The Role of the Stress Experience in Supporting Positive Effects Following Psilocybin: a Randomized, Controlled Clinical Trial Using the Cortisol Synthesis Inhibitor Metyrapone in Healthy Adults

The purpose of this study is to determine the importance in the acute stress response induced by psilocybin (the primary component of "magic mushrooms") in facilitating positive outcomes. Participants in this study will be given psilocybin in combination with a placebo or metyrapone, a cortisol synthesis inhibitor medication, on four different occasions.

Start Date01 Sep 2025

Sponsor / Collaborator

University of Calgary

NCT06556277

/ RecruitingNot Applicable

Acute Consequences of Glucocorticoid Secretion in Overweight and Obese Individuals During Maximum Calorie Intake: a Double-blind, Randomized, Placebo-controlled, Cross-over Study

The investigator aim to understand whether food-induced glucocorticoids influence fat mass in overweight and obese people.
In a randomized, cross-over study, 23 overweight and obese volunteers will receive a block and replace therapy that mimics physiological glucocorticoid (GC) rhythm (metyrapone plus hydrocortisone) or placebo. Participants will undergo two identical overfeeding periods with each treatment. With the block and replace therapy food-induced GC peak will be suppressed. Metabolic and immunological parameters will be compared to reveal the effects of GCs during excessive overfeeding, particularly to understand changes in body fat.

Start Date01 Sep 2024

Sponsor / Collaborator-

NCT06106295

/ RecruitingPhase 2IIT

Metyrapone Intervention in Patients With Mild Autonomous Cortisol Secretion (MACS)

The purpose of this study is to find out whether the study drug, metyrapone, is safe and effective in treating participants with Mild Autonomous Cortisol Secretion (MACS).

Start Date19 Dec 2023

Sponsor / Collaborator

Mayo Clinic

100 Clinical Results associated with Metyrapone

100 Translational Medicine associated with Metyrapone

100 Patents (Medical) associated with Metyrapone

4,643

Literatures (Medical) associated with Metyrapone

01 Apr 2025·JOURNAL OF NEUROENDOCRINOLOGY

Corticotropin‐releasing hormone receptor 1 mediates the enhanced locomotor activity and metabolic demands to an acute thermal stress in adult zebrafish

Article

Author: Shvartsburd, Zachary ; Vijayan, Mathilakath M.

Abstract:

We recently showed that Crh‐Crhr1 signalling is essential for acute stress‐related locomotor activity in zebrafish larvae. However, the possibility that Crhr1 activation may also initiate the acute metabolic demands for stress coping was unexplored. Here, we tested the hypothesis that Crhr1 signalling is essential for the thermal stressor‐induced increases in the acute metabolic rate, a key response for coping with the enhanced energy demands during stress. We tested this by using a wildtype (WT) and a ubiquitous Crhr1 knockout (crhr1−/−) zebrafish and subjecting them to an acute thermal stressor (TS: +5°C above ambient for 60 min). The TS induced the heat shock proteins response in both genotypes, but the elevated cortisol response observed in the WT was absent in the crhr1−/− mutant. The TS also increased the locomotor activity and the metabolic rate in the WT fish, but this response was inhibited in the crhr1−/− mutants. To test if this was due to a lack of TS‐induced cortisol elevation in the crhr1−/− mutant, we mimicked the response in the WT fish by treating them with metyrapone, an 11β‐hydroxylase inhibitor. While metyrapone inhibited the TS‐induced cortisol elevation in the WT, it did not affect the metabolic rate. The lack of Crhr1 also reduced the swimming performance, and the lower Ucrit in the mutants corresponded with alterations in muscle energy metabolism. Together, our results indicate that Crh‐Crhr1 signalling, independent of downstream cortisol action, is essential for the TS‐induced acute hyperlocomotor activity and the associated increases in the metabolic demand for stress coping.

