NEPVs for cortisol and ACTH predicted nonremission after TSS for CD.
Background We do not fully understand how hypercortisolism causes central hypothyroidism or what factors influence recovery of the hypothalamic-pituitary-thyroid axis. We evaluated thyroid function during and after cure of Cushing’s syndrome (CS). Methods We performed a retrospective cohort study of adult patients with CS seen from 2005 – 2018 (cohort 1, c1, n=68) or 1985 – 1994 (cohort 2, c2, n=55) at a clinical research center. Urine (UFC) and diurnal serum cortisol (F: ~8AM and ~midnight (PM)), morning triiodothyronine (T3), free thyroxine (FT4) and thyroid stimulating hormone (TSH) (c1) or hourly TSH from 1500-1900h (day) and 2400-04000h (night) (c2), were measured before and after curative surgery. Results While hypercortisolemic, 53% of c1 had central hypothyroidism (low/low normal fT4 + unelevated TSH). Of those followed long-term, 31% and 44% had initially subnormal FT4 and T3, respectively, which normalized 6—12 months after cure. Hypogonadism was more frequent in hypothyroid (69%) compared to euthyroid (13%) patients. Duration of symptoms, AM and PM F, ACTH, and UFC were inversely related to TSH, FT4 and/or T3 levels (r -0.24 to -0.52, P <0.0001 to 0.02). In c2, the nocturnal surge of TSH (mIU/L) was subnormal before (day 1.00±0.04 vs night 1.08±0.05, p=0.3) and normal at a mean of 8 months after cure (day 1.30±0.14 vs night 2.17±0.27, p=0.01). UFC >1000 μg /day was an independent adverse prognostic marker of time to thyroid hormone recovery. Conclusions Abnormal thyroid function, likely mediated by subnormal nocturnal TSH, is prevalent in Cushing’s syndrome and is reversible after cure.
ContextHypertension associated with Cushing's syndrome (CS) increases cardiovascular risk. The time‐course of improvement after cure is unclear.ObjectiveTo describe the time‐course and predictors of blood pressure (BP) normalization during one year after surgical cure of CS.DesignRetrospective chart review of 75 hypertensive adults cured of CS (72 with ACTH‐dependent CS; 3 with adrenal adenoma). Hypertension was defined as current use of antihypertensives, a systolic BP >130 mm Hg, or diastolic BP >80 mm Hg.Main Outcome Measure(s)Remission of hypertension: BP ≤130/80 mm Hg and no antihypertensive medications. Improvement in hypertension: BP >130/80 mm Hg and decreased number or dose of medications, or blood pressure ≤130/80 with continued use of medications at constant dose.ResultsAt postoperative discharge, 17 (23%, P < .001), 51 (68%, P < .001) and 7 (9%) patients had remission, improvement in hypertension or no change. Twenty‐nine had no follow‐up. Others achieved remission at 3 (n = 5), 6 (n = 6), or 12‐months (n = 5). At the last evaluation, 33/75 (44%) had remission, 36/75 (48%) had improved hypertension and 6 were unchanged. Patients with improvement discontinued a median of one medication (P < .001). At 12‐months, 27/42 (64%) patients had normal BP (P < .002). Longer estimated duration of CS (P = .0106), younger age (P = .0022), and lower baseline body mass index (P = .0413) predicted hypertension remission.ConclusionsAbout 80% of CS patients experienced BP normalization or improvement within 10 days of cure, but about half failed to normalize BP by one year. BP should be monitored after cure, and antihypertensive medications adjusted to avoid unwanted cardiovascular effects.
Background Increased tissue cortisol availability has been implicated in abnormal glucose and fat metabolism in patients with obesity, metabolic syndrome, and type 2 diabetes (T2DM). Our objective was to evaluate whether blockade of glucocorticoid receptor (GR) with mifepristone ameliorates insulin resistance (IR) in overweight/obese subjects with glucose intolerance. Methods We conducted a randomized, double-blinded, placebo-controlled, cross-over study in overweight/obese individuals (n=16, 44% female) with pre-diabetes or mild T2DM but not clinical hypercortisolism. Mifepristone (50 mg every 6 hours) or placebo was administered for 9 days, followed by crossover to the other treatment arm after a washout period of 6 to 8 weeks. At baseline and following each treatment, oral glucose tolerance test (OGTT) and frequently sampled intravenous glucose tolerance test (FSIVGTT) were performed. Insulin sensitivity was measured using FSIVGTT (primary outcome: insulin sensitivity index; SI) and OGTT (Matsuda index, MI, and oral glucose insulin sensitivity index, OGIS). Hepatic and adipose insulin resistance were assessed using hepatic insulin resistance index (HIRI), and adipose tissue insulin sensitivity index (Adipo-SI) and adipo-IR, derived from the FSIVGTT. Results Mifepristone administration did not alter whole-body glucose disposal indices of insulin sensitivity (SI, MI, and OGIS). GR blockade significantly improved Adipo-SI (61.7±32.9 vs. 42.8±23.9; p=0.002) and reduced Adipo-IR (49.9±45.9 vs. 65.5±43.8; p=0.004), and HIRI (50.2±38.7 vs. 70.0±44.3; p=0.08). Mifepristone increased insulin clearance but did not affect insulin secretion or β-cell glucose sensitivity. Conclusion Short-term mifepristone administration improves adipose and hepatic insulin sensitivity among obese individuals with hyperglycemia without hypercortisolism.
