Use of ketoconazole in the treatment of Cushing's syndrome

An older, but still useful, abstract:

J Clin Endocrinol Metab. 1986 Dec;63(6):1365-71.

 

Loli P, Berselli ME, Tagliaferri M.

Abstract

The therapeutic value of ketoconazole for long term treatment of patients with Cushing's syndrome was studied. Seven patients with Cushing's disease and one with an adrenal adenoma received 600-800 mg/day ketoconazole for 3-13 months. Plasma ACTH, cortisol, and dehydroepiandrosterone sulfate levels and urinary cortisol, 17-ketosteroid, and tetrahydro-11-deoxycortisol excretion were determined periodically during the treatment period.

Plasma ACTH and cortisol responses to CRH stimulation were determined before and during treatment. Rapid and subsequently persistent clinical improvement occurred in each patient; plasma dehydroepiandrosterone sulfate and urinary 17-ketosteroid and cortisol excretion decreased soon after the initiation of treatment, subsequently remaining normal or nearly so throughout the treatment period. Urinary tetrahydro-11-deoxycortisol excretion increased significantly. Plasma cortisol levels decreased. Plasma ACTH levels did not change, and individual plasma ACTH and cortisol increments in response to CRH were comparable before and during treatment. The cortisol response to insulin-induced hypoglycemia improved in one patient and was restored to normal in another.

The seven patients tested recovered normal adrenal suppressibility in response to a low dose of dexamethasone during ketoconazole treatment. Ketoconazole is effective for long term control of hypercortisolism of either pituitary or adrenal origin. Its effect appears to be mediated by inhibition of adrenal 11 beta-hydroxylase and 17,20-lyase, and it, in some unknown way, prevents the expected rise in ACTH secretion in patients with Cushing's disease.

From http://www.ncbi.nlm.nih.gov/pubmed/3023421

 

A New Link in the Stress Response Could Mean Better Treatment Soon

Hoping to pave the way for improved treatment options, researchers have found that they can significantly reduce our response to stress.

 

A team at Tufts University appears to have found an important step in the body's stress reaction, and blocking this step from occurring can significantly reduce the response. The finding may pave the way for improved treatments for depression and anxiety.

The stress cascade is governed by the brain's hypothalamus, which communicates with the pituitary and adrenal glands, which in turn secrete stress hormones like cortisol. Disruptions in this pathway are also connected with problems like postpartum depression, obesity, Cushing's syndrome (hypercortisolism), premenstrual syndrome (PMS), epilepsy, and osteoporosis, according to the study's press release.

Using mice as their subjects, the researchers set out to fill in some of the blanks in the cascade of events that leads to the secretion of the stress hormone coriticosterone (the mouse equivalent to our cortisol). They used brain samples from mice, and tracked the activity of the brain cells that release corticotrophin-releasing hormone (CRH), which ultimately stimulates the secretion of stress hormones.

They discovered that specific "neurosteroids" are needed to bind to receptors on the CRH neurons to activate them, serving as an important early step in the stress response. The team reasoned that disrupting the synthesis of the neurosteroids should significantly reduce the stress response by stopping it almost before it begins.

This is just what they found. When they blocked the neurosteroids' synthesis in live mice, their coriticosterone levels were reduced after stressful situations compared to normal mice. Additionally, if neurosteroid synthesis was halted, the mice did not show anxiety-like behaviors after they had been stressed.

One of the authors, Jamie Maguire, said that the data "suggest that these receptors may be novel targets for control of the stress-control pathway. Our next work will focus on modulating these receptors to treat disorders associated with stress, including epilepsy and depression-like behaviors."

The study is published in The Journal of Neuroscience.

From http://www.theatlantic.com/health/archive/2012/01/a-new-link-in-the-stress-response-could-mean-better-treatment-soon/250570/

Effects of Hormone Stimulation on Brain Scans for Cushing's Disease

This study is currently recruiting participants.

