Cushing's syndrome
Encyclopedia
Cushing's syndrome is a hormone disorder caused by high levels of cortisol
in the blood. This can be caused by taking glucocorticoid
drugs, or by tumors that produce cortisol or adrenocorticotropic hormone
(ACTH) or CRH
Cushing's disease
refers to one specific cause of the syndrome: a tumor (adenoma
) in the pituitary gland
that produces large amounts of ACTH, which in turn elevates cortisol. It is the most common cause of Cushing's syndrome, responsible for 70% of cases excluding glucocorticoid related cases.
This pathology was described by Harvey Cushing
in 1932. The syndrome is also called Itsenko-Cushing syndrome, hyperadrenocorticism or hypercorticism
Cushing's syndrome is not confined to humans and is also a relatively common condition in domestic dogs and horses. It also occurs in cats, but rarely.
It should not be confused with Cushing's triad
, a disease state resulting from increased intracranial pressure.
, particularly of the trunk and face with sparing of the limbs (central obesity
). A common sign is the growth of fat pads along the collar bone and on the back of the neck (buffalo hump) and a round face often referred to as a "moon face
." Other symptoms include hyperhidrosis
(excess sweating), telangiectasia
(dilation of capillaries), thinning of the skin (which causes easy bruising and dryness, particularly the hands) and other mucous membranes, purple or red striae (the weight gain in Cushing's syndrome stretches the skin, which is thin and weakened, causing it to hemorrhage) on the trunk, buttocks, arms, legs or breasts, proximal muscle weakness (hips, shoulders), and hirsutism
(facial male-pattern hair growth), baldness
and/or cause hair to become extremely dry and brittle. In rare cases, Cushing's can cause hypercalcemia, which can lead to skin necrosis. The excess cortisol may also affect other endocrine systems and cause, for example, insomnia
, inhibited aromatase
, reduced libido
, impotence, amenorrhoea
/oligomenorrhea
and infertility
due to elevations in androgens. Patients frequently suffer various psychological disturbances, ranging from euphoria
to psychosis
. Depression
and anxiety
are also common.
Other striking and distressing skin changes that may appear in Cushing's syndrome include facial acne, susceptibility to superficial dermatophyte
and malassezia infections, and the characteristic purplish, atrophic striae on the abdomen.
Other signs include polyuria
(and accompanying polydipsia
), persistent hypertension
(due to cortisol's enhancement of epinephrine
's vasoconstrictive effect) and insulin resistance
(especially common in ectopic ACTH production), leading to hyperglycemia
(high blood sugar
) and insulin resistance which can lead to diabetes mellitus
. Insulin resistance is accompanied by skin changes such as acanthosis nigricans
in the axilla and around the neck, as well as skin tags in the axilla. Untreated Cushing's syndrome can lead to heart disease
and increased mortality
. Cushing's syndrome due to excess ACTH may also result in hyperpigmentation
,This is due to Melanocyte-Stimulating Hormone production as a byproduct of ACTH synthesis from Pro-opiomelanocortin (POMC). Cortisol can also exhibit mineralcorticoid activity in high concentrations, worsening the hypertension and leading to hypokalemia
(common in ectopic ACTH secretion). Furthermore, gastrointestinal disturbances, opportunistic infections and impaired wound healing (cortisol is a stress hormone, so it depresses the immune and inflammatory responses). Osteoporosis
is also an issue in Cushing's syndrome since osteoblast activity is inhibited. Additionally, Cushing's may cause sore and aching joints, particularly in the hip, shoulders, and lower back.
The most common cause of Cushing's syndrome is exogenous administration of glucocorticoid
s prescribed by a health care practitioner to treat other diseases (called iatrogenic
Cushing's syndrome). This can be an effect of steroid treatment of a variety of disorders such as asthma
and rheumatoid arthritis
, or in immunosuppression
after an organ transplant. Administration of synthetic ACTH is also possible, but ACTH is less often prescribed due to cost and lesser utility. Although rare, Cushing's syndrome can also be due to the use of medroxyprogesterone
Endogenous Cushing's syndrome results from some derangement of the body's own system of secreting cortisol. Normally, ACTH is released from the pituitary gland
when necessary to stimulate the release of cortisol from the adrenal gland
s.
and thereby cause the total cortisol level to be elevated. However, the total free cortisol, which is the active hormone in the body, as measured by a 24 hour urine collection for urinary free cortisol, is normal.
