Symptoms of Cushing’s Disease and When to See Your Doctor

Cushing's disease is a rare hormonal disorder caused by excessive cortisol production, often due to a benign pituitary tumor. This leads to symptoms like weight gain, high blood pressure, and mood changes. Early detection is essential for effective treatment and reducing the risk of complications like cardiovascular disease and osteoporosis.

Cushing's disease can look like other, more common conditions, including diabetes or cardiovascular disease, so medical providers need to be aware of it and know when to refer for proper symptom assessment, diagnosis, and treatment.

This article covers the symptoms of Cushing's Disease and the importance of seeking prompt medical attention. The goal is to encourage early diagnosis and improve patient outcomes.

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Understanding Cushing's Disease

Cushing's disease is the second most common cause of Cushing's syndrome.

While Cushing's disease is a relatively rare endocrine disease, recognizing the signs and providing the proper medical attention can save lives.

What is Cushing's Disease?

Cushing's disease is an endocrine disorder caused by excessive production of adrenocorticotropic hormone (ACTH), usually due to a benign pituitary tumor, often a small pituitary microadenoma (a tumor smaller than 10 mm).

Pathophysiologically, the elevated ACTH in Cushing's disease disrupts the normal circadian rhythm of cortisol production, resulting in persistently high cortisol levels. This causes both glucocorticoid and mineralocorticoid effects that result in serious complications that can be missed in the early stages.

Cushing's disease, the second most common form of Cushing's syndrome, typically goes undiagnosed for 3 to 6 years. It mainly affects women aged 30-60 [4, 71].

With a mortality rate of 10-11%, untreated Cushing's disease increases the risk of cardiovascular issues, infections, and mental health disorders.

Effective treatment requires a multidisciplinary approach, including surgery, medication, and ongoing monitoring to manage the complex symptoms.

The Impact of Elevated Cortisol on the Body

Cortisol, a glucocorticoid hormone, is normally important in various processes, such as metabolism, immune response, and stress management.

However, in Cushing's disease, the chronic elevation of cortisol disrupts normal physiological functions, causing the characteristic symptoms of Cushing's disease.

Excess cortisol in Cushing's disease has both glucocorticoid and mineralocorticoid effects.

Many of the glucocorticoid effects of excess cortisol include:

Muscle weakness
Bone loss (osteoporosis)
Hyperglycemia
Insulin resistance
Weight gain
Increased risk of cardiovascular disease

Excess cortisol's glucocorticoid and mineralocorticoid effects contribute to hypertension, sodium retention, and potassium depletion.

Cushing's disease is also associated with neuropsychiatric and cognitive symptoms due to prolonged exposure to high levels of cortisol. Symptoms can include emotional instability, depression, anxiety, impulsivity, and cognitive deficits.

How is Cushing's Disease Different Than Cushing's Syndrome?

Cushing's syndrome is the broad term for prolonged exposure to high cortisol levels, often due to long-term corticosteroid use (iatrogenic) or, less commonly, from the body's overproduction of cortisol (endogenous).

Cushing's disease is a subtype of Cushing's syndrome. It is caused by a pituitary adenoma, which accounts for 80% of endogenous cases.

Who is at Risk for Cushing's Disease?

The most common cause of Cushing's syndrome is the use of corticosteroid medications [5, 68].

Cushing's disease, as a subtype of Cushing's syndrome, is less commonly diagnosed. Women are at a higher risk for Cushing's disease, being up to eight times more likely than men to develop Cushing's disease. The peak incidence of Cushing's syndrome occurs in adults aged 25-40.

Common Symptoms of Cushing's Disease

While the variability and subtlety of symptoms can make diagnosis challenging, Cushing's disease has several hallmark symptoms. These symptoms and the mechanisms behind their development in Cushing's disease are discussed below.

Weight Gain and Fat Distribution

Cushing's Disease leads to weight gain and abnormal fat distribution:

Central Obesity

In Cushing's disease, high levels of cortisol cause fat to accumulate in central areas like the abdomen, trunk, and face, leading to characteristic features such as abdominal weight gain, "moon face," and "buffalo hump."

Cortisol promotes fat storage by converting sugars into fat while slowing down fat breakdown, especially in these central regions.

