Normal 24-hour Urinary Free Cortisol Research Articles

Intensity-Modulated Radiotherapy (IMRT) for the Treatment of Cushing's Disease

Aim to investigate the efficacy and toxicity of IMRT in treating Cushing's Disease (CD). A total of 78 of 115 patients with CD treated with IMRT at our institute from April 2012 to August 2021 were included in the study. The radiation doses were usually 45-50 Gy in 25 fractions. After IMRT, endocrine evaluations were performed every 6 months and magnetic resonance imaging (MRI) annually. Endocrine remission was defined as suppression of 1 mg dexamethasone test (DST) or normal 24-hour urinary free cortisol level (24hUFC). Endocrine recurrence was considered when patients who have reached hormonal remission showed no suppression of 1 mg DST and relapse of clinical features. The outcome of endocrine remission, tumor control and complications were retrieved from medical record. At a median follow-up time of 36.8 months, the endocrine remission rate at 1, 2, 3 and 5 years were 28.5%, 50.2%, 62.5% and 74.0%, respectively. The median time to remission was 24 months (95% CI: 14.0-34.0). Endocrine recurrence was found in 5 patients (13.5%) till the last follow-up. The recurrence-free rate at 1, 2, 3 and 5 years after endocrine remission was 98.2%, 93.9%, 88.7% and 88.7%, respectively. The tumor control rate was 98%. The overall incidence of new onset hypopituitarism was 23.1%, with hypothyroidism serving as the most common individual axis deficiency. Univariate analysis indicated that only higher Ki-67 index (P = 0.044) was significant favorable factors for endocrine remission. But no prognostic factors for endocrine remission were found in the multivariate analysis. IMRT was a highly effective second-line therapy with low side effect profile for CD patients. Endocrine remission, tumor control and recurrence rates were comparable to previous reports on FRT and SRS.

Intensity-modulated radiotherapy for cushing's disease: single-center experience in 70 patients.

Intensity-modulated radiotherapy (IMRT) is a modern precision radiotherapy technique for the treatment of the pituitary adenoma. Aim to investigate the efficacy and toxicity of IMRT in treating Cushing's Disease (CD). 70 of 115 patients with CD treated with IMRT at our institute from April 2012 to August 2021 were included in the study. The radiation doses were usually 45-50 Gy in 25 fractions. After IMRT, endocrine evaluations were performed every 6 months and magnetic resonance imaging (MRI) annually. Endocrine remission was defined as suppression of 1 mg dexamethasone test (DST) or normal 24-hour urinary free cortisol level (24hUFC). The outcome of endocrine remission, endocrine recurrence, tumor control and complications were retrieved from medical record. At a median follow-up time of 36.8 months, the endocrine remission rate at 1, 2, 3 and 5 years were 28.5%, 50.2%, 62.5% and 74.0%, respectively. The median time to remission was 24 months (95%CI: 14.0-34.0). Endocrine recurrence was found in 5 patients (13.5%) till the last follow-up. The recurrence-free rate at 1, 2, 3 and 5 years after endocrine remission was 98.2%, 93.9%, 88.7% and 88.7%, respectively. The tumor control rate was 98%. The overall incidence of new onset hypopituitarism was 22.9%, with hypothyroidism serving as the most common individual axis deficiency. Univariate analysis indicated that only higher Ki-67 index (P=0.044) was significant favorable factors for endocrine remission. IMRT was a highly effective second-line therapy with low side effect profile for CD patients. Endocrine remission, tumor control and recurrence rates were comparable to previous reports on FRT and SRS.

Efficacy of whole-sellar gamma knife radiosurgery for magnetic resonance imaging-negative Cushing's disease.

