Comprehensive Study Notes on the Anatomy and Physiology of the Adrenal Gland

Functional Anatomy of the Adrenal Glands

• General Characteristics: The adrenal glands are a pair of endocrine glands, with $2$ glands in total, each positioned superiorly to (on top of) each kidney.

• Gross Structural Division: Each adrenal gland is composed of two distinct components with different origins and functions:

  • Outer Cortex: This region is responsible for the secretion of steroid hormones, specifically mineralocorticoids, glucocorticoids, and androgens.

  • Inner Medulla: This central region is responsible for the secretion of catecholamines, specifically epinephrine, norepinephrine, and dopamine.

• Basic Regulatory Control:

  • Adrenocortical Secretion: Primarily controlled by Adrenocorticotropic Hormone ($ACTH$).

  • Mineralocorticoid Secretion: Subject to independent regulation by Angiotensin $II$ ($Ag II$).

The Adrenal Medulla: Catecholamines and Secretory Mechanisms

• Composition: The adrenal medulla functions as a sympathetic ganglion and constitutes approximately $28\%$ of the total mass of the adrenal gland.

• Function: Medullary hormones prepare the body for emergency situations, commonly referred to as the "fight or flight" response.

• Cell Types and Secretion:

  • Epinephrine-Secreting Cells: Constitute $90\%$ of the medullary cells.

  • Norepinephrine-Secreting Cells: Constitute $10\%$ of the medullary cells.

  • Dopamine-Secreting Cells: The specific presence or nature of dedicated dopamine cells is unknown, though dopamine is a precursor and is secreted in specific contexts.

• Paraganglia: These are groups of cells that resemble those found in the adrenal medulla, located near the thoracic and abdominal sympathetic ganglia.

• Mechanism of Secretion:

  • Initiation: Secretion is triggered by the release of acetylcholine from preganglionic neurons that innervate the secretory cells.

  • Calcium Mediation: Acetylcholine causes calcium ions ($Ca^{2+}$) to enter the cells from the extracellular fluid ($ECF$).

  • Granule Rupture: The influx of calcium leads to the rupture of storage granules.

  • Release: The granules release catecholamines, Adenosine Triphosphate ($ATP$), and proteins simultaneously via exocytosis.

• Adrenal Medullary Chemistry:

  • Receptor Mediation: The effects of catecholamines are mediated through $\alpha_1$, $\alpha_2$, $\beta_1$, $\beta_2$, and $\beta_3$ adrenergic receptors.

  • Half-Life: Catecholamines have a rapid clearance, with a half-life of approximately $2\,\text{minutes}$ in circulation.

  • Additional Secreted Substances:

    • Opioid Peptides: The precursor molecule is preproenkephalin; the primary circulating molecule is metenkephalin.

    • Adrenomedullin: A vasopressor polypeptide.

Synthesis, Metabolism, and Physiological Effects of Adrenal Medullary Hormones

• Metabolism of Catecholamines:

  • Process: Catecholamines are first methoxylated and then oxidized to Vanillyl Mandelic Acid ($VMA$).

  • Excretion: Secreted catecholamines are found in the urine as either free or conjugated forms of metanephrine and normetanephrine, or as $VMA$.

• Stimuli for Increased Secretion:

  • Norepinephrine ($NE$): Significantly increased during heavy exercise and in the presence of phaeochromocytoma.

  • Epinephrine ($E$): Increased during cigarette smoking, hypoglycemia, exercise, surgery, ketoacidosis, myocardial infarction, and pheochromocytoma.

• Physiological Effects of Epinephrine and Norepinephrine:

  • Metabolic: Increased metabolic rate, stimulation of glycogenolysis, mobilization of free fatty acids, and increased plasma lactate levels.

  • Cardiovascular: Exert positive inotropic (increased contractility) and chronotropic (increased heart rate) effects. Both cause peripheral vasoconstriction.

  • Central Nervous System ($CNS$): Promotes alertness. Epinephrine specifically evokes higher levels of anxiety and fear than norepinephrine.

  • Electrolytes and Hormones: Causes an equivocal rise in potassium and increases the secretion of both insulin and glucagon.

• Physiological Effects of Dopamine:

  • Vascular: Causes vasoconstriction in most tissues but leads to renal and mesenteric vasodilation.