is in the brain and the pituitary gland
sits just below it. The paraventricular nucleus (PVN) of the hypothalamus releases corticotropin-releasing hormone
(CRH), which stimulates the pituitary gland to release adrenocorticotropin (ACTH). ACTH travels via the blood to the adrenal gland, where it stimulates the release of cortisol
. Cortisol is secreted by the cortex of the adrenal gland
from a region called the zona fasciculata
in response to ACTH. Elevated levels of cortisol exert negative feedback
on the pituitary, which decreases the amount of ACTH released from the pituitary gland. Strictly, Cushing's syndrome refers to excess cortisol of any etiology. One of the causes of Cushing's syndrome is a cortisol secreting adenoma in the cortex of the adrenal gland. The adenoma causes cortisol levels in the blood to be very high, and negative feedback on the pituitary from the high cortisol levels causes ACTH levels to be very low. Cushing's disease refers only to hypercortisolism secondary to excess production of ACTH from a corticotrophic pituitary adenoma
. This causes the blood ACTH levels to be elevated along with cortisol from the adrenal gland. The ACTH levels remain high because a tumor causes the pituitary to be unresponsive to negative feedback from high cortisol levels.
Cushing's Syndrome was also the first autoimmune disease identified in humans.
(administration of dexamethasone and frequent determination of cortisol and ACTH level), or a 24-hour urinary measurement for cortisol offer equal detection rates. Dexamethasone is a glucocorticoid
and simulates the effects of cortisol, including negative feedback
on the pituitary gland
. When dexamethasone is administered and a blood sample is tested, high cortisol would be indicative of Cushing's syndrome because there is an ectopic source of cortisol or ACTH (e.g.: adrenal adenoma) that is not inhibited by the dexamethasone. A novel approach, recently cleared by the US FDA, is sampling cortisol in saliva
over 24 hours, which may be equally sensitive, as late night levels of salivary cortisol are high in Cushingoid patients. Other pituitary hormone levels may need to be ascertained. Performing a physical examination
to determine any visual field
defect may be necessary if a pituitary lesion is suspected, which may compress the optic chiasm
causing typical bitemporal hemianopia.
When any of these tests are positive, CT scanning of the adrenal gland and MRI of the pituitary gland
are performed to detect the presence of any adrenal or pituitary adenoma
s or incidentaloma
s (the incidental discovery of harmless lesions). Scintigraphy
of the adrenal gland with iodocholesterol scan is occasionally necessary. Very rarely, determining the ACTH levels in various veins in the body by venous catheterization, working towards the pituitary (petrosal sinus
sampling) is necessary.
U - Urinary free cortisol and glucose increase
S - Striae, Suppressed immunity
H - Hypercortisolism, Hypertension, Hyperglycemia, Hypercholesterolemia, Hirsutism
I - Iatrogenic (Increased administration of corticosteroids)
N - Noniatrogenic (Neoplasms)
G - Glucose intolerance, Growth retardation
If an adrenal adenoma
is identified it may be removed by surgery. An ACTH-secreting corticotrophic pituitary adenoma
should be removed after diagnosis. Regardless of the adenoma's location, most patients will require steroid replacement postoperatively at least in the interim as long-term suppression of pituitary ACTH and normal adrenal tissue does not recover immediately. Clearly, if both adrenals are removed, replacement with hydrocortisone or prednisolone
is imperative.
In those patients not suitable for or unwilling to undergo surgery, several drugs have been found to inhibit cortisol synthesis (e.g. ketoconazole
, metyrapone
) but they are of limited efficacy.
Removal of the adrenals in the absence of a known tumor is occasionally performed to eliminate the production of excess cortisol. In some occasions, this removes negative feedback from a previously occult pituitary adenoma, which starts growing rapidly and produces extreme levels of ACTH, leading to hyperpigmentation. This clinical situation is known as Nelson's syndrome
.
s) is the most common form of Cushing's syndrome. The incidence of pituitary tumors may be relatively high, as much as one in five people, but only a minute fraction are active and produce excessive hormones.
Adults with the disease may also have symptoms of extreme weight gain, excess hair growth in women, high blood pressure, and skin problems. In addition, they may show:
Cortisol
Cortisol is a steroid hormone, more specifically a glucocorticoid, produced by the adrenal gland. It is released in response to stress and a low level of blood glucocorticoids. Its primary functions are to increase blood sugar through gluconeogenesis; suppress the immune system; and aid in fat,...
in the blood. This can be caused by taking glucocorticoid
Glucocorticoid
Glucocorticoids are a class of steroid hormones that bind to the glucocorticoid receptor , which is present in almost every vertebrate animal cell...
drugs, or by tumors that produce cortisol or adrenocorticotropic hormone
Adrenocorticotropic hormone
Adrenocorticotropic hormone , also known as 'corticotropin', 'Adrenocorticotrophic hormone', is a polypeptide tropic hormone produced and secreted by the anterior pituitary gland. It is an important component of the hypothalamic-pituitary-adrenal axis and is often produced in response to biological...
