Cushing's syndrome

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Furqan M M. M.B.B.S[2]

Cushing’s Syndrome is an endocrine disorder caused by high levels of cortisol in the blood from a variety of causes, including primary pituitary adenoma (known as Cushing’s disease), primary adrenal hyperplasia or neoplasia, ectopic ACTH production (e.g., from a small cell lung cancer), and iatrogenic (steroid use). Cushing’s syndrome was first identified by Dr. Harvey Cushing (an American physician, surgeon, and endocrinologist) in 1932 as a polyglandular disorder. It was later named as Cushing’s syndrome. Normally, cortisol is released from the adrenal gland in response to ACTH being released from the pituitary gland. Both Cushing’s syndrome and Cushing’s disease are characterized by elevated levels of cortisol in the blood, but the cause of elevated cortisol differs between the two. Cushing’s disease specifically refers to a tumor in the pituitary gland that stimulates the excessive release of cortisol from the adrenal gland by releasing large amounts of ACTH. In Cushing’s disease, ACTH levels do not respond to negative feedback from the high levels of cortisol. Cushing’s disease is particularly common in females. Annually, there are around 2–5 new cases per million people worldwide. Common risk factors in the development of Cushing’s disease are female gender and genetic factors. Symptoms of Cushing’s syndrome include rapid weight gain, particularly of the trunk and face with sparing of the limbs (central obesity), a round face often referred to as a “moon face“, excessive sweating, insomnia, reduced libido, impotence, amenorrhea, infertility and psychological disturbances, ranging from euphoria to psychosis. Depression and anxiety. Cushing’s syndrome may progress to develop amenorrhoea, infertility, and psychological disturbances. If left untreated, patients with Cushing’s syndrome may progress to develop diabetes, cardiovascular and psychiatric complications. The prognosis depends on the severity of the disease. When Cushing’s is suspected, either a dexamethasone suppression test (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. 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. CT scan of the adrenal gland is performed to detect the presence of the adrenal adenoma and the cause of ectopic ACTH. CT scan is preferred over MRI in these cases. MRI of the pituitary gland is performed to detect the presence of the pituitary adenoma. The medications usually used for the treatment of Cushing’s syndrome are Pasireotide, Cabergoline, Ketoconazole, and Metyrapone. The choice of medical therapy should be individualized. It is guided by drug efficacy, side effects, individual patient factors, and cost. If an adrenal adenoma is identified it may be removed by either laparoscopic or open adrenalectomy. 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.

Cushing’s syndrome was first identified by Dr. Harvey Cushing (an American physician, surgeon, and endocrinologist) in 1932 as a polyglandular disorder. It was later named as Cushing’s syndrome.

Cushing’s syndrome may be classified according to the source of cortisol into four subtypes; Endogenous, exogenous, familial Cushing’s Syndrome, and pseudo-Cushing’s syndrome.

Both the hypothalamus and the pituitary gland are part of the brain. The hypothalamus releases corticotropin-releasing hormone (CRH), which stimulates the pituitary gland to release corticotropin (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 due to 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 corticotropic [[[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. Cortisol can also exhibit mineralocorticoid activity in high concentrations, causing worsening of hypertension and hypokalemia (common in ectopic ACTH secretion).

Cushing’s syndrome occurs when the body is exposed to high levels of corticosteroids for a long period of time. Many people develop Cushing’s syndrome because they take glucocorticoids, (steroid hormones that are chemically similar to naturally produced cortisol) such as prednisone for asthma, rheumatoid arthritis, lupus, and other inflammatory diseases. Glucocorticoids are also used to suppress the immune system after transplantation to keep the body from rejecting the new organ or tissue. Other people may develop Cushing’s syndrome as a result of excessive cortisol production due to adrenal or extra-adrenal causes.

Cushing’s syndrome must be differentiated from other diseases that cause hypertension, obesity, and hyperandrogenism, such as metabolic syndrome X and pseudo-Cushing’s syndrome.

Cushing’s disease is particularly common in females. Annually, there are around 2–5 new cases per million people worldwide.

Common risk factors in the development of Cushing’s disease are female gender and genetic factors.

There is insufficient evidence to recommend routine screening for Cushing’s syndrome.

Cushing’s disease may present initially as rapid weight gain, a round face often referred to as a “moon face“, and insomnia. It may progress to amenorrhoea, infertility, and psychological disturbances. If left untreated, patients with Cushing’s syndrome may develop diabetes, cardiovascular and psychiatric complications. The prognosis depends on the severity of the disease.

Symptoms of Cushing’s syndrome include rapid weight gain, particularly of the trunk and face with sparing of the limbs (central obesity), a round face also known as a “moon face“, excessive sweating, insomnia, reduced libido, impotence, amenorrhea, infertility and psychological disturbances, ranging from euphoria to psychosis and may also include depression and anxiety.

Patients with Cushing’s syndrome usually appear obese. Physical examination of patients with Cushing’s syndrome is remarkable for moon-like faces, easy bruising, purple skin stria, and hirsutism.

When Cushing’s disease is suspected, either a dexamethasone suppression test (administration of dexamethasone and frequent determination of cortisol and ACTH level) or a 24-hour urinary measurement of cortisol may be used for detection. 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. 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 also need to be ascertained.

There are no electrocardiogram findings associated with Cushing’s syndrome.

AnX-Ray may be helpful to identify the causes of ectopic ACTH in Cushing’s syndrome such as lung carcinoma, bronchial carcinoid, and thymic carcinoid.

