Adrenal Insufficiency and Addison Disease

Overview

Definition

Adrenal insufficiency (AI) is the deficiency in adrenal 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, 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, and 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.

Forms of adrenal insufficiency

• Primary (Addison’s disease): dysfunction or destruction of 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
• Secondary: conditions that cause deficiency in 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 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) secretion Secretion Coagulation Studies
• Tertiary: conditions that cause deficiency in the hypothalamic secretion Secretion Coagulation Studies of 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)

Epidemiology

• Annual 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: 4–6 cases per million people
• Secondary AI is more common than primary adrenal disorders.
• Autoimmune AI affects women more often than men.
• Most patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship are diagnosed in the 6th decade of life.

Etiology

Etiology of primary adrenal insufficiency

• Autoimmune:
  • Sporadic Sporadic Selective IgA Deficiency
  • Autoimmune polyendocrine syndrome type I (APECED (autoimmune polyendocrinopathy, candidiasis Candidiasis Candida is a genus of dimorphic, opportunistic fungi. Candida albicans is part of the normal human flora and is the most common cause of candidiasis. The clinical presentation varies and can include localized mucocutaneous infections (e.g., oropharyngeal, esophageal, intertriginous, and vulvovaginal candidiasis) and invasive disease (e.g., candidemia, intraabdominal abscess, pericarditis, and meningitis). Candida/Candidiasis, ectodermal dystrophy) syndrome):
    • Addison’s disease
    • Chronic mucocutaneous candidiasis Chronic mucocutaneous candidiasis A clinical syndrome characterized by development, usually in infancy or childhood, of a chronic, often widespread candidiasis of skin, nails, and mucous membranes. It may be secondary to one of the immunodeficiency syndromes, inherited as an autosomal recessive trait, or associated with defects in cell-mediated immunity, endocrine disorders, dental stomatitis, or malignancy. Adaptive Immune Response
    • Hypoparathyroidism Hypoparathyroidism Hypoparathyroidism is defined as reduced parathyroid hormone (PTH) levels due to poor function of the parathyroid glands. The cause of hypoparathyroidism is most commonly iatrogenic following neck surgery, but it can also be associated with genetic or autoimmune disorders as well as infiltrative diseases causing destruction of the normal parathyroid tissue. Hypoparathyroidism
    • Primary gonadal failure
    • Hypoplasia Hypoplasia Hypoplastic Left Heart Syndrome (HLHS) of the dental enamel Enamel A hard thin translucent layer of calcified substance which envelops and protects the dentin of the crown of the tooth. It is the hardest substance in the body and is almost entirely composed of calcium salts. Under the microscope, it is composed of thin rods (enamel prisms) held together by cementing substance, and surrounded by an enamel sheath. Teeth: Anatomy 
    • Nail dystrophy
  • Autoimmune polyendocrine syndrome type II:
    • Addison’s disease
    • Primary hypothyroidism Primary Hypothyroidism Hypothyroidism
    • Primary hypogonadism Primary Hypogonadism Myotonic Dystrophies
    • 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 type 1 Type 1 Spinal Muscular Atrophy
    • Pernicious anemia Pernicious anemia A megaloblastic anemia occurring in children but more commonly in later life, characterized by histamine-fast achlorhydria, in which the laboratory and clinical manifestations are based on malabsorption of vitamin B12 due to a failure of the gastric mucosa to secrete adequate and potent intrinsic factor. Megaloblastic Anemia
    • Vitiligo Vitiligo Vitiligo is the most common depigmenting disorder and is caused by the destruction of melanocytes. Patients present with hypo- or depigmented macules or patches which often occur on the face, hands, knees, and/or genitalia. Vitiligo
    • Celiac disease Celiac disease Celiac disease (also known as celiac sprue or gluten enteropathy) is an autoimmune reaction to gliadin, which is a component of gluten. Celiac disease is closely associated with HLA-DQ2 and HLA-DQ8. The immune response is localized to the proximal small intestine and causes the characteristic histologic findings of villous atrophy, crypt hyperplasia, and intraepithelial lymphocytosis. Celiac Disease
• 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:
  • Tuberculosis Tuberculosis Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis complex bacteria. The bacteria usually attack the lungs but can also damage other parts of the body. Approximately 30% of people around the world are infected with this pathogen, with the majority harboring a latent infection. Tuberculosis spreads through the air when a person with active pulmonary infection coughs or sneezes. Tuberculosis
  • Fungal 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 ( coccidioidomycosis Coccidioidomycosis Coccidioidomycosis, commonly known as San Joaquin Valley fever, is a fungal disease caused by Coccidioides immitis or Coccidioides posadasii. When Coccidioides spores are inhaled, they transform into spherules that result in infection. Coccidioidomycosis is also a common cause of community-acquired pneumonia and can cause severe disease in the immunocompromised. Coccidioides/Coccidioidomycosis, histoplasmosis Histoplasmosis Histoplasmosis is an infection caused by Histoplasma capsulatum, a dimorphic fungus. Transmission is through inhalation, and exposure to soils containing bird or bat droppings increases the risk of infection. Most infections are asymptomatic; however, immunocompromised individuals generally develop acute pulmonary infection, chronic infection, or even disseminated disease. Histoplasma/Histoplasmosis)
  • Cytomegalovirus Cytomegalovirus CMV is a ubiquitous double-stranded DNA virus belonging to the Herpesviridae family. CMV infections can be transmitted in bodily fluids, such as blood, saliva, urine, semen, and breast milk. The initial infection is usually asymptomatic in the immunocompetent host, or it can present with symptoms of mononucleosis. Cytomegalovirus
  • HIV HIV Anti-HIV Drugs
• Infiltrations:
  • Sarcoidosis Sarcoidosis Sarcoidosis is a multisystem inflammatory disease that causes noncaseating granulomas. The exact etiology is unknown. Sarcoidosis usually affects the lungs and thoracic lymph nodes, but it can also affect almost every system in the body, including the skin, heart, and eyes, most commonly. Sarcoidosis
  • Amyloid
  • Hemochromatosis Hemochromatosis A disorder of iron metabolism characterized by a triad of hemosiderosis; liver cirrhosis; and diabetes mellitus. It is caused by massive iron deposits in parenchymal cells that may develop after a prolonged increase of iron absorption. Hereditary Hemochromatosis
• Malignancies:
  • Metastases
  • Lymphoma Lymphoma A general term for various neoplastic diseases of the lymphoid tissue. Imaging of the Mediastinum
• Intra-adrenal hemorrhage (Waterhouse–Friderichsen syndrome) after meningococcal septicemia
• Adrenoleukodystrophies
• Congenital Congenital Chorioretinitis 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
• ACTH resistance Resistance Physiologically, the opposition to flow of air caused by the forces of friction. As a part of pulmonary function testing, it is the ratio of driving pressure to the rate of air flow. Ventilation: Mechanics of Breathing syndromes (familial glucocorticoid resistance Resistance Physiologically, the opposition to flow of air caused by the forces of friction. As a part of pulmonary function testing, it is the ratio of driving pressure to the rate of air flow. Ventilation: Mechanics of Breathing)
• Bilateral adrenalectomy Adrenalectomy Excision of one or both adrenal glands. Cushing Syndrome
• Drug-induced (e.g., mitotane, ketoconazole Ketoconazole Broad spectrum antifungal agent used for long periods at high doses, especially in immunosuppressed patients. Azoles, etomidate Etomidate Imidazole derivative anesthetic and hypnotic with little effect on blood gases, ventilation, or the cardiovascular system. It has been proposed as an induction anesthetic. Intravenous Anesthetics, suramin, aminoglutethimide)

