Hormones and Receptors: Types and Mechanisms

Hormones and Receptors: Classification

• Steroid hormones are derived from cholesterol and produced by the adrenal glands and gonads.
• Steroid hormones are hydrophobic, requiring transport proteins to travel through the bloodstream.
• They diffuse across the cell membrane and bind to receptors to activate genes in the nucleus.
• Non-steroid hormones are peptides or proteins and are hydrophilic, not needing transport proteins.
• Non-steroid hormones bind to cell surface receptors, changing their shape and activating proteins/enzymes to alter gene expression without entering the cell.
• Amino-acid hormones derive from tyrosine and include thyroid hormones, epinephrine, and norepinephrine.

Pituitary Gland (Hypophysis) Anatomy

• The pituitary gland is a small, oval-shaped structure located ventrally on the cerebrum.
• It is slightly larger than a pea and suspended by the infundibulum.
• The pituitary sits in the hypophyseal fossa, surrounded by the sella turcica of the sphenoid bone.
• Often called the "master gland", it interfaces the central nervous system with the endocrine system.
• Controls crucial functions like metabolism, growth, sexual maturation, reproduction, and blood pressure.
• The pituitary has two functional lobes: the anterior (adenohypophysis) and posterior (neurohypophysis) lobes.

Anterior Pituitary (Adenohypophysis)

• The anterior pituitary originates from the adenohypophyseal or Rathke's pouch, derived from oral ectoderm.
• It is composed of three parts: pars distalis, pars tuberalis, and pars intermedia.
• The pars distalis is the largest part and is responsible for most of the anterior pituitary's secretory activity.
• The pars tuberalis is a posterior extension into the infundibular stalk.
• The pars intermedia is a thin, avascular epithelial layer that borders the posterior lobe.

Hypothalamus: Anterior Pituitary Regulation

• The hypothalamus regulates anterior pituitary activity, responding to changes in body temperature, energy needs, and electrolyte balance.
• The hypothalamus communicates via vascular and neural pathways.
• Neurosecretory neurons in the paraventricular and arcuate nuclei produce neurohormones called hypothalamic-releasing hormones.
• Examples of hypothalamic-releasing hormones include thyrotropin-releasing hormone, corticotropin-releasing hormone, gonadotropin-releasing hormone, growth hormone-releasing hormone (somatocrinin), growth hormone-inhibiting hormone (somatostatin), and dopamine (prolactin-inhibiting hormone/prolactostatin).

Hypophyseal Portal System

• Hypothalamic hormones are released into the median eminence and travel to the anterior pituitary via the hypophyseal portal system.
• The hypophyseal portal system is a vascular pathway consisting of veins draining blood from one capillary bed to another one between the hypothalamus and anterior pituitary.
• The primary capillary network, formed by the superior hypophyseal artery, merges to form long and short hypophyseal portal veins.
• Hypothalamic hormones act on adenohypophysis glandular cells, stimulating or inhibiting hormone release.
• Anterior pituitary hormones are carried to the cavernous sinus and systemic circulation via hypophyseal veins.

Posterior Pituitary (Neurohypophysis)

• The posterior pituitary originates from neural ectoderm of the diencephalon.
• It is essentially an extension of hypothalamic neural tissue and includes the infundibular stalk and pars nervosa.
• The infundibular stalk contains unmyelinated axons from neurons in the supraoptic and paraventricular nuclei, forming the hypothalamo-hypophyseal tract which connects the hypothalamus to the pituitary gland.
• Vesicles with neurohormones are transported from the hypothalamus to the neurohypophysis via axons.
• The pars nervosa stores and releases antidiuretic hormone (vasopressin) and oxytocin, both produced in the hypothalamus.
• Hormones are stored in neuron terminal endings and released into the bloodstream upon action potentials.
• The capillary bed receives the hormones, drained by hypophyseal veins to the cavernous sinus and systemic circulation.

Anterior Pituitary Histology

• The anterior pituitary contains two main cell groups: chromophils and chromophobes.
• Chromophils have darkly stained cytoplasm and include acidophils and basophils.
• Acidophils stain dark red, including somatotrophs (secrete growth hormone) and lactotrophs (secrete prolactin).
• Basophils stain purplish-blue and secrete MSH, ACTH, LH, FSH, and TSH.
• Chromophobes have lightly stained cytoplasm.

