Journalist Handbook Special focus on Cushing’s...

Journalist HandbookSpecial focus on Cushing’s disease Provided by Novartis Oncology

2 | Journalist Handbook

Contents

Note to JournalistsThe Internet has presented patients with the resources to understand their illness, and a majority of people today (68%) will first research their symptoms online to be better informed when speaking with their doctor1. Unfortunately, for people affected by a rare condition called Cushing’s disease, which is generally believed to be one to two people per million annually worldwide but estimates vary. Patients experience many signs and symptoms, including weight gain, depression, diabetes, fatigue and high blood pressure, which are also indicative of other illnesses2,3.

To help increase your understanding of this often over-looked and misdiagnosed disease, the following handbook has been developed by Novartis Oncology to provide you with background about Cushing’s disease.

The following provides essential information needed to better understand the clinical manifestations of the disease, the necessary steps to obtain a proper diagnosis and disease management.

This handbook also provides information that may assist in your reporting of Cushing’s disease and other medical topics, including a glossary of commonly used terms that are associated with Cushing’s disease and a listing of medical resources, including government and non-governmental organizations, and medical publications that provide scientifically accurate information about endocrine disorders

We hope you find the handbook useful as you consider reporting on Cushing’s disease in the near future.

We hope you find the handbook useful as you consider reporting on Cushing’s disease in the near future.

3 Cushing’s disease: A Rare Endocrine Disorder 4 Definition & Epidemiology5 Mechanism of Disease6 Clinical Manifestations6 Complications7 Diagnosing Cushing’s disease9 Disease Management

10 Selected Resources 10 Sources for Medical Reporting •MedicalJournals •MedicalConferences10 Medical Literature Databases 10 Clinical Trial Databases 10 Government Agencies and Resources 11 Professional Medical Organizations11 Patient and Disease-Related Organizations 11 Peer-Reviewed Journals

12 Commonly Used Terms 12 Statistical Terms12 Clinical Trial Terms

13 Cushing’s disease Glossary

14 References

Special focus on Cushing’s disease | 3

Cushing’s disease: A Rare Endocrine Disorder

As we begin our overview of Cushing’s disease – which is a rare endocrine disorder – it is important to provide a brief summary

of the endocrine system4. The endocrine system includes eight major glands through-out the body that produce hormones, which travel through the bloodstream to tissues or organs, affecting body processes from head to toe, such as growth and development, metabolism, sexual function, reproduction and mood. The endocrine system plays a critical role in many bodily functions and regulation of these processes contributes to a person’s overall health5.

Endocrine disorders occur when hormone levels are imbalanced. Hormone levels that are too high or too low may be caused by an endocrine disorder. An endocrine disorder may also occur if the body does not respond to hormones the way it is supposed to5.

There are many different endocrine disorders that impact various parts of the body5. Diabetes, the most common endo-crine disorder, was estimated to affect nearly 366 million people aged 20-79 worldwide in 2011 and is associated with long-term complications that affect almost every part of the body6,7. Cushing’s disease, a less well-known disorder of the endocrine system affects a much smaller portion of the global population but can also have endur-ing effects on the body2,8.

Cushing’s disease is caused by a tumor on the pituitary gland, an endo-crine gland positioned at the base of the brain8. Because this disease affects only a small portion of the global population and presents with a constellation of symptoms easily mistaken for other diseases when looked at individually and not taken as a whole, it can be difficult to recognize and often takes years for patients to receive a correct diagnosis9,10.

Hormone levels that are too high or too low may be caused by an endocrine disorder.


What is Cushing’s disease?

To explain Cushing’s disease, we first have to explain Cushing’s syndrome. Cushing’s syndrome is an endocrine disorder caused by excessive cortisol (hypercortisolism), a vital hormone that regulates metabolism, maintains cardiovascular function and helps the body respond to stress5. Many people have Cushing’s syndrome because they are regularly exposed to medicine(s) that con-

tinually add too much cortisol to the body (referred to as an exogenous – outside the body – cause)11. Others have Cushing’s syn-drome due to an internal trigger that causes the adrenal glands to overproduce cortisol – (referred to as an endogenous – inside the body – cause)12.

