyroid hormones triiodothyronine, free thyroxine and thyrotropin.”

Shekhar and colleagues conducted a retrospective review of two groups of adults aged 18 to 60 years with Cushing’s syndrome. The first group was evaluated at the NIH Clinical Center from 2005 to 2018 (n = 68; mean age, 43.8 years; 62% white), and the second group was evaluated from 1985 to 1994 (n = 55; mean age, 37.2 years; 89% white). The first cohort was followed for 6 to 12 months to observe the pattern of thyroid hormone changes after surgical cure of adrenocorticotropic hormone-dependent Cushing’s syndrome. The second group underwent diurnal thyroid-stimulating hormone evaluation before treatment and during remission for some cases.

Urinary free cortisol and morning thyroid hormone levels were collected for all participants. In the second group, researchers evaluated diurnal patterns of TSH concentrations with hourly measurements from 3 to 7 p.m. and midnight to 4 p.m. In the first group, adrenocorticotropic hormone and serum cortisol were measured.

In the first cohort, seven participants were receiving levothyroxine for previously diagnosed primary or central hypothyroidism. Of the remaining 61 adults, 32 had untreated central hypothyroidism. Thirteen participants had free T4 at the lower limit of normal, and 19 had subnormal levels. There were 29 adults with subnormal levels of T3 and seven with subnormal TSH.

Before surgery, 36 participants in the first group had central hypothyroidism. Six months after surgery, central hypothyroidism remained for 10 participants. After 12 months, the number of adults with central hypothyroidism dropped to six. Preoperative T3 and TSH levels were negatively associated with morning and midnight cortisol, adrenocorticotropic hormone and urinary free cortisol. In post hoc analysis, a baseline urinary free cortisol of more than 1,000 g per day was adversely associated with baseline and 6-month T3 and free T4 levels.

In the second group, there were 51 participants not on thyroid-modifying drugs who had a thyroid function test 6 or 12 months after surgery. Before surgery, free T4 levels were subnormal in 17 participants, T3 levels were subnormal in 22, and TSH levels were in the lower half of the reference range or below in all but one participant.

After surgery, two participants had below normal free T4, one had subnormal T3, and TSH levels were in the lower half of the reference range or below in 23 of 48 participants. Before surgery, there was no difference in mean TSH between daytime and nighttime. A mean 8 months after surgery, the second group had a normal nocturnal TSH surge from 1.3 mIU/L during the day to 2.17 mIU/L at night (P = .01). The nocturnal TSH increase persisted as long as 3 years in participants who had follow-up evaluations.

“We found a very high prevalence of thyroid hormone deficiency that appears to start at the level of the hypothalamus-pituitary gland and extend to the tissue level,” Shekhar said. “Some of these patients may experience thyroid hormone deficiency symptoms, such as fatigue, depression, cold intolerance, weight gain, etc, as a result of systematic and tissue-level thyroid hormone deficiency. We also noted a strong correlation between hypothyroidism and hypogonadism, which implies that hypothyroid patients are also likely to suffer adverse reproductive effects. Thus, it is imperative to perform thorough thyroid hormone assessment in patients with Cushing’s syndrome, and thyroid hormone supplementation should be considered for these patients unless cure of Cushing’s syndrome is imminent.”

Researchers said providers should routinely screen for hypothyroidism in adults with Cushing’s syndrome. Even after thyroid function is restored, regular follow-up should also be conducted.

Further research is needed to investigate thyroid dysfunction in iatrogenic Cushing’s syndrome and the impact of these findings on euthyroid sick syndrome, Shekhar said.

For more information:

Skand Shekhar, MD, can be reached at skand.shekhar@nih.gov.

From https://www.healio.com/news/endocrinology/20210208/thyroid-dysfunction-highly-prevalent-in-cushings-syndrome

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

Does a normal urine free cortisol result rule out Cushing’s syndrome?

ENDO_2015

 

March 07, 2015

SAT 379-412-Cushing’s Syndrome

Does a normal urine free cortisol result rule out Cushing’s syndrome?

ST Sharma, LK Nieman

Summary: Researchers conducted this study to assess the diagnostic accuarcy of urine free cortisol (UFC) and 24-hour urine 17-hydroxycorticosteroids (170HCS) in patients with Cushing’s syndrome, concluding that in patients with mild CS, UFC can be falsely normal or only minimally elevated. Further, they found that to help in making a diagnosis and prevent treatment delays, clinicians may consider incorporating multiple collections and use of complimentary screening tests including 24-hour urine 17OHCS and late night salivary cortisol (LNSC) testing.

