Cushing Syndrome

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: Anatomy
  • Adrenocorticotropic hormone Adrenocorticotropic hormone An anterior pituitary hormone that stimulates the adrenal cortex and its production of corticosteroids. Acth is a 39-amino acid polypeptide of which the n-terminal 24-amino acid segment is identical in all species and contains the adrenocorticotropic activity. Upon further tissue-specific processing, acth can yield alpha-msh and corticotropin-like intermediate lobe peptide (clip). Adrenal Hormones (ACTH)-independent condition
• Secondary hypercortisolism:
  • Cushing’s disease:
    • ↑ Pituitary Pituitary A small, unpaired gland situated in the sella turcica. It is connected to the hypothalamus by a short stalk which is called the infundibulum. Hormones: Overview and Types ACTH production leading to adrenal gland hyperplasia Hyperplasia An increase in the number of cells in a tissue or organ without tumor formation. It differs from hypertrophy, which is an increase in bulk without an increase in the number of cells. Cellular Adaptation
    •  ACTH-dependent condition
  • Ectopic ACTH syndrome: ↑ ACTH production outside the pituitary Pituitary A small, unpaired gland situated in the sella turcica. It is connected to the hypothalamus by a short stalk which is called the infundibulum. Hormones: Overview and Types 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: Anatomy (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 Iatrogenic Any adverse condition in a patient occurring as the result of treatment by a physician, surgeon, or other health professional, especially infections acquired by a patient during the course of treatment. Anterior Cord Syndrome 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 Iatrogenic Any adverse condition in a patient occurring as the result of treatment by a physician, surgeon, or other health professional, especially infections acquired by a patient during the course of treatment. Anterior Cord Syndrome 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 Incidence The number of new cases of a given disease during a given period in a specified population. It also is used for the rate at which new events occur in a defined population. It is differentiated from prevalence, which refers to all cases in the population at a given time. Measures of Disease Frequency of small-cell lung carcinoma
• Increased risk of cardiovascular mortality Mortality All deaths reported in a given population. Measures of Health Status compared to the general population

