16 - Endocrine

Endocrine System

• Transfer of information through chemical signals

• Acts with nervous system to coordinate and integrate activity of body cells

• Influences metabolic activities via hormones transported in blood

• Response slower but longer lasting than nervous system

Chemical classes of hormones

1. Amino acid-based hormones

   • Amino acid derivatives, peptides, and proteins

2. Steroids

   • Synthesized from cholesterol

   • Gonadal and adrenocortical hormones

Mechanism of Hormone Action depends on

chemical nature and receptor location

1. water-soluble hormones

2. Lipid-soluble hormones

Water-soluble hormone mechanism

• (all amino acid–based hormones except thyroid hormone)

  • Act on plasma membrane receptors

  • Act via G protein second messengers

  • Cannot enter cell

Lipid-soluble hormone mechanism

• (steroid and thyroid hormones)

  • Act on intracellular receptors that directly activate genes

  • Can enter cell

Target cell activation depends on what factors

1. concertation

2. receptor availability

3. binding ability

Hormones influence number of their _

• receptors

  • Upregulation—target cells form more receptors in response to low hormone levels

  • Downregulation—target cells lose receptors in response to high hormone levels

Control of Hormone Release

• Blood levels of hormones

  • Controlled by negative feedback systems

  • Vary only within narrow, desirable range

• Endocrine gland stimulated to synthesize and release hormones in response to

  • Humoral stimuli

  • Neural stimuli

  • Hormonal stimuli

Hormones circulate in blood either

free or bound

• Steroids and thyroid hormone are attached to plasma proteins

• All others circulate without carriers

Concentration of circulating hormone reflects

• Rate of release

• Speed of inactivation and removal from body

Hormones removed from blood by

1. Degrading enzymes

2. Kidneys

3. Liver

Half-life (in hormones)

time required for hormone's blood level to decrease by half

• Varies from fraction of minute to a week

Interaction of Hormones at Target Cells

• Multiple hormones may act on same target at same time

1. Permissiveness

2. Synergism

3. Antagonism

Permissiveness

one hormone cannot exert its effects without another hormone being present

Synergism

more than one hormone produces same effects on target cell → amplification

Antagonism

one or more hormones oppose(s) action of another hormone

Plots used in Endocrinology

1. Scatchard plot

2. Titration curve

3. Dose Response Curve

Scatchard plot

• plots bound/free….showing affinity

• Plots total amount of bound ligand/free concentration against total bound ligand.

• -K = Association constant for ligand receptor binding

• Bmax = Number of binding sites for ligand

• Affinity of receptor for ligand and # of binding sites

Titration Curve

• Plots amount of bound ligand against the logarithm of the free ligand concentration.

• Used to identify the concentration of ligand at which ½ of receptors are occupied, shows how affinity is determined above and below Kd

Dose-response Curve

• Uses a biological response (instead of receptor occupancy) to show hormone effects.

• ED50 = concentration of hormone at 50% max target cell activity

Dose-response curves can be

• upregulated or downregulated

  • Sensitivity of target tissues to hormones can change with conditions

Maximal response of a target tissue can be altered by changing:

1. Number of active cells in the tissue

2. Number of receptor molecules in the tissue

3. Effectiveness of each receptor molecule

Dose response curves show mechanisms by

which target tissue responsiveness to a hormone can change

• Upregulation/downregulation: Alteration in the number of active receptors

  • Exposure to a ligand almost always results in downregulation of (fewer) receptors

  • Some hormones amplify their action with upregulation  FSH, estradiol

    • positive feedback loops, amplifying action

• Desensitization changes the concentration dependence of the target tissue

Half-Life and metabolic clearance rate (MCR) describe

MCR is inversely related to _

the half life

Hypothalamus

• The portion of the brain that maintains the body’s homeostasis

• Link between the endocrine and nervous systems (through the pituitary gland)

• Produces releasing and inhibiting hormones, which stop and start the production of other hormones throughout the body

Pituitary gland lodes

1. posterior pituitary (lobe)

2. anterior lobe

posterior pituitary (lobe)

• Downgrowth of hypothalamic neural tissue

• Neural connection to hypothalamus (hypothalamic hypophyseal tract)

• Nuclei of hypothalamus synthesize neurohormones oxytocin (produced in similar quantities in male and female) and antidiuretic hormone (ADH)

• Neurohormones are transported to and stored in posterior pituitary

Steps of oxytocin and ADH release from pituitary galnd

1. Hypothalamic neurons synthesize oxytocin or antidiuretic hormone (ADH)

2. Oxytocin and ADH are transported down the axons of the hypothalamic- hypophyseal tract to the posterior pituitary.

3. Oxytocin and ADH are stored in axon terminals in the posterior pituitary.

4. When hypothalamic neurons fire, action potentials arriving at the axon terminals cause oxytocin or ADH to be released into the blood

