Cushing's syndrome occurs when your body makes too much cortisol (hypercortisolism) over a long period of time. Cortisol is a steroid hormone that's normally produced by your adrenal glands to help regulate your body's response to stress. In Cushing disease, excess growth (hyperplasia) or a benign tumor in the pituitary gland causes a release of too much adrenocorticotropic hormone (ACTH). ACTH signals the adrenal glands to release more cortisol into the bloodstream.
When you have too much cortisol in the blood for a long period of time, it causes characteristic symptoms of Cushing disease, such as a fatty hump in between the shoulders, a rounded face or "moon face," purple or pink stretch marks on the skin, changes in blood pressure and blood sugar regulation, bone loss, and mood issues.
When possible, treatment of Cushing disease involves surgery to remove the pituitary tumor. In some cases, medications (steroidogenesis inhibitors, agents that decrease adrenocorticotropic hormone levels, or glucocorticoid receptor antagonists) and/or radiation to the pituitary may be used. An integrative medicine approach to Cushing disease aims to individualize management for optimal control of hypercortisolism and management of comorbidities.
Cushing's syndrome is fairly rare, affecting 40 to 70 people out of 1 million each year. Within this population, over 70% of cases in adults and approximately 60% to 70% of cases in children and adolescents are due to Cushing disease. This condition is more common in women and occurs most frequently in people between the ages of 20 and 50.
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What is Cushing Disease?
Cushing disease is a condition where the endocrine system gets out of balance, and too much cortisol is produced. Cortisol is a steroid hormone that's normally produced by your adrenal glands to help regulate your body's response to stress. In normal amounts, cortisol helps the body regulate metabolism, manage blood sugar levels, reduce inflammation, maintain blood pressure, balance salt, and water intake, and convert fat, carbohydrates, and proteins into energy. Most cells within the body have cortisol receptors and are impacted by this hormone. Cortisol secretion from the adrenal glands is controlled by two glands (the hypothalamus and the pituitary gland) in the brain, forming a signaling system referred to as the hypothalamic-pituitary-adrenal (HPA) axis. Normally, the pituitary gland releases adrenocorticotropic hormone (ACTH) to stimulate the production of the hormone cortisol by the adrenal glands.
In Cushing disease, excess growth (hyperplasia) or an almost always benign tumor (adenoma) in the pituitary gland causes a release of too much ACTH. ACTH signals the adrenal glands to release more cortisol into the bloodstream resulting in too high levels of cortisol in the body.
What's The Difference Between Cushing's Syndrome And Cushing Disease?
Both Cushing's syndrome and Cushing disease are due to too much cortisol in the body. Cushing's syndrome can be due to excess cortisol that comes from anywhere produced within or taken from outside of the body.
Cushing disease is one type of Cushing's syndrome. It occurs when the excess cortisol is due to a pituitary tumor or expansion of the pituitary gland producing too much ACTH that stimulates the adrenal glands to make too much cortisol. Cushing disease is the most common form of endogenous (from within the body) Cushing's syndrome and accounts for around 70% of Cushing's syndrome cases.
Other forms of Cushing's syndrome include exogenous Cushing's syndrome, which occurs in people taking glucocorticoid (corticosteroid or steroid) hormones; Cushing's syndrome, caused by an adrenal tumor that releases excess cortisol; and ectopic Cushing's syndrome when a tumor outside of the pituitary gland in locations like the lung, thymus, thyroid, or pancreas produces ACTH.
What Causes Cushing's Disease?
Cushing disease is caused by the pituitary gland producing too much ACTH. The pituitary gland (hypophysis) is a small pea-sized gland located in the brain. It is found at the base of your brain below your hypothalamus in a small chamber known as the sella turcica. It is often referred to as the body's 'master gland' because it releases several hormones and controls the activity of many other hormone-secreting glands.
Your pituitary gland has two main sections: the anterior pituitary (front lobe) and the posterior pituitary (back lobe). ACTH is one of the hormones released from the anterior pituitary. This hormone travels in the bloodstream to the adrenals, where it stimulates the adrenal glands to release cortisol. ACTH also impacts how the adrenal glands release androgens (sex hormones) and can stimulate an increase in other hormones such as adrenaline/epinephrine and noradrenaline/norepinephrine.
When the pituitary gland grows too much (hyperplasia) or develops a tumor (adenoma), it may produce too much ACTH leading to Cushing's disease. About 10% of pituitary adenomas make too much ACTH.
