Cushing’s Syndrome

Cushing’s syndrome or hypercortisolism is a disorder characterized by features resulting from chronic exposure to excess glucocorticoids Glucocorticoids Glucocorticoids are a class within the corticosteroid family. Glucocorticoids are chemically and functionally similar to endogenous cortisol. There are a wide array of indications, which primarily benefit from the antiinflammatory and immunosuppressive effects of this class of drugs. Glucocorticoids. Cushing’s syndrome may be exogenous, due to chronic glucocorticoid intake, or endogenous, due to increased adrenal secretion of cortisol or adrenocorticotropic hormone (ACTH) production from the pituitary gland Pituitary gland The pituitary gland, also known as the hypophysis, is considered the "master endocrine gland" because it releases hormones that regulate the activity of multiple major endocrine organs in the body. The gland sits on the sella turcica, just below the hypothalamus, which is the primary regulator of the pituitary gland. Pituitary Gland or ectopic sources. Exogenous or iatrogenic hypercortisolism is the most common cause. Typical clinical features of hypercortisolism include central obesity Obesity Obesity is a condition associated with excess body weight, specifically with the deposition of excessive adipose tissue. Obesity is considered a global epidemic. Major influences come from the western diet and sedentary lifestyles, but the exact mechanisms likely include a mixture of genetic and environmental factors. Obesity, thin and bruisable skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin, abdominal striae, secondary hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension, hyperglycemia, and proximal muscle weakness. The initial diagnostic approach is to establish hypercortisolism via urinary and salivary cortisol tests along with low-dose dexamethasone suppression test. Once the elevated cortisol levels are confirmed, the etiology is determined based on ACTH levels, confirmatory biochemical tests, and subsequent imaging studies. Treatment options depend on the cause, and include surgery and medical therapy.

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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

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Overview

Definition

Cushing’s syndrome or hypercortisolism is a disorder characterized by features resulting from chronic exposure to excess glucocorticoids Glucocorticoids Glucocorticoids are a class within the corticosteroid family. Glucocorticoids are chemically and functionally similar to endogenous cortisol. There are a wide array of indications, which primarily benefit from the antiinflammatory and immunosuppressive effects of this class of drugs. Glucocorticoids.

Types of Cushing’s syndrome

  • Primary hypercortisolism:
    • ↑ Production of glucocorticoids Glucocorticoids Glucocorticoids are a class within the corticosteroid family. Glucocorticoids are chemically and functionally similar to endogenous cortisol. There are a wide array of indications, which primarily benefit from the antiinflammatory and immunosuppressive effects of this class of drugs. Glucocorticoids by adrenal glands Adrenal Glands The adrenal glands are a pair of retroperitoneal endocrine glands located above the kidneys. The outer parenchyma is called the adrenal cortex and has 3 distinct zones, each with its own secretory products. Beneath the cortex lies the adrenal medulla, which secretes catecholamines involved in the fight-or-flight response. Adrenal Glands
    • Adrenocorticotropic hormone (ACTH)-independent condition
  • Secondary hypercortisolism:
    • Cushing’s disease: 
      • ↑ Pituitary ACTH production leading to adrenal gland hyperplasia
      •  ACTH-dependent condition
    • Ectopic ACTH syndrome: ↑ ACTH production outside the pituitary and adrenal glands Adrenal Glands The adrenal glands are a pair of retroperitoneal endocrine glands located above the kidneys. The outer parenchyma is called the adrenal cortex and has 3 distinct zones, each with its own secretory products. Beneath the cortex lies the adrenal medulla, which secretes catecholamines involved in the fight-or-flight response. Adrenal Glands (such as in lung cancer Lung cancer Lung cancer is the malignant transformation of lung tissue and the leading cause of cancer-related deaths. The majority of cases are associated with long-term smoking. The disease is generally classified histologically as either small cell lung cancer or non-small cell lung cancer. Symptoms include cough, dyspnea, weight loss, and chest discomfort. Lung Cancer)
  • Exogenous/iatrogenic Cushing’s syndrome: medical use of glucocorticoids Glucocorticoids Glucocorticoids are a class within the corticosteroid family. Glucocorticoids are chemically and functionally similar to endogenous cortisol. There are a wide array of indications, which primarily benefit from the antiinflammatory and immunosuppressive effects of this class of drugs. Glucocorticoids causing hypercortisolism

Epidemiology

  • Iatrogenic Cushing’s syndrome is the most common form. 
  • Primary hypercortisolism:
    • More common in women
    • Adrenal tumors affect 2 age groups the most: peaks in the 1st 10 years, and again around 40 years of age (carcinomas) and 50 years of age (adenomas).
  • Secondary hypercortisolism:
    • Cushing’s disease: 
      • 5–6 times more common than primary hypercortisolism
      • More common in women
      • Age group most affected: 25–45 years of age
    • Ectopic ACTH:
      • More common after 50 years of age
      • Follows incidence of small-cell lung carcinoma
  • Increased risk of cardiovascular mortality compared to the general population