CT scan of the adrenal gland is performed to detect the presence of the adrenal adenoma and the cause of ectopic ACTH. CT scan is preferred over MRI in these cases.

MRI of the pituitary gland is performed to detect the presence of the pituitary adenoma.

There are no electrocardiography or ultrasound findings associated with Cushing’s disease.

Scintigraphy of the adrenal gland with iodocholesterol scan is occasionally necessary.

The medications usually used for the treatment of Cushing’s syndrome are pasireotide, cabergoline, ketoconazole, and metyrapone. The choice of medical therapy should be individualized. It is guided by drug efficacy, side effects, individual patient factors, and cost.

If an adrenal adenoma is identified, it may be removed by either laparoscopic or open adrenalectomy. An ACTH-secreting corticotropic 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. If both adrenals are removed, replacement with hydrocortisone or prednisolone is imperative.

There are no primary preventive measures available for Cushing’s syndrome.

There are no secondary preventive measures available for Cushing’s syndrome.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Furqan M M. M.B.B.S[2] Mohamad Alkateb, MBBCh [3]

Cushing’s syndrome was first identified by Dr. Harvey Cushing (an American physician, surgeon, and endocrinologist) in 1932 as a polyglandular disorder. It was later named as Cushing’s syndrome.

• In 1924, the Soviet neurologist Nikolai Mikhailovich Itsenko reported two patients with pituitary adenoma. The resulting excessive adrenocorticotropic hormone secretion led to the production of large amounts of cortisol by the adrenal glands.
• The disease associated with this increased secretion of cortisol was described by Harvey Cushing in 1932, after Cushing was presented with a unique case of the disease.
• In 1910, the American neurosurgeon Harvey Cushing (1869-1939) was presented with a case of a 23-year-old woman called Minnie G whose symptoms included painful obesity, amenorrhea, hypertrichosis (abnormal hair growth), underdevelopment of secondary sexual characteristics, hydrocephalus and cerebral tension.^[1][2]
• This combination of symptoms was not yet described as any medical disorder at that time.^[1] However, Cushing was confident that Minnie’s symptoms were due to dysfunction of the pituitary gland, and resembled those associated with an adrenal tumor.
• He introduced the term “pluriglandular syndrome” to describe this disorder. This was later identified as Cushing’s syndrome.^[3] Given this conviction, and his knowledge of the three anterior pituitary cell types, Cushing hypothesized that if acidophil hyperpituitarism (excess secretion from the acidophil cells) caused acromegaly, then an excess of basophil cells must be involved in another pituitary disorder that involves sexual dysfunction (amenorrhea in females and erectile dysfunction in males) and could explain Minnie’s symptoms.^[1] Experimental evidence and case reports by Cushing led to his publication in 1932 on pituitary basophilism as the cause of Cushing’s disease. In this publication, the clinical symptoms of the disease, named after Harvey Cushing, were described.^[4][5]
• Out of the 12 cases with hypercortisolism described in Cushing’s monograph on the pituitary body, 67% died within a few years after symptom presentation, whereas Minnie G. survived for more than 40 years after symptom presentation, despite the fact that she did not receive any treatments for a pituitary tumor.^[1] The prolonged survival led to the uniqueness of Minnie’s case. The reason behind this survival remains a mystery since an autopsy of Minnie was refused after her death.^[1] However, the most likely explanation, proposed by J. Aidan Carney and based on statistical evidence, was that the basophil adenoma Minnie might have harbored underwent partial infarction, leading to symptom regression.^[1] The other hypothesis was that Minnie might have suffered from Primary Pigmented Nodular Adrenocortical Disease (PPNAD), which when associated with Cushing’s syndrome (Carney complex) can infrequently cause spontaneous symptom regression of the latter.^[1]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Mohamad Alkateb, MBBCh [2] Furqan M M. M.B.B.S[3]

Cushing’s syndrome may be classified according to the source of cortisol into four subtypes; Endogenous, exogenous, familial Cushing’s Syndrome, and pseudo-Cushing’s syndrome.

Cushing’s syndrome is classified into two main subtypes:^[1][2][3]

• Exogenous:

• Also called iatrogenic Cushing’s syndrome. It is due to chronic glucocorticoid intake for inflammatory conditions, such as allergies, asthma, autoimmune diseases, and after organ transplantation.

• Endogenous:

• Benign tumors:

• Pituitary adenoma
• Adrenal adenoma
• Adrenal micronodular hyperplasia
• Ectopic adenomas, which are originated from locations other than the pituitary or adrenal glands, mostly from the lungs, pancreas, thyroid, or thymus.

• Malignant tumors:

• Adrenal cancer
• Cancer in places other than the pituitary or adrenal glands, mostly in the lungs, pancreas, thyroid, or thymus

• Familial Cushing’s Syndrome:

• Patients with rare genetic diseases like multiple endocrine neoplasia type 1 (MEN 1) and primary pigmented micronodular adrenal disease are more susceptible to develop tumors in glands that affect cortisol secretion. As a result, these patients will develop Cushing’s syndrome.

• Pseudo-Cushing’s Syndrome:

• It is due to alcoholism, depression or other psychiatric disorders, obesity, pregnancy, and poorly controlled diabetes.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Furqan M M. M.B.B.S[2]

Both the hypothalamus and the pituitary gland are part of the brain. The hypothalamus releases corticotropin-releasing hormone (CRH), which stimulates the pituitary gland to release adrenocorticotropic hormone (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 corticotroph 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. Cortisol can also exhibit mineralocorticoid activity in high concentrations, worsening hypertension and leading to hypokalemia (common in ectopic ACTH secretion).