Posterior Pituitary Histology

• The posterior pituitary consists of lightly stained unmyelinated axons that carry oxytocin and ADH.
• Herring bodies are dilated nerve terminals that release oxytocin or ADH.
• Pituicytes are branched supporting glial cells.

Thyroid Gland Anatomy

• The thyroid gland has two lobes (right and left) connected by an isthmus, located on the anterior and lateral sides of the trachea and inferior larynx.
• Each lobe has superior and inferior poles.

Parathyroid Gland Anatomy

• There are typically four parathyroid glands, with two located on the posterior side of each thyroid lobe.
• The parathyroid glands are around 6 mm long, 3-4 mm wide, and 1-2 mm deep, weighing about 50-60 mg.

Thyroid Gland Vascular Supply

• The arterial supply includes the superior and inferior thyroid arteries.
• The superior thyroid artery comes off the external carotid artery, branching into anterior, posterior, and lateral branches.
• The inferior thyroid artery arises from the thyrocervical trunk (subclavian artery) with ascending/superior and inferior branches.
• Venous drainage is via superior, middle, and inferior thyroid veins, forming a thyroid venous plexus.
• Superior and middle thyroid veins drain into the internal jugular vein.
• Inferior thyroid veins either drain into the left or right brachiocephalic vein or the superior vena cava.

Parathyroid Gland Vascular Supply

• Arterial supply is from the inferior thyroid arteries (thyrocervical trunk).
• Venous drainage follows the thyroid veins via the thyroid venous plexus.

Thyroid Gland Innervation

• The thyroid gland receives sympathetic and parasympathetic innervation that affects blood vessel constriction or dilation.
• Sympathetic innervation is from the superior, middle, and inferior cervical ganglia.
• Parasympathetic innervation is provided by the vagus nerve (CN X) via the external branch of the superior laryngeal nerve and the recurrent laryngeal nerve.

Parathyroid Gland Innervation

• The parathyroid glands receive only sympathetic innervation from the superior and middle cervical ganglia.

Pancreas Anatomy

• The pancreas is a retroperitoneal organ with both exocrine and endocrine functions.
• As an exocrine gland, it secretes pancreatic juices into the duodenum for digestion.
• As an endocrine gland, it secretes insulin and glucagon into the bloodstream to regulate blood sugar.
• The pancreas is divided into the head, uncinate process, neck, body, and tail.
  • The head sits within the duodenum's curvature, to the right of the superior mesenteric artery.
  • The uncinate process projects medially from the head's inferior portion, posterior to the SMA.
  • The neck is anterior to the superior mesenteric vessels, posterior to the pylorus of the stomach.
  • The body is to the left of the superior mesenteric vessels and posterior to the stomach.
  • The tail is anterior to the left kidney and medial to the spleen.

Pancreas Blood Supply and Innervation

• Most of the pancreas (except the head and uncinate process) are supplied by pancreatic branches of the splenic artery.
• The head and uncinate process are supplied by anterior and posterior inferior pancreaticoduodenal arteries (branches of the superior mesenteric artery).
• They are also supplied by anterior and posterior superior pancreaticoduodenal arteries (branches of the gastroduodenal artery).
• Venous drainage is via pancreatic veins into the superior mesenteric and splenic veins.
• Sympathetic innervation is from greater and lesser splanchnic nerves.
• Parasympathetic innervation is from the vagus nerve, passing through the celiac and superior mesenteric plexuses.

Pancreas Histology

• The pancreas is a large gland with both exocrine and endocrine functions.
• Most of the pancreas consists of exocrine glands, producing about 1.5 liters of alkaline digestive enzymes daily.
• Small clusters of endocrine cells are located in the islets of Langerhans.
• A thin collagenous capsule surrounds the pancreas, extending into septa forming lobules.

Islets of Langerhans

• Islets of Langerhans are clusters of cells containing four main types:
  • Beta cells (70%) secrete insulin.
  • Alpha cells secrete glucagon.
  • Delta cells secrete somatostatin.
  • PP cells secrete pancreatic polypeptide.

