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 Tlevels 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

Gender-related Differences in the Presentation and Course of Cushing’s Disease

2003 Apr;88(4):1554-8.  doi: 10.1210/jc.2002-021518.

Abstract

Cushing’s disease (CD) presents a marked female preponderance, but whether this skewed gender distribution has any relevance to the presentation and outcome of CD is not known.

The aim of the present study was the comparison of clinical features, biochemical indices of hypercortisolism, and surgical outcome among male and female patients with CD. The study population comprised 280 patients with CD (233 females, 47 males) collected by the Italian multicentre study.

Epidemiological data, frequency of clinical signs and symptoms, urinary free cortisol (UFC), plasma ACTH and cortisol levels, responses to dynamic testing, and surgical outcome were compared in female and male patients.

Male patients with CD presented at a younger age, compared with females (30.5 +/- 1.93 vs. 37.1 +/- 0.86 yr, P < 0.01), with higher UFC and ACTH levels (434.1 +/- 51.96 vs. 342.1 +/- 21.01% upper limit of the normal range for UFC, P < 0.05; 163.9 +/- 22.92 vs. 117.7 +/- 9.59% upper limit of the normal range for ACTH, P < 0.05).

No difference in ACTH and cortisol responses to CRH, gradient at inferior petrosal sinus sampling, and cortisol inhibition after low-dose dexamethasone was recorded between sexes. In contrast, the sensitivity of the high-dose dexamethasone test was significantly lower in male than in female patients.

Of particular interest, symptoms indicative of hypercatabolic state were more frequent in male patients; indeed, males presented a higher prevalence of osteoporosis, muscle wasting, striae, and nephrolitiasis. Conversely, no symptom was more frequent in female patients with CD.

Patients with myopathy, hypokalemia, and purple striae presented significantly higher UFC levels, compared with patients without these symptoms. Lastly, in male patients, pituitary imaging was more frequently negative and immediate and late surgical outcome less favorable.

In conclusion, CD appeared at a younger age and with a more severe clinical presentation in males, compared with females, together with more pronounced elevation of cortisol and ACTH levels.

Furthermore, high-dose dexamethasone suppression test and pituitary imaging were less reliable in detecting the adenoma in male patients, further burdening the differential diagnosis with ectopic ACTH secretion. Lastly, the postsurgical course of the disease carried a worse prognosis in males. Altogether, these findings depict a different pattern for CD in males and females.

From https://pubmed.ncbi.nlm.nih.gov/12679438/

Long-acting pasireotide provides ‘sustained biochemical improvements’ in Cushing’s disease

For patients with persistent or recurring Cushing’s disease, monthly pasireotide therapy was safe and effective, leading to normal urinary free cortisol levels in 47% of patients after 2 years, according to findings published in Clinical Endocrinology.

Maria Fleseriu headshot 2019

Maria Fleseriu

“The management of Cushing’s syndrome, and particularly Cushing’s disease, remains challenging,” Maria Fleseriu, MD, FACE, professor of neurological surgery and professor of medicine in the division of endocrinology, diabetes and clinical nutrition in the School of Medicine at Oregon Health & Science University and director of the OHSU Northwest Pituitary Center, told Endocrine Today. “Long-acting pasireotide provided sustained biochemical improvements and clinical benefit in a significant proportion of patients with Cushing’s disease who elected to continue in this extension study. There were many adverse events reported overall, but no new safety signals emerging over long-term treatment.”

In the last decade, medical treatment for Cushing’s disease has progressed from a few steroidogenesis inhibitors to three novel drug groups: new inhibitors for steroidogenic enzymes with possibly fewer adverse effects, pituitary-directed drugs that aim to inhibit the pathophysiological pathways of Cushing’s disease, and glucocorticoid receptor antagonists that block cortisol’s action, Fleseriu, who is also an Endocrine Today Editorial Board member, said.

In an open-label extension study, Fleseriu and colleagues analyzed data from 81 adults with confirmed Cushing’s disease with mean urinary free cortisol not exceeding the upper limit of normal, who transitioned from a 12-month, randomized controlled trial where they were assigned 10 mg or 30 mg once-monthly intramuscular pasireotide (Signifor LAR, Novartis). During the main study, researchers recruited participants with mean urinary free cortisol level concentration 1.5 to five times the upper limit of normal, normal or greater than normal plasma and confirmed pituitary source of Cushing’s disease. Participants who elected to continue in the extension were considered biochemical responders or benefited from the study drug per the clinical investigator, Fleseriu said.

“As in all extension studies, the bias is inherent that patients deemed responders tend to continue, but for any type of treatment for pituitary tumors, and particularly Cushing’s disease, long-term, robust data on efficacy and safety parameters is essential,” Fleseriu said.

Median overall exposure to pasireotide at the end of the extension study was 23.9 months, with nearly half of patients receiving at least 1 year of treatment during the extension phase. Researchers found that improvements in clinical signs of hypercortisolism were sustained throughout the study and median urinary free cortisol remained within normal range. Overall, 38 participants (47%) had controlled urinary free cortisol at month 24 (after 12 months of treatment during the extension phase), with researchers noting that the proportion of participants with controlled or partially controlled urinary free cortisol was stable throughout the extension phase.