Corticotroph adenoma delineation in Cushing's disease (CD) patients with previous surgery can be challenging. This study investigated the outcome of whole-sellar gamma knife radiosurgery (GKRS) in MRI-negative, but hormone-active CD patients with prior failed treatment attempts. We retrospectively analyzed data of nine CD cases who underwent whole-sellar GKRS between April 2008 and April 2020 at a single center. Remission was determined as normal morning serum cortisol, normal 24-hour urinary free cortisol (UFC) or extended postoperative requirement for hydrocortisone replacement. Median age was 35.0 years, and most of the cases were female (89%). All subjects had undergone previous surgery. The mean pre-GKRS morning serum cortisol and 24-hour UFC were 27.5 μg/dL and 408.0 μg, respectively. Target volume varied from 0.6 to 1.8 cc, and the median margin dose was 28 Gy. The median duration of endocrine follow-up was 105 months, and initial endocrine remission was achieved in eight subjects (89%) at a median time of 22 months. The actuarial initial remission was 44% at two years, 67% at four years, and 89% at six years. The mean recurrence-free survival was 128 months. Age and pre-GKRS morning serum cortisol was found to be predictors for initial and durable endocrine remissions. New-onset hypopituitarism was observed in two of five patients (40%). None of the patients developed new neurological deficits and had GKRS-related adverse events during the follow-up. Whole-sellar GKRS is a safe and efficient method to manage MRI-negative CD and provides similar GKRS outcome rates as in MRI-positive CD.

Efficacy and Safety of Stereotactic Radiotherapy in Cushing's Disease: A Single Center Experience.

To determine the efficacy and safety of stereotactic radiotherapy (RT) in patients with Cushing's disease (CD). The study included 38 patients [31 patients who received gamma knife radiosurgery (GKS) and 7 patients who received cyberknife hypofractionated RT (HFRT)] with CD. Hormonal remission was considered if the patient had suppressed cortisol levels after low dose dexamethasone, normal 24-hour urinary free cortisol (UFC), and lack or regression of clinical features. Biochemical control after RT was observed in 52.6% of the patients with CD and median time to hormonal remission was 15 months. Tumor size control was obtained in all of the patients. There was no significant relationship between remission rate and laboratory, radiological and pathological variables except for preoperative UFC. Remission rate was higher in patients with lower preoperative UFC. Time to remission increased in parallel to postoperative cortisol and 1mg DST level. Although medical therapy before RT did not affect the rate of- and time to remission, medical therapy after RT prolonged the time to hormonal remission. In this current single center experience, postoperative cortisol and 1mg DST levels were found as the determinants of time to remission. Although medical therapy before RT did not affect the rate of- and time to remission, medical therapy after RT prolonged the time to biochemical control . This latter finding might suggest a radioprotective effect of cortisol lowering medication use on peri-RT period.

SUN-377 Adrenal Incidentaloma Evaluation in Critical Illness: A Diagnostic Dilemma

