Endocrine summary

The Endocrine System

• Functional system for communication between cells.
• Major functions:
  • Maintaining homeostasis (e.g., metabolism, blood glucose levels (BGL), water balance).
  • Regulation of reproduction, growth, and development.
• Hormones are released from endocrine organs, travel via the bloodstream to target cells (only cells with specific receptors).
  • Examples: Insulin, glucagon, GLP-1, leptin, ghrelin, CCK.
• Three broad groups of hormones:
  • Peptide.
  • Steroid.
  • Amine (thyroid).

Peptide Hormones

• Structure:
  • Peptide = chain of 3-200+ amino acids.
  • Polypeptide: peptide chains connected.
  • Protein: Multiple peptides.
  • Proteins: DNA unwound, mRNA is transcribed and mRNA is translated into proteins and peptides.
• Properties:
  • Solubility: Water soluble, allowing them to move freely in plasma.
  • Storage: Stored in large amounts in secretory vesicles (like insulin).
  • Half-life: Don’t stay around for long; broken down after binding to target receptors. Stored in large amounts in the cytosol of endocrine cells to counteract rapid breakdown.
• Secretion: Exocytosis is triggered by an influx of calcium.
  • A build-up of Ca^{2+} near vesicles (due to Ca^{2+} voltage-gated channels opening and release from the ER) causes them to move and release the active hormone.
• Transport: Mostly circulate freely in the blood (water soluble).
• Receptors: Membrane-spanning with extracellular ligand-binding site.
  • Being water-soluble, they cannot enter the cell; they bind to membrane-spanning receptors, activating a second messenger inside the cell to perform the function.

Biosynthesis of Peptide Hormones

• Manufactured by a large range of endocrine tissues.
• Each hormone is produced from a specialized cell within the tissue.
• Specialized endocrine cells synthesize, store, and secrete peptide hormones.
• Cell structures involved in protein synthesis and processing:
  • Transcription of mRNA ⇒ Ribosomes on RER ⇒ processing by Golgi ⇒ Vesicular storage ⇒ Release via exocytosis.
  • mRNA is transcribed from a DNA strand.
  • mRNA contains codons (groups of 3 base pairs) that code for specific amino acids.
  • Ribosomes read mRNA in groups of 3 base pairs.
  • Early protein binds to RER; a signal sequence is cleaved (binds to receptors on the surface of RER), targeting protein synthesis and is cleaved off when there is a suffiicent ammount.
  • Ribosome unit continues to read mRNA until completion; then, the ribosome dissociates from mRNA, and the protein is synthesized.
  • Vesicles in RER containing peptide or protein move into the Golgi apparatus where further processing occurs to turn it into an active protein hormone, then packaged into vesicles ready for release.
  • DNA in the nucleus -> mRNA.
  • The nuclear membrane is continuous with the RER membrane.
  • Ribosomes from RER begin to read mRNA and start to make protein.
  • The signal sequence of the early protein binds to the RER.
  • Protein synthesized in RER is transferred to the Golgi apparatus for processing.
  • The Golgi processes proteins into vesicles and secretes them into the cytosol.
  • Exocytosis occurs when conditions are right (e.g., increase in Ca^{2+}).

Processing of Peptide Hormones

• When a peptide hormone is synthesized from its constituent amino acids (first being made and signal sequence is attached):
  • It is a Preprohormone (inactive).
  • At the RER, the signal peptide is cleaved, and the polypeptide becomes a Prohormone, which is still inactive (gets rid of signal sequence, gets rid of ‘pre’).
  • The prohormone is transferred to the Golgi, further modified if required and packaged for secretion.

