Phys: ENDOCRINE

CHEMICAL MESSENGERS:

1. Neurotransmitters:
1. released by axon terminals of neurons into synaptic junctions
2. act locally to control nerve cell functions
2. Endocrine hormones
1. released by glands or specialized cells into blood
2. influence the function of target cells at another location in the body
3. Neuroendocrine
1. secreted by neurons into blood
2. influenced function of target cells at another location
4. Paracrines
1. secreted by cells into extracellular fluid
2. affect neighboring target cells of a different type
5. Autocrines
1. secreted by cells into extracellular fluid
2. affect function of same cells at produced them
6. Cytokines
1. peptides (proteins) secreted by cells into extracellular fluid
2. *secreted substances may function as autocrines, paracrines or endocrine hormones
3. eg. interleukins and other lymphokines that are secreted by helper cells at act on other cells of the immune system

Endorine hormones affect many different types of cells throughout the body:

• Growth Hormone: from anterior pituitary gland - causes growth throughout body
• Thyroxine:  from thyroid - incr rate of chemical rxns in almost all body's cells
• Adrenocorticotropic Hormone (ACTH): from anterior pituitary gland - stim the adrenal cortex causing it to secrete adrenocortical hormones
• Thyrotropin-releasing hormone (TRH): from anterior pituitary - stim secretion of thyroid stimulating hormone (TSH)

Growth hormone released during REM sleep

Neg feedback: somatostatin turns off growth hormone

somatomedia C (insulin-like) --> IGF1 (insulin like growth factor 1) stim condrocytes and osteocytes > bone matrix

3 CLASSES OF HORMONES

1. PROTEIN-BASED: *most hormones are polypeptides/proteins
• hormones secreted by anterior and posterior pituitary
• pancrease --> insulin, glucagon
• parathyroid gland --> parathyroid hormone
• H2O loving - hydrophylic
• synthesized on rough endoplasmic reticulum of endocrine cell
• release initiated by increase in calcium levels or incr in cAMP (2nd messenger)
• stored in secretory vesicles until needed
• packaged in Golgi Apparatus (post office)
• exocytosed
• polypeptides with 100+ amino acids = protein
• less than 100 AA = peptides
2. STEROIDS
• secreted by adrenal  cortex (cortisol, aldosterone)
• ovaries (estrogen, progesterone)
• testes (testosterone)
• placenta (estrogen, progesterone)
• -en or -one = steroid-based
• manufactured from cholesterold
• lipid soluble (only lipid soluble hormone)
• not storage material, no need to do so (liver conjugates it; when cirrhotic liver can't conjugate them --> incr estrogen --> 2ndary female sex characteristics in males)
• d/t high lipid solubility they diffuse across cell membranes and readily enter the bloodstream and interstitial fluid
• large volumes of cholesterol esters are readily available in cytoplasm
• stores are quickly mobilized to create new steroid molecules
3. TYROSINE DERIVATIVES: an amino acid; amine hormones
• secreted by thyroid --> thyroxine, triiodothyrinine
• adrenal medulla secretes AA based epi and NE
• formed by enzymatic action within cytoplasmic compartments of glandular cells
• H2O loving
• thyroid is stored as thyroglobulin (protein)
• released from its protein storage matrix and enters bloodstream (slow releaser)
• complexes in bloodstream with thyroxine-binding globulin which helps control its release to target tissues

AMINES: EPI & NE

• Formed in adrenal medulla, released by adrenal medullary cells by exocytosis
• Epi:NE  4:1
• circulates in plasma in free form or in conjugation with other substances

Catecholamine Creation:

Phenylalanine --> Tyrosine --> DOPA --> Dopamine (+Dopamine B hydroxylate) --> NE --> Epi

Metabolism:

1. Extraneural (outside cell): Catechol-O-Methyl Transferase (COMT)
1. Epi --> metanephrine
2. NE --> normetanephrine
3. Dopamine --> methoxytyramine
2. Inside SANS nerve fibers: Monoamine Oxidase (MAO) deaminates amino neurotransmitters in SANS nerve fibers.  Found near mitochondria membrane
1. MAO Type A: deaminates Epi, NE, dopamine
2. MAO Type B: deaminates only dopamine
3. Epi --> vanillylmandelic acid
4. NE --> vanillylmandelic acid
5. Dopamine --> homovanillic acid

Epinephrine:

• Formed in adrenal medulla under action of: phenylethanolamine-N-methyltransferase
• process called methylation found only in adrenal medulla
• NE and epi differ in number of methyl groups they possess

Catecholamine Storage

• stored in chromaffin vesicles located in adrenal medulla
• NE complexes with ATP and is bonded to protein within chromaffin cells
• NE released by exocytosis
• Calcium essential for exocytosis of NE

HORMONE RECEPTOR ACTIVATION
Formation of hormone receptor complex: The activated receptor initiates hormonal effects

TYPES OF RECEPTORS:

1. Ion Channel Linked Receptors
1. eg. ACh or NE combined with receptors in the postsynaptic membrane
2. this results in opening or closing of ion channels for Na, K, Ca, etc
2. G Protein Coupled Hormone Receptors (Guanisine)
1. 7 trans-membrane receptors or Trimeric G proteins
2. can be inhibitory or stimulatory

     3.   Enzyme-linked Hormone Receptors

1. Enzymes pass through the membrane receptor and initiate their intended response
2. eg. Leptin (secreted by fat cells) important in regulating appetite and energy balance
3. Leptin receptor is member of cytokine receptor family that rely on enzymes from outside the receptor as it possesses no enzymes of its own 



HORMONAL CONTROL: NEGATIVE FEEDBACK
The action of released substance tends to suppress further release
Negative feedback prevents oversecretion of the  hormone or over activity of the gland



DOWN-REGULATION

• High plasma concentrations of NE result in decr density of B adrenergic receptors
• chronic tx of pt with B2 agonists results in tachyphylaxis d/t down regulation and a decr in receptor density --> will require more drug to have same effect
• the phosphorylation site in the GPCR is responsible for the down regulation process
• the receptor becomes "uncoupled" and removed from sarcolemma membranes through a sequestration process
• temporarily stored for later use or
• destroyed and recycled

HYPOTHALAMUS
*Small but extremely important part of diencephalon
*contributes to control of endocrine, autonomic, and behavioral functions

Roles:

1. controls release of 8 major hormones by hypophysis (AKA pituitary)
2. temperature regulation
3. control of food and water intake
4. sexual behavior and reproduction
5. control of daily physiological cycles and behaviors
6. mediation of emotional responses (pleasure, rage, olfactory)
7. plays a role in pain perception and modulation

Hypothalamic control of Pituitary Hormones:

• Hormonal secretion is controlled by nervous or hormonal signals from hypothalamus
• The hypothalamus is connected to the pituitary by the hypophysial stalk

PITUITARY GLAND (HYPOPHYSIS)

• 1 cm; 1 gm
• sits in sella turcica at base of brain (turkish saddle)
• Has 2 distinct portions that are embryologically different
• between the 2 structures (ant and post pituitary) a small avascular structure known as pars intermedia is found.  Avascular divider that has no function in humans --> similar to corpus callosum in brain

Anterior Pituitary = Adeno-hypophysis

• Arises from Rathkey's pouch, an invagination of the pharyngeal epithelium
• cells are epithelial in origin
• secretes 6 important hormones:
1. Growth hormone
2. adrenocorticotropin
3. thyrotropin
4. prolactin
5. follicle stimulating hormone
6. luteinizing hormone

Anterior Pituitary control:
Hypothalamic releasing or inhibitory hormones are secreted in the hypothalamus.  These substances travel to the anterior pituitary via the hypothalamic hypophysial portal system.
This vascular system coalesces (comes together) at the median eminence ("prominence") where the substances are released to affect the anterior pituitary function.
The substances control the release or the non release of anterior pituitary hormones