  • Cardiovascular: Exerts a positive inotropic effect, increasing systolic blood pressure with no change to diastolic blood pressure.

  • Clinical Use: Useful in treating cardiogenic shock and neurogenic shock resulting from trauma.

  • Renal: Induces natriuresis (sodium excretion) by inhibiting renal $Na/K\,ATPase$.

• Regulation of Medullary Secretion:

  • Neural Control: Secretion is low during sleep and increases during emergency situations as part of a diffuse sympathetic discharge.

  • Selective Secretion: $NE$ is selectively increased by familiar emotional stresses, while epinephrine is selectively increased during unfamiliar emotional stresses.

The Adrenal Cortex: Zones and Hormonal Classes

• Composition: The adrenal cortex represents $72\%$ of the total adrenal gland mass. It is divided into three distinct functional zones:

  • Zona Glomerulosa ($15\%$): Produced primarily aldosterone (a mineralocorticoid).

  • Zona Fasciculata ($50\%$): Produces primarily glucocorticoids (cortisol).

  • Zona Reticularis ($7\%$): Produces primarily androgens or sex hormones (androstenedione, DHEA).

• Universal Secretion: All cortical zones are capable of secreting corticosterone.

• Tropic Hormone Effects:

  • Hypophysectomy (Removal of Pituitary): Causes the zona fasciculata and zona reticularis to atrophy immediately. The zona glomerulosa remains unchanged due to its regulation by Angiotensin $II$.

  • ACTH Influence: Injections or stimuli causing endogenous $ACTH$ secretion result in hypertrophy of the zona fasciculata and reticularis, but have no effect on the zona glomerulosa.

• Steroid Hormone Classes:

  • C19 Steroids: Primarily have androgenic activity (e.g., androstenedione).

  • C21 Steroids: Function as mineralocorticoids or glucocorticoids.

  • C18 Steroids: Estrogenic activity (less common direct secretion).

• Primary Secretions by Hormone Class:

  • Mineralocorticoids: Include aldosterone and deoxycorticosterone; they predominantly affect sodium ($Na^+$) and potassium ($K^+$) excretion.

  • Glucocorticoids: Include cortisol and corticosterone; they predominantly affect glucose and protein metabolism. Humans secrete predominantly cortisol.

  • Androgens: Include dehydroepiandrosterone ($DHEA$) and androstenedione. Most are secreted free, though $DHEA$ is conjugated with sulfate.

Steroid Biosynthesis, Enzymatic Pathways, and Mechanisms of Action

• Biosynthetic Pathway Overview:

  1. Cholesterol is the parent molecule.

  2. Pregnenolone: Formed via the action of cholesterol desmolase (stimulated by $ACTH$ or $Ag II$).

  3. Progesterone: Converted from pregnenolone by $3\beta$-hydroxysteroid dehydrogenase.

  4. 11-Deoxycorticosterone: Converted from progesterone via $21\beta\,hydroxylase$ ($CYP\,21A2$) in the smooth ER.

  5. Corticosterone: Converted from 11-deoxycorticosterone via $11\beta\,hydroxylase$.

  6. Aldosterone: Converted from corticosterone via aldosterone synthase ($AS$) (stimulated by $Ag II$).

• Key Enzymatic Conversions:

  • $21\beta\,hydroxylase$: Catalyzes hydroxylation of progesterone to 11-deoxycorticosterone and $17\alpha$-hydroxyprogesterone to 11-deoxycortisol.

  • $11\beta\,hydroxylase$: Converted precursors (11-deoxycorticosterone and 11-deoxycortisol) into corticosterone and cortisol respectively.

• Glucocorticoid and Mineralocorticoid Activity Ratios:

  • Cortisol: Glucocorticoid ($1.0$), Mineralocorticoid ($1.0$).

  • Corticosterone: Glucocorticoid ($0.3$), Mineralocorticoid ($15$).

  • Aldosterone: Glucocorticoid ($0.3$), Mineralocorticoid ($3000$).

  • Deoxycorticosterone: Glucocorticoid ($0.2$), Mineralocorticoid ($100$).

  • Dexamethasone: Glucocorticoid ($25$), Mineralocorticoid ($\sim 0$).