28 Mar 2025·Oxford Medical Case Reports

Ectopic ACTH-secreting pheochromocytoma without typical signs of Cushing syndrome

Article

Author: Mendoza-García, Jesús G ; Tenorio-Aguirre, Erika K ; Medina-Julio, David ; Soto-Montes, Zeltzin ; Solis-Coronado, Orlando D ; Martínez-Sánchez, Froylan D

Abstract:

This case report describes a 42-year-old female with a rare pheochromocytoma presenting without classic Cushingoid features but with uncontrolled hypertension, type 2 diabetes, and recurrent headaches. Despite the absence of typical signs, biochemical analysis revealed elevated cortisol and ACTH levels, and imaging showed a 6 cm adrenal mass. The patient was stabilized preoperatively with alpha-blockers and metyrapone before undergoing a successful laparoscopic adrenalectomy. Histopathology confirmed pheochromocytoma with aggressive features. Postoperatively, her blood pressure and symptoms improved, and her cortisol levels normalized. This case underscores the diagnostic challenges of ACTH-secreting pheochromocytomas without classic hypercortisolism signs and emphasizes the need for thorough endocrine and imaging assessments. Surgical resection remains the definitive treatment, with long-term follow-up essential to monitor for recurrence. This case contributes to the limited literature on the coexistence of pheochromocytoma and ectopic ACTH secretion.

17 Mar 2025·JCEM Case Reports

Successful Medical Management of Cushing Disease With Metyrapone Throughout Pregnancy: A Report of 2 Cases

Article

Author: Geer, Eliza B ; Theodorou, Angeliki

Abstract:

Cushing syndrome (CS) in pregnancy is a rare disorder with challenging diagnostic and therapeutic considerations. For patients with medically managed CS planning pregnancy, bilateral adrenalectomy is advised before conception. To our knowledge, no case of Cushing disease (CD) medically treated throughout pregnancy with cortisol synthesis inhibition has been described. We present 2 cases of CD in pregnancy managed with metyrapone, a non-Food and Drug Administration-approved drug for pregnancy. The first case involves a 31-year-old woman with recurrent CD who conceived twins via in vitro fertilization while on metyrapone. She had an uneventful pregnancy, delivering healthy twins at 37 weeks. Postpartum, she developed hypertension, which resolved spontaneously, and remained on metyrapone, with stable cortisol levels and normal development of her twins. The second case describes a 29-year-old woman with recurrent CD since adolescence, status post 2 transsphenoidal resections and gamma knife radiosurgery, who conceived naturally on metyrapone. After an uncomplicated pregnancy, she developed postpartum preeclampsia requiring temporary antihypertensive therapy. Both cases showed favorable maternal and fetal outcomes, highlighting metyrapone as a therapeutic option for managing CD during pregnancy.

News (Medical) associated with Metyrapone

15 May 2025

·www.prnewswire.com

Cushing's Disease Market Poised for Significant Growth Across the 7MM During the Study Period (2020-2034) with Rising Awareness and Diagnostic Improvements | DelveInsight