Cushing’s disease is the most common form of endogenous Cushing’s syndrome, accounting for about 70% of all cases9,11. It is caused when excessive cortisol pro-duction is triggered by a non-cancerous adrenocorticotropic hormone (ACTH)-secreting pituitary adenoma (tumor)8.

This rare and potentially debilitating endocrine disorder affects approximately one to two people per million per year with a current estimated prevalence of 39.1 cases per million2,14. Cushing’s disease most commonly affects adults from 20 to

50 years old and affects women as much as three times more often than men4,11.

To date, no known causes or risk factors have been identified for development of the non-cancerous tumors in the pituitary gland that cause Cushing’s disease11.

Cushing’s disease is a debilitat-ing endocrine disorder caused by excess cortisol in the body due to the presence of a non-cancerous pituitary tumor3,8.


Mechanism of disease

In someone not affected by Cushing’s disease, the adrenal gland secretes the hor-mone cortisol, commonly known to prompt the “fight or flight” reaction, in response to stimulation by ACTH, which is produced by the pituitary gland15,16. ACTH is secreted in response to two other hormones, cor-ticotropin releasing hormone (CRH) and vasopressin, both of which are secreted from the hypothalamus (a part of the fore-brain). This mechanism is controlled by a negative feedback loop, with cortisol driving the cycle by influencing both CRH and vaso-pressin in the hypothalamus, and ACTH in the pituitary16.

In healthy individuals, cortisol is secreted in a circadian rhythm. Levels are highest in the morning (7:00-9:00 AM) and gradually decline throughout the day, beginning to rise again at approximately 3:00 AM.

The presence of ACTH-secreting pituitary tumors results in the loss of the negative feedback of cortisol to both the hypothala-mus and pituitary. This finally results in continuouscortisol secretion by the adrenal gland and subsequent loss of circadian rhythm12,18. This condition is clinically referred to as Cushing’s disease3.

The presence of ACTH-secreting pituitary tumors results in the loss of the negative feedback of cortisol to both the hypothalamus and pituitary.

The hypothalamus sends CRH to the pituitary, which responds by secreting ACTH. ACTH then causes the adrenals to release cortisol into the bloodstream4,16,17.


Clinical manifestations

The clinical manifestations of Cushing’s disease caused by hypercortisolism are broad and diverse but can be grouped into three main categories that include, but are not limited to:

Physical• Weight gain3

• Central obesity (abdomen that sticks out with thin arms and legs)4

•Moon face (round, red and full)9

• Purple striae (stretch marks) on the abdomen, thighs and breasts4

• Buffalo hump (collection of fat on the back of the neck)4

•Acne or skin infections9

•Thin skin/bruising9

• Hirsutism (excessive and unusual hair growth in females)4

•Muscle weakness3

•Headache9

•Osteoporosis9

Hormonal/Psychiatric •Depression, anxiety4

•Mood swings, irritability4

• Impotence4

• Irregular or absent menstruation4

Metabolic/Cardiovascular •Cardiovascular disease19

•Severe fatigue3

•Metabolic disturbance4 • Increased thirst and urination4

Additional clinical manifestations include backaches, swelling, appetite changes, memory problems, sleeping problems, repeated infections, hair loss and slow wound healing. When viewed individu-ally, many of the signs and symptoms of Cushing’s disease can be caused by more common health conditions, so it is impor-tant for patients to accurately convey the entire constellation of symptoms they are experiencing to a healthcare professional12.

Complications

There are many serious health complica-tions associated with Cushing’s disease, including: osteoporosis and subsequently fractures, diabetes, high blood pressure (hypertension), hyperglycemia, cardiovascu-lar disease, lipid disorders, infections, high cholesterol, kidney stones and blood clotting disorders9,16,20. Some of these complications can lead to heart problems such as excess blood clotting and high cholesterol and triglycerides20. Cushing’s disease may also reduce thyroid function (hypothyroidism) and cause infertility8,20.