• Cellular Mechanisms of Action:

  • ACTH Mechanism: Binds to high-affinity receptors on adrenocortical plasma membranes. This activates adenylyl cyclase via $G_s$, increasing $cAMP$. $cAMP$ activates Protein Kinase A ($PKA$), which phosphorylates cholesteryl ester hydrolase, increasing free cholesterol for pregnenolone conversion. Prolonged activity increases Cytochrome $P450$ synthesis.

  • Angiotensin II Mechanism: Binds to $AT_1$ receptors in the zona glomerulosa. Acts via G-protein to activate Phospholipase C ($PLC$), increasing Protein Kinase C ($PKC$). This fosters conversion of cholesterol to pregnenolone and facilitates aldosterone synthase action.

  • Aldosterone Genomic Mechanism: Binds to a cytoplasmic receptor; the complex moves to the nucleus to alter mRNA transcription. This increases $ENaC$ (epithelial sodium channel) activity (rapid effect) and $ENaC$ synthesis (slow effect).

Transport, Metabolism, and Excretion of Adrenocortical Steroids

• Cortisol Transport:

  • Bound primarily to transcortin (corticosteroid-binding globulin or $CBG$, an $\alpha$-globulin).

  • Small amounts bound to albumin.

  • Half-life: $60-90\,\text{minutes}$.

  • Free vs. Bound: Bound cortisol acts as a reservoir. Free cortisol is the total plasma cortisol minus the protein-bound portion.

• Regulation of CBG:

  • Synthesized in the liver.

  • Increased by: Estrogen, pregnancy.

  • Decreased by: Cirrhosis, nephrotic syndrome, multiple myeloma.

  • If $CBG$ increases, free cortisol initially drops, stimulating $ACTH$ to restore balance.

• Metabolism of Cortisol:

  • Reduced in the liver to dihydrocortisol, then to tetrahydrocortisol.

  • Tetrahydrocortisol is conjugated with glucuronic acid via the glucuronyl transferase system.

  • Rate Limitation: Hepatic inactivation is depressed in liver disease, surgery, and stress, leading to high free cortisol levels.

• Excretion:

  • Excreted as $17$-ketosteroid derivatives or $20$-hydroxy derivatives.

  • Cortisol undergoes enterohepatic circulation.

  • $15\%$ is excreted in the stool.

• Aldosterone Metabolism: Slightly bound to plasma protein. Converted to a tetrahydroglucuronide derivative or an $18$-glucuronide (acid-labile conjugate). Less than $1\%$ is excreted free.

• 17-Ketosteroids:

  • Derivatives of cortisol, cortisone, and testosterone (mainly adrenal androgens).

  • Include DHEA and androstenedione.

  • Daily excretion: $15\,\text{mg}$ in men; $10\,\text{mg}$ in women.

  • Etiocholanolone: A metabolite of adrenal androgens; can cause fever if the unconjugated form accumulates.

Physiological and Metabolic Effects of Glucocorticoids and Androgens

• Adrenal Androgen Effects:

  • Excess amounts: Cause precocious pseudopuberty in males (secondary sex characteristics without testicular growth) and pseudohermaphroditism/adrenogenital syndrome in females.

  • Anabolic effects: Promote protein anabolism and growth.

  • Age Trend: $DHEAS$ increases until the early $20$'s, then falls significantly in old age.

  • Peripheral Conversion: Androstenedione is converted to testosterone and estrogens (via aromatization) in fat and peripheral tissues (critical source of estrogen for postmenopausal women and men).

• Metabolic Effects of Glucocorticoids:

  • Protein: Increased catabolism.

  • Carbohydrates: Increased blood glucose via hepatic gluconeogenesis (anti-insulin action).

  • Lipids: In diabetics, glucocorticoids raise plasma lipid levels and increase ketone body formation.

• Permissive Actions (Glucocorticoids must be present for other hormones to work):

  • Lipolytic effects of catecholamines.

  • Calorigenic effects of glucagon and catecholamines.

  • Pressor responses and bronchodilation mediated by catecholamines.

• Hematologic/Immune effects:

  • Decrease: Circulating eosinophils (sequestration in spleen/lungs), basophils, and lymphocytes (via inhibition of mitotic activity/lymphopenia and apoptosis).