(ACTH) or CRH
Cushing's disease
Cushing's disease
Cushing's disease is a cause of Cushing's Syndrome characterised by increased secretion of adrenocorticotropic hormone from the anterior pituitary. This is most often as a result of a pituitary adenoma...
refers to one specific cause of the syndrome: a tumor (adenoma
Adenoma
An adenoma is a benign tumor of glandular origin. Adenomas can grow from many organs including the colon, adrenal glands, pituitary gland, thyroid, prostate, etc. Although these growths are benign, over time they may progress to become malignant, at which point they are called adenocarcinomas...
) in the pituitary gland
Pituitary gland
In vertebrate anatomy the pituitary gland, or hypophysis, is an endocrine gland about the size of a pea and weighing 0.5 g , in humans. It is a protrusion off the bottom of the hypothalamus at the base of the brain, and rests in a small, bony cavity covered by a dural fold...
that produces large amounts of ACTH, which in turn elevates cortisol. It is the most common cause of Cushing's syndrome, responsible for 70% of cases excluding glucocorticoid related cases.
This pathology was described by Harvey Cushing
Harvey Cushing
Harvey Williams Cushing, M.D. , was an American neurosurgeon and a pioneer of brain surgery, and the first to describe Cushing's syndrome...
in 1932. The syndrome is also called Itsenko-Cushing syndrome, hyperadrenocorticism or hypercorticism
Cushing's syndrome is not confined to humans and is also a relatively common condition in domestic dogs and horses. It also occurs in cats, but rarely.
It should not be confused with Cushing's triad
Cushing's triad
Cushing's triad is a clinical triad variably defined as either hypertension, bradycardia, andirregular respiration , or less commonly as widened pulse pressure , irregular respiration, and bradycardia...
, a disease state resulting from increased intracranial pressure.
Signs and symptoms
Symptoms include rapid weight gainObesity
Obesity is a medical condition in which excess body fat has accumulated to the extent that it may have an adverse effect on health, leading to reduced life expectancy and/or increased health problems...
, particularly of the trunk and face with sparing of the limbs (central obesity
Central obesity
Abdominal obesity, colloquially known as belly fat or clinically as central obesity, is the accumulation of abdominal fat resulting in an increase in waist size...
). A common sign is the growth of fat pads along the collar bone and on the back of the neck (buffalo hump) and a round face often referred to as a "moon face
Moon face
Moon face, or moon facies, is a medical sign where the face swells up into a rounded shape.It is often associated with Cushing's syndrome or steroid treatment , which has led to it being known as Cushingoid facies or steroid facies respectively...
." Other symptoms include hyperhidrosis
Hyperhidrosis
Hyperhidrosis is the condition characterized by abnormally increased perspiration, in excess of that required for regulation of body temperature.-Classification:Hyperhidrosis can either be generalized or localized to specific parts of the body...
(excess sweating), telangiectasia
Telangiectasia
Telangiectasias /tɛ.læn.dʒiː'ɛk.teɪ.ʃi:ə/ are small dilated blood vessels near the surface of the skin or mucous membranes, measuring between 0.5 and 1 millimeter in diameter. They can develop anywhere on the body but are commonly seen on the face around the nose, cheeks, and chin...
(dilation of capillaries), thinning of the skin (which causes easy bruising and dryness, particularly the hands) and other mucous membranes, purple or red striae (the weight gain in Cushing's syndrome stretches the skin, which is thin and weakened, causing it to hemorrhage) on the trunk, buttocks, arms, legs or breasts, proximal muscle weakness (hips, shoulders), and hirsutism
Hirsutism
Hirsutism or frazonism is the excessive hairiness on women in those parts of the body where terminal hair does not normally occur or is minimal - for example, a beard or chest hair. It refers to a male pattern of body hair and it is therefore primarily of cosmetic and psychological concern...
(facial male-pattern hair growth), baldness
Baldness
Baldness implies partial or complete lack of hair and can be understood as part of the wider topic of "hair thinning". The degree and pattern of baldness can vary greatly, but its most common cause is male and female pattern baldness, also known as androgenic alopecia, alopecia androgenetica or...
and/or cause hair to become extremely dry and brittle. In rare cases, Cushing's can cause hypercalcemia, which can lead to skin necrosis. The excess cortisol may also affect other endocrine systems and cause, for example, insomnia
Insomnia
Insomnia is most often defined by an individual's report of sleeping difficulties. While the term is sometimes used in sleep literature to describe a disorder demonstrated by polysomnographic evidence of disturbed sleep, insomnia is often defined as a positive response to either of two questions:...
