Endocrine System

Endocrine System

1. What do hormones do?

   • There are four main areas in which hormones are important
   • Development
     • Growth (both of organs//tissue but also overall body growth), cell differentiation
   • Metabolism
     • Carbohydrate metabolism, energy storage (glucose being taken up), metabolic rate (which on a cellular level directly controls body temperature)
   • Reproduction
     • Sexual maturation and behavior (e.g. maternal bonding between mothers and infants), maintanance of pregnancy, lactation
   • Fluid Balance
     • Water balance, salt levels, blood volume

2. Endocrine Glands

   • Their prime function is to make and secrete hormones (hypothalamus not mentioned because it's not exactly its prime function)
   • Pituitary
     • It is very small => about the size of a pea, protected by a bony cavity called the sella turcica
     • Hangs down from the hypothalamus, suspended from the pituitary stalk (aka infundibulum)
     • Latin name for pituitary gland is the hypophysis => thus removal of the pituitary gland is called a hypophysectomy
     • The pituitary gland is actually made of two separate lobes: *Anterior lobe (adenohypophysis) => epithelial tissue, classic endocrine organ *Posterior lobe (neurohypophysis) => nervous tissue, an extension of the hypothalamus
     • Embryonic Development of the Pituitary Gland
       • In the developing embryo, tissue outgrowth from: *the diencephalon, which will ultimately form the hypothalamus *and the roof of the mouth begins => the two growing tissues meet and then the anterior lobe separates from the roof of the mouth an forms a sort of sleeve on the posterior lobe
     • Posterior Pituitary Gland
       • Structure
         • This essentially consists of nerve cell axons from the hypothalamus, also forming the pituitary stalk
         • The hypothalamus has many collections of cell bodies of axons that terminate there. A nucleus is a group of nerve cell bodies
         • There are two nuclei whose axons terminate in the posterior pituitary gland: *Supraoptic nucleus *Paraventricular nucleus
       • Hormones
         • The posterior pituitary gland secretes two hormones only: *oxytocin *Anti-Diuretic Hormone (ADH) These are both peptide hormones
         • The hormones are synthesized in cell bodies in the hypothalamus and then transported down the axons to be stored in vesicles at the base and then released into leaky capillaries when nerve impulses travel down these axons
         • ADH
           • Anti-diuretic Hormone (ADH) also called vasopressin
           • Stimulus for secretion
             • ADH secretionis stimulated directly by increased plasma osmolality (usually due to an increase in plasma Na+)
             • ADH secretion is also stimulated by low blood pressure. Osmoreceptors in the hypothalamus detet osmolality changes and send a signal to ADH neurons. Reduced blood pressure is detected by baroreceptors in the heart and send a signal to ADH neurons in the hypothalamus
           • Actions
             • ADH stimulates increased water resorption at the kidney and so decreases osmolality and increases blood volume and blood pressure
           • Deficiency of ADH
             • Causes a rare metabolic disorder called diabetes insipidus, which causes symptoms of polyuria (large volumes of dilute urine) and hypotension
         • Oxytocin
           • Stimulus for Secretion
             • Stretching of the cervix during birth and suckling of the baby at the breast stimulates oxytocin secretion (positive feedback effects)
           • Actions
             • Stimulates smooth muscle cells in the uterus to stimulate uterine contractions during childbirth and stimulates milk ejection after birth and maternal behavior.  Also causes ejaculation in men during intercourse
           • Deficiency of Oxytocin
             • Causes a failure to progress in labour and difficulty with breastfeeding
     • Anterior Pituitary Gland
       • Produces a number of different hormones, from a number of different cells, with a number of different effects  So how can this system be controlled?
       • Structure
         • Larger than the posterior pituitary gland
         • Made up of three parts> *the pars distalis *the pars intermedia (which adjoins the posterior lobe) *the pars tuberalis (which forms a sleeve around the pituitary stalk)
       • Removal
         • Causes: *growth and lactation to stop *atrophy of the thyroid gland, gonads and adrenal cortex *disturbances in salt & water levels and carbohydrate & protein metabolism
       • Hormones
         • Glycoproteins
           • 3 hormones grouped together because they are glycoproteins They are formed of two different subunits => the alpha subunit is identical in all 3 but the beta subunits are specific for each one
           • Thyroid-Stimulating Hormone (TSH)
             • Stimulates the thyroid gland to secrete its hormones
           • Gonadotrophins
             • Luteinising Hormone (LH) and Follicle-Stimulating Hormone (FSH) stimulate the ovaries/testes => thus collectively termed gonadotrophins
             • Trophic means they stimulate secretion of hormones from the gonads but also stimulate growth of these glands
             • Follicle-Stimulating Hormone (FSH)
             • Luteinising Hormone (LH)
         • Growth Hormone (GH)
           • Stimulates growth and metabolism
         • Prolactin (Prl)
           • stimulates milk production within the mammary glands (then oxytocin stimulates its ejection)
         • Adrenocorticotrophic Hormone (ACTH)
           • stimulates the adrenal cortex to secrete its hormones => it is trophic, therefore it also stimulates growth of the adrenal cortex
         • Melanocyte Stimulating Hormone (MSH)
           • is closely related to ACTH, involved in skin and hair pigmentation
         • Where are they secreted from?
           • Each of these hormones is secreted by a different cell type within the anterior pituitary: *Gonadotrophins secrete LH and FSH *Somatotrophs secrete GH *Corticotrophs secrete ACTH and MSh *Thyrotrophs secrete TSH *Lactotrophs secrete Prl
       • Experimental Evidence
         • We know that the anterior pituitary is classic epithelial tissue, not nervous tissue but it is affected by external stimuli. Mating in rabbits stimulates females to produce LH which is responsible for ovulation. So, how does a nervous signal cause the anterior pituitary to secrete hormones if t here is no direct neural connection? *Direct electrical stimulation of anterior pituitary doesn't cause ovulation *but if you electrically stimulate certain nuclei within the hypothalamus, it does result in LH release!
         • Hypothesis
           • The hypothalamus and anterior pituitary are seperate, however, there are cell bodies in the hypothalamus which have their nerve endings in the median eminence (at the base of the hypothalamus)
           • The median eminence is associated with a mass of capillaries, which drain down into larger blood vessels that serve the anterior pituitary
           • The hypothesis is that hormones are produced in the cell bodies of the hypothalamus, are released at nerve terminals in the median eminence and then travel down via larger blood vessels to the anterior pituitary. Here, they control the release of anterior pituitary hormones
           • This blood system is of great physiological importance and is called the hypothalamic-hypophyseal-portal system. It is closed off from the general circulation
     • Hypothalamic-Pituitary Axis
       • Hypothalamic Hormones controlling the anterior Pituitary
         • e.g. Thyrotrophin Releasing Hormone (TRH) is synthesised in the neurones in the hypothalamus and then secreted at terminals near the median eminence. The TRH is then carried to the anterior pituitary, where it stimulates thyrotrophs to secrete thyroid-stimulating hormone (TSH)
         • Thus, the hypothalamic hormones stimulate or inhibit the productin of anterior pituitary hormones. However, there are OTHER factors involved in the control of the hypothalamic-pituitary axis...