Many of the signs and symptoms of Cushing’s disease can be caused by more common health conditions…

High blood pressure(called hypertension)

Impaired glucosemetabolism/diabetes

Obesity

Infections

Heart disease

High cholesteroland triglycerides(called hyperlipidemia)

Stroke

Excess clotting of the blood(called hypercoagulability)


Diagnosing cushing’s disease

Diagnosing Cushing’s disease is challenging for several reasons. The most difficult step is recognizing Cushing’s syndrome, which must be done first. Once Cushing’s syn-drome has been identified, doctors can run a number of tests to determine the cause of excess cortisol, which will determine if the patient’s Cushing’s syndrome is actually Cushing’s disease12.

As noted earlier, many of the signs and symptoms of excess cortisol are indistin-guishable from other health conditions when looked at individually. Because of this, healthcare professionals may delay testing for this rare disease in order to eliminate more common conditions such as depression or other psychiatric disorders, alcoholism, weight problems caused by improper diet and/or exercise, diabetes or polycystic ovarian syndrome12. Additionally, clinical manifestations of the disease do not present the same way in all people affected – people may have all or some of the symptoms at any given time9.

As a result, the process for diagnosing Cushing’s disease is often lengthy. The time to diagnosis for a patient is on average six

years from the time they notice symptoms. To accurately confirm a suspected diagnosis of Cushing’s disease, there are a variety of tests a doctor will employ10.

Diagnosis generally happens in three phases, with patients often visiting several medical specialists.

Phase 1: The first step to diagnose Cushing’s syndrome is for a patient to pro-vide the doctor with a complete medical history, including any known conditions and current medications12. Many medicines used

for allergies, respiratory problems and skin problems contain glucocorticoid medicines, which may cause similar signs and symptoms associated with exogenous Cushing’s syndrome11,20.

After evaluating this information, doctors may test for hypercortisolism if any of the following characteristics and/or symptoms are present:•Moon face9

•Purple striae4

•Easy bruising9

•Central obesity4

•Diabetes4

• Adrenal tumor found during an ultrasound or similar procedure12

Test for Cushing’s disease20

ACTH MeasurementPha

se 3

Imaging TestsCorticotropin-releasing hormone

(CRH) stimulation test

Patients Medical History12,20

Known ConditionsPha

se 1

Current medications

Key signs/symptoms: Moon face, purple striae, easy bruising,

central obesity, diabetes, hirutism, adrenal tumor

Pha

se 2 Test for Cushing’s Syndrome4,12

Urinary-free cortisol (UFC) test

Late-night salivary cortisol test

Late-night plasma cortisol test

Dexamethasone suppression test (DST) (Overnight or 48-hour)


Phase 2: To confirm a diagnosis of Cushing’s syndrome, a doctor can employ several types of tests to measure the level of cortisol in the body. These tests should only be done when exogenous hypercortisolism is ruled out12.

Specifically, there are four tests that are used to identify Cushing’s syndrome. These tests measure the amount of cortisol in samples of urine, blood, or saliva to determine how much cortisol is circulating in the body. If the tests show that the level of cortisol is too high, a diagnosis of Cushing’s syndrome can be confirmed12.

Tests for Cushing’s syndrome

Urinary-free cortisol (UFC) test

What it measures: Cortisol in urine20

Why it’s used: Almost all people with Cushing’s syndrome have high urine corti-sol levels. This test only measures the type of cortisol that causes Cushing’s syndrome, called, “circulating, free cortisol”12

How it’s done: Urine samples are collected at every opportunity throughout a 24-hour period and provided to a lab for testing12

Late-night salivary cortisol test

What it measures: Cortisol in saliva20

Why it’s used: Cushing’s syndrome will cause elevated levels of cortisol in saliva at night, when levels are usually lowest12

How it’s done: A saliva sample is obtained between 11:00 PM and 12:00 AM on two different nights and provided to a lab for testing18

The timing of the collection should be adjusted to the time of sleep-ing if a person’s bedtime is usually long after midnight33

Late-night plasma cortisol test

What it measures: Cortisol in the blood20

Why it’s used: Cushing’s syndrome will cause elevated levels of cortisol in the blood at night, when levels are usually lowest20

How it’s done: A blood sample is obtained at night while the patient is sleeping in a hospital and provided to a lab for testing20

Dexamethasone suppression test (DST)