Symptoms of Cushing's Disease
The elevated cortisol levels in Cushing disease cause characteristic symptoms that can be observed in changes in appearance, mood, and cognition, as well as other physiological impacts.
Some characteristic changes in appearance that occur in people with Cushing disease include:
- increased fat deposits in the neck and above the collarbone, and upper back with a fatty hump between the shoulders
- a rounded face (moon faces)
- wide purple or pink stretch marks on the skin (found on the chest, abdomen, armpits, and flanks)
- unexplained and rapid weight gain with a rounder face and abdomen
- skin changes such as fragile skin, bruising without injury, acne, hair growth, and red cheeks
Chronically elevated cortisol in Cushing disease also impacts mood and thinking with changes such as:
- memory loss or brain fog
- depression
- anxiety
- irritability
Since elevated cortisol levels impact the whole body and many physiologic processes such as blood sugar and blood pressure regulation and bone health, other symptoms of Cushing disease can include:
- fatigue
- muscle weakness
- headaches
- increased thirst and urination
- menstrual cycle changes
- decreased or no desire for sex (low libido)
- erection problems in men
- excess hair growth on the face, neck, chest, abdomen, and thighs in women
Complications of Cushing's Disease
Cortisol is normally released during stressful situations and has many physiologic impacts throughout the body. It plays an important role in controlling the body's use of carbohydrates, proteins, and fats; reducing the immune system's response to swelling and inflammation; regulating blood pressure and cardiovascular function; impacting the strength and structure of bones; and keeping water and salt balanced in the body.
Therefore, when cortisol is elevated over long periods of time in Cushing disease, complications can develop. Bones can become fragile with osteoporosis and bone fractures like compression fractures of the spine occurring. Since blood glucose may be elevated over time, metabolic syndrome and type 2 diabetes can potentially develop. In addition, cardiovascular impacts, including high blood pressure (hypertension), heart attack, stroke, and blood clots, especially in leg veins, may occur. Infections may also be more likely due to changes in the function of the immune system.
Since cortisol suppresses gonadotropin-releasing hormone (GnRH), which controls the menstrual cycle in women, and testosterone and sperm production in men, menstrual irregularities, low sperm, and low testosterone can result and together can contribute to infertility.
How is Cushing's Disease Diagnosed?
Although diagnosing Cushing disease can sometimes be challenging because the symptoms can have various causes and elevated cortisol levels can happen in cycles, cortisol testing is usually done to help establish the diagnosis. Cortisol can be tested in the saliva, urine, or blood.
Conventionally, cortisol is measured in the saliva between 11:00 p.m. and midnight. In healthy people, cortisol levels are very low at this time, but in people with Cushing Disease, levels are often elevated.
Cortisol can also be measured in the urine that has been collected over 24 hours.
Alternatively, a steroid test can be used to confirm a diagnosis of Cushing disease. In this test, cortisol levels are measured in the morning after taking a late-night dose of the drug dexamethasone, a laboratory-made steroid. Normally, dexamethasone suppresses the body's production of cortisol, so levels will drop very low in healthy people, but in people with Cushing Disease, this drop does not happen.
If symptoms and signs suggest elevated cortisol, which is confirmed by these tests showing high cortisol levels, ACTH levels are then measured in the blood. In people with Cushing disease, cortisol levels are high, while ACTH levels are high or normal.
The next step in the diagnosis of Cushing disease is usually imaging of the brain and pituitary gland with an MRI scan to identify overgrowth or any tumors. Inferior petrosal sinus sampling (IPSS) can also be done to take a sample of blood from the veins that drain the pituitary gland and measure ACTH levels there compared to in the veins in the chest.
Functional Medicine Labs to Help Individualize Treatment for Cushing's Disease
Functional medicine approaches aim to identify and address the root causes of a particular health condition, taking into account an individual's unique genetic, environmental, and lifestyle factors. While diagnosing and treating Cushing's disease typically involves conventional medical practices, functional medicine can complement the traditional approach by providing additional insights and personalized treatment options. Below are some common specialty labs ran by integrative medicine practitioners:
HPA Axis Function
Various functional medicine laboratory tests can help with assessing cortisol and other related hormone levels in the body that may be impacted by Cushing disease through analyzing blood, urine, saliva, or a combination.
