Overview

Regions of the adrenal gland

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 have 2 primary areas with separate functions and regulatory mechanisms.

• Adrenal medulla:
  • Inner portion
  • Secretes catecholamines
  • Functions in conjunction with the sympathetic nervous system Nervous system The nervous system is a small and complex system that consists of an intricate network of neural cells (or neurons) and even more glial cells (for support and insulation). It is divided according to its anatomical components as well as its functional characteristics. The brain and spinal cord are referred to as the central nervous system, and the branches of nerves from these structures are referred to as the peripheral nervous system. General Structure of the Nervous System
• Adrenal cortex:
  • Outer portion
  • All cortical hormones are synthesized from cholesterol
  • Has 3 different zones:
    • Zona glomerulosa: secretes 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
    • Zona fasciculata: secretes 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
    • Zona reticularis: secretes 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
  • Part of the hypothalamic-pituitary-adrenal (HPA) axis

Hypothalamic-pituitary-adrenal (HPA) axis

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 secreted by the adrenal cortex (not the medulla) are controlled by, and help regulate, the HPA axis.

• 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 (paraventricular nucleus) secretes corticotropin-releasing hormone (CRH).
• CRH stimulates the anterior pituitary to release adrenocorticotropic hormone (ACTH).
• ACTH stimulates the adrenal cortex to synthesize and release all of the cortical hormones:
  • Mineralocorticoids
  • Glucocorticoids
  • Androgens 
• Negative inhibition within the HPA axis:
  • ACTH inhibits further CRH release.
  • Cortisol (the primary glucocorticoid) inhibits both CRH and ACTH.
• Other factors that can stimulate the HPA axis:
  • Stresses:
    • Physical (e.g., exercise)
    • Mental (e.g., fear)
    • Biochemical (e.g., low blood sugar)
  • Biologic rhythms:
    • Circadian rhythms
    • Rhythms associated with growth and development

Adrenal Cortex Hormones: Mineralocorticoids

Mineralocorticoid overview

• Primary hormone: aldosterone
• Secreted from the zona glomerulosa within the adrenal cortex
• Synthesized by aldosterone synthase
• Regulation:
  • Partially under the control of ACTH
  • Renin-angiotensin-aldosterone system (see below)
• Effects:
  • ↑ Blood pressure (↑ water reabsorption from the kidneys Kidneys The kidneys are a pair of bean-shaped organs located retroperitoneally against the posterior wall of the abdomen on either side of the spine. As part of the urinary tract, the kidneys are responsible for blood filtration and excretion of water-soluble waste in the urine. Kidneys)
  • ↑ Serum Na⁺ (↓ urinary excretion of Na⁺)
  • ↓ Serum K⁺ (↑ urinary excretion of K⁺)
  • ↑ Serum pH (↑ urinary excretion of H⁺)

The renin-angiotensin-aldosterone system (RAAS)

The RAAS is one of the primary regulators of blood pressure, total body water, serum sodium levels, and pH balance in the body.

• Angiotensinogen: secreted by hepatocytes
• Renin: 
  • Secreted by the macula densa cells within the kidneys Kidneys The kidneys are a pair of bean-shaped organs located retroperitoneally against the posterior wall of the abdomen on either side of the spine. As part of the urinary tract, the kidneys are responsible for blood filtration and excretion of water-soluble waste in the urine. Kidneys 
  • Converts angiotensinogen to angiotensin I 
• ACE:
  • Secreted by pulmonary vascular endothelium
  • Converts angiotensin I to angiotensin II
• Angiotensin II: 
  • Stimulates the zona glomerulosa in the adrenal cortex to release aldosterone 
  • Induces vasoconstriction of the efferent renal arteriole
  • Stimulates Na⁺ and water reabsorption in the renal tubules
• Aldosterone:
  • Stimulates production of the following proteins within the principle cells in the distal renal tubules:
    • Na⁺/K⁺-ATPase on the basolateral side
    • Epithelia sodium channels (ENaCs) on the lumen side: allow Na⁺ reabsorption from the lumen into the principal cells
    • Renal outer medullary potassium channel (ROMK) on the lumen side: allows excretion of K⁺ into the urine
  • Stimulates Na⁺ reabsorption from the renal tubules
    • Water follows the Na⁺ 
    • Creates a negative electrical gradient across the lumen, promoting the secretion of K⁺ and H⁺ into the urine
• Factors that normally trigger the RAAS (and thus ↑ aldosterone):
  • ↓ Renal perfusion:
    • ↓ Blood pressure
    • ↓ Effective blood volume
  • ↑ Serum potassium (K⁺)
  • ↓ Sodium delivery to the kidney
  • ↑ Sympathetic tone