Etiology

  • ACTH-dependent causes:
    • Cushing’s disease:
      • Pituitary microadenoma: 90% 
      • Pituitary macroadenoma
    • Ectopic ACTH syndrome:
      • Carcinoid tumors Carcinoid tumors Carcinoid tumors are small, well-differentiated, slow-growing neuroendocrine tumors (NET). Carcinoid syndrome describes the signs and symptoms associated with unregulated vasoactive hormone production by neuroendocrine tumors. Carcinoid tumors are most commonly found in the GI and bronchopulmonary tracts. Carcinoid Tumors and Syndrome
      • Small-cell lung carcinoma
      • Pancreatic tumors
      • Thymus Thymus A single, unpaired primary lymphoid organ situated in the mediastinum, extending superiorly into the neck to the lower edge of the thyroid gland and inferiorly to the fourth costal cartilage. It is necessary for normal development of immunologic function early in life. By puberty, it begins to involute and much of the tissue is replaced by fat. Lymphatic Drainage System tumors
    • Ectopic corticotropin-releasing hormone (CRH) syndrome leads to ↑ ACTH and subsequent adrenal hyperplasia
    • Iatrogenic (treatment with exogenous ACTH)
  • ACTH-independent causes:
    • Iatrogenic (treatment with glucocorticoids Glucocorticoids Glucocorticoids are a class within the corticosteroid family. Glucocorticoids are chemically and functionally similar to endogenous cortisol. There are a wide array of indications, which primarily benefit from the antiinflammatory and immunosuppressive effects of this class of drugs. Glucocorticoids)
    • Adrenal adenoma and carcinoma
    • Primary pigmented nodular adrenocortical disease
    • Bilateral macronodular adrenal hyperplasia
    • McCune-Albright syndrome
  • Pseudo-Cushing’s syndrome (physiological hypercortisolism):
    • Pregnancy Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-HCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care
    • Obstructive sleep apnea Obstructive sleep apnea Obstructive sleep apnea (OSA) is a disorder characterized by recurrent obstruction of the upper airway during sleep, causing hypoxia and fragmented sleep. Obstructive sleep apnea is due to a partial or complete collapse of the upper airway and is associated with snoring, restlessness, sleep interruption, and daytime somnolence. Obstructive Sleep Apnea
    • Uncontrolled diabetes mellitus Diabetes mellitus Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus
    • Obesity (women with polycystic ovarian syndrome Polycystic ovarian syndrome Polycystic ovarian syndrome (PCOS) is the most common endocrine disorder of reproductive-age women, affecting nearly 5%-10% of women in the age group. It is characterized by hyperandrogenism, chronic anovulation leading to oligomenorrhea (or amenorrhea), and metabolic dysfunction. Polycystic Ovarian Syndrome)
    • Severe depression
    • Stress
    • Intense exercise