“Interestingly, the median salivary cortisol level decreased but remained above normal (1.3 times upper limit of normal) at 3 years,” Fleseriu said.

As seen in other pasireotide studies, and expected based on the mechanism of action, researchers observed hyperglycemia-related adverse events in 39.5% of participants, with diabetes medications initiated or escalated in some patients, Fleseriu said. However, mean fasting glucose and HbA1c were stable during the extension phase, after increasing in the main study. Within the cohort, 81.5% had type 2 diabetes at baseline (entering extension phase) and 88.9% patients had type 2 diabetes at last assessment.

“Pasireotide acts at the tumor level, and tumor shrinkage is seen in many patients,” Fleseriu said. “In this study, 42% and 32.1% had a measurable microadenoma or macroadenoma, respectively, on MRI at the start of pasireotide treatment; an adenoma was not visible in almost a quarter of patients at 2 years.”

Among patients with a measurable adenoma at baseline and at month 24 (n = 35), 85.7% experienced a reduction of at least 20% or a 20% change in tumor volume between the two time points. Improvements in median systolic and diastolic blood pressure, BMI and waist circumference were sustained during the extension, Fleseriu said.

“The long-term safety profile of pasireotide was favorable and consistent with that reported during the first 12 months of treatment,” the researchers wrote. “These data support the use of long-acting pasireotide as an effective long-term treatment option for some patients with [Cushing’s disease].”

Fleseriu said individualized treatment selecting patients who will derive benefit from therapy will be crucial, balancing both efficacy and the potential risks and costs. – by Regina Schaffer

Disclosures: Fleseriu reports she has received consultant fees and her institution has received research support from Novo Nordisk and Pfizer. Please see the study for all other authors’ relevant financial disclosures.

From https://www.healio.com/endocrinology/neuroendocrinology/news/online/%7B5da4611f-34b2-4306-80b8-46babd2aad4a%7D/long-acting-pasireotide-provides-sustained-biochemical-improvements-in-cushings-disease?page=2

Bilateral Adrenocortical Adenomas Causing Adrenocorticotropic Hormone-Independent Cushing’s Syndrome

Adrenocorticotropic hormone (ACTH)-independent Cushing’s syndrome (CS) is mostly due to unilateral tumors, with bilateral tumors rarely reported. Its common causes include primary pigmented nodular adrenocortical disease, ACTH-independent macronodular adrenal hyperplasia, and bilateral adrenocortical adenomas (BAAs) or carcinomas. BAAs causing ACTH-independent CS are rare; up to now, fewer than 40 BAA cases have been reported. The accurate diagnosis and evaluation of BAAs are critical for determining optimal treatment options. Adrenal vein sampling (AVS) is a good way to diagnose ACTH-independent CS.

A 31-year-old woman had a typical appearance of CS. The oral glucose tolerance test showed impaired glucose tolerance and obviously increased insulin and C-peptide levels. Her baseline serum cortisol and urine free cortisol were elevated and did not show either a circadian rhythm or suppression with dexamethasone administration. The peripheral 1-deamino-8-D-arginine-vasopressin (DDVAP) stimulation test showed a delay of the peak level, which was 1.05 times as high as the baseline level. Bilateral AVS results suggested the possibility of BAAs. Abdominal computed tomography showed bilateral adrenal adenomas with atrophic adrenal glands (right: 3.1 cm × 2.0 cm × 1.9 cm; left: 2.2 cm × 1.9 cm × 2.1 cm). Magnetic resonance imaging of the pituitary gland demonstrated normal findings. A left adenomectomy by retroperitoneoscopy was performed first, followed by resection of the right-side adrenal mass 3 mo later. Biopsy results of both adenomas showed cortical tumors. Evaluations of ACTH and cortisol showed a significant decrease after left adenomectomy but could still not be suppressed, and the circadian rhythm was absent. Following bilateral adenomectomy, this patient has been administered with prednisone until now, all of her symptoms were alleviated, and she had normal blood pressure without edema in either of her lower extremities.

BAAs causing ACTH-independent CS are rare. AVS is of great significance for obtaining information on the functional state of BAAs before surgery.

World journal of clinical cases. 2019 Apr 26 [Epub]

Yu-Lin Gu, Wei-Jun Gu, Jing-Tao Dou, Zhao-Hui Lv, Jie Li, Sai-Chun Zhang, Guo-Qing Yang, Qing-Hua Guo, Jian-Ming Ba, Li Zang, Nan Jin, Jin Du, Yu Pei, Yi-Ming Mu

Department of Endocrinology, Chinese People’s Liberation Army General Hospital, Beijing 100853, China., Department of Endocrinology, Chinese People’s Liberation Army General Hospital, Beijing 100853, China. guweijun301@163.com., Department of Pathology, Chinese People’s Liberation Army General Hospital, Beijing 100853, China.

From https://www.urotoday.com/recent-abstracts/urologic-oncology/adrenal-diseases/112782-bilateral-adrenocortical-adenomas-causing-adrenocorticotropic-hormone-independent-cushing-s-syndrome-a-case-report-and-review-of-the-literature.html

Metyrapone Reduced Urinary-Free Cortisol Levels in Cushing Syndrome

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

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

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

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

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

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

This study was supported by Novartis.

Reference

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

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

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