What it measures: Cortisol in the blood20

Why it’s used: Normally, low doses of the corticosteroid dexamethasone will reduce cortisol levels but in a person with Cushing’s syndrome, these doses will not have an effect11

How it’s done: There are two DST test options; overnight and 48-hour. Once a sample is collected, a lab test is done to determine if cortisol levels were reduced11

Overnight DST (short test): A 1-mg dose of dexamethasone is taken between 11:00 PM and 12:00 AM. The next morning a blood sample is taken between 8:00 AM and 9:00 AM11,20

48-hour DST (long test): A 0.5-mg dose of dexamethasone is taken every 6 hours for 48 hours. Six hours following the last dose, a blood sample is taken at the doctor’s office11,20

To confirm a diagnosis of Cushing’s syndrome, a doctor can employ several types of tests to measure the level of cortisol in the body.


Phase 3: If a diagnosis of Cushing’s syn-drome is confirmed, additional tests will be conducted to determine why the patient’s body is producing too much cortisol and confirm if it’s due to a pituitary tumor (Cushing’s disease) or a different form of Cushing’s syndrome11.

Disease management guidelines

The first line and most common manage-ment approach for Cushing’s disease is surgical removal of the tumor, known as selective adenomectomy, usually performed via transsphenoidal route4. Using a micro-scope and small instruments, a surgeon approaches the pituitary gland through

a nostril or an opening made below the upper lip. The reported initial success rate for pituitary surgery for Cushing’s disease varies between 60% and 86%, however up to 25% of patients suffer from recurrence even after apparent remission34.

If surgery is not appropriate or effec-tive, other management options include radiation to the pituitary gland, stereotactic radiosurgery or gamma knife radiation, and in extreme cases full removal of the adrenal glands, called an adrenalectomy4. Patients undergoing adrenalectomies will require lifelong mineralocorticoid and glucocorticoid replacement35. For radiation treatment alone, it may take several months or years before patients experience improvement in their symptoms; therefore, cortisol-inhibiting drugs can be required4. While there is no cure, treatments are available that may help3.

Tests for Cushing’s disease

ACTH Measurement

What it measures: ACTH in the blood20

Why it’s used: To determine tumor location. Normal to high ACTH levels may be indicative of a tumor in the pitu-itary gland, and would confirm a diagnosis of Cushing’s disease9,20

How it’s done: A blood sample is collected and provided to a lab for testing20

Imaging Tests

What it measures: Location/presence of a tumor20

How it’s done: If ACTH levels are high, a magnetic resonance imaging (MRI) or computerized tomography (CT) test will be conducted to confirm the location and presence of a tumor in the pituitary gland20 However sometimes the tumor will be too small to be detected by imaging4

Corticotropin-releasing hormone (CRH) stimulation test

What it measures: How CRH changes ACTH and cortisol levels20

Why it’s used: To confirm the presence of a pituitary tumor if ACTH measurement or imaging tests are inconclusive4

How it’s done: Blood tests are used to measure ACTH and cortisol levels, then a CRH intravenous injection is given, after which blood tests are repeated several times to recheck ACTH levels. If these levels have increased, this helps to confirm the presence of a pituitary tumor and therefore a diagnosis of Cushing’s disease20

Inferior Petrosal Sinus Sampling

What it measures: ACTH in the blood from the inferior petrosal sinuses21

Why it’s used: To confirm the presence of a pituitary tumor if ACTH measurement or imaging tests are inconclusive21

How it’s done: Tests are used to measure ACTH levels in blood taken from the inferior petrosal sinus, which collects venous drainage from the pituitary gland21


Selected Resources

This section provides an overview on where

to obtain credible information regarding

Cushing’s disease.

Sources for medical reporting

Medical JournalsArticles published in peer-reviewed medical

journals provide the primary source for

credible medical news. In peer review jour-

nals, independent experts screen submitted

scientific papers to ensure that they meet

the accepted standards of their discipline.

Medical journals such as The Lancet,

the British Medical Journal, The New England

Journal of Medicine (NEJM) and the Journal

of the American Medical Association (JAMA)

encapsulate many different aspects of

medicine and appeal to a wide variety of

healthcare professionals. Specialty medi-

cal journals that focus on endocrinology

include European Journal of Endocrinology,

Clinical Endocrinology, Journal of Clinical

Endocrinology & Metabolism, Endocrine

Reviews, Neuroendocrinology and Endocrine

Pathology.