Etiology

• ACTH-dependent causes:
  • Cushing’s disease:
    • Pituitary Pituitary A small, unpaired gland situated in the sella turcica. It is connected to the hypothalamus by a short stalk which is called the infundibulum. Hormones: Overview and Types microadenoma Microadenoma Pituitary Adenomas: 90% 
    • Pituitary Pituitary A small, unpaired gland situated in the sella turcica. It is connected to the hypothalamus by a short stalk which is called the infundibulum. Hormones: Overview and Types macroadenoma Macroadenoma Pituitary Adenomas
  • 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: Anatomy tumors
  • Ectopic corticotropin-releasing hormone Corticotropin-releasing hormone A peptide of about 41 amino acids that stimulates the release of adrenocorticotropic hormone. Crh is synthesized by neurons in the paraventricular nucleus of the hypothalamus. After being released into the pituitary portal circulation, crh stimulates the release of acth from the pituitary gland. Crh can also be synthesized in other tissues, such as placenta; adrenal medulla; and testis. Hypothalamic and Pituitary Hormones (CRH) syndrome leads to ↑ ACTH and subsequent adrenal hyperplasia Hyperplasia An increase in the number of cells in a tissue or organ without tumor formation. It differs from hypertrophy, which is an increase in bulk without an increase in the number of cells. Cellular Adaptation
  • Iatrogenic Iatrogenic Any adverse condition in a patient occurring as the result of treatment by a physician, surgeon, or other health professional, especially infections acquired by a patient during the course of treatment. Anterior Cord Syndrome (treatment with exogenous ACTH)
• ACTH-independent causes:
  • Iatrogenic Iatrogenic Any adverse condition in a patient occurring as the result of treatment by a physician, surgeon, or other health professional, especially infections acquired by a patient during the course of treatment. Anterior Cord Syndrome (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 Hyperplasia An increase in the number of cells in a tissue or organ without tumor formation. It differs from hypertrophy, which is an increase in bulk without an increase in the number of cells. Cellular Adaptation
  • McCune-Albright syndrome
• Pseudo-Cushing’s syndrome (physiological hypercortisolism):
  • Pregnancy Pregnancy The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and Care
  • Obstructive sleep apnea Sleep apnea Repeated cessation of breathing for > 10 seconds during sleep and results in sleep interruption, fatigue, and daytime sleepiness. Obstructive Sleep Apnea
  • Uncontrolled diabetes Diabetes 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 mellitus
  • 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 (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 Hypothalamus The hypothalamus is a collection of various nuclei within the diencephalon in the center of the brain. The hypothalamus plays a vital role in endocrine regulation as the primary regulator of the pituitary gland, and it is the major point of integration between the central nervous and endocrine systems. Hypothalamus secretes CRH → release of ACTH from the anterior pituitary Pituitary A small, unpaired gland situated in the sella turcica. It is connected to the hypothalamus by a short stalk which is called the infundibulum. Hormones: Overview and Types gland
  • ACTH release:
    • Like CRH, the release of ACTH is pulsatile, following the circadian rhythm Circadian Rhythm The regular recurrence, in cycles of about 24 hours, of biological processes or activities, such as sensitivity to drugs or environmental and physiological stimuli. Cranial Nerve Palsies.
    • ↑ 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 Zona Fasciculata The wide middle zone of the adrenal cortex. This zone produces a series of enzymes that convert pregnenolone to cortisol (hydrocortisone) via 17-alpha-hydroxyprogesterone. Adrenal Glands: Anatomy ( cortisol Cortisol Glucocorticoids) and zona reticularis Zona Reticularis The inner zone of the adrenal cortex. This zone produces the enzymes that convert pregnenolone, a 21-carbon steroid, to 19-carbon steroids (dehydroepiandrosterone; and androstenedione) via 17-alpha-hydroxypregnenolone. Adrenal Glands: Anatomy ( 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 Zona Glomerulosa The narrow subcapsular outer zone of the adrenal cortex. This zone produces a series of enzymes that convert pregnenolone to aldosterone. The final steps involve three successive oxidations by cytochrome p-450 cyp11b2. Adrenal Glands: Anatomy ( aldosterone Aldosterone A hormone secreted by the adrenal cortex that regulates electrolyte and water balance by increasing the renal retention of sodium and the excretion of potassium. Hyperkalemia) is primarily regulated by the renin-angiotensin system and potassium Potassium An element in the alkali group of metals with an atomic symbol k, atomic number 19, and atomic weight 39. 10. It is the chief cation in the intracellular fluid of muscle and other cells. Potassium ion is a strong electrolyte that plays a significant role in the regulation of fluid volume and maintenance of the water-electrolyte balance. Hyperkalemia levels.
• Cortisol Cortisol Glucocorticoids:
  • Metabolic effects:
    • ↓  Glucose Glucose A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. Lactose Intolerance 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 Lipolysis The metabolic process of breaking down lipids to release free fatty acids, the major oxidative fuel for the body. Lipolysis may involve dietary lipids in the digestive tract, circulating lipids in the blood, and stored lipids in the adipose tissue or the liver. A number of enzymes are involved in such lipid hydrolysis, such as lipase and lipoprotein lipase from various tissues. Nonalcoholic Fatty Liver Disease → release of fatty acids Acids Chemical compounds which yield hydrogen ions or protons when dissolved in water, whose hydrogen can be replaced by metals or basic radicals, or which react with bases to form salts and water (neutralization). An extension of the term includes substances dissolved in media other than water. Acid-Base Balance into the circulation Circulation The movement of the blood as it is pumped through the cardiovascular system. ABCDE Assessment
    • ↓ Protein storage → myopathy Myopathy Dermatomyositis, bone resorption Bone resorption Bone loss due to osteoclastic activity. Bones: Remodeling and Healing
  • ↑ Smooth muscle (vasculature) sensitivity to catecholamines Catecholamines A general class of ortho-dihydroxyphenylalkylamines derived from tyrosine. Adrenal Hormones and angiotensin II Angiotensin II An octapeptide that is a potent but labile vasoconstrictor. It is produced from angiotensin I after the removal of two amino acids at the c-terminal by angiotensin converting enzyme. The amino acid in position 5 varies in different species. To block vasoconstriction and hypertension effect of angiotensin II, patients are often treated with ace inhibitors or with angiotensin II type 1 receptor blockers. Renal Sodium and Water Regulation (leading to ↑ blood pressure)
  • Anti-inflammatory actions:
    • Apoptosis Apoptosis A regulated cell death mechanism characterized by distinctive morphologic changes in the nucleus and cytoplasm, including the endonucleolytic cleavage of genomic DNA, at regularly spaced, internucleosomal sites, I.e., DNA fragmentation. It is genetically-programmed and serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth. Ischemic Cell Damage of T cells T cells Lymphocytes responsible for cell-mediated immunity. Two types have been identified – cytotoxic (t-lymphocytes, cytotoxic) and helper T-lymphocytes (t-lymphocytes, helper-inducer). They are formed when lymphocytes circulate through the thymus gland and differentiate to thymocytes. When exposed to an antigen, they divide rapidly and produce large numbers of new T cells sensitized to that antigen. T cells: Types and Functions
    • ↓ Antibody production
    • ↓ Neutrophil migration
• 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:
  • Dehydroepiandrosterone Dehydroepiandrosterone A major C19 steroid produced by the adrenal cortex. It is also produced in small quantities in the testis and the ovary. Dehydroepiandrosterone (DHEA) can be converted to testosterone; androstenedione; estradiol; and estrone. Androgens and Antiandrogens ( DHEA DHEA A major C19 steroid produced by the adrenal cortex. It is also produced in small quantities in the testis and the ovary. Dehydroepiandrosterone (dhea) can be converted to testosterone; androstenedione; estradiol; and estrone. Androgens and Antiandrogens) and dehydroepiandrosterone Dehydroepiandrosterone A major C19 steroid produced by the adrenal cortex. It is also produced in small quantities in the testis and the ovary. Dehydroepiandrosterone (DHEA) can be converted to testosterone; androstenedione; estradiol; and estrone. Androgens and Antiandrogens 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 DHEA A major C19 steroid produced by the adrenal cortex. It is also produced in small quantities in the testis and the ovary. Dehydroepiandrosterone (dhea) can be converted to testosterone; androstenedione; estradiol; and estrone. Androgens and Antiandrogens:
    • 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 Testosterone A potent androgenic steroid and major product secreted by the leydig cells of the testis. Its production is stimulated by luteinizing hormone from the pituitary gland. In turn, testosterone exerts feedback control of the pituitary LH and FSH secretion. Depending on the tissues, testosterone can be further converted to dihydrotestosterone or estradiol. Androgens and Antiandrogens) 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. Noncontraceptive Estrogen and Progestins).
    • Testes Testes Gonadal Hormones 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 Sodium A member of the alkali group of metals. It has the atomic symbol na, atomic number 11, and atomic weight 23. Hyponatremia and water reabsorption 
  • Regulation of potassium Potassium An element in the alkali group of metals with an atomic symbol k, atomic number 19, and atomic weight 39. 10. It is the chief cation in the intracellular fluid of muscle and other cells. Potassium ion is a strong electrolyte that plays a significant role in the regulation of fluid volume and maintenance of the water-electrolyte balance. Hyperkalemia excretion