The Cushing's disease pipeline possesses some drugs in mid and late-stage development to be approved in the near future. The emerging landscape holds a diverse range of therapeutic alternatives for treatment, including relacorilant, clofutriben, atumelnant, and others. The expected launch of these therapies shall further create a positive impact on the Cushing's disease market. LAS VEGAS, May 15, 2025 /PRNewswire/ -- DelveInsight's Cushing's Disease Market Insights report includes a comprehensive understanding of current treatment practices, Cushing's disease emerging drugs, market share of individual therapies, and current and forecasted market size from 2020 to 2034, segmented into 7MM [the United States, the EU4 (Germany, France, Italy, and Spain) and the United Kingdom, and Japan]. Key Takeaways from the Cushing's Disease Market Report According to DelveInsight's analysis, the market size for Cushing's disease was found to be USD 1 billion in the 7MM in 2024. In 2024, among all the current therapies for Cushing's disease, the highest revenue was generated by Mifepristone (KORLYM and generics) in the US. Based on DelveInsight's assessment in 2024, the 7MM had approximately 37K diagnosed prevalent cases of Cushing's disease. These cases are expected to rise due to advancements in diagnostic capabilities and increased awareness about the disease during the forecast period (2025–2034). Leading Cushing's disease companies developing emerging therapies, such as Corcept Therapeutics, Sparrow Pharmaceuticals, Crinetics Pharmaceuticals, H. Lundbeck, Stero Therapeutics, and others, are developing novel Cushing's disease drugs that can be available in the Cushing's disease market in the coming years. The promising Cushing's disease therapies in the pipeline include DUPIXENT (dupilumab), Linerixibat (GSK2330672), NEMLUVIO/MITCHGA (nemolizumab), Volixibat, and others. In March 2025, Corcept Therapeutics announced that the FDA had assigned a PDUFA target action date of December 30, 2025, for relacorilant to treat patients with endogenous hypercortisolism. In February 2025, Crinetics Pharmaceuticals mentioned that the company anticipates beginning enrollment for Atumelnant (CRN04894) in Phase Ib/IIa trials for Cushing's disease in late 2025 or early 2026. In October 2024, Sparrow Pharmaceuticals announced that clofutriben had been granted Orphan Drug Designation (ODD) by the US FDA for the treatment of endogenous Cushing's syndrome. Discover which therapies are expected to grab the major Cushing's disease market share @ Cushing's Disease Market Report Cushing's Disease Overview Cushing's disease is a rare but serious endocrine disorder caused by a pituitary tumor that triggers excessive cortisol production. It presents with a variety of symptoms such as weight gain, fatigue, mood disturbances, high blood pressure, and impaired glucose tolerance. Cushing's syndrome is responsible for 80–85% of hypercortisolism cases, with 75–80% of those linked to ACTH-producing pituitary adenomas. Without treatment, the 5-year survival rate is only about 50%, emphasizing the urgent need for effective therapies. Diagnosing Cushing's disease is especially difficult because it is rare, shares symptoms with other disorders, and presents in various ways. Only 40–60% of patients have a detectable tumor on standard Magnetic Resonance Imaging (MRI), and the diagnosis is often delayed by an average of 7 years. Cushing's Disease Epidemiology Segmentation The Cushing's disease epidemiology section provides insights into the historical and current Cushing's disease patient pool and forecasted trends for the 7MM. It helps recognize the causes of current and forecasted patient trends by exploring numerous studies and views of key opinion leaders. The Cushing's disease market report proffers epidemiological analysis for the study period 2020–2034 in the 7MM segmented into: Total Prevalent Cases of Cushing's Disease Total Diagnosed Prevalent Cases of Cushing's Disease Gender-Specific Diagnosed Prevalent Cases of Cushing's Disease Age-Specific Diagnosed Prevalent Cases of Cushing's Disease Cushing's Disease Treatment Market The primary treatment for Cushing's disease is usually transsphenoidal surgery to remove the pituitary tumor, which often leads to remission. However, some patients may experience a recurrence. When surgery is unsuccessful or not an option, medical therapies are used to control cortisol levels. Various medications are available for managing Cushing's disease, especially in cases where surgery is ineffective or not feasible. One such drug is KORLYM, developed by Corcept Therapeutics, approved for treating hyperglycemia in patients with Cushing's syndrome who also have Type 2 diabetes or glucose intolerance. In 2024, a generic version by Teva Pharmaceuticals entered the market, adding competition, and Corcept itself has released a generic version as well. Other approved options include S IGNIFOR and SIGNIFOR LAR, ISTURISA, and RECORLEV. In addition, off-label drugs like ketoconazole, metyrapone, cabergoline, mitotane, and etomidate are also used in the U.S., with some marketed in Europe by HRA Pharma. SIGNIFOR (pasireotide), developed by Recordati, was the first drug specifically approved for Cushing's disease by the FDA in 2012, and also gained EU approval. Recordati also markets SIGNIFOR LAR, a long-acting injectable version approved by the FDA and Japan's PMDA in 2018. This formulation, administered intramuscularly once every four weeks, shares the same mechanism as SIGNIFOR but offers a different delivery route. Recordati is recognized as a leading player in this therapeutic area. Another key product from the company is ISTURISA (osilodrostat), the first FDA-approved oral drug that inhibits cortisol production by targeting the enzyme 11β-hydroxylase (CYP11B1), which is involved in the final step of cortisol synthesis. Its oral administration makes it more convenient for patients compared to injectable therapies. ISTURISA is also being studied for pediatric use in an