Etiology of secondary and tertiary adrenal insufficiency

Consequence of dysfunction of the 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 and 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:

• Secondary:
  • 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
    • Pituitary tumors Pituitary tumors Neoplasms which arise from or metastasize to the pituitary gland. The majority of pituitary neoplasms are adenomas, which are divided into non-secreting and secreting forms. Hormone producing forms are further classified by the type of hormone they secrete. Pituitary adenomas may also be characterized by their staining properties. Pituitary tumors may compress adjacent structures, including the hypothalamus, several cranial nerves, and the optic chiasm. Chiasmal compression may result in bitemporal hemianopsia. Pituitary Adenomas and surgery
    • Granulomatous disease Granulomatous disease A defect of leukocyte function in which phagocytic cells ingest but fail to digest bacteria, resulting in recurring bacterial infections with granuloma formation. When chronic granulomatous disease is caused by mutations in the cybb gene, the condition is inherited in an X-linked recessive pattern. When chronic granulomatous disease is caused by cyba, ncf1, ncf2, or ncf4 gene mutations, the condition is inherited in an autosomal recessive pattern. Common Variable Immunodeficiency (CVID) ( tuberculosis Tuberculosis Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis complex bacteria. The bacteria usually attack the lungs but can also damage other parts of the body. Approximately 30% of people around the world are infected with this pathogen, with the majority harboring a latent infection. Tuberculosis spreads through the air when a person with active pulmonary infection coughs or sneezes. Tuberculosis, sarcoid, eosinophilic granuloma)
    • Postpartum 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 infarction ( Sheehan’s syndrome Sheehan’s syndrome Postpartum pituitary necrosis caused by blood loss during childbirth. Hypopituitarism)
  • Isolated ACTH deficiency:
    • Lymphocytic hypophysitis (selective corticotroph absence)
    • POMC gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics mutations
    • TPIT gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics mutations
  • Familial cortisol-binding globulin deficiency
• Tertiary:
  • Prolonged high-dose glucocorticoid use
  • Effect of Cushing’s syndrome treatment:
    • Chronic elevation 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 (e.g., from tumor Tumor Inflammation effects) has suppressed the 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– 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–adrenal axis.
    • The patient still has low cortisol Cortisol Glucocorticoids levels (due to chronic suppression Suppression Defense Mechanisms) up to a year after surgery and requires glucocorticoid therapy.