, inhibited aromatase
Aromatase
Aromatase is an enzyme responsible for a key step in the biosynthesis of estrogens. It is a member of the cytochrome P450 superfamily , which are monooxygenases that catalyze many reactions involved in steroidogenesis. In particular, aromatase is responsible for the aromatization of androgens into...
, reduced libido
Libido
Libido refers to a person's sex drive or desire for sexual activity. The desire for sex is an aspect of a person's sexuality, but varies enormously from one person to another, and it also varies depending on circumstances at a particular time. A person who has extremely frequent or a suddenly...
, impotence, amenorrhoea
Amenorrhoea
Amenorrhoea , amenorrhea , or amenorrhœa, is the absence of a menstrual period in a woman of reproductive age. Physiological states of amenorrhoea are seen during pregnancy and lactation , the latter also forming the basis of a form of contraception known as the lactational amenorrhoea method...
/oligomenorrhea
Oligomenorrhea
Oligomenorrhea is infrequent menstruation. More strictly, it is menstrual periods occurring at intervals of greater than 35 days, with only four to nine periods in a year. Also, menstrual periods should have been regularly established previously before the development of infrequent flow...
and infertility
Infertility
Infertility primarily refers to the biological inability of a person to contribute to conception. Infertility may also refer to the state of a woman who is unable to carry a pregnancy to full term...
due to elevations in androgens. Patients frequently suffer various psychological disturbances, ranging from euphoria
Euphoria (emotion)
Euphoria is medically recognized as a mental and emotional condition in which a person experiences intense feelings of well-being, elation, happiness, ecstasy, excitement and joy...
to psychosis
Psychosis
Psychosis means abnormal condition of the mind, and is a generic psychiatric term for a mental state often described as involving a "loss of contact with reality"...
. Depression
Clinical depression
Major depressive disorder is a mental disorder characterized by an all-encompassing low mood accompanied by low self-esteem, and by loss of interest or pleasure in normally enjoyable activities...
and anxiety
Anxiety
Anxiety is a psychological and physiological state characterized by somatic, emotional, cognitive, and behavioral components. The root meaning of the word anxiety is 'to vex or trouble'; in either presence or absence of psychological stress, anxiety can create feelings of fear, worry, uneasiness,...
are also common.
Other striking and distressing skin changes that may appear in Cushing's syndrome include facial acne, susceptibility to superficial dermatophyte
Dermatophyte
Dermatophytes are a common label for a group of three types of fungus that commonly causes skin disease in animals and humans. These anamorphic genera are: Microsporum, Epidermophyton and Trichophyton. There are about 40 species in these three genera...
and malassezia infections, and the characteristic purplish, atrophic striae on the abdomen.
Other signs include polyuria
Polyuria
Polyuria is a condition usually defined as excessive or abnormally large production or passage of urine . Frequent urination is sometimes included by definition, but is nonetheless usually an accompanying symptom...
(and accompanying polydipsia
Polydipsia
Polydipsia is a medical symptom in which the patient displays excessive thirst. The word derives from the Greek πολυδιψία, which is derived from πολύς + δίψα...
), persistent hypertension
Hypertension
Hypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. What that means is that the heart is having to work harder than it should to pump the blood around the body. Blood pressure involves two measurements, systolic and...
(due to cortisol's enhancement of epinephrine
Epinephrine
Epinephrine is a hormone and a neurotransmitter. It increases heart rate, constricts blood vessels, dilates air passages and participates in the fight-or-flight response of the sympathetic nervous system. In chemical terms, adrenaline is one of a group of monoamines called the catecholamines...
's vasoconstrictive effect) and insulin resistance
Insulin resistance
Insulin resistance is a physiological condition where the natural hormone insulin becomes less effective at lowering blood sugars. The resulting increase in blood glucose may raise levels outside the normal range and cause adverse health effects, depending on dietary conditions. Certain cell types...
(especially common in ectopic ACTH production), leading to hyperglycemia
Hyperglycemia
Hyperglycemia or Hyperglycæmia, or high blood sugar, is a condition in which an excessive amount of glucose circulates in the blood plasma. This is generally a glucose level higher than 13.5mmol/l , but symptoms may not start to become noticeable until even higher values such as 15-20 mmol/l...
(high blood sugar
Blood sugar
The blood sugar concentration or blood glucose level is the amount of glucose present in the blood of a human or animal. Normally in mammals, the body maintains the blood glucose level at a reference range between about 3.6 and 5.8 mM , or 64.8 and 104.4 mg/dL...
) and insulin resistance which can lead to diabetes mellitus
Diabetes mellitus
Diabetes mellitus, often simply referred to as diabetes, is a group of metabolic diseases in which a person has high blood sugar, either because the body does not produce enough insulin, or because cells do not respond to the insulin that is produced...