  • Increase: Neutrophils, platelets, and red blood cells.

  • Cytokines: Decrease secretion of $IL-2$, leading to reduced lymphocyte proliferation.

• Anti-inflammatory and Pharmacologic Actions:

  • Inhibit the inflammatory response to injury and suppress allergic reactions by preventing histamine release.

  • Mechanism: Inhibition of phospholipase $A_2$, reducing leukotrienes, thromboxanes, prostaglandins, and prostacyclin.

  • Caveat: Glucocorticoids mask infection symptoms, which may lead to fatal delays in treatment.

• Other Effects:

  • Vascular: Essential for vascular reactivity to catecholamines. Absence causes capillary dilation and failure to compensate for hypovolemia.

  • CNS: Cause irritability, apprehension, inability to concentrate, and slow EEG waves.

  • Development: Accelerate surfactant maturation in the fetal lungs.

  • Hormonal Interference: Large doses decrease Growth Hormone and $TSH$ secretion.

Clinical Pathologies: Adrenal Insufficiency, Hyperplasia, and Excess

• Congenital Adrenal Hyperplasia (CAH):

  • Caused by enzymatic defects (e.g., cholesterol desmolase, $3\beta\,HSD$, $17\alpha\,hydroxylase$, $21\beta\,hydroxylase$, $11\beta\,hydroxylase$).

  • 21$\beta$-hydroxylase Deficiency: Accounts for $90\%$ of cases. Leads to reduced cortisol and aldosterone, causing increased $ACTH$ (hyperplasia) and a buildup of precursor steroids.

  • Adrenogenital Syndrome: Precursors are shunted to androgen production, causing virilization (masculinization), salt-wasting, and hypovolemia.

  • Treatment: Exogenous glucocorticoids restore the deficit and inhibit $ACTH$ to stop abnormal androgen secretion.

• Addison’s Disease (Adrenal Insufficiency):

  • Results in sodium loss and shock (mineralocorticoid deficiency).

  • Fasting-precipitated hypoglycemia.

  • Inability to excrete a water load (water intoxication) due to high vasopressin levels and low $GFR$.

  • Warning: Glucose infusion alone in this state can cause high fever, collapse, and death.

• Cushing’s Syndrome (Glucocorticoid Excess):

  • ACTH Dependent: Pituitary tumors (Cushing Disease) or ectopic $ACTH$ secretion.

  • ACTH Independent: Adrenal tumors, hyperplasia, or exogenous steroid administration.

  • Physical Features: Moon face, facial plethora, buffalo hump, pendulous abdomen (truncal obesity), purple striae (rupture of subdermal tissue), thin skin, easy bruisability (ecchymosis), and poor wound healing.

  • Physical Complications: Hypertension, hyperglycemia, osteoporosis (bone fractures), muscle atrophy (weakness of trunk and extremities), thin hair, acne, bronze skin (if $ACTH$ is high), and increased facial hair.

  • Immunological: Reduced immunity and high liability to infection due to lymphoid tissue loss.

• Pheochromocytoma:

  • Catecholamine-secreting tumor of the medulla or paraganglia.

  • Causes sustained hypertension; in $15\%$ of cases, secretion is episodic with bouts of palpitations, headache, glycosuria, and extreme systolic hypertension.

Regulation and Control Systems

• Glucocorticoid Regulation:

  • ACTH bursts: Secreted in irregular pulses throughout the day.

  • Circadian Rhythm: Maximum output between $4:00\,\text{am}$ and $10:00\,\text{am}$. Nadir (lowest point) achieved by midnight.

  • Stress response: Hypothalamic $CRH$ mediates responses to emergencies.

    • Amygdaloid nuclei: Mediate fear and emotional stress.

    • Suprachiasmatic nuclei: The biological clock driving diurnal rhythms.

    • Nociceptive pathways: Trigger $ACTH$ in response to injury.

  • Negative Feedback: Free glucocorticoids inhibit $ACTH$ secretion in proportion to their circulating levels.

• Therapeutic Caution: Abruptly stopping large doses of exogenous steroids causes an Addisonian crisis because the atrophic adrenal glands are unable to respond to the sudden lack of exogenous supply.