The exact mechanism is complex and involves cortisol's action on various enzymes and hormones that regulate fat metabolism and distribution, but it directs fat accumulation in central areas.

Fat Pads

Just as patients with Cushing's disease develop characteristic central obesity and moon face, they can also develop fat pads on the back of their neck, upper back, and shoulders, also known as "buffalo hump."

But while the buffalo hump can occur in Cushing's syndrome, it is also seen in other conditions such as obesity and type 2 diabetes, so it is not considered a specific symptom of Cushing's disease.

Therefore, a comprehensive evaluation, including biochemical tests, is needed to confirm the diagnosis.

Skin Changes

Cushing's Disease also leads to skin changes:

Thinning Skin

Cortisol has a strong impact on skin structure and growth, primarily because its receptors are mostly found in the deeper layers of the skin.

Excess cortisol disrupts the production of key factors for skin health, including collagen, which maintains skin thickness and promotes healing.

As a result, the skin becomes thinner, wounds heal more slowly, and overall, the skin becomes more fragile and prone to atrophy.

Purple Stretch Marks (Striae)

Pink or purple stretch marks can appear on the body in Cushing's disease, often across the belly, thighs, breasts, and buttocks, and in other places where the skin can stretch.

Excess cortisol suppresses collagen synthesis, weakening the skin's structure. This weakening, combined with stretching forces accompanying weight gain, forms these characteristic striae.

Acne and Increased Hair Growth

In Cushing's syndrome, facial acne and hirsutism (excess hair growth) are linked to increased adrenal androgens and cortisol secretion.

Women and prepubertal children with Cushing's syndrome often develop fine, downy facial hair, in addition to acne and hirsutism, and may also experience hair thinning at the temples.

Muscle Weakness and Fatigue

While Cushing's disease causes central weight gain, it also causes muscle wasting and weakness in the limbs, which can cause the individual to develop a large belly with much thinner arms and legs.

This is due to the complex interplay of glucocorticoid functions. High levels of cortisol (glucocorticoids) contribute to muscle wasting by disrupting the balance between muscle protein synthesis and degradation.

Cortisol inhibits protein synthesis while enhancing protein breakdown, a key mechanism in muscle atrophy. Cortisol also upregulates transcription factors that contribute to increased muscle protein degradation.

Mood Changes

Cortisol has powerful effects on mood and cognitive function due to the abundance of glucocorticoid receptors in the brain, especially those in the limbic region.

Excess cortisol is thought to affect the hippocampus, a brain region involved in mood regulation and memory, which leads to structural changes like hippocampal volume loss, decreased neurogenesis, and brain atrophy.

Depression and Anxiety

The pathophysiology of cortisol's effects on mood involves dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis.

Elevated cortisol levels and HPA axis dysregulation are associated with depressive symptoms, anxiety, and cognitive deficits, likely due to cortisol's neurotoxic effects on the brain.

Cognitive Impairment

Chronic exposure to elevated cortisol levels in Cushing's disease is associated with cognitive deficits, particularly in verbal learning, memory, and visual-spatial processing.

Excessively high cortisol levels have been associated with more rapid cognitive aging.

High Blood Pressure

High cortisol in Cushing's disease causes hypertension through multiple pathways involving both glucocorticoid and mineralocorticoid functions.

Cortisol raises plasma and extracellular fluid volumes, heightens the body's responsiveness to catecholamines, and contributes to elevated blood pressure. It also impacts the renin-angiotensin system by reducing plasma renin and angiotensin II levels while increasing sensitivity to pressor effects.

Cortisol also inhibits nitric oxide, a vasodilator.

Each of these mechanisms is thought to contribute to the hypertension often seen in Cushing's disease.

Bone Health Issues

Osteoporosis

High levels of glucocorticoids commonly lead to secondary osteoporosis through several mechanisms.

For example, excess glucocorticoids increase bone resorption while decreasing bone formation. They also impair calcium absorption in the intestines and increase calcium excretion through urine, which then causes a compensatory rise in parathyroid hormone (PTH) levels.

Elevated PTH further stimulates bone resorption, exacerbating bone loss and osteoporosis.

Back Pain

Back pain can be a common complaint among those suffering from Cushing's disease. This is primarily due to the influence of the osteoporotic process.