. Insulin resistance is accompanied by skin changes such as acanthosis nigricans
Acanthosis nigricans
Acanthosis nigricans is a brown to black, poorly defined, velvety hyperpigmentation of the skin. It is usually found in body folds, such as the posterior and lateral folds of the neck, the axilla, groin, umbilicus, forehead, and other areas.-Causes:...
in the axilla and around the neck, as well as skin tags in the axilla. Untreated Cushing's syndrome can lead to heart disease
Heart disease
Heart disease, cardiac disease or cardiopathy is an umbrella term for a variety of diseases affecting the heart. , it is the leading cause of death in the United States, England, Canada and Wales, accounting for 25.4% of the total deaths in the United States.-Types:-Coronary heart disease:Coronary...
and increased mortality
Death
Death is the permanent termination of the biological functions that sustain a living organism. Phenomena which commonly bring about death include old age, predation, malnutrition, disease, and accidents or trauma resulting in terminal injury....
. Cushing's syndrome due to excess ACTH may also result in hyperpigmentation
Hyperpigmentation
In dermatology, hyperpigmentation is the darkening of an area of skin or nails caused by increased melanin.-Causes:Hyperpigmentation may be caused by sun damage, inflammation, or other skin injuries, including those related to acne vulgaris...
,This is due to Melanocyte-Stimulating Hormone production as a byproduct of ACTH synthesis from Pro-opiomelanocortin (POMC). Cortisol can also exhibit mineralcorticoid activity in high concentrations, worsening the hypertension and leading to hypokalemia
Hypokalemia
Hypokalemia or hypokalaemia , also hypopotassemia or hypopotassaemia , refers to the condition in which the concentration of potassium in the blood is low...
(common in ectopic ACTH secretion). Furthermore, gastrointestinal disturbances, opportunistic infections and impaired wound healing (cortisol is a stress hormone, so it depresses the immune and inflammatory responses). Osteoporosis
Osteoporosis
Osteoporosis is a disease of bones that leads to an increased risk of fracture. In osteoporosis the bone mineral density is reduced, bone microarchitecture is deteriorating, and the amount and variety of proteins in bone is altered...
is also an issue in Cushing's syndrome since osteoblast activity is inhibited. Additionally, Cushing's may cause sore and aching joints, particularly in the hip, shoulders, and lower back.
Exogenous vs. endogenous
Hormones that come from outside the body are called exogenous; hormones that come from within the body are called endogenous.The most common cause of Cushing's syndrome is exogenous administration of glucocorticoid
Glucocorticoid
Glucocorticoids are a class of steroid hormones that bind to the glucocorticoid receptor , which is present in almost every vertebrate animal cell...
s prescribed by a health care practitioner to treat other diseases (called iatrogenic
Iatrogenesis
Iatrogenesis, or an iatrogenic artifact is an inadvertent adverse effect or complication resulting from medical treatment or advice, including that of psychologists, therapists, pharmacists, nurses, physicians and dentists...
Cushing's syndrome). This can be an effect of steroid treatment of a variety of disorders such as asthma
Asthma
Asthma is the common chronic inflammatory disease of the airways characterized by variable and recurring symptoms, reversible airflow obstruction, and bronchospasm. Symptoms include wheezing, coughing, chest tightness, and shortness of breath...
and rheumatoid arthritis
Rheumatoid arthritis
Rheumatoid arthritis is a chronic, systemic inflammatory disorder that may affect many tissues and organs, but principally attacks synovial joints. The process produces an inflammatory response of the synovium secondary to hyperplasia of synovial cells, excess synovial fluid, and the development...
, or in immunosuppression
Immunosuppression
Immunosuppression involves an act that reduces the activation or efficacy of the immune system. Some portions of the immune system itself have immuno-suppressive effects on other parts of the immune system, and immunosuppression may occur as an adverse reaction to treatment of other...
after an organ transplant. Administration of synthetic ACTH is also possible, but ACTH is less often prescribed due to cost and lesser utility. Although rare, Cushing's syndrome can also be due to the use of medroxyprogesterone
Endogenous Cushing's syndrome results from some derangement of the body's own system of secreting cortisol. Normally, ACTH is released from the pituitary gland
Pituitary gland
In vertebrate anatomy the pituitary gland, or hypophysis, is an endocrine gland about the size of a pea and weighing 0.5 g , in humans. It is a protrusion off the bottom of the hypothalamus at the base of the brain, and rests in a small, bony cavity covered by a dural fold...
when necessary to stimulate the release of cortisol from the adrenal gland
Adrenal gland
In mammals, the adrenal glands are endocrine glands that sit atop the kidneys; in humans, the right suprarenal gland is triangular shaped, while the left suprarenal gland is semilunar shaped...
s.