Thyroid Gland Histology

• Thyroid gland follicles are filled with colloid, consisting of thyroglobulin and thyroid hormones.
  • Epithelial cells secrete thyroid hormones, arranged in a single cuboidal layer with round central nuclei and dark chromatin.
• Parafollicular cells (C cells) secrete calcitonin and are granular, larger than follicular cells, and located in the periphery or between follicles.

Parathyroid Gland Histology

• The parathyroid gland has a thin fibrous capsule extending inward with nerves, lymphatics, and blood vessels, forming irregular lobules.
• Up to 40% is adipose tissue.
• Two cell types are present: chief (principal) cells and oxyphil cells.
  • Chief cells are the majority, smaller in size, with dark, round, central nuclei and pale cytoplasm, and secrete PTH.
  • Oxyphil cells are much larger with dark nuclei, eosinophilic cytoplasm, more mitochondria, and increase in number with age.
  • Oxyphil cells do not secrete PTH.

Adrenal Gland Anatomy

• Paired endocrine glands sit on the superior pole of each kidney and secrete steroid and catecholamine hormones.
• Steroid hormones (cortisol, aldosterone) control stress response, fluid balance, and ion homeostasis.
• Catecholamine hormones (epinephrine, norepinephrine) are secreted during sympathetic responses.
• The right gland is pyramid-shaped and posterior to the inferior vena cava and liver.
• The left gland is semilunar, anterior to the diaphragm's right crus, and posterior to the stomach, pancreas, and spleen.

Adrenal Gland Blood Supply

• Arterial supply includes superior, middle, and inferior suprarenal arteries.
  • The superior suprarenal artery arises from the inferior phrenic artery.
  • The middle suprarenal artery arises from the abdominal aorta.
  • The inferior suprarenal arteries arise from the renal arteries.
• Venous drainage is via right and left suprarenal veins.
  • The right suprarenal vein drains into the inferior vena cava.
  • The left suprarenal vein drains into the left renal vein, often joined by the left inferior phrenic vein.

Adrenal Gland Histology

• The adrenal gland has an outer connective tissue capsule, an outer cortex (steroid hormone production: cortisol, androgens), and an inner medulla (catecholamine production).

Adrenal Cortex Histology

• The adrenal cortex has three zones: zona glomerulosa, zona fasciculata, and zona reticularis.
  • The zona glomerulosa (superficial, 15%), just beneath the capsule, secretes mineralocorticoids (aldosterone) and contains ovoid clusters of columnar/pyramidal cells with lipid-filled cytoplasm, separated by fibrous trabeculae.
  • The zona fasciculata (largest, 65-80%) secretes primarily glucocorticoids (cortisol) and small amounts of androgenic sex hormones; it is composed of cells arranged in long columns with a larger amount of lipid-filled cytoplasm.
  • The zona reticularis (10%) secretes primarily gonadocorticoids or sex hormones; it contains an irregular network of cords with wide capillaries, smaller cells, pink cytoplasm, round central nuclei, and less lipid.

Adrenal Medulla Histology

• The adrenal medulla is centrally located and contains chromaffin cells (modified postganglionic sympathetic neurons) that secrete epinephrine and norepinephrine.
• It holds large medullary veins draining into the suprarenal veins, and cells are arranged in clusters with numerous capillaries throughout.

Growth Hormone (Somatotropin)

• Growth hormone (GH) regulates body growth and its secretion is controlled by the hypothalamic-pituitary axis.
• The hypothalamus secretes growth hormone-releasing hormone (GHRH) into the hypophyseal-portal system.
  • GHRH binds to somatotroph cell receptors, causing release of GH.