Hypercortisolism

• ACTH-dependent causes:
  • Cushing’s disease:
    • Pituitary Pituitary A small, unpaired gland situated in the sella turcica. It is connected to the hypothalamus by a short stalk which is called the infundibulum. Hormones: Overview and Types adenoma secreting ACTH
    • ↑ ACTH → bilateral adrenal hyperplasia Bilateral Adrenal Hyperplasia Hyperaldosteronism and hyperfunction → ↑ cortisol Cortisol Glucocorticoids
    • ACTH secretion Secretion Coagulation Studies is resistant to glucocorticoid feedback inhibition.
  • Ectopic ACTH syndrome:
    • Occurs in malignant and neuroendocrine tumors Neuroendocrine tumors Tumors whose cells possess secretory granules and originate from the neuroectoderm, i.e., the cells of the ectoblast or epiblast that program the neuroendocrine system. Common properties across most neuroendocrine tumors include ectopic hormone production (often via apud cells), the presence of tumor-associated antigens, and isozyme composition. Gastrinoma
    • ↑ Ectopic ACTH → ↑  cortisol Cortisol Glucocorticoids 
  • Ectopic CRH syndrome:
    • Secretion Secretion Coagulation Studies of CRH by a tumor Tumor Inflammation
    • ↑ CRH → pituitary Pituitary A small, unpaired gland situated in the sella turcica. It is connected to the hypothalamus by a short stalk which is called the infundibulum. Hormones: Overview and Types hyperplasia Hyperplasia An increase in the number of cells in a tissue or organ without tumor formation. It differs from hypertrophy, which is an increase in bulk without an increase in the number of cells. Cellular Adaptation → ACTH hypersecretion → ↑  cortisol Cortisol Glucocorticoids
    • Generally with loss of glucocorticoid negative feedback Negative feedback Hypothalamic and Pituitary Hormones
• ACTH-independent causes:
  • Iatrogenic Iatrogenic Any adverse condition in a patient occurring as the result of treatment by a physician, surgeon, or other health professional, especially infections acquired by a patient during the course of treatment. Anterior Cord Syndrome:
    • 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 Atrophy Decrease in the size of a cell, tissue, organ, or multiple organs, associated with a variety of pathological conditions such as abnormal cellular changes, ischemia, malnutrition, or hormonal changes. Cellular Adaptation 
    • Most common: prednisone Prednisone A synthetic anti-inflammatory glucocorticoid derived from cortisone. It is biologically inert and converted to prednisolone in the liver. Immunosuppressants
  • Cortisol-secreting adrenal adenomas and carcinomas:
    • Tumors secrete cortisol Cortisol Glucocorticoids, suppressing ACTH and leading to pituitary Pituitary A small, unpaired gland situated in the sella turcica. It is connected to the hypothalamus by a short stalk which is called the infundibulum. Hormones: Overview and Types corticotroph atrophy Atrophy Decrease in the size of a cell, tissue, organ, or multiple organs, associated with a variety of pathological conditions such as abnormal cellular changes, ischemia, malnutrition, or hormonal changes. Cellular Adaptation.
    • 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 Suppression Defense Mechanisms (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 Amenorrhea Absence of menstruation. Congenital Malformations of the Female Reproductive System).
  • Macronodular adrenal hyperplasia Hyperplasia An increase in the number of cells in a tissue or organ without tumor formation. It differs from hypertrophy, which is an increase in bulk without an increase in the number of cells. Cellular Adaptation:
    • Involves aberrant membrane receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors in the adrenal cortex Adrenal Cortex The outer layer of the adrenal gland. It is derived from mesoderm and comprised of three zones (outer zona glomerulosa, middle zona fasciculata, and inner zona reticularis) with each producing various steroids preferentially, such as aldosterone; hydrocortisone; dehydroepiandrosterone; and androstenedione. Adrenal cortex function is regulated by pituitary adrenocorticotropin. Adrenal Glands: Anatomy 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 and Types (e.g., vasopressin, gastric inhibitory peptide Gastric inhibitory peptide A gastrointestinal peptide hormone of about 43-amino acids. It is found to be a potent stimulator of insulin secretion and a relatively poor inhibitor of gastric acid secretion. Gastrointestinal Neural and Hormonal Signaling)
    • 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: Anatomy are significantly enlarged with macronodules.
  • Primary pigmented nodular adrenocortical disease:
    • Also known as micronodular adrenal hyperplasia Hyperplasia An increase in the number of cells in a tissue or organ without tumor formation. It differs from hypertrophy, which is an increase in bulk without an increase in the number of cells. Cellular Adaptation
    • Can be sporadic Sporadic Selective IgA Deficiency 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 PRKAR1A Schwannoma 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 Fibrous Fibrocystic Change 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. Skin: Structure and Functions 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 Hypersecretion of thyroid hormones from the thyroid gland. Elevated levels of thyroid hormones increase basal metabolic rate. Thyrotoxicosis and Hyperthyroidism, acromegaly Acromegaly A condition caused by prolonged exposure to excessive human growth hormone in adults. It is characterized by bony enlargement of the face; lower jaw (prognathism); hands; feet; head; and thorax. The most common etiology is a growth hormone-secreting pituitary adenoma. Acromegaly and Gigantism, and Cushing’s syndrome
    • Adrenal effect caused by a somatic mutation Somatic Mutation Non-Hodgkin Lymphomas in the alpha subunit of Gs protein → constant activation mimicking ACTH stimulation