Pathophysiology

Hormonal regulation

  • Hypothalamic-pituitary-adrenal (HPA) axis
    • Hypothalamus secretes CRH → release of ACTH from the anterior pituitary gland Pituitary gland The pituitary gland, also known as the hypophysis, is considered the "master endocrine gland" because it releases hormones that regulate the activity of multiple major endocrine organs in the body. The gland sits on the sella turcica, just below the hypothalamus, which is the primary regulator of the pituitary gland. Pituitary Gland
    • ACTH release:
      • Like CRH, the release of ACTH is pulsatile, following the circadian rhythm.
      • ↑ In the early morning hours (before awakening), with peak levels in the morning (approximately 8:30 a.m.) and ↓ in the evening
    • Adrenal gland (cortex):
      • ACTH mainly stimulates the zona fasciculata (cortisol) and zona reticularis ( androgens Androgens Androgens are naturally occurring steroid hormones responsible for development and maintenance of the male sex characteristics, including penile, scrotal, and clitoral growth, development of sexual hair, deepening of the voice, and musculoskeletal growth. Androgens and Antiandrogens).
      • Zona glomerulosa (aldosterone) is primarily regulated by the renin-angiotensin system and potassium levels.
  • Cortisol:
    • Metabolic effects:
      • ↓ Glucose uptake by cells and ↑ gluconeogenesis Gluconeogenesis Gluconeogenesis is the process of making glucose from noncarbohydrate precursors. This metabolic pathway is more than just a reversal of glycolysis. Gluconeogenesis provides the body with glucose not obtained from food, such as during a fasting period. The production of glucose is critical for organs and cells that cannot use fat for fuel. Gluconeogenesis
      • ↑ Lipolysis → release of fatty acids Fatty acids Fatty acids are integral building blocks of lipids, and can be classified as unsaturated or saturated based on the presence/absence of carbon-carbon double bonds within their nonpolar chains. Fatty Acids and Lipids into the circulation
      • ↓ Protein storage → myopathy, bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones resorption
    • ↑ Smooth muscle (vasculature) sensitivity to catecholamines Catecholamines A general class of ortho-dihydroxyphenylalkylamines derived from tyrosine. Adrenal Hormones and angiotensin II (leading to ↑ blood pressure)
    • Anti-inflammatory actions: 
      • Apoptosis of T cells T cells T cells, also called T lymphocytes, are important components of the adaptive immune system. Production starts from the hematopoietic stem cells in the bone marrow, from which T-cell progenitor cells arise. These cells migrate to the thymus for further maturation. T Cells
      • ↓ Antibody production
      • ↓ Neutrophil migration
  • Androgens:
    • Dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) are the androgens Androgens Androgens are naturally occurring steroid hormones responsible for development and maintenance of the male sex characteristics, including penile, scrotal, and clitoral growth, development of sexual hair, deepening of the voice, and musculoskeletal growth. Androgens and Antiandrogens secreted in excess. 
    • DHEA:
      • Weak androgenic activity
      • Precursor can be peripherally converted to more potent androgens Androgens Androgens are naturally occurring steroid hormones responsible for development and maintenance of the male sex characteristics, including penile, scrotal, and clitoral growth, development of sexual hair, deepening of the voice, and musculoskeletal growth. Androgens and Antiandrogens (e.g., testosterone) and estrogens (e.g., estradiol Estradiol The 17-beta-isomer of estradiol, an aromatized C18 steroid with hydroxyl group at 3-beta- and 17-beta-position. Estradiol-17-beta is the most potent form of mammalian estrogenic steroids. Menstrual Cycle).
      • Testes are the main source of androgens Androgens Androgens are naturally occurring steroid hormones responsible for development and maintenance of the male sex characteristics, including penile, scrotal, and clitoral growth, development of sexual hair, deepening of the voice, and musculoskeletal growth. Androgens and Antiandrogens in men. 
  • Mineralocorticoids Mineralocorticoids Mineralocorticoids are a drug class within the corticosteroid family and fludrocortisone is the primary medication within this class. Fludrocortisone is a fluorinated analog of cortisone. The fluorine moiety protects the drug from isoenzyme inactivation in the kidney, allowing it to exert its mineralocorticoid effect. Mineralocorticoids:
    • Regulation of renal sodium Renal Sodium Renal Na+ and water regulation work in tandem to control how fluid is distributed throughout the compartments of the body. Sodium is the body's dominant extracellular solute, and is responsible for the osmotic force that keeps differing amounts of water in each compartment. Changes in Na+ balance are sensed by the body through changes in blood volume. Renal Sodium and Water Regulation and water reabsorption 
    • Regulation of potassium excretion

Hypercortisolism

  • ACTH-dependent causes:
    • Cushing’s disease:
      • Pituitary adenoma Pituitary adenoma Pituitary adenomas are tumors that develop within the anterior lobe of the pituitary gland. Non-functioning or non-secretory adenomas do not secrete hormones but can compress surrounding pituitary tissue, leading to hypopituitarism. Secretory adenomas secrete various hormones depending on the cell type from which they evolved, leading to hyperpituitarism. Pituitary Adenomas secreting ACTH
      • ↑ ACTH → bilateral adrenal hyperplasia and hyperfunction → ↑ cortisol
      • ACTH secretion is resistant to glucocorticoid feedback inhibition.
    • Ectopic ACTH syndrome:
      • Occurs in malignant and neuroendocrine tumors
      • ↑ Ectopic ACTH → ↑ cortisol 
    • Ectopic CRH syndrome:
      • Secretion of CRH by a tumor
      • ↑ CRH → pituitary hyperplasia → ACTH hypersecretion → ↑ cortisol
      • Generally with loss of glucocorticoid negative feedback
  • ACTH-independent causes:
    • Iatrogenic:
      • Synthetic glucocorticoids Glucocorticoids Glucocorticoids are a class within the corticosteroid family. Glucocorticoids are chemically and functionally similar to endogenous cortisol. There are a wide array of indications, which primarily benefit from the antiinflammatory and immunosuppressive effects of this class of drugs. Glucocorticoids → ↓ CRH and ACTH → bilateral adrenocortical atrophy 
      • Most common: prednisone
    • Cortisol-secreting adrenal adenomas and carcinomas:
      • Tumors secrete cortisol, suppressing ACTH and leading to pituitary corticotroph atrophy.
      • Hyperaldosteronism Hyperaldosteronism Hyperaldosteronism is defined as the increased secretion of aldosterone from the zona glomerulosa of the adrenal cortex. Hyperaldosteronism may be primary (resulting from autonomous secretion), or secondary (resulting from physiological secretion due to stimulation of the RAAS). Classically, hyperaldosteronism presents with hypertension, hypokalemia, and metabolic alkalosis. Hyperaldosteronism can occur. 
      • Excessive glucocorticoids Glucocorticoids Glucocorticoids are a class within the corticosteroid family. Glucocorticoids are chemically and functionally similar to endogenous cortisol. There are a wide array of indications, which primarily benefit from the antiinflammatory and immunosuppressive effects of this class of drugs. Glucocorticoids interfere with central regulation and result in gonadotropin suppression (resulting in hypogonadism Hypogonadism Hypogonadism is a condition characterized by reduced or no sex hormone production by the testes or ovaries. Hypogonadism can result from primary (hypergonadotropic) or secondary (hypogonadotropic) failure. Symptoms include infertility, increased risk of osteoporosis, erectile dysfunction, decreased libido, and regression (or absence) of secondary sexual characteristics. Hypogonadism and amenorrhea).
    • Macronodular adrenal hyperplasia:
      • Involves aberrant membrane receptors in the adrenal cortex stimulated by other hormones Hormones Hormones are messenger molecules that are synthesized in one part of the body and move through the bloodstream to exert specific regulatory effects on another part of the body. Hormones play critical roles in coordinating cellular activities throughout the body in response to the constant changes in both the internal and external environments. Hormones: Overview (e.g., vasopressin, gastric inhibitory peptide)
      • Adrenal glands are significantly enlarged with macronodules.
    • Primary pigmented nodular adrenocortical disease:
      • Also known as micronodular adrenal hyperplasia
      • Can be sporadic or familial (Carney’s syndrome)
      • Characterized by myxomas, multiple endocrine gland disorders, and lentigines
      • Bilateral adrenal gland disease with pigmented nodules that are autonomously functioning
      • Associated with PRKAR1A mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations
    • McCune-Albright syndrome:
      • Triad of polyostotic fibrous dysplasia, café-au-lait skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin pigmentation, and precocious puberty Precocious puberty Precocious puberty (PP) is the appearance of secondary sexual characteristics due to elevated sex hormones before the age of 6-8 in girls and 9 in boys. Excess hormone secretion may occur only at the level of the sex hormone or may involve the whole hypothalamic-pituitary-gonadal axis. Precocious Puberty (autonomous endocrine hyperfunction)
      • Also associated with hyperthyroidism Hyperthyroidism Thyrotoxicosis refers to the classic physiologic manifestations of excess thyroid hormones and is not synonymous with hyperthyroidism, which is caused by sustained overproduction and release of T3 and/or T4. Graves' disease is the most common cause of primary hyperthyroidism, followed by toxic multinodular goiter and toxic adenoma. Thyrotoxicosis and Hyperthyroidism, acromegaly Acromegaly Acromegaly and gigantism are caused by an excessive production of growth hormone (GH) by the pituitary gland. Acromegaly is usually produced by pituitary tumors secreting GH or, less commonly, by extrapituitary disorders. Acromegaly and Gigantism, and Cushing’s syndrome
      • Adrenal effect caused by a somatic mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations in the alpha subunit of Gs protein → constant activation mimicking ACTH stimulation