Pathophysiology

Hormonal regulation

• Hypothalamic– 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–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, release 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).
    • The 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 Renin A highly specific (leu-leu) endopeptidase that generates angiotensin I from its precursor angiotensinogen, leading to a cascade of reactions which elevate blood pressure and increase sodium retention by the kidney in the renin-angiotensin system. Renal Sodium and Water Regulation–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. Metabolic Dysfunction-associated Steatotic Liver Disease (MASLD) → 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 (producing ↑ blood pressure)
  • Antiinflammatory 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:
  • 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 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 sulfate (DHEA-S) 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 great quantities. 
  • 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).
    • In males, the 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.
• 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

Adrenal insufficiency

Primary AI:

• Manifestations emerge when > 90% of 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 ( 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, fasciculata, and reticularis) is destroyed.
• Hypocortisolism, hypoaldosteronism Hypoaldosteronism Hypoaldosteronism is a hormonal disorder characterized by low levels of aldosterone. These low levels can be caused by decreased aldosterone production or a peripheral resistance to aldosterone. When hypoaldosteronism occurs as a result of an acquired decrease in renin production, the condition is more commonly referred to as renal tubular acidosis (RTA) type 4. Hypoaldosteronism, and hypoandrogenism (men still produce 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 testes Testes Gonadal Hormones) 
• Compensatory ↑ ACTH:
  • Leads to hyperpigmentation Hyperpigmentation Excessive pigmentation of the skin, usually as a result of increased epidermal or dermal melanin pigmentation, hypermelanosis. Hyperpigmentation can be localized or generalized. The condition may arise from exposure to light, chemicals or other substances, or from a primary metabolic imbalance. Malassezia Fungi
  • Both ACTH and ɑ-melanin-stimulating hormone are derived from pro-opiomelanocortin (POMC) → melanocytes Melanocytes Mammalian pigment cells that produce melanins, pigments found mainly in the epidermis, but also in the eyes and the hair, by a process called melanogenesis. Coloration can be altered by the number of melanocytes or the amount of pigment produced and stored in the organelles called melanosomes. The large non-mammalian melanin-containing cells are called melanophores. Skin: Structure and Functions stimulated

Secondary AI:

• ↓ ACTH → hypocortisolism and hypoandrogenism
• 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 production preserved (as primary regulation is through the renin Renin A highly specific (leu-leu) endopeptidase that generates angiotensin I from its precursor angiotensinogen, leading to a cascade of reactions which elevate blood pressure and increase sodium retention by the kidney in the renin-angiotensin system. Renal Sodium and Water Regulation–angiotensin system)
• No hyperpigmentation Hyperpigmentation Excessive pigmentation of the skin, usually as a result of increased epidermal or dermal melanin pigmentation, hypermelanosis. Hyperpigmentation can be localized or generalized. The condition may arise from exposure to light, chemicals or other substances, or from a primary metabolic imbalance. Malassezia Fungi, as ACTH is not increased

Tertiary AI:

• ↓ CRH → ↓ ACTH → hypocortisolism and hypoandrogenism
• 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 production preserved

