Thyroid dysfunction highly prevalent in Cushing’s syndrome
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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.
Perspective
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Clear progress in treating Cushing’s syndrome and Cushing’s disease has been made, but achieving patients’ optimal outcome is still lagging, including management of hypopituitarism in these patients.
Patients with ACTH-secreting adenomas, even smaller ones, have been found to have a higher than expected prevalence of central hypothyroidism compared with other patients with pituitary adenomas of the same size. This is presumed to be due to glucocorticoid-induced suppression of the hypothalamic-pituitary-thyroid axis.
Excess cortisol can decrease thyroid hormone action at multiple levels, including hypothalamus, pituitary, liver and other peripheral tissues. However, timeline and thyroid axis recovery pattern after treatment of Cushing’s syndrome remain less studied.
In this excellent research by Shekhar and colleagues, one of the largest to date, albeit retrospective, the authors focused on two separate cohorts: one with 68 Cushing’s disease patients looking at temporal pattern of thyroid hormone changes after surgical cure, on glucocorticoid low-dose replacement; and another with 55 Cushing’s syndrome patients with diurnal TSH evaluation before treatment and, for few cases, also during remission.
An interesting finding was that untreated central hypothyroidism was higher than previously thought, in approximately half of patients. The authors also observed normalization of nocturnal TSH secretion, T3 and T4 levels after treatment. Furthermore, preoperative cortisol exposure has been correlated with diminished thyroid hormone both before and after the surgery; thus, we can predict which patients are at higher risk for developing thyroid dysfunction.
Patients with central hypothyroidism also had a significantly higher prevalence of gonadal dysfunction compared with those without central hypothyroidism, highlighting the need for further screening of all pituitary functions in patients with Cushing’s syndrome.
I agree with the authors that a wait-and-watch approach in patients with mild central hypothyroidism without clinical symptoms can be taken after curative surgery, as most will recover over time. Nevertheless, a few patients in this study and in our practice developed new hypothyroidism, thus thyroid function as well as other pituitary ones, including growth hormone and gonadal axis, should be serially evaluated and, if low, replaced as needed.
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