Clinical Presentation

Table: Signs and symptoms of Cushing’s syndrome
Skin
  • Acne, facial plethora, violaceous striae/stretch marks, easy bruising, hirsutism
  • Secondary hypercortisolism: hyperpigmentation (both ACTH and ɑ-melanin-stimulating hormone are derived from pro-opiomelanocortin → melanocyte stimulated)
Body fat Moon facies, central obesity Obesity Obesity is a condition associated with excess body weight, specifically with the deposition of excessive adipose tissue. Obesity is considered a global epidemic. Major influences come from the western diet and sedentary lifestyles, but the exact mechanisms likely include a mixture of genetic and environmental factors. Obesity, buffalo hump (dorsocervical fat pad)
Bone Short stature (decreased linear growth in children), osteopenia, osteoporosis Osteoporosis Osteoporosis refers to a decrease in bone mass and density leading to an increased number of fractures. There are 2 forms of osteoporosis: primary, which is commonly postmenopausal or senile; and secondary, which is a manifestation of immobilization, underlying medical disorders, or long-term use of certain medications. Osteoporosis, ↑ risk of avascular necrosis
Muscle Proximal myopathy, weakness
Metabolism Elevated glucose/diabetes, dyslipidemia
Reproductive Amenorrhea in women, decreased libido
Cardiovascular Atherosclerosis Atherosclerosis Atherosclerosis is a common form of arterial disease in which lipid deposition forms a plaque in the blood vessel walls. Atherosclerosis is an incurable disease, for which there are clearly defined risk factors that often can be reduced through a change in lifestyle and behavior of the patient. Atherosclerosis, hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension, edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema
GI Ulcers
Neuropsychiatric Irritability, depression, emotional lability, sleep Sleep Sleep is a reversible phase of diminished responsiveness, motor activity, and metabolism. This process is a complex and dynamic phenomenon, occurring in 4-5 cycles a night, and generally divided into non-rapid eye movement (NREM) sleep and REM sleep stages. Physiology of Sleep disturbance, psychosis
Ophthalmologic Cataracts (steroids affect gene transcription Transcription Transcription of genetic information is the first step in gene expression. Transcription is the process by which DNA is used as a template to make mRNA. This process is divided into 3 stages: initiation, elongation, and termination. Stages of Transcription of lens epithelial cells)
Immune system Increased WBC count, increased susceptibility to infection

Mnemonic

To recall the most common clinical features of Cushing’s syndrome, remember CUSHINGOID”:

  • Cataracts
  • Ulcers
  • Skin: striae, thinning, bruising
  • Hypertension, hirsutism, hyperglycemia
  • Infections
  • Necrosis (avascular necrosis of the femoral head)
  • Glucose elevation
  • Osteoporosis, osteopenia, obesity
  • Immunosuppression
  • Diabetes, depression
Cushingoid symptoms

The common clinical manifestations of hypercortisolism

Image by Lecturio.