Medical ConferencesResearchers share preliminary and updated

results of their work at medical confer-

ences23. Typical formats for presentation of

information at medical conferences include:

• Presentation abstract: a synopsis of the

study submitted for presentation at a

medical conference. The sponsoring orga-

nization will publish the accepted abstracts

prior to or during the conference, in an

abstract book and often online, and may

make them available to reporters23.

• Oral presentation: research that has been

selected for presentation by means of a

live lecture during the conference (usually

with slides)24

• Poster presentation: the study is sum-

marized on a large paper poster board,

illustrating the research methods and

outcomes in text and graphics. Typically,

a poster presentation allows viewers to

discuss the study with one or more of the

researchers24.

Caution: Check with individual journals and

conference sponsors for their embargo policies.

Tip: Sign up with journals and conference

sponsors to receive email alerts of upcoming

publications and meetings.

Medical literature databases

• Thompson Reuters: http://science.thom-

sonreuters.com/mjl/

•PubMed (US): www.pubmed.gov

Clinical trial databases

• International Clinical Trials Registry

Platform (WHO): www.who.int/ictrp

• Clinical Trials (USA): www.clinicaltrials.gov/

Government agencies and resources

• European Medicines Agency (EU):

www.ema.europa.eu

• National Endocrine and Metabolic Disease

Information Service (USA): http://www.

endocrine.niddk.nih.gov/

• US Food and Drug Administration (USA):

www.fda.gov

• World Health Organization: www.who.int


Professional medical organizations

• Addison & Cushing International

Federation: www.nvacp.nl

• American Association of Clinical

Endocrinologists: https://www.aace.com/

• European Neuroendocrine Association:

http://www.eneassoc.org/

• European Organisation for Rare Diseases:

http://www.eurordis.org/

• European Register on Cushing’s Syndrome:

http://www.lohmann-birkner.de/ercusyn/

• European Society for Immunodeficiencies:

http://www.esid.org

• European Society of Endocrinology:

http://www.euro-endo.org/

• Instituto de Investigatión de Enfermedades

Raras: http://iier.isciii.es/er/

• The Endocrine Society:

http://www.endo-society.org/

Patient and disease-related organizations

• Canadian Organization for Rare Disorders

(CA): http://raredisorders.ca/

• Cushing’s Help and Support (USA):

http://www.cushings-help.com/

• Cushing’s Support and Research

Foundation (USA): http://www.csrf.net/

• Cushing’s Understanding Support & Help

Organization (USA): http://www.cush.org/

• Hormone Health Network (USA):

http://www.hormone.org/

• Magic Foundation (USA):

http://www.magicfoundation.org

• National Adrenal Diseases Foundation

(USA): http://www.nadf.us/

• National Organization for Rare Disorders

(USA): http://www.rarediseases.org/

• Netzwerk Hypophysen–und

Nebennierenerkrankungen e.V. (German

Pituitary and Adrenal Network) (DE):

www.glandula-online.de

• Pituitary Network Association (USA):

http://www.pituitary.org

• The Pituitary Foundation (UK): www.pitu-

itary.org.uk

Peer-reviewed medical journals

Novartis does not endorse and is not

responsible for the content of any of the

listed resources. Please note that this is not

an exhaustive list of resources.

American Journal of Physiology:

Endocrinology and Metabolism:

Publishes original, mechanistic studies on

the physiology of endocrine and metabolic

systems. (http://ajpendo.physiology.org/)

Clinical Endocrinology: Publishes papers

and reviews, which focus on the clinical

aspects of endocrinology, including the

clinical application of molecular endocrinol-

ogy. (http://www.wiley.com/bw/journal.

asp?ref=0300-0664)

Endocrine Practice: Official journal of

the American College of Endocrinology

and the American Association of Clinical

Endocrinologists. Published to enhance

the healthcare of patients with endocrine

diseases through continuing education

of practicing endocrinologists. (http://aace.

metapress.com/home/main.mpx)

Endocrine Reviews: Publishes comprehen-

sive, authoritative, and timely review articles

balancing both experimental and clinical

endocrinology themes and crystallizing

the most significant clinical experience

and current research in endocrinology and

related areas. (http://edrv.endojournals.org/)

Endocrinology: Publishes biomedical

research ranging from subcellular mecha-

nisms to whole animal physiology. Topics

include bone and mineral, growth factors;

reproductive/steroids, neuroendocrinology/

signal transduction, thyroid, and physiology.