Insulin Example

• The insulin gene gets transcribed by mRNA, which is read by ribosomes.
• This contains the signal sequence meaning it is Preproinsulin.
• Once the signal sequence is cleaved off, it becomes Proinsulin.
• Proinsulin is made and released into the lumen of the ER.
• Proinsulin moves into the Golgi apparatus and is cleaved at 2 sites to produce insulin and C-peptide, which is the active hormone.
• From here, it sits in vesicles ready to be extracted through exocytosis, once we get a trigger that allows calcium influx to the cytosol from voltage-gated calcium channels and release of calcium from the endoplasmic reticulum.
• The vesicles are walked to the surface by proteins called kinesins.

Cell Membrane Receptors

• Peptide hormones (water-soluble) vs. properties of membranes (lipid).
• Cannot diffuse through the membrane, requiring a messenger to interact with cell membrane receptors to get their message across.
• Cells can receive messages from many hormones and must express the right receptor; cells express multiple receptors.
• Actions of hormone-receptor binding can lead to:
  • Membrane effects (e.g., GLUT4 to membrane to take up glucose).
  • Cytoplasmic effects (enzyme activation/inhibition).
  • Nuclear effects (change proteins being made - DNA transcription).

Peptide Hormones

• Receptors: Membrane-spanning (transmembrane) with extracellular ligand-binding site (outside the cell where hormones bind).
• Examples: Glucagon, epinephrine, insulin.
• Mechanisms of action: Mainly intracellular 2nd messengers (e.g., AC, PKA, PI).

Classes of Membrane Receptors

1. Ligand-gated ion channels

• Multiple subunit transmembrane proteins.
• The channel opens and closes; ion transport is controlled by binding to a site on the receptor.
• “Ionotropic receptors.”
• Example: Acetylcholine binds to the nicotinic receptor at the neuromuscular junction.
• When a protein hormone binds to the receptor (which is also a channel), if not bound the channel is in closed state, once bound the channel can pass through the membrane (charged species can pass through cell and change membrane potential in cell).

2. G Protein-Coupled Receptors (GPCRs)

• Most common.
• Binds guanine nucleotide (in the form of GDP and GTP).
• The largest family of receptors (1000+).
• Single polypeptide chain with 7 transmembrane helices (domains).
• A peptide hormone binds on the outside of the cell, causing the chain to link the intracellular part and bind to a G protein.
• Function: The receptor is the link between ligand/signaling molecules (extracellular) and G-protein (intracellular).
• Heterotrimeric: Three different protein subunits (alpha, beta, gamma).
• Activated alpha-subunit: Can bind GDP/GTP.
• Stimulates or inhibits adenylyl cyclase.
• Large family, multiple types: different G protein subunits.
  • Example: G-alphas = stimulatory = activates AC; G-alpha i = inhibitory = inhibits AC.
• Different subtypes: One hormone can interact with numerous downstream pathways.
  • Example: Dopamine binds to D1 and D2.

Adenylyl Cyclase

• A membrane-bound enzyme.
• Activated (or inhibited) by the alpha subunit.
• AC catalyzes the reaction: ATP -> cAMP.
• cAMP: Cyclic-adenosine monophosphate (a second messenger).
• A second messenger that activates protein kinase A (PKA) (enzymes that phosphorylate things).
• cAMP binds to the inactive PKA complex causing a conformational change that releases the active part of the enzyme.

3. Catalytic/Enzyme Receptors

• Are enzymes themselves (catalyze reactions).
• Example: Tyrosine Kinase receptors (phosphorylates other proteins).
• Phosphorylate tyrosine residues on themselves and/or other proteins.
• Recall: Insulin receptor - 2 alpha subunits (extracellular, where insulin binds) and 2 beta subunits that span across the membrane.
• Insulin binding changes conformation of alpha/beta chains and activates tyrosine kinase (on beta chains) on the intracellular part on beta subunits -> phosphorylates each other and other proteins; an enzyme.
• Transfers phosphate group to another signaling component.