Diagnosis

Diagnosis of hypercortisolism

Clinical features increase suspicion of diagnosis:

  • Many signs and symptoms are nonspecific.
  • Biochemical tests are needed to establish the diagnosis.

Exclude use of exogenous glucocorticoids Glucocorticoids Glucocorticoids are a class within the corticosteroid family. Glucocorticoids are chemically and functionally similar to endogenous cortisol. There are a wide array of indications, which primarily benefit from the antiinflammatory and immunosuppressive effects of this class of drugs. Glucocorticoids:

  • Review of oral, injected, inhaled, and topical glucocorticoid use and dosages
  • Review of drug interactions (e.g., ritonavir delays clearance of inhaled/injected steroids)

Initial tests for hypercortisolism:

  • Late-night salivary cortisol 
  • 24-hour urinary free cortisol (UFC) excretion 
  • 1 mg dexamethasone-suppression test ((DST) 1 mg of dexamethasone administered in the late evening suppresses endogenous cortisol production the next morning))
    • Normal cutoff for suppression of serum cortisol (post-dexamethasone): < 1.8 μg/dL (50 nmol/L)
    • If cortisol is not suppressed (i.e., cortisol > 1.8 μg/dL or 50 nmol/L) → hypercortisolism 
  • Longer low-dose DST (2 mg/day for 48 hours)

Abnormal results prompt additional evaluation:

  • Exclude physiological hypercortisolism.
  • Retest especially if high index of suspicion
  • Consult an endocrinologist regarding the identification of the cause of hypercortisolism.
Algorithm to confirm diagnosis of cushing syndrome

Algorithm to diagnose hypercortisolism or Cushing’s syndrome (CS):
In patients clinically suspected with CS, the 1st step is to rule out the exogenous use of glucocorticoids Glucocorticoids Glucocorticoids are a class within the corticosteroid family. Glucocorticoids are chemically and functionally similar to endogenous cortisol. There are a wide array of indications, which primarily benefit from the antiinflammatory and immunosuppressive effects of this class of drugs. Glucocorticoids. Once excluded, initial tests to check for elevated cortisol levels include late-night (LN) salivary cortisol, 24-hour urinary free cortisol (UFC), and 1 mg dexamethasone suppression test (DST). Once elevated cortisol levels are confirmed, evaluate whether the elevation is from physiological hypercortisolism. Once physiologic causes are excluded, proceed with additional testing to identify the etiology (which can be primary or secondary).

Image by Lecturio.

Identification of the cause

After confirming elevated cortisol levels, determining the etiology starts with ACTH.