The secretion of cortisol is controlled by hypothalamic-pituitary axis by the following mechanism:^[1][2]

• Paraventricular nuclei in the hypothalamus release corticotropin releasing hormone (CRH).
• CRH is transferred to anterior pituitary via the portal veins.
• CRH stimulates the activity of corticotrophs; cells that produce proopiomelanocortin (POMC) in the anterior pituitary.
• Corticotrophs produce adrenocorticotropic hormone (ACTH) by the post-translational modification of POMC.
• ACTH is drained into systemic circulation via the pituitary capillaries and stimulates the adrenal cortex (zona fasciculata) to produce cortisol.
• Cortisol acts on hypothalamus and pituitary through a feedback mechanism to regulate the secretion of CRH and ACTH.

The pathophysiology of Cushing’s syndrome is linked to hypercortisolism which can develop by excess ACTH secretion or excess cortisol secretion by adrenal glands. The underlying mechanisms are usually genetic mutations or overexpression of proteins.^{[1][2][3][4][5]}

1. Excess ACTH secretion
   • The excess ACTH secretion can be due to the pituitary adenoma or ectopic (non-pituitary) ACTH secretion. ACTH stimulates the adrenal cortex to release cortisol and is not regulated by the feedback mechanism.
     1. Pituitary adenoma: Various gene mutations are involved in the development of pituitary adenoma commonly USP8, MEN1, CDKIs, and CDKN1B/p27Kip1. Many proteins are also overexpressed like Brg1, HDAC2, TR4, PTTG, and EGFR. It is the most important cause of ACTH-dependent cushing’s syndrome and is also called cushing’s disease. It is considered that the corticotroph tumors are resistant to glucocorticoid negative feedback inhibition which results in the pathological adrenal cortisol secretion.
     2. Ectopic ACTH secretion: The molecular defects in the neuroendocrine tumors leading to ectopic ACTH secretion from gastroenteropancreatic tumors are largely unknown. Germline menin mutations or RET oncogene mutations in multiple endocrine neoplasias (MEN) may be responsible. Ectopic secretion of ACTH can be seen as a manifestation of the paraneoplastic syndrome in small cell lung carcinoma and carcinoid tumors(bronchial and thymus).
2. Excess secretion of cortisol by adrenal gland
   • Excess secretion of the cortisol by the adrenal gland is due to the adrenal causes independent of ACTH secretion.
     1. Benign Adrenocortical adenoma: Common defects leading to adrenocortical adenoma are mutations or activation of the cAMP-dependent or β-catenin signaling pathways and aberrant expression and function of various G-protein-coupled receptors (GPCR).
     2. Adrenal cortical carcinoma It is associated with germline TP53 mutations and MEN syndrome.
     3. Bilateral adrenal hyperplasia: It is associated with MEN1, familial adenomatous polyposis, and fumarate hydratase gene mutations. Several inactivating mutations of armadillo repeat containing 5 genes (ARMC5, chromosome 16p11.2) are also identified.

Cushing’s syndrome is associated with the following conditions:^[6]

• Carney complex
• McCune-Albright syndrome
• Multiple Endocrine Neoplasia Type 1 (MEN 1)

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Furqan M M. M.B.B.S[2]

Cushing’s syndrome occurs when the body’s tissues are exposed to high levels of corticosteroids for a long period. Many people develop Cushing’s syndrome because they take glucocorticoids, (steroid hormones that are chemically similar to naturally produced cortisol) such as prednisone for asthma, rheumatoid arthritis, lupus, and other inflammatory diseases. Glucocorticoids are also used to suppress the immune system after transplantation to keep the body from rejecting the new organ or tissue. Other people develop Cushing’s syndrome because their bodies produce too much cortisol due to adrenal or extra-adrenal causes.

The major causes of Cushing’s syndrome are:^{[1][2][3][4][5]}

• Excess ACTH secretion
  • Pituitary Adenomas: These benign, or noncancerous, tumors of the pituitary gland secrete extra ACTH. Most people with the disorder have a single adenoma. This form of the syndrome is known as Cushing’s disease.
  • Ectopic ACTH Syndrome: Some benign or more often, cancerous tumors that arise outside the pituitary can produce ACTH. This condition is known as ectopic ACTH syndrome. Lung cancer causes more than half of these cases. Rarely, bronchial and thymic carcinoids also cause ectopic secretion of ACTH.
• Excess secretion of cortisol by adrenal glands:
  • Adrenal Tumors: In rare cases, an abnormality of the adrenal glands, most often an adrenal tumor, causes Cushing’s syndrome. Adrenal tumors are four to five times more common in women than men, and the average age of onset is about 40. Most of these cases involve noncancerous tumors of adrenal tissue called adrenal adenomas, which secrete excess cortisol.
  • Adrenocortical carcinomas (Adrenal cancers): These are the least common cause of Cushing’s syndrome. With adrenocortical carcinomas, cancer cells secrete excess levels of several adrenocortical hormones, including cortisol and adrenal androgens, a type of male hormone. Adrenocortical carcinomas usually cause very high hormone levels and rapid development of symptoms.

