• Composed of a network of glands that work to exert homeostatic control over diverse body systems. 
  • There are 2 types of gland
    • Exocrine glands
      • Secrete hormones onto epithelial surfaces via a duct
      • Less vascular
      • Have ducts or a hollow lumen for the release of hormones. 
    • Endocrine glands
      • Secrete hormones directly into the circulatory system.
      • Effects are slow and prolonged.
      • Do not have ducts like other glands
      • They have high vascularity and intracellular vacuoles or granules in which hormones are stored prior to being released.
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Glands and class of hormones

  • Glands
    • Pineal
    • Pancreas
    • Thyroid
    • Hypothalamus
    • Adrenal Cortex
    • Adrenal medulla 
    • Anterior pituitary 
    • Posterior pituitary
    • Parathyroid
    • GI tract
    • Ovaries/testes
    • Stomach
  • Class of hormone
    • Endocrine - pass into blood and act on distant cells
    • Local hormones - act on target cells close to release site
    • Paracrines - act on neighbouring cells
    • Autocrines - act on the same cell
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Overview 2

  • Many organs of the body (bone, kidney, liver, heart and gonads) have secondary functions and can also release endocrine hormones. 
  • Endocrine hormones exert and enormous range of effects within the body
    • They are very important sources of both natural products and the medicines derived from them.
  • The downside of ther potency is that they can be highly damaging if used incorrectly or excessively.
    • Studies have shown that corticosteroid hormones are the leading cause of adverse effects of all drug classes. 
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Control of endocrine hormone secretion

  • There is a 5 step circular mechanism by which endocrine hormones are regulated and secreted. As it is circular, the starting point it arbitrary.
    • Stage 1
      • The blood flowing through the hypothalamus is detected as being too low in the level of throid hormones. 
    • Stage 2
      • The hypothalamus detects this low level and then synthesises a releasing factor, thyrotropin releasing hormone (TRH), which then passes in this case to the anterior pituitary. 
    • Stage 3
      • The pituitary is stimulated by the TRH to release thyroid stimulating hormone (TSH), which is released directy into the blood stream and detected by thyroid epithelial cells, which increase the production of the 2 main thyroid hormones (T3 and T4)
    • Stage 4
      • Levels of thyroid hormone increase in the blood.
    • Stage 5
      • The increasing levels of hormone are detected by the hypothalamus which reduces the amount of releasing factors it produces. 
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Control of endocrine hormone secretion 2

  • The hypothalamus monitors hormone levels in the blood and if the levels are too low, it secreted releasing factors 
    • This is a result of positive feedback
  • Once the level of hormone starts to get too high, negative feedback occurs and the secretion of releasing factors is reduced and the production of the hormone falls.
  • Anterior pituitary is stimulated by hormones, posterior is stimulated by electrical impulses.
  • ADH and Oxytocin are made in the hypothalamus and stored in the posterior pituitary.
  • Tropic hormones
    • F (FSH)
    • L (LIT)
    • A (ACT4)
    • T (TSH)
  • Direct hormones
    • P (Prolactin)
    • E (Endorphins)
    • G (Growth hormones)
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Hormones of the anterior pituitary

  • Adenohypophysis
  • Largely regulated by the release of releasing factors from the hypothalamus.
    • They reach the pituitary via the blood stream (hypophyseal portal system).

      Hormones of the posterior pituitary

      • Neurohypophysis
      • Consists largely of nerve terminals of nerve cells 
        • Originate in the supraoptic and paraventricular nuclei of the hypothalamus.
        • The axons form the hypothalamic-hypophyseal tract and terminate in close proximity to the capillaries of the posterior pituitary.
      • Peptides (vasopressin and oxytocin) are synthesised in the hypothalamic nuclei
        • They pass down axons into the posterior pituitary, where they are stored and eventually secreted. 
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Thyroid gland

  • Thyroid hormones are synthesised within the thyroid gland
    • The two most physiologically important hormones produced are T3 and T4, with 3 and 4 iodine molecules attached respectively. 
    • The synthesis and secretion of both T3 and T4 are regulated by thyroid stimulating hormone (thyrotropin)
  • TSH stimulates transcription of the carrier gene which permits the entry of iodine into follicle cells.
  • The enzyme thyroperoxidase enzymatically facilitates the incorporation of iodide onto tyrosine residues of thyroglobulin and this produces T3 and T4 within the lumen of the thyroid follicle.
    • It is then endocytosed back into the follicle cell and then secreted into the plasma of the blood.  
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T3 and T4 mechanism