Second Messengers

• First messenger: Peptide hormone interacting with receptor.
• Hormones and receptors can use different second messenger systems (not always the same ones).
• Second messengers: Allow signal amplification.
• Cells do not need huge numbers of receptors.
• Examples:
  • Adenylyl cyclase
  • Cyclic AMP (cAMP)
  • Protein kinase A (PKA)
  • Inositol triphosphate (IP3)

Steroid Hormones

• Solubility: Lipid soluble.
• Examples: Glucocorticoids, mineralocorticoids, sex steroids.
• Synthesized:
  • Adrenal cortex: Cortisol, Aldosterone.
  • Gonads: Ostergon, progesterone, testosterone.
• Synthesized on demand (not stored) from precursor cholesterol stored in lipid droplets in cells.
• Synthesis is controlled by hormones from the hypothalamus that act on the pituitary gland, then send hormones from there onto our endocrine cells to make steroid hormones.

Synthesis

• Cholesterol precursor
  • From liver (80%): Packed as VLDL, lipoprotein lipase converts VLDL to LDL.
  • From diet - fats get formed in chylomicrons that enter through lacteals which enter into the bloodstream, chylomicrons are acted on by lipoprotein lipase and chylomicrons get taken up by the liver. The liver repackages cholesterol + some made inside and triglycerides - and send out back into the bloodstream as VLDL.
  • Lipoprotein lipase also acts on VLDL by chopping up triglycerides.
  • When cholesterol concentration is higher in lipoproteins than in triglycerides, we move to LDL -> chops up fat so lipoprotein becomes more dense.
  • Cholesterol is made from Acetyl CoA within the cell
  • LDL -> LDL receptor: Recognizes external Apo B-100 protein on the surface (detected by endocrine cells that can take up LDL).
  • Receptor-mediated endocytosis (Lipoprotein comes in with Apo B sticking out - receptor sees this and endocytosis LDL and take it into the cell): LDL enters into the cell within a vesicle.
  • LDL combines with a lysosome and lysosomal hydrolases chop up LDL and release free cholesterol.
  • Cholesterol -> pregnenolone (common precursor to steroid hormones).
  • Pregnenolone -> testosterone, estradiol, cortisol, aldosterone (depending on cell).
    *Remnant chylomicrons from diet, taken up by hepatocyte in liver.
    *Cholesterol is packaged into VLDL - goes into bloodstream and chopped up into LDL.
    *Apo B protein expressed and is picked up by LDL receptor, endocytosed into cell and fused to lysosome - free cholesterol is released.
• Properties: Diffuse through the cell membrane (different from peptide hormones).

Other Properties

• Secretion (out of the adrenal gland/gonad): Diffuse through the cell membrane.
• Entry into the target cell is also by diffusion.
• Don’t like to hang out in aqueous environments in plasma - mostly bound to transport proteins.
• Transport: Mostly (>95%) bound to transport proteins in the blood (e.g., Albumin).
• Metabolized in the liver and broken down to bile acids.
• Removal is by the liver and urinary excretion.
• Receptors: Cytoplasm, nuclear.
• Mechanism of action: activated receptors bind to DNA and regulate gene transcription.
• Response time: Hours, days.

Steroid Hormone Receptors

• Are nuclear or intracellular cytoplasmic receptors (located inside the cell).
• Are ligand-activated transcription factors (something that binds to a specific site on the DNA causes unwinding of DNA and allows transcription).
• Linked extracellular signals to gene transcription.
• When activated by a ligand, they bind to a specific DNA site to initiate mRNA transcription and then protein synthesis.

Two Types

1. Cytoplasmic receptors: Complex to chaperone proteins (Held in shape by binding to chaperone proteins as They don’t like to be in cytoplasm by themselves).

   • Example: Heat shock proteins (HSP).

2. Hormone binds to chaperone/receptor complex, causing a conformational change.

• Chaperone dissociates from receptor/ligand complex, which is now an active transcription factor.