Patients with CS can develop spontaneous surgical abdomen with rapid decompensation within hours. Prompt recognition is critical in the successful treatment of these patients.
Background: It is well known that persistent hypercortisolemia suppresses thyroid and gonadal function. However, there are few data on the degree and type of derangement or the course of recovery of these axes after cure. To investigate this, we studied the pre- and post-surgical characteristics of the gonadal and thyroid axis hormones in CS patients (pts). Methods: We retrospectively reviewed records of 23 adult CS pts admitted to our protocols from 2010 - 2018 who received curative surgery with follow-up for 6 - 12 months (6M-12M). We recorded morning serum free T4 (fT4) and TSH, and morning LH, FSH, estradiol (E, premenopausal only) or testosterone (T, in men only) values before (0M), and 6M and 12M after definitive surgery. The rate of abnormal values was calculated at each timepoint. Data were analyzed using SPSS 23 software and are shown as percentage, mean ± SD or median(Interquartile Range). Results: Pt age was 45.6 ± 10.8 years; 21 (91%) were female. Before surgery fT4 (Nl: 0.9 - 1.7ng/dL) and TSH (Nl: 0.27 - 4.2mcIU/mL) were low normal. Subnormal values were seen for LH (13%), FSH (9.5%), E (14.2%, Nl: 15 - 350 pg/mL) and T (100%, n=2, Nl: 181-758ng/dL). fT4 increased from 0.96 ± 0.2 at 0M to 1.12 ± 0.13 at 12M (p=0.016), remaining in the lower half of the normal range. TSH increased significantly from 0M (0.98 ± 0.57) to 6M (2.8 ± 1.4) and 12M (2.9 ± 0.13) (p<0.0005 for both). In premenopausal women (n=14), there was a statistically significant (SS) change from 0M to 12M in both serum E (38.9 pg/mL (21.4 - 51) to 132.3 pg/mL (84.2 - 388), p=0.028) and LH levels (2.9 U/L (3.3 - 5.9) to 7.5 (3.6 - 13.6), nl(follicular phase): 1-12 U/L, p=0.019); the change in E, LH and FSH at 6M and in FSH at 12M was not SS. Menses were documented only in 8; resumption of normal cycles occurred 2 - 11 months after surgery. In postmenopausal females(n=7) there were no SS changes in LH or FSH from OM (LH: 21.4+11.1, nl: 11-40 U/L; FSH 54.3+30.5, nl: 22-153 U/L) to 6M or 12M. One man was taking T at 0M and one had a low T level at 0M (88.2 ng/dL) that normalized (357 ng/dL, nl: 181 - 758ng/dL ) at 6M.Conclusions: HPT and HPG axes improved after cure. While the HPT axis may start recovery at 6M, reflected by SS rise in TSH at 6M, HPG axis recovery was more homogeneous. Larger studies are needed to uncover the effects of hypercortisolemia on Hypothalamic-Pituitary-End organ axes and timelines of their recovery after treatment.