Control of Growth Hormone Release

• Increased GH release stimuli:
  • Hypoglycemia
  • Epinephrine (from adrenal glands)
  • Estrogen and Testosterone (during puberty)
• Decreased GH release (negative feedback):
  • Increased GHRH in blood signals the hypothalamus to stop GHRH production.
  • Somatomedins (from liver, muscle, and bone) signal anterior pituitary cells to halt GH production and signal the hypothalamus to make somatostatin.
  • Somatostatin (growth hormone inhibiting hormone) inhibits GHRH from acting on pituitary somatotroph cells, and is also produced by pancreatic delta cells - which blocks release of insulin, glucagon, gastrin, & vasoactive intestinal peptides

Effects of Growth Hormone

• GH has direct and indirect effects.
• Direct effects:
  • Stimulation of cellular metabolism, thus tissue growth.
  • Adipose tissue: Triggers lipolysis, providing substrates for other cells.
  • Liver: Triggers gluconeogenesis and glycogenolysis, releasing glucose.
  • Tissues: Increases insulin resistance, increasing blood glucose levels.
• Indirect effects:
  • Stimulation of IGF-1 release
  • IGF-1 binds to insulin-like growth factor 1 receptors and insulin receptors, promoting cellular metabolism, preventing cell death, and increasing cell division and differentiation.
  • Muscles: Muscle growth by stimulating amino acid uptake, increasing protein synthesis.
  • Bones: Acts on epiphyseal plates of long bones and stimulating osteoblasts and chondrocytes, promoting bone growth.

Antidiuretic Hormone (ADH) / Vasopressin

• ADH is a peptide hormone that reduces excessive urine production (anti-diuresis).
• Source: Paraventricular and supraoptic nuclei in the hypothalamus.
  • ADH travels down neuron axons and is released into the posterior pituitary, then the bloodstream.

Triggers of ADH Release

• Increased blood osmolarity (detected by supraoptic nuclei).
  • Hypothalamus initiates thirst response and increases ADH production.
• Low blood pressure (detected by baroreceptors in the carotid artery and arch of aorta).
  • Triggers hypothalamus to increase ADH secretion.

Target Cells of ADH

• Kidneys:
  • Distal convoluted tubule (principal cells) via Vasopressin receptor 2 (AVPR2).
  • Collecting duct cells via Vasopressin receptor 2 (AVPR2).
• Arteries:
  • Smooth muscle cells.

Actions of ADH

• AVPR2 Receptors: Increase water reabsorption in the kidneys.
  • G protein activation signals increasing cAMP.
  • Promotes cell production of water channel proteins (aquaporin 2) in the apical surface.
  • Aquaporins trigger water to leave lumen destined to leave the body, entering kidney cells and the bloodstream (decreasing blood osmolarity).
• Smooth muscle cells in arteries: Increase blood pressure. ADH makes vascular smooth muscle cells constrict, increasing peripheral vascular resistance -> increasing blood presssure. This increase in blood pressure is detected by baroreceptors which inhibit the hypothalamus, stopping ADH secretion via negative feedback.

Insulin

• Source: Pancreas (Islets of Langerhans - Beta cells).
• Control of Release - triggers:
  • ↑ Glucose blood levels --> beta cells secrete insulin into the blood.
  • Hormones Glucagon and Cortisol indirectly, increasing blood glucose, fatty acid, and amino acid levels.
  • Acetylcholine (parasympathetic nervous system) stimulates secretion.
• Control of Release - inhibitors:
  • Norepinephrine (sympathetic nervous system).
  • Somatostatin (hormone).

Insulin Actions - Target Cells

• Insulin is an anabolic hormone, converting small molecules into large storage molecules inside target cells.
  • Small molecules: Glucose, Fatty acids, Amino acids.
  • Storage Molecules: Glycogen, Fat/adipose tisse, Proteins.
• Target Cells and Actions:
  • Liver: Glucose → glycogen, inhibits gluconeogenesis
    • Excess glucose is sent to adipose tissue to be stored as fat, converting glucose into fatty acids that are then transported to the adipose tissue to be stored if glycogen reserves are reached.
  • Adipose Tissue: Fatty acids → fat
• Skeletal muscle :
  • Amino acids and glucose uptake into muscle cells
  • Amino acids → protein → muscle growth

Glucagon

• Source: Alpha cells in the Langerhans islets of Pancreas.
• Production of Glucagon: Preproglucagon → Proglucagon → Glucagon
• (Glucagon is stored inside granules in the alpha cells)