ongoing Phase II trial (NCT03708900). RECORLEV, originally developed by Strongbridge Biopharma and later acquired by Xeris Pharmaceuticals, was approved by the FDA in 2021. It is indicated for adults with endogenous Cushing's syndrome who are not surgical candidates or did not achieve a cure through surgery. Unlike ISTURISA, RECORLEV works by inhibiting cortisol production at multiple points in the steroidogenesis pathway, offering a distinct mechanism of action. To know more about Cushing's disease treatment guidelines, visit @ Cushing's Disease Management Cushing's Disease Pipeline Therapies and Key Companies Relacorilant (CORT125134): Corcept Therapeutics Clofutriben (SPI-62): Sparrow Pharmaceuticals Atumelnant (CRN04894): Crinetics Pharmaceuticals Lu AG13909: H. Lundbeck ST-002: Stero Therapeutics Discover more about Cushing's disease drugs in development @ Cushing's Disease Clinical Trials Cushing's Disease Market Dynamics The Cushing's disease market dynamics are expected to change in the coming years. Although Cushing's disease is generally considered a rare condition, growing awareness and recent advances in research suggest that diagnoses may rise in the future; despite a seemingly crowded market, many current hypercortisolism treatments fail to normalize cortisol levels effectively and pose significant side effects highlighting a substantial opportunity for innovation, especially given the limited therapies specifically targeting Cushing's disease and the potential of newer oral alternatives like ISTURISA and RECORLEV to offer greater flexibility compared to SC and intramuscular options such as SIGNIFOR and SIGNIFOR LAR. Furthermore, potential therapies are being investigated for the treatment of Cushing's disease, and it is safe to predict that the treatment space will significantly impact the Cushing's disease market during the forecast period. Moreover, the anticipated introduction of emerging therapies with improved efficacy and a further improvement in the diagnosis rate are expected to drive the growth of the Cushing's disease market in the 7MM. However, several factors may impede the growth of the Cushing's disease market. Due to non-specific guidelines and recommendations, patients with Cushing's disease often face suboptimal care, delayed diagnosis, and inconsistent treatment approaches, further compounded by the diagnostic complexity, frequent misdiagnosis, and symptom overlap with more common conditions, which leave many undiagnosed or untreated; while existing therapies such as ketoconazole and metyrapone approved in Europe based on limited retrospective data and used off-label in the US despite high costs are widely trusted and entrenched in clinical practice, posing a significant barrier to the adoption of emerging therapies. Moreover, Cushing's disease treatment poses a significant economic burden and disrupts patients' overall well-being and QOL. Furthermore, the Cushing's disease market growth may be offset by failures and discontinuation of emerging therapies, unaffordable pricing, market access and reimbursement issues, and a shortage of healthcare specialists. In addition, the undiagnosed, unreported cases and the unawareness about the disease may also impact the Cushing's disease market growth. Scope of the Cushing's Disease Market Report Therapeutic Assessment: Cushing's Disease current marketed and emerging therapies Cushing's Disease Market Dynamics: Key Market Forecast Assumptions of Emerging Cushing's Disease Drugs and Market Outlook Competitive Intelligence Analysis: SWOT analysis and Market entry strategies Unmet Needs, KOL's views, Analyst's views, Cushing's Disease Market Access and Reimbursement Download the report to understand which factors are driving Cushing's disease market trends @ Cushing's Disease Market Trends Table of Contents Related Reports Cushing's Syndrome Market Cushing's Syndrome Market Insights, Epidemiology, and Market Forecast – 2034 report deliver an in-depth understanding of the disease, historical and forecasted epidemiology, as well as the market trends, market drivers, market barriers, and key Cushing's syndrome companies including Corcept Therapeutics, Crinetics Pharmaceuticals, Cyclacel Pharmaceuticals, Sparrow Pharmaceuticals, Stero Therapeutics, among others. Cushing's Syndrome Pipeline Cushing's Syndrome Pipeline Insight – 2025 report provides comprehensive insights about the pipeline landscape, pipeline drug profiles, including clinical and non-clinical stage products, and the key Cushing's syndrome companies, including Corcept Therapeutics, Crinetics Pharmaceuticals, Cyclacel Pharmaceuticals, Sparrow Pharmaceuticals, Stero Therapeutics, among others. Endogenous Cushing's Syndrome Market Endogenous Cushing's Syndrome Market Insights, Epidemiology, and Market Forecast – 2034 report deliver an in-depth understanding of the disease, historical and forecasted epidemiology, as well as the market trends, market drivers, market barriers, and key endogenous Cushing's syndrome companies including Corcept Therapeutics, Crinetics Pharmaceuticals, Sparrow Pharmaceuticals, among others. Endogenous Cushing's Syndrome Pipeline Endogenous Cushing's Syndrome Pipeline Insight – 2025 report provides comprehensive insights about the pipeline landscape, pipeline drug profiles, including clinical and non-clinical stage products, and the key endogenous Cushing's syndrome companies, including Corcept Therapeutics, Crinetics Pharmaceuticals, Sparrow Pharmaceuticals, among others. About DelveInsight DelveInsight is a leading Business Consultant and Market Research firm focused exclusively on life sciences. It supports pharma companies by providing comprehensive end-to-end solutions to improve their performance. Get hassle-free access to all the healthcare and pharma market research reports through our subscription-based platform PharmDelve . Contact Us Shruti Thakur [email protected] +14699457679 Logo: SOURCE DelveInsight Business Research, LLP WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