Osteoporosis significantly increases the risk of vertebral fractures. These fractures are common and can cause spinal deformities and imbalance, leading to chronic back pain. When multiple vertebral fractures occur, they can cause a kyphotic deformity, leading to further pain and disability.

Reproductive and Sexual Health Symptoms

Reproductive and sexual health symptoms are also common amongst this population:

Menstrual Irregularities

In up to 80% of cycling women with Cushing's disease, menstrual irregularities, including oligomenorrhea (irregular periods), amenorrhea (no periods in premenopausal women), and polymenorrhea (more frequent periods), can occur.

This is due to the complex relationship between cortisol and female and male reproductive hormones. High cortisol levels can impair normal hypothalamic-pituitary-gonadal (HPG) axis function, causing a range of upsetting menstrual changes.

It does this in part by interfering with the secretion of gonadotropin-releasing hormone (GnRH) from the hypothalamus, leading to disruptions in the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH), which are essential for normal ovarian function and menstrual regularity.

Erectile Dysfunction

Up to 69% of men with endogenous hypercortisolism, as in Cushing's disease, report decreased libido. This condition may also lead to erectile dysfunction, although the exact prevalence of ED in these patients is not fully known.

Several mechanisms may contribute to this, including:

Disruption of the hypothalamic-pituitary-gonadal (HPG) axis, which may reduce testosterone production
A direct negative impact of high cortisol on sexual function (cortisol levels typically decline with the initiation of penile erection)
Metabolic conditions like diabetes, obesity, and hypertension which can all impact erectile function

Less Common But Noteworthy Symptoms

While these aren't the most common, they are still important to explore and understand:

Increased Thirst and Urination

People with Cushing's disease can present with polyuria (excessive urination) and polydipsia (excessive thirst), contributing to a clinical picture that may be mistaken for diabetes.

These symptoms are typical in Cushing's due to the body's response to prolonged exposure to high cortisol levels, which can disrupt normal fluid balance and increase thirst and urination.

Headaches and Visual Disturbances

Cushing's disease is most often linked to small brain tumors known as pituitary microadenomas (tumors smaller than 10 mm), which typically do not cause headaches or visual disturbances.

While visual disturbances are often expected with larger pituitary adenomas, this finding in Cushing's disease is rare.

However, headaches and visual disturbances may occasionally be seen in Cushing's disease. Because large brain tumors in Cushing's disease are uncommon, intracranial hypertension should be considered as a cause for these symptoms.

Decreased Immunity

Elevated cortisol levels in Cushing's syndrome cause a profound immune system suppression, impacting all immune cell types.

This suppression involves increased cell death, disrupted immune regulation, and weakened responses, making patients more prone to infections, including viral and opportunistic ones.

Cortisol-induced lymphopenia, or decreased white blood cell counts, further increases infection susceptibility. This decreased immune function, combined with thinning skin, also contributes to slower wound healing.

Unusual Fatigue Despite Rest

Cortisol is closely linked with energy metabolism. High cortisol levels have been linked to fatigue.

When to See Your Doctor

Cushing's disease can be mistaken for other conditions. If you're feeling unwell, it's essential to consult your doctor for evaluation and treatment.

Recognizing the Symptoms

Unexplained weight gain, muscle weakness, high blood pressure, or mood changes should not be ignored. These could signal Cushing's Disease or another endocrine or metabolic issue.

Because these symptoms can be subtle and worsen over time, it's essential to seek medical advice if they persist.

Importance of Early Medical Consultation

Early diagnosis is crucial in managing Cushing's disease effectively. Prompt medical consultation can stop symptom progression and reduce the risk of serious complications.

If your symptoms persist or worsen, don't delay seeking medical help—early intervention can significantly improve your quality of life.

Diagnostic Process

Expect a thorough diagnostic process, including a physical exam, hormone assessments, and possibly imaging studies like CT scans or MRIs. These tests help confirm the diagnosis and guide the treatment plan.

Who to See

Consult an endocrinologist for diagnosis and management of Cushing's Disease. These specialists are experts in hormone-related disorders and can provide the precise care you need. Early referral to a specialist ensures a more accurate diagnosis and tailored treatment.