Median Eminence:
considered Circumventricular --> secretions here circumvent the BBB (outside the ventricles; not inhibited by BBB)

Releasing and inhibitory factors control the secretion of the anterior pituitary:

• Hypothalamic Factor --> Hormones released from the anterior pituitary
• Thyrotropin releasing h. --> TSH
• corticotropin releasing h. --> adrenocorticotropin
• growth hormone releasing factor --> growth h.
• growth hormone inhibitory factor (somatostatin) --> anti-growth h.
• gonadotropin releasing hormone --> follicle stim h. and luteinizing h.
• prolactin inhibitory and prolactin releasing h. --> release of prolactin or inhibition of prolactin release

Posterior Pituitary = Neuro-hypophysis (glial cells)

• embyonic origins are from neural tissue growth from hypothalamus; large number of glial type cells (pituicytes)
• pituicytes are supporting cells for terminal nerve fibers that originate in the super optic and paraventricular nucleic of hypothalamus
• secretes 2 peptide hormones:
1. antidiuretic hormone (ADH) --> formed in super optic nuclei
2. oxytocin --> formed in paraventricular nuceli
• each site is capable of producing about 1/6th as much of the second hormone as its primary hormone if needed (redundency)

GROWTH HORMONE

• Stimulates cartilate and bone growth
• releases fatty acids from stored adipose tissue for energy
• fat is preferentially metabolized under growth hormone influence
• may lead to ketogenic effect d/t acedo-acetic acid formation
• contributes to fatty liver

Abnormalities:
Pan hypopituitarism: global decrease in all anterior pituitary hormones; may be congenital or acquired (cranial pharyngeoma; chromophobe tumor)

Dwarfism: all body parts develop in proportion to one another but at a greatly decreased rate.  Most do not experience puberty d/t lack of gonadotropin hormones.  1/3 of dwarfs demonstrate normal sexual function and simply lack growth hormone

Gigantism: in children, all body parts grow rapidly and teenagers may grow 8 ft tall d/t open epiphyseal plates; hyperglycemia d/t beta cell burnout in pancreas is common

Acromegaly: in adults with closed epiphyseal plates, bones become thicker and soft tissues proliferate; commonly affects cranial bones and airway management (fiber optic; glidescope); skull, protrusion of madible, hands, feet

ADRENAL GLANDS
2 each, weighing 4 gm; located on superior poll of kidneys

Adrenal Medulla (20% of gland)
SANS system - secretes Epi and NE

Adrenal Cortex (80% of gland)
secretes corticosteroids synthesized from steroid cholesterol

1. Mineralocorticoids - Aldoesterone - affect minerals such as Na and K
2. Glucocorticoids - Cortisol - affect glucose levels, protein and fat metabolism and stress response; 3/4
3. Androgens - sex hormones

Zones of Adrenal Cortex

• Zona Glomerulosa (15%) - secretes aldosterone, primarily controlled by angiotensin 2 and K levels
• Zona Fasciculata (75%) - secretes cortisol and corticosterone controlled by ACTH; most important
• Zona Reticularis (10%) - deepest layer, secretes androgen or sex hormones, controlled by ACTH; least important

G-F-R

THYROID GLAND
weighs 20 gm in adults

• secretes thyroxin (T4) 93% of total secretion, and triiodothyronine (T3)
• secretion increased the metabolic rate of all cells
• lack of thyroid hormone can drop basal metabolic rate below 50% of normal
• thyroid secretion is controlled primarily by thyroid stimulating hormone (TSH)
• thyroid gland also secretes calcitonin important for calcium metabolism

Iodine is required for formation of thyroxine

• 1 mg/week required to prevent iodine deficiency
• to prevent deficiency, common table salt is iodized
• thyroid hormone have slow onset and long duration of action