  Steroid hormone comes into the cell by diffusion through the membrane - binds to steroid receptors. Causes change in conformation and releases heat shock protein and allows the receptor to move into the nucleus. Here it dimerizes another steroid receptor and binds to a specific site on DNA - called steroid or hormone response element. Once it binds it then results in transcription of specific genes downstream

• Nuclear receptors: Act in the same way but are located in the nucleus so don’t need to be held in shape by chaperone proteins.

• Located in the nucleus and become an active transcription factor when a steroid ligand binds.

• Steroid hormone receptors bind to a specific site (Response element) on DNA.

• Where it binds (binding domain; determined by the receptor type) regulates which gene will be transcribed.

• Specifically, where the response element is (where they bind) will determine what proteins and enzymes are made in response.

Amines

• A class of hormones derived from amino acids.
• Contain an amino group (hence the name).

Three Groups

1st group = catecholamines

• Share a ‘catechol’ group.
• Modified from tyrosine
• Tyrosine -> Dopamine -> Norepinephrine -> Epinephrine.
  • Water soluble.

2nd group = Thyroid hormones

• Thyroxine and Triiodothyronine.
• Made from tyrosine as well.
  • Lipid soluble.

3rd group = Serotonin

• Modified from tryptophan.

  • Water soluble.

• Share properties of both peptide and steroid hormones depending on the classes.

Hormone Actions

• Agonist: Binds to receptor + activates cell signal transduction = effect inside the cell.
• Antagonist: Binds/blocks receptor = blocks cell signal transduction = no effect inside the cell.
• Partial agonist: Binds to receptor, partially activates cell signaling pathways = a particle effect.
• Constitutive activity: Receptors have a basal level of activity independent of a ligand (triggering some sort of signal).
• Complementary action: Several hormones contributing to a physiological function.

Example

• Neuromuscular junction - ACh is released onto the ACh receptor on muscle cells, which binds to its muscle contraction. ACh is an agonist of myosin.

• Belladonna plant: Produces atropine compound, atropine binds to the ACh receptor and acts as an antagonist. Stops anything else from binding - you stop any muscle contraction and leads to paralysis and death.

• Botox - Inhibitor of ACh release; turns it into a partial agonist and gets released at the same rate and relaxes muscles.

Receptor Regulation

• Cells can modify their sensitivity to a given hormone by increasing or decreasing their receptor populations = Homeostasis.

• Up-regulation: The cell increases the number of receptors and can increase sensitivity

  • Can occur if insufficient ligand is available.

  • Can occur if the cell requires a greater effect.

  • Example: Uterine oxytocin receptors in late pregnancy (want contractions to increase in force - upregulate receptors to increase effect).

• Down-regulation: The cell decreases the number of receptors and can decrease sensitivity

  • Can occur if there is too much ligand available.

  • Olanzapine - an antipsychotic drug used to treat mental disorders: Schizophrenia, bipolar, depression

  • Associated with metabolic side effects

  • Drug blocks the receptor, and there the cell makes more receptors = upregulation

• Different subtypes: One hormone can interact with numerous downstream pathways

  • Example: Dopamine binds to D1 receptor (activate) and D2 (inactivates) and many more

  • Norepinephrine binds to alpha1 (activate) and alpha 2 (inactivates) subtypes.

• AC + PLC pathways - different effects in the cell.

Same hormone having different effects in different cells depending on what subtype is available.

Hormone Clearance

How are the signals triggered by hormones switched off? How are they cleared.

• Liver and kidneys: Degradation and excretion via bile or urine.

• Degradation in target cells, degradation from the rectpot, degradation by releasing cell (re-uptake) by endocrine cell.

Bound vs. Unbound Hormones

• Bound hormones = greater half-life (amount of time it takes to reduce concentration of hormone by half).

• Extends half-life of hormone: Time for hormone to fall by half its original concentration.

• Longer the half-life, the longer it takes to get rid of it.

• Binding proteins: Hormones that bind to proteins (e.g., lipid-soluble hydrophobic hormones) are cleared from the blood much more slowly than “free” (water-soluble hydrophilic) hormones.