Control of Release

• What Triggers Glucagon Secretion/Release from the Alpha Cells?
  • Low blood glucose (detected by the alpha cells),
  • Adrenaline (Sympathetic Nervous System).
  • Cholecystokinin (From Intestinal Cells, helps with Digestion and Absorption).
• What Inhibits Glucagon Secretion/Release from the Alpha Cells?
• High blood glucose (again, detected by the alpha cells) - High blood glucose → alpha cells stop secreting glucagon - Beta cells start secreting insulin which also inhibits glucagon secretion
• Somatostatin: a hormone that keeps the pancreas from releasing too much of its hormones
• Growth hormone

Glucagon Effects

• Glucagon is a catabolic hormone, promoting breakdown of large storage molecules into smaller “energy molecules” in the blood.
• Glucagon targets the liver and adipose tissue.
  • Storage molecules: glycogen, fat
  • Energy molecules: glucose, fatty acids
• Glucagon Receptor: Transmembrane that activates intracellular proteins
• Target Cells and Actions:
• Liver:
  • Breakdown of glycogen stores Glycogen → glucose Glucose released into the blood
  • Glucose production = gluconeogenesis Glucose is produced from lactic acid and from noncarbohydrate molecules Glucose is released into the blood
  • Fat breakdown Lipolysis Fatty acids are released into the blood
• Adipose tissue
  • Fat breakdown Lipolysis Fatty acids are released into the blood

Interplay of Glucagon and Insulin

• Tightly regulates Glucose Levels:
  • Fasting = alpha cells secrete glucagon
  • After a Meal = glycemia rises --> beta cells secrete insulin = inhibits glucagon secretion
  • Glycemia Drops = insulin production drops --> glucagon is secreted again

Cortisol

• A glucocorticoid produced and secreted by the zona fasciculata.
  • Most important of the glucocorticoids
• Control of cortisol production: Hypothalamus-pituitary axis
  • Hypothalamus secretes corticotropin releasing hormone (CRH) to anterior pituitary gland
  • CRH binds to corticotroph cells, stimulating them to release adrenocorticotropic hormone (ACTH) into the bloodstream.
  • ACTH is then transported to cortex of adrenal glands, converting cholesterol to cortisol.
  • Release Pattern: NOT stored- Secreted as it is produced.
  • Secretion is pulsatile throughout the day, peaking in the morning around 6am.
  • Secreted in response to stressful stimuli, like hypoglycemia, low blood sugar, infections, caffeine, sleep deprivation, and stress.
• RECEPTORS:
  • Nearly every cell in the body has receptors for cortisol (intracellular receptors.)
• FUNCTIONS:
  • Immune Response inhibits two causes of inflammation, promoting an overall anti- inflammatory state
  • Cellular Metabolism Adipose Tissue: Triggers Lipolysis Liver: Triggers Gluconeogenesis & Triggers increased Glycogen Storage Muscles: Stimulates Proteolysis, generating amino acids that serve as substrates for gluconeogenesis General Tissues: Increases Insulin Resistance in Tissues = Increases Blood Glucose Levels Blood Vessels: Up-regulates -1 adrenergic receptors in blood vessels = Vasoconstriction = Increases Blood Pressure Bone: Inhibits Osteoblasts Decreases Bone Formation

Negative Feedback of Cortisol

• Cortisol signals the hypothalamus to stop secreting corticotropin releasing hormone (CRH) Decreases Anterior Pituitary Secretion Of Adrenocorticotropic Hormone (ACTH)
• Cortisol Signals Directly Into The Anterior Pituitary To Stop The Release Of Adrenocorticotropic Hormone (ACTH).

Thyroid Hormones

• Two versions:

  • Triiodothyronine – T3: Half-life = 1-2 days
  • Thyroxine/ Tetraiodothyronine - T4: Half-life = 6-8 days

• Source: Follicular cells in the thyroid gland

• Follicular cells endocytose thyroglobulin in a vesicle à fuses with the lysosome à thyroglobulin is cleaved by the lysosomed à T3 + T4 released into blood stream via monocarboxylate transporter (MCT)

• Hypothalamus Pituitary Axis controls release: - Low levels of thyroid hormone in bloodstream à hypothalamus secretes thyrotropin releasing hormone (TRH) à TRH binds to a surface protein on thyrotroph cells in the anterior pituitary à thyrotroph cells release the hormone thyroid stimulating hormone (TSH- aka thyrotropin) into bloodstream - TSH travels to the thyroid gland à binds to membrane TSH receptors of follicular cells à T3 + T4 are produced and released.

