Hypercortisolism

What is Hypercortisolism?

Hyperactivity of the adrenal gland often leads to a condition called Hypercortisolism (HCM). This happens when your body is exposed to too much cortisol, a type of hormone, or similar hormones. It can often result in high levels of cortisol in your blood, known as hypercortisolemia. Over time, this condition can lead to a specific syndrome called Cushing Syndrome.

Cushing Syndrome is a group of symptoms that you experience when your body has been exposed to excessive cortisol over a long period. It can occur either due to a condition within the body (endogenous) or due to external factors like medication (exogenous). The most common type of externally caused Cushing Syndrome comes from the inappropriate use of medicines containing hormones, like cortisol.

Two sub-types of internally caused Cushing Syndrome are those that are dependent on a hormone called ACTH (adrenocorticotropic hormone) and those that are not. The connection between an excess of cortisol and Cushing Syndrome is named after Dr. Harvey W. Cushing, who first recognized it and described patients with high levels of cortisol due to a pituitary gland tumor. In his honor, Cushing Disease is the term used to refer to Cushing Syndrome caused by a pituitary gland tumor.

Identifying, diagnosing, and managing Hypercortisolism (HCM) can be challenging because the symptoms can vary significantly from person to person. While severe, advanced Cushing Syndrome presents fairly obvious symptoms and laboratory results and is quite rare. Other forms of Hypercortisolism, such as those caused by medication, those that don’t have all the exact symptoms (subclinical Cushing Syndrome), or those that are intermittent or cyclic in nature, are often more common and harder to recognize, diagnose, and manage.

What Causes Hypercortisolism?

Identifying the cause of having too much cortisol, a condition known as hypercortisolism, is broken down into three steps. Firstly, it needs to be confirmed whether true hypercortisolism is present or not. This is set by looking at symptoms and lab test results, as well as ruling out other possible diagnoses. The process includes distinguishing between actual corticosteroid overproduction caused by disease, and pseudo-Cushing syndrome, which is a state that resembles the symptoms of the disease but does not result from an underlying disorder. Applying a specific screening test can assist in identifying what triggers the situation.

After it’s certain that the person indeed has true hypercortisolism, the next tier involves figuring out if its production is ACTH-dependent or independent. ACTH is a hormone that sparks the adrenal glands to generate cortisol. Checking carefully during this stage is crucial because the hypercortisolism condition could be artificially induced or due to false symptoms.

The last part of the analysis process involves making sure of the exact body part and type of disease causing the condition.

There’s a subtype of hypercortisolism that is seen often named iatrogenic Cushing Syndrome. It’s estimated that more than 10 million individuals in the US are given medical doses of glucocorticoids, a type of corticosteroid, every year. Though not everyone develops hypercortisolism, it is suspected that incidents of iatrogenic Cushing syndrome are reported less than their real occurrence. In this subtype, it’s also essential to think about the possibility of factitious Cushing syndrome, which is a less common instance where symptoms of hypercortisolism are produced artificially.

A substantial study retrospectively examined the triggers of Cushing syndrome in approximately 630 patients, without considering artificial causes, at the Vanderbilt University Medical Center found:

• 68% had ACTH dependent Cushing disease
• 12% had ectopic ACTH Cushing syndrome, where ACTH comes out of non-pituitary glands,
• 10% had functional adrenal adenomas, benign tumours on the adrenal gland,
• 8% had adrenal carcinomas, malignant tumours on the adrenal gland,
• Less than 1% each had ectopic CRH syndrome, micronodular adrenal hyperplasia, and macronodular adrenal hyperplasia, conditions where the adrenal gland is overly active,
• About 1.5% had pseudo-Cushing syndrome due to severe depression or persistent alcoholism.

Risk Factors and Frequency for Hypercortisolism

Diagnosing hypercorticism (HCM) can be quite challenging, which makes it difficult to determine the exact number of cases. The numbers can vary greatly depending on who you’re studying: the average person, people seeing a primary care provider, or people at specialty clinics. Also, the numbers can shift depending on if you’re only looking at adults or also considering kids.

The main form of HCM is iatrogenic Cushing syndrome (ICS). Recent studies suggest that Secondary Cushing syndrome (SCS) might be more common than we previously thought. One Danish study spanning 11 years found that per year Cushing syndrome occurred 1.2 to 1.7 times per million people (Cushing disease), 0.6/million (adrenal adenoma), and 0.2/million (adrenal carcinoma). A more recent U.S.-based study found a rate of 39.5 to 48.6 per million people per year, which varies significantly from the Danish study.

The rate at which Cushing disease (the most common form of natural Cushing syndrome) occurs differs greatly between studies, with estimates ranging from 1.2 to 25 million cases each year.

There’s some indication that ectopic Cushing syndrome (EcCS) might be more common than we think, but most studies show it makes up about 10-15% of all Cushing syndrome patients. The most common cause of EcCS is small cell lung cancer, but only 1% of people with this type of cancer contract EcCS, equating to around 300 new cases each year in the United States.

Lesions on the adrenal gland that cause ACTH-independent CS are being prioritized as they become more prevalent. These are now seen more frequently because of advances in imaging technology like CT and MRI scans, which are used to assess various vague abdominal complaints. Depending on whether you’re looking at images or autopsy data, these adrenal gland bumps occur in roughly 1.3 to 8.7% of people.

All other causes, including big and small lumps over the adrenal gland and irregular CRH syndrome, are quite rare. However, doctors need to keep them in mind as possibilities when diagnosing unusual health presentations.

In general, Cushing syndrome is more common in women (3 to 8 times as likely), no matter if it’s caused by the pituitary or adrenal gland or if it’s because of a benign or malignant factor. But among patients with EcCS, men have typically had a higher prevalence, probably due to higher rates of smoking and thus, more cases of small-cell lung cancer. As more women have started smoking and fewer men do so, the gender difference in EcCS prevalence has narrowed compared to 30 years ago.

Cushing’s disease commonly affects individuals aged between 25 and 45 years while EcCs is more common in people over 50 years old. Cushing’s syndrome is less frequent in kids, and only 30% of pediatric Cushing syndrome patients have Cushing disease, a percentage much lower than in adults. Early research shows that boys are more likely than girls to get Cushing syndrome before puberty, but in teenagers, the female likelihood observed in adults is also seen.

Adrenal tumors leading to Cushing’s syndrome show a two-peaked age pattern: one peak in the first decade of life, and the second peak at around age 40 for adrenal cancers and age 50 for adrenal adenomas.

Signs and Symptoms of Hypercortisolism

Hypertrophic Cardiomyopathy (HCM) is a condition that may not present characteristic symptoms in all patients, making it a condition that is often both overdiagnosed and underdiagnosed. Since the signs associated with HCM can be varied and non-specific, a high level of suspicion is required as part of the medical evaluation process. Clinicians often need to combine the findings of a physical examination with appropriate diagnostic lab tests in order to confirm a diagnosis of HCM.

It is recommended that patients who fall into high-risk groups should be screened for HCM. These groups include young adults with early signs of conditions like osteoporosis, hypertension, or diabetes, individuals with face redness (facial plethora), muscle weakness near the body (proximal myopathy), wide stretch marks, easy bruising, or incidental adrenal tumours.

The positive diagnosis of HCM is also dependent on taking a comprehensive medical history from the patient, especially focusing on potential exposure to corticosteroids. This history should include all medication prescribed, recreational drug use, incidence cases of psychological disorders, and any possible occupational exposure to corticosteroids.

The main symptom of HCM is progressive weight gain, particularly around the center of the body, though it can sometimes be more general. Other symptoms can include:

• Blood pressure problems, like headaches and dizziness
• Symptoms related to high blood sugar levels, such as increased thirst or urination
• Issues related to the reproductive system, like menstrual irregularities in women or erectile dysfunction in men
• Easily bruising
• Muscle weakness
• Sleep issues and mood swings
• In women, the appearance of excess hair growth (hirsutism) or severe acne

Patients with HCM are also more likely to have mental health issues, presenting with severe mood swings and even severe psychotic episodes. This is particularly the case if there is no previous history of mental health issues.

In terms of physical examination, clinicians often look for certain characteristic signs. These include a round face (“moon face”), red cheeks (malar flushing), deposits of fat on the back of the neck (“buffalo hump”) and in the hollows above the collarbones (supraclavicular fat pads). Raised blood pressure and thinning skin are also common signs of HCM.

In addition to these typical symptoms, HCM can also present alongside other health conditions. Its impact can vary greatly depending on its duration and severity, ranging from reproductive and skin conditions to issues with the metabolism, bones, heart, nervous system, and even an increased risk of infections.

The disease is risky to life due to its associated complications, including heart problems such as severe hypertension, diabetes, and an increased risk of blood clots. It can also increase the chance of developing heart failure or a specific type of heart disease known as dilated cardiomyopathy. This makes early recognition and appropriate management of HCM extremely crucial.

Testing for Hypercortisolism

If your doctor suspects that you have hypercortisolism (HCM), which is a condition marked by an overproduction of the hormone cortisol, a series of tests will need to be done. HCm, often non-specific in its symptoms, is critical to diagnose early to avoid serious health risks.

Firstly, a range of screening tests are conducted, followed by confirmatory tests, and then determining the underlying cause of the HCm. This diagnosis is typically confirmed when at least two different screening tests are significantly higher than normal. The specific tests used can differ based on each individual case and how likely the doctor thinks that HCM could be the cause.

Commonly used screening tests include salivary cortisol tests, which measure cortisol levels in the body, and the 1mg dexamethasone suppression test, which checks how well your body processes this medication. If initial findings are negative but your doctor still suspects HCM, these tests may need to be repeated — particularly in situations where symptoms might come and go.

If your screening tests come back abnormal, further tests will be needed to understand the type of HCM you might have. Some forms of HCM are closely associated with issues in the adrenal glands rather than the pituitary glands, for example. Therefore, the exact criteria for diagnosing and tests used may vary.

The purpose of these further tests is to distinguish between pathological HCm, which indicates that the body is producing too much cortisol due to an underlying disease, and physiological HCm, where the increased cortisol levels are a normal response of the body to stress, illness or injury.

One specific test used in this stage, the combined dexamethasone CRH test, checks for elevated levels of cortisol and potentially adrenocorticotropic hormone (ACTH) after the administration of medication. The levels of these hormones can help differentiate between physiological and pathological HCM.

Next, based on your symptoms and test results, doctors will determine whether the HCM is ACTH dependent or independent, which can give them clues about the possible underlying cause. They will measure your ACTH levels over time, as these levels tend to fluctuate throughout the day. Certain levels of ACTH are strongly indicative of whether the HCM is ACTH dependent or not.

Moving on to the next step of diagnosis, for those with ACTH dependent HCM, the challenge is distinguishing between pituitary-based HCM and EcCS, two different conditions that can cause this type of HCM. This often involves more specialized tests and in some cases, medical imaging.

Importantly, imaging tests, which can help identify abnormal growths, should not be performed until a biochemical diagnosis of HCM has been made. This approach helps to avoid confusion caused by incidental findings that might not be the cause of the HCM.

Whether you have ACTH independent or dependent HCM will influence the next steps in terms of imaging. For ACTH dependent HCM, doctors will often focus on imaging the adrenal glands, unless the clinical history suggests a different source. High-resolution CT scans are often the go-to imaging technique for this. Depending on the results, more investigative measures like adrenal venous sampling might be needed. Conversely, for ACTH independent HCM, the focus will be on locating and identifying the source of excess cortisol, which can significantly vary in location and be challenging to locate, requiring careful use of numerous diagnostic tools.

Overall, diagnosing HCM is a careful and sometimes lengthy process that involves several steps. It starts with initial screening tests and followed by more specialized tests or imaging as needed, to accurately identify the cause of the elevated cortisol levels in your body.

Treatment Options for Hypercortisolism

Treating a condition known as Hypercortisolism or HCM (an excessive amount of cortisol hormone in your blood), involves addressing the clinical effects, the specific causes, and any related health issues that might arise with HCM.

When HCM is due to an overuse of glucocorticoids (a type of medication), the main approach is to carefully lower the use of these medications, ideally completely stopping their use. This can sometimes be challenging depending on why they were originally prescribed, how long, and at what dose they had been used. As some patients may have developed adrenal insufficiency (a condition where the adrenal glands do not produce enough hormones) from stopping the medication, ongoing tests and monitoring could be needed while the patient’s dose is gradually reduced.

Some patients may need to stay on adrenal hormone replacement therapy, which involves taking hydrocortisone or similar medications, along with another medication called fludrocortisone that can help balance the hormones in the body. However, for some patients, weaning down to the smallest necessary dose might be required to control other health conditions.

The main goal in managing HCM is to restore normal levels of cortisol production, to remove any tumors causing the excess cortisol, and to try to avoid long-term dependence on medications. However, these goals may not always be achievable for all patients due to various individual circumstances.

In some situations, when a definitive diagnosis for the underlying cause of HCM is being delayed, control of HCM and any arising complications such as hyperglycemia (high blood sugar levels), hypertension (high blood pressure), osteoporosis (weak or brittle bones), etc., may become the priority until a clear diagnosis is made.

Medical treatments play a significant role when surgical interventions are either delayed or fail to cure the condition. Some medications work by blocking the effects of cortisol or reducing its production in the body. Although these can vary in how effective they are.

In more serious cases of HCM, caused by pituitary cancers that have spread to other parts of the body, surgical treatment is rarely able to provide a cure, and the prognosis is poor, with patients often needing further treatments like chemotherapy.

In some extreme circumstances, surgical removal of both adrenal glands, known as bilateral adrenalectomy, might be considered. After this procedure, patients would need lifelong hormone replacement therapy.

The manner in which patients with HCM arising from other causes are treated greatly depends on the location of the lesions causing the condition. Generally, surgical resection (cutting away the lesion) offers the best potential for a cure, along with certain medications to control the HCM until the lesion can be identified and removed.

For patients with HCM caused by an adrenal adenoma (a noncancerous tumor of the adrenal gland), removal of the affected adrenal gland offers the best potential for a cure. The removal can usually be done laparoscopically (using small incisions), as long the adenoma is less than 6 cm in diameter.

On rare occasions, HCM might occur during pregnancy. Medication treatment is often not an option due to potential harmful effects on the baby. In such cases, surgical intervention is usually the best option, preferably during the second trimester of pregnancy.

What else can Hypercortisolism be?

When doctors suspect Hypercortisolism (HCM), there are many other conditions they need to rule out, all of which can cause symptoms that mimic HCM. These include:

• Pregnancy
• Extreme obesity
• Severe depression
• Chronic alcoholism
• Uncontrolled diabetes
• Eating disorders like bulimia nervosa and night eating disorder
• Chronic lymphedema and lipoedema
• Partial lipodystrophy syndromes (congenital and acquired)
• Dercum disease (painful growth of fatty tissue)
• Hypothalamic obesity syndromes like Prader-Willi syndrome, Frolich’s syndrome, and Bardet Biedl syndrome
• In rare cases in children, POMC and leptin-deficient associated obesity syndromes and Soto syndrome (a condition of excessive physical growth and size).
• Some disorders related to fluid buildup in the body, including poor nutritional status (including a condition in children called Kwashiorkor), congestive heart failure, liver cirrhosis with fluid accumulation in the abdomen, and nephrotic syndrome (a kidney disorder)
• Excessive use of various hormones, steroids, and other drugs
• Severe physical stress
• Severe malnutrition and anorexia nervosa
• Excessive exercise
• Female athlete triad (a condition with eating disorders, lack of menstrual period, and weakened bones)
• Ovarian dysfunction
• Genetic conditions making the body resist the action of certain hormones.
• Rare disorders like non-adrenal cortisol secretion, normal Cushing syndrome, and biochemical HCM without obvious physical signs.

It’s important for the healthcare provider to consider all these possibilities and conduct proper tests to make an accurate diagnosis.

What to expect with Hypercortisolism

Hypercortisolism is a serious medical condition that can lead to significant health problems and can be fatal if not treated. Most often, the cause of death from hypercortisolism is heart-related complications, like acute coronary syndromes, or issues associated with blood circulation, like thromboembolic events, and hypertension complications. There is also a risk of opportunistic bacterial and fungal infections. In studies, the death rate was as high as 50% within five years after symptoms appeared if effective treatments were not applied.

However, there’s good news. Most cases of hypercortisolism caused by pituitary disorders (HCM) are curable, and HCM should be manageable, even if it requires drastic measures such as bilateral adrenalectomy or mitotane therapy. The exact cause of HCM can affect how good the prognosis is, malignant lesions like small cell lung carcinoma and adreno-cortical carcinoma have the worst prognosis, while benign adrenal adenomas or benign carcinoids offer the best prognosis.