  • Example: Thyroid, steroid, and growth hormone are generally long-term hormones.

• Peptide hormones unbound = short-term hormones.

• Peptide hormones are stored in secretory granules ready to go - secretary has to be made on demand.

• Increases ‘pool’ of hormone in the blood, minimizing fluctuations.

Metabolic Clearance Rate (MCR)

• The volume of blood that is totally cleared of the substance per unit of time.

• A measure of the efficiency of its removal from the circulation.

• Units: Volume/time (e.g., ml/min, l/hr).

• The faster the MCR, the shorter the half-life.

  • Example: 5L/min (only have 5L blood in body) - completely clear substance in 1 minute, t_{1/2} = 30 seconds (half).

  • Example: 1L/min (5 minutes to clear the 5L of blood), t_{1/2} = 2.5 minutes to reach the half-life.

Immunoassay for Hormonal Measurements

• Example: ELISA (enzyme-linked immunosorbent assay), RIA - radioimmunoassay.

• Can also use HPLC.

• Use antibodies to bind specific hormones, then bind another antibody with enzymes that can create a color reaction. Create a standard curve using different concentration and the amount absorbance. Then can look at the color and measure the color and absorbance at any time - and look at concentration of protein in well.

RIA

• Radioimmunosorbant assay is similar but uses a radioactive antibody.

• Measure radioactivity levels within the wells.

Factors Influencing Hormone Action

• Cells receive exposure to many hormones.

Response can be regulated by:

1. Action of receptor subtype: Agonist/antagonist/partial agonist, etc.

2. Density of receptor: Up or down regulation.

3. Strength of signal

   • Binding affinity: The strength at which the hormone binds to the receptor.

   • Synthesis, storage & secretion rates of hormone: Regulated by feedback loops, diurnal, biological clocks.

   • Clearance rate (metabolism and excretion).

   • Binding protein concentration (lipid soluble hormones will impact this).

4. Other:

   • Adaptation or addiction = desensitization (receptor changes).

   • Disease, e.g.,

     • Insulin resistance due to insulin receptor desensitization.

     • Hashimoto disease: Autoimmune against thyroid gland (thyroid hormone reduction).

Central Coordination: Hypothalamus and the Pituitary Gland

Hypothalamus

• Integrating center for homeostatic functions (endocrine system and neural inputs).

• Functional link between the nervous system and endocrine systems.

• Passes message onto the pituitary gland.

Pituitary gland

• Receives input from the hypothalamus.

• Hypothalamus - composer; works out what should be done (writes the music).

• Pituitary gland - conductors; takes music and controls the orchestra.

• Secondary targets -> endocrine cells and tissues.

• Orchestra - produces music.

• Ultimate targets - audience.

• Anterior pituitary (adenohypophysis): glandular tissue; epithelial origin.

• Posterior pituitary (neurohypophysis): neural tissue.

• Hypothalamic organ.

Vasculature of the Pituitary Gland

Anterior pituitary:

• Highly Vascular.

• Primary capillary plexus: Receives blood from the superior hypophyseal artery - Works on portal system - primary hypophyseal portal system: Hypothalamus secretes hormones into Primary plexus -> that goes to secondary plexus.

• Secondary capillary plexus: Sits in anterior lobe: Small branches among endocrine cells - Carry hypothalamic hormones down into the anterior lobe and can interact with other adrenal cells (trop cells) to secrete hormones.

• Portal Veins: Between the two capillary networks.

• System called ‘hypophyseal portal system’.

• One-way system.

Posterior pituitary

• Arterial blood via inferior hypophyseal artery - then supply capillary bed in posterior lobe of the pituitary gland.

• The signal coming from the hypothalamus gland is released from the axons directly onto the cells - they release their hormones into the bloodstream.

• Hormones exit via the hypophyseal vein to the general circulation.