Clinical Presentation

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 Avascular Necrosis Hip Fractures of the femoral head)
• Glucose elevation
• Osteoporosis, osteopenia, obesity
• Immunosuppression
• Diabetes, depression

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 Ritonavir An HIV protease inhibitor that works by interfering with the reproductive cycle of HIV. It also inhibits cytochrome p-450 cyp3a. Anti-HIV Drugs delays clearance of inhaled/injected steroids Steroids A group of polycyclic compounds closely related biochemically to terpenes. They include cholesterol, numerous hormones, precursors of certain vitamins, bile acids, alcohols (sterols), and certain natural drugs and poisons. Steroids have a common nucleus, a fused, reduced 17-carbon atom ring system, cyclopentanoperhydrophenanthrene. Most steroids also have two methyl groups and an aliphatic side-chain attached to the nucleus. Benign Liver Tumors)

Initial tests for hypercortisolism:

• Late-night salivary cortisol Cortisol Glucocorticoids 
• 24-hour urinary free cortisol Cortisol Glucocorticoids (UFC) excretion 
• 1 mg dexamethasone-suppression test ((DST) 1 mg of dexamethasone Dexamethasone An anti-inflammatory 9-fluoro-glucocorticoid. Antiemetics administered in the late evening suppresses endogenous cortisol Cortisol Glucocorticoids production the next morning))
  • Normal cutoff for suppression Suppression Defense Mechanisms of serum cortisol Cortisol Glucocorticoids (post-dexamethasone): < 1.8 μg/dL (50 nmol/L)
  • If cortisol Cortisol Glucocorticoids is not suppressed (i.e., cortisol Cortisol Glucocorticoids > 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 Identification Defense Mechanisms of the cause of hypercortisolism.