  • ACTH levels:
    • Identify ACTH-independent versus ACTH-dependent etiologies.
    • Results:
      • ↓ ACTH (< 5 pg/mL): primary hypercortisolism (ACTH-independent)
      • ↑ ACTH (> 20 pg/mL): secondary hypercortisolism (ACTH-dependent)
      • Intermediate ACTH (5–20 pg/mL): likely ACTH-dependent (further tests needed)
  • If with ↓ ACTH:
    • Etiology is ACTH-independent (adrenal gland).
    • Proceed with CT or MRI of the adrenal glands Adrenal Glands The adrenal glands are a pair of retroperitoneal endocrine glands located above the kidneys. The outer parenchyma is called the adrenal cortex and has 3 distinct zones, each with its own secretory products. Beneath the cortex lies the adrenal medulla, which secretes catecholamines involved in the fight-or-flight response. Adrenal Glands.
    • Possible adrenal mass, bilateral hyperplasia, or macronodular adrenal hyperplasia
  • If with ↑ or intermediate ACTH:
    • Etiology is likely ACTH-dependent.
    • Proceed with tests to identify Cushing’s syndrome versus ectopic Cushing’s syndrome.
    • CRH test: 
      • ACTH concentration is measured before and after administration of CRH. 
      • ↑ ACTH: Cushing’s disease (pituitary adenoma)
      • No ↑ ACTH: ectopic ACTH syndrome
    • High-dose DST: 
      • 8 mg dexamethasone is administered.
      • Cortisol is suppressed: Cushing’s disease (pituitary adenoma)
      • Cortisol is not suppressed: ectopic ACTH syndrome
    • If etiology is:
      • Cushing’s disease → proceed with pituitary MRI
      • Ectopic → search for tumor/malignancy 
  • Inferior petrosal sinus sampling (IPSS):
    • Directly determines ACTH secretion from the pituitary gland Pituitary gland The pituitary gland, also known as the hypophysis, is considered the "master endocrine gland" because it releases hormones that regulate the activity of multiple major endocrine organs in the body. The gland sits on the sella turcica, just below the hypothalamus, which is the primary regulator of the pituitary gland. Pituitary Gland:
      • Determines central-to-peripheral ACTH gradient by measuring ACTH from the petrosal and peripheral veins Veins Veins are tubular collections of cells, which transport deoxygenated blood and waste from the capillary beds back to the heart. Veins are classified into 3 types: small veins/venules, medium veins, and large veins. Each type contains 3 primary layers: tunica intima, tunica media, and tunica adventitia. Veins after CRH administration
      • Gradient of ≥ 3 after CRH → Cushing’s disease (pituitary)
    • Disadvantages: invasive, expensive, and associated with possible risks
    • Complications: cerebrovascular accident Cerebrovascular accident An ischemic stroke (also known as cerebrovascular accident) is an acute neurologic injury that occurs as a result of brain ischemia; this condition may be due to cerebral blood vessel occlusion by thrombosis or embolism, or rarely due to systemic hypoperfusion. Ischemic Stroke, thromboembolism
    • Performed in certain situations:
      • Mixed responses in CRH and DSTs
      • No pituitary tumor or lesion is < 6 mm on MRI
Table: Summary of steps in identifying the etiology of Cushing’s syndrome
ACTH level Etiology and additional tests Identifying the cause
↓ ACTH: ACTH-independent Adrenal gland (possible adenoma, carcinoma, hyperplasia) Obtain CT scan/MRI of the adrenal gland.
↑ or intermediate ACTH: likely ACTH-dependent Cushing’s disease:
  • ↑ ACTH in CRH test
  • Excess cortisol suppressed in high-dose dexamethasone suppression test
Obtain pituitary MRI.
Ectopic ACTH syndrome (such as lung cancer Lung cancer Lung cancer is the malignant transformation of lung tissue and the leading cause of cancer-related deaths. The majority of cases are associated with long-term smoking. The disease is generally classified histologically as either small cell lung cancer or non-small cell lung cancer. Symptoms include cough, dyspnea, weight loss, and chest discomfort. Lung Cancer, carcinoid):
  • No ↑ ACTH in CRH test
  • Excess cortisol not suppressed in high-dose dexamethasone test
Workup for malignancy:
  • Chest X-ray
  • CT scan/MRI
ACTH: adrenocorticotropic hormone
CRH test: corticotropin-releasing hormone test

Management and Prognosis

Exogenous Cushing’s syndrome

  • Stop glucocorticoids Glucocorticoids Glucocorticoids are a class within the corticosteroid family. Glucocorticoids are chemically and functionally similar to endogenous cortisol. There are a wide array of indications, which primarily benefit from the antiinflammatory and immunosuppressive effects of this class of drugs. Glucocorticoids.
  • Gradual withdrawal is necessary while switching to an alternative medication.
  • If unable to discontinue, consider lowering the dose.

Primary adrenal disease

  • Functional adenoma: unilateral adrenalectomy
  • Primary pigmented nodular adrenocortical disease and macronodular adrenal hyperplasia: 
    • Bilateral adrenalectomy 
    • Adrenal enzyme inhibitors (metyrapone or ketoconazole) can be given prior to surgery.
  • Adrenal carcinoma:
    • Resectable tumor: adrenalectomy (+/- radiotherapy for incomplete resection)
    • Unresectable tumor/advanced disease: mitotane, metyrapone, or ketoconazole

Cushing’s disease (pituitary adenoma)

  • Transsphenoidal surgery to remove adenoma
  • Medical therapy (to prepare for the procedure, or if surgery is contraindicated or unsuccessful):
    • Adrenal enzyme inhibitors
    • Cabergoline (dopamine agonist) or pasireotide (somatostatin analog)
    • Mifepristone (for hyperglycemia in Cushing’s syndrome)
  • Radiotherapy: 
    • Used when surgical methods fail to achieve remission
    • Can be the primary treatment option in individuals < 18 years of age
  • Adrenalectomy: option in cases of persistent or recurrent Cushing’s disease

Ectopic ACTH syndrome

  • Resectable tumor: surgical excision
  • Unresectable tumor: Use adrenal enzyme inhibitors (metyrapone, ketoconazole, mitotane).