Background: Hypercortisolemia adversely affects thyroid hormone secretion. We previously described the temporal pattern of thyroid function recovery in 23 patients (1). However, the factors leading to suppression and recovery of the hypothalamic-pituitary-thyroid (HPT) axis in Cushing’s syndrome (CS) are not fully understood. We performed two separate studies to investigate these factors. Methods: In study 1, we examined patients (pts, n=62) with CS who underwent curative surgery and recorded their serum morning and evening cortisol, ACTH, tumor volume and duration of symptoms and 24-hour urine free cortisol (UFC) at baseline and the morning serum free T4, TSH and T3 at six-month intervals after cure. Data were log-transformed and Pearson correlations were performed. Linear mixed models were used to study factors that predict recovery of thyroid function. In study 2, we examined the diurnal variation of TSH by performing hourly TSH measurement between 3—7 PM and 12—4 AM on a cohort of pts (n=45) before surgery. Wilcoxon Signed-Rank method was used for comparisons of mean TSH across time and Pearson correlations were performed on log-transformed data. P values <.05 were considered significant. Results: Study 1: In this larger cohort, we confirmed previous findings of suppressed or low normal fT4 and TSH values with active hypercortisolism, with normalization after cure that reflected changes in the T3:TSH, fT4:TSH and T3:fT4 ratios. There were inverse linear correlations between log10 UFC, serum AM and PM cortisol; and log10 TT3, fT4 and TSH before surgery. Independent negative prognosticators of circulating fT4 recovery included UFC greater than 1000mcg/day (nl: 3.5—45mcg/day), duration of symptoms of less than one year, and ACTH levels greater than 60pg/mL(nl: 5—45pg/mL) Study 2: The nocturnal (12 - 4AM) TSH surge was reduced, so that the difference in day and night TSH values was not statistically significant; this contrasts with the 30—50% nocturnal TSH increase above daytime values seen in healthy subjects. There was an inverse relationship between UFC and nocturnal TSH, daytime TSH and TBG values, but there was no direct relationship between UFC and percent changes in nocturnal TSH values. Conclusions: Our findings suggest that a deficit in TSH stimulation of the thyroid gland may explain the reduction in T3 and T4 levels. There is a dose-response relationship between various measures of hypercortisolemia and both thyroid hormones and the pattern of TSH secretion. Finally, the severity of hypercortisolism correlates with a longer time to recovery of the HPT axis in pts with CS after curative surgery. 1. Shekhar S et al. HPG and HPT Axes in Cushing Syndrome. J Endocr Soc, 3 S1, April May 2019
Background: Cyclical Cushing’s syndrome (CCS) is characterized by alternating periods of endogenous hypercortisolism and eucortisolism. A literature survey of 60 adult patients with CCS found 15 to have ectopic ACTH secretion (EAS) (1). The duration and frequency of hypercortisolemia are unpredictable, creating a diagnostic challenge. Objective: Describe biochemical and clinical characteristics of patients with CCS due to occult or histologically proven ectopic ACTH-secreting neuroendocrine tumor (NET). Methods: We conducted a retrospective medical record review of 12 adults with EAS admitted to our institution. Inclusion required 1) evidence of ectopic ACTH tumor from biochemical testing (CRH stimulation, 8 mg dexamethasone suppression [DST], and/or inferior petrosal sinus sampling [IPSS]) or pathology results and 2) cycles of hypercortisolism (Hi-F) to eucortisolism (Eu-F) off medical treatment. Results: Average age on admission was 61 (46-79) years; 58% were women. All 12 had biochemical evidence of ACTH-dependent Hi-F. IPSS results suggested EAS in 9 patients, 8 of whom had Hi-F for more than two months, and 1 whose cycles occurred every 5 - 7 days. IPSS was consistent with Cushing’s disease (CD) in 2 patients after Hi-F of only 6 -7 weeks and one with Eu-F on admission, estimated duration < 4 weeks. DST suggested EAS in 9 patients, and CD in the one with recent Eu-F. CRH was consistent with EAS in 10 patients, but suggested CD in 2 with marginal increases in ACTH (34.5%, 38%) but not cortisol. 7 patients had ACTH-secreting tumor on pathology (5 pulmonary, 1 pancreas, 1 appendix NET), and 5 had occult presumed EAS. Time from one Hi-F episode to the next ranged from 1 week to 6 years with Hi-F duration of 3 days to 5 years. 24-hour urine free cortisol (UFC) levels were 17 - 301 times the upper reference range (RR) during Hi-F periods. During Eu-F, lowest UFCs were within RR in 9 patients and subnormal in 3. Hypokalemia occurred in 11 patients with Hi-F; increasing values paralleled movement to Eu-F. Conclusion: Patients with possible ectopic ACTH-secretion and CCS may pose a diagnostic challenge: clinical and biochemical evidence of hypercortisolemia may not be present, depending on the timing and/or duration of hypercortisolism. Furthermore, test results may inappropriately suggest Cushing’s disease if performed after less than 8 weeks of hypercortisolism, or with recent eucortisolism. Thus, weekly UFC measurement may facilitate diagnosis of cyclical Cushing’s syndrome and determine appropriate timing of dynamic testing such as inferior petrosal sinus sampling. Potassium may be a useful marker to determine when medical treatment can be tapered or stopped. 1. Meinardi JR, et al. Eur J Endocrinol. 157:245, 2007.
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