Adrenal Cortex Hormones: Glucocorticoids and Androgens

Glucocorticoids

• 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:
  • Cortisol 
  • Corticosterone
• Secreted from the zona fasciculata
• Effects: respond to immediate stressors
  • ↑ Immediately available energy through: 
    • Fat and protein catabolism → ↑ blood amino acid Amino acid Amino acids (AAs) are composed of a central carbon atom attached to a carboxyl group, an amino group, a hydrogen atom, and a side chain (R group). Basics of Amino Acids and lipid levels
    • 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
    • Appetite stimulation
  • ↑ RBCs
  • ↑ Serum calcium from bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones resorption (leads to ↓ bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones mineral density over time)
  • Antiinflammatory effects:
    • ↓ Inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation
    • ↓ Blood vessel permeability
    • Long-term exposure suppresses the immune system.
• Regulated by the HPA axis

Androgens

• 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: 
  • DHEA
  • Androstenedione 
• Secreted from the zona reticularis
• Androgens can be converted to testosterone and estrogens in peripheral tissue (primary source of estrogen Estrogen Compounds that interact with estrogen receptors in target tissues to bring about the effects similar to those of estradiol. Estrogens stimulate the female reproductive organs, and the development of secondary female sex characteristics. Estrogenic chemicals include natural, synthetic, steroidal, or non-steroidal compounds. Ovaries in postmenopausal women).
• Effects:
  • Important for secondary sex characteristics
  • Stimulates axillary, pubic, and male-pattern facial hair

Hormones Secreted by the Adrenal Medulla

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 their regulation

• The adrenal medulla secretes catecholamines:
  • Epinephrine (80%)
  • Norepinephrine (20%)
• Synthesized from dopamine within chromaffin cells (modified sympathetic neurons)
• Controlled by the sympathetic nervous system Nervous system The nervous system is a small and complex system that consists of an intricate network of neural cells (or neurons) and even more glial cells (for support and insulation). It is divided according to its anatomical components as well as its functional characteristics. The brain and spinal cord are referred to as the central nervous system, and the branches of nerves from these structures are referred to as the peripheral nervous system. General Structure of the Nervous System (rather than 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):
  • Preganglionic nerve fibers synapse Synapse The junction between 2 neurons is called a synapse. The synapse allows a neuron to pass an electrical or chemical signal to another neuron or target effector cell. Synapses and Neurotransmission with the chromaffin cells.
  • Acetylcholine from the preganglionic nerve fibers stimulates the nicotinic type 2 receptors on the chromaffin cells.
  • Chromaffin cells release the catecholamines directly into the blood.
  • Catecholamines stimulate α- and β-adrenergic receptors throughout the body.

Effects

The primary purpose of the medullary catecholamines is to supplement the effects of the sympathetic nervous system Nervous system The nervous system is a small and complex system that consists of an intricate network of neural cells (or neurons) and even more glial cells (for support and insulation). It is divided according to its anatomical components as well as its functional characteristics. The brain and spinal cord are referred to as the central nervous system, and the branches of nerves from these structures are referred to as the peripheral nervous system. General Structure of the Nervous System. Because these substances are released directly into the bloodstream as hormones, their effects last longer than when catecholamines are released as neurotransmitters. These effects include characteristics of the fight-or-flight response:

• ↑ Blood pressure
• ↑ HR
• ↑ Circulation to skeletal muscles
• ↑ Respirations and bronchodilation
• ↑ Blood glucose levels by:
  • Stimulating glycogenolysis 
  • Stimulating gluconeogenesis 
  • Inhibiting 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 release
• ↓ Digestion Digestion Digestion refers to the process of the mechanical and chemical breakdown of food into smaller particles, which can then be absorbed and utilized by the body. Digestion and Absorption

Clinical Relevance

There are a number of clinical conditions that result from abnormalities of the adrenal hormones. Some of the most clinically important include:

• Pheochromocytoma Pheochromocytoma Pheochromocytoma is a catecholamine-secreting tumor derived from chromaffin cells. The majority of tumors originate in the adrenal medulla, but they may also arise from sympathetic ganglia (also referred to as paraganglioma). Symptoms are associated with excessive catecholamine production and commonly include hypertension, tachycardia, headache, and sweating. Pheochromocytoma: rare catecholamine-secreting tumors arising from the chromaffin cells of the adrenal medulla. The presentation of pheochromocytoma is typically with treatment-resistant 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, episodic headaches, sweating, and tachycardia. Diagnosis is made via laboratory assessment showing elevated serum catecholamines and adrenal imaging studies. These tumors are benign 90% of the time, and surgical resection is the only curative treatment.
• Adrenal insufficiency Adrenal Insufficiency Adrenal insufficiency (AI) is the inadequate production of adrenocortical hormones: glucocorticoids, mineralocorticoids, and adrenal androgens. Primary AI, also called Addison’s disease, is caused by autoimmune disease, infections, and malignancy, among others. Adrenal insufficiency can also occur because of decreased production of adrenocorticotropic hormone (ACTH) from disease in the pituitary gland (secondary) or hypothalamic disorders and prolonged glucocorticoid therapy (tertiary). Adrenal Insufficiency and Addison’s Disease: refers to the inadequate 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, 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. Diagnosis is made by measuring cortisol levels and ACTH levels and with ACTH stimulation testing. Management involves glucocorticoid and mineralocorticoid replacement therapy.
  • Addison’s disease Addison’s Disease Adrenal insufficiency (AI) is the inadequate production of adrenocortical hormones: glucocorticoids, mineralocorticoids, and adrenal androgens. Primary AI, also called Addison’s disease, is caused by autoimmune disease, infections, and malignancy, among others. Adrenal Insufficiency and Addison’s Disease (primary adrenal insufficiency): Etiologies include autoimmune disease, infections, and malignancy, among others. 
  • Secondary and tertiary adrenal insufficiency: due to the decreased production of ACTH within the pituitary. This insufficiency can also occur because of prolonged glucocorticoid therapy. 
• Congenital adrenal hyperplasia Congenital adrenal hyperplasia 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 (CAH): group of 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 Inheritancedisorders that cause a deficiency of an enzyme (most commonly 21-hydroxylase) needed in cortisol, aldosterone, and androgen synthesis. Clinical manifestations include ambiguous genitalia in genotypic females, salt wasting, and 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. A less severe form, known as nonclassical CAH, also exists; this form typically presents in puberty Puberty Puberty is a complex series of physical, psychosocial, and cognitive transitions usually experienced by adolescents (11-19 years of age). Puberty is marked by a growth in stature and the development of secondary sexual characteristics, achievement of fertility, and changes in most body systems. Puberty. Lifelong glucocorticoid replacement is needed. 
• Cushing syndrome: condition 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. Etiologies include chronic glucocorticoid intake, increased adrenal secretion of cortisol, and increased pituitary or ectopic secretion of ACTH. Typical clinical features include central obesity Obesity Obesity is a condition associated with excess body weight, specifically with the deposition of excessive adipose tissue. Obesity is considered a global epidemic. Major influences come from the western diet and sedentary lifestyles, but the exact mechanisms likely include a mixture of genetic and environmental factors. Obesity, thin, bruisable skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin, abdominal striae, secondary hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension, hyperglycemia, and proximal muscle weakness. Diagnosis involves urinary and/or salivary cortisol testing along with a low-dose dexamethasone suppression test, measurement of ACTH levels, and possibly imaging. 
• 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: increased secretion of aldosterone from the adrenal cortex. 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 may be primary (resulting from autonomous secretion (known as Conn syndrome)) or secondary (resulting from physiologic secretion caused by stimulation of the RAAS). 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 presents with 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, hypokalemia Hypokalemia Hypokalemia is defined as plasma potassium (K+) concentration < 3.5 mEq/L. Homeostatic mechanisms maintain plasma concentration between 3.5-5.2 mEq/L despite marked variation in dietary intake. Hypokalemia can be due to renal losses, GI losses, transcellular shifts, or poor dietary intake. Hypokalemia, and metabolic alkalosis Metabolic alkalosis The renal system is responsible for eliminating the daily load of non-volatile acids, which is approximately 70 millimoles per day. Metabolic alkalosis also occurs when there is an increased loss of acid, either renally or through the upper GI tract (e.g., vomiting), increased intake of HCO3-, or a reduced ability to secrete HCO3- when needed. Metabolic Alkalosis. Diagnosis involves measuring plasma aldosterone and renin activity levels, along with imaging to look for hormone-secreting tumors. Management involves the use of aldosterone receptor antagonists and surgical excision of any aldosterone-secreting tumors.
• 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: condition resulting from low levels of aldosterone. 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 can be caused by decreased aldosterone production or by a peripheral resistance to aldosterone. When the condition occurs as a result of an acquired decrease in renin production from the kidneys Kidneys The kidneys are a pair of bean-shaped organs located retroperitoneally against the posterior wall of the abdomen on either side of the spine. As part of the urinary tract, the kidneys are responsible for blood filtration and excretion of water-soluble waste in the urine. Kidneys, the condition is referred to as renal tubular acidosis Renal Tubular Acidosis Renal tubular acidosis (RTA) is an imbalance in physiologic pH caused by the kidney's inability to acidify urine to maintain blood pH at physiologic levels. Renal tubular acidosis exist in multiple types, including distal RTA (type 1), proximal RTA (type 2), and hyperkalemic RTA (type 4). Renal Tubular Acidosis ( RTA RTA Renal tubular acidosis (RTA) is an imbalance in physiologic pH caused by the kidney's inability to acidify urine to maintain blood pH at physiologic levels. Renal tubular acidosis exist in multiple types, including distal RTA (type 1), proximal RTA (type 2), and hyperkalemic RTA (type 4). Renal Tubular Acidosis) type 4. Most individuals are asymptomatic and diagnosed when routine lab evaluation demonstrates 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 a mild hyperchloremic metabolic acidosis Metabolic acidosis The renal system is responsible for eliminating the daily load of non-volatile acids, which is approximately 70 millimoles per day. Metabolic acidosis occurs when there is an increase in the levels of new non-volatile acids (e.g., lactic acid), renal loss of HCO3-, or ingestion of toxic alcohols. Metabolic Acidosis, prompting further workup.