Outcomes and prognosis

  • With treatment: 
    • Signs and symptoms regress in months to a year.
    • Some complications ( hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension, diabetes) may persist but improve over time.
    • Patients at risk for adrenal insufficiency Adrenal Insufficiency Adrenal insufficiency (AI) is the inadequate production of adrenocortical hormones: glucocorticoids, mineralocorticoids, and adrenal androgens. Primary AI, also called Addison’s disease, is caused by autoimmune disease, infections, and malignancy, among others. Adrenal insufficiency can also occur because of decreased production of adrenocorticotropic hormone (ACTH) from disease in the pituitary gland (secondary) or hypothalamic disorders and prolonged glucocorticoid therapy (tertiary). Adrenal Insufficiency and Addison’s Disease (e.g., bilateral adrenalectomy) would need glucocorticoid replacement.
  • Nelson syndrome can develop in up to 25% of patients who undergo bilateral adrenalectomy:
    • Enlarging pituitary tumor occurring after bilateral adrenalectomy
    • Presumed to be from growing ACTH-secreting cells in a previously undetected pituitary adenoma
    • With no adrenal glands Adrenal Glands The adrenal glands are a pair of retroperitoneal endocrine glands located above the kidneys. The outer parenchyma is called the adrenal cortex and has 3 distinct zones, each with its own secretory products. Beneath the cortex lies the adrenal medulla, which secretes catecholamines involved in the fight-or-flight response. Adrenal Glands, there is no glucocorticoid negative feedback; thus, pituitary growth is facilitated.
    • In Cushing’s disease, radiotherapy is performed before bilateral adrenalectomy to reduce the risk of Nelson syndrome.
  • Cushing’s syndrome is fatal without treatment, and mortality is related to:
    • Cardiovascular disease
    • Thromboembolic events
    • Infections
  • If hypercortisolism is associated with a tumor, the prognosis is related to the nature (e.g., malignancy) of the tumor and the severity of hypercortisolism.

Clinical Relevance

  • Pituitary adenoma Pituitary adenoma Pituitary adenomas are tumors that develop within the anterior lobe of the pituitary gland. Non-functioning or non-secretory adenomas do not secrete hormones but can compress surrounding pituitary tissue, leading to hypopituitarism. Secretory adenomas secrete various hormones depending on the cell type from which they evolved, leading to hyperpituitarism. Pituitary Adenomas: tumors that develop within the anterior lobe of the pituitary gland Pituitary gland The pituitary gland, also known as the hypophysis, is considered the "master endocrine gland" because it releases hormones that regulate the activity of multiple major endocrine organs in the body. The gland sits on the sella turcica, just below the hypothalamus, which is the primary regulator of the pituitary gland. Pituitary Gland. Pituitary adenomas Pituitary adenomas Pituitary adenomas are tumors that develop within the anterior lobe of the pituitary gland. Non-functioning or non-secretory adenomas do not secrete hormones but can compress surrounding pituitary tissue, leading to hypopituitarism. Secretory adenomas secrete various hormones depending on the cell type from which they evolved, leading to hyperpituitarism. Pituitary Adenomas are classified based on size (micro- or macroadenomas) and their ability to secrete hormones Hormones Hormones are messenger molecules that are synthesized in one part of the body and move through the bloodstream to exert specific regulatory effects on another part of the body. Hormones play critical roles in coordinating cellular activities throughout the body in response to the constant changes in both the internal and external environments. Hormones: Overview. Non-functioning or non-secretory adenomas do not secrete hormones Hormones Hormones are messenger molecules that are synthesized in one part of the body and move through the bloodstream to exert specific regulatory effects on another part of the body. Hormones play critical roles in coordinating cellular activities throughout the body in response to the constant changes in both the internal and external environments. Hormones: Overview but compress the surrounding pituitary tissue, leading to hypopituitarism Hypopituitarism Hypopituitarism is a condition characterized by pituitary hormone deficiency. This condition primarily results from a disease of the pituitary gland, but it may arise from hypothalamic dysfunction. Pituitary tumors are one of the most common causes. The majority of cases affect the anterior pituitary lobe (adenohypophysis), which accounts for 80% of the gland. Hypopituitarism. Secretory adenomas secrete various hormones Hormones Hormones are messenger molecules that are synthesized in one part of the body and move through the bloodstream to exert specific regulatory effects on another part of the body. Hormones play critical roles in coordinating cellular activities throughout the body in response to the constant changes in both the internal and external environments. Hormones: Overview depending on the cell type they evolve from and lead to hyperpituitarism.
  • Paraneoplastic syndrome: a constellation of signs and symptoms that arise from substances produced by the tumor and not by a direct effect of the tumor. Conditions can range from immunological responses to the presence of a neoplasm in the body that leads to antibody production (Lambert-Eeaton syndrome). Hormones, peptides, or cytokines produced by the tumor also result in paraneoplastic syndrome (Cushing’s syndrome due to ectopic ACTH secretion).
  • Adrenal insufficiency: an inadequate production of the following adrenocortical hormones Hormones Hormones are messenger molecules that are synthesized in one part of the body and move through the bloodstream to exert specific regulatory effects on another part of the body. Hormones play critical roles in coordinating cellular activities throughout the body in response to the constant changes in both the internal and external environments. Hormones: Overview by the adrenal glands Adrenal Glands The adrenal glands are a pair of retroperitoneal endocrine glands located above the kidneys. The outer parenchyma is called the adrenal cortex and has 3 distinct zones, each with its own secretory products. Beneath the cortex lies the adrenal medulla, which secretes catecholamines involved in the fight-or-flight response. Adrenal Glands: glucocorticoids Glucocorticoids Glucocorticoids are a class within the corticosteroid family. Glucocorticoids are chemically and functionally similar to endogenous cortisol. There are a wide array of indications, which primarily benefit from the antiinflammatory and immunosuppressive effects of this class of drugs. Glucocorticoids, mineralocorticoids, and adrenal androgens Androgens Androgens are naturally occurring steroid hormones responsible for development and maintenance of the male sex characteristics, including penile, scrotal, and clitoral growth, development of sexual hair, deepening of the voice, and musculoskeletal growth. Androgens and Antiandrogens. Primary adrenal insufficiency Adrenal Insufficiency Adrenal insufficiency (AI) is the inadequate production of adrenocortical hormones: glucocorticoids, mineralocorticoids, and adrenal androgens. Primary AI, also called Addison’s disease, is caused by autoimmune disease, infections, and malignancy, among others. Adrenal insufficiency can also occur because of decreased production of adrenocorticotropic hormone (ACTH) from disease in the pituitary gland (secondary) or hypothalamic disorders and prolonged glucocorticoid therapy (tertiary). Adrenal Insufficiency and Addison’s Disease, also called Addison’s disease, is caused by afflictions in the gland itself. Secondary adrenal insufficiency Adrenal Insufficiency Adrenal insufficiency (AI) is the inadequate production of adrenocortical hormones: glucocorticoids, mineralocorticoids, and adrenal androgens. Primary AI, also called Addison’s disease, is caused by autoimmune disease, infections, and malignancy, among others. Adrenal insufficiency can also occur because of decreased production of adrenocorticotropic hormone (ACTH) from disease in the pituitary gland (secondary) or hypothalamic disorders and prolonged glucocorticoid therapy (tertiary). Adrenal Insufficiency and Addison’s Disease occurs due to decreased production of ACTH either from prolonged glucocorticoid therapy, or pituitary or hypothalamic disease.
  • Small-cell lung carcinoma: highly aggressive lung cancer Lung cancer Lung cancer is the malignant transformation of lung tissue and the leading cause of cancer-related deaths. The majority of cases are associated with long-term smoking. The disease is generally classified histologically as either small cell lung cancer or non-small cell lung cancer. Symptoms include cough, dyspnea, weight loss, and chest discomfort. Lung Cancer that is often metastatic at the time of diagnosis. About 15% of all lung cancers are secondary to small-cell lung carcinomas. Apart from the pulmonary manifestations of dyspnea Dyspnea Dyspnea is the subjective sensation of breathing discomfort. Dyspnea is a normal manifestation of heavy physical or psychological exertion, but also may be caused by underlying conditions (both pulmonary and extrapulmonary). Dyspnea, cough, and cachexia, small-cell lung carcinomas can present with Cushing’s syndrome due to ectopic production of ACTH. Diagnosis of the cancer is based on imaging studies and biopsy. Treatment depends on whether the disease is limited or extensive.

