Dynamics of postoperative serum cortisol after transsphenoidal surgery for Cushing’s disease: implications for immediate reoperation and remission

OBJECTIVESuccessful transsphenoidal surgery for adrenocorticotropin hormone (ACTH)–producing pituitary tumors is associated with subnormal postoperative serum cortisol levels, which may guide decisions regarding immediate reoperation. However, little is known about the detailed temporal course of changes in serum cortisol in the immediate postoperative period, and the relationship of postoperative cortisol dynamics to remission and late recurrence.METHODSA single-center retrospective cohort analysis was performed for all patients undergoing pituitary surgery from 2007 through 2015. Standardized diagnostic and treatment algorithms were applied to all patients with potential Cushing’s disease (CD), including microsurgical transsphenoidal adenomectomy (TSA) by a single surgeon. All patients had serum cortisol levels drawn at 6-hour intervals for 72 hours after surgery, and were offered reoperation within 3 days for normal or supranormal postoperative cortisol levels. Primary outcomes were 6-month remission and late recurrence; secondary outcomes were persistent postoperative hypocortisolism and surgical morbidity. Discriminatory levels of postoperative serum cortisol for predicting remission were calculated at various intervals after surgery using receiver operating characteristic (ROC) curves.RESULTSAmong 89 patients diagnosed with CD, 81 underwent initial TSA for a potentially curable lesion; 23 patients (25.8%) underwent an immediate second TSA. For the entire cohort, 6-month remission was achieved in 77.8% and late recurrences occurred in 9.5%, at a mean of 43.5 months. Compared with patients with a single surgery, those with an immediate second TSA had similar rates of remission (78.3% vs 77.6%) and late recurrence (5.6% vs 11.1%). The rate of hypocortisolism for patients with 2 surgeries (12/23, 52.2%) was significantly greater than that for patients with single surgeries (13/58, 22.4%; p < 0.001). There was no difference in the incidence of CSF leaks between the first and second operations. Remission was achieved in 58 (92.1%) of 64 patients who completed the 2-surgery protocol. The temporal course of postoperative serum cortisol levels among patients varied considerably, with subnormal nadir levels < 2 μg/dl occurring between 12 hours and 66 hours. Patients achieving remission had significantly lower mean serum cortisol levels at every time point after surgery (p < 0.01). By ROC curve analysis, nadir cortisol levels < 2.1 μg/dl were predictive of 6-month remission for the entire cohort over 3 days (positive predictive value [PPV] = 94%); discriminating cortisol levels for predicting remission on postoperative day (POD) 2 were < 5.4 μg/dl (PPV = 97%), although patients with remission after postoperative cortisol levels of 2–5 μg/dl had a significantly higher rate of late recurrence.CONCLUSIONSThere is substantial variation in the temporal course of serum cortisol levels over the first 72 hours after TSA for CD, with nadir levels predictive for remission occurring as late as POD 3. Although a cortisol level of 2.1 μg/dl at any point was an accurate predictor of 6-month remission, levels less than 5.4 μg/dl on POD 2 were reasonably accurate. These data may enable decisions regarding the efficacy of an immediate second surgical procedure performed during the same hospitalization; immediate reoperation is associated with excellent remission rates and low recurrence rates in patients otherwise unlikely to achieve remission, but carries a higher risk of permanent hypocortisolism.

Download Full-text

Dynamics of Serum Cortisol Levels after Transsphenoidal Surgery in a Cohort of Patients with Cushing’s Disease

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2003-031170 ◽

2004 ◽

Vol 89 (3) ◽

pp. 1131-1139 ◽

Cited By ~ 77

Author(s):

G. A. F. S. Rollin ◽

N. P. Ferreira ◽

M. Junges ◽

J. L. Gross ◽

M. A. Czepielewski

Keyword(s):

Cushing’S Disease ◽

Transsphenoidal Surgery ◽

Serum Cortisol ◽

Cushing's Disease ◽

Cortisol Levels

Download Full-text

Utility of the Immediate Postoperative Cortisol Concentrations in Patients With Cushing's Disease

Neurosurgery ◽

10.1227/01.neu.0000374722.50042.ff ◽

2010 ◽

Vol 67 (3) ◽

pp. 688-695 ◽

Cited By ~ 24

Author(s):

Michael E. Sughrue ◽

Jugal K. Shah ◽

Jessica K. Devin ◽

Sandeep Kunwar ◽

Lewis S. Blevins

Keyword(s):