Background: Adrenal incidentalomas (AIs) are a “disease of modern technology” with a prevalence of ~5%, expected to increase as imaging modalities become more sensitive and widely available. While the majority of AIs are benign, ~15% are malignant or associated with hormone over secretion, thus all AIs require prompt investigation. The recommended diagnostic testing for AIs is validated in healthy outpatient subjects, with no established algorithm for the inpatient/critical illness setting. Clinical Case: A 66 year-old male with hypertension and type 2 DM, recent myocardial infarction, presented in cardiogenic shock. His course was complicated by an episode of cardiac arrest with successful resuscitation. Due to inotrope and intra-aortic balloon pump dependency, he was urgently evaluated for left ventricular assist device (LVAD). A non-contrast abdominal CT obtained during pre-LVAD workup, showed a 2.4 x 1.9 cm right adrenal nodule of indeterminate density. The review of systems was positive for erectile dysfunction, and negative for easy bruising, facial plethora, fractures, proximal muscle weakness or weight changes. Physical examination revealed absence of Cushingoid features. Laboratory testing showed an abnormal overnight 1mg dexamethasone suppression test (DST) (12.1 mcg/dL , n: < 1.8 mcg/dL), elevated ACTH (75pg/mL, n: 7-69pg/mL), elevated AM serum cortisol (40.7 mcg/dL, n: 5-23 mcg/dL), elevated PM serum cortisol (21.7 mcg/dL, n: 3-15 mcg/dL). He had normal 24-hour urinary free cortisol, serum DHEAS, plasma renin activity and aldosterone concentration. Repeat adrenal CT scan showed a 1.6 x 1.9 cm R adrenal nodule, non-contrast density 33 HU, venous phase 99 HU and delayed phase 55 HU (washout 45%) concerning for pheochromocytoma. However, plasma and urine metanephrines and catecholamines were normal. The absence of Cushingoid features and evidence of ACTH dependent hypercortisolism with normal diurnal variation (despite an abnormal DST) ruled out Cushing’s syndrome, and the patient successfully underwent LVAD surgery. A literature review revealed only 2 AI cases evaluated during critical illness. While both cases had an abnormal DST without normal diurnal variation, only one case had similar ACTH dependent hypercortisolemia. Conclusion: This case illustrates the dilemma surrounding the evaluation of AIs in the setting of critical illness, the lack of inpatient/critical illness specific guidelines and the importance of clinical assessment. Furthermore, it suggests a possible diagnostic approach that can be considered in similar clinical situations.

SAT-487 Unusual Case of Plurihormonal Pituitary Macroadenoma

Introduction Plurihormonal Pituitary adenoma is defined as an adenoma that expresses more than one hormone on immunohistochemistry. The most common combination in these adenomas includes growth hormone (GH) and prolactin (PRL). Case Description: A 65-year-old woman known to have known to have type 2 diabetes, hypertension, and class-III obesity, presented with an intractable headache and blurring vision. She also had significant worsening of her diabetes control recently despite being on insulin. CT brain and later Magnetic resonance imaging (MRI) pituitary showed a large sellar mass which measured 2.9 cm x 1.5 cm, compressing the neurophysis and the optic chiasm. Her initial investigations showed elevated corticotrophin (ACTH) level 33.6 pmol/L (1.03 - 10.7), prolactin level was high at 66.3 ng/ml (5.18 - 26.53ng/ml) and the rest of anterior pituitary hormones and IGF-1 were normal apart from primary hypothyroidism. She didn’t particularly look cushingoid, apart from the rounded face and central obesity. Cushing’s disease was confirmed on a failure of cortisol to suppress to 1mg dexamethasone (serum cortisol 783 nmol/L) and high 24-hour urinary free Cortisol at 391 ug/24 (6-123. She underwent transsphenoidal surgery (TSS) for decompression of the optic chiasm which was successful to normalize the visual fields, however, a residual tumor was still present on follow up MRI after 3 months. Interestingly, immunohistochemistry showed staining for ACTH, GH, and prolactin, Ki67 was less than 2%. Follow up evaluation showed a normal response to 1 mg suppression test and normal 24-hour urinary free cortisol. Conclusions: We present a very interesting case of plurihormonal pituitary adenoma with triple immunohistochemical stating for ACTH, GH, and Prolactin, This triple immunostaining combination is very rare and only reported in the literature once. In contrast to the other case, our patient is diagnosed in a post-menopausal woman who didn't experience florid cushingoid symptoms and she never experienced any hormonal symptoms of acromegaly or hyperprolactinemia

Outcome of Transsphenoidal Surgery for Cushing Disease: A Single-Center Experience over 20 Years