         • Thyrotrophin Releasing Hormone (TRH)
           • Stimulates the release of TSH
         • Gonadotrophin Releasing Hormone (GnRH)
           • Stimulates the release of FSH and LH
         • Growth Hormone Releasing Hormone (GHRH)
           • Stimulates the release of GH
           • Work in Opposition to each other
         • Somatostatin
           • Inhibits release of GH
         • Corticotrophin Releasing Hormone
           • Stimulates release of ACTH
         • Prolactin Releasing Factors (e.g TRH)
           • stimulates release of prolactin
           • Work in Opposition to each other
         • Dopamine
           • Inhibits prolactin release, thus, some antipsychotics which reduce dopamine levels, cause lactation as a side-effect
       • Hormonal Rhythms
         • Circadian Rhythms
           • 24-hour cycles or daily cycles => GH is released in pulses during sleep, which differs from GH release during the day
         • Pulsatile Rhythms
           • Every 1/2 - 2 hour period => LH is released in pulses from midnight to 8 am, in gaps of 1/2 hour to 2 hours. This is influenced by: *seasonal cycles *environmental influences *nervous system
       • Feedback Control
         • Feedback from the periphery signals (usually negative signals), which act on  both the anterior pituitary and  the hypothalamus. 
         • For example, in the case of TRH => TRH acts upon thyrotrophs to release TSH. TSH stimulates the thyroid to release certain hormones and when these enter the general circulation and are in high enough concentrations, they act upon both thyrotrophs and the hypothalamus to reduce the output of thyroid hormones
   • Thyroid
     • Largest of pure endocrine glands (sole function is to produce hormones)
     • very good blood supply
     • Located below larynx (voice box), in front of the trachea
     • Weighs 10-25 g
     • Has 2 lobes joined by a thin band of tissue called the Isthmus => butterfly shaped
     • Histology of the Thyroid Gland
       • The thyroid gland is composed of follicles => more than a million of these
       • Each follicle is a single layer of cells => nuclei stained blue around the outside of the follice => on the outside there is a big gap which is filled with a colloid (proteinaceous fluid), thyroid hormones are stored in this colloid
       • Thus the thyroid gland is unique in that it's the only endocrine gland to store its hormones in an extracellular compartment
     • Hormones
       • The follicles synthesise 2 hormones, Thyroxine (T4) and Triiodothyronine (T3). They are both  derived from tyrosine, thus thyroid hormones are amine hormones. They have iodine atoms attached to them, which is obtained from DIET
       • T3 and T4 are stored in this colloid, bound to thyroglobulin
       • In the first step, tyrosine is used to synthesize thyroglobulin, which is essentially the backbone onto which the hormones bind, a so-called 'protein-template' This step occurs within the follicle
       • Thyroglobulin then moves into the colloid where it is stored
       • Is also responsible for calcitonin and plasma Ca2+ control
       • Synthesis of T4
         • A tyrosine residue containing 2 iodine atoms is called diiodotyrosine (dit). Two of these molecules come together to form thyroxine (T4). Note, the thyroxine remains attached to the thyroglobulin and remains in the colloid; same applies for below. All 4 possible iodination sites are iodinated. It can be converted to T3, as more T3 is required, thus acting as a store, since it is more structurally stable
       • Synthesis of T3
         • A tyrosine residue containing 1 iodine atom is called monoiodotyrosine (MIT). One DIT and one MIT come together to form triiodothryonine (T3). 3 out of 4 iodination sites are iodinated and depending on which sites are iodinated, T3 and reverse T3 (inactive)
       • Secretion of Thyroid Hormones
         • The colloid and iodinated thyroglobulin is then reabsorbed into the follice cells of the thyroid by endocytosis
         • Once in the follicle, the endosomes fuse with lysosomes, which contain hydrolytic enzymes. Thyroglobulin is broken down by these enzymes within lysozomes to release T3 and T4
         • T3 and T4, which are fat=soluble, are secreted into the blood stream
         • The remaining thyroglobulin is recycled back into the colloid for the next stage of hormone synthesis
         • Once secreted> * more than 99% of all T3 and T4 secreted will bind to plasma proteins due to their poor water solubility => about 70% is bound to thyroxine-binding-globulin (TBG) => about 30% is bound to thyroxine-binding pre-albumin (TBPG) and albumin
         • Only 0.4% T3 and 0.04% T4 remain unbound in the blood. It is only this unbound fraction of T3 that is responsible for hormonal activity. T3 is MUCH more biologically active than T4. T4 may be converted to T3 in the peropheral tissues by the enzyme 5-deiodinase
       • Action of Thyroid
         • Thyroid hormones are lipid soluble, thus can cross cell membranes and bind to intracellular receptors (as do steroid hormones), and modulate gene expression by either stimulating or inhibiting gene transcription
         • Cellular Effects
           • Thyroid hormones affect virtually every cell in the body. Their effects include:  *increased protein synthesis, e.g. structural proteins, etc *Increased cellular respiration due to increased need for ATP, thus a greater amount of ATPases produced *cell growth and maturation as a result of protein synthesis
         • Effects on the whole body
           • Increased food intake Increased oxygen consumption Increased cardiac output and ventilation Increased thermogenisis
         • In children
           • Thyroid hormones play an essential role in normal neural, muscular and skeletal development
           • Deficiency of T3 during development
             • Causes: *Abnormal brain and skeletal development in foetus *This results in cretinism (mental retardation and dwarfism) This under-secretion of thyroid hormones may be due to lack of iodine in diet
           • Excess of T3 during development
             • May result in premature osteoporosis due to abnormal bone turnover
       • The Role of TSH and Negative Feedback
         • TSH stimulates all steps in the synthesis of T3 and T4 and stimulates growth of the gland. However, if iodine is lacking from the diet and the thyroid is unable to produce sufficient levels of thyroid hormones, then the negative feedback effect is removed and TSH will rise in an attempt to increase the amount of thyroid hormones being produced. The TSH will exert its trophic effect on the thyroid, causing an enlarged thyroid in a condition known as 'goitre'
     • Iodine uptake into follicles
       • Dietary iodine is needed for the synthesis of thyroid hormones. It is taken into the follicle cell by a Na+/I- symport transporter in the plasma membrane, linked to the activity of Na+/K+ ATPase pump, which maintains a low intracellular sodium concentration, thus creating a concentration gradient allowing sodium into the cell. Iodine is rapidly taken up into the colloid, thus creating a concentration gradient allowing further entry of iodine via the symport
     • Iodination of thyroglobulin
       • Free iodine in the follicular lumen attaches to the tyrosine residues on the thyroglobulin molecules in a process called iodination
       • Iodination occurs at the apical membrane (colloid facing-membrane) of follicular cells and involves hydrogen peroxide and the enzume thyroid peroxidase. 