Hypothalamic-Pituitary Peptide Hormones

• ‘Releasing’ and “inhibiting” factors from the hypothalamus influence anterior pituitary hormonal secretion.

• Tropic hormones: Hormones that target other endocrine glands.

• The posterior pituitary is directly regulated by neural input from the hypothalamus.

Feedback Regulation in the Hypothalamic-Pituitary Axis (HPA)

• Hormones are under tight feedback control - generally but not always negative.

• Short-loop feedback: Pituitary -> hypothalamus.

• Long-loop feedback: Downstream hormone from the periphery -> hypothalamus/pituitary.

• Negative or positive feedback.

• The more important a physiological system is, the more redundancy there is in its regulation; this has lots of redundancy.

Posterior Pituitary: Oxytocin + Vasopressin

• Is neural - an extension of the hypothalamus.

• Secretes 2 neurohormones:

  • Oxy (rapid) tocin (childbirth) - Oxytocin: Can be stimulated by breastfeeding, childbirth.

    • Lactation and contracts in uterus.

    • Positive feedback system: Increases concentration and continues to release more and more.

• Arginine vasopressin:

  • AKA: Antidiuretic hormone (ADH).

  • Release of ADH results in the incorporation of aquaporin channels (water channels).

  • Decrease urine excretion (opposite to diuretic).

  • Increase water permeability of the distal tubules (where aquapore channels insert) and the collecting ducts of the kidney.

  • Inserts channels into the tubule to allow water out of the filtrate into the body (high concentration regions in the medulla).

Clinical relevance: Diabetes insipidus.

Anterior Pituitary

• Primarily a collection of endocrine cells, called ‘troph cells,’ as they release tropic hormones.

• Tropic hormones: Influence the secretion of other hormones by targeting other endocrine glands - a hormone that results in a release of another hormone.

• Secretes 6 peptide hormones - controlled by the hypothalamus.

• Hormone release is controlled by the hypothalamus (the composer).

*Neurotransmitter - In italics -

• Released from hypothalamus - goes via the pituitary portal system -> anterior pituitary - results in release of other hormones.

• Hypothalamus (composer) - sends signals down to anterior pituitary -> sends signals out to target tissues.

(GnRH, CRH, GHRH, GHIH, TRH)

• Example: The hypothalamus is producing gonadotropin-releasing hormone (GnRH) - acts on the anterior pituitary to release luteinizing hormone and follicle-stimulating hormone - acts on the gonads to produce testosterone, estradiol, and progesterone.

Follicle-stimulating hormone (FSH) / Luteinizing Hormone (LH)

• Stimulated by hypothalamus gonadotropin-releasing hormones (GnRH) action on AP.

Male

• FSH - stimulates spermatogenesis and Sertoli cell function (S).

• LH - Stimulates Leydig cells to synthesize testosterone (L).

Female

• FSH - Stimulates the growth of granulosa cells in primary ovarian follicles & stimulates local estradiol synthesis, which stimulates follicular development (stimulates follicle growth).

• LH - Initiates ovulation and stimulates to formation of the corpus luteum (stimulate the formation of the corpus luteum via ovulation).

Female Hypothalamic-Pituitary-Gonadal Axis

• Hypothalamus = composer - Gonadotropin-releasing hormone (GnRH).

• Portal vein -> Anterior Pituitary -> releases follicle-stimulating hormone and luteinizing hormone.

• Stimulate ovaries, which stimulate the release of estrogen and progesterone (feedback to the hypothalamus and pituitary).

Follicular phase

• The hypothalamus increases gonadotropin-releasing hormone.

• The anterior pituitary increases FSH + LH = follicular development.

• Low levels of two hormones.

• Granulosa cells: Increase estradiol (estrogen) which = +ve feedback to the anterior pituitary. Constant growth of follicle during this phase and an increasing amount of granulosa cells. As granulosa cells produce more estrogen - it can be seen that estrogen levels continue to rise. It gets to a point where estrogen levels become greater than FSH levels - indicates the follicle has gotten quite large and ready for ovulation (hence the switch to the positive feedback system).