Drug ApprovalOrphan DrugPhase 2

10 Jul 2024

·www.esteve.com

ESTEVE ACQUIRES HRA PHARMA RARE DISEASES

ESTEVE has completed the acquisition of HRA Pharma Rare Diseases, a business specialized in rare diseases, from Perrigo Company plc. With this acquisition, ESTEVE expands its portfolio in rare and severe diseases adding, to the current existing offer, three new medications to treat Cushing's syndrome and adrenocortical carcinoma: Metopirone, Lysodren, and Ketoconazole HRA. HRA Pharma Rare Diseases has been a leading company for over 15 years in rare and severe diseases, providing the best care and services to individuals living with rare diseases, and is committed to supporting healthcare professionals worldwide. "This acquisition allows us to accelerate our international expansion, strengthening our global presence and ability to better address unmet needs, thus improving the lives of more people," highlights Staffan Schüberg, Chief Executive Officer of ESTEVE. With annual net revenues in 2023 of approximately 50 million euros, HRA Pharma Rare Diseases has a presence in numerous European countries and the United States with a team of 49 individuals. This agreement represents an investment of up to 275 million euros, structured with an initial fixed contribution and future variable payments tied to revenue. Share

Acquisition

26 Apr 2024

·firstwordpharma.com

Perrigo to divest rare diseases unit to Spain's Esteve for €275 million

Perrigo is offloading its HRA Pharma Rare Diseases business to Barcelona-based pharmaceutical company Esteve Healthcare for a total of up to €275 million ($294 million) and plans to use the proceeds to help pay down its debt.The transaction, which includes €190 million in cash upfront plus up to €85 million in potential earnouts if certain sales targets are reached, is expected to close in the third quarter.The unit's three-product portfolio includes the Cushing's syndrome treatments Metopirone (metyrapone) and ketoconazole, as well as Lysodren (mitotane), which is prescribed to treat adrenal cortical carcinoma. Staffan Schüberg, chief executive at Esteve, said the deal is "another step towards the company's vision of being an international and specialist pharma company."Meanwhile, Perrigo CEO Patrick Lockwood-Taylor said the divestment "further supports our position as a leading fast-moving consumer goods company," adding that the upfront cash proceeds would allow the company "to reduce net leverage to below 4.0x by the end of 2024."

AcquisitionDrug Approval

100 Deals associated with Metyrapone

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KEGG	Wiki	ATC	Drug Bank
D00410	Metyrapone	V04CD01	DB01011

R&D Status

Approved

10 top approved records.

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Indication	Country/Location	Organization	Date
Adrenal Insufficiency	-	Novartis AG	30 May 2014
Cushing Syndrome	Australia	CHIESI Farmaceutici SpA	02 Aug 1991
Pituitary ACTH Hypersecretion	United States	HRA Pharma Rare Diseases SAS	04 Dec 1961