Clinical Presentation

Primary adrenal insufficiency

• Glucocorticoid + mineralocorticoid + androgen deficiency
• ↓ 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:
  • Fatigue Fatigue The state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli. Fibromyalgia
  • Weight loss Weight loss Decrease in existing body weight. Bariatric Surgery/ anorexia Anorexia The lack or loss of appetite accompanied by an aversion to food and the inability to eat. It is the defining characteristic of the disorder anorexia nervosa. Anorexia Nervosa
  • Myalgia Myalgia Painful sensation in the muscles. Ion Channel Myopathy/joint pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways
  • Abdominal pain Abdominal Pain Acute Abdomen/ diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea
  • Hypotension Hypotension Hypotension is defined as low blood pressure, specifically < 90/60 mm Hg, and is most commonly a physiologic response. Hypotension may be mild, serious, or life threatening, depending on the cause. Hypotension
  • Hypoglycemia Hypoglycemia Hypoglycemia is an emergency condition defined as a serum glucose level ≤ 70 mg/dL (≤ 3.9 mmol/L) in diabetic patients. In nondiabetic patients, there is no specific or defined limit for normal serum glucose levels, and hypoglycemia is defined mainly by its clinical features. Hypoglycemia
  • Hyponatremia Hyponatremia Hyponatremia is defined as a decreased serum sodium (sNa+) concentration less than 135 mmol/L. Serum sodium is the greatest contributor to plasma osmolality, which is very tightly controlled via antidiuretic hormone (ADH) release from the hypothalamus and by the thirst mechanism. Hyponatremia (due to ↑ antidiuretic hormone Antidiuretic hormone Antidiuretic hormones released by the neurohypophysis of all vertebrates (structure varies with species) to regulate water balance and osmolarity. In general, vasopressin is a nonapeptide consisting of a six-amino-acid ring with a cysteine 1 to cysteine 6 disulfide bridge or an octapeptide containing a cystine. All mammals have arginine vasopressin except the pig with a lysine at position 8. Vasopressin, a vasoconstrictor, acts on the kidney collecting ducts to increase water reabsorption, increase blood volume and blood pressure. Hypernatremia)
• ↓ 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:
  • Hypotension Hypotension Hypotension is defined as low blood pressure, specifically < 90/60 mm Hg, and is most commonly a physiologic response. Hypotension may be mild, serious, or life threatening, depending on the cause. Hypotension
  • Salt craving
  • Hyperkalemia Hyperkalemia Hyperkalemia is defined as a serum potassium (K+) concentration >5.2 mEq/L. Homeostatic mechanisms maintain the serum K+ concentration between 3.5 and 5.2 mEq/L, despite marked variation in dietary intake. Hyperkalemia can be due to a variety of causes, which include transcellular shifts, tissue breakdown, inadequate renal excretion, and drugs. Hyperkalemia, hyponatremia Hyponatremia Hyponatremia is defined as a decreased serum sodium (sNa+) concentration less than 135 mmol/L. Serum sodium is the greatest contributor to plasma osmolality, which is very tightly controlled via antidiuretic hormone (ADH) release from the hypothalamus and by the thirst mechanism. Hyponatremia
• ↓ 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:
  • ↓ Axillary and pubic hair
  • Loss of libido Loss of libido Male Sexual Dysfunction 
  • Amenorrhea Amenorrhea Absence of menstruation. Congenital Malformations of the Female Reproductive System in women 
• Hyperpigmentation Hyperpigmentation Excessive pigmentation of the skin, usually as a result of increased epidermal or dermal melanin pigmentation, hypermelanosis. Hyperpigmentation can be localized or generalized. The condition may arise from exposure to light, chemicals or other substances, or from a primary metabolic imbalance. Malassezia Fungi from ↑ ACTH

Secondary and tertiary adrenal insufficiency

• Glucocorticoid + androgen deficiency
• Mineralocorticoid production preserved
• No hyperpigmentation Hyperpigmentation Excessive pigmentation of the skin, usually as a result of increased epidermal or dermal melanin pigmentation, hypermelanosis. Hyperpigmentation can be localized or generalized. The condition may arise from exposure to light, chemicals or other substances, or from a primary metabolic imbalance. Malassezia Fungi

Adrenal crisis

Adrenal crisis is the acute decompensation of adrenal function that can be triggered by another disease, surgery, stress, or increased glucocorticoid inactivation ( hyperthyroidism Hyperthyroidism Hypersecretion of thyroid hormones from the thyroid gland. Elevated levels of thyroid hormones increase basal metabolic rate. Thyrotoxicosis and Hyperthyroidism).

Presentation:

• Hypovolemic shock Hypovolemic Shock Types of Shock (from reduced volume and mineralocorticoid deficiency)
• Can mimic acute abdomen Acute Abdomen Acute abdomen, which is in many cases a surgical emergency, is the sudden onset of abdominal pain that may be caused by inflammation, infection, perforation, ischemia, or obstruction. The location of the pain, its characteristics, and associated symptoms (e.g., jaundice) are important tools that help narrow the differential diagnosis. Acute Abdomen (abdominal tenderness, nausea Nausea An unpleasant sensation in the stomach usually accompanied by the urge to vomit. Common causes are early pregnancy, sea and motion sickness, emotional stress, intense pain, food poisoning, and various enteroviruses. Antiemetics, vomiting Vomiting The forcible expulsion of the contents of the stomach through the mouth. Hypokalemia, fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever)
• Decreased responsiveness progressing to coma Coma Coma is defined as a deep state of unarousable unresponsiveness, characterized by a score of 3 points on the GCS. A comatose state can be caused by a multitude of conditions, making the precise epidemiology and prognosis of coma difficult to determine. Coma

Diagnosis

Initial tests for hypocortisolism

• Morning serum cortisol Cortisol Glucocorticoids:
  • Normal: 10–20 µg/dL 
  • ≥ 18 µg/dL is a reassuring level and predicts a normal cosyntropin test.
  • Low cortisol Cortisol Glucocorticoids (≤ 3 µg/dL): strongly suggests AI
• ACTH levels:
  • Obtain baseline level simultaneously with morning cortisol Cortisol Glucocorticoids:
    • ↑ ACTH: suggests primary AI
    • ↓  Or normal ACTH: suggests secondary/tertiary AI
• Standard high-dose ACTH-stimulation test:
  • Obtain baseline cortisol Cortisol Glucocorticoids and ACTH.
  • 250 µg of IV or IM ACTH (1-24)/cosyntropin administered, with measurement of serum cortisol Cortisol Glucocorticoids concentrations at 30 and 60 minutes 
  • Low cortisol Cortisol Glucocorticoids (< 18–20 µg/dL) after 30 and 60 minutes indicates AI.
    • Primary AI: confirmed if with ↑ basal ACTH
    • Secondary AI: confirmed if with ↓ or low normal basal ACTH
• Basal renin Renin A highly specific (leu-leu) endopeptidase that generates angiotensin I from its precursor angiotensinogen, leading to a cascade of reactions which elevate blood pressure and increase sodium retention by the kidney in the renin-angiotensin system. Renal Sodium and Water Regulation, 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, and electrolyte levels help in interpretation, especially in primary AI.