This study investigated the outcome of transsphenoidal surgery (TSS) for Cushing disease (CD) and the influence of our surgical strategy on remission rates and postoperative pituitary function. We retrospectively reviewed data from 71 patients with CD who underwent microscope navigation TSS (MN-TSS) in Saint-Luc Hospital between 1996 and 2017. True remission was defined as normal fasting cortisol level, normal 24-hour urinary free cortisol, or continued need for hydrocortisone replacement for 1 year after surgery. Overall remission rate after 1 or repeated MN-TSS was 83%. Highest remission rate was found in patients with macroadenomas (92%). Successful first MN-TSS was correlated with a high final remission rate (95%), whereas failed first MN-TSS was correlated with a low final remission rate (36%). Although day 1 cortisol levels were significantly lower in patients with long-term remission, high levels were still observed in a few patients, especially those who had had CD for many years. We found a low rate of postoperative pituitary long-term hypofunction (9.7%). MN-TSS is a safe and effective procedure to treat CD, allowing remission rates of 83%. One-year remission period after first surgery is correlated with a final remission rate of 95%. Although day 1 morning cortisol value is the most significant predictor for long-term remission, some patients with CD for many years may keep high postoperative cortisol levels and be in later remission, likely because of secondary adrenal hyperplasia. Our focused approach with microscope navigation resulted in low rates of postoperative pituitary hypofunction and kept a recurrence rate comparable to that in the literature.

Outcome of Microscopic Transsphenoidal Surgery in Cushing Disease: A Case Series of 96 Patients

To analyze the results of transsphenoidal surgery in patients with Cushing disease and outcome. Retrospective analysis of the records of 96 patients with Cushing disease from 1997 to 2012. There were 73 females and 23 males, with a mean follow-up of 44 months (range, 3-13 years). The sex ratio was significantly different in children and teenagers versus adults. Magnetic resonance imaging showed microadenoma, macroadenoma, and no adenoma in 66, 18, and 12 patients, respectively. There was no surgical mortality. Early remission (normal 24-hour urinary free cortisol and basal serum cortisol <5 μg/dL) was achieved in 94.8%. Regression analysis showed that only tumor size, cavernous sinus extension, and tumor consistency influenced remission. Recurrence was seen in 21.9%. Regression analysis showed that age, preoperative basal cortisol levels, and follow-up duration influenced recurrence. Correlation analysis showed that there was a significant negative correlation between patient age and the follow-up period. After detection of recurrence, 17 patients underwent repeat transsphenoidal surgery that resulted in remission in 12 patients (70.6%). The other 5 patients were referred for gamma knife radiosurgery or bilateral adrenalectomy. Transsphenoidal surgery is a safe and highly efficient procedure in the treatment of Cushing disease. Macroadenomas, cavernous sinus invasion, and harder tumor consistencies, however, are associated with lower remission rates (higher disease persistence) and younger age, higher preoperative cortisol levels, and longer follow-up periods are associated with higher recurrence.

Current state of the art in the diagnosis and surgical treatment of Cushing disease: early experience with a purely endoscopic endonasal technique

Object Transsphenoidal pituitary surgery is the primary therapy for Cushing disease because of its potential to produce lasting remission without the need for long-term drug or hormone replacement therapy. The authors evaluated the current role of pure endoscopic endonasal pituitary surgery in the treatment of Cushing disease. Methods Twenty-five patients underwent pure endoscopic surgery for confirmed Cushing disease. Thirteen patients had microadenomas and seven had macroadenomas; magnetic resonance images obtained in five patients were only suspicious or nondiagnostic, and thus they underwent inferior petrosal sinus sampling. Two patients had evidence of cavernous sinus involvement. Final histological results were consistent with adrenocorticotropin hormone (ACTH)–secreting adenoma in 20 patients. Results Twenty patients (80%) had clinical remission and laboratory confirmation of hypocortisolemia (serum cortisol < 100 nmol/L requiring substitution therapy), suppression to low-dose dexamethasone, and normal 24-hour urinary free cortisol. The median follow-up period was 17 months (range 3–32 months). There was no recurrence at the time of the last follow-up. Three patients presented with new anterior pituitary deficiency, but no one had permanent diabetes insipidus. In one patient a cerebrospinal fluid leak developed but later resolved following lumbar drainage. Treatment failure was attributable to involvement of the cavernous sinus in two patients, incomplete tumor removal in one, negative exploration in one, and nodular corticotroph hyperplasia of the pituitary gland in one. Conclusions Early results indicated that endoscopic endonasal surgery is a safe and effective treatment for ACTH-producing adenomas. The rate of remission in this study is comparable to those in previous series, and the rate of major postoperative complications is extremely low. Further studies with a larger number of patients and longer follow-ups are required to determine whether this more minimally invasive pure endoscopic approach should become the standard of care for the surgical treatment of Cushing disease.