- In pituitary Cushing's, a benign pituitary adenoma secretes ACTH. This is also known as Cushing's disease and is responsible for 70% of endogenous Cushing's syndrome.
- In adrenal Cushing's, excess cortisol is produced by adrenal gland tumors, hyperplastic adrenal glands, or adrenal glands with nodular adrenal hyperplasia.
- Finally, tumors outside the normal pituitary-adrenal system can produce ACTH that affects the adrenal glands. This final etiology is called ectopic or paraneoplastic Cushing's disease and is seen in diseases like small cellSmall cell carcinomaSmall cell carcinoma is a type of highly malignant cancer that most commonly arises within the lung, although it can occasionally arise in other body sites, such as the cervix and prostate....
lung cancerLung cancerLung cancer is a disease characterized by uncontrolled cell growth in tissues of the lung. If left untreated, this growth can spread beyond the lung in a process called metastasis into nearby tissue and, eventually, into other parts of the body. Most cancers that start in lung, known as primary...
.
Pseudo-cushing's syndrome
Elevated levels of total cortisol can also be due to estrogen found in oral contraceptive pills that contain a mixture of estrogen and progesterone. Estrogen can cause an increase of cortisol-binding globulinTranscortin
Transcortin, also corticosteroid-binding globulin or CBG, is officially called serpin peptidase inhibitor, clade A , member 6.It is an alpha-globulin.-Binding:...
and thereby cause the total cortisol level to be elevated. However, the total free cortisol, which is the active hormone in the body, as measured by a 24 hour urine collection for urinary free cortisol, is normal.
Pathophysiology
The hypothalamusHypothalamus
The Hypothalamus is a portion of the brain that contains a number of small nuclei with a variety of functions...
is in the brain and the pituitary gland
Pituitary gland
In vertebrate anatomy the pituitary gland, or hypophysis, is an endocrine gland about the size of a pea and weighing 0.5 g , in humans. It is a protrusion off the bottom of the hypothalamus at the base of the brain, and rests in a small, bony cavity covered by a dural fold...
sits just below it. The paraventricular nucleus (PVN) of the hypothalamus releases corticotropin-releasing hormone
Corticotropin-releasing hormone
Corticotropin-releasing hormone , originally named corticotropin-releasing factor , and also called corticoliberin, is a polypeptide hormone and neurotransmitter involved in the stress response...
(CRH), which stimulates the pituitary gland to release adrenocorticotropin (ACTH). ACTH travels via the blood to the adrenal gland, where it stimulates the release of cortisol
Cortisol
Cortisol is a steroid hormone, more specifically a glucocorticoid, produced by the adrenal gland. It is released in response to stress and a low level of blood glucocorticoids. Its primary functions are to increase blood sugar through gluconeogenesis; suppress the immune system; and aid in fat,...
. Cortisol is secreted by the cortex of the adrenal gland
Adrenal gland
In mammals, the adrenal glands are endocrine glands that sit atop the kidneys; in humans, the right suprarenal gland is triangular shaped, while the left suprarenal gland is semilunar shaped...
from a region called the zona fasciculata
Zona fasciculata
The zona fasciculata constitutes the middle zone of the adrenal cortex, sitting directly beneath the zona glomerulosa. Constituent cells are organized into bundles or "fascicles"....
in response to ACTH. Elevated levels of cortisol exert negative feedback
Negative feedback
Negative feedback occurs when the output of a system acts to oppose changes to the input of the system, with the result that the changes are attenuated. If the overall feedback of the system is negative, then the system will tend to be stable.- Overview :...
on the pituitary, which decreases the amount of ACTH released from the pituitary gland. Strictly, Cushing's syndrome refers to excess cortisol of any etiology. One of the causes of Cushing's syndrome is a cortisol secreting adenoma in the cortex of the adrenal gland. The adenoma causes cortisol levels in the blood to be very high, and negative feedback on the pituitary from the high cortisol levels causes ACTH levels to be very low. Cushing's disease refers only to hypercortisolism secondary to excess production of ACTH from a corticotrophic pituitary adenoma
Pituitary adenoma
Pituitary adenomas are tumors that occur in the pituitary gland, and account for about 15% of intracranial neoplasms. Tumors which exceed 10 mm in size are defined as macroadenomas, and those smaller than 10 mm are referred to as microadenomas...
. This causes the blood ACTH levels to be elevated along with cortisol from the adrenal gland. The ACTH levels remain high because a tumor causes the pituitary to be unresponsive to negative feedback from high cortisol levels.