Additional tests for hypothalamic– 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–adrenal function

Performed when initial tests are indeterminate

• Metyrapone test:
  • Metyrapone blocks conversion of 11-deoxycortisol to cortisol Cortisol Glucocorticoids.
  • Oral metyrapone given, followed by obtaining 11-deoxycortisol and cortisol Cortisol Glucocorticoids after 24 hours
  • Primary AI: ↑ ACTH but no increase in 11-deoxycortisol and cortisol Cortisol Glucocorticoids 
  • Secondary/tertiary AI: low ACTH, no increase in 11-deoxycortisol and cortisol Cortisol Glucocorticoids 
• Insulin-induced hypoglycemia Hypoglycemia Hypoglycemia is an emergency condition defined as a serum glucose level ≤ 70 mg/dL (≤ 3.9 mmol/L) in diabetic patients. In nondiabetic patients, there is no specific or defined limit for normal serum glucose levels, and hypoglycemia is defined mainly by its clinical features. Hypoglycemia test:
  • Insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin causes ↓ 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, which in turn, triggers cortisol Cortisol Glucocorticoids secretion Secretion Coagulation Studies in normal circumstances.
  • Inject insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin.
  • 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, ACTH, and cortisol Cortisol Glucocorticoids are measured in intervals.
  • Primary AI: ↑ ACTH without increase in cortisol Cortisol Glucocorticoids despite hypoglycemia Hypoglycemia Hypoglycemia is an emergency condition defined as a serum glucose level ≤ 70 mg/dL (≤ 3.9 mmol/L) in diabetic patients. In nondiabetic patients, there is no specific or defined limit for normal serum glucose levels, and hypoglycemia is defined mainly by its clinical features. Hypoglycemia
  • Secondary AI: Inadequate ↑ in cortisol Cortisol Glucocorticoids and ACTH at the onset of hypoglycemia Hypoglycemia Hypoglycemia is an emergency condition defined as a serum glucose level ≤ 70 mg/dL (≤ 3.9 mmol/L) in diabetic patients. In nondiabetic patients, there is no specific or defined limit for normal serum glucose levels, and hypoglycemia is defined mainly by its clinical features. Hypoglycemia 
  • Contraindicated in cardiovascular disease and seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures
• 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 test differentiates secondary from tertiary adrenal insufficiency.
  • Secondary AI: no ACTH response
  • Tertiary AI: ↑ ACTH response
  • Does not make a difference in therapy

Diagnosing the etiology

In suspected primary AI:

• Review medications (rule out drug-induced AI).
• Adrenocortical antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins: Types and Functions or antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins: Types and Functions against 21-hydroxylase:
  • Autoimmune adrenalitis
  • Autoimmune polyendocrine syndrome (proceed with other tests for hypoparathyroidism Hypoparathyroidism Hypoparathyroidism is defined as reduced parathyroid hormone (PTH) levels due to poor function of the parathyroid glands. The cause of hypoparathyroidism is most commonly iatrogenic following neck surgery, but it can also be associated with genetic or autoimmune disorders as well as infiltrative diseases causing destruction of the normal parathyroid tissue. Hypoparathyroidism, 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, thyroid Thyroid The thyroid gland is one of the largest endocrine glands in the human body. The thyroid gland is a highly vascular, brownish-red gland located in the visceral compartment of the anterior region of the neck. Thyroid Gland: Anatomy disease)
• Plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products very-long-chain 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 (VLCFAs):
  • In male patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with isolated Addison’s disease and negative autoantibodies Autoantibodies Antibodies that react with self-antigens (autoantigens) of the organism that produced them. Blotting Techniques 
  • Elevated in adrenoleukodystrophy ( genetic testing Genetic Testing Detection of a mutation; genotype; karyotype; or specific alleles associated with genetic traits, heritable diseases, or predisposition to a disease, or that may lead to the disease in descendants. It includes prenatal genetic testing. Myotonic Dystrophies required)
• In children in whom AI presents in infancy or childhood:
  • Serum 17-hydroxyprogesterone (17-OHP)
  • Routine newborn Newborn An infant during the first 28 days after birth. Physical Examination of the Newborn screening Screening Preoperative Care
• CT 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:
  • Tuberculous adrenalitis: spotty calcifications late in the disease 
  • May detect malignancy Malignancy Hemothorax such as lymphoma Lymphoma A general term for various neoplastic diseases of the lymphoid tissue. Imaging of the Mediastinum and adrenal metastases
  • Adrenal infiltration ( sarcoidosis Sarcoidosis Sarcoidosis is a multisystem inflammatory disease that causes noncaseating granulomas. The exact etiology is unknown. Sarcoidosis usually affects the lungs and thoracic lymph nodes, but it can also affect almost every system in the body, including the skin, heart, and eyes, most commonly. Sarcoidosis, amyloidosis Amyloidosis Amyloidosis is a disease caused by abnormal extracellular tissue deposition of fibrils composed of various misfolded low-molecular-weight protein subunits. These proteins are frequently byproducts of other pathological processes (e.g., multiple myeloma). Amyloidosis, hemochromatosis Hemochromatosis A disorder of iron metabolism characterized by a triad of hemosiderosis; liver cirrhosis; and diabetes mellitus. It is caused by massive iron deposits in parenchymal cells that may develop after a prolonged increase of iron absorption. Hereditary Hemochromatosis) 
  • Adrenal hemorrhage

