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


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., Department of Pathology, Chinese People’s Liberation Army General Hospital, Beijing 100853, China.


Etomidate drip quickly curbs severe hypercortisolism


VITALS  Key clinical point: The anesthetic induction agent etomidate is a potent suppressor of cortisol synthesis in the adrenal cortex at subhypnotic doses, making it a safe and effective agent for management of severe hypercortisolism in Cushing’s syndrome.

Major finding: Continuous infusion of etomidate using a standardized protocol resulted in a reduction in serum cortisol from a mean of 138 mcg/dL to a goal range of 10-20 mcg/dL in an average of 64 hours.

Data source: This was a retrospective case series involving six patients with severe hypercortisolism caused by adrenocorticotropic hormone–dependent Cushing’s syndrome.

Disclosures: The study was carried out with institutional funds. The presenter reported having no financial conflicts.

Continuous intravenous infusion of etomidate safely and swiftly gains control of severe hypercortisolism in patients with adrenocorticotropic hormone–dependent Cushing’s syndrome when conventional presurgical oral treatment is problematic.

“From our cumulative experience, we have now developed a standardized titrated etomidate infusion protocol, which should provide clinicians with a simple, safe, and effective means to lower serum cortisol in patients with severe clinical, metabolic, and neuropsychiatric consequences of prodigious hypercortisolism as a bridge to definitive medical or surgical therapy,” explained Dr. Katarzyna G. Zarnecki at the joint meeting of the International Congress of Endocrinology and the Endocrine Society.

Etomidate (Amidate) is a sedative hypnotic agent with an excellent cardiovascular safety profile. It is widely used in emergency settings, such as reduction of dislocated joints and cardioversion. It suppresses adrenal steroidogenesis by potently inhibiting 11-beta hydroxylase. Fortunately for endocrinologic purposes, etomidate suppresses cortisol synthesis even at subhypnotic doses. In using it off label for management of severe hypercortisolism, it’s essential to keep the drug at subhypnotic doses, meaning not more than 0.3 mg/kg per hour, emphasized Dr. Zarnecki of the University of Wisconsin, Milwaukee.

Dr. Zarnecki and her coworkers utilize as their standard etomidate infusion protocol an initial 5-mg bolus followed by an infusion at 0.02 mg/kg per hour, with dose titration in increments of 0.01-0.02 mg/kg per hour every 4-6 hours based on changes in serum cortisol level. The goal is to bring the cortisol down to a target range of 10-20 mcg/dL.

She presented an illustrative six-patient series in which she and her colleagues turned to continuous infusion of etomidate because conventional oral therapy would have taken too long to rein in the severe hypercortisolism or because medication side effects were intolerable.

Mean baseline pretreatment serum cortisol was 138 mcg/dL, with an adrenocorticotropic hormone level of 419 pg/mL. Five of the six patients reached the goal of 10-20 mcg/dL in an average time of 64 hours. The mean rate of serum cortisol reduction was 1.93 mcg/dL per hour. The average etomidate infusion rate at the time the target level was reached was 0.07 mg/kg per hour, with a maximum rate of 0.1 mg/kg per hour. Monitoring via the Richmond Agitation Sedation Scale confirmed that none of the patients experienced sedative effects.

In the sole patient who didn’t reach goal, etomidate therapy was suspended because the patient entered palliative care because of extensive tumor progression.

Dr. Zarnecki reported having no financial conflicts of interest.

From Clinical Endocrinology News

%d bloggers like this: