scholarly journals Cushing’s Disease: Not Always Black and White

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A580-A581
Author(s):  
Kajal Shah ◽  
Alan Chang ◽  
Natalie Jarahzadeh
Keyword(s):  
Weight Gain ◽  
Pituitary Adenoma ◽  
Cushing’S Disease ◽  
Pituitary Surgery ◽  
Cushing's Disease ◽  
Nuclear Staining ◽  
Corticotroph Adenoma ◽  
Post Surgery ◽  
Free Cortisol ◽  
Initial Symptoms

Abstract Cushing’s Disease is a well known entity but the difficulty of diagnosis is often underappreciated. Given the wide spectrum of clinical presentation and pitfalls with each diagnostic evaluation, diagnosis of Cushing’s Disease (CD) is often difficult in clinical practice, even with pathological analysis. A 37 year old female with a history of Cushing’s Disease presented for her third transphenoidal resection to our institution. She was diagnosed with a pituitary microadenoma 16 years ago based on MRI, as she had persistent headaches and vision abnormalities. The patient also reported unexplained weight gain, “buffalo hump”, and moon facies at the time. She was diagnosed with CD due to an abnormal 1 mg overnight dexamethasone suppression test (DST) with AM cortisol of 3.03 ug/dl (normal <1.8 microgram/dl). She was on an oral contraceptive pill (OCP) at the time. The patient underwent her first pituitary transsphenoidal resection and was symptom free for about 10 years, after which she had a recurrence of her initial symptoms. She had another abnormal DST while on an OCP and pituitary MRI revealed growth of the pituitary adenoma. Patient underwent a second pituitary surgery with benign postoperative course with a recurrence about 5 years later. The workup prior to her third surgery revealed an abnormal DST while on OC pills with the 8am cortisol being 3.36 ug/dl (<1.8ug/dl), urinary free cortisol 35.4 mcg/24 hour (4-50 mcg/24 hour). 8am ACTH done on a separate day was 48 pg/ml (6-50 pg/ml) with a cortisol of 14.5 ug/dl. Midnight salivary cortisol was not performed. Interval history was still positive for weight gain and headaches, hence she was referred for her third pituitary surgery. Post surgery, the patient was on a short taper of hydrocortisone and 8am cortisol was 32 ug/dl the next day. After a discussion with the pathologist, it was determined that the pathology was suggestive of a corticotroph adenoma with moderate ACTH staining and patchy nuclear staining for TPIT, although the pathologist stated that it was difficult to be certain due to the small tissue size. From the current literature, this patient had an incomplete and equivocal biochemical work up while on OCPs but still had tissue diagnosis supporting CD. Whether this was a recurrence of Cushing’s disease, silent corticotroph adenoma, or non-functioning pituitary adenoma is unclear. This case illustrates the multiple challenges in the diagnosis of Cushing’s disease that may be encountered. 1.Braun LT et al. Recurrence after pituitary surgery in adult Cushing’s disease: a systematic review on diagnosis and treatment. Endocrine. 2020;70(2):218-231.

A critical evaluation of transsphenoidal pituitary surgery in the treatment of Cushing's disease: Prediction of outcome

1990 ◽  
Vol 123 (4) ◽  
pp. 423-430 ◽  
Author(s):  
Richard D Arnott ◽  
Richard G Pestell ◽  
Penelope A McKelvie ◽  
J Keith Henderson ◽  
Peter M McNeill ◽  
...  
Keyword(s):  
Pituitary Adenoma ◽  
Cushing’S Disease ◽  
Critical Evaluation ◽  
Pituitary Surgery ◽  
Urinary Free Cortisol ◽  
Cushing's Disease ◽  
Late Relapse ◽  
Free Cortisol ◽  
Transsphenoidal Pituitary Surgery ◽  
Cortisol Excretion

Abstract. Twenty-eight patients underwent transsphenoidal pituitary surgery for Cushing's disease. Selective surgical procedures were performed in 26. In 19 patients pituitary adenoma was confirmed histologically and 5 had clumps or clusters of ACTH-staining cells. At follow-up after 22.3 (range 5-56) months 21 (75%) patients remained in clinical and biochemical remission. The 24-h urinary free cortisol performed between 1 and 4 weeks postoperatively while patients took replacement doses of dexamethasone (0.5 to 0.75 mg per day) was found to predict outcome. All patients with suppressed urinary free cortisol excretion have remained in remission, 3 with levels in the normal range have suffered late relapse after initial remission, and 4 with elevated urinary free cortisol excretion were regarded as having failed to remit. Furthermore, all patients with unsuccessful outcomes had no pituitary adenoma and 3 had features consistent with corticotrope nodular hyperplasia at histological examination compared to only 2 and 1, respectively, of patients still in remission. We conclude that 24-h urinary free cortisol performed at 1 to 4 weeks postoperatively whilst on low-dose dexamethasone and the histological findings may predict outcome following transsphenoidal pituitary surgery in Cushing's disease.

scholarly journals SAT-271 Block and Replace Therapy Successfully Improved Symptoms in Recurrent Cyclic Cushing’s Disease

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Risa Kamigaki ◽  
Hiraku Kameda ◽  
Hiroshi Iesaka ◽  
Rimi Izumihara ◽  
Yuki Ohe ◽  
...  
Keyword(s):  
Weight Gain ◽  
Pituitary Adenoma ◽  
Cushing’S Disease ◽  
Brain Mri ◽  
Urinary Free Cortisol ◽  
Cushing's Disease ◽  
Subjective Symptoms ◽  
Free Cortisol ◽  
Level Elevation ◽  
Cortisol Levels

Abstract BACKGROUND: Cyclic Cushing’s disease is rare and treatments have not been established for post-surgical recurrent cases. Here, we report a patient with recurrent cyclic Cushing’s disease, whose subjective symptoms improved by administration of metyrapone and hydrocortisone. Clinical Case: A 45-year-old woman had exhibited face and peripheral edema, hyperphagia, weight gain, hair loss and limb numbness since September X-10. In May X-9, her ACTH and cortisol levels were high (87.8 pg/mL and 28.8 µg/dL, respectively), and she was referred to our department. A brain MRI revealed a pituitary adenoma of 7mm in diameter. Because blood ACTH and cortisol levels turned normal and typical Cushingoid features were absent at the admission to our department, cyclic Cushing’s disease was suspected. Later in September, because subjective symptoms recurred accompanied with blood cortisol level elevation, she was diagnosed as cyclic Cushing’s disease with the examinations including inferior petrosal sinus sampling. Transsphenoidal surgery was performed in November, and immunohistology confirmed ACTH-producing pituitary adenoma based on ACTH positivity. After the surgery, endocrine test results were normalized and subjective symptoms were ameliorated. In March X-3, the blood ACTH level increased again; however, no subjective symptoms were observed. From May X, she had experienced limb numbness, hyperphagia and weight gain again. MRI showed no apparent recurrence, but endocrine tests showed the activity of Cushing’s disease. Urinary free cortisol (UFC) increased to 300–400 µg/day in a 1-week cycle, indicating the recurrence of cyclic Cushing’s disease. Metyrapone treatment was initiated, and the patient was finally discharged after block and replace therapy with metyrapone 2,000 mg/day and hydrocortisone 15 mg/day. After metyrapone treatment, subjective symptoms improved and UFC was normalized. Conclusion: Block and replace therapy with metyrapone and hydrocortisone may be effective for recurrent cyclic Cushing’s disease, especially in cases with a very short cycle.

Osilodrostat: A Novel Steroidogenesis Inhibitor to Treat Cushing’s Disease

2020 ◽  
pp. 106002802096880
Author(s):  
John A. Dougherty ◽  
Divya Sanjaykumar Desai ◽  
Javier Barrios Herrera
Keyword(s):  
Cushing’S Disease ◽  
Qt Interval ◽  
Data Extraction ◽  
Pituitary Surgery ◽  
Cushing's Disease ◽  
Pivotal Phase ◽  
Qt Interval Prolongation ◽  
Free Cortisol ◽  
Significant Difference ◽  
Life Threatening

Objective: To review data on efficacy and safety of osilodrostat (Isturisa), a novel oral steroidogenesis inhibitor for treatment of Cushing’s disease (CD), a life-threatening endocrine disorder. Data Sources: A PubMed/CINAHL search from inception to September 25, 2020, was performed using the following keywords: osilodrostat, 11-beta hydroxylase, pituitary, ACTH hypersecretion, and Cushing’s disease. Study Selection and Data Extraction: Phase 2 and 3 clinical trials and supplementary documents investigating osilodrostat were obtained from a primary literature search, the manufacturer’s website, and the Food and Drug Administration website. These articles evaluated the clinical pharmacology, efficacy, safety, adverse events, warnings, and precautions for osilodrostat. Data Synthesis: Osilodrostat was efficacious and safe in the treatment of CD in mostly middle-aged Caucasian women. A pivotal phase 3 study revealed a significant difference in 24-hour mean urinary free cortisol (primary end point) between osilodrostat and placebo (86% vs 29%; P < 0.001). Relevance to Patient Care and Clinical Practice: Osilodrostat provides a potent and consistent effect in reducing life-threatening supraphysiological levels of cortisol in patients with CD. Hypocortisolism adverse effects can be mitigated by slowly increasing osilodrostat’s dose at ≥2-week intervals. QT interval prolongation was noted; therefore, the QT interval must be monitored by the electrocardiogram. Increased levels of cortisol precursors during treatment with osilodrostat may increase the risk of hypokalemia, edema, and hypertension. Conclusions: Osilodrostat was efficacious in decreasing cortisol levels and safe in treating patients who have failed or are ineligible for pituitary surgery. Although risks exist, a pivotal clinical trial revealed efficacy in 86% of participants.

scholarly journals High Prevalence of Adrenal Remnant Tissue in Patients Undergoing Bilateral Adrenalectomy for Cushing’s Disease

2020 ◽  
Author(s):  
Julian B. Wilson ◽  
Mohan Zopey ◽  
Jaimie Augustine ◽  
Randolph Schaffer ◽  
Manfred Chiang ◽  
...  
Keyword(s):  
Cushing’S Disease ◽  
Signs And Symptoms ◽  
Pituitary Surgery ◽  
Serum Cortisol ◽  
Bilateral Adrenalectomy ◽  
Cushing's Disease ◽  
Adrenal Tissue ◽  
Number Of Patients ◽  
Free Cortisol ◽  
Endogenous Cortisol

AbstractBilateral adrenalectomy (BLA) is a treatment option for patients with Cushing’s Disease (CD) if transsphenoidal pituitary surgery fails or is not a therapeutic option. For most patients, BLA eliminates endogenous glucocorticoid and mineralocorticoid production, but for a small number of patients, endogenous secretion of adrenal hormones from adrenal tissue continues or recurs, leading to signs and symptoms of hypercortisolism. If adrenal tissue is confined to the adrenal bed, it is considered adrenal remnant tissue, while if it is outside the adrenal bed, it is considered adrenal rest tissue. We retrospectively evaluated morning serum cortisol, nighttime serum cortisol, nighttime salivary cortisol, and 24-h urine free cortisol on at least three occasions in 10 patients suspected of having endogenous cortisol production. Imaging of adrenal remnant tissue was also reviewed. Ten of 51 patients who underwent BLA during this time period had adrenal remnant/rest tissue marked by detectable endogenous glucocorticoid production; 9 of the 10 patients had signs and symptoms of hypercortisolism. Localization and treatment proved difficult. We conclude that the incidence of adrenal remnant/rest tissue in those undergoing BLA following unsuccessful pituitary surgery was 12% although there may have been a selection bias affecting this prevalence. The first indication of remnant tissue occurrence is a reduction in glucocorticoid replacement with symptoms of hypercortisolism. If this occurs, endogenous cortisol production should be tested for by cortisol measurements using a highly specific cortisol assay while the patient is taking dexamethasone or no glucocorticoid replacement. Endocrinologists need to monitor the development of both adrenal remnant tissue and Nelson’s syndrome following BLA.

scholarly journals Fluconazole for Hypercortisolism in Cushing’s Disease: A Case Report and Literature Review

2020 ◽  
Vol 11 ◽  
Author(s):  
Yiming Zhao ◽  
Weiwei Liang ◽  
Feng Cai ◽  
Qun Wu ◽  
Yongjian Wang
Keyword(s):  
Case Report ◽  
Pituitary Adenoma ◽  
Literature Review ◽  
Cushing’S Disease ◽  
Pituitary Surgery ◽  
Cortisol Concentration ◽  
Cushing's Disease ◽  
Radiological Findings ◽  
Increased Risk ◽  
Transsphenoidal Resection

BackgroundCushing’s disease is associated with an increased risk of pulmonary fungal infection, which could be a relative contraindication for pituitary adenoma excision surgery.CaseWe report a case of a patient with Cushing’s disease and pulmonary Cryptococcus neoformans. A 48-year-old woman was admitted to our hospital because of moon face and edema. Laboratory and radiological findings suggested a diagnosis of Cushing’s disease and pulmonary cryptococcus infection. Fluconazole 400 mg per day was administered intravenously and continued orally for 3 months. Both cryptococcus infection and hypercortisolism relieved and transsphenoidal resection was performed.ConclusionCushing’s disease can be effectively treated with fluconazole to normalize cortisol concentration prior to pituitary surgery. Fluconazole is an alternative treatment especially in Cushing’s disease patients with cryptococcal pneumonia.

scholarly journals Persistent cortisol response to desmopressin predicts recurrence of Cushing’s disease in patients with post-operative corticotropic insufficiency

2020 ◽  
Vol 182 (5) ◽  
pp. 489-498 ◽  
Author(s):  
S Cambos ◽  
K Mohammedi ◽  
F Castinetti ◽  
C Saie ◽  
J Young ◽  
...  
Keyword(s):  
Cushing’S Disease ◽  
Predictive Value ◽  
Pituitary Surgery ◽  
Cushing's Disease ◽  
Cortisol Response ◽  
Post Surgery ◽  
High Negative Predictive Value ◽  
Low Probability ◽  
Incremental Prognostic Value

Objective Cushing’s disease (CD) may recur despite corticotropic insufficiency (COI) following pituitary surgery. The predictive value of the desmopressin test (DT) for recurrence in this setting remains controversial. We have evaluated whether the disappearance of the response to DT predicts a low probability recurrence in a large cohort of patients with post-operative COI. Design Multicentre retrospective study. Methods Ninety-five patients with CD (women 82%, age 41 ± 14 years), responding preoperatively to DT and with early post-operative COI (08 00 am cortisol: <138 nmol/L), underwent a DT within 3 months post-surgery. Association between DT findings and the prediction of recurrence was tested using regression and ROC analyses. Results Recurrence occurred in 17/95 patients within 29 to 91 months. The cortisol peak (327, 95% CI (237–417) vs 121 (79–164) nmol/L, P = 0.0001) and absolute increment during DT (208 (136–280) vs 56 (22–90) nmol/L, P = 0.005) were greater in the recurrence vs remission group. Cortisol peak (AUC: 0.786 (0.670–0.902)) and increment (0.793 (0.672–0.914)) yielded a higher prognostic performance for recurrence than did the early post-operative 08 00 am cortisol (0.655 (0.505–0.804)). In the context of COI, cortisol peak >100 nmol/L and increment >30 nmol/L had a high negative predictive value (94, 95% CI (88–100) and 94, (88–100), respectively). Patients with a cortisol peak ≤100 nmol/L (vs >100) or an increment ≤30 nmol/L (vs >30) were less likely to have CD recurrence (odds ratios: 0.12, 95% CI (0.03–0.41) and 0.11 (0.02–0.36), respectively). Conclusion The disappearance of the response to the post-operative DT was independently associated with a lower odds of CD recurrence and offers an incremental prognostic value, which may help to stratify patients with COI and refine their follow-up according to the risk of recurrence.

scholarly journals Five years follow up of patients with Сushing’s disease with and without visualized pituitary adenoma on MRI, who underwent transsphenoidal adenomectomy

2017 ◽  
Vol 63 (5) ◽  
pp. 276-281
Author(s):  
Patimat M. Khandaeva ◽  
Zhanna E. Belaya ◽  
Lyudmila Ya. Rozhinskaya ◽  
Aleksandr V. Vorontsov ◽  
Andrey Yu. Grigoriev ◽  
...  
Keyword(s):  
Pituitary Adenoma ◽  
Cushing’S Disease ◽  
Remission Rate ◽  
Serum Cortisol ◽  
Urinary Free Cortisol ◽  
Cushing's Disease ◽  
Surgery Complications ◽  
Free Cortisol ◽  
Transsphenoidal Adenomectomy

The remission rate of Cushing’s disease in patients after neurosurgery varies from 59 to 94%, while the recurrence rate is 3 to 46%. Aim — to evaluate the five-year outcome in neurosurgery patients with Cushing’s disease (CD), depending on preoperative MRI-based identification of pituitary adenoma. Material and methods. The study included 105 neurosurgery patients with histologically confirmed CD. CD remission was confirmed by the development of adrenal insufficiency and/or normalization of serum cortisol and 24-hour urinary free cortisol (24h UFC) levels, as well as by clinical remission. Results. Pituitary adenoma was not visualized by gadolinium MRI in 35 cases. The size of visualized pituitary adenoma varied from 0.3 to 29 mm. After first neurosurgery, remission was achieved in 87 (82.8%) patients. After second neurosurgery, remission occurred in 12 patients. Radiation therapy was conducted in 24 patients. Six patients had bilateral adrenalectomy. Two patients died during remission: one patient died from stroke two years after neurosurgery, and the other patient died due to surgery complications. During five-year follow-up after neurosurgery, remission continued in 76 (72.8%) patients, including 27 (77%) of 35 patients without MRI-detected adenoma and 49 (70%) of 70 patients with MRI-detected pituitary adenoma, p=0.15. Sixty-six patients developed recurrence, and 14 patients had active hypercortisolism. Conclusion. There was no correlation between the rate of preoperative MRI-based detection of pituitary adenoma and the rate of remission in neurosurgery patients with Cushing’s disease during the five year follow-up. The size of pituitary adenoma was a risk factor for adenoma recurrence.

scholarly journals Rapidly progressive ACTH-dependent Cushing’s disease masquerading as ectopic ACTH-producing Cushing’s syndrome: illustrative case

2021 ◽  
Vol 2 (1) ◽  
Author(s):  
Siyuan Yu ◽  
Michael Karsy ◽  
Jeffrey Miller ◽  
Stephanie R. Beldick ◽  
Mark T. Curtis ◽  
...  
Keyword(s):  
Pituitary Adenoma ◽  
Cavernous Sinus ◽  
Cushing’S Syndrome ◽  
Cushing’S Disease ◽  
Rapid Evolution ◽  
Cushing's Syndrome ◽  
Cushing's Disease ◽  
Illustrative Case ◽  
Ectopic Acth ◽  
Free Cortisol

BACKGROUND Cushing’s disease (CD) remains a challenging condition to diagnose and treat. This case study highlights the challenges of diagnosing CD when faced with discrepant clinical, biochemical, and radiological findings. OBSERVATIONS A 62-year-old man presented with rapid evolution of symptoms, including depression, fatigue, and extreme muscle atrophy, which resulted in the patient being a wheelchair user over the course of a few months. His rapid clinical course in conjunction with hypercortisolemia in the setting of a pituitary macroadenoma involving the cavernous sinus, two large pulmonary nodules, and urine-free cortisol levels in the thousands suggested an aggressive ectopic adrenocorticotropic hormone (ACTH) source. After extensive testing ruled out CD from an ectopic source and because of the patient’s abrupt clinical deterioration, the authors concluded that the source was likely an aggressive pituitary adenoma. Therefore, the authors performed an endonasal transsphenoidal approach for resection of the pituitary adenoma involving the cavernous sinus, and the patient was scheduled for radiosurgery to control tumor progression. LESSONS Although extremely high levels of cortisol and ACTH are associated with ectopic Cushing’s syndrome, they may also indicate an aggressive form of CD. Suspicion should be maintained for hypercortisolemia from a pituitary source even when faced with discrepant information that may suggest an ectopic source.

scholarly journals Management of Persistent Cushing’s Disease Despite Prior Pituitary Adenoma Resection in a Pregnant Patient