In suspected secondary/tertiary AI:

• Workup of 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 (e.g., thyroid-stimulating hormone Thyroid-stimulating hormone A glycoprotein hormone secreted by the adenohypophysis. Thyrotropin stimulates thyroid gland by increasing the iodide transport, synthesis and release of thyroid hormones (thyroxine and triiodothyronine). Thyroid Hormones (TSH))
• MRI of the 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 and 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

Management

Chronic adrenal insufficiency

Primary AI:

• Glucocorticoid replacement:
  • Oral hydrocortisone Hydrocortisone The main glucocorticoid secreted by the adrenal cortex. Its synthetic counterpart is used, either as an injection or topically, in the treatment of inflammation, allergy, collagen diseases, asthma, adrenocortical deficiency, shock, and some neoplastic conditions. Immunosuppressants (in 2 to 3 divided doses to mimic diurnal rhythm)
  • Situations of stress require escalated doses (e.g., surgery, infection).
• Mineralocorticoid replacement:
  • Prevention of hyperkalemia Hyperkalemia Hyperkalemia is defined as a serum potassium (K+) concentration >5.2 mEq/L. Homeostatic mechanisms maintain the serum K+ concentration between 3.5 and 5.2 mEq/L, despite marked variation in dietary intake. Hyperkalemia can be due to a variety of causes, which include transcellular shifts, tissue breakdown, inadequate renal excretion, and drugs. Hyperkalemia, loss of fluids and sodium Sodium A member of the alkali group of metals. It has the atomic symbol na, atomic number 11, and atomic weight 23. Hyponatremia
  • Fludrocortisone Fludrocortisone A synthetic mineralocorticoid with anti-inflammatory activity. Mineralocorticoids daily
  • Dose increased in warm weather due to salt loss in perspiration
  • Monitor BP, electrolytes Electrolytes Electrolytes are mineral salts that dissolve in water and dissociate into charged particles called ions, which can be either be positively (cations) or negatively (anions) charged. Electrolytes are distributed in the extracellular and intracellular compartments in different concentrations. Electrolytes are essential for various basic life-sustaining functions. Electrolytes, renin Renin A highly specific (leu-leu) endopeptidase that generates angiotensin I from its precursor angiotensinogen, leading to a cascade of reactions which elevate blood pressure and increase sodium retention by the kidney in the renin-angiotensin system. Renal Sodium and Water Regulation
• Adrenal androgen replacement:
  • In women, the adrenal gland is 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.
  • 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 may improve loss of libido Loss of libido Male Sexual Dysfunction and/or low energy levels in women.
• Underlying causes must be treated (e.g., resection of tumors, antibiotics for 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).

Secondary and tertiary AI:

• Glucocorticoid replacement:
  • Similar to primary AI
  • ACTH not used for monitoring and titration of glucocorticoid dose
• Mineralocorticoid replacement rarely required
• Replacement of other 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 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 if indicated