Confidence Interval ◽

Cortisol Level ◽

Cushing’S Disease ◽

Transsphenoidal Surgery ◽

Fixed Effects ◽

Serum Cortisol ◽

Cushing's Disease ◽

Recurrence Rates ◽

Cumulative Rate ◽

Cortisol Levels

Abstract BACKGROUND Several investigators have recommended serial measurements of serum cortisol in the days following pituitary surgery to identify patients at risk of recurrence. OBJECTIVE We systematically reviewed the literature on this topic and analyzed the usefulness of this test in our own patient population. METHODS We identified studies publishing data regarding recurrence rates after transsphenoidal surgery for Cushing's disease, focusing on studies with data regarding patients with early postoperative cortisol levels. We determined a cumulative relative risk of having a subnormal vs normal cortisol level postoperatively using a fixed-effects meta-analysis model. Additionally, we analyzed our own patients with Cushing's disease undergoing transsphenoidal surgery and performed Kaplan-Meier analysis of recurrence-free survival for patients with undetectable, subnormal but detectable, and normal immediate 8 AM serum cortisol levels. RESULTS Fourteen studies met inclusion criteria. The length of follow-up varied between 32 and 115 months. The cumulative rate of recurrence in the group of patients with subnormal cortisol levels was 9% (95% confidence interval: 6%–12%). The cumulative rate of recurrence in the group with normal cortisol levels was 24% (95% confidence interval: 17%–31%). We analyzed 73 of our own patients and found similar recurrence rates in patients with subnormal vs normal early postoperative cortisol levels (4% vs 22%, χ2 test, P < .05). CONCLUSION Although a subnormal early postoperative cortisol level is predictive of improved outcome after transsphenoidal surgery for Cushing's disease, it is not analogous with cure, nor is a normal level completely predictive of future failure.

Download Full-text

Diagnosis and selective cure of Cushing's disease during pregnancy by transsphenoidal surgery

Acta Endocrinologica ◽

10.1530/eje.0.1320722 ◽

1995 ◽

Vol 132 (6) ◽

pp. 722-726 ◽

Cited By ~ 31

Author(s):

RJM Ross ◽

SL Chew ◽

L Perry ◽

K Erskine ◽

S Medbak ◽

...

Keyword(s):

Cushing’S Disease ◽

Transsphenoidal Surgery ◽

Serum Cortisol ◽

Cushing's Disease ◽

Successful Outcome ◽

Small Female ◽

Free Cortisol ◽

Cortisol Levels ◽

Biochemical Features ◽

Mr Scanning

Ross RJM, Chew SL, Perry L, Erskine K, Medbak S, Afshar F. Diagnosis and selective cure of Cushing's disease during pregnancy by transsphenoidal surgery. Eur J Endocrinol 1995;132:722–6. ISSN 0804–4643 The diagnosis of Cushing's Disease during pregnancy is complex because the biochemical features are obscured by changes in the normal hypothalamo-pituitary-adrenal axis that occur during gestation. To date, treatment has not been successful and there is a high incidence of maternal and fetal complications. We report the case of a 24-year-old woman with Cushing's disease who presented during her 16th week of pregnancy. Diagnosis was confirmed by the finding of elevated serum and urinary free cortisol levels with loss of the normal circadian rhythm of serum cortisol. Cortisol levels failed to suppress after a low-dose dexamethasone test but suppressed after a high-dose test. There was an exaggerated serum cortisol and plasma adrenocorticotrophin (ACTH) response to corticotrophinreleasing hormone (CRH). Magnetic resonance (MR) scanning demonstrated a pituitary tumour and cure was effected by transsphenoidal surgery where tumour immunostaining for ACTH was removed. Postoperatively the patient made an uncomplicated recovery; serum cortisol and plasma ACTH levels were undetectable at 9 days following surgery and recovery of the hypothalamo-pituitary axis occurred at 99 days after surgery. Caesarean section was performed at 38 weeks of pregnancy and a healthy but small female infant was delivered. This case illustrates the biochemical features of Cushing's disease during pregnancy and is the first report of the use of CRH testing and MR scanning in this clinical situation. The cure by surgery and successful outcome for mother and infant, with preservation of normal anterior pituitary function, suggest that transsphenoidal surgery may be the treatment of choice. RJM Ross, Dept of Endocrinology, St Bartholomew's Hospital, London ECIA 7BE, UK

Download Full-text

Surgical management of pediatric Cushing's disease: an analysis of 15 consecutive cases at a specialized neurosurgical center

Arquivos Brasileiros de Endocrinologia & Metabologia ◽

10.1590/s0004-27302010000100004 ◽

2010 ◽

Vol 54 (1) ◽

pp. 17-23 ◽

Cited By ~ 17

Author(s):

Ricardo Santos de Oliveira ◽

Margaret de Castro ◽

Sonir Roberto Rauber Antonini ◽

Carlos Eduardo Martinelli Júnior ◽

Ayrton Custódio Moreira ◽

...