Verified on August 2011 by National Institutes of Health Clinical Center (CC)

First Received on October 21, 2011.   No Changes Posted

Sponsor:	National Institute of Neurological Disorders and Stroke (NINDS)
Information provided by:	National Institutes of Health Clinical Center (CC)
ClinicalTrials.gov Identifier:	NCT01459237

  Purpose

Background:

• Cushing's disease can be caused by a tumor of the pituitary gland, a small gland about the size of a pea located at the base of the brain. These tumors produce high levels of hormones, which cause obesity, diabetes, and growth problems. The cure for this type of Cushing's disease is to have surgery that removes the tumor but leaves the pituitary gland alone. Currently, magnetic resonance imaging scans are the best way to find these tumors. However, many of these tumors do not show up on the scan.
• Positron emission tomography (PET) scans use radioactive chemicals to light up parts of the body that are more active, such as tumors. Researchers want to try to make the small Cushing's disease tumors more active to help them show up on the scans. A special hormone will be given before the scan to make the tumors more active.

Objectives:

- To test the use of hormone stimulation to improve brain scans for Cushing's disease tumors.

Eligibility:

- Individuals at least 8 years of age who will be having surgery to remove Cushing's disease tumors.

Design:

• Participants will be screened with a medical history, physical exam, blood and urine tests, and imaging studies.
• They will have three brain scans before surgery. The first scan is a magnetic resonance imaging scan to show a full picture of the brain. The second and third scans are PET scans.
• The first PET scan will be given without the special hormone. The second PET scan will be done more than 24 hours but less than 14 days after the first PET scan. The second PET scan will be given with the special hormone.
• Participants will have tumor removal surgery through another study protocol....

Condition
Pituitary Neoplasm

Study Type:	Observational
Official Title:	Prospective Evaluation of the Effect of Corticotropin-Releasing Hormone Stimulation on 18F-Fludeoxyglucose High-Resolution Positron-Emission Tomography in Cushing's Disease

Resource links provided by NLM:

MedlinePlus related topics: Cancer Cushing's Syndrome Nuclear Scans Pituitary Tumors

Drug Information available for: Corticotropin Corticotropin-releasing hormone

U.S. FDA Resources 

Further study details as provided by National Institutes of Health Clinical Center (CC):

Estimated Enrollment:	30
Study Start Date:	October 2011

Detailed Description:

Objective

Preoperative imaging identification and localization of adrenocorticotropin hormone (ACTH)-secreting pituitary adenomas is critical for the accurate diagnosis and the successful surgical treatment of Cushing's disease (CD). Unfortunately, over 40 percent of CD patients do not have a visible pituitary adenoma on magnetic resonance (MR)-imaging (the most sensitive imaging modality for ACTH-positive adenoma detection and localization). Lack of MR-imaging for diagnosis and to guide surgical resection results in significantly higher rates of surgical failure compared to cases associated with adenomas visible on MR-imaging. Because ACTH-adenomas are metabolically active compared to the surrounding pituitary gland, (18)F-fludeoxyglucose ((18)F-FDG) positron emission tomography (PET)-imaging in CD patients could be used to detect adenomas not detectable on MR-imaging. Moreover, corticotropin-releasing hormone (CRH) can be given to selectively increase the metabolic activity of ACTH-secreting pituitary adenomas to increase the likelihood of their detection and localization by (18)F -FDG PET-imaging. To determine the effect of CRH stimulation on (18)F-FDG uptake using PET-imaging in CD, we will perform (18)F-FDG high-resolution PET-imaging (with and without CRH stimulation) in CD patients.

Study Population

Thirty male and female CD patients 8 years and older will participate in this study.

Study Design

This is a single center trial to determine the effect of CRH stimulation on (18)F-FDG uptake in high-resolution PET-imaging of ACTH-adenomas in CD patients. CD patients will undergo (18)F-FDG high-resolution PET-imaging without CRH stimulation and (18)F-FDG high-resolution PET-imaging with intravenous CRH stimulation. The order of the PET scans will be randomized and the second PET scan will occur greater than 24 hours but less than 14 days after initial PET-imaging. For (18)F-FDG PET-imaging with CRH stimulation, intravenous (18)F-FDG will be given just before CRH administration. The PET images will be read by radiologists who are blinded to the administration of CRH. Within 12 weeks after completion of the last (18)F-FDG high-resolution PET-imaging scan, patients will undergo surgical resection of the pituitary adenoma. Surgical and histological confirmation of adenoma location will be used to assess the diagnostic and localization accuracy of PET-imaging and to compare to preoperative MR-imaging results in CD patients. Inferior petrosal sinus sampling (IPSS) results will be compared with imaging results and with surgical and histological findings.