  • There is a large pool of T4 in the body
    • It has a low turnover rate and is mainly found in the circulation
  • There is a small pool of T3 in the body
    • It has a fast turnover rate and is found mainly intracellularly 
  • Within target cells, T4 is converted to T3 by deiodinase (D2) located on the endoplasmic reticulum.
    • T3 then interacts with a nuclear receptor to regulate gene transcription 
  • T3 and T4 stimulate metabolism
    • This causes increase oxygen consumption and increased metabolic rate
    • It also regulates growth and development.
    • T3 translocates to the nucleus and binds to the thyroid receptor.
  • Cellular uptake of thyroid hormones is by transmembrane transporters.
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  • An overactive thyroid can lead to a syndrome of a high metabolic rate, increased skin temperature, sweating, sensitivity to heat, tremor, tachycardia and weight loss, despite an increase in appetite. 
  • Treatment options
    • Radio-iodine
      • Radioactive iodine can be injected to be taken up selectively by the thyroid where radioactive decay then causes cell damage.
      • This can eventually lead to hypothyroidism so this is only used once drugs are ineffective 
    • Carbimazole
      • A thioureylene which decreases the synthesis of thyroid hormones by reducing the iodination of thyroglobulin through inhibition of thyroperoxidase.
    • Propylthiouracil
      • A thyroperoxidase inhibitor used when carbimazole is ineffective
    • Iodine
      • When given in high doses it reduces the vascularity of the thyroid gland, reduces hormone secretion. 
      • The effects are short lasting so it is not used long term, usually given 10-14 days before a thyroidectomy to reduce hormone release caused by the physical handling of the gland by a surgeon.
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Grave's Disease

  • Caused by diffuse, toxic goitre.
  • Its an autoimmune disease where thyroid stimulating immunoglobulins are directed at the TSH receptor.
    • This increases thyroxine secretions.
  • This condition leads to a characteristic sign of protruding eyeballs.
  • Toxic nodular goitre is caused by a by a benign tumour developing in the thyroid gland.
  • Beta blockers
    • Propranolol or atenolol
    • Used to treat symptoms but do not affect the thyroid gland directly.
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  • An auto-immune or drug induced condition which leads to low metabolic rate, slow speech, lethargy, bradycardia, sensitivity to cold, mental impairment and characteristic thickening of the skin.
  • Hashimoto's thyroiditis is a chronic autoimmune disease directed against thyroglobulin and thyroid tissue.
  • Cases of thyroid hormone deficiency (1 in 3000-4000 births) leads to growth retardation and mental deficiency.
    • Thyroxine or levothyroxine given orally mimic the effects of endrogenous hormones
      • Treatment choice as maintenance therapy.
    • Lyothyronine (T3) can be given as an injection in emergencies
      • It has a quicker onset but a reduced duration of action compared with T4
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Adrenal glands and HPA axis

  • Both adrenal glands are located above the kidneys in capsules of fat
  • Consist of two separate endocrine organs
    • Adrenal cortex - the outer layer
    • Adrenal medulla - surrounded by the adrenal cortex.
  • Adrenal cortex hormones (adrenocorticosteroids) have two distinct classes of action
    • Glucocorticoid activity
      • Influence carbohydrate and protein metabolism 
      • Have potent antinflammatory effects
      • Derived from the zona fasciculata of the adrenal cortex.
    • Mineralcorticoid activity
      • Affect water and electrolyte balance
      • Are derived from the zona glomerulosa of the adrenal cortex.
  • The zona reticularis produces pre cursors to the androgens.
  • Steroid hormones are based on four ring structures
    • 3 cyclohexyl rings and 1 cyclopentane ring
  • The biosyntehsis of steroids all originate with cholesterol to form the main classes of glucocorticoids, mineralcorticoids, progestogens, oestrogens and androgens.
    • Cholesterol is first converted to pregnenolone and this is further metabolised to the active steroids.
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Biosynthesis of adrenal corticosteroids

