Causes of Cushing’s Syndrome

Cushing’s syndrome—also referred to as hypercortisolism—is fairly rare. However, researchers have boiled down a few key causes of Cushing’s syndrome, which you’ll read about below.

The cause of Cushing’s syndrome boils down to: Your body is exposed to too much cortisol. There are a few ways that this over-exposure can happen, including taking certain medications and having a tumor on your pituitary gland or adrenal gland.

Can Taking Corticosteroids Cause Cushing’s Disease?
One particular type of medication can cause Cushing’s syndrome: corticosteroids. But rest assured: Not all steroid medications cause Cushing’s syndrome. It’s more common to develop Cushing’s syndrome from steroids you take in pill form or steroids you inject. Steroid creams and steroids you inhale are not common causes of Cushing’s syndrome.

Some steroid medications have the same effect as the hormone cortisol does when produced in your body. But as with an excessive production of cortisol in your body, taking too much corticosteroid medications can, over time, lead to Cushing’s syndrome.

It’s common for people with asthma, rheumatoid arthritis, and lupus to take corticosteroids. Prednisone (eg, Deltasone) is an example of a corticosteroid medication.

Other Cushing’s Disease Causes
Your body can over-produce cortisol or adrenocorticotropic hormone (ACTH). The pituitary gland secretes ACTH, which is in charge of stimulating the adrenal glands to produce cortisol, and the adrenal glands are responsible for releasing cortisol into the bloodstream.

Cortisol performs important tasks in your body, such as helping to maintain blood pressure and regulate how your body metabolizes proteins, fats, and carbohydrates, so it’s necessary for your body to maintain normal levels of it.

The following can cause excessive production of cortisol or ACTH, leading to Cushing’s syndrome.

  • Pituitary gland tumors: A benign (non-cancerous) tumor of the pituitary gland can secrete an excess amount of ACTH, which can cause Cushing’s syndrome. Also known as pituitary adenomas, benign tumors of the pituitary gland affect women 5 times more often than men.
  • Adrenal gland tumors: A tumor in one of your adrenal glands can lead to Cushing’s syndrome by causing too much cortisol to enter your bloodstream. Most of these tumors are non-cancerous (called adrenal adenomas).

    Cancerous adrenal tumors—called adrenocortical carcinomas—are relatively rare. These types of tumors typically cause extremely high levels of cortisol and very rapid development of symptoms.

  • Other tumors in the body: Certain tumors that develop outside the pituitary gland can also produce ACTH. When this happens, it’s known as ectopic ACTH syndrome. Ectopic means that something is in an abnormal place or position. In this case, only the pituitary gland should produce ACTH, so if there is a tumor producing ACTH and it isn’t located on the pituitary, it’s ectopic.

    It’s unusual to have a tumor that secretes ACTH outside the pituitary. These tumors are usually found in the pancreas, lungs, or thyroid, and they can be benign or malignant (cancerous).

    The most common forms of ACTH-producing tumors are small cell lung cancer, which accounts for about 13% of all lung cancer cases, and carcinoid tumors—small, slow-growing tumors that arise from hormone-producing cells in various parts of the body.

  • Familial Cushing’s syndrome: Although it’s rare, Cushing’s syndrome can develop from an inherited tendency to have tumors on one or more of your endocrine glands. Some inherited conditions, such as multiple endocrine neoplasia (MEN 1), can involve tumors that over-produce cortisol or ACTH, leading to Cushing’s syndrome.

If you think you could have Cushing’s syndrome or you have questions about the causes of Cushing’s syndrome, talk to your doctor immediately.

Written by | Reviewed by Daniel J. Toft MD, PhD, adapted from  http://www.endocrineweb.com/conditions/cushings-syndrome/cushings-syndrome-causes

Day 14, Cushing’s Awareness Challenge 2016

Way back when we first got married, my husband thought we might have a big family with a lot of kids.  He was from a family of 6 siblings, so that’s what he was accustomed to.  I am an only child so I wasn’t sure about having so many.

I needn’t have worried.

In January, 1974 I had a miscarriage.  I was devastated. My father revealed that my mother had also had a miscarriage.  I had no idea.

At some point after this I tried fertility drugs.  Clomid and another drug.  One or both drugs made me very angry/depressed/bitchy (one dwarf I left off the image)  Little did I know that these meds were a waste of time.