Identification Identification Defense Mechanisms of the cause

After confirming elevated cortisol Cortisol Glucocorticoids 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: Anatomy.
  • Possible adrenal mass Mass Three-dimensional lesion that occupies a space within the breast Imaging of the Breast, bilateral hyperplasia Hyperplasia An increase in the number of cells in a tissue or organ without tumor formation. It differs from hypertrophy, which is an increase in bulk without an increase in the number of cells. Cellular Adaptation, or macronodular adrenal hyperplasia Hyperplasia An increase in the number of cells in a tissue or organ without tumor formation. It differs from hypertrophy, which is an increase in bulk without an increase in the number of cells. Cellular Adaptation
• 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 Pituitary A small, unpaired gland situated in the sella turcica. It is connected to the hypothalamus by a short stalk which is called the infundibulum. Hormones: Overview and Types adenoma)
    • No ↑ ACTH: ectopic ACTH syndrome
  • High-dose DST:
    • 8 mg dexamethasone Dexamethasone An anti-inflammatory 9-fluoro-glucocorticoid. Antiemetics is administered.
    • Cortisol Cortisol Glucocorticoids is suppressed: Cushing’s disease ( pituitary Pituitary A small, unpaired gland situated in the sella turcica. It is connected to the hypothalamus by a short stalk which is called the infundibulum. Hormones: Overview and Types adenoma)
    • Cortisol Cortisol Glucocorticoids is not suppressed: ectopic ACTH syndrome
  • If etiology is:
    • Cushing’s disease → proceed with pituitary Pituitary A small, unpaired gland situated in the sella turcica. It is connected to the hypothalamus by a short stalk which is called the infundibulum. Hormones: Overview and Types MRI
    • Ectopic → search for tumor Tumor Inflammation/ malignancy Malignancy Hemothorax 
• Inferior petrosal sinus sampling ( IPSS IPSS Benign Prostatic Hyperplasia):
  • Directly determines ACTH secretion Secretion Coagulation Studies from the pituitary Pituitary A small, unpaired gland situated in the sella turcica. It is connected to the hypothalamus by a short stalk which is called the infundibulum. Hormones: Overview and Types 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: Histology after CRH administration
    • Gradient of ≥ 3 after CRH → Cushing’s disease ( pituitary Pituitary A small, unpaired gland situated in the sella turcica. It is connected to the hypothalamus by a short stalk which is called the infundibulum. Hormones: Overview and Types)
  • 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 Thromboembolism Obstruction of a blood vessel (embolism) by a blood clot (thrombus) in the blood stream. Systemic Lupus Erythematosus
  • Performed in certain situations:
    • Mixed responses in CRH and DSTs
    • No pituitary Pituitary A small, unpaired gland situated in the sella turcica. It is connected to the hypothalamus by a short stalk which is called the infundibulum. Hormones: Overview and Types tumor Tumor Inflammation or lesion is < 6 mm MM Multiple myeloma (MM) is a malignant condition of plasma cells (activated B lymphocytes) primarily seen in the elderly. Monoclonal proliferation of plasma cells results in cytokine-driven osteoclastic activity and excessive secretion of IgG antibodies. Multiple Myeloma on MRI

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 Hyperplasia An increase in the number of cells in a tissue or organ without tumor formation. It differs from hypertrophy, which is an increase in bulk without an increase in the number of cells. Cellular Adaptation:
  • Bilateral adrenalectomy 
  • Adrenal enzyme inhibitors ( metyrapone Metyrapone An inhibitor of the enzyme steroid 11-beta-monooxygenase. It is used as a test of the feedback hypothalamic-pituitary mechanism in the diagnosis of Cushing syndrome. Adrenal Insufficiency and Addison Disease or ketoconazole Ketoconazole Broad spectrum antifungal agent used for long periods at high doses, especially in immunosuppressed patients. Azoles) can be given prior to surgery.
• Adrenal carcinoma:
  • Resectable tumor Tumor Inflammation: adrenalectomy (+/- radiotherapy for incomplete resection)
  • Unresectable tumor Tumor Inflammation/advanced disease: mitotane, metyrapone Metyrapone An inhibitor of the enzyme steroid 11-beta-monooxygenase. It is used as a test of the feedback hypothalamic-pituitary mechanism in the diagnosis of Cushing syndrome. Adrenal Insufficiency and Addison Disease, or ketoconazole Ketoconazole Broad spectrum antifungal agent used for long periods at high doses, especially in immunosuppressed patients. Azoles