Current state of the art in the diagnosis and surgical treatment of Cushing disease: early experience with a purely endoscopic endonasal technique

Transsphenoidal pituitary surgery is the primary therapy for Cushing disease because of its potential to produce lasting remission without the need for long-term drug or hormone replacement therapy. The authors evaluated the current role of pure endoscopic endonasal pituitary surgery in the treatment of Cushing disease. Twenty-five patients underwent pure endoscopic surgery for confirmed Cushing disease. Thirteen patients had microadenomas and seven had macroadenomas; magnetic resonance images obtained in five patients were only suspicious or nondiagnostic, and thus they underwent inferior petrosal sinus sampling. Two patients had evidence of cavernous sinus involvement. Final histological results were consistent with adrenocorticotropin hormone (ACTH)-secreting adenoma in 20 patients. Twenty patients (80%) had clinical remission and laboratory confirmation of hypocortisolemia (serum cortisol < 100 nmol/L requiring substitution therapy), suppression to low-dose dexamethasone, and normal 24-hour urinary free cortisol. The median follow-up period was 17 months (range 3-32 months). There was no recurrence at the time of the last follow-up. Three patients presented with new anterior pituitary deficiency, but no one had permanent diabetes insipidus. In one patient a cerebrospinal fluid leak developed but later resolved following lumbar drainage. Treatment failure was attributable to involvement of the cavernous sinus in two patients, incomplete tumor removal in one, negative exploration in one, and nodular corticotroph hyperplasia of the pituitary gland in one. Early results indicated that endoscopic endonasal surgery is a safe and effective treatment for ACTH-producing adenomas. The rate of remission in this study is comparable to those in previous series, and the rate of major postoperative complications is extremely low. Further studies with a larger number of patients and longer follow-ups are required to determine whether this more minimally invasive pure endoscopic approach should become the standard of care for the surgical treatment of Cushing disease.

Gamma Knife surgery for Cushing's disease

In this study the authors address the efficacy and safety of Gamma Knife surgery (GKS) in patients with adrenocorticotropic hormone-secreting pituitary adenomas. A review of data collected from a prospective GKS database between January 1990 and March 2005 was performed in patients with Cushing's disease. All but one patient underwent resection for a pituitary tumor, without achieving remission. Successful endocrine outcome after GKS was defined as a normal 24-hour urinary free cortisol (UFC) concentration posttreatment after a minimum of 1 year of follow up. Patient records were also evaluated for changes in tumor volume, development of new hormone deficiencies, visual acuity, cranial nerve neuropathies, and radiation-induced imaging changes. Ninety evaluable patients had undergone GKS, with a mean endocrine follow-up duration of 45 months (range 12-132 months). The mean dose, to the tumor margin was 23 Gy (median 25 Gy). Normal 24-hour UFC levels were achieved in 49 patients (54%), with an average time of 13 months after treatment (range 2-67 months). In the 49 patients in whom a tumor was visible on the planning magnetic resonance (MR) image, a decrease in tumor size occurred in 39 (80%), in seven patients there was to change in size, and tumor growth occurred in three patients. Ten patients (20%) experienced a relapse of Cushing's disease after initial remission; the mean time to recurrence was 27 months (range 6-60 months). Seven of these patients underwent repeated GKS, with three patients achieving a second remission. New hormone deficiencies developed in 20 patients (22%), with hypothyroidism being the most common endocrinopathy after GKS. Five patients experienced new visual deficits or third, fourth, or sixth cranial nerve deficits; two of these patients had undergone prior conventional fractionated radiation therapy, and four of them had received previous GKS. Radiation-induced changes were observed on MR images in three patients; one had symptoms attributable to these changes. Gamma Knife surgery is an effective treatment for persistent Cushing's disease. Adenomas with cavernous sinus invasion that are not amenable to resection are treatable with the Gamma Knife. A second GKS treatment appears to increase the risk of cranial nerve damage. These results demonstrate the value of combining two neurosurgical treatment modalities-microsurgical resection and GKS-in the management of pituitary adenomas.