Eventually,  I did get pregnant and our wonderful son, Michael was born.  It wasn’t until he was seven that I was finally, actually diagnosed with Cushing’s.

When I had my early Cushing’s symptoms, I thought I was pregnant again but it was not to be.

I’ll never forget the fall when he was in second grade.  He was leaving for school and I said goodbye to him.  I knew I was going into NIH that day for at least 6 weeks and my future was very iffy.  The night before, I had signed my will – just in case.  He just turned and headed off with his friends…and I felt a little betrayed.

Michael wrote this paper on Cushing’s when he was in the 7th grade. From the quality of the pages, he typed this on typing paper – no computers yet!

Click on each page to enlarge.

When Michael started having headache issues in middle school, I had him tested for Cushing’s.  I had no idea yet if it could be familial but I wasn’t taking any chances.  It turned out that my father had also had some unnamed endocrine issues.  Hmmm…

I survived my time and surgery at NIH and Michael grew up to be a wonderful young man, if an only child.  🙂

After I survived kidney cancer (Day Twelve, Cushing’s Awareness Challenge 2015) Michael and I went zip-lining – a goal of mine after surviving that surgery.  This photo was taken in a treetop restaurant in Belize.

For the mathematically inclined, this is his blog.  Xor’s Hammer.  I understand none of it.  He also has a page of Math and Music, which I also don’t understand.

I know it doesn’t fit into a Cushing’s awareness post but just because I’m a very proud mama – Michael got a PhD in math from Cornell and his thesis was Using Tree Automata to Investigate Intuitionistic Propositional Logic

 

proud-mom

 

What Genes are Related to Cushing’s Disease?

genetic

 

The genetic cause of Cushing disease is often unknown. In only a few instances, mutations in certain genes have been found to lead to Cushing disease. These genetic changes are called somatic mutations. They are acquired during a person’s lifetime and are present only in certain cells. The genes involved often play a role in regulating the activity of hormones.

Cushing disease is caused by an increase in the hormone cortisol, which helps maintain blood sugar levels, protects the body from stress, and stops (suppresses) inflammation. Cortisol is produced by the adrenal glands, which are small glands located at the top of each kidney. The production of cortisol is triggered by the release of a hormone called adrenocorticotropic hormone (ACTH) from the pituitary gland, located at the base of the brain. The adrenal and pituitary glands are part of the hormone-producing (endocrine) system in the body that regulates development, metabolism, mood, and many other processes.

Cushing disease occurs when a noncancerous (benign) tumor called an adenoma forms in the pituitary gland, causing excessive release of ACTH and, subsequently, elevated production of cortisol. Prolonged exposure to increased cortisol levels results in the signs and symptoms of Cushing disease: changes to the amount and distribution of body fat, decreased muscle mass leading to weakness and reduced stamina, thinning skin causing stretch marks and easy bruising, thinning of the bones resulting in osteoporosis, increased blood pressure, impaired regulation of blood sugar leading to diabetes, a weakened immune system, neurological problems, irregular menstruation in women, and slow growth in children. The overactive adrenal glands that produce cortisol may also produce increased amounts of male sex hormones (androgens), leading to hirsutism in females. The effect of the excess androgens on males is unclear.

Most often, Cushing disease occurs alone, but rarely, it appears as a symptom of genetic syndromes that have pituitary adenomas as a feature, such as multiple endocrine neoplasia type 1 (MEN1) or familial isolated pituitary adenoma (FIPA).

Cushing disease is a subset of a larger condition called Cushing syndrome, which results when cortisol levels are increased by one of a number of possible causes. Sometimes adenomas that occur in organs or tissues other than the pituitary gland, such as adrenal gland adenomas, can also increase cortisol production, causing Cushing syndrome. Certain prescription drugs can result in an increase in cortisol production and lead to Cushing syndrome. Sometimes prolonged periods of stress or depression can cause an increase in cortisol levels; when this occurs, the condition is known as pseudo-Cushing syndrome. Not accounting for increases in cortisol due to prescription drugs, pituitary adenomas cause the vast majority of Cushing syndrome in adults and children.

Read more about familial isolated pituitary adenoma.

 

How do people inherit Cushing disease?

Most cases of Cushing disease are sporadic, which means they occur in people with no history of the disorder in their family. Rarely, the condition has been reported to run in families; however, it does not have a clear pattern of inheritance.