Cushing’s disease ( pituitary Pituitary A small, unpaired gland situated in the sella turcica. It is connected to the hypothalamus by a short stalk which is called the infundibulum. Hormones: Overview and Types 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 Dopamine One of the catecholamine neurotransmitters in the brain. It is derived from tyrosine and is the precursor to norepinephrine and epinephrine. Dopamine is a major transmitter in the extrapyramidal system of the brain, and important in regulating movement. Receptors and Neurotransmitters of the CNS agonist) or pasireotide ( somatostatin Somatostatin A 14-amino acid peptide named for its ability to inhibit pituitary growth hormone release, also called somatotropin release-inhibiting factor. It is expressed in the central and peripheral nervous systems, the gut, and other organs. SRIF can also inhibit the release of thyroid-stimulating hormone; prolactin; insulin; and glucagon besides acting as a neurotransmitter and neuromodulator. In a number of species including humans, there is an additional form of somatostatin, srif-28 with a 14-amino acid extension at the n-terminal. Gastrointestinal Secretions analog)
  • Mifepristone Mifepristone A progestational and glucocorticoid hormone antagonist. Its inhibition of progesterone induces bleeding during the luteal phase and in early pregnancy by releasing endogenous prostaglandins from the endometrium or decidua. As a glucocorticoid receptor antagonist, the drug has been used to treat hypercortisolism in patients with nonpituitary Cushing syndrome. Antiprogestins and Selective Progesterone Modulators (for hyperglycemia Hyperglycemia Abnormally high blood glucose level. Diabetes Mellitus in Cushing’s syndrome)
• Radiotherapy: 
  • Used when surgical methods fail to achieve remission Remission A spontaneous diminution or abatement of a disease over time, without formal treatment. Cluster Headaches
  • 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 Tumor Inflammation: surgical excision
• Unresectable tumor Tumor Inflammation: Use adrenal enzyme inhibitors ( metyrapone Metyrapone An inhibitor of the enzyme steroid 11-beta-monooxygenase. It is used as a test of the feedback hypothalamic-pituitary mechanism in the diagnosis of Cushing syndrome. Adrenal Insufficiency and Addison Disease, ketoconazole Ketoconazole Broad spectrum antifungal agent used for long periods at high doses, especially in immunosuppressed patients. Azoles, mitotane).

Outcomes and prognosis Prognosis A prediction of the probable outcome of a disease based on a individual’s condition and the usual course of the disease as seen in similar situations. Non-Hodgkin Lymphomas

• 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 Diabetes 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) may persist but improve over time.
  • Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship at risk for adrenal insufficiency Adrenal Insufficiency Conditions in which the production of adrenal corticosteroids falls below the requirement of the body. Adrenal insufficiency can be caused by defects in the adrenal glands, the pituitary gland, or the hypothalamus. Adrenal Insufficiency and Addison Disease (e.g., bilateral adrenalectomy) would need glucocorticoid replacement.
• Nelson syndrome can develop in up to 25% of patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship who undergo bilateral adrenalectomy:
  • Enlarging pituitary Pituitary A small, unpaired gland situated in the sella turcica. It is connected to the hypothalamus by a short stalk which is called the infundibulum. Hormones: Overview and Types tumor Tumor Inflammation occurring after bilateral adrenalectomy
  • Presumed to be from growing ACTH-secreting cells in a previously undetected pituitary Pituitary A small, unpaired gland situated in the sella turcica. It is connected to the hypothalamus by a short stalk which is called the infundibulum. Hormones: Overview and Types 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: Anatomy, there is no glucocorticoid negative feedback Negative feedback Hypothalamic and Pituitary Hormones; thus, pituitary Pituitary A small, unpaired gland situated in the sella turcica. It is connected to the hypothalamus by a short stalk which is called the infundibulum. Hormones: Overview and Types 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 Mortality All deaths reported in a given population. Measures of Health Status is related to:
  • Cardiovascular disease
  • Thromboembolic events
  • Infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease
• If hypercortisolism is associated with a tumor Tumor Inflammation, the prognosis Prognosis A prediction of the probable outcome of a disease based on a individual’s condition and the usual course of the disease as seen in similar situations. Non-Hodgkin Lymphomas is related to the nature (e.g., malignancy Malignancy Hemothorax) of the tumor Tumor Inflammation and the severity of hypercortisolism.