Stereotactic radiosurgery for Cushing disease.

The most common cause of Cushing syndrome is Cushing disease, in which hypercortisolism is produced by a functional adrenocorticotropic hormone-producing adenoma of the anterior pituitary gland. The common therapies available include microsurgical resection, conventional fractionated radiotherapy, and stereotactic radiosurgery (SRS). In this article the authors review the indications, results, and complications associated with SRS in the treatment of Cushing disease. In as many as 90% of patients SRS results in disease remission, which is defined as a normal 24-hour urinary free cortisol level and a normal or subnormal morning serum cortisol level. Although in most patients who are subsequently cured a marked decrease in the serum cortisol level is demonstrated within 3 months after treatment, a biochemical cure may be delayed up to 3 years in some cases. Complications following SRS for pituitary adenomas are uncommon, particularly in patients with microadenomas, which are most commonly seen in Cushing disease. The most common complication is hypopituitarism, which occurs in up to 50% of patients with a mean latency period of 5 years. Radiation-induced optic neuropathy has been reported in less than 2% of cases and induction of a secondary neoplasm in less than 1% of cases. For patients with Cushing disease, the rate of endocrinological cure following SRS appears to be similar to that attained using microsurgical resection. In contrast to surgery, SRS has the benefit of being noninvasive and associated with a very low incidence of diabetes insipidus, although hypopituitarism may be more common with SRS. With continued follow-up patient reviews and additional experience with SRS, it may become possible to make more definitive statements regarding SRS as the initial treatment for patients with Cushing disease.

Reduced hypothalamic-pituitary and sympathoadrenal responses to hypoglycemia in women with fibromyalgia syndrome

PURPOSE: To perform a detailed comparison of the hypothalamic-pituitary-adrenal axis and the sympathoadrenal system in women with and without fibromyalgia. SUBJECTS AND METHODS: Fifteen premenopausal women who met the 1990 American College of Rheumatology criteria for the diagnosis of fibromyalgia and 13 healthy, premenopausal women were enrolled. We measured baseline 24-hour urinary free cortisol levels and evening and morning adrenocorticotropic hormone (ACTH) and cortisol levels, performed stepped hypoglycemic hyperinsulinemic clamp studies in which serum glucose levels were decreased from 5.0 to 2.2 mmol/L, and compared the effects of infusions of placebo and ACTH. RESULTS: Women with fibromyalgia had normal 24-hour urinary free cortisol levels and normal diurnal patterns of ACTH and cortisol. There was a significant, approximately 30%, reduction in the ACTH and epinephrine responses to hypoglycemia in women with fibromyalgia compared with controls. Prolactin, norepinephrine, cortisol, and dehydroepiandrosterone responses to hypoglycemia were similar in the two study groups. In subjects with fibromyalgia, the epinephrine response to hypoglycemia correlated ( P = 0.01) inversely with overall health status as measured by the fibromyalgia impact questionnaire. Graded ACTH infusion revealed similar increases in cortisol in women with fibromyalgia and healthy controls. CONCLUSIONS: Patients with fibromyalgia have an impaired ability to activate the hypothalamic-pituitary portion of the hypothalamic-pituitary-adrenal axis as well as the sympathoadrenal system, leading to reduced ACTH and epinephrine responses to hypoglycemia.