Cortisol is released according to our circadian rhythm, with the timing of cortisol release significantly impacting health. Testing cortisol levels throughout the day can give insight into the production and timing of cortisol release and help evaluate the cause of symptoms related to elevated cortisol.
The diurnal cortisol profile is a salivary test that is easy to do at home. It measures cortisol levels four times throughout the day to get a comprehensive view of the HPA axis/adrenal function. In healthy people, cortisol should be highest in the morning upon waking and lowest at night before sleep.
A more complete hormone test like the DUTCH Complete (Dried Urine) gives a broader overview of hormone and HPA axis function. It measures daily and free cortisol patterns and other related sex and adrenal hormones and metabolites like estrogen, progesterone, testosterone, melatonin, and thyroxine. Similarly, the Doctor's Data Adrenal Function profile or ZRT Laboratory's Adrenal Stress Profile uses saliva to assess the HPA axis and adrenal function, reporting cortisol levels from four times during the day plus DHEA. These results can provide a baseline hormone assessment and be repeated to monitor treatment.
A single blood level of cortisol can be assessed with the Access Medical Labs' Cortisol test.
Gut Health
Since chronically elevated cortisol can negatively impact the microbiome of the GI tract via the gut-brain axis, impacting the permeability of the small intestine, digestion, absorption, immune function, and more, a comprehensive gut test like the GI-MAP can be used to measure gut bacteria, inflammatory and leaky gut markers, parasites, and yeast to assess the gut and guide individualized treatment aimed at restoring balance.
Micronutrient Tests
Cushing's syndrome and chronic stress can deplete certain nutrients, impair nutrient absorption, or increase nutrient excretion. Identifying specific deficiencies can help guide targeted interventions to restore optimal nutrient levels.
Blood Sugar Balance
A comprehensive evaluation of metabolic health can help with assessing complications of elevated cortisol, like metabolic syndrome and type 2 diabetes.
Several tests are used to assess how the body handles sugars, including fasting glucose, hemoglobin A1c which measures average blood sugar level over the previous six weeks, fasting insulin, and C-peptide, a marker that the body is producing insulin.
These can help to identify insulin resistance, where sugars remain in the blood, causing inflammation and damage to blood vessels, which over time, leads to type 2 diabetes. Glucose tolerance testing and insulin tolerance testing can further look at how the body handles and processes sugars.
Lipid Levels
To further assess metabolic balance, a lipid panel including total cholesterol, HDL ("good" cholesterol), LDL ("bad" cholesterol), and triglycerides looks at the balance of fats and cholesterol in the blood. Additional lipid metabolism indicators include Lipoprotein(a), LDL particle number, and ApoB-containing lipoproteins (ApoB).
Conventional Treatment for Cushing's Disease
Conventional treatment of Cushing disease usually involves surgery to remove the pituitary tumor. This can often be done with transsphenoidal microsurgery through the nasal sinuses.
In some cases, medications (steroidogenesis inhibitors, agents that decrease adrenocorticotropic hormone levels, or glucocorticoid receptor antagonists) and/or radiation to the pituitary may be used. One type of medication that may be used in some cases is a dopamine agonist, such as cabergoline, which works to reduce ACTH levels and cortisol production. Pasireotide is another medication that can help to reduce ACTH levels and cortisol production and is given by injection under the skin. Alternatively, mifepristone may be used to stop cortisol from working on the receptors throughout the body.
Complementary and Integrative Medicine Management for Cushing's Disease
While the definitive treatment of Cushing disease caused by a pituitary adenoma or hyperplasia usually involves removing the tumor or reducing the excess pituitary tissue, an integrative medicine approach to Cushing disease aims to individualize management for optimal control of cortisol levels and management of comorbidities.
Nutrition for Cushing's Disease Management
Nutrition in Cushing disease management can help to balance cortisol levels and provide optimal nutrients for reducing the risk of complications like weak bones and blood sugar imbalances. Since stress can contribute to increased cortisol and chronic inflammation, an anti-inflammatory diet can be helpful in modulating cortisol levels to some degree and in supporting gut health. An anti-inflammatory diet like the Mediterranean diet focuses on high-fiber plant-based foods like fruits, vegetables, and whole grains, as well as healthy types of fats from olive oil and fatty fish. Probiotic-rich foods such as yogurts, sauerkraut, and kimchi can also play a beneficial role in supporting the microbiome to keep blood sugar and hormones more balanced. Reducing the amount of added salt or sodium consumed in processed foods in the diet can help balance blood pressure and reduce fluid retention.