Adrenal crisis

• Acute AI is a life-threatening emergency!
• Clinical suspicion of adrenal crisis requires immediate therapy even before diagnosis is established.
• Serum cortisol Cortisol Glucocorticoids and electrolytes Electrolytes Electrolytes are mineral salts that dissolve in water and dissociate into charged particles called ions, which can be either be positively (cations) or negatively (anions) charged. Electrolytes are distributed in the extracellular and intracellular compartments in different concentrations. Electrolytes are essential for various basic life-sustaining functions. Electrolytes are drawn and treatment is given.
• In some cases, samples of blood are held for possible later testing (ACTH, renin Renin A highly specific (leu-leu) endopeptidase that generates angiotensin I from its precursor angiotensinogen, leading to a cascade of reactions which elevate blood pressure and increase sodium retention by the kidney in the renin-angiotensin system. Renal Sodium and Water Regulation, 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) if initial cortisol Cortisol Glucocorticoids suggests AI.
• 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/mineralocorticoid deficiency leads to:
  • Wasting of sodium Sodium A member of the alkali group of metals. It has the atomic symbol na, atomic number 11, and atomic weight 23. Hyponatremia (↓ Na⁺)
  • Positively charged ions (↑ K⁺ and H⁺) are retained → hyperkalemia Hyperkalemia Hyperkalemia is defined as a serum potassium (K+) concentration >5.2 mEq/L. Homeostatic mechanisms maintain the serum K+ concentration between 3.5 and 5.2 mEq/L, despite marked variation in dietary intake. Hyperkalemia can be due to a variety of causes, which include transcellular shifts, tissue breakdown, inadequate renal excretion, and drugs. Hyperkalemia and non–anion-gap metabolic acidosis Acidosis A pathologic condition of acid accumulation or depletion of base in the body. The two main types are respiratory acidosis and metabolic acidosis, due to metabolic acid build up. Respiratory Acidosis
• Initial management:
  • IV fluid resuscitation Resuscitation The restoration to life or consciousness of one apparently dead. . Neonatal Respiratory Distress Syndrome (avoid hypotonic Hypotonic Solutions that have a lesser osmotic pressure than a reference solution such as blood, plasma, or interstitial fluid. Renal Sodium and Water Regulation solution, which can worsen hyponatremia Hyponatremia Hyponatremia is defined as a decreased serum sodium (sNa+) concentration less than 135 mmol/L. Serum sodium is the greatest contributor to plasma osmolality, which is very tightly controlled via antidiuretic hormone (ADH) release from the hypothalamus and by the thirst mechanism. Hyponatremia)
  • Blood drawn (serum cortisol Cortisol Glucocorticoids, ACTH, 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, renin Renin A highly specific (leu-leu) endopeptidase that generates angiotensin I from its precursor angiotensinogen, leading to a cascade of reactions which elevate blood pressure and increase sodium retention by the kidney in the renin-angiotensin system. Renal Sodium and Water Regulation, and chemistries)
  • IV hydrocortisone Hydrocortisone The main glucocorticoid secreted by the adrenal cortex. Its synthetic counterpart is used, either as an injection or topically, in the treatment of inflammation, allergy, collagen diseases, asthma, adrenocortical deficiency, shock, and some neoplastic conditions. Immunosuppressants (has mineralocorticoid activity): 100-mg bolus, then 50 mg every 6 hours
  • Alternatives:
    • Prednisolone Prednisolone A glucocorticoid with the general properties of the corticosteroids. It is the drug of choice for all conditions in which routine systemic corticosteroid therapy is indicated, except adrenal deficiency states. Immunosuppressants
    • Prednisone Prednisone A synthetic anti-inflammatory glucocorticoid derived from cortisone. It is biologically inert and converted to prednisolone in the liver. Immunosuppressants
    • Dexamethasone Dexamethasone An anti-inflammatory 9-fluoro-glucocorticoid. Antiemetics
  • Treat hypoglycemia Hypoglycemia Hypoglycemia is an emergency condition defined as a serum glucose level ≤ 70 mg/dL (≤ 3.9 mmol/L) in diabetic patients. In nondiabetic patients, there is no specific or defined limit for normal serum glucose levels, and hypoglycemia is defined mainly by its clinical features. Hypoglycemia.
• Search for underlying condition and treat accordingly.