Familial Cushing’s Syndrome

• Most cases of Cushing’s syndrome are not inherited. Rarely, however, Cushing’s syndrome results from an inherited tendency to develop tumors of one or more endocrine glands. Endocrine glands release hormones into the bloodstream. With primary pigmented micronodular adrenal disease, children or young adults develop small cortisol-producing tumors of the adrenal glands. With multiple endocrine neoplasia type 1 (MEN1), hormone-secreting tumors of the parathyroid glands, pancreas, and pituitary develop; Cushing’s syndrome in MEN1 may be due to pituitary, ectopic, or adrenal tumors.

The following drugs can also cause the Cushing’s syndrome.

• Betamethasone dipropionate
• Betamethasone valerate
• Dexamethasone
• Prednisolone
• Ritonavir
• Triamcinolone
• Diflorasone
• Amcinonide

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Furqan M M. M.B.B.S[2]

Cushing’s syndrome must be differentiated from other diseases that cause hypertension, obesity, and hyperandrogenism, such as Metabolic syndrome X and pseudo-Cushing’s syndrome.

The table below summarizes the findings that differentiate Cushing’s disease from other conditions that may cause hypertension, hyperandrogenism, and obesity. Facial plethora, skin changes, osteoporosis, nephrolithiasis and neuropsychiatric conditions should raise the concern for Cushing’s syndrome.^[1][2][3][4]

