Hormones and Signal Transduction

Lecture Hall Timeline

• 1:30-2:15: PollEv questions and focused review
• 2:20-3:05: Meet with group, work on case/questions
• 3:05-3:15: Break
• 3:15-4:15: Review case/questions, submit assignment
• 4:20: Class end

Questions & Review

• A & P: Hormones, Hypothalamus, Pituitary (Anterior/Posterior), Adrenals (Cortex/Medulla), Thyroid, Parathyroid, Pineal
• Pathophysiology: DI & SIADH, Hyperthyroidism & thyroid storm, Cushing's & adrenal insufficiency, DKA/HHS
• Group work: Endocrine case

Hormones

• Chemical substance produced by specialized cells, transported to distant cells, exerting regulatory effects
• Structural categories: water-soluble or lipid-soluble
• Classified as: Peptide hormones, Amino acid hormones, Steroid hormones
• Peptide Hormone: Water-soluble polypeptide chains, bind onto effector cell receptors, inducing a cascade effect, ends with "in" or "ine"
• Amino Acid Hormone: Water-soluble, derived from tyrosine and tryptophan, enzymatic conversion, bind to receptors, ends with "in" or "ine"
• Steroid Hormone: Lipid-soluble, crosses effector cell membrane, binds to cytoplasmic receptor, passage into the nucleus, binding to DNA, initiating transcription, ends with "ol" or "one"

Hormone Regulation

• Hormone secretion patterns: Diurnal, Pulsatile & Circadian, Levels of circulating substrates
• Feedback systems: Negative & positive, Endocrine/Hormonal factors, Chemical/Humoral factors, Neural control

Hormone Receptors

• Sensitivity determined by receptor number, hormone affinity and conditions (pH, body temp)
• Can increase (up-regulation) or decrease (down-regulation) in response to hormone levels
• Diet, pH, temperature, and mutations can influence up/down-regulation

Hormone Signal Transduction

• Hormones are the first messengers
• Water-soluble hormones attach to plasma membrane receptors: G-protein linked receptors, ion channel receptors, enzyme-linked receptors
• Lipid-soluble hormones attach to: Plasma membrane receptors, Cytoplasmic receptors, Nuclear membrane receptors

G-Protein Linked Receptors

• Hormones attach to plasma membrane receptors
• Activated G-protein reacts with GTP
• GTP activates plasma membrane adenylyl cyclase enzyme
• Adenylyl cyclase converts ATP to cAMP, a second messenger
• cAMP activates protein kinase (PKA)
• PKA activates several intracellular enzymes
• Affects transcription results in synthesis of proteins, producing target cell response

Ion Channel Receptors

• Hormones/neurotransmitters open ion channels by direct attachment or attachment to g-protein linked channels
• Changes membrane potential

Enzyme Linked Receptors

• Hormone attachment activates several enzyme systems
• Example (Leptin): Leptin (first messenger) attaches to plasma membrane enzyme receptor; Janus kinase 2 (JAK2), a second messenger is phosphorylated, activated; signal transduction & activator (STAT) proteins are phosphorylated and activated, transcription of genes for protein synthesis, other enzyme systems are activated

Steroid Hormone Action

• Steroid hormone enters target cell
• Hormone binds to receptor, induces conformational change
• Hormone-receptor complex binds to DNA, induces start of transcription
• Amplification of signal occurs, many mRNAs are produced
• Each transcript further translated, amplifying the signal

Hypothalamus

• Located below thalamus, above midbrain (ventral diencephalon), connected to the pituitary gland
• Composed of nuclei (clusters of neuron cell bodies), axons connecting nervous and endocrine systems
• Nuclei produce hormones, hormone stimulating/inhibiting factors for transportation to pituitary gland

Hypothalamic Function

• Maintains homeostasis: temperature regulation, food & water intake, sexual behavior, daily cycles, emotional/stress responses, metabolism, growth

Pituitary Gland (Hypophysis)

• Pea-sized gland attached to hypothalamus
• Receives hormones for storage/release (from hypothalamus)
• Stimulatory/inhibitory factors, promote/inhibit synthesis/release of hormones
• Master gland controlling most other endocrine glands
• Partitioned into anterior and posterior portions

Posterior Pituitary (Neurohypophysis)