• Causes LH surge = ovulation: Oocyte released from follicle (now called corpus luteum).
  The levels are: Large LH spike triggers ovulation -> Corpus luteum.

Luteal phase

• CL increases progesterone + estradiol: Inhibit the hypothalamus + pituitary (decreases FSH + LH levels).

• Results in a major reduction in estrogen and progestin - going back to the start of the cycle again.

• A major decrease in estrogen and progesterone -> degeneration of endometrium -> menses (remove inhibition on hypothalamus + pituitary).

• Increase gonadotropins (LH and FSH) = next cycle.

Estrogen and mental health

• Alterations in hormonal levels affect neural signaling.

• Fluctuations in progesterone and estrogen from ovary - Feedback to the brain = Heightened emotion: Anger, depression, violence.

• Preliminary research: Estrogen therapy has antipsychotic properties for
  Schizophrenia in men and women.

*Work done in exercise and sports science; looking at the effect of hormones in females and their injury rates.

Association at which stage in the menstrual cycle and ACL injury - more injury than expected in the ovulatory phase and fewer during the follicular phase.
*Another paper stated:
The likelihood of ACL injury does not remain constant during the menstrual cycle - and could be significantly greater during the preovulatory phase

Male Hypothalamic-pituitary-gonadal Axis

• Gonadotropin-releasing hormone (GnRH).

• Portal veins -> anterior pituitary.

• Follicle-stimulating hormone + luteinizing hormone - Stimulate hormonal secretion from testes = Testosterone + Estradiol (Feed back to the hypothalamus and pituitary to control levels).

• Hypothalamus increase gonadotropin-releasing hormone.

• Anterior pituitary increases gonadotropins: FSH + LH.

LH to leydig cells

• A testicle, adjacent seminiferous tubules = Synthesis of enzymes that support cholesterol -> testosterone: To sertoli and to the hypothalamus and AP (-ve feedback). LH acts on leydig cells -> G protein coupled receptor has alpha sub unit, which results in the synthesis of proteins. The proteins are enzymes that are involved in converting cholesterol through to testosterone. Testosterone is produced and enters the bloodstream and goes into sertoli cells, when in the bloodstream it enters the negative feedback loop and goes back to hypothalamus and pituitary.

FSH -> sertoli cell

• Inside seminiferous tubules of testicle (help with production of sperm) - Gene transcription in nucleus makes: FSH binding to G protein is a stimulatory alpha subunit which causes protein synthesis, which goes to activate several different proteins and enzymes.

  • Androgen-Binding protein: Maintains increasing testosterone levels = supports spermatogenesis and maturation (spermatids to full sperm).

  • Also results in the transcription of aromatase (acts on testosterone from leydig cell and converts it into estradiol -> forms part of neg feedback after going back into bloodstream. - To hypothalamus and AP = -ve feedback.

  • Also enter back into Leydig cells = to modulate LH and testosterone production response by the Leydig cell).

From hypothalamus to anterior pituitary

(GnRH), (CRH), (GHRH), (GHIH), (TRH).

• Corticotropin-releasing hormone comes from the hypothalamus, acts on the pituitary gland and releases adrenocorticotropic hormone (ACTH) onto the adrenal cortex. Then it releases mineralocorticoids + glucocorticoids such as cortisol.

Hypothalamic-pituitary-adrenal axis

• The hypothalamus secretes Corticotropin-releasing hormone (CRH).

• Anterior pituitary -> adrenocorticotropic hormone (ACTH).

• Adreno - act on the adrenal gland, cortico - releasing corticoids, tropic - causing release of more hormones (a hormone that results in corticoid hormone release from another tissue, example includes: releasing acth from pituitary).