Negative Feedback:

• High Levels of Thyroid Hormones: - Inhibits hypothalamus production of TRH - Inhibits anterior pituitary gland production of TSH - = Acts to lower thyroid hormone secretion from thyroid gland

Transport of Thyroid Hormone in the Bloodstream:

• T3 and T4 bind to circulating plasma proteins: - Thyroxine Binding Globulin (TBG) - Albumin - Transthyretin

• Bound T3 + T4 are not active act as reservoir of hormone

• Unbound T3 + T4 are active

Targets of Thyroid Hormone

• Thyroid hormone targets almost every cell of the body aside from brain, spleen, and gonads. Effects of Thyroid Hormone: A. General Effects: - ALL tissues except brain , spleen , gonads:Increases activity of the Na-K ATPase Increases oxygen consumption Increases metabolic rate B. Catabolic Effects:Increases proteolysis, lipolysis, and gluconeogenesis - Does this by increasing catecholamine, glucagon + GH activity C. Cardiovascular System: Increases -1 adrenergic receptors, contractility of heart, and heart rate Increases cardiac output D: Growth & Development: Crucial for Central Nervous System development & Increases bone formation & Bones of Maturation

Parathyroid Hormone :

• Background info: : Extracellular calcium, the calcium in the blood and interstitium, is split almost equally into diffusible calcium and non-diffusible calcium.
  • Diffusible Calcium: Diffuses across cell membranes (small enough). Includes two categories: a) Free-ionized calcium: Involved in cellular processes, such as neuronal action potentials, contraction of skeletal, smooth, and cardiac muscle, hormone secretion and blood coagulation b) Complexed calcium: Positively charged calcium is linked to negatively charged molecules (phosphate and oxalate). Forms a molecule that’s electrically neutralIs not useful for cellular processes
  • Non-Diffusible calcium: Bound to large negatively charged proteins -Example: Albumin! too large to membrane and not involved in the cellular processes

Source, Release and Function of Parathyroid Hormone

• Source : Parathyroid Glands/ ChiefCells
• Control of Parathyroid Hormone Release:
  • Normal-high Calcium inhibits PTH release.
  • Low Calcium stimulates PTH release. Targets/Actions: Parathyroid hormone works to increase extracellular calcium in three ways. -Bones: PTH binds to receptors on osteoblaststhey release cytokinesàmultiple macrophage precursors to fuse together to form an osteoclastàosteoclasts break down the bone=Calcium and phosphate are released into the blood *But! * In the blood, phosphate binds to calcium forms a complex calcium can’t be used in cellular processes.
• Kidneys: Tubular cells of the kidneys’ proximal convoluted tubules

• PTH binds to receptors, stopping sodium and phosphate cotransporters on the apical surface of tubular cellsPhosphate is NOT- reabsorbed into the bloodstreamà phosphate leaves the body in the urine= decreases serum phosphate

Parathyroid cont. Effect on serum Calcium and Vitamin D

• Principal cells of the distal convoluted tubules PTH binds to receptors->cells start making more calcium, sodium channels embed on the apical surface=> More calcium is taken out of the forming urine, and put back into bloodstream = Increases serum calcium
  • Action on action on proximal tubular cells:
  • Activates an enzyme called 1-alpha-hydroxylase converts an inactive version of vitamin D into active vitamin D! Active vit D => gastrointestinal tract => enterocytes of the small intestine =>Increase the activities of the calcium channels on the cell membrane cells absorb more calcium from food = increases serum calcium

An overview of the classification of hormones, including steroid and non-steroid types, and their mechanisms of action. Steroid hormones, derived from cholesterol, bind to receptors in the nucleus, while non-steroid hormones bind to cell surface receptors.