Metabolic disorders most commonly result from the irregular functioning of the body. Hormones are the prime messengers that are crucial for various bodily processes. Cushing syndrome is a metabolic disorder caused by excess secretion of cortisol. Cortisol is a hormone secreted by the adrenal glands known as the ‘stress hormone’. Cortisol helps to
- Maintain blood pressure
- Maintain blood glucose
- Decrease inflammation
- Turn food into energy i.e. glucose
- Increase muscle tone
- Manage respiration
- Balance the salt in the body
- Memory formation1,2
Prolonged exposure to cortisol causes Cushing syndrome. The most common cushingoid features are buffalo hump, rounded face, acne, facial hair in women and loss of libido in men. These symptoms are due to the medical usage of corticosteroids for any underlying conditions. Any tumour in the pituitary gland can also cause increased secretion of cortisol. When Cushing syndrome happens this way, it's called Cushing disease.
Adrenal glands are two small glands situated over the kidneys that secrete cortisol when activated by the adrenocorticotropic hormone (ACTH). ACTH is secreted by the anterior pituitary gland, which is then activated by corticotropin-releasing hormone (CRH) secreted by the hypothalamus.
Thus it is a sequence of events and a complex procedure that results in the release of cortisol which helps to maintain various crucial functions of the body. Any irregularity can affect cortisol production. For example, when external medications are taken, cortisol levels rapidly increase in the bloodstream which acts as a negative feedback loop on the entire process, and results in cortisol not being produced. It has also been shown that long-term intake of medications can cause disturbances in the sequential procedure and further cause Cushing's syndrome and Cushing's disease.²
Causes of Cushing’s syndrome
Cushing's syndrome is classified as exogenous and endogenous. Exogenous entails that the aetiology originates from outside of the body, such as due to the usage of glucocorticosteroid medications. Endogenous means that the cause of the syndrome arises within the body, such as growing tumours in the pituitary or adrenal glands, hence resulting in excess production of cortisol. Exogenous origin is the most common and endogenous is of rare occurrence.
Cortisol is a steroid hormone secreted by the adrenal glands and plays a vital role in the body’s response to stress. It is a catabolic hormone that promotes the breakdown of fats into glucose and the conversion of glucose into simpler molecules This process leads to an increase in glucose concentration in the blood and can also contribute to insulin resistance.
Therefore, excess production can cause
- Increased insulin resistance
- Type 2 diabetes
- Increased neutrophils
- Reduced lymphocytes and interleukin production
- Weakened the immune response
Endogenous Cushing syndrome origin
Endogenous Cushing syndrome is caused by tumours located in glands such as the pituitary and adrenal glands which are important in cortisol secretion. These are rare incidence and must be addressed and treated as soon as possible.³
Exogenous Cushing syndrome origin
Reduced cortisol production due to external corticosteroid medications may hamper adrenal function, particularly the hypothalamus-pituitary-adrenal axis (HPA axis).
Cushing disease versus Cushing syndrome
Cushing syndrome is caused by increased cortisol levels in the body that result from external or internal sources. External factors include medications, while internal factors include pituitary tumours. Cushing disease is a type of Cushing syndrome caused due to internal factors like hypersecretion of cortisol from the pituitary gland or adrenal gland tumours.
Signs and symptoms of Cushing syndrome
Common symptoms of Cushing syndrome are:2
- Weight gain
- Delayed wound healing
- Easy bruising
- Back pain
- Mood swings
- Emotional reactivity
- Reduced bone density
- Recurrent bone fractures
Symptoms more prevalent in men are loss of sexual desire and erection problems.
Symptoms more prevalent in women are irregular periods, facial hair, excessive sweating, Infertility, reduced immunity and higher susceptibility to infections.
Psychological problems like depression and cognitive disorders- forgetting more often.
Risks associated with Cushing’s syndrome
The Cushing syndrome is fatal if left untreated. Health problems associated with hypercortisolism include:
- Heart attack
- Memory issues
- Weight gain
- High blood pressure
- High cholesterol
- Broken bones
- Type 2 diabetes
- Impaired fasting glucose¹,²,³
Cushing's syndrome diagnosis
Several symptoms are most commonly associated with this condition. It is important to note that other medical conditions include weight gain, weakness, and emotional disturbances. If an individual is on glucocorticosteroids for any medical conditions and experiences these symptoms, a medical professional may suspect the development of Cushing’s syndrome. To confirm the diagnosis, blood and saliva analyses, as well as imaging tests, must be completed.
24-hour urine sample
A 24-hour urine sample is collected from the individual to study their cortisol levels. In a healthy individual, urine cortisol levels should not be persistently high. Therefore, if high levels are analysed, this can help to reveal a hypercortisolism diagnosis.
Late-night salivary cortisol test
A late-night salivary cortisol test is a diagnostic tool used to evaluate cortisol levels in saliva during the nighttime. Cortisol levels decrease during the evening and reach their lowest point at night. However, Cushing syndrome can cause elevated cortisol levels during the night. As a result, if the tests reveal increased cortisol levels at night, a medical professional might consider Cushing syndrome a diagnosis.
Low-dose dexamethasone suppression test
This diagnostic technique evaluates the HPA axis function. A small dose of dexamethasone is administered to an individual. We can notice low cortisol levels after administering dexamethasone (negative feedback). But that's not the case with Cushing syndrome.