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A592-A593
Author(s):  
Amanda Leiter ◽  
Raj Shrivastava ◽  
Yevgeniya Pozharny ◽  
Nirali Shah
Keyword(s):  
Pituitary Adenoma ◽  
High Risk ◽  
Cavernous Sinus ◽  
Cushing’S Disease ◽  
Residual Disease ◽  
Pregnant Patient ◽  
Urinary Free Cortisol ◽  
Cushing's Disease ◽  
Free Cortisol ◽  
Serious Disease

Abstract Introduction: Cushing’s Disease (CD) in pregnancy is a rare, but serious disease that adversely impacts maternal and fetal outcomes. As the sole use of metyrapone in the management of CD has been rarely reported, we describe our experience using it to treat a pregnant patient with pre-existing CD. Clinical Case: The patient is a 29-year-old woman with a history of hypertension (HTN), who was diagnosed with CD a year prior to becoming pregnant based on elevated urinary free cortisol (UFC) 209 ug/24h (Reference Range (RR) 6 - 42), positive 1 mg dexamethasone suppression test, elevated ACTH 61 pg/mL (RR 0-46). and an 8 x 8 x 8 mm pituitary adenoma on magnetic resonance imaging (MRI). She underwent trans-sphenoidal adenoma resection 3 months prior to becoming pregnant; however, was found to have persistent disease based on a repeat MRI showing a residual 8 x 8 x 9 mm adenoma extending into the cavernous sinus and UFC 290 ug/24h. The patient discovered 6 weeks later that she was pregnant. She was referred to endocrinology at 12 weeks’ gestation, where she was experiencing easy bruising and taking labetalol 400 mg twice daily for HTN. UFC was 768 ug/24h and midnight salivary cortisols were 0.175 and 0.625 ug/dL (RR &lt;0.010 - 0.090). Surgery was deemed to be high risk given the proximity of the tumor to the cavernous sinus and likelihood of residual disease. She was started on metyrapone 250 mg twice a day, and was uptitrated to 1000mg three times daily by the time of delivery with a UFC of 120 ug/24h (goal &lt; 150 ug/24h). Her pregnancy was also complicated by diet-controlled gestational diabetes and cervical insufficiency requiring cerclage. Otherwise, her HTN was well controlled on labetolol and she remained normokalemic. The patient was induced at 37 weeks gestation and was given stress dose steroids along with metyrapone. She delivered a healthy baby boy without any complications. Discussion: CD during pregnancy is a rare disease, with the best outcomes in published cases seen with surgical intervention. This case highlights the use of metyrapone, a steroidogenesis inhibitor, as a sole therapy in cases where surgery is deemed to be high risk and unlikely curative due to location of the tumor. While it is effective in reducing cortisol levels, close surveillance of patients is required for worsening HTN, hypokalemia, and potential adrenal insufficiency. Though no fetal adverse events have been reported, the medication does cross the placenta and longterm effects are unknown.

scholarly journals MANAGEMENT OF ENDOCRINE DISEASE: Can we cure Cushing’s disease? A personal view

2018 ◽  
Vol 178 (5) ◽  
pp. R183-R200 ◽  
Author(s):  
X Bertagna
Keyword(s):  
Pituitary Adenoma ◽  
Cushing’S Disease ◽  
Pituitary Surgery ◽  
Cushing's Disease ◽  
Therapeutic Approaches ◽  
Personal View ◽  
Endocrine Disease ◽  
Adrenal Axis ◽  
Default Options ◽  
Pituitary Adrenal Axis

One of today’s challenges in endocrinology is the treatment of Cushing’s disease: Although pituitary surgery has the potential to ‘cure’ the patient and restore a completely normal pituitary adrenal axis, there are immediate failures and late recurrences that will ultimately require alternate therapeutic approaches. Their high number is in direct correlation with their serious limitations and they all appear to be ‘default options’. This ‘personal view’ tries to shed some light on the inescapable difficulties of the current treatments of Cushing’s disease and to provide some optimistic view for the future where the pituitary adenoma should be the ‘reasonable obsession’ of a successful therapeutist.

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