Clinical Relevance

• Pituitary Pituitary A small, unpaired gland situated in the sella turcica. It is connected to the hypothalamus by a short stalk which is called the infundibulum. Hormones: Overview and Types adenoma: tumors that develop within the anterior lobe Anterior lobe Cerebellum: Anatomy of the pituitary Pituitary A small, unpaired gland situated in the sella turcica. It is connected to the hypothalamus by a short stalk which is called the infundibulum. Hormones: Overview and Types gland. Pituitary Pituitary A small, unpaired gland situated in the sella turcica. It is connected to the hypothalamus by a short stalk which is called the infundibulum. Hormones: Overview and Types 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 and Types. Non-functioning or non-secretory adenomas Non-Secretory Adenomas Pituitary 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 and Types but compress the surrounding pituitary Pituitary A small, unpaired gland situated in the sella turcica. It is connected to the hypothalamus by a short stalk which is called the infundibulum. Hormones: Overview and Types 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 and Types depending on the cell type they evolve from and lead to hyperpituitarism Hyperpituitarism Disease of the glandular, anterior portion of the pituitary resulting in hypersecretion of adenohypophyseal hormones such as growth hormone; prolactin; thyrotropin; luteinizing hormone; follicle stimulating hormone; and adrenocorticotropic hormone. Hyperpituitarism usually is caused by a functional adenoma. Hyperprolactinemia.
• Paraneoplastic syndrome: a constellation of signs and symptoms that arise from substances produced by the tumor Tumor Inflammation and not by a direct effect of the tumor Tumor Inflammation. Conditions can range from immunological responses to the presence of a neoplasm in the body that leads to antibody production (Lambert-Eeaton syndrome). 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 and Types, peptides, or cytokines Cytokines Non-antibody proteins secreted by inflammatory leukocytes and some non-leukocytic cells, that act as intercellular mediators. They differ from classical hormones in that they are produced by a number of tissue or cell types rather than by specialized glands. They generally act locally in a paracrine or autocrine rather than endocrine manner. Adaptive Immune Response produced by the tumor Tumor Inflammation also result in paraneoplastic syndrome (Cushing’s syndrome due to ectopic ACTH secretion Secretion Coagulation Studies).
• Adrenal insufficiency Adrenal Insufficiency Conditions in which the production of adrenal corticosteroids falls below the requirement of the body. Adrenal insufficiency can be caused by defects in the adrenal glands, the pituitary gland, or the hypothalamus. Adrenal Insufficiency and Addison Disease: 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 and Types 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: Anatomy: 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 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, 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 Primary adrenal insufficiency An adrenal disease characterized by the progressive destruction of the adrenal cortex, resulting in insufficient production of aldosterone and hydrocortisone. Clinical symptoms include anorexia; nausea; weight loss; muscle weakness; and hyperpigmentation of the skin due to increase in circulating levels of acth precursor hormone which stimulates melanocytes. Adrenal Insufficiency and Addison Disease, also called Addison’s disease, is caused by afflictions in the gland itself. Secondary adrenal insufficiency Secondary adrenal insufficiency Deficiency in pituitary adrenocorticotropic hormone (ACTH) secretion. Adrenal Insufficiency and Addison Disease occurs due to decreased production of ACTH either from prolonged glucocorticoid therapy, or pituitary Pituitary A small, unpaired gland situated in the sella turcica. It is connected to the hypothalamus by a short stalk which is called the infundibulum. Hormones: Overview and Types 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 Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma. Treatment depends on whether the disease is limited or extensive.