       • A fast process, oxidation
     • Management of Thyroid Disease
       • T3 and T4 are key in thyroid disease because they are responsible for: *Controlling the Metabolic Rate => all about energy consumption => when a cell needs energy => T3 must be present to activate a protein which leads to energy being used => note that T3 is the more metabolically active form *Growth and Development => mainly key in children => in the past would come across "cretins" => individuals with severely stunted physical and mental health due to congenital hypothyroidism
       • Release of Hormones
         • Finely balanced release of hormones => one hormone triggers the release of another
         • Negative feedback loop keeps balance
         • When the balance is disrupted, you get conditions that people suffer from
         • The hormones we are interested in are TSH (Thyroid Stimulating Hormone) and T3 and T4
         • Have negative feed-back loop => when T3 and T4 are high => get negative feedback that reducs the TSH release Also when they are low, the negative feedback loop sends signals to increase the release of TSH
       • Hyperthyroidism
         • Hyperthyroidism is less common than hypothyroidism
         • Characterized by an excessive production of thyroid hormones => get an increase in metabolic rate
         • More common in women Patients  typically present between the ages of 30-50 years of age
         • Key tests to be done to make diagnosis (aside from clinical symptoms) are the TFT's (Thyroid Function Tests) => Global test done to measure T3, T4 and TSH concentrations
         • As can be seen from the diagram, in hyperthyroidism, T3 and T4 levels will be elevated and TSH levels will be reduced This is as expected, as the negative feedback loop will be telling the anterior pituitary to reduce the level of TSH to try and lower the T3 and T4 levels
         • Signs and Symptoms
           • *Feeling of 'buzzing' => lots of energy *Weightloss => a lot of energy being used *Tremor (sometimes) *Cardiac-related symptoms => i.e. tachycardia, AF, palpitations => when patients present with AF at less than 50 years, one of the first tests to do is TFT's *Can be very irritable, nervous, restless, can't sleep very well *Heat intolerance *Often sweat a lot *Goitre => enlargement of the thyroid gland => can sometimes visibly see it on patients *Diarrhoea *Eye symptoms with Grave's Disease => the eyes will protrude out   =>Grave's Disease is the         commonest cause of                 hyperthyroidism (~75% of         cases) => IgG                             autoantibodies stimulate the   TSH receptor => leads to         hyperthyroidism *Hypertension & Heart Failure => again, related to cardiac symptoms   =>hypertension, because of     all of this energy                         consumption => then                 because the heart is not           beating properly =>                   eventually leads to heart           failure
         • Causes
           • *Grave's Disease (~75% of cases) *Benign nodules => often develop on thyroid gland and stimulate excess release of hormones *Thyroiditis => inflammation of the thyroid gland *Pituitary or thyroid tumour *Drug induced (e.g. amiodarone, thyroxine) => e.g. in thyroxine, if treating a patient for hypothyroidism with thyroxine => if you overdo it, can cause hyperthyroidism
         • Treatment
           • Drug Treatment
             • Treat with antithyroid drugs: *2 drugs used (in the UK, some others worldwide, but mainly these): Carbimazole and Prophylthiouracil *They reduce the levels of T3 and T4 produced (i.e. reduce the synthesis)
             • Two types of drug regimens: *Titration Regimen (first line, more common) Start with a slightly higher dose (4-6 weeks) Carbimazole: 20-60 mg in 2-3 divided doses Prophylthiouracil: 300-600 mg in a single or divided dose When you gain control and reach a state of euthyroid (state of normal thyroid function), go onto a lower maintainance dose: Carbimazole: 5-15 mg OD Prophylthiouracil: 50-150 mg OD *Block-Response Regimen: Can block thyroid synthesis of T3 and T4 entirely with higher doses of antithyroid drugs and then replace by giving physiological levels of levothyroxine *Side effects: Rashes, fever, nausea, GI upset, arthralgia (aches in the joints), hypothyroidism (by giving too high a dose), bone marrow suppression (neutropenia/agranulocytosis => rare but key side-effect) *Can achieve remission (unlike in hypothyroidism) => particularly if cause is Grave's disease => autoantibodies may simply go away =>After 12-18 months, can start taking patient off treatment => if they stay in remission, they can come off entirely => if not, simply start them back on the maintenance dose (a lot of tinkering!)
             • Counselling Patients
               • One of the key side-effects is bone-marrow suppression => can lead to neutropenia/agranulocytosis Need to counsel patients that they need to seek medical attention if they get any symptoms such as: *sore throat *mouth ulcers *high fever Also, STOP THE DRUG IMMEDIATELY
               • Advise patients that it will take at least 5-10 days to see any improvement in symptoms
               • Also advise that patients should expect to gain weight => need to monitor => don't want them to then become obese
             • Concurrent Treatment
               • Betablockers sometimes given alongside treatment to combat symptoms => particularly symptoms such as: palpitations, anxiety, tremor, diarrhoea, sweating Only while trying to reach euthyroid state => once there, no longer needed
           • Non-drug treatments
             • Usually reserved for patients that can´t achieve euthyroid state with drug therapy or in the case of some sort of cancer
             • Radioactive Iodine - I131
               • Administered to the patient; accumulates in the tissue and destroys the tissue
               • Risk of cancer => are giving radioactive material
               • Less control => how much is destroyed is not under your control => can push patient into hypothyroid state
             • Surgery
               • Can remove part or all of the gland
               • Risk of taking too much and pushing patient into hypothyroid state
               • Can also affect the parathyroid glands => push patient into hypoparathyroidism => affects Ca2+ levels
               • Indicated if: *patient has thyroid cancer *the goitre is very large *other treatments have failed
           • Monitoring
             • Need to monitor: *T3 *T4 *TSH *FBC => because of risk of neutropenia/agranulocytosis
       • Hypothyroidism
         • *Reduced production of thyroid hormones *reduction in metabolic rate => slowing down (vs. 'buzzing' of hyperthyroidism) *Common disorder => one of common chronic disorders *More common in women than men *When doing TFTs: T3 and T4 will be lowered while TSH will be elevated *How common is it?   =>3.5 per 1000 (women)   =>0.6 per 1000 (men) *Age of onset: ~30-60 years of age
         • Signs and Symptoms
           • *Weight gain *Constipation *Fatigue, weakness *Cold intolerance *Bradycardia, low cardiac output, heart failure *Dry skin, hairloss (especially if women present with hair loss => test TFT's straight away) *Hoarseness *Depression *Infertility
         • Causes
           • *Hashimoto's thyroiditis => autoimmune destruction of the gland => reduces release of T3 and T4 *Low iodine in diet *Treatment for hyperthyroidism *Drug-induced (amiodarone, lithium) *Hypothalamic disorders
         • Treatment
           • *Relatively simple => just replace the hormone! *Can give either Levothyroxine (T4) or Lio-thyronine (T3) => T4 is preferred option
           • Levothyroxine (T4)
             • Longer half-life => allows for once daily dosing