The various syndromes that have Cushing disease as a feature can have different inheritance patterns. Most of these disorders are inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder.

From http://ghr.nlm.nih.gov/condition/cushing-disease

Day Fifteen, Cushing’s Awareness Challenge 2015

Way back when we first got married, my husband thought we might have a lot of kids.  He was from a family of 6 siblings, so that’s what he was accustomed to.  I am on only child so I wasn’t sure about having so many.

I needn’t have worried.

In January, 1974 I had a miscarriage.  I was devastated. My father revealed that my mother had also had a miscarriage.  I had no idea.

At some point after this I tried fertility drugs.  Clomid and another drug.  One or both drugs made me very angry/depressed/bitchy (one dwarf I left off the image)  Little did I know that these meds were a waste of time.

Eventually,  I did get pregnant and my wonderful son, Michael was born.  It wasn’t until he was seven that I was finally, actually diagnosed with Cushing’s.

When I had my early Cushing’s symptoms, I thought I was pregnant again but it was not to be.

I’ll never forget the fall when he was in second grade.  He was leaving for school and I said good bye to him.  I knew I was going into NIH that day for at least 6 weeks and my future was very iffy.  The night before, I had signed my will – just in case.  He just turned and headed off with his friends…and I felt a little betrayed.

Michael wrote this paper on Cushing’s when he was in the 7th grade. From the quality of the pages, he typed this on typing paper – no computers yet!

Click on each page to enlarge.

When Michael started having headache issues in middle school, I had him tested for Cushing’s.  I had no idea yet if it could be familial but I wasn’t taking any chances.  It turned out that my father had also had some unnamed endocrine issues.  Hmmm…

I survived my time and surgery at NIH and Michael grew up to be a wonderful young man, if an only child.  🙂

After I survived kidney cancer (Day Twelve, Cushing’s Awareness Challenge 2015) Michael and I went zip-lining – a goal of mine after surviving that surgery.  This was taken in a treetop restaurant in Belize.

For the mathematically inclined, this is his blog.  Xor’s Hammer.  I understand none of it.  He also has a page of Math and Music, which I also don’t understand.

ARMC5 Mutations in Macronodular Adrenal Hyperplasia with Cushing’s Syndrome

adrenal-hyperplasia

 

Guillaume Assié, M.D., Ph.D., Rossella Libé, M.D., Stéphanie Espiard, M.D., Marthe Rizk-Rabin, Ph.D., Anne Guimier, M.D., Windy Luscap, M.Sc., Olivia Barreau, M.D., Lucile Lefèvre, M.Sc., Mathilde Sibony, M.D., Laurence Guignat, M.D., Stéphanie Rodriguez, M.Sc., Karine Perlemoine, B.S., Fernande René-Corail, B.S., Franck Letourneur, Ph.D., Bilal Trabulsi, M.D., Alix Poussier, M.D., Nathalie Chabbert-Buffet, M.D., Ph.D., Françoise Borson-Chazot, M.D., Ph.D., Lionel Groussin, M.D., Ph.D., Xavier Bertagna, M.D., Constantine A. Stratakis, M.D., Ph.D., Bruno Ragazzon, Ph.D., and Jérôme Bertherat, M.D., Ph.D.

N Engl J Med 2013; 369:2105-2114 November 28, 2013 DOI: 10.1056/NEJMoa1304603

BACKGROUND

Corticotropin-independent macronodular adrenal hyperplasia may be an incidental finding or it may be identified during evaluation for Cushing’s syndrome. Reports of familial cases and the involvement of both adrenal glands suggest a genetic origin of this condition.

METHODS

We genotyped blood and tumor DNA obtained from 33 patients with corticotropin-independent macronodular adrenal hyperplasia (12 men and 21 women who were 30 to 73 years of age), using single-nucleotide polymorphism arrays, microsatellite markers, and whole-genome and Sanger sequencing. The effects of armadillo repeat containing 5 (ARMC5) inactivation and overexpression were tested in cell-culture models.