Oxytocin vs ADH

• Each composed of nine amino acids

• Almost identical – differ in two amino acids

• very different physiological effects

Oxytocin

• Strong stimulant of uterine contraction

• Released during childbirth

• Hormonal trigger for milk ejection

  • suckling increases production

• Acts as neurotransmitter in brain

• is in males, but greater in females

  • play role in affectionate actions

ADH

• aka Vasopressin

• Inhibits or prevents urine formation

• Regulates water balance

• Targets kidney tubules → reabsorb more water

• Release also triggered by pain, low blood pressure, and drugs

• Inhibited by alcohol, diuretics

• High concentrations → vasoconstriction

ADH pathologies

1. Diabetes insipidus

2. Syndrome of inappropriate ADH secretion (SIADH)

Diabetes insipidus

• cause by things like head trauma

  • common in comatose patients

• ADH deficiency due to hypothalamus or posterior pituitary damage

• Must keep well-hydrated

Syndrome of inappropriate ADH secretion (SIADH)

• Retention of fluid, headache, disorientation

• Fluid restriction; blood sodium level monitoring

• caused by things like meningitis and cancers

Anterior Lobe

• Originates as outpocketing of oral mucosa

• master endocrine gland in body

• Vascular connection to hypothalamus

  • Hypophyseal portal system

    • Primary capillary plexus

    • Hypophyseal portal veins

    • Secondary capillary plexus

    • Carries releasing and inhibiting hormones to anterior pituitary to regulate hormone secretion

Release of hormones from Anterior Lobe

1. When appropriately stimulated, hypothalamic neurons secrete releasing or inhibiting hormones into the primary capillary plexus

2. Hypothalamic hormones travel through portal veins to the anterior pituitary where they stimulate or inhibit release of hormones made in the anterior pituitary.

3. In response to releasing hormones, the anterior pituitary secretes hormones into the secondary capillary plexus. This in turn empties into the general circulation.

Anterior Pituitary Hormones

1. Growth hormone (GH)

2. Thyroid-stimulating hormone (TSH) or thyrotropin

3. Adrenocorticotropic hormone (ACTH)

4. Follicle-stimulating hormone (FSH)

5. Luteinizing hormone (LH)

6. Prolactin (PRL)

• All are proteins

• All except GH activate cyclic AMP second messenger systems at their targets

• TSH, ACTH, FSH, and LH are all tropic hormones (regulate secretory action of other endocrine glands

Growth Hormone

• aka: GN or Somatotropin

• Produced by somatotropic cells

• Direct actions on metabolism

• Indirect actions on growth

• Mediates growth via growth-promoting proteins – insulin-like growth factors (IGFs)

• IGFs stimulate

  • Uptake of nutrients → DNA and proteins

  • Formation of collagen and deposition of bone matrix

• Major targets—bone and skeletal muscle

  • but do exist in all tissues

GH actions on metabolism

• Increases blood levels of fatty acids; encourages use of fatty acids for fuel; protein synthesis

• Decreases rate of glucose uptake and metabolism – conserving glucose

• → Glycogen breakdown and glucose release to blood (anti-insulin effect)

GH release chiefly regulated by _

• hypothalamic hormones

  • Growth hormone–releasing hormone (GHRH)

    • Stimulates release

  • Growth hormone–inhibiting hormone (GHIH) (somatostatin)

    • Inhibits release

• Ghrelin (hunger hormone) also stimulates release but plays less of a role

Homeostatic Imbalances of Growth Hormone

• Hypersecretion

  • In children results in gigantism

  • In adults results in acromegaly

• Hyposecretion

  • In children results in pituitary dwarfism

Thyroid Stimulating Hormone

• aka Thyrotropin

• Produced by thyrotropic cells of anterior pituitary

• Stimulates normal development and secretory activity of thyroid

• Release triggered by thyrotropin-releasing hormone from hypothalamus

• Inhibited by rising blood levels of thyroid hormones that act on pituitary and hypothalamus

Adrenocorticotropic Hormone

• aka Corticotropin

• Secreted by corticotropic cells of anterior pituitary

• Stimulates adrenal cortex to release corticosteroids

Regulation of ACTH release

• Triggered by hypothalamic corticotropin-releasing hormone (CRH) in daily rhythm

• Internal and external factors such as fever, hypoglycemia, and stressors can alter release of CRH

Gonadotropins

• Follicle-stimulating hormone (FSH) and luteinizing hormone (LH)

• Secreted by gonadotropic cells of anterior pituitary

• FSH stimulates gamete (egg or sperm) production

• LH promotes production of gonadal hormones

• Absent from the blood in prepubertal individuals

Regulation of gonadotropin release

• Triggered by gonadotropin-releasing hormone (GnRH) during and after puberty

• Suppressed by gonadal hormones (feedback)

Prolactin

• aka PRL

• Secreted by prolactin cells of anterior pituitary

• Stimulates milk production

• Role in males not well understood

• Regulation of PRL release

  • Primarily controlled by prolactin-inhibiting hormone (PIH) (dopamine)

• Blood levels rise toward end of pregnancy

• Suckling stimulates PRL release and promotes continued milk production

  • similar to oxytocin

• Hypersecretion causes inappropriate lactation, lack of menses, infertility in females, and impotence in males

Thyroid Gland

• Two lateral lobes connected by median mass called isthmus

• Composed of follicles (follicular cells) that produce glycoprotein thyroglobulin