The health professional asks you to take dexamethasone at 11 p.m. and give a blood sample for testing at 8 a.m. the next day. Another approach is to ask the patient to take dexamethasone continuously every 6 hours for 48 hours. Blood is taken after 6 hours of the last dose.
High-dose dexamethasone test
The suspected individual is given high doses of dexamethasone. Cortisol levels decrease after dexamethasone administration in this condition. There is a possibility that one has a pituitary tumour. You might have an ectopic tumour if your cortisol levels do not decrease.
If positive, a Dexamethasone-Corticotropic Releasing Hormone (CRH) test is done. The hypothalamus secretes CRH, which activates the pituitary gland to release ACTH, which stimulates the adrenal gland to release cortisol. When CRH and dexamethasone are administered, cortisol levels will be lower than normal. So, Cushing syndrome can be diagnosed with higher cortisol levels even after this administration. False positive results can also occur with anxiety, depression, uncontrolled diabetes, alcoholism and obsessive pulmonary disorder.¹
Management and treatment for Cushing syndrome
Cushing syndrome is often caused by the long-term use of medications containing corticosteroids. Treatment involves gradually reducing corticosteroid dosage to allow the adrenal glands to recover their normal functioning. As the external medications are reduced, the adrenal function will slowly recover.
Medical professionals manage blood pressure, glucose levels, and fractures after tapering medication doses. Health professionals can advise alternative medications like immunosuppressants instead of steroid medications to control conditions like asthma and rheumatoid arthritis.
As prescribed by a medical professional Cushing disease is treated with surgery followed by radiotherapy. When the adrenal gland or pituitary gland is removed, the body cannot produce cortisol throughout life, resulting in the condition called Addison's disease. One must depend on external cortisol administration in such cases.⁵,6
How is Cushing syndrome diagnosed?
Cushing's syndrome is diagnosed by blood, saliva or urine samples. Your doctor will prescribe a diagnostic test based on your symptoms. Increased cortisol levels can be noticed in all diagnostic tests. When dexamethasone is given, cortisol production reduces in general, which can be observed in the case of Cushing's syndrome.
How can I prevent Cushing’s syndrome?
Cortisol is an important hormone necessary for the body. It is a problem only when it is higher than the normal range. When you are on glucocorticosteroid medication, ask your health provider to monitor your cortisol levels. There is no way to prevent tumours in the adrenal or pituitary glands that cause Cushing's disease.
Who is at risk of Cushing’s syndrome?
Cushing's syndrome affects adults mainly from 25-50. It can also affect children. Long-term glucocorticosteroid users are at high risk of Cushing's syndrome. Glucocorticosteroids are given to treat inflammatory conditions like asthma, and rheumatoid arthritis. Assigned females at birth compared to assigned males at birth have a high incidence rate of Cushing's syndrome. Though tumours of pituitary and adrenal glands also report the incidence of Cushing's syndrome, iatrogenic incidence was found to be more common.
When should I see a doctor?
Contact your doctor if you find out you have any of these symptoms like unexplained weight gain, fat deposition in the upper part of the body, depression etc. Though these might be so common, most of the time go unnoticed. Whenever one intends to use glucocorticosteroid medications and experiences the above symptoms, it's better to contact the medical professional as soon as possible. If not addressed Cushing's syndrome can result in many risk factors diabetes mellitus, hypertension, fractures due to osteoporosis, and pituitary gland enlargement.
Cushing syndrome or Cushing disease is the body's indication that there is a disturbance in cortisol metabolism, which otherwise cannot be identified as an early case. Therefore, it is required to be aware of the symptoms, causes and treatment of Cushing syndrome to have a better insight into their health.
- Cushing’s Syndrome | NIDDK. National Institute of Diabetes and Digestive and Kidney Diseases. Available from: https://www.niddk.nih.gov/health-information/endocrine-diseases/cushings-syndrome (accessed February 5, 2023).
- Cushing syndrome - Symptoms and causes. Mayo Clinic, Available from: https://www.mayoclinic.org/diseases-conditions/cushing-syndrome/symptoms-causes/syc-20351310 (accessed February 5, 2023).
- Chaudhry, Hammad S., and Gurdeep Singh. ‘Cushing Syndrome’. StatPearls, StatPearls Publishing, 2023. PubMed, Available from: http://www.ncbi.nlm.nih.gov/books/NBK470218/.
- Cheng, Yu, et al. ‘Case Report: Three Rare Cases of Ectopic ACTH Syndrome Caused by Adrenal Medullary Hyperplasia’. Frontiers in Endocrinology, vol. 12, July 2021, p. 687809. DOI.org (Crossref), Available from: https://www.frontiersin.org/articles/10.3389/fendo.2021.687809/full
- Cushing Syndrome: Causes, Symptoms & Treatment. Cleveland Clinic, Available from: https://my.clevelandclinic.org/health/diseases/5497-cushing-syndrome (accessed February 5. 5, 2023).
- Ferriere, Amandine, and Antoine Tabarin. ‘Cushing’s Syndrome: Treatment and New Therapeutic Approaches’. Best Practice & Research. Clinical Endocrinology & Metabolism, vol. 34, no. 2, Mar. 2020, p. 101381. PubMed, Available from: https://pubmed.ncbi.nlm.nih.gov/32035797/