RESULTS

The most frequent somatic chromosome alteration was loss of heterozygosity at 16p (in 8 of 33 patients for whom data were available [24%]). The most frequent mutation identified by means of whole-genome sequencing was in ARMC5, located at 16p11.2. ARMC5 mutations were detected in tumors obtained from 18 of 33 patients (55%). In all cases, both alleles of ARMC5 carried mutations: one germline and the other somatic. In 4 patients with a germline ARMC5 mutation, different nodules from the affected adrenals harbored different secondary ARMC5 alterations. Transcriptome-based classification of corticotropin-independent macronodular adrenal hyperplasia indicated that ARMC5 mutations influenced gene expression, since all cases with mutations clustered together. ARMC5 inactivation decreased steroidogenesis in vitro, and its overexpression altered cell survival.

CONCLUSIONS

Some cases of corticotropin-independent macronodular adrenal hyperplasia appear to be genetic, most often with inactivating mutations of ARMC5, a putative tumor-suppressor gene. Genetic testing for this condition, which often has a long and insidious prediagnostic course, might result in earlier identification and better management. (Funded by Agence Nationale de la Recherche and others.)

Supported in part by grants from Agence Nationale de la Recherche (ANR-10-Blan-1136), CorticomedullosurrĂ©nale Tumeur Endocrine Network (Programme Hospitalier de Recherche Clinique grant AOM95201), Assistance Publique–HĂ´pitaux de Paris (Clinical Research Center Grant Genhyper P061006), Institut National du Cancer (Recherche Translationelle 2009-RT-02), the Seventh Framework Program of the European Commission (F2-2010-259735), INSERM (Contrat d’Interface, to Dr. AssiĂ©), the Conny-Maeva Charitable Foundation, and the intramural program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

Drs. Assié, Libé, Espiard, Rizk-Rabin, Ragazzon, and Bertherat contributed equally to this article.

We thank Drs. J. Chelly and M. Delpech of the cell bank of Cochin Hospital and Dr. B. Terris of the tumor bank of Cochin Hospital for their help in sample collection; Dr. E. Clauser of the oncogenetic unit of Cochin Hospital for help in microsatellite analysis; Drs. J. Guibourdenche and E. Clauser of the hormone biology unit of Cochin Hospital for cortisol assays; Drs. F. Tissier and Pierre Colin for pathological analysis; Anne Audebourg for technical assistance; J. Metral and A. de Reynies of the Cartes d’IdentitĂ© des Tumeurs program of Ligue Nationale contre le Cancer for help in genomics studies and fruitful discussions; Dr. P. Nietschke of the bioinformatics platforms of Paris Descartes University for helpful discussions; all the members of the Genomics and Signaling of Endocrine Tumors team and of the genomic platform of Cochin Institute for their help in these studies; and the patients and their families, as well as the physicians and staff involved in patient care, for their active participation.

SOURCE INFORMATION

From INSERM Unité 1016, Centre National de la Recherche Scientifique Unité Mixte de Recherche 8104, Institut Cochin (G.A., R.L., S.E., M.R.-R., A.G., W.L., O.B., L.L., S.R., K.P., F.R.-C., F.L., L. Groussin, X.B., B.R., J.B.), Faculté de Médecine Paris Descartes, Université Paris Descartes, Sorbonne Paris Cité (G.A., S.E., A.G., O.B., L.L., M.S., K.P., F.R.-C., L. Groussin, X.B., J.B.), Department of Endocrinology, Referral Center for Rare Adrenal Diseases (G.A., R.L., O.B., L. Guignat, L. Groussin, X.B., J.B.), and Department of Pathology (M.S.), Assistance Publique–Hôpitaux de Paris, Hôpital Cochin, and Unit of Endocrinology, Department of Obstetrics and Gynecology, Hôpital Tenon (N.C.-B.) — all in Paris; Unit of Endocrinology, Centre Hospitalier du Centre Bretagne, Site de Kério, Noyal-Pontivy (B.T.), Unit of Endocrinology, Hôtel Dieu du Creusot, Le Creusot (A.P.), and Department of Endocrinology Lyon-Est, Groupement Hospitalier Est, Bron (F.B.-C.) — all in France; and the Section on Endocrinology and Genetics, Program on Developmental Endocrinology and Genetics and the Pediatric Endocrinology Inter-Institute Training Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD (C.A.S.).

Address reprint requests to Dr. Bertherat at Service des Maladies Endocriniennes et Métaboliques, Centre de Référence des Maladies Rares de la Surrénale, Hôpital Cochin, 27 rue du Faubourg St. Jacques, 75014 Paris, France, or at jerome.bertherat@cch.aphp.fr.

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