Keyword(s):

Cushing’S Disease ◽

Transsphenoidal Surgery ◽

Pediatric Patients ◽

Serum Cortisol ◽

Plasma Cortisol Level ◽

Hormone Deficiency ◽

Cushing's Disease ◽

Specialized Center ◽

Biochemical Cure

OBJECTIVE: The aim of this study was to review the results of surgery for pediatric patients with Cushing's disease who were less than 18 years old and underwent transsphenoidal surgery in a specialized center during a 25-year period. SUBJECTS AND METHODS: Retrospective study, in which the medical records, histology and pituitary imaging of 15 consecutive pediatric patients with Cushing's disease (mean age: 13 years) were evaluated by the same team of endocrinologists and a neurosurgeon from 1982 to 2006. Patients were considered cured when there was clinical adrenal insufficiency and serum cortisol levels were below 1. 8 µg/dL or 50 nmol/L after one, two, three, or seven days following surgery; they therefore required cortisone replacement therapy. Follow-up was for a median time of 11.5 years (range: 2 to 25 years). RESULTS: Clinical and biochemical cure was achieved in 9/15 patients (60%) exclusively after transsphenoidal surgery. Hypopituitarism was observed in four patients; growth hormone deficiency, in two; permanent diabetes insipidus, in one case. CONCLUSIONS: Cushing's disease is rare in children and adolescents. Transsphenoidal surgery is an effective and safe treatment in most of these patients. Plasma cortisol level < 1. 8 µg/dL following surgery is the treatment goal and is a good predictive factor for long-term cure of Cushing's disease.

Download Full-text

SAT-266 Accelerated Osteoporosis - a Rare Presentation of Cushing’s Disease

Journal of the Endocrine Society ◽

10.1210/jendso/bvaa046.863 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

Author(s):

Vijaykumar Sekar ◽

Joseph Hughes ◽

Sugam Gouli

Keyword(s):

Cushing’S Disease ◽

Low Dose ◽

Incidental Finding ◽

Serum Cortisol ◽

Cushing's Disease ◽

Adrenal Hyperplasia ◽

Bilateral Adrenal Hyperplasia ◽

Cortisol Levels ◽

Post Menopausal ◽

Dexamethasone Suppression

Abstract Background: Osteoporosis in post-menopausal women is usually due to bone loss from estrogen deficiency and/or age. Secondary osteoporosis (SO) is less common. Up to 30% of postmenopausal women and 50% of men with osteoporosis may have an underlying cause. Cushing’s disease (CD) is one cause of SO but rarely the presenting symptoms. The prevalence of osteoporosis (69.6% vs 37.8%) is significantly higher in patients with adrenal rather than pituitary CD. Diagnosing CD remains a challenge to physicians in spite of advances in diagnostic techniques. We report a case of CD in a post-menopausal woman presenting as accelerated osteoporosis. Clinical Case A 63-year-old Caucasian female with a history of hypertension and hysterectomy in her 50s on transdermal estrogen was referred to our Endocrine clinic for evaluation of osteoporosis and incidental finding of bilateral adrenal hyperplasia on CT spine. The patient rapidly developed kyphoscoliosis within the past 2 years. She was debilitated by pain and decreased mobility from compression fractures and spinal stenosis, and underwent thoracic and lumbar fusion surgery. On physical examination, her heart rate was 64 beats per minute, blood pressure 130/92 mmHg, weight 188 lbs. and Height 5.1 ft; a year ago it was 5.5 ft. Her face appeared round but not red. Buffalo hump and supraclavicular pad were noted. No striae or bruises noted. Healing surgical scars over the thoracic and lumbar spine were violaceous. The patient’s urine free cortisol levels, tested a month apart, were 190 mcg and 132 mcg (n 3.5-45 mcg/24h). Midnight salivary cortisol levels taken consecutive nights were 160 ng/dL and 513 ng/dL (n < 100 ng/dL). Morning Serum Cortisol and ACTH were 20.2 ug/dL and 14 pg/mL (n Cortisol 6.0-27.0 ug/dL and ACTH 7.2-63 pg/mL). Following low dose (1mg) dexamethasone suppression testing, her serum cortisol were 12.6 ug/dL, ACTH levels were 32 pg/mL and dexamethasone were 187 ng/dL (n < 30 ng/dL). 25-Hydroxy D total, TSH, Free T4, PTH intact, calcium, renin, aldosterone and SPEP levels were normal. Renal and liver functions were normal except alkaline phosphatase was 142 U/L (n 34-104 U/L). Pituitary MRI with contrast showed pituitary microadenoma. The patient was referred to a neurosurgeon and is planned for an inferior petrosal sinus sampling prior to transsphenoidal resection. Conclusion Cushing’s disease as a cause of osteoporosis is rare. Diagnosis of Cushing’s can be challenging in patients without obvious signs, as in our patient who was referred to an endocrinologist due to incidental finding of bilateral adrenal hyperplasia. A high degree of clinical suspicion is needed when investigating CD, as initial test results can be indecisive. As in our patient, initial ACTH and cortisol levels were normal, the low dose dexamethasone suppression test helped us direct our diagnosis towards CD.