  • The hypothalamus releases corticotrophin releasing factor (CRF)
    • This stimulates the anterior pituitary to release adrenocorticotrophic hormone (ACTH)
      • This then stimulates glucocorticoid production in the adrenal cortex.
  • Cyclical control of steroid production is known as the HPA
    • Negative and positive feedback is detected in the blood by the hypothalamus.
  • If a natural or synthetic steroid is given to a patient, it exerts a negative feedback on the hypothalamus
    • This reduces the production of ACTH, meaning the body will reduce natural production of hormones such as hydrocortisone (cortisol).
      • This is the reason that corticosteroid treatment must not be stopped abruptly but should be tailored over time to enable the hypothalamus to stimulate normal steroid production.
  • Mineralocorticoids are subject to the renin angiotensin system.
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Glucose control

  • Blood glucose is the most important factor in the stimulation of insulin secretion.
  • The most important regulatory hormone is insulin
    • Increased blood glucose stimulates insulin secretion
    • Reduced blood glucose reduces insultin secretion 
  • Once insulin is secreted and enters the blood stream it will act on key targets (insulin responsive tissues) to mediate its effects.
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The endocrine pancreas

  • The pancreas contains both endocrine and exocrine tissue
    • Exocrine tissue makes up 99% of the pancreas and is arranged into numerous small masses (acini).
      • The principle function is the production of digestive enzymes which are released when required into a series of progessively larger ducts. 
    • Endocrine pancreas refers to the cells within the pancreas which synthesise and secrete hormones.
      • It composed of approx a million cell clusters designated as the Islets of Langerhans.
        • Islets are composed of 4 main cell types, each of which produces a difference endocrine product.
          • Alpha cells secrete glucagon which increases blood glucose by breaking glycogen down into glucose. 
          • Beta cells secrete insulin which lowers blood glucose by facilitating glucose uptake into tissues and promited the synthesis of glycogen to glucose. They also secrete amylin which delays gastric emptying and opposes insulin by stimulating glycogen breakdown in striated muscle.
          • Delta cells secrect somatostatin which inhibits the secretion of glucagon and insulin
          • Gamma cells secrete pancreatic polypeptide of unknown function.
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Factors regulating insulin secretion at a bodily l

  • Blood glucose is the most important factor stimulating insulin production.
  • Amino and fatty acids, gastrointestinal tracts hormones (GIT) and incretins such as glucogen-like peptide 1 (GLP-1) and gastric inhibitory peptide (GIP) also enhance insulin secretion.
    • Incretins also inhibit pancreatic glucagon secretion from alpha cells and slow the rate of absorbtion of digested foods by decreasing gastric emptying.
  • Parasympathetic nerves can also act on muscarinic receptors to stimulate insulin secretion
    • Alpha2 adrenoceptors can inhibit insulin secretion.
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Stimulation of insulin secretion

  • After an increase in blood glucose, glucose enters pancreatic B cells via GLUT2, a glucose transporter
  • Glucose is phosphorylated by glucokinase to G6P
  • G6P is metabolised by glycolysis and the TCA cycle
    • This increases intracellular ATP and decreases ADP
  • The change in ratio of ATP to ADP results in the inhibition of the ATP sensitive potassium ion channel.
    • This causes potassium to accumulate within the cell, meaning the cell becomes slightly more positive, leading to partial membrane depolarisation and triggering voltage gated caclium ion channels.
  • Calcium ions then move in the pancreatic B cell.
    • This stimulates exocytosis of secretory granules that contain insulin.
  • The sulphonylurea group of antidiabetic medication binds to sites on the ATP sensitive potassium channel to inhibit channel conductance
    • This results in membrane depolarisation, so calcium ions can enter and insulin is released.
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Insulin and it's targets

  • Insulin promotes the uptake and storage of glucose, amino and fatty acids into insulin responsive tissue
    • Including skeletal muscle and adipose tissue 
  • It inhibits hepatic glucose output and promites hepatic glycogen formation
    • It does this by converting glucose to glycogen
  • The overal consequence of insulin secretion is the rapid movement of nutrients from the blood into the tissues
    • To be used to meet the energy and metabolic demands of the body.
  • If insulin levels of responsiveness of tissues to insulin action are inadequire, hyperglycaemia occurs.
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Molecular mechanism of insulin