• Receives peptide hormones produced in hypothalamic nuclei
• Oxytocin & ADH/arginine-vasopressin are synthesized and packaged in vesicles with carrier proteins
• Vesicles move down pituitary stalk, stored in posterior pituitary gland
• Glutamate & GABA neurotransmitters can stimulate/inhibit hormone release

Posterior Pituitary Hormones

• Oxytocin: Stimulates uterus contraction, milk ejection, positive feedback mechanism
• ADH (Vasopressin): Formation/concentration of urine (facultative water reabsorption), response to increased blood osmolarity, regulates water reabsorption

Antidiuretic Hormone

• Antidiuretic hormone (ADH, or arginine vasopressin) regulates water reabsorption in the collecting tubules of the kidneys
• ADH secretion from the posterior pituitary triggered by increased serum osmolarity
• Binds to V2 receptors, stimulating aquaporin channels' translocation for water reabsorption in the renal distal tubules/collecting ducts
• Maintaining blood osmolarity

Hypothalamic-Pituitary Alterations

• SIADH: Excessive ADH, without appropriate feedback from hypothalamus; excess water retention, dilutional hyponatremia
• Diabetes Insipidus (DI): Deficient ADH; often caused by inadequate ADH, renal tubular collecting ducts' insensitivity or excessive fluid intake -Excessive water loss leads to increased serum osmolality, decreased urine output

Thyroid Gland

• Located in the anterior neck, lying over trachea
• Composed of right and left lobes, connected by isthmus
• Follicular cells surround follicular lumen, trapping iodine, synthesizing and storing thyroid hormones
• C cells secrete calcitonin
• Synthesis of thyroid hormones: Iodide absorbed from GIT, iodide travels into follicular cells and is converted to iodine, and then attached to thyroglobulin for T3 and T4 (with 2 iodine and 3 iodine respectively)

Thyroid Hormones

• T3 (triiodothyronine) is more biologically potent than T4 (thyroxine)
• T4 is converted to T3 peripherally in liver and kidneys
• Small amounts of T4 deiodinated to inactive reverse T3
• Thyroid hormones regulate many bodily functions

Secretion and Conversion of T4 & T3

• Hypothalamus releases TRH to pituitary
• Pituitary releases TSH to thyroid
• TSH triggers thyroid peroxidase to produce T3/T4
• 93% of T4 and 7% of T3 is used immediately
• Conversion of T4 to T3 in liver (60%)

Factors Affecting T3 to T4 Conversion

• Contributing factors: nutrients (iron, iodine, tyrosine), vitamins; inhibiting factors: stress, infection, toxins; factors to increase conversion T4 to T3 - selenium; zinc; factors to increase conversion T4 to RT3—Stress, trauma, low calorie diet, inflammation, certain medications

Functions of Thyroid Hormones

• Act via nuclear receptors in target cells
• Global metabolic and development effects
• T4 and T3 either diffuse or are carried through the lipid portion of the cell membrane or are carried through a transporter
• Hormones bind to mitochondrial and nuclear surfaces (T3 has highest affinity)
  • Binding to receptors alters transcription of specific genes (suppresses or activates)

Functions of Thyroid Hormones (Metabolism)

• Increased gluconeogenesis /glucose hepatic production, available necessary amino acids, glycerol, specific enzymes
• Increased glycolysis/available free glucose,
• Increased proteolysis in muscle, amino acids available for gluconeogenesis, increased protein synthesis
• Increased lipolysis/triglyceride degradation in adipose tissue, glycerol and fatty acids, lipogenesis

Functions of Thyroid Hormones (Cardiovascular)

• Systemic arteriole dilation, decreased SVR/afterload
• Increased circulating blood volume/preload, dilated vessels, stimulates renin-angiotensin system
• Increases heart rate, regulating action potential duration and repolarization currents, and regulates genes in pacemaker cells
• Increases force of contraction

Feedback Mechanisms of the Hypothalamic Pituitary Axis (HPA)

• Increased levels of thyroid hormones signal the hypothalamus to stop secreting TSH.
• Most feedback systems are negative where increased levels of a substance inhibit further release of stimulating factors.

Alterations in Thyroid Function (Hyperthyroidism)

• Graves disease: Primary autoimmune; TSH-producing adenomas
• Goiter: Enlargement of thyroid gland; TSH-secreting pituitary adenoma can progress to thyroid storm.

Alterations in Thyroid Function (Thyroid Storm/Crisis)

• Sudden, dramatic increase in circulating thyroid hormones.
• May result from undiagnosed or poorly controlled hyperthyroidism, precipitated by stress, infection, surgery.