Cushing's Syndrome was also the first autoimmune disease identified in humans.
Diagnosis
When Cushing's syndrome is suspected, either a dexamethasone suppression testDexamethasone suppression test
The dexamethasone suppression test is designed to diagnose and differentiate among the various types of Cushing's syndrome and other hypercortisol states.It has also been used in the research of depression.-Physiology:...
(administration of dexamethasone and frequent determination of cortisol and ACTH level), or a 24-hour urinary measurement for cortisol offer equal detection rates. Dexamethasone is a glucocorticoid
Glucocorticoid
Glucocorticoids are a class of steroid hormones that bind to the glucocorticoid receptor , which is present in almost every vertebrate animal cell...
and simulates the effects of cortisol, including negative feedback
Negative feedback
Negative feedback occurs when the output of a system acts to oppose changes to the input of the system, with the result that the changes are attenuated. If the overall feedback of the system is negative, then the system will tend to be stable.- Overview :...
on the pituitary gland
Pituitary gland
In vertebrate anatomy the pituitary gland, or hypophysis, is an endocrine gland about the size of a pea and weighing 0.5 g , in humans. It is a protrusion off the bottom of the hypothalamus at the base of the brain, and rests in a small, bony cavity covered by a dural fold...
. When dexamethasone is administered and a blood sample is tested, high cortisol would be indicative of Cushing's syndrome because there is an ectopic source of cortisol or ACTH (e.g.: adrenal adenoma) that is not inhibited by the dexamethasone. A novel approach, recently cleared by the US FDA, is sampling cortisol in saliva
Saliva
Saliva , referred to in various contexts as spit, spittle, drivel, drool, or slobber, is the watery substance produced in the mouths of humans and most other animals. Saliva is a component of oral fluid. In mammals, saliva is produced in and secreted from the three pairs of major salivary glands,...
over 24 hours, which may be equally sensitive, as late night levels of salivary cortisol are high in Cushingoid patients. Other pituitary hormone levels may need to be ascertained. Performing a physical examination
Physical examination
Physical examination or clinical examination is the process by which a doctor investigates the body of a patient for signs of disease. It generally follows the taking of the medical history — an account of the symptoms as experienced by the patient...
to determine any visual field
Visual field
The term visual field is sometimes used as a synonym to field of view, though they do not designate the same thing. The visual field is the "spatial array of visual sensations available to observation in introspectionist psychological experiments", while 'field of view' "refers to the physical...
defect may be necessary if a pituitary lesion is suspected, which may compress the optic chiasm
Optic chiasm
The optic chiasm or optic chiasma is the part of the brain where the optic nerves partially cross...
causing typical bitemporal hemianopia.
When any of these tests are positive, CT scanning of the adrenal gland and MRI of the pituitary gland
Pituitary gland
In vertebrate anatomy the pituitary gland, or hypophysis, is an endocrine gland about the size of a pea and weighing 0.5 g , in humans. It is a protrusion off the bottom of the hypothalamus at the base of the brain, and rests in a small, bony cavity covered by a dural fold...
are performed to detect the presence of any adrenal or pituitary adenoma
Adenoma
An adenoma is a benign tumor of glandular origin. Adenomas can grow from many organs including the colon, adrenal glands, pituitary gland, thyroid, prostate, etc. Although these growths are benign, over time they may progress to become malignant, at which point they are called adenocarcinomas...
s or incidentaloma
Incidentaloma
In medicine, an incidentaloma is a tumor found by coincidence without clinical symptoms or suspicion. It is a common problem: up to 7% of all patients over 60 may harbor a benign growth, often of the adrenal gland, which is detected when diagnostic imaging is used for the analysis of unrelated...
s (the incidental discovery of harmless lesions). Scintigraphy
Scintigraphy
Scintigraphy is a form of diagnostic test used in nuclear medicine, wherein radioisotopes are taken internally, and the emitted radiation is captured by external detectors to form two-dimensional images...
of the adrenal gland with iodocholesterol scan is occasionally necessary. Very rarely, determining the ACTH levels in various veins in the body by venous catheterization, working towards the pituitary (petrosal sinus
Inferior petrosal sinus
The inferior petrosal sinuses, within the human head, are beneath the brain and allow blood to drain from the center of the head.They drain on either side inferiorly from the cavernous sinus and join with the sigmoid sinus to form the internal jugular vein, which continues inferiorly to drain...
sampling) is necessary.