Even with effective therapy, withdrawal symptoms from HCM can take a while to clear up. It usually takes 2 to 12 months for symptoms to resolve, and some effects, like weight gain, high blood pressure, and glucose intolerance may remain. Bone density loss begins to improve about six months after treatment, with calcium and vitamin supplements, bisphosphonate therapy, and hormone-replacement therapy aiding recovery. However, the decline in the quality of life caused by HCM only improves to a degree after treatment, and some psychological effects typically remain.

In children, HCM can cause a decline in intelligence and cognitive function, even after they’ve been cured. This decline continues, even with the absence of psychological problems and even after the reversal of cerebral atrophy. However, children tend to show improved bone density and growth rate after treatment for HCM, but some deficits may remain.

Possible Complications When Diagnosed with Hypercortisolism

Hypercortisolism is a condition that affects nearly every organ system in our body, either directly or indirectly. Here’s a simplified list of the health problems and complications associated with Hypercortisolism:

• Loss of bone density, leading to conditions like osteopenia, osteoporosis or osteonecrosis, especially related to external sources of the condition. Hips are most commonly affected.
• Heart and blood vessel disorders like high blood pressure, faster development of vascular diseases (including heart disease, cerebrovascular disease, and peripheral vascular disease), and dilated cardiomyopathy.
• Disruptions in fat metabolism, leading to high levels of triglycerides and cholesterol.
• Risk of metabolic syndrome, a cluster of conditions that increase the risk of heart disease, stroke, and type 2 diabetes.
• Increased blood sugar levels which could lead to diabetes along with its complications.
• Obesity, specifically around the abdomen with thin arms and legs (often described as an “apple on sticks” appearance).
• Slow growth in children, muscle weakness, reduced fertility, and an increased risk of skin and systemic infections (especially bacterial and fungal ones).
• Various skin conditions like skin thinning, bruises, stretch marks, repeated infections, darkening of skin in certain conditions, hair loss, excessive body hair, poor wound healing, and more.
• Eye problems, the most common being cataracts and open-angle glaucoma. Protruding eyes have also been described, especially with external steroid exposure.
• Numerous mental health issues such as steroid psychosis, depression, bipolar disorder, chronic anxiety, etc. Severe cases may show memory loss and dementia-like symptoms.
• Overall reduction in quality of life and an increased risk of blood clotting disorders, including a higher risk for deep vein thrombosis and embolism.
• Increased risk of developing adrenal insufficiency and steroid withdrawal syndrome after successful treatment of Hypercortisolism. Bilateral adrenalectomy can lead to the development of Nelson syndrome.
• Sleep disruptions like sleep deprivation, chronic insomnia, obstructive sleep apnea, and obesity hypoventilation syndrome.
• In terms of economic impact, this condition significantly increases healthcare costs. Some reports suggest that it raises total health management costs by four times compared to age and gender-matched healthy individuals. The estimated annual cost of care for Cushing’s disease in the United States alone is around $35000.

In rare cases of Hypercortisolism during pregnancy, the mother may experience high blood sugar or gestational diabetes, high blood pressure disorders, preeclampsia, heart failure, psychiatric disorders, and increased chances of miscarriage. Such pregnancies may result in premature birth, slowed growth of the baby in the womb, and the baby may also develop adrenal insufficiency after birth.

Preventing Hypercortisolism

The most common form of HCM (hypertrophic cardiomyopathy) comes from external sources, often through the use of glucocorticoids. This hormone-based medication needs to be used carefully, so it’s vital that patients understand both its benefits and potential downsides. Issues like side effects, dependency and even possible misuse due to feelings of happiness and wellbeing that they can bring should be clearly explained.

The primary care provider, like your usual doctor or an endocrinologist (a doctor who specializes in hormones), should be the main point of contact coordinating with other doctors who might also be prescribing glucocorticoids. They need to consider alternatives that have fewer side effects, ensure smallest doses for the shortest time, and carefully monitor to gradually reduce the patient’s reliance on these hormone-based medications.

There may be situations where stopping glucocorticoids is medically unfeasible. In such cases, the same healthcare team should partner with the patient and other specialists to closely monitor for any potential side effects from long-term use.

For those who have HCM due to the body’s internal production of hormones (called endogenous HCM), the doctors should clearly explain the root cause, all possible treatments, and the prognosis of the condition. The patient must also be prepared for possibly drastic changes in hormone levels when moving from excess cortisol to adrenal deficiency after effective treatment. Precautionary measures should be utilized to ensure the patient’s safety in these circumstances.