Thyroid Storm Diagnosis

• Includes measurements for thermoregulatory dysfunction, gastrointestinal-hepatic dysfunction, cardiovascular dysfunction, mental dysfunction etc.

The Adrenal Gland

• Anatomically associated with each kidney, sharing the same blood supply
• Two layers: cortex (3 layers of cells) and medulla.

Adrenal Cortex Hormones (Mineralocorticoids)

• Zona glomerulosa synthesizes and secretes mineralocorticoids—Regulated by the Renin-Angiotensin-Aldosterone system which responds to Na+ & H2O depletion or hyperkalemia
• Angiotensin II stimulates aldosterone secretion binds to receptors in distal renal nephrons epithelial cells and stimulates Na⁺ and water retention, K⁺ and H⁺ depletion

Adrenal Cortex Hormones (Glucocorticoids)

• Zona fasciculata synthesizes and secretes glucocorticoids which are stimulated by ACTH from the anterior pituitary.
• Effects: Metabolic, anti-inflammatory/immunosuppressive, and growth-suppressing.

Hormones of the Adrenal Medulla

• Chromaffin cells (pheochromocytes) store epinephrine and norepinephrine in secretory granules, working closely with the sympathetic nervous system to respond to stress
• Sympathetic preganglionic nerve fibers stimulated by stress to secrete acetylcholine
• Chromaffin cells depolarize, leading to exocytosis of granules, release of epinephrine and norepinephrine
• Catecholamines bind to alpha and beta receptors.

Adrenal Gland Vascular Supply

• Adrenal blood supply flows into cortical arteries then branches into capillary networks (cortex & medulla), draining into a central medullary vein.
• This arrangement exposes the medulla to high concentrations of glucocorticoids.

Effects of a & b Receptor Stimulation

• Activation of beta receptors increases myocardial force and rate of contraction, and may lead to arrhythmias.
• Activation of alpha receptors causes vasoconstriction
• Activation of beta receptors causes bronchial dilation and a decrease in airway resistance.

Stress Response

• Short-term stress: involves activation of sympathetic nervous system and adrenal medulla, resulting in increased heart rate, blood pressure, and release of catecholamines
• Prolonged stress: activates hypothalamic-pituitary-adrenal (HPA) axis, and involves the release of cortisol.

Adrenal Abnormalities (Cushing Syndrome/Disease)

• Cushing syndrome: Clinical manifestations from chronic exposure to high cortisol levels from various causes (e.g., pituitary tumor, exogenous corticosteroids)
  • Symptoms/signs vary and can include changes in body shape and distribution of fat, high blood pressure, high blood sugar and susceptibility to infections

Cushing's Disease/Syndrome

• Possible causes: ACTH-dependent pituitary tumors (70%), adrenal tumors, unknown cause (15%); exogenous causes: taking medications containing corticosteroids (15%)
• Signs and symptoms of excess cortisol, (e.g., upper body obesity, buffalo hump, full moon face, thin extremeties, fragile skin bruising)

Adrenal Insufficiency

• Decrease of circulating cortisol and/or aldosterone, lack of stimulation from hypothalamus and pituitary gland
• Inability of adrenal glands to produce cortisol and aldosterone
• Causes include autoimmune disorders, tuberculosis, fungal infections.
• Symptoms include fatigue, postural dizziness, syncope etc, decreased libido, amenorrhea.

Insulin

• Secreted by beta cells in response to elevated blood glucose
• Stimulates liver to convert glucose to glycogen
• Promotes increased potassium levels in cells
• GLUT4 transporters are stored in cytoplasmic vesicles, and released into the cell membrane to allow glucose transport

Glucagon

• Secreted by alpha cells in response to low blood glucose
• Stimulates glycogenolysis in the liver release of glucose into the blood; used for energy.
• Promotes gluconeogenesis: the synthesis of glucose from non-carbohydrate sources
• Used for energy during periods of fasting.

Types of Diabetes

• Type 1: usually autoimmune, short history, acute onset, not typically overweight, rare, insulin deficiency, requires insulin at diagnosis, often random diagnosis
• Type 2: usually older age, insidious onset, often overweight, insulin resistance, common, diet and lifestyle change can reverse it
• Gestational: first detected during pregnancy, often overweight, insulin resistance, placental hormones, becoming more common, diet and lifestyle plus medications affecting growing baby, family history