(http://endo.endojournals.org/)

European Journal of Endocrinology:

Publishes original clinical and translational

research papers, reviews and commentaries

in pediatric and adult endocrinology.

(http://www.eje-online.org/)

Growth Hormone & IGF Research:

Publishes research on the regulation of

growth and metabolism in humans, ani-

mals, tissues and cells. (www.sciencedirect.

com/science/journal/aip/10966374)

Journal of Clinical Endocrinology &

Metabolism: Publishes endocrine clinical

research and clinical practice reviews to

provide in-depth coverage of new develop-

ments of the diagnosis and treatment of

endocrine and metabolic disorders. Regular

features of special interest include clini-

cal trials, clinical reviews, clinical practice

guidelines, case seminars and controver-

sies in clinical endocrinology, as well as

original reports of endocrine and metabolic

research. (http://jcem.endojournals.org/)

Molecular and Cellular Endocrinology:

Publishes full-length original research papers,

invited reviews and book reviews related

to biochemical and molecular aspects of

endocrine research and cell regulation.

(http://www.elsevier.com/locate/mce)

The Journal of the American Medical

Association: Publishes articles on a diverse

range of medical topics. (www.jama.ama-

assn.org)

The Lancet: Publishes medical news, origi-

nal research, and reviews on all aspects of

clinical medicine and public health. (http://

www.thelancet.com/)

The Lancet Diabetes & Endocrinology:

Focuses upon timely news, views, research

and reviews in diabetes, endocrinology

and metabolism. The new journal, which is

launching August 2013, will cover a wide

breadth and diversity of topics of interest

to clinicians, specialists and researchers,

including adrenal disorders, neuroendo-

crinology, pediatric endocrinology and

pituitary disorders. (www.thelancet.com/

diabetes-endocrinology)

The New England Journal of Medicine:

Publishes new medical research findings,

review articles, and editorial opinion on

a wide variety of topics of importance to

biomedical science and clinical practice.

Material is published with an emphasis

on internal medicine and specialty areas

including allergy/immunology, cardiology,

endocrinology, gastroenterology, hematol-

ogy, kidney disease, oncology, pulmonary

disease, rheumatology, HIV, and infectious

diseases. (www.nejm.org)


Commonly used terms

The following terms frequently appear

in journal articles and conference

presentations:

Statistical terms

Confidence interval (CI): describes how pre-

cise a particular result is and suggests how

reliable it may be beyond the specific study.

In a clinical trial, the CI indicates the limits

within which the difference between two

treatments is likely to lie. CIs are reported

as a range of values above and below the

study finding; the more narrow the range,

the more precise the result. For example, a

disease that is present in 25% of a popula-

tion with a CI of plus or minus 5% means

that the actual value can lie anywhere

between 20% and 30%25.

Mean: the sum of a set of numbers divided

by how many numbers are in the set. In a

clinical study, there will always be patients

who will fall above or below the mean26.

Median: the middle value in a set of

measurements26.

P-value (probability value): a measure of

probability that a difference between groups

during an experiment happened by chance.

For example, a p-value of .01 (p = 0.01)

means there is a 1 in 100 (1%) chance

the result occurred by chance. In a clinical

trial, the lower the p-value, the more likely

it is that the difference between groups was

caused by the treatment being studied25.

Statistical significance: results that are

statistically significant are unlikely to be

due to chance. A p-value less than 0.05

(meaning that the result would have arisen

by chance on less than one occasion in 20)

is generally considered statistically signifi-

cant. In clinical trials, the level of statistical

significance depends on the number of

participants studied and the observations

made, as well as the magnitude of differ-

ences observed27,28.

Clinical trial terms

Blinded trial: a study in which the patients

(single-blinded) or the patients and their

doctors (double-blinded) do not know

which drug or treatment is being given;

the opposite of an open label study29.