Conditions Causes Associated features Diagnostic approach Cushing’s syndrome Iatrogenic Pituitary adenoma Adrenal tumor Adrenal hyperplasia Ectopic ACTH secretion Obesity Hypertension PCOS/hyperandrogenism Oligomenorrhea/hypogonadism Osteoporosis Myopathy/cutaneous wasting Neuropsychiatric problems Kidney stones 24-hour urine cortisol Midnight salivary cortisol Low dose dexamethasone challenge test CRH stimulation High dose dexamethasone test MRI brain CT/MRI adrenals Pseudo-Cushing’s syndrome Obesity Alcoholism Depression HIV Obesity Hypertension PCOS/hyperandrogenism Oligomenorrhea/hypogonadism Urinary free cortisol Midnight salivary cortisol Low dose dexamethasone challenge test Glucose tolerance test Loperamide test Metabolic syndrome X Familial/genetic Obesity Insulin resistance Obesity Hypertension PCOS/hyperandrogenism Oligomenorrhea/hypogonadism Dyslipidemia Diabetes/Glucose intolerance Waist circumference Low-density lipoproteins High-density lipoproteins Glucose tolerance test Fasting blood sugar HbA1c Differentials based on virilization and hirsutism Cushing’s syndrome must be differentiated from diseases that cause virilization and hirsutism in female:[5][6][7] Disease name Steroid status Other laboratory Important clinical findings Cushing’s syndrome Increase cortisol & metabolites Variable other steroids Variable mineralocorticoid excess Cushingoid appearance Non-classic type of 21-hydroxylase deficiency Increased: 17-hydroxyprogesterone Exaggerated Androstenedione, DHEA, and 17-hydroxyprogesterone in response to ACTH Low testosterone levels No symptoms in infancy and male Virilization in females 11-β hydroxylase deficiency Increased: DOC 11-Deoxy-Cortisol Decreased: Cortisol Corticosterone Aldosterone Low testosterone levels Hypertension and hypokalemia Virilization 3 beta-hydroxysteroid dehydrogenase deficiency Increased: DHEA 17-hydroxypregnenolone Pregnenolone Decreased: Cortisol Aldosterone Low testosterone levels Salt-wasting adrenal crisis in infancy Mild virilization of genetically female infants Undervirilization of genetically male infants, making it the only form of CAH which can cause ambiguous genitalia in both genetic sexes. Polycystic ovary syndrome High DHEAS and androstenedione levels Low testosterone levels Polycystic ovaries in sonography Obesity PCOS is the most common cause of hirsutism in women No evidence another diagnosis Adrenal tumors Variable levels depends on tumor type Low testosterone level Older age Rapidly progressive symptoms Ovarian virilizing tumor Variable levels depends on tumor type Testosterone is high Older age Rapidly progressive symptoms Hyperprolactinemia Normal levels of most of steroids Increased prolactin Infertility, galactorrhea Differentials based on galactorrhea, amenorrhea and infertility Cushing’s syndrome should also be differentiated from other causes of hyperprolactinemia that may present as galactorrhea, amenorrhea, (in females) and infertility (in both males and females) including: Physiological: Normal pregnancy[8] Pathological: Pituitary tumors (other than prolactinoma):[9] Somatotroph adenoma: Acromegaly Corticotroph adenoma: Cushing’s syndrome Suprasellar tumors (tumors present in the region of the pituitary stalk) Hypothyroidism[10] Chronic renal failure[11] Liver disease[12] Cirrhosis (with or without encephalopathy) Viral hepatitis (with encephalopathy) Seizure disorder[13][14] Medication-induced: Antipsychotic medications:[15] Haloperidol Risperidone Antiemetic medications: Metoclopramide[16] Domperidone[17] Antihypertensive medications: Methyldopa[18] Verapamil[19] Disease Clinical Findings Laboratory findings Management Somatotroph adenoma: Acromegaly Clinical features of acromegaly are due to high level of human growth hormone (hGH): Soft tissue swelling of the hands and feet Brow and lower jaw protrusion Enlarged hands Enlarged feet Arthritis and carpal tunnel syndrome Increase in teeth spacing Macroglossia (enlarged tongue) Heart failure Kidney failure Compression of the optic chiasm leading to loss of vision in the outer visual fields (typically bitemporal hemianopia) Headache Diabetes mellitus Hypertension Cardiomegaly Elevated insulin-like growth factor-1 (IGF-1) levels Elevated growth hormone levels Medical management: Octreotide Bromocriptine Surgical management: Endonasal transsphenoidal surgery Radiation therapy Corticotroph adenoma: Cushing’s syndrome Clinical features of Cushing’s syndrome are due to increased levels of cortisol: Rapid weight gain, particularly of the trunk and face with sparing of the limbs (central obesity) Proximal muscle weakness A round face often referred to as a “moon face“ Excess sweating Headache The excess cortisol may also affect other endocrine systems and cause, for example: Insomnia Reduced libido Impotence Amenorrhea Infertility Patients frequently suffer various psychological disturbances, ranging from euphoria to psychosis. Depression and anxiety are also common. Dexamethasone suppression test 24 hour urinary measurement of cortisol Medical management: Pasireotide Cabergoline Ketoconazole Metyrapone Mitotane Mifepristone Surgical management: Transsphenoidal pituitary resection Hypothyroidism Clinical features of hypothyroidism are due to deficiency of thyroxine: Fatigue Cold intolerance Decreased sweating Hypothermia Coarse skin Weight gain Hoarseness Goiter Fullness in the throat and neck Depression Emotional lability Attention deficit Elevated TSH Low T4 Low T3 Elevated anti-thyroid antibodies(anti-TPO) Levothyroxine Chronic renal failure There are no pathognomonic symptoms associated with chronic renal failure. Common non-specific symptoms of chronic renal failure include: Malaise Nausea Unintentional weight loss Pruritus Lower extremity edema Sleep disorders Urinalysis: Albuminuria Hematuria Pyuria Red cell or white cell casts and crystals Fluid and electrolyte disturbances: Hyponatremia Hyperkalemia Hyperphosphatemia Hyperchloremia Metabolic acidosis Hypocalcemia Endocrine and metabolic disturbances: Hyperuricemia Hypertriglyceridemia Decreased HDL levels Vitamin D deficiency Increased Parathyroid hormone levels Hematologic abnormalities: Normocytic normochromic anemia Lymphocytopenia Leukopenia Thrombocytopenia Medical management: Blood pressure management Control of blood glucose Protein restriction Management of anemia Management of electrolyte disturbance Dialysis Surgical management Kidney transplant Liver disease: Cirrhosis The clinical features of liver cirrhosis are very nonspecific. These include: Right upper quadrant abdominal pain Fever Fatigue and weakness Loss of appetite Diarrhea Nausea and vomiting Weight loss Abdominal pain and bloating when fluid accumulates in the abdomen Itching Menstrual irregularities Elevated aminotransferases (AST & ALT) Elevated alkaline phosphatase (ALP) Elevated gamma-glutamyl transpeptidase Elevated bilirubin Low albumin Elevated prothrombin time Elevated globulin Hyponatremia Anemia Leukopenia and neutropenia Thrombocytopenia Medical management: Treatment is usually directed towards the treatment of complications like ascites, esophageal varices, hepatic encephalopathy, hepatorenal syndrome, and spontaneous bacterial peritonitis. Some chronic constitutional symptoms that should be treated include: Pruritis: Cholestyramine is the drug of choice Hypogonadism: Topical testosterone preparations Osteoporosis: Calcium and vitamin D Pain management: NSAIDS, celecoxib, opioids Nutrition: Adequate caloric and protein intake, and multivitamin supplementation Surgical management: Liver transplantation Seizure disorder The clinical features of seizure disorder may include: Change in alertness, orientation and time perception Mood changes, such as unexplainable fear, panic, joy, or laughter Changes in sensation of the skin, usually spreading over the arm, leg, or trunk Vision changes, including seeing flashing lights Rarely, hallucinations (seeing things that aren’t there) Falling, loss of muscle control, occurs very suddenly Muscle twitching that may spread up or down an arm or leg Muscle tension or tightening that causes twisting of the body, head, arms, or legs Shaking of the entire body Tasting a bitter or metallic flavor Electroencephalogram Medical management: Antiepileptic medications Medication-induced Clinical features of hyperprolactinemia after a specific period of regular medication ingestion Discontinuation of the medication for 3 days and remeasurement of prolactin levels[20] Change to alternate medication Differentials based on irregular menstruation and hirsutism Cushing’s syndrome must be differentiated from other causes of irregular menses and hirsutism. The differentials include: Disease Differentiating Features Pregnancy Pregnancy should always be excluded in a patient with a history of amenorrhea Features include amenorrhea or oligomenorrhea, abnormal uterine bleeding, nausea/vomiting, cravings, weight gain (although not in the early stages and not if vomiting), polyuria, abdominal cramps and constipation, fatigue, dizziness/lightheadedness, and increased pigmentation (moles, nipples) Uterine enlargement is detectable on abdominal examination at approximately 14 weeks of gestation Ectopic pregnancy may cause oligomenorrhea, amenorrhea, or abnormal uterine bleeding with abdominal pain and sometimes subtle or absent physical symptoms and signs of pregnancy Hypothalamic amenorrhea Diagnosis of exclusion Seen in athletes, people on crash diets, patients with significant systemic illness, and those experiencing undue stress or anxiety Predisposing features are as follows weight loss, particularly if features of anorexia nervosa are present or the BMI is <19 kg/m2 Recent administration of depot medroxyprogesterone, which may suppress ovarian activity for 6 months to a year Use of dopamine agonists (eg, antidepressants) and major tranquilizers Hyperthyroidism In patients with weight loss related to anorexia nervosa, fine hair growth (lanugo) may occur all over the body, but it differs from hirsutism in its fineness and wide distribution Primary amenorrhea Causes include reproductive system abnormalities, chromosomal abnormalities, or delayed puberty If secondary sexual characteristics are present, an anatomic abnormality (eg, imperforate hymen, which is rare) should be considered If secondary sexual characteristics are absent, a chromosomal abnormality (eg, Turner syndrome ) or delayed puberty should be considered Cushing syndrome Cushing syndrome is due to excessive glucocorticoid secretion from the adrenal glands, either primarily or secondary to stimulation from pituitary or ectopic hormones; can also be caused by exogenous steroid use Features include hypertension, weight gain (central distribution), acne, and abdominal striae. Patients have low plasma sodium levels and elevated plasma cortisol levels on dexamethasone suppression testing Hyperprolactinemia Mild hyperprolactinemia may occur as part of PCOS-related hormonal dysfunction Other causes include stress, lactation, and use of dopamine antagonists A prolactinoma of the pituitary gland is an uncommon cause and should be suspected if prolactin levels are very high (>200 ng/mL) Physical examination findings are usually normal As in patients with PCOS, hyperprolactinemia may be associated with mild galactorrhea and oligomenorrhea or amenorrhea; however, galactorrhea also can occur with nipple stimulation and/or stress when prolactin levels are within normal ranges A large prolactinoma may cause headaches and visual field disturbance due to pressure on the optic chiasm, classically a gradually increasing bi-temporal hemianopsia Ovarian or adrenal tumor Benign ovarian tumors and ovarian cancer are rare causes of excessive androgen secretion; adrenocortical tumors also can increase the production of sex hormones Abdominal swelling or mass, abdominal pain due to fluid leakage or torsion, dyspareunia, abdominal ascites, and features of metastatic disease may be present Features of androgenization include hirsutism, weight gain, oligomenorrhea or amenorrhea, acne, clitoral hypertrophy, deepening of the voice, and high serum androgen (eg, testosterone, other androgens) levels In patients with an androgen-secreting tumor, serum testosterone is not suppressed by dexamethasone Congenital adrenal hyperplasia Congenital adrenal hyperplasia is a rare genetic condition resulting from 21-hydroxylase deficiency The late-onset form presents at or around menarche Patients have features of androgenization and subfertility Affects approximately 1% of hirsute patients More common in Ashkenazi Jews (19%), inhabitants of the former Yugoslavia (12%), and Italians (6%) Associated with high levels of 17-hydroxyprogesterone A short adrenocorticotropic hormone stimulation test with measurement of serum17-hydroxyprogesterone confirms the diagnosis Assays of a variety of androgenic hormones help define other rare adrenal enzyme deficiencies, which present similarly to 21-hydroxylase deficiency Anabolic steroid abuse Anabolic steroids are synthetic hormones that imitate the actions of testosterone by increasing muscle bulk and strength Should be considered if the patient is a serious sportswoman or bodybuilder Features include virilization (including acne and hirsutism), often increased muscle bulk in male pattern, oligomenorrhea or amenorrhea, clitoromegaly, gastritis, hepatic enlargement, alopecia, and aggression Altered liver function test results are seen Hirsutism Hirsutism is excessive facial and body hair, usually coarse and in a male pattern of distribution Approximately 10% of women report unwanted facial hair There is often a family history and typically some Mediterranean or Middle Eastern ancestry May also result from use of certain medications, both androgens, and others including danazol, glucocorticoids, cyclosporine, and phenytoin Menstrual history is normal When the cause is genetic, the excessive hair, especially on the face (upper lip), is present throughout adulthood, and there is no virilization When secondary to medications, the excessive hair is of new onset, and other features of virilization, such as acne and deepened voice, may be present Less common differentials Cushing’s syndrome must be differentiated from other adrenal tumors such as adrenocortical adenoma, adrenal metastasis, and adrenal medullary tumors: Differential Diagnosis Clinical picture Imagings Laboratory tests Adrenocortical carcinoma Mass effect symptoms Symptoms related to excess glucocorticoid Symptoms related to excess mineralocorticoid Symptoms related to excess androgen or estrogen secretion Irregular shape Non-homogeneous density because of central areas of low attenuation due to tumor necrosis Tumor calcification Diameter usually >4 cm Unilateral location High unenhanced CT attenuation values (>20 HU) Non-homogeneous enhancement on CT with intravenous contrast Delay in contrast medium washout (10 minutes after administration of contrast, an absolute contrast medium washout of less than 50 percent) Hypointensity compared with liver on T1 weighted MRI and high to intermediate signal intensity on T2 weighted MRI High standardized uptake value (SUV) on FDG–PET-CT study Evidence of local invasion or metastases Adrenal androgens (DHEAS) Androstenedione Bioavailable testosterone should be measured in every patient. 