Cortisol mobilizes glucose into the bloodstream by releasing stored sugars, decreasing insulin sensitivity, and breaking down muscle protein. A Mediterranean diet can help with blood sugar control, reduce inflammation, support gut health, improve HDL cholesterol and triglyceride levels, and regulate the HPA axis to help modulate the stress response. This way of eating is linked to a lower risk of metabolic syndrome, as eating meals at regular intervals and consuming foods rich in fiber slows carbohydrate absorption. This can also help to prevent the increase in cortisol levels caused by quickly absorbed carbohydrates.
Since inflammation is also a driver of bone loss, which can occur with Cushing disease, an anti-inflammatory diet provides building blocks for the body to build and maintain bone strength. Calcium is one of the key minerals that make up bones and is essential for bone mineral density. Natural food sources of calcium, such as green leafy vegetables, tofu, and nuts, are preferred over supplementation to lower the risk of kidney stones and cardiovascular complications.
In addition to calcium, incorporating adequate vitamin D and K into the diet to maintain healthy levels helps keep bones strong. Bone mineralization relies on Vitamin D3 to increase calcium absorption in the intestines and decrease bone turnover. Optimal levels of vitamin D can be measured with laboratory testing and obtained from dietary sources like salmon, mushrooms, cod liver oil, sardines, or liver. This vitamin is also made naturally by the body when the skin is exposed to mid-day sunlight or can be obtained via supplementation when needed.
Another important vitamin for bone mineralization is Vitamin K2. This nutrient can be obtained in foods such as fermented soybeans in natto, eel, beef liver, sauerkraut, and egg yolks. Vitamin K2 is also created by the bacteria in the gut microbiome, so it is important to maintain a balanced microbiome to maintain strong bones and balance inflammation.
Supplements and Herbs for Cushing's Disease Management
Supplements can play a potential role in supporting the balance of hormones and managing some of the complications of Cushing disease.
Phosphatidylserine is a naturally occurring phospholipid that can be found in cell membranes that have potent inhibitory effects on the HPA axis. It can potentially help slow the production of ACTH and resulting cortisol and has been shown to blunt the effects of physical and psychological stress.
Probiotic supplements support a healthy gut microbiome to balance hormones, improve blood glucose control, improve gut barrier function, modulate inflammation, and reduce insulin resistance.
Exercise for Cushing Disease Management
Balanced exercise can help rebalance cortisol by changing receptor sensitivity to cortisol. Exercise is key for managing stress and keeping hormones balanced. It is also important for managing weight, keeping bones strong, and maintaining muscle strength to prevent injury and fractures. Weight-bearing activities, including walking, jogging, yoga, tai chi, and strength and resistance training, can help maintain healthy bones.
Mind Body and Stress Reduction Techniques for Cushing's Disease Management
Stress-management techniques, including yoga, qigong, spa bathing, and relaxation programs, reduce cortisol levels, both during the activity and for a significant interval afterward.
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Summary
Cushing disease is one type of Cushing's syndrome where too much cortisol is released in the body. In Cushing disease, excess growth (hyperplasia) or a benign tumor (adenoma) in the pituitary gland causes a release of too much ACTH hormone that alerts the adrenal glands to release more cortisol into the bloodstream.
This chronically-elevated cortisol results in characteristic symptoms of Cushing disease, such as a fatty hump between the shoulders, a rounded face, pink or purple stretch marks on the skin, changes in blood pressure and blood sugar regulation, bone loss, and mood issues.
Laboratory testing can assess levels of cortisol in the saliva, blood, and/or urine, as well as look at the body's response to giving a steroid medication. MRI imaging of the brain is used to visualize any enlargement or tumors in the pituitary gland.
Treatment of Cushing disease involves surgery to remove the pituitary tumor. In some cases, medications (steroidogenesis inhibitors, agents that decrease adrenocorticotropic hormone levels, or glucocorticoid receptor antagonists) and/or radiation to the pituitary may be used. An integrative medicine approach to Cushing disease aims to individualize management for optimal control of hypercortisolism and management of comorbidities by helping to keep bones strong, balancing blood sugar, reducing inflammation, and contributing to reduced cortisol in the body.
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