             • Treatment is generally life-long => once that reduction in T3/T4 levels happen, it is there constantly => just have to keep replacing it
             • Starting dose depends on whether patient has a preexisting cardiac condition: *No condition: 50-100 mcg OD => do TFT's after 4-6 weeks => if they need more, increase 25-50 mcg => do another test after another 4-6 weeks => etc *TSH is key marker => once it hits acceptable level => keep on maintainance dose (75-150 mcg per day or 1.6 mcg/kg/day)
             • KEY COUNSELLING POINT Taken on an empty stomach to enhance absorption => key to counsel patients to take before breakfast
             • Monitoring: T3, T4 and TSH (key marker)
             • NOTE: In elderly/cardiac patients => have slowed metabolism => if suddenly increase energy consumption with big dose => heart won't be able to cope *Starting dose: 25 mcg OD => increase slowly, by 25 mcg every 4-6 weeks *Maintenance dose is same
             • Adverse effects are rare => main risk is going too far in the other direction and pushing them into hyperthyroidism => monitor TFTs
             • Interactions
               • Drugs preventing absorption: *Calcium Salts *Ferrous Sulphate *Aluminium Hydroxide *Cholestyramine
               • Drugs increasing clearance (increase metabolic rate in liver): *Phenytoin *Carbamazepine *Phenobarbitone *Rifampicin
               • Doesn't mean you can't use these drugs => simply means requirements will be higher => e.g. patient on phenytoin might need dose of 175-200 mcg OD to compensate for the effect the phenytoin is having on the clearance
           • Liothyronine (T3)
             • *Won't see much *Is active component of thyroid gland => has very short half-life *very quick onset of action => generally reserved for patients that tolerate symptoms very well until they suddenly collapse => Myxoedema coma => don't tinker with dose => just give them straight (25-50 mcg iv) (assuming there are no cardiac problems) to bring them out of coma
       • Amiodarone
         • Amiodarone is a common drug used for Atrial Fibrillation (AF) => one of the commonest arrhythmia's that you see => prevalence is increasing because of aging population
         • Amiodarone has iodine in its structure (see diagram)  This has implications for patients taking it
         • Amiodarone has a high volume of distribution => have to fill up a large compartment of  the body to get the effects that we want => thus give loading dose => want to get loads into the body to start off with because it goes into extravascular tissue Therefore has a long elimination half-life => binds to lots of tissues => thus takes some time to get out of the system once you stop taking it
         • Patients on amiodarone generate 6-12 mg of free iodine per day => however, WHO suggest optimal intake of iodine is 0.15-0.30 mg per day
         • 50% of patients on amiodarone demonstrate abnormal TFT's => upsets fine hormonal balance
         • Unpredictable as well => can be either hyper-or hypothyroidism: *Can get inhibition of thyroidal iodine uptake and thyroid hormone synthesis *Can get intracellular inhibition of T4 conversion to T3 *Can get inhibition of T4 entry into cells *Can get direct antagonism of T3 at cardiac tissue level
         • Although 50% of patients show abnormal thyroid function, only a small percentage go on to have hyper- or hypothyroidism => some sort of physiological balancing act going on *Amiodarone induced hypothyroidism: 6-13% *Amiodarone induced hyperthyroidism: 2-12%
         • Treatment is individualised: *Withdraw the drug => if it truly is hyper/hypothyroidism, withdrawing the amiodarone should allow you to get the euthyroid state back   =>note: because of the high     volume of distribution =>           could take 1-2 months               before start seeing any             effects *Or manage the condition => if prescriber feels that amiodarone is the best drug for patients AF/cardiac condition => simply treat (carbimazole for hyperthyroidism and levothyroxine for hypothyroidism) So will often see these prescribed alongside amiodarone (3rd person in amiodarone/warfarin marriage!)
   • Parathyroids
     • Calcium Homeostasis
       • Importance of Calcium in the Body
         • Stability of Membrane Potential => the resting potential is critically dependent on calcium
         • Muscle Contraction => calcium is involved in its initiation throughout the body => whether skeletal, smooth or cardiac => the interactions of actin and myosin are triggered by changes in intracellular calcium levels
         • Blood Coagulation => can't form blood clots without calcium being present
         • Bone formation => is major component of skeleton => when we are born, we are largely cartilaginous => not a lot of calcium in our bones => ossification really occurs post-nataly => all of t his calcium has to come in via our diet
         • Acetylcholine release => dependant on calcium
       • Plasma Calcium Distribution
         • A little over half of the calcium circulating in the blood is ionised => it is free
         • A little under half is bound to plasma proteins (largely albumin)
         • The free, ionised calcium is what is available for cell use => but bound and ionised calcium exist in equilibrium => if the free calcium levels lower, some of the bound calcium ions will become free and replace those levels => proportions remain same even if total calcium levels go down
         • A very small amount exists in more complex calcium compounds circulating in the blood => much less freely available (e.g. calcium phosphate)
         • It's important to keep the plasma calcium levels constant (especially the ionised calcium levels) as this is what is influencing the resting membrane potential of the cells (both nerves and muscles)
         • Two situations that occur if the free, ionised plasma calcium gets too low: *Milk fever/Hypocalcaemia *Hypocalcemic Tetany (Trousseau's sign) (Carpopedal spasm)
         • Milk Fever / Hypocalcaemia
           • Very common for vets to see this in animals
           • Signs: *Restlessness *Nervous *Excitable *Trembling/ataxia (because the muscle potentials are becoming unstable => getting spontaneous contraction) *Muscle tetany can lead to convulsions and eventually death if left untreated (because respiratory muscles become paralyzed) *Heart failure (beats become irregular)
           • Most commonly seen in animals that have very large offspring (e.g. cows) or multiple offspring (e.g. dogs) => puts a huge load on the animals calcium reserves if they are lactating => its free calcium will go down => will start mobilizing reserves from its skeleton
           • Doesn't tend to occur in humans
         • Hypocalcemic Tetany (Trousseau's Sign) (Carpopedal Spasm)
           • Tend to see it in people who are nervous or frightened
           • Get spasm in muscle because free, ionised calcium has gone down => for reasons we don't really understand, the muscles of the hands and the feet are particularly sensitive
           • What tends to happen to nervous/frightened people is they tend to hyperventilate => level of CO2 in blood goes down => get alkalosis => less bicarbonated hydrogen ions in the blood because CO2 is gone => pH value goes up => the changes the charge on the albumin => albumin is negatively charged, H+ is positively charged => get rid of the H+ and there is more negatively charged albumin available => more calcium binds to the albumin => free calcium goes down => makes cell membranes unstable => get these contractions
           • Treatment is simple: get plastic/paper bag, place over nose and mouth and have patient breath in and out => patient rebreaths CO2 they are producing => blood CO2 goes up => pH is corrected => calcium comes off albumin again