Clinical trial: a research study that tests

the effectiveness and safety of medications,

devices, and/or treatment paradigms in

humans27.

• Phase I clinical trial: initial studies con-

ducted with a small number of volunteers

with or without the disease (can be fewer

than 80) to assess the safety and various

dose ranges for an experimental treat-

ment28.

• Phase II clinical trial: mid-stage studies

(which occur after a Phase I trial) typically

involving a larger number of patient

volunteers to further assess safety

and effectiveness of an experimental

treatment28.

• Phase III clinical trial: large trials (which

occur after Phase II) carried out to con-

firm the effectiveness of an experimental

treatment, and identify adverse events.

Phase III trials are conducted to compare

an experimental treatment to commonly

used treatments, and collect informa-

tion to evaluate the overall risk/benefit

ratio. Phase III trials provide the basis for

applications with regulatory agencies for

authorization to market a new drug28.

• Endpoint: an overall measurable outcome

that the study is designed to evaluate.

The primary endpoint(s) measure out-

comes related to the main objective of the

study and secondary endpoints evaluate

measures for other related questions in

the study27,30.

Non-inferiority trial: a study intended to

show that the effect of a treatment is not

worse than that of an active control, by no

more than a specified range31.

Open-label trial: a study in which both the

patients and the doctors know which treat-

ment is being given; opposite of a blinded

study31.

Post-hoc analysis: an examination of data,

after a clinical trial has concluded, for

analyses that were not specified previously32.

Prospective trial: a study or clinical trial in

which participants are identified and then

followed forward in time25.

Randomized trial: a study in which the

participants are assigned by chance to

separate groups that compare different

treatments. Large, randomized, double-

blind, controlled prospective clinical trials

are considered to provide the highest qual-

ity of scientific evidence25,30.

Retrospective study: a study that compares

patients with the disease or condition under

study (cases) and a similar group of people

who do not have the disease or condition

(controls). Researchers study the medical

and lifestyle histories of the people in

each group to learn what factors may be

associated with the disease or condition.

A retrospective study is also called a

case-control study27.

Sub-analysis study: a study that examines

data from a subset of patients from a

clinical trial27.


Glossary

Key terms for use in interpreting information

and developing stories on Cushing’s disease.

Adenoma: a non-cancerous tumor of a glan-

dular structure or of glandular origin23.

Adenomectomy: is the surgical removal of

the tumor by a surgeon who approaches the

pituitary gland through a nostril or an opening

made below the upper lip. This process is the

first line and most common disease manage-

ment approach for Cushing’s disease4.

Adrenalectomy: is the surgical removal of

the adrenal glands, which may occur if sur-

gery or other disease management options

are not appropriate or effective. It is also

known as a bilateral adrenalectomy4.

Adrenal glands: either of a pair of com-

plex endocrine organs near the anterior

medial border of the kidney consisting of

a mesodermal cortex that produces gluco-

corticoid, mineralocorticoid and androgenic

hormones, and an ectodermal medulla that

produces epinephrine and norepinephrine23.

Adrenocorticotropic hormone (ACTH): a

protein hormone of the anterior lobe of

the pituitary gland that stimulates the

adrenal cortex23.

Cardiovascular: of, relating to, or involving

the heart and blood vessels23.

Cholesterol: a steroid alcohol present in

animal cells and body fluids that regu-

lates membrane fluidity, functions as a

precursor molecule in various metabolic

pathways; as a constituent of LDL, it may

cause arteriosclerosis23.

Corticotropin-releasing hormone (CRH): a

substance secreted by the median eminence

of the hypothalamus that regulates the

release of ACTH by the anterior lobe of the

pituitary gland23.

Cortisol: a glucocorticoid produced by the

adrenal cortex upon stimulation by ACTH

that mediates various metabolic processes

(such as gluconeogenesis), has anti-inflam-

matory and immunosuppressive properties,

and whose levels in the blood may become

elevated in response to physical or psycho-

logical stress23.

CT (CAT) scan: a sectional view of the body

constructed by computed tomography23.