17-hydroxyprogesterone Serum estradiol in men and postmenopausal women Cortisol level Fasting serum cortisol at 8 AM following a 1 mg dose of dexamethasone at bedtime Adrenal adenoma Symptoms related to excess glucocorticoid Symptoms related to excess mineralocorticoid Round, homogeneous with sharp margination Unilateral with diameter less than 4 cm Low unenhanced CT attenuation values (<10 HU) Rapid contrast medium washout after administration of contrast An absolute contrast medium washout of more than 50 percent Chemical shift: evidence of lipid on MRI Isointensity with liver on both T1 and T2 weighted MRI sequences Cortisol level Fasting serum cortisol at 8 AM following a 1 mg dose of dexamethasone at bedtime Renin (PRA) or plasma renin concentration (PRC): very low in patients with primary aldosteronism, usually less than 1 ng/mL per hour for PRA and usually undetectable for PRC[21] Cushing’s syndrome Rapid weight gain, particularly of the trunk and face with limbs sparing (central obesity) Proximal muscle weakness A round face often referred to as a “moon face“ Excess sweating Headache Imaging may show mass if presents 24-hour urine cortisol Midnight salivary cortisol Low-dose dexamethasone suppression test; high cortisol level after the dexamethasone test is suggestive of hypercortisolism. Pheochromocytoma Palpitations especially in epinephrine-producing tumors. Anxiety often resembling that of a panic attack Sweating Headaches occur in 90 % of patients. Paroxysmal attacks of hypertension but some patients have normal blood pressure. It may be asymptomatic and discovered incidentally after screening for MEN patients. Increased attenuation on non-enhanced CT (>20 HU) Increased mass vascularity Delay in contrast medium washout (10 minutes after administration of contrast, an absolute contrast medium washout of less than 50 percent) High signal intensity on T2 weighted MRI Cystic and hemorrhagic changes Variable size and may be bilateral Plasma fractionated metanephrines  24-hour urinary fractionated metanephrines Adrenal metastasis Symptoms and signs of primary malignancy especially lung cancer General constitutional symptoms: Fever Fatigue Weight loss Irregular shape and non-homogeneous nature Tendency to be bilateral High un-enhanced CT attenuation values (>20 HU) and enhancement with intravenous contrast on CT Delay in contrast medium washout (10 minutes after administration of contrast, an absolute contrast medium washout of less than 50 percent) Isointensity or slightly less intense than the liver on T1 weighted MRI and high to intermediate signal intensity on T2 weighted MRI (representing an increased water content) Elevated standardized uptake value on FDG–PET scan References ↑ Boscaro M, Barzon L, Fallo F, Sonino N (2001). “Cushing’s syndrome”. Lancet. 357 (9258): 783–91. doi:10.1016/S0140-6736(00)04172-6. PMID 11253984. ↑ Findling JW, Raff H (2001). “Diagnosis and differential diagnosis of Cushing’s syndrome”. Endocrinol. Metab. Clin. North Am. 30 (3): 729–47. PMID 11571938. ↑ Newell-Price J, Trainer P, Besser M, Grossman A (1998). “The diagnosis and differential diagnosis of Cushing’s syndrome and pseudo-Cushing’s states”. Endocr. Rev. 19 (5): 647–72. doi:10.1210/edrv.19.5.0346. PMID 9793762. ↑ “How Is Metabolic Syndrome Diagnosed? – NHLBI, NIH”. ↑ Hohl A, Ronsoni MF, Oliveira M (2014). “Hirsutism: diagnosis and treatment”. Arq Bras Endocrinol Metabol. 58 (2): 97–107. PMID 24830586. Vancouver style error: initials (help) ↑ White PC, Speiser PW (2000). “Congenital adrenal hyperplasia due to 21-hydroxylase deficiency”. Endocr. Rev. 21 (3): 245–91. doi:10.1210/edrv.21.3.0398. PMID 10857554. ↑ Melmed, Shlomo (2016). Williams textbook of endocrinology. Philadelphia, PA: Elsevier. ISBN 978-0323297387.= ↑ Rigg LA, Lein A, Yen SS (1977). “Pattern of increase in circulating prolactin levels during human gestation”. Am J Obstet Gynecol. 129 (4): 454–6. PMID 910825.CS1 maint: Multiple names: authors list (link) ↑ Levy A (2004). “Pituitary disease: presentation, diagnosis, and management”. J Neurol Neurosurg Psychiatry. 75 Suppl 3: iii47–52. doi:10.1136/jnnp.2004.045740. PMC 1765669. PMID 15316045. ↑ Snyder PJ, Jacobs LS, Utiger RD, Daughaday WH (1973). “Thyroid hormone inhibition of the prolactin response to thyrotropin-releasing hormone”. J Clin Invest. 52 (9): 2324–9. doi:10.1172/JCI107421. PMC 333037. PMID 4199418.CS1 maint: Multiple names: authors list (link) ↑ Sievertsen GD, Lim VS, Nakawatase C, Frohman LA (1980). “Metabolic clearance and secretion rates of human prolactin in normal subjects and in patients with chronic renal failure”. J Clin Endocrinol Metab. 50 (5): 846–52. doi:10.1210/jcem-50-5-846. PMID 7372775.CS1 maint: Multiple names: authors list (link) ↑ Jha SK, Kannan S (2016). “Serum prolactin in patients with liver disease in comparison with healthy adults: A preliminary cross-sectional study”. Int J Appl Basic Med Res. 6 (1): 8–10. doi:10.4103/2229-516X.173984. PMC 4765284. PMID 26958514. ↑ Ben-Menachem, Elinor (2006). “Is Prolactin a Clinically Useful Measure of Epilepsy?”. Epilepsy Currents. 6 (3): 78–79. doi:10.1111/j.1535-7511.2006.00104.x. ISSN 1535-7597. ↑ Trimble MR (1978). “Serum prolactin in epilepsy and hysteria”. Br Med J. 2 (6153): 1682. PMC 1608938. PMID 737437. ↑ David SR, Taylor CC, Kinon BJ, Breier A (2000). “The effects of olanzapine, risperidone, and haloperidol on plasma prolactin levels in patients with schizophrenia”. Clin Ther. 22 (9): 1085–96. doi:10.1016/S0149-2918(00)80086-7. PMID 11048906.CS1 maint: Multiple names: authors list (link) ↑ McCallum RW, Sowers JR, Hershman JM, Sturdevant RA (1976). “Metoclopramide stimulates prolactin secretion in man”. J Clin Endocrinol Metab. 42 (6): 1148–52. doi:10.1210/jcem-42-6-1148. PMID 777023.CS1 maint: Multiple names: authors list (link) ↑ Sowers JR, Sharp B, McCallum RW (1982). “Effect of domperidone, an extracerebral inhibitor of dopamine receptors, on thyrotropin, prolactin, renin, aldosterone, and 18-hydroxycorticosterone secretion in man”. J Clin Endocrinol Metab. 54 (4): 869–71. doi:10.1210/jcem-54-4-869. PMID 7037817.CS1 maint: Multiple names: authors list (link) ↑ Steiner J, Cassar J, Mashiter K, Dawes I, Fraser TR, Breckenridge A (1976). “Effects of methyldopa on prolactin and growth hormone”. Br Med J. 1 (6019): 1186–8. PMC 1639736. PMID 1268617.CS1 maint: Multiple names: authors list (link) ↑ Fearrington EL, Rand CH, Rose JD (1983). “Hyperprolactinemia-galactorrhea induced by verapamil”. Am J Cardiol. 51 (8): 1466–7. PMID 6682619.CS1 maint: Multiple names: authors list (link) ↑ Melmed S, Casanueva FF, Hoffman AR, Kleinberg DL, Montori VM, Schlechte JA; et al. (2011). “Diagnosis and treatment of hyperprolactinemia: an Endocrine Society clinical practice guideline”. J Clin Endocrinol Metab. 96 (2): 273–88. doi:10.1210/jc.2010-1692. PMID 21296991.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link) ↑ Manolopoulou J, Fischer E, Dietz A, Diederich S, Holmes D, Junnila R; et al. (2015). “Clinical validation for the aldosterone-to-renin ratio and aldosterone suppression testing using simultaneous fully automated chemiluminescence immunoassays”. J Hypertens. 33 (12): 2500–11. doi:10.1097/HJH.0000000000000727. PMID 26372319.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link) Template:WH Template:WS