Methods:

  • For this retrospective study, researchers included all CS patients evaluated at the National Institutes of Health (NIH) from 2009 to 2014.
  • The screening tests used for CS included UFC, 17OHCS, midnight serum cortisol and low dose (1 mg overnight or 2-day 2 mg/day) dexamethasone suppression test (DST).
  • They defined abnormal as values above reference range for UFC, 17OHCS and LNSC, a midnight serum cortisol ≥7.5 mcg/dL, and post-dexamethasone cortisol values ≥1.8 mcg/dL.
  • Hourly 24-hour sampling for cortisol was performed in a few cases with a mild clinical phenotype and equivocal test results.
  • Researchers measured UFC using liquid chromatography/tandem mass spectrometry (LC-MS/MS), and 17OHCS was measured using colorimetric methodology with Porter-Silber reaction (reported as mg/g of creatinine).
  • For this study, they used the mean of the first two UFC and 17OHCS values (appropriate collection by urine volume and creatinine) obtained within 30 days of initial NIH presentation.

Results:

  • In all, 72 patients were diagnosed with CS (aged 18-77 years, 51 females), 51 of whom had CD, 10 had ectopic CS, and 2 had an adrenal source of Cushing’s based on pathology.
  • Biochemical tests such as inferior petrosal sinus sampling (IPSS) suggested ectopic CS, but no tumor was found (occult) in 6 patients.
  • In 2 patients with failed transsphenoidal surgery, IPSS was indicative of a pituitary source, and one patient did not complete evaluation for ACTH-dependent CS.
  • UFC results were available in all patients, 17OHCS in 70, LNSC in 21, midnight serum cortisol in 68, and DST results in 37 patients.
  • UFC was falsely normal in 6 patients and only minimally elevated (<2 x ULN) in 13 patients (normal renal function, no history of cyclicity, all had CD); of these 19 patients, 24-hour 17OHCS was abnormal in all, LNSC was abnormal in 12, midnight serum cortisol was abnormal in 18, and DST was abnormal in 12 patients.
  • Hourly 24-hour sampling for cortisol performed in 3 of these patients revealed abnormal nadir (>7.5 mcg/dL) and mean daily serum cortisol (>9 mcg/dL) levels.

From http://www.mdlinx.com/endocrinology/conference-abstract.cfm/ZZ5BA369FDE9DE4CED82CB6A7CD5BFD1BE/42581/?utm_source=confcoveragenl&utm_medium=newsletter&utm_content=abstract-list&utm_campaign=abstract-ENDO2015&nonus=0

What would Harvey Cushing say about Cushing’s disease today?

harvey-book

(BPT) – More than 80 years ago renowned neurosurgeon, Dr. Harvey Cushing, discovered a tumor on the pituitary gland as the cause of a serious, hormone disorder that leads to dramatic physical changes in the body in addition to life-threatening health concerns. The discovery was so profound it came to be known as Cushing’s disease. While much has been learned about Cushing’s disease since the 1930s, awareness of this rare pituitary condition is still low and people often struggle for years before finding the right diagnosis.

Read on to meet the man behind the discovery and get his perspective on the present state of Cushing’s disease.

* What would Harvey Cushing say about the time it takes for people with Cushing’s disease to receive an accurate diagnosis?

Cushing’s disease still takes too long to diagnose!

Despite advances in modern technology, the time to diagnosis for a person with Cushing’s disease is on average six years. This is partly due to the fact that symptoms, which may include facial rounding, thin skin and easy bruising, excess body and facial hair and central obesity, can be easily mistaken for other conditions. Further awareness of the disease is needed as early diagnosis has the potential to lead to a more favorable outcome for people with the condition.

* What would Harvey Cushing say about the advances made in how the disease is diagnosed?

Significant progress has been made as several options are now available for physicians to use in diagnosing Cushing’s disease.

In addition to routine blood work and urine testing, health care professionals are now also able to test for biochemical markers – molecules that are found in certain parts of the body including blood and urine and can help to identify the presence of a disease or condition.

* What would Harvey Cushing say about disease management for those with Cushing’s disease today?

Patients now have choices but more research is still needed.

There are a variety of disease management options for those living with Cushing’s disease today. The first line and most common management approach for Cushing’s disease is the surgical removal of the tumor. However, there are other management options, such as medication and radiation that may be considered for patients when surgery is not appropriate or effective.