Cushing’s disease: Cushing’s syndrome

caused by excessive cortisol production trig-

gered by a non-cancerous ACTH-secreting

pituitary tumor23.

Cushing syndrome: is an endocrine disorder

caused by excessive cortisol, a vital hor-

mone that regulates metabolism, maintains

cardiovascular function and helps the body

respond to stress5.

Dexamethasone: a synthetic glucocorti-

coid also used in the form of an acetate or

sodium phosphate, especially as an anti-

inflammatory and antiallergic agent23.

Diabetes: A chronic, progressive disease in

which the body does not produce or prop-

erly use insulin5.

Ectopic: occurring in an abnormal position23.

Endocrinologist: a medical professional

who studies the glands and hormones of the

body and their related disorders23.

Endogenous: caused by factors within

the body or mind or arising from internal

structural or functional causes. Cushing’s

disease is an endogenous disease caused

by a tumor on the pituitary gland23.

Exogenous: caused by factors (such as food

or a traumatic factor) or an agent (such as

a disease-producing organism) from outside

the organism or system23.

Glucocorticoid: any of a group of corticoste-

roids (such as cortisol or dexamethasone)

that are involved in carbohydrate, protein

and fat metabolism; that tend to increase

liver glycogen and blood sugar by increasing

gluconeogenesis; and that are used widely

in medicine (such as in the alleviation of the

symptoms of rheumatoid arthritis)23.

High blood pressure: means that the body’s

blood flow is causing too much pressure

against artery walls23.

Hirsutism: excessive growth of facial/body

hair of normal or abnormal distribution23.

Hormone: product of living cells that circu-

lates in body fluids (such as blood) or sap

and produces a specific, often stimulatory,

effect on the activity of cells usually remote

from a hormone’s point of origin23.

Hypercortisolism: a state of overproduction of

cortisol in the body, often a result of tumor(s)

in the adrenal or pituitary glands23.

Hypothyroidism: deficient activity of the

thyroid gland; also, a resultant bodily con-

dition characterized by lowered metabolic

rate and general loss of vigor 23.

Infertility: not fertile; incapable of or

unsuccessful in achieving pregnancy over a

considerable period of time (such as a year)

in spite of determined attempts by hetero-

sexual intercourse without contraception23.

Magnetic resonance imaging (MRI): a non-

invasive diagnostic technique that produces

computerized images of internal body tis-

sues and is based on nuclear magnetic

resonance of atoms within the body induced

by the application of radio waves23.

Malignant: tending to produce death or

deterioration; especially tending to infiltrate,

metastasize, and terminate fatally23.

Metabolic disturbance: a combination

of problems that includes excess weight

around the waist, high blood pressure,

abnormal levels of cholesterol and triglycer-

ides in the blood and insulin resistance3.

Obesity: a high body mass index (that is,

the amount of fat in the body). Central obe-

sity is when high BMI occurs in the middle

part of the body (around the abdominal

area), while arms and legs remain thin20.

Osteoporosis: a condition that especially

affects older women and is characterized

by decrease in bone mass with decreased

density and enlargement of bone spaces,

producing porosity and brittleness23.

Pituitary gland: a small, vascular endocrine

organ that is attached to the brainstem.

The pituitary gland has several parts associ-

ated with various hormones that directly or

indirectly affect most basic bodily functions

and include substances that exert a control-

ling and regulating influence on other

endocrine organs by controlling growth and

development or modifying the contraction of

smooth muscle, renal function and repro-

duction26.

Steroid hormone: any of numerous hor-

mones (such as estrogen, testosterone,

cortisone and aldosterone) having the

characteristic ring structure of steroids and

formed in the body from cholesterol 26.

Triglycerides: any of a group of fats that

are formed from one molecule of glycerol

and three molecules of one or more fatty

acids; they are widespread in fat tissue26.

Tumor: an abnormal non-cancerous or

malignant new growth of tissue that pos-

sesses no physiologic function and arises

from uncontrolled usually rapid cellular

proliferation26.

Urinary-free cortisol: these measurements

are used in the diagnosis of hypercorti-

solism caused by Cushing’s syndrome or

Cushing’s disease4.


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*Note: This handbook is intended for use by ex-US journalists to assist

with reporting on Cushing’s disease.

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