       • Calcium Balance
         • Our largest reserve of calcium is in the bones
         • We also have calcium in the blood, which is continuously exchanging calcium with the bones => calcium constantly going into and out of the bones
         • We can conserve calcium in the kidneys => if the plasma calcium falls, more calcium can be resorbed in the kidneys to bring the calcium up again => if calcium goes up, more can be excreted => can regulate the amount that is lost in the urine
         • We get all of our calcium in our food => can increase absorption of calcium from the gut or we can reduce it
         • Plasma concentration of calcium is generally around 2.0 -2.5 mM => can be quite a bit higher in  the extracellular fluid (~22 mM)
         • This level is maintained by these exchanges: *Taking in ~25 mmol a day in diet => there is ~40 mmol in the gut at any one time => absorb ~15 mmol from the gut => can secrete into the gut excess calcium to get rid of it (~12 mmol) => can excrete via the faeces (~22 mmol) *Can move calcium from the intracellular fluid => has ~275 mmol in it => can be exchanged with the plasma *Can exchange between plasma and bone
         • There are two pools of calcium in bone: *The exchangable pool: can be rapidly exchanged => rapid exchange account for ~ 500 mmol every day *The more stable pool:  where most of the calcium is => this calcium is mineralized in the bone => takes much longer to mobilize => can resorb ~7.5 mmol of that in 24 hours => can build bone up by ~7.5 mmol in 24 hours
         • Hence constant recycling of calcium in the stable bone => bone can be broken down by osteoclasts and rebuilt by osteoblasts
         • Calcium is filtered in urine (~250 mmol per day) => vast majority is resorbed in kidney => calcium lost in urine is on average ~2.5 mmol per day
         • All of these values can be altered to keep us in calcium balance => these are just average values
       • Bone Remodelling
         • We are able to remodel our bones
         • The two cell types that do this are: *Osteoclasts: break down the bone mineral *Osteoblasts: build up the bone mineral
         • Break down by activating osteoclasts => they have acid hydrolase lysozomes in their cells => these lysozomes are released => produce a very acidic environment around the osteoclast => acid breaks down the bone and releases calcium => remodel the bone
         • Osteoblasts can be recruited => build bone up => so if the bone is damaged => can be remodelled => if we fracture a bone => it is the osteoblasts that actually rebuild it
         • Important to remember that bones are constantly changing => if you put stress on it => it thickens in response
         • Bone is crystalline structure => if you deform a crystal => get a charge developing across it (piezoelectric effect) => that's what attracts the osteoblasts => they will model a bone under stress
         • This is why astronauts in space get osteoporosis => their bones demineralize because they are living in a gravity-free environment => not much stress being put on the bone => osteoclasts become dominant over the osteoblasts
       • Hormonal Control of Plasma Calcium
         • The movement of calcium is regulated by two protein hormones: *Parathyroid Hormone (PTH): increases plasma Ca2+ => activates all the mechanisms which can put calcium into the blood => will mobilise Ca2+ from bone => increase gut absorption => will decrease kidney excretion *Calcitonin: decreases plasma Ca2+ => works in opposition to PTH => its role is arguable => tends to build up bone => its main role seems to be to move calcium into the bone
         • PTH also works closely with vitamin D3 => vitamin D3 is very necessary to absorb sufficient calcium from the diet
         • Parathyroid hormone is produced in the parathyroid gland; calcitonin is produced in the C-cells (parafollicular cells) of the thyroid
         • There are 4 parathyroid glands stuck on the back of the back of the thyroid gland => they are quite distinct bits of tissue => just happen to be attached to the thyroid gland
         • The c-cells (parafollicular cells) are buried inside the thyroid gland but play no part in thyroid hormone production
         • The activity of the c-cells (parafollicular cells) and the parathyroid glands are completely independant of the pituitary they are autonomous endocrine glands they are sensitive to the circulating levels of calcium in the blood *parathyroid glands are sensitive to a fall in Ca2+ => will raise the secretion of PTH *C-cells (parafollicular cells) are sensitive to a rise in Ca2+ => will release calcitonin to push Ca2+ into the skeleton
         • Parathyroid Hormone
           • Like most hormones, first made as a much larger protein => a pre-protein => then chopped into pieces in the endoplasmic reticulum
           • It is 34 amino acids long => a short, straight polypeptide
           • Its actions are: *to increase osteoclast activity => will enhance the breakdown of bone and mobilisation of calcium from the bone => because it is in the form of calcium phosphate => break that down and both calcium and phosphate plasma levels go up => the phosphate tends to be excreted, so don't tend to see as big a rise in phosphate plasma levels *Thus increases PO4(3-) (phosphate) excretion in the kidney and decreases Ca2+ excretion => the kidney will push out most of the phosphate but will absorb more of the calcium *Increases the formation of active vitamin D3 in the body => raises the activity of the enzyme alpha-1-hydroxylase in the kidney => converting the inactive precursor of vitamin D3 to the active vitamin D3
           • Stimulus to PTH release is a fall in plasma Ca2+
           • Control of PTH secretion is directly stimulated by plasma Ca2+ levels => no pituitary control
           • Receptor that controls PTH secretion has 7 transmembrane domains => the extracellular domain is sensitive to circulating Ca2+ levels *e.g. if the Ca2+ levels go down => a signal will go through the protein to the cytoplasmic domain => will activate G-protein => will cause PTH release *So directly senses the the circulating Ca2+ levels
           • Is a simple feedback => if levels of Ca2+ in the blood fall => will release PTH => causes bones to pump out calcium due to activity of osteoclasts => will excrete less calcium in urine => will enhance absorption of calcium, via vitamin D, from the intestine => enhances production of vitamin D => indirect enhancement of absorption of Ca2+ from gut => these 3 things bring blood Ca2+ levels back to a normal value
           • PTH Disorders
             • Excess PTH: *Get demineralisation of bone => get osteoporosis *Get hypercalcaemia => high levels of circulating Ca2+ *Get Ca2+ deposited elsewhere => levels get so high that you get kidney stones and stones in soft tissue => Calcium starts to crystalize out in association with PO4(3-) in places where it shouldn't *Normally produced by a tumour in one of the 4 parathyroid glands => gets out of control and pushes out large amounts of PTH
             • Deficiency of PTH: *Hypocalcaemia => plasma levels of calcium go down *Get muscle spasms and tetany *This is the only time you would see something like milk fever in humans => very rare => ultimately fatal => muscles get paralyzed => you asphyxiate *In humans, largely due to surgery => e.g. patient has thyroid tumour => overproducing thyroid hormone => surgeon cuts out part of the thyroid gland => can end up also cutting out the parathyroid gland *But can replace it => PTH is a protein => must be injected => would get destroyed in gut
           • Acquiring Vitamin D
             • Acquire from plants => 7-dehydrocholesterol (phytosteroid) found in most plant food