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Furqan M M. M.B.B.S[2]

Cushing’s disease is particularly common in females. Annually, there are around 2–5 new cases per million people worldwide.

The prevalence of Cushing’s syndrome is 39-79 per million.^[1][2]

The overall incidence of endogenous Cushing’s syndrome is approximately 2–5 new cases per million people per year.^[1]

There is no age predilection for Cushing’s syndrome.

Cushing’s disease is more common in females with a female-to-male ratio of 3:1.^[1]

There is no racial predilection for Cushing’s syndrome.

Cushing’s syndrome has a worldwide distribution.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Furqan M M. M.B.B.S[2]

Common risk factors in the development of Cushing’s disease are female gender and genetic factors.

The risk factors for Cushing’s syndrome are:^[1]

1. Female gender
2. Genetic predisposition

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There is insufficient evidence to recommend routine screening for Cushing’s syndrome.

There is insufficient evidence to recommend routine screening for Cushing’s syndrome.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Furqan M M. M.B.B.S[2]

Cushing’s disease can lead to The symptoms of Cushing’s syndrome usually start with symptoms such as rapid weight gain, a round face often referred to as a “moon face“, and insomnia. It may progress to develop amenorrhoea, infertility and psychological disturbances. If left untreated, patients with Cushing’s syndrome may progress to develop diabetes, cardiovascular and psychiatric complications. The prognosis depends on the severity of the disease.

The symptoms of Cushing’s syndrome usually start with symptoms such as rapid weight gain, a round face often referred to as a “moon face“, and insomnia. It may progress to develop amenorrhoea, infertility, and psychological disturbances. If left untreated, patients with Cushing’s syndrome may progress to develop diabetes mellitus and cardiovascular complications.

Cushing’s syndrome can lead to the following complications:^[1][2]

• Insulin resistance (especially common in ectopic ACTH production)
• Hyperglycemia (high blood sugars)
• Diabetes mellitus
• Osteoporosis
• Cardiovascular complications:
  • Hypertension
  • Myocardial infarction
  • Left ventricular dysfunction
  • Cerebrovascular disease
• Hypercoagulable state as a result of:
  • Activated coagulation cascade
  • Impaired fibrinolysis.
• Major depression
• Anxiety disorders
• Opportunistic infections
• Sepsis

The prognosis for those with Cushing’s syndrome varies depending on the cause of the disease. Most cases of Cushing’s syndrome can be cured. Many individuals with Cushing’s syndrome show significant improvement with treatment, although some may find recovery complicated by various aspects of the causative illness. Some kinds of tumors may recur. Mortality in patients with Cushing’s syndrome is increased even after the apparently successful treatment.^[3]

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