* What would Harvey Cushing say about the importance of ongoing monitoring in patients with Cushing’s disease?

Routine check-ups and ongoing monitoring are key to successfully managing Cushing’s disease.

The same tests used in diagnosing Cushing’s disease, along with imaging tests and clinical suspicion, are used to assess patients’ hormone levels and monitor for signs and symptoms of a relapse. Unfortunately, more than a third of patients experience a relapse in the condition so even patients who have been surgically treated require careful long-term follow up.

* What would Harvey Cushing say about Cushing’s disease patient care?

Cushing’s disease is complex and the best approach for patients is a multidisciplinary team of health care professionals working together guiding patient care.

Whereas years ago patients may have only worked with a neurosurgeon, today patients are typically treated by a variety of health care professionals including endocrinologists, neurologists, radiologists, mental health professionals and nurses. We are much more aware of the psychosocial impact of Cushing’s disease and patients now have access to mental health professionals, literature, patient advocacy groups and support groups to help them manage the emotional aspects of the disease.

Learn More

Novartis is committed to helping transform the care of rare pituitary conditions and bringing meaningful solutions to people living with Cushing’s disease. Recognizing the need for increased awareness, Novartis developed the “What Would Harvey Cushing Say?” educational initiative that provides hypothetical responses from Dr. Cushing about various aspects of Cushing’s disease management based on the Endocrine Society’s Clinical Guidelines.

For more information about Cushing’s disease, visit www.CushingsDisease.com or watch educational Cushing’s disease videos on the Novartis YouTube channel at www.youtube.com/Novartis.

 

From http://www.jsonline.com/sponsoredarticles/health-wellness/what-would-harvey-cushing-say-about-cushings-disease-today8087390508-253383751.html

Genetic mutation lowers obesity in Cushing’s syndrome

London E. J Clin Endocrinol Metab. 2013; doi:10.1210/jc.2013-1956.

Among adult patients with Cushing’s syndrome, those with mutations in PRKAR1A, the gene that controls cAMP-dependent protein kinase, are less obese than their counterparts without these mutations, according to a recent study.

The retrospective study evaluated adrenalectomy samples from 51 patients with Cushing’s syndrome, 13 with PRKAR1A mutations and 32 without. Of the 51 patients, 40 were female and 11 were male, and patients ranged in age from 4 to 74 years.

A non-Cushing’s syndrome comparison group consisting of 6 adrenalectomy patients with aldosterone producing adenomas (APAs) was included. Additional comparison groups comprising clinical data from 89 patients with Cushing’s disease and 26 with hyperaldosteronism were also studied.

Researchers recorded the weight, height and BMI of all patients, and measured abdominal subcutaneous adipose tissue (ScAT) and periadrenal adipose tissue (PAT) using computed tomography. PAT was collected and frozen for evaluation; the extracts were assessed for levels of cAMP and protein kinase (PKA) activity, as well as for protein and mRNA expression of subunits of PKA. Diurnal cortisol levels and urine-free cortisol were also measured preoperatively.

The study found that in adults with Cushing’s syndrome, the mean BMI of those with PRKAR1A mutations was lower than that of patients with noPRKAR1A mutations (P<.05), and was not inconsistent with the hyperaldosteronism comparison group.

In pediatric patients with adrenal Cushing’s syndrome, the presence of PRKAR1A mutation did not have an impact on mean BMI z-scores. However, in comparison with pediatric patients with pituitary Cushing’s disease, the BMI z-scores were significantly lower in pediatric Cushing’s disease patients with PRKAR1Amutations (P<.05). Patients with Cushing’s syndrome without PRKAR1A mutations had significantly more PAT and ScAT than non-Cushing’s syndrome patients. Additionally, the ratio of basal-to-total (cAMP-triggered) PKA activity was significantly lower in patients with PRKAR1A mutations, suggesting greater proportions of active PKA (P<.005).

“These findings have obvious implications in the establishment of the diagnosis of CS in patients with PRKAR1A mutations: These patients may be leaner than other patients with [Cushing’s syndrome],” the study authors wrote. “Perhaps more importantly, our findings point to the importance of cAMP and or PKA signaling in the regulation of adiposity.”

Disclosures: The researchers report no relevant financial disclosures.

From http://www.healio.com/endocrinology/adrenal/news/online/%7B693f94cd-359d-4c52-8e0d-bfd0e4a51d03%7D/genetic-mutation-lowers-obesity-in-cushings-syndrome

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