References

  1. Arlt, W. (2018). Disorders of the adrenal cortex. Jameson, J., Fauci, A.S., Kasper, D.L., Hauser, S.L., Longo, D.L., Loscalzo, J.(Eds.), Harrison’s Principles of Internal Medicine, 20e. McGraw-Hill.
  2. Chrousos, G. (2015). Glucocorticoid therapy and Cushing syndrome. Medscape. Retrieved February 27, 2021, from https://emedicine.medscape.com/article/921086-clinical
  3. James, E.R. (2007). The etiology of steroid cataract. J Ocul Pharmacol Ther. 23(5):403-20. doi: 10.1089/jop.2006.0067. PMID: 17900234.
  4. Marik, P.E. (2014). Critical illness–related corticosteroid insufficiency. Hall, J.B., & Schmidt, G.A., Kress J.P.(Eds.), Principles of Critical Care, 4e. McGraw-Hill.
  5. Nieman, L. (2019). Causes and pathophysiology of Cushing syndrome. UpToDate. Retrieved February 27, 2021, from https://www.uptodate.com/contents/causes-and-pathophysiology-of-cushings-syndrome
  6. Nieman, L. (2021) Epidemiology and clinical manifestations of Cushing syndrome. UpToDate. Retrieved February 27, 2021, from https://www.uptodate.com/contents/epidemiology-and-clinical-manifestations-of-cushings-syndrome
  7. Nieman, L. (2019) Overview of treatment of Cushing syndrome. UpToDate. Retrieved February 29, 2021, from https://www.uptodate.com/contents/overview-of-the-treatment-of-cushings-syndrome?search=overview
  8. Nieman, L (2021) Medical therapy of hypercortisolism. UpToDate. Retrieved February 29, 2021, from https://www.uptodate.com/contents/medical-therapy-of-hypercortisolism-cushings-syndrome
  9. Nieman, L., Biller, B., Findling, J., Newell-Price, J., Savage, M., Stewart, P., Montori, V. (2008). The Diagnosis of Cushing Syndrome: An Endocrine Society Clinical Practice Guideline, The Journal of Clinical Endocrinology & Metabolism, Volume 93, Issue 5, pp. 1526–1540. https://doi.org/10.1210/jc.2008-0125
  10. Thau, L., Gandhi, J., Sharma, S. (2021). Physiology, Cortisol. StatPearls. https://www.ncbi.nlm.nih.gov/books/NBK538239/

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