             • Has to be converted in skin via sunlight into cholecalciferol => still inative form => but is form in dietary supplements *sunlight is very important => in UK, only enough sunlight for 6 months/year => other 6 months, we are living off stored vit D
             • It is a fat-soluble vitamin => stored in fat => sees us through winter, particularly if we have good fat reserves
             • Vitamin D3 deficiency becoming worrying phenomena => due to increasingly indoor lifestyle
             • Cholecalciferol converted in liver to 25-hydroxycholecalciferol => then converted in kidney via enzyme alpha-1-hydroxylase to active form => also makes inactive form => but if more vitamin D3 is needed, more of the active form is made => unknown what mechanism is behind this
             • Conversion in kidney is PTH dependant
             • Actions of active vitamin D3 are: *Increased Ca2+ uptake from the gut *There's a calcium-binding protein synthesised in small intestine => is resorbed bound to calcium =>happens relatively slowly => relying on vitamin D3 to increase gene expression of that protein *Increases Ca2+ resorption in the kidney *Mobilises Ca2+ and PO4(3-) from the bones
             • *Rickets is the classic disease of vitamin D deficiency => if you lack vitamin D3 => bones don't ossify properly => can't put enough calcium in the bones to ossify them => if the bones haven't ossified by the time a child starts walking => they will bend => can either bend in or out in a bow-legged fashion => get skeletal deformation => once that has happened => can't get rid of it *Disease of poverty, poor nutrition and lack of sunlight => people worried will start back with our increasingly indoor lifestyle 
             • Control of production of Vitamin D3
               • Have a balance in production of vitamin D3 => if the plasma Ca2+ levels fall in the extracellular fluid or plasma: *Increases secretion of PTH *In turn, increases 1-alpha-hydroxylase activity in the kidney => have plenty of precursor to vitamin D3 => activation of 1-alpha-hydroxylase increases the formation of the active form (1,25-(OH)2D3) and decreases the formation of the inactive form (24,25-(OH)2D3)
         • Calcitonin Secretion
           • Is produced by the C-cells (parafollicular cells) of the thyroid gland => lie between the follicles in the thyroid 
           • C-cells are sensitive to the circulating, extracellular fluid levels of calcium => if the calcium levels go up, more calcitonin (CT) is secreted
           • Calcitonin is a short polypeptide => 32 amino acids => similar length => major difference is that calcitonin has a disulphide bridge
           • Actions: *Inhibits bone resorption => reduces osteoclast activity => shifts calcium into bones *Increases Ca2+ excretion in urine Somewhat opposite effect to PTH
           • Plasma calcium and PTH and CT secretion: *If we look at the plasma levels of both of the hormones, we can see that if   =>Ca2+ conc increased -> increased CT conc   =>Ca2+ conc decreased -> increased PTH conc *But under normal physiological levels of plasma Ca2+ => both hormones are normally circulating
           • Actions of Calcitonin: *Rise in calcium results directly in rise in calcitonin secretion *Results in a raise in plasma CT levels  *This results in reduced osteoclast activity => less calcium is being returned to the blood  *Also results in more Ca2+ being excreted by the kidneys *Overall level of Ca2+ in blood is reduced
           • Role of calcitonin: *Currently somewhat under discussion *No diseases known which are a result of excess or deficiency in calcitonin *Thought that CT may be there, constantly circulating, to help protect the skeleton => keeping skeletal calcium stores high *PTH thought to cover min-to-min/hour-to-hour regulation of plasma Ca2+ levels => while calcitonin consistently pushing Ca2+ bit-by-bit into the skeleton *Structure of peptide is known => synthetic analogues are clinically significant => e.g. CT supplements used to treat osteoporosis (can be taken as nasal spray
   • Islets of Langerhans
     • in Pancreas
   • Adrenals
     • Location and Structure
       • Each kidney has an adrenal gland located on its upper pole
       • The arterial blood supply arrives via the abdominal aorta and renal arteries The venous blood supply leaves via the renal veins and inferior vena cava
       • The adrenal cortex secretes hormones from three distinct zones:  *Glomerulosa *Fasciculata *Reticularis
       • The adrenal medulla is distinct from the adrenal cortex and secretes catecholamines from chromaffin cells
     • Glucocorticoids - Cortisol
       • This is the major glucocorticoid hormone produced by the adrenal cortex and *is essential to life. * It's important in: *maintaining metabolic balances *responding to stress => physiological concentrations may increase 10-fold in response to stress!
       • Physiological concentrations are necessary for maintaining normal cell function. The basal secretory rate is 10-30 mg per day with the highest levels being in the morning
       • The most important cellular effects of cortisol
         • Stress Response
           • Maintainance of vascular tone
         • Immune Response
           • Immunosuppressive and anti-inflammatory actions
         • Fat Metabolism
           • Increased lipolysis on fat cells, leading to increased mobilisation of glycerol and fatty acids for energy
         • Protein Metabolism
           • Increased mobilisation of amino acids in skeletal tissue and muscles
           • Facilitate increased carbohydrate metabolism
         • Carbohydrate Metabolism
           • Increased gluconeogenisis and hepatic enzymes that support gluconeogenisis
       • Cushing's Syndrome
         • Many physiological effects of glucocorticoids can be seen in this syndrome, where there is an overproduction of glucocorticoids
         • Mild facial hirsutism in women, oily skin and acne
           • due to excess adrenal androgens
           • Hirsutism => excessive hair growth => tends to be dark and thick (vs. light and fine) Grows in unwanted places, i.e. facial hair (in women), between groin and naval, neck, chest, etc
         • Round 'Moon Face' with red cheeks
           • due to increased fat deposition
         • Bruising and slow wound healing
           • due to collagen breakdown and suppressed immune system
         • Centripetal obesity, particularly across the shoulders and around the middle
           • due to increased appetite and fat deposition in these areas
         • Severe skeletal muscle wasting and weakness (thin arms and legs) may prevent standing up from a squatting position
           • due to increased protein metabolism
         • Stretch marks (striae) and thin skin
           • due to degradation of connective tissue, especially collagen in the skin
         • Other effects of hypercortisolism
           • Which are also symptoms of Cushing's Syndrome, but are not visible externally
           • Hypertension
             • Excess cortisol binds to the mineralocorticoid receptor, resulting in salt and water retention
           • Osteoporosis
             • due to increased calcium metabolism in the bone, and inhibition of osteoblast function and enhanced osteoclast binding and decreased calcium absorption
           • Diabetes
             • this may occur due to changes in glucose metabolism
           • Infections
             • due to: *suppression of the immune system by decreasing peripheral lymphocytes *inhibiting neutrophil accumulation *suppressing histamine *suppressing prostaglandin synthesis
         • • Iatrogenic Cushing´s
             • Iatrogenic, or non-spontaneous, Cushing´s occurs as a result of overadministration of pharmacological corticosteroids, e.g. Prednisolone
       • What controls glucocorticoid secretion?