Mnemonic
C - Central obesity, Cervical fat pads, Collagen fibre weakness, Comedones (acne)U - Urinary free cortisol and glucose increase
S - Striae, Suppressed immunity
H - Hypercortisolism, Hypertension, Hyperglycemia, Hypercholesterolemia, Hirsutism
I - Iatrogenic (Increased administration of corticosteroids)
N - Noniatrogenic (Neoplasms)
G - Glucose intolerance, Growth retardation
Treatment
Most Cushing's syndrome cases are caused by steroid medications (iatrogenic). Consequently, most patients are effectively treated by carefully tapering off (and eventually stopping) the medication that causes the symptoms.If an adrenal adenoma
Adenoma
An adenoma is a benign tumor of glandular origin. Adenomas can grow from many organs including the colon, adrenal glands, pituitary gland, thyroid, prostate, etc. Although these growths are benign, over time they may progress to become malignant, at which point they are called adenocarcinomas...
is identified it may be removed by surgery. An ACTH-secreting corticotrophic pituitary adenoma
Pituitary adenoma
Pituitary adenomas are tumors that occur in the pituitary gland, and account for about 15% of intracranial neoplasms. Tumors which exceed 10 mm in size are defined as macroadenomas, and those smaller than 10 mm are referred to as microadenomas...
should be removed after diagnosis. Regardless of the adenoma's location, most patients will require steroid replacement postoperatively at least in the interim as long-term suppression of pituitary ACTH and normal adrenal tissue does not recover immediately. Clearly, if both adrenals are removed, replacement with hydrocortisone or prednisolone
Prednisolone
Prednisolone is the active metabolite of prednisone, which is also used as a drug.-Uses:Prednisolone is a corticosteroid drug with predominant glucocorticoid and low mineralocorticoid activity, making it useful for the treatment of a wide range of inflammatory and auto-immune conditions such as...
is imperative.
In those patients not suitable for or unwilling to undergo surgery, several drugs have been found to inhibit cortisol synthesis (e.g. ketoconazole
Ketoconazole
Ketoconazole is a synthetic antifungal drug used to prevent and treat fungal skin infections, especially in immunocompromised patients such as those with AIDS or those on chemotherapy. Ketoconazole is sold commercially as an anti-dandruff shampoo, topical cream, and oral tablet.Ketoconazole is...
, metyrapone
Metyrapone
Metyrapone is a drug used in the diagnosis of adrenal insufficiency and occasionally in the treatment of Cushing's syndrome .-Mechanism:...
) but they are of limited efficacy.
Removal of the adrenals in the absence of a known tumor is occasionally performed to eliminate the production of excess cortisol. In some occasions, this removes negative feedback from a previously occult pituitary adenoma, which starts growing rapidly and produces extreme levels of ACTH, leading to hyperpigmentation. This clinical situation is known as Nelson's syndrome
Nelson's syndrome
Nelson's syndrome is the rapid enlargement of a pituitary adenoma that occurs after the removal of both adrenal glands.-Pathophysiology:Removal of both adrenal glands, or bilateral adrenalectomy, is an operation for Cushing's syndrome...
.
Epidemiology
Iatrogenic Cushing's syndrome (caused by treatment with corticosteroidCorticosteroid
Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex. Corticosteroids are involved in a wide range of physiologic systems such as stress response, immune response and regulation of inflammation, carbohydrate metabolism, protein catabolism, blood electrolyte...
s) is the most common form of Cushing's syndrome. The incidence of pituitary tumors may be relatively high, as much as one in five people, but only a minute fraction are active and produce excessive hormones.
Adults with the disease may also have symptoms of extreme weight gain, excess hair growth in women, high blood pressure, and skin problems. In addition, they may show:
- muscle and bone weakness
- osteoporosisOsteoporosisOsteoporosis is a disease of bones that leads to an increased risk of fracture. In osteoporosis the bone mineral density is reduced, bone microarchitecture is deteriorating, and the amount and variety of proteins in bone is altered...
- diabetes mellitusDiabetes mellitusDiabetes mellitus, often simply referred to as diabetes, is a group of metabolic diseases in which a person has high blood sugar, either because the body does not produce enough insulin, or because cells do not respond to the insulin that is produced...
- hypertensionHypertensionHypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. What that means is that the heart is having to work harder than it should to pump the blood around the body. Blood pressure involves two measurements, systolic and...
- moodiness, irritability, or depression
- sleep disturbances
- menstrual disorders such as amenorrhea in women and decreased fertility in men
- baldnessBaldnessBaldness implies partial or complete lack of hair and can be understood as part of the wider topic of "hair thinning". The degree and pattern of baldness can vary greatly, but its most common cause is male and female pattern baldness, also known as androgenic alopecia, alopecia androgenetica or...
- hypercholesterolemiaHypercholesterolemiaHypercholesterolemia is the presence of high levels of cholesterol in the blood. It is not a disease but a metabolic derangement that can be caused by many diseases, notably cardiovascular disease...