Developing

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Endogenous Cushing Syndrome	Phase 3	Belgium	HRA Pharma Development SARL	01 Apr 2015
Endogenous Cushing Syndrome	Phase 3	Germany	HRA Pharma Development SARL	01 Apr 2015
Endogenous Cushing Syndrome	Phase 3	Hungary	HRA Pharma Development SARL	01 Apr 2015
Endogenous Cushing Syndrome	Phase 3	Italy	HRA Pharma Development SARL	01 Apr 2015
Endogenous Cushing Syndrome	Phase 3	Poland	HRA Pharma Development SARL	01 Apr 2015
Endogenous Cushing Syndrome	Phase 3	Romania	HRA Pharma Development SARL	01 Apr 2015
Endogenous Cushing Syndrome	Phase 3	Spain	HRA Pharma Development SARL	01 Apr 2015
Endogenous Cushing Syndrome	Phase 3	Turkey	HRA Pharma Development SARL	01 Apr 2015

Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


MACS (ENDO2024)	Not Applicable	-	15	Metyrapone 250mg-500mg at 6pm and 250mg at 10pm	krtntapdal(lnzkuqqxpx) = gqueywprso cbeqgoqjtf (bpggmcekhp, 5.5) View more	Positive	01 Jun 2024
NCT06106295 (MACS, ENDO2024)	Phase 2	cortisol \| ACTH \| DHEAS	30	Metyrapone 250 mg	zwbdubqgsg(ojwisrmohq) = xkwpowwwda hvhalmkvqx (tcehddxexl, 25 - 34) View more	-	01 Jun 2024
LBSAT59 (ENDO2022)	Not Applicable	ACTH \| cortisol \| DHEAS	22	Metyrapone (Patients with OIAI)	ynqbwuviaj(urergvpvpo) = ivtrwpvyeh jofmbmsvmr (hgnqdcblhx, 8.1 - 51) View more	-	01 Nov 2022
LBSAT59 (ENDO2022)	Not Applicable	ACTH \| cortisol \| DHEAS	22	Metyrapone (Patients without OIAI)	ynqbwuviaj(urergvpvpo) = dsdftskcqc jofmbmsvmr (hgnqdcblhx, 5.9 - 55) View more	-	01 Nov 2022
NCT02297945 (PROMPT, ENDO2021)	Phase 3	Endogenous Cushing Syndrome 24 hours urine free cortisol (UFC)	50	Metyrapone	ggjhwymlbp(xycjnzcbfm) = kvaccnwocf fpbsibnkmg (vhvaqzjyzn, 291 - 8476) View more	Positive	03 May 2021
ENDO2021	Not Applicable	Cushing Syndrome AM serum cortisol \| PM serum cortisol \| ACTH ... View more	-	Metyrapone	injkqjqnnf(yujafdqpxj) = pnidmqjdlf egcnjoicqi (mnsugggnyk ) View more	Positive	03 May 2021
MON-905 (ENDO2020)	Not Applicable	Pituitary ACTH Hypersecretion	-	Metyrapone 1,000 mg/day	hkfbxmculk(rusuqxtclb) = pyurprvkwv kmtezxsayk (cxrlzrzpxq ) View more	Positive	08 May 2020
MON-905 (ENDO2020)	Not Applicable	Pituitary ACTH Hypersecretion	-	Dexamethasone 0.1-10 nM	uawkmrmpmn(ffmsghilmj) = qvqylusgaf rxoisxatnt (icwutghvej ) View more	Positive	08 May 2020
SUN-LB068 (ENDO2019)	Not Applicable	Neuroendocrine Tumors \| Ectopic ACTH Syndrome	-	Metyrapone	gaqyifiiak(mnyfnfihhn) = fknghziizr cubetokpoo (zsboeqvqgu ) View more	Positive	30 Apr 2019
SAT-446 (ENDO2019)	Not Applicable	Prader-Willi Syndrome	45	Metyrapone (Adults with Prader-Willi Syndrome)	koatwfyoup(szbldtqusn) = ihxchbvzfi ccvudkpzjc (kyssdzbtia )	Positive	30 Apr 2019
ESPE2016	Not Applicable	Cushing Syndrome	-	Metyrapone	zlajrjkyps(jmgzffaxey) = uyobijpakz xjogfcybzc (xeurkqswbi )	-	10 Sep 2016
Pubmed \| J Clin Endocrinol Metab	Not Applicable	Cushing Syndrome	195	Metyrapone	mxtouozler(qfbrlculqd) = dvtcmbqpgk jxwglnybbo (kztddqnady ) View more	Positive	01 Nov 2015

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