Outcome Measures

The primary objective of this study is to determine the effect of CRH stimulation on (18)F-FDG uptake in high-resolution PET-imaging for CD. To assess and compare (18)F-FDG uptake without and with CRH stimulation, we will compare (18)F-FDG standardized uptake values (SUVs) in the region of interest (pituitary gland and pituitary adenoma). Secondary objectives include determining if CRH stimulation enhances detection of ACTH-adenomas as demonstrated on (18)F-FDG high-resolution PET-imaging and assessing the accuracy and sensitivity of (18)F-FDG high-resolution PET-imaging detection of ACTH-adenomas compared to MR-imaging. Measures to assess for these secondary objectives include comparing (18)F-FDG high-resolution PET-imaging (with and without CRH stimulation) detection to (1) MR-imaging detection of adenomas, (2) IPSS results, and (3) actual tumor location confirmed by histological findings to location predicted by PET- and MR-imaging within patients.

  Eligibility

Ages Eligible for Study:	8 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

• INCLUSION CRITERIA:

To be eligible for entry into the study, patients must meet all the following criteria:

1. Be 8 years of age or older and able to undergo PET-imaging without needing general anesthesia.
2. Able to provide informed consent (or guardian is able to provide consent in case of minor).
3. Clinical diagnosis of CD based on medical records.
4. Medically able to undergo resection of pituitary adenoma and planning to undergo surgical resection of adenoma within 12 weeks of PET-imaging.
5. Normal liver enzymes: tests should be completed within 14 days before injection of the radiopharmaceutical; SGOT, SGPT less than or equal to 5 times ULN; bilirubin less than or equal to 2 times ULN.

EXCLUSION CRITERIA:

Candidates will be excluded if they meet any of the following criteria:

1. Pregnant or nursing women.
2. Contraindication to MR-scanning, including pacemakers or other implanted electrical devices, brain stimulators, some types of dental implants, aneurysm clips (metal clips on the wall of a large artery), metallic prostheses (including metal pins and rods, heart valves, and cochlear implants), permanent eyeliner, implanted delivery pump, or shrapnel fragments
3. Severe chronic renal insufficiency (glomerular filtration rate < 30 mL/min/1.73 m(2)), hepatorenal syndrome or post-liver transplantation.
4. Elevated blood glucose level above 200 mg/dL on the day of the scan prior to (18)F-FDG administration.

  Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT01459237

Contacts

Contact: Patient Recruitment and Public Liaison Office	(800) 411-1222	prpl@mail.cc.nih.gov
Contact: TTY	1-866-411-1010

Locations

United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike	Recruiting
Bethesda, Maryland, United States, 20892

Sponsors and Collaborators

National Institute of Neurological Disorders and Stroke (NINDS)

  More Information

Additional Information:

NIH Clinical Center Detailed Web Page  

Publications:

Alzahrani AS, Farhat R, Al-Arifi A, Al-Kahtani N, Kanaan I, Abouzied M. The diagnostic value of fused positron emission tomography/computed tomography in the localization of adrenocorticotropin-secreting pituitary adenoma in Cushing's disease. Pituitary. 2009;12(4):309-14. Epub 2009 Apr 22.

Arnaldi G, Angeli A, Atkinson AB, Bertagna X, Cavagnini F, Chrousos GP, Fava GA, Findling JW, Gaillard RC, Grossman AB, Kola B, Lacroix A, Mancini T, Mantero F, Newell-Price J, Nieman LK, Sonino N, Vance ML, Giustina A, Boscaro M. Diagnosis and complications of Cushing's syndrome: a consensus statement. J Clin Endocrinol Metab. 2003 Dec;88(12):5593-602. Review.

Batista D, Gennari M, Riar J, Chang R, Keil MF, Oldfield EH, Stratakis CA. An assessment of petrosal sinus sampling for localization of pituitary microadenomas in children with Cushing disease. J Clin Endocrinol Metab. 2006 Jan;91(1):221-4. Epub 2005 Oct 11.