• Colloid (fluid with thyroglobulin + iodine) fills lumen of follicles and is precursor of thyroid hormone

• Parafollicular cells produce the hormone calcitonin

Thyroid Hormone Structure

• Actually two related compounds

  • T₄ (thyroxine); has 2 tyrosine molecules + 4 bound iodine atoms

  • T₃ (triiodothyronine); has 2 tyrosines + 3 bound iodine atoms

Thyroid Hormone

• Affects virtually every cell in body

• Major metabolic hormone

• Increases metabolic rate and heat production (calorigenic effect)

• Regulation of tissue growth and development

  • Development of skeletal and nervous systems

  • Reproductive capabilities

• Maintenance of blood pressure

Synthesis of Thyroid Hormone

• Thyroid gland stores hormone extracellularly

• Thyroglobulin synthesized and discharged into follicle lumen

• Iodides (I–) actively taken into cell and released into lumen

• Iodide oxidized to iodine (I2),

• Iodine attaches to tyrosine, mediated by peroxidase enzymes

• Iodinated tyrosines link together to form T₃ and T₄

• Colloid is endocytosed and vesicle is combined with a lysosome

• T₃ and T₄ are cleaved and diffuse into bloodstream

Transport and Regulation of TH

• T₄ and T₃ transported by thyroxine-binding globulins (TBGs)

• Both bind to target receptors, but T₃ is ten times more active than T₄

• Peripheral tissues convert T₄ to T₃

• Negative feedback regulation

Negative feedback regulation of TH release

• Rising TH levels provide negative feedback inhibition on release of TSH

• Hypothalamic thyrotropin-releasing hormone (TRH) can overcome negative feedback during pregnancy or exposure to cold

Homeostatic Imbalances of TH

• Hyposecretion in adults—myxedema; goiter if due to lack of iodine

• Hyposecretion in infants—cretinism

  • leads to neurological defects if not treated

• Hypersecretion—most common type is Graves' disease

  • obvious sign, eyeball protursion

Calcitonin

• Produced by parafollicular (C) cells

• No known physiological role in humans

• Antagonist to parathyroid hormone (PTH)

• At higher than normal doses

  • Inhibits osteoclast activity and release of Ca2+ from bone matrix

  • Stimulates Ca2+ uptake and incorporation into bone matrix

Parathyroid Glands

• Four to eight tiny glands embedded in posterior aspect of thyroid

• Contain oxyphil cells (function unknown) and parathyroid cells that secrete parathyroid hormone (PTH) or parathormone

• PTH—most important hormone in Ca2+ homeostasis

  • causes degradation of bone to increase Ca2+ in blood

Parathyroid Hormone

• Functions

  • Stimulates osteoclasts to digest bone matrix and release Ca2+ to blood

  • Enhances reabsorption of Ca2+ and secretion of phosphate by kidneys

  • Promotes activation of vitamin D (by kidneys); increases absorption of Ca2+ by intestinal mucosa

• Negative feedback control: rising Ca2+ in blood inhibits PTH release

Homeostatic Imbalances of PTH

• Hyperparathyroidism due to tumor

  • Bones soften and deform

  • Elevated Ca2+ depresses nervous system and contributes to formation of kidney stones

• Hypoparathyroidism following gland trauma or removal or dietary magnesium deficiency

  • Results in tetany, respiratory paralysis, and death

Adrenal Glands

• aka suprarenal

• Paired, pyramid-shaped organs atop kidneys

• Structurally and functionally are two glands in one

  • Adrenal medulla—nervous tissue; part of sympathetic nervous system

  • Adrenal cortex—three layers of glandular tissue that synthesize and secrete corticosteroids

Adrenal Cortex

• Three layers of cortex produce the different corticosteroids

  1. Zona glomerulosa—mineralocorticoids

  2. Zona fasciculata—glucocorticoids

  3. Zona reticularis—gonadocorticoids

Mineralocorticoids

• Regulate electrolytes (primarily Na+ and K+) in ECF

  • Importance of Na+: affects ECF volume, blood volume, blood pressure, levels of other ions

  • Importance of K+: sets RMP of cells

• Aldosterone most potent mineralocorticoid

  • Stimulates Na+ reabsorption and water retention by kidneys; elimination of K+

Aldosterone

• Most potent mineralocorticoid

  • Stimulates Na+ reabsorption and water retention by kidneys; elimination of K+

  Release triggered by

  • Decreasing blood volume and blood pressure

  • Rising blood levels of K+

Mechanisms of Aldosterone Secretion

• Renin-angiotensin-aldosterone mechanism: decreased blood pressure stimulates kidneys to release renin → triggers formation of angiotensin II, a potent stimulator of aldosterone release

• Plasma concentration of K+: increased K+ directly influences zona glomerulosa cells to release aldosterone

• ACTH: causes small increases of aldosterone during stress

• Atrial natriuretic peptide (ANP): blocks renin and aldosterone secretion to decrease blood pressure

Homeostatic Imbalances of Aldosterone

Aldosteronism—hypersecretion due to adrenal tumors

• Hypertension and edema due to excessive Na+

• Excretion of K+ leading to abnormal function of neurons and muscle