Download Full-text

Evaluation of Cushing's disease remission after transsphenoidal surgery based on early serum cortisol dynamics

Clinical Endocrinology ◽

10.1111/cen.12300 ◽

2013 ◽

Vol 80 (3) ◽

pp. 411-418 ◽

Cited By ~ 27

Author(s):

Fabíola Costenaro ◽

Ticiana C. Rodrigues ◽

Guilherme A. F. Rollin ◽

Nelson P. Ferreira ◽

Mauro A. Czepielewski

Keyword(s):

Cushing’S Disease ◽

Transsphenoidal Surgery ◽

Serum Cortisol ◽

Cushing's Disease ◽

Disease Remission

Download Full-text

Etomidate in the management of severe Cushing’s disease and MRSA bacteraemia in a district general hospital in the United Kingdom

Endocrinology Diabetes and Metabolism Case Reports ◽

10.1530/edm-19-0044 ◽

2019 ◽

Vol 2019 ◽

Author(s):

Stephanie Wei Ping Wong ◽

Yew Wen Yap ◽

Ram Prakash Narayanan ◽

Mohammad Al-Jubouri ◽

Ashley Grossman ◽

...

Keyword(s):

Intensive Care Unit ◽

Intensive Care ◽

General Hospital ◽

Cushing’S Disease ◽

District General Hospital ◽

Serum Cortisol ◽

Cushing's Disease ◽

High Morbidity ◽

List Type ◽

Cortisol Levels

Summary We report our experience on managing a case of florid Cushing’s disease with Methicillin-resistant Staphylococcus aureus (MRSA) sepsis using intravenous etomidate in the intensive care unit of a UK district general hospital. Learning points: Severe Cushing’s syndrome is associated with high morbidity and mortality. Etomidate is a safe and effective medical therapy to rapidly lower cortisol levels even in the context of severe sepsis and immunosuppression. Etomidate should ideally be administered in an intensive care unit but is still feasible in a district general hospital. During treatment with etomidate, accumulation of serum 11β-deoxycortisol (11DOC) levels can cross-react with laboratory cortisol measurement leading to falsely elevated serum cortisol levels. For this reason, serum cortisol measurement using a mass spectrometry assay should ideally be used to guide etomidate prescription.

Download Full-text

Prediction of Recurrence after Transsphenoidal Surgery for Cushing’s Disease: The Use of Machine Learning Algorithms

Neuroendocrinology ◽

10.1159/000496753 ◽

2019 ◽

Vol 108 (3) ◽

pp. 201-210 ◽

Cited By ~ 7

Author(s):

Yifan Liu ◽

Xiaohai Liu ◽

Xinyu Hong ◽

Penghao Liu ◽

Xinjie Bao ◽

...