  • Peptide hormone that targets the adrenal glands: cortex.

• ACTH stimulates the growth of the cells of the adrenal cortex.

• Adrenal cortical cells produce corticosteroids - Glucocorticoids + mineralocorticoids.

Adrenocorticotropic hormone (ACTH)

• CRH -> ACTH = corticosteroids from adrenal cortex

• Two major classes

1. Mineralocorticoids

Regulate ion retention by kidneys

• Example: Aldosterone: The main mineralocorticoid targets kidneys

• Activates Na^{+} reabsorption by kidney tubules

• Increases the number of sodium-potassium channels in the luminal membrane, and sodium potassium ATPase numbers in the basal membrane of the distal collecting tubule and collecting duct. Results in reabsorption of sodium and an increase in the reabsorption of water.

• Water will follow [high solute] = low water excretion in filtrate = increase in extracellular volume = Increase in blood pressure

2. Glucocorticoids

Influence blood glucose levels (catabolic)

• Example: cortisol: Main glucocorticoid targets Liver, fat, muscle which Increases plasma glucose and AA levels - stored fat and glycogen release that to increase available energy).

• -ve feedback to the hypothalamus and AP: decrease CRH + ACTH (tropic hormones).

Corticosteroids Biosynthesis and Mechanisms of Action

• Corticosteroids are steroid hormones - ENDOCRINE 1, slow to start acting but last a long time.

• Aldosterone has both cytoplasmic and nuclear receptors.

• Once at target tissues, they can diffuse across the membrane and bind to receptors that cause gene transcription.

• Cortisol has a cytoplasmic receptor.

• Binds to cytosolic receptor that is bound to a chaperone protein - once cortisol binds, there is a conformational change thats releases heat shock protein and allows receptor to travel into the nucleus (Shuttles to nucleus = transcription factor on DNA).

• Binds to glucocorticoid response element and results in the transcription of DNA into mRNA and translation into proteins.

• Synthesizes enzymes for gluconeogenesis ect.

Control of ACTH secretion

• Primary stimulus = CRH (corticotropin-releasing hormone from the hypothalamus).

• ACTH secretion by the anterior pituitary shows diurnal variation or circadian rhythm (Fluctuates from day to night - difference in energy we need to produce).

• ACTH is also secreted in stress-related bursts.

From hypothalamus to anterior pituitary

(GnRH), (CRH), (GHRH), (GHIH), (TRH). Acts directly though growth hormone and secondary peptide.

Hypothalamic-Pituitary-Growth Hormone Axis

• The hypothalamus secretes:

1. Growth hormone-releasing hormone (GHRH)

• Anterior pituitary -> stimulates growth hormone release (GH) (Acts on multiple tissues and is mostly involved directly in increasing energy levels).

• Targeted to many organs, widespread effect on body = energy and growth (via IGF-1) effects.

2. Growth hormone-inhibiting hormone (GHIH) (somatostatin)

• Anterior pituitary -> blocks release of growth hormone from the anterior pituitary = slows energy release and cell growth

• GH stimulates insulin-like growth factor (IGF-1) release from liver and other soft tissues. * IGF-1 stimulates bone and soft tissue growth - as growth hormone does not do that directly - growth hormone acts on the liver, the liver than releases IGF and that is what causes increase in both bone and muscle mass.

Hypothalamic-Pituitary-Thyroid Axis

• Thyroid hormone - from the hypothalamus you have TRH which acts on TSH, which acts on the thyroid to release little thyroxine

• The hypothalamus secretes: Thyrotropin-releasing hormone (TRH) -> happens via the portal vein

• Anterior pituitary releases thyroid-stimulating hormone (TSH) (AKA: thyrotropin)

• TSH acts on the thyroid. Stimulates secretion of T3 and T4 hormones from thyroid gland.

• Negative feedback: T3 and T4 inhibit hypothalamus and AP to regulate the levels.

• Thyrotrophs