Clinical Relevance

• 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: 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 hormone deficiency, resulting from a disease 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 (commonly tumors), but may arise from hypothalamic dysfunction: The anterior lobe Anterior lobe Cerebellum: Anatomy produces growth hormone, follicle-stimulating hormone, luteinizing hormone, TSH, ACTH, and prolactin Prolactin A lactogenic hormone secreted by the adenohypophysis. It is a polypeptide of approximately 23 kd. Besides its major action on lactation, in some species prolactin exerts effects on reproduction, maternal behavior, fat metabolism, immunomodulation and osmoregulation. Breasts: Anatomy. Loss of antidiuretic hormone Antidiuretic hormone Antidiuretic hormones released by the neurohypophysis of all vertebrates (structure varies with species) to regulate water balance and osmolarity. In general, vasopressin is a nonapeptide consisting of a six-amino-acid ring with a cysteine 1 to cysteine 6 disulfide bridge or an octapeptide containing a cystine. All mammals have arginine vasopressin except the pig with a lysine at position 8. Vasopressin, a vasoconstrictor, acts on the kidney collecting ducts to increase water reabsorption, increase blood volume and blood pressure. Hypernatremia and oxytocin occurs in posterior lobe Posterior lobe Cerebellum: Anatomy damage. Diagnosis is via hormone levels, provocation tests, and brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification imaging. Treatment is hormonal replacement.
• Syndrome of inappropriate antidiuretic hormone Antidiuretic hormone Antidiuretic hormones released by the neurohypophysis of all vertebrates (structure varies with species) to regulate water balance and osmolarity. In general, vasopressin is a nonapeptide consisting of a six-amino-acid ring with a cysteine 1 to cysteine 6 disulfide bridge or an octapeptide containing a cystine. All mammals have arginine vasopressin except the pig with a lysine at position 8. Vasopressin, a vasoconstrictor, acts on the kidney collecting ducts to increase water reabsorption, increase blood volume and blood pressure. Hypernatremia ( SIADH SIADH Syndrome of inappropriate antidiuretic hormone secretion (SIADH) is a disorder of impaired water excretion due to the inability to suppress the secretion of antidiuretic hormone (ADH). SIADH is characterized by impaired water excretion leading to dilutional hyponatremia, which is mainly asymptomatic but may cause neurologic symptoms. S Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH)): disorder of impaired water excretion due to the inability to suppress the secretion Secretion Coagulation Studies of ADH/vasopressin: This disorder can be due to disease, medications, ectopic secretion Secretion Coagulation Studies by cancer, or hereditary causes (nephrogenic SIADH SIADH Syndrome of inappropriate antidiuretic hormone secretion (SIADH) is a disorder of impaired water excretion due to the inability to suppress the secretion of antidiuretic hormone (ADH). SIADH is characterized by impaired water excretion leading to dilutional hyponatremia, which is mainly asymptomatic but may cause neurologic symptoms. S Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH)). SIADH SIADH Syndrome of inappropriate antidiuretic hormone secretion (SIADH) is a disorder of impaired water excretion due to the inability to suppress the secretion of antidiuretic hormone (ADH). SIADH is characterized by impaired water excretion leading to dilutional hyponatremia, which is mainly asymptomatic but may cause neurologic symptoms. S Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) also occurs in cortisol Cortisol Glucocorticoids deficiency. Loss of cortisol Cortisol Glucocorticoids results in absence of negative feedback Negative feedback Hypothalamic and Pituitary Hormones on ADH secretion Secretion Coagulation Studies, increasing ADH. Low cortisol Cortisol Glucocorticoids also triggers increased CRH, an ADH secretagogue. Hyponatremia Hyponatremia Hyponatremia is defined as a decreased serum sodium (sNa+) concentration less than 135 mmol/L. Serum sodium is the greatest contributor to plasma osmolality, which is very tightly controlled via antidiuretic hormone (ADH) release from the hypothalamus and by the thirst mechanism. Hyponatremia and hypoosmolality are findings. Management depends on the underlying etiology.
• Congenital Congenital Chorioretinitis 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 ( CAH CAH Congenital adrenal hyperplasia (CAH) consists of a group of autosomal recessive disorders that cause a deficiency of an enzyme needed in cortisol, aldosterone, and androgen synthesis. The most common subform of cah is 21-hydroxylase deficiency, followed by 11β-hydroxylase deficiency. Congenital Adrenal Hyperplasia):  inherited autosomal recessive Autosomal recessive Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal recessive diseases are only expressed when 2 copies of the recessive allele are inherited. Autosomal Recessive and Autosomal Dominant Inheritance disease characterized by enzyme deficiency that impairs adrenal hormone production, which results in the overproduction of the hormone precursor: 95% of CAH CAH Congenital adrenal hyperplasia (CAH) consists of a group of autosomal recessive disorders that cause a deficiency of an enzyme needed in cortisol, aldosterone, and androgen synthesis. The most common subform of cah is 21-hydroxylase deficiency, followed by 11β-hydroxylase deficiency. Congenital Adrenal Hyperplasia is due to the absence of the enzyme 21-hydroxylase, leading to inability to produce cortisol Cortisol Glucocorticoids, and often accompanied by salt wasting. Females exhibit atypical genitalia from virilizing effects (increased androgen from 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). Neonatal screening Screening Preoperative Care is by measurement of 17-OHP (elevated). Management involves glucocorticoid and mineralocorticoid therapy. 
• Adrenoleukodystrophy: a rare X-linked X-linked Genetic diseases that are linked to gene mutations on the X chromosome in humans or the X chromosome in other species. Included here are animal models of human X-linked diseases. Common Variable Immunodeficiency (CVID) genetic disorder caused by a mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations in the ABCD1 gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics and associated with buildup of VLCFAs: This buildup causes destruction of the myelin sheath of nerves, 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, and testes Testes Gonadal Hormones. Children have learning disabilities Learning disabilities Conditions characterized by a significant discrepancy between an individual’s perceived level of intellect and their ability to acquire new language and other cognitive skills. These may result from organic or psychological conditions. Relatively common subtypes include dyslexia, dyscalculia, and dysgraphia. DiGeorge Syndrome, behavior problems, and quadriparesis. Adrenoleukodystrophy can present in adulthood, with young adults having spinal cord Spinal cord The spinal cord is the major conduction pathway connecting the brain to the body; it is part of the CNS. In cross section, the spinal cord is divided into an H-shaped area of gray matter (consisting of synapsing neuronal cell bodies) and a surrounding area of white matter (consisting of ascending and descending tracts of myelinated axons). Spinal Cord: Anatomy and gonadal dysfunction. Adrenal insufficiency is one of the manifestations. Diagnosis is via a VLCFA panel. Treatment options include glucocorticoid therapy, hematopoietic-cell transplantation, and supportive interventions.