Keyword(s):

Machine Learning ◽

Cushing’S Disease ◽

Predictive Models ◽

Transsphenoidal Surgery ◽

Characteristic Curve ◽

Serum Cortisol ◽

Machine Learning Algorithms ◽

Cushing's Disease ◽

Morning Serum Cortisol ◽

Better Than

Background: There are no reliable predictive models for recurrence after transsphenoidal surgery (TSS) for Cushing’s disease (CD). Objectives: This study aimed to develop machine learning (ML)-based predictive models for CD recurrence after initial TSS and to evaluate their performance. Method: A total of 354 CD patients were included in this retrospective, supervised learning, data mining study. Predictive models for recurrence were developed according to 17 variables using 7 algorithms. Models were evaluated based on the area under the receiver operating characteristic curve (AUC). Results: All patients were followed up for over 12 months (mean ± SD 43.80 ± 35.61). The recurrence rate was 13.0%. Age (p < 0.001), postoperative morning serum cortisol nadir (p = 0.002), and postoperative (p < 0.001) and preoperative (p = 0.04) morning adrenocorticotropin (ACTH) level were significantly related to recurrence. AUCs of the 7 models ranged from 0.608 to 0.781. The best performance (AUC = 0.781, 95% CI 0.706, 0.856) appeared when 8 variables were introduced to the random forest (RF) algorithm, which was much better than that of logistic regression (AUC = 0.684, p = 0.008) and that of using only postoperative morning serum cortisol (AUC = 0.635, p < 0.001). According to the feature selection algorithms, the top 3 predictors were age, postoperative serum cortisol, and postoperative ACTH. Conclusions: Using ML-based models for prediction of the recurrence after initial TSS for CD is feasible, and RF performs best. The performance of most of ML-based models was significantly better than that of some conventional models.

Download Full-text

Low immediate postoperative serum-cortisol nadir predicts the short-term, but not long-term, remission after pituitary surgery for Cushing’s disease

BMC Endocrine Disorders ◽

10.1186/s12902-015-0055-9 ◽

2015 ◽

Vol 15 (1) ◽

Cited By ~ 11

Author(s):

Jon Ramm-Pettersen ◽

Helene Halvorsen ◽

Johan Arild Evang ◽

Pål Rønning ◽

Per Kristian Hol ◽

...

Keyword(s):

Cushing’S Disease ◽

Pituitary Surgery ◽

Serum Cortisol ◽

Cushing's Disease ◽

Short Term ◽

Postoperative Serum

Download Full-text

ACTH Dependent Cushing’s Syndrome: A 72-Hour Trial of Octreotide will Identify Patients with Pituitary Dependent and Ectopic ACTH Overproduction

Journal of Advances in Medicine and Medical Research ◽

10.9734/jammr/2020/v32i1330554 ◽

2020 ◽

pp. 65-70

Author(s):

Omayma Elshafie ◽

Nicholas Woodhouse

Keyword(s):

Cushing’S Syndrome ◽

Cushing’S Disease ◽

Somatostatin Receptors ◽

Serum Cortisol ◽

Cushing's Syndrome ◽

Cushing's Disease ◽

Pituitary Tumours ◽

Ectopic Acth ◽

Suppression Test ◽

Cortisol Levels

Aims: To determine whether the use of an octreotide suppression test will reliably distinguish pituitary from ectopic ACTH overproduction. Somatostatin receptors are expressed in NETs, but are downgraded in the pituitary as the result of hypercortisolaemia. Octreotide should therefore lower ACTH and cortisol levels in patients with NETs but not in patients with Cushing’s disease and pituitary tumors. Methodology: A cross sectional study was performed in 13 patents with ACTH dependent Cushing’s (8 women, 5 men) with ages ranging between 21 to 40 years were studied. Serum cortisol concentrations were measured at 0800 hrs before and during the administration of. Octreotide at a dosage of 100 mcg subcutaneously every 8 hours for 72 hours. Results: The serum cortisol concentrations returned to normal in 4 patients who were later documented to have ectopic disease, two with typical bronchial carcinoids and two with pancreatic NETs and metastatic disease. The other 9 patients had no suppression in serum cortisol concentrations and were documented later to have pituitary tumours. Conclusion: These results indicate that a short trial of octreotide will identify patients with ectopic disease as evidenced by a fall in serum cortisol levels whereas in those with Cushing’s disease and pituitary tumours serum cortisol levels remains unchanged. Recommendation: We recommend all patients with ACTH dependent Cushing’s syndrome have an octreotide suppression test, even if the MRI shows an adenoma, so as to exclude the possibility of a pituitary incidentaloma in a patient with ectopic disease, or false localization from IPSS to the pituitary gland due to ectopic CRH secretion.

Download Full-text