         • Corticotrophin-Releasing Hormone (CRH)
           • Released from the hypothalamus to stimulate the anterior pituitary to secrete ACTH
         • Arginine Vasopressin (aka AVP/ADH - Antidiuretic Hormone)
           • Secreted by the posterior pituitary to augment CRH Together, they stimulate a larger rise in ACTH than CRH alone can
         • Adrenocorticotrophic Hormone (ACTH)
           • Is secreted by the posterior pituitary and stimulates the adrenal cortex to release glucocorticoids (mainly cortisol) and also stimulates secretion of adrenal androgens (mainly androstenedione and dihydroepiandrosterone (DHEA))
         • Breakdown of the Control Mechanism
           • Problems can occur in the hypothalamus, i.e. defects in CRH production
           • Problems can occur in the pituitary, i.e. defects in ACTH secretion or bioactivity
           • Problems can occur in the adrenal gland, i.e. defects in cortisol biosynthesis or secretion
           • Pituitary adenoma (tumours) may be present in 20% of people => many are small and benign A few grow and can cause problems due to secretion of large amounts of pituitary hormones, e.g. ACTH Treatment by surgery, drugs (somatostatin/prolactin analogues) or radiotherapy is possible
           • Causes of Cushing´s Syndrome
             • The hypercortisolism seen in Cushing´s Syndrome may be due to a number of possible causes
             • Cushing´s Disease
               • It is the most common form of Cushing´s Syndrome, and refers specifically to the pituitary-dependent cause of excess cortisol. This is often an overproduction of ACTH from a pituitary tumour, which stimulates the adrenal cortex to produce excess corticosteroids This is the cause in 85% of all cases
             • Certain Lung Cancers and other Tumours
               • Certain lung cancers and other tumours outside the pituitary gland may produce ACTH
             • Benign or malignant Cancers of the Adrenal Gland
           • Hypocortisolism - Cortisol Deficiency (aka Addison´s Disease)
             • A rare disease, caused by destruction of the adrenal gland The causes of Addison's disease: *used to be due to TB (now mainly in 3rd world countries) *Now HIV (AIDS) is becoming another significant disease causing it (mainly in 3rd world) *Usually unknown but could be autoimmune
             • Results in: *reduction in mobilization of substrates    =>hypoglycaemia    =>weight loss *Increased susceptibility to stress *Pigmentation    =>this is a result of ACTH stimulation of melanocyte-stimulating hormone (MSH) due to negative feedback effects of low cortisol levels
         • Note that there is another primary control of ACTH: circadian or diurnal rhythms of daylight and darkness
           • Cortisol levels fall at night as a direct result of a fall in ACTH levels, helping the body to reduce its activity prior to falling asleep
           • Cortisol levels begin to rise in the early morning, as a direct result of rising ACTH
           • This leads to a peak in cortisol secretion in the early morning, helping the body become active in the morning
       • Cortisol and Stress
         • Cortisol has widespread actions to restore homeostasis after stress, preventing the body from overreacting to stress, which may otherwise threaten survival
         • Stress examples include: injury, trauma, infection, illness, temperature changes, mental stress, etc
         • In the absence of cortisol, even minor illnesses can be FATAL
         • Cortisol also counteracts insulin by mobilising amino acids, carbohydrates and glycerol/fatty acids
         • But prolonged stress causes continued cortisol secretion, which leads to: *muscle wastage *immune and inflammatory response *hyperglycaemia
         • Similar problems can occur with long-term use of glucocorticoids
       • Cortisol and negative feedback
         • Cortisol also has a negative feedback on its own production *It affects the pituitary and to a lesser affect the hypothalamus *High levels of cortisol suppress ACTH, CRH and AVP (vasopressin) production
         • Challenge test for negative feedback
           • The use of synthetic drugs on the negative feedback control of the anterior pituitary, e.g. Metyrapone (blocks cortisol production), Dexamethasone
     • MIneralocorticoids - Aldosterone
       • Aldosterone acts on the kidney (distal tubule), promoting the exchange of sodium and potassium ions (reabsorption of Na+ into the blood).  This causes three primary physiological effects: *Increased reabsorption of sodium: sodium loss in urine is decreased *Increased reabsorption of water: with consequent expansion of extracellular fluid volume, an osmotic effect which maintains BP *Increased renal excretion of potassium
       • Destruction of the adrenal glands leads to DEATH within a few days, due to: *Dramatic rise in potassium concentration in extracellular fluid *Massive fall in sodium concentration in extracellular fluid *Extracellular fluid and blood volume plummets *Heart begins to function poorly, cardiac output declines and shock ensues
       • However, these effects can largely be prevented by giving salt replacements and mineralocorticoids
       • Stimulation of Aldosterone Secretion
         • *Drop in Na+ levels in blood *Rise in K+ levels in blood
   • Gonads

3. Delivery of Hormones

   • There are 4 main ways to deliver hormones around the body
   • Classical Delivery
     • Endocrine cell secretes hormone into the blood => delivered to target cell via the circulatory system
   • Neuroendocrine Delivery
     • Secreted from a neuroendocrine cell => hormone secreted from nerve cells in the hypothalamus into the blood stream => same as the classical delivery system, simply secretion from a neuroendocrine cell instead of an endocrine cell
     • Neuro-secretion
       • When hormones are secreted by neurons, they travel down the axon and are stored inside vesicles within little swellings in the nerves called 'Herring bodies' Secretory neurons have specialized nerve endings that have 'caps' to store hormones within vesicles
       • Generation of an action potential in these neurons causes the hormones to be released by exocytosis into the capillaries These capillaries are fenestrated, i.e. they have 'gaps' enabling the hormones to enter easily
   • Paracrine Agents
     • Hormones that don't actually reach the blood stream => are secreted by the endocrine cell => act on a neighbouring cell
   • Autocrine Agents
     • Hormones that don't actually reach the blood stream => are secreted by the endocrine cell => act back on the same cell that secreted them

4. Structures of Hormones

   • Hormones have different effects due to their differing structures. The structure of the hormone determines: *The mechanism of action at the target cell *How the hormone is carried in the blood *The circulating half-life (time taken for it to be broken down, i.e. the duration of action)
   • There are 3 main types of hormone structures: *Proteins/peptides (most common) *Steroids *Amines
   • The two major groups of hormones act as follows: *Steroids and thyroid hormones     => because they are fat-soluble, they are able to enter cells easily =>Consequently, they bind to an intracellular receptor (which may be in the cytoplasm or in the nucleus) => they then all carry out their end response which is altering gene transcription *Peptides, proteins, glycoproteins, catecholamines: => not able to enter cells because they're not fat-soluble =>therefore, they have to bind to a receptor on the outside surface of their target cell => they then require a second messenger to exert their final response within the cell
   • Proteins/Peptides
     • This is the structure of the majority of hormones There are many different types: *Some are very small => only 3-9 amino acids *Some are large => long-chain proteins (i.e. polypeptides), e.g. insulin, which has 51 amino acids
     • They are synthesized by DNA transcription and translation. They are mostly synthesized as follows: *First as large preprohormones, which are cleaved by proteolytic enzymes to form prohormones *Prohormones are stored in the cell as granules in secretory vesicles *The active hormone is released by exocytosis, which is stimulated by an increase in cytosolic calcium. They only become biologically active when released into the bloodstream *After release, peptide hormones diffuse into 'leaky' capillaries *They are water-soluble (polar), so are able to dissolve and travel freely in the blood (don't need to be bound to anything). This causes them to have a short half-life *All hormones are from the hypothalamus, pituitary, parathyroids, GI tract and pancreas
     • e.g. oxytocin, ADH (from posterior pituitary
     • Receptors for Lipid-insoluble hormones
       • Applies to proteins, peptides, glycoproteins, catecholamines
       • These have to bind to a receptor outside of the cell. there are different types of extracellular receptors. They each have a part outside the cell, as well as a part which spans the membrane and a part inside the cell *Monomeric receptors => simple receptors with only a single unit crossing the plasma membrane *Multimeric receptors => several membrane-spanning subunits and extracellular subunits *Receptors with SEVEN membrane-spanning domains (also termed as mutlimeric)
       • So the hormone binds to the outer part, which results in a conformational change in the inner part. This is how the hormone exerts its response within the cell without being able to enter it
       • This conformational change is achieved by three different pathways: *ion channels *enzyme-linked  *G-protein-linked These pathways are called Signal Transduction Mechanisms
       • Signal Transduction via cell surface receptors #1: Ion Channels
         • Very simple!
         • The hormone binds to the extracellular part of the receptor This causes an ion channel in the membrane to open up, allowing a movement of specific ions along a concentration gradient from the outside to the inside of the cell The end result is a change in the concentration of specific ions
       • Signal Transduction via cell surface receptors #2: Enzyme-linked pathway (tyrosine kinase)
         • The receptor has a dual function. The outside part is the receptor and the intracellular part is the enzyme tyrosine kinase
         • The binding of the hormone to the receptor activates the tyrosine kinase
         • Tyrosine kinase transfers a phosphate group to another protein/enzyme. The phosphorylation of the tyrosine part of the target protein is the end result => it will alter the activity of the second protein/enzyme (e.g. it may phosphorylate cAMP)
       • Signal Transduction via cell surface Receptors #3: G-protein linked pathway
         • The receptor has a protein linked to it called a G-protein (G as in guanine)
         • When the hormone binds to the receptor, it activates that G-protein Once it is activated, it 'shuffles' along across to an effector protein and activates it
         • That effector protein is an enzyme which is partially embedded in the membrane. It may be one of two enzymes:  *adenylyl cyclase *phospholipase C
         • If the effector protein is adenylyl cyclase, it stimulates the production of large amounts of cAMP (i.e. the second messenger), which activates another enzyme (protein kinase enzyme) within the cell. This enzyme ultimately affects the cells' response (by phosphorylating an enzyme and altering its activity)
         • If the effector protein is phospholipase C, it stimulates an increase in calcium ions (the second messengers), which affects another enzyme within the cell, which causes the final response.
         • Consider that hormones are present in the blood in tiny amounts (like a pinch of salt in a swimming pool), but one hormone binding to its receptor will activate many G-proteins, meaning many 2nd messengers will be produced. Very few hormones can elicit an enormous effect - this is called AMPLIFICATION
   • Steroids
     • Their structures are based on three 6-carbon rings and one 5-carbon ring (fat soluble lipids, derived from cholesterol)
     • They are synthesized in the mitochondria and smooth endoplasmic reticulum (SER)
     • Unlike proteins/peptides, they are not stored in glands (but they *may* be stored in fat tissues, *because they are fat-soluble*, that's just an incidental thing though), so hormone release is purely dependent on rate of synthesis
     • They are able to diffuse across the plasma membrane => because the cell membrane is a lipid bilayer, so they can dissolve through that easily)
     • They don't diffuse in the blood because they are non-polar. They circulate in the blood bound to carrier proteins, e.g. albumin. Therefore, they have long half-lives (binding to carrier proteins protects them from breakdown)
     • They are produced by the adrenal cortex, gonads and placenta (e.g. oestrogen)
     • Receptors for Lipid-soluble Hormones
       • i.e. for steroids, thyroid hormones
       • The receptor that they bind to is a protein. It has 3 areas (domains): *One where a hormone binds to the receptor (hormone binding domain). Upon binding, the receptor is activated and a receptor/hormone complex is formed *One  domain binds to DNA (this is because all of these hormones, after binding to a receptor, result in gene transcription, so that receptor has to bind to DNA) *One domain allows other molecules in the cell (called transcription factors) to bind to it. These may be co-activators or co-repressors. This means they can stimulate the activity of the hormone more, or they can inhibit the activity of the hormone => allow variety in the end response
       • Mechanism of Steroid Action
         • Before the hormone binds to the receptor, there is a large masking protein, which sits on the DNA binding site. Its purpose is to prevent binding to DNA prior to the hormone binding to the receptor.
         • When the hormone binds to the receptor, the whole configurational shape of the receptor changes => the masking protein moves away, meaning the DNA binding site is exposed
         • The hormone-receptor complex then moves into the nucleus
         • Then, dimerization occurs => a single hormone/receptor complex doesn't bind to DNA alone It binds as a pair (of 2 such complexes) => the pair is called the dimer.  Note: a dimer may exist as a homo-dimer (where both hormones are the same) or a hetero-dimer (where the two hormones are different)
         • The dimer binds to an area on DNA which is called the Hormone Responsive Element (HRE).  This area on the DNA is upstream from the genes which are going to be transcribed.  The binding stimulates transcription of the genes. 
   • Amines
     • These are modified amino acids, derived from tyrosine. Split into two groups with different characteristics: *Thyroid hormones *Catecholamines
     • Catecholamines
       • Similar characteristics to peptides Water-soluble => do NOT cross cell-membranes circulate unbound in blood => short half-lives Stored intra-cellularly in secretory granules, e.g. adrenaline
     • Thyroid Hormones
       • Have similar characteristics to steroid hormones Are lipid-soluble => can cross cell-membranes circulate in blood bound to carrier proteins => long half-lives unlike steroid hormones, they are stored in the thyroid gland, bound to thyroglobulin
       • i.e. T3 and T4
   • Eicosanoids
     • Local hormones! These are local chemical messengers which exert a wide variety of effects in many different organs and tissues, e.g. prostaglandins, leukotrienes, thromboxanes
     • They are derived from arachidonic acid (fatty acid present in plasma membrane phospholipids)
     • They carry out Autocrine or Paracrine activity (acting on neighbouring cells or back on the cell)
     • Effects of prostaglandin include *Immune system => promote the inflammatory process *Reproductive System => play role in evolution *Digestive system => inhibit gastric secretion

5. What stimulates hormone release?

   • Four main stimuli: *Changes in plasma concentration of mineral ions, e.g. calcium, potassium, sodium *Changes in plasma concentration of organic nutrients, e.g. glucose *Another hormone (or paracrine agent) acting on the endocrine cell. So one hormone can stimulate another hormone (e.g. negative feeback control) *Neurotransmitters released from neurons contacting endocrine cells. So some nerves can stimulate hormone release, e.g. in the autonomic nervous system, nerves may stimulate the adrenal medulla, which secretes adrenaline and noradrenaline
   • Negative Feedback Control
     • There are three very important negative feedback controls: *This is a homeostatic method which prevents hormone levels from fluctuating to a large degree *It happens specifically between the hypothalamus and target glands (e.g. the adrenal/thyroid glands) *Hormone 1 from the hypothalamus stimulates the pituitary to produce hormone 2. Hormone 2 then stimulates the target gland to produce hormone 3. *Because hormone 2 is secreted into the bloodstream, it can be detected by the hypothalamus. If hormone 2 levels are high, this will have a negative feedback effect on the hypothalamus and so it will reduce the production of hormone 1 (short loop feedback) *Similarly, too much hormone 3 will be detected both by the pituitary and hypothalamus and cause a reduction in hormone 2 and hormone 1 release (long loop feedback). Additionally, hormone 3 is detected by the target gland which secreted it in the first place, resulting in a decrease in hormone 3 release (ultra-short loop feedback)
     • Note: sometimes negative feedback is overridden.  E.g. prior to ovulation, LH from the anterior pituitary gland stimulates the ovaries to secrete EL, which in turn stimulates the anterior pituitary to secrete MORE LH, resulting in a surge of LH, which results in ovulation (Positive Feedback)
     • Hormonal Rhythms
       • Negative Feedback may be modified by the nervous system: *Circadian Rhythms => a rhythm over 24 hours shows that growth hormones are released predominantly during sleep *Pulsatile Rhythms => pulses of LH secreted from about midnight to 8 am. These pulses can be 30 min - 2 hours apart *Some animals have seasonal rhythms => e.g. sheep can only mate in autumn and give birth in the spring (their reproduction is controlled by light levels, i.e. length of days)

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