  • Insulin binds to receptors on insulin responsive target cells.
    • Short term actions because of this
      • Immediate metabolic effects
        • Recruiting glucose transporters (GLUT 4) to the plasma membrane so glucose can not move into the cell.
          • GLUT 4 is an insulin sensitive glucose tranporter present in muscle and fat cells.
        • Activation of the enzyme glycogen synthase
          • This promotes glycogen synthesis as well as inhibiting glucogenesis and glycogen breakdown.
        • Generally governed by kinase and phospholipase enzymes.
    • Long term actions
      • Promote gene expression and they synthesis of key enzymes involved in the regulation of blood glucose. cell growth and cell division.
  • Occupied receptors aggregate into clusters which are subsequently internalised into vesicles
    • This results in downregulation of the receptor at the membrane 
    • The receptors are eventually recycled back to the plasma membrane.
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Insulin receptors mechanism

  • Insulin binds to its cognate receptors on target cells.
    • The receptors are composed of 2 alpha and 2 beta subunits
      • The beta subunits possess intrinsic kinase activity
  • Insulin blinding to the alpha subunits on the extracellular side of the membrane promotes autophosphorylation of tyrosine residues on the intracellular portion of the receptor.
  • Rapid tyrosine phosphoryation of adaptor proteins also occurs. 
    • Insulin receptor substrate (IRS-1) is a substrate/adapter protein
      • It contains 22 tyrosine residues
  • Phosphorylated tyrosine residues act as docking sites for signalling proteins
    • Signalling proteins contain SH2 domains such as PI3 kinase.
      • PI3 kinase phosphorylates the 3' position on the inositol head group of PIP2 to generate PIP3.
      • PIP3 recruits protein kinase B which mediates 2 important signalling responses
        • 1. Promotes the movement of GSVs to the plasma membrane, meaning after vesicle fusion, glucose is able to cross the membrane more readily.
        • 2. Posphorylates and deactivates glycogen synthase kinase which leads to the activation of glycogen synthase and the synthesis of glycogen.
    • Proteins which contain SH2 domains bind phospho-tyrosine motifs.
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Type 1 diabetes mellitus

  • Caused primarily by a T-cell mediated autoimmune response
    • Leads to the destruction of pancreatic B cells.
    • The stimulus is still unknown
  • Damage to B cells can occur over a number of years
    • After significant destruction (~90%) the onset of polyuria, polydipsa and polyphagia can be abrupt.
  • Increased urine volume is caused by osmotic diuresis
    • This results from increased concentrations of urinary glucose, causing increased concentration ketone bodies.
  • Ketone bodies are the result of fat metabolism.
    • They are toxic to the brain as it exclusively uses glucose for energy.
  • As the body is unable to uptake and store glucose effectively, it percieves itself in a state of starvation and results to breaking down fat.
  • Characterised by weight loss and hindered growth in children.
  • Insulin levels are lower than normal and the patient will often require insulin replacement to prevent ketosis.
    • Can lead to diabetic coma and premature death
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Insulin Therapy

  • Administration has to be parenteral, routinely subcutaneously.
    • This is because insulin is a peptide so it is quickly destroyed in the GI tract.
  • Emergency situations may warrant intravenous administation (diabetic ketoacidosis).
  • Has a half life of around 10 minutes from activation as it is activated in the liver and kidneys.
  • 10% is excreted in the urine
  • Renal impairment reduces insulin dosage requirements.
  • Its important to avoid wide fluctuations in plasma insulin concentrations commonly associated with subcutaneous injections and can potentially lead to hypoglycemia.
  • The aim is to mimic natural insulin secretion, which occurs throughout the night and in response to meals, returning to basal level after 2-4 hours.
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Insulin analogues

  • Rapid acting - Insulin Aspart (Novorapid) and Insulin Lispro (Humalog)
    • Onset of action is 15 minutes
    • Duration of action is 2-5 hours
    • Mimics the effect of insulin secreted in response to a meal
    • Administered immediately before or just after a meal
  • Short acting - Soluble insulin (Actrapid)
    • Onset of action is 30-60 minutes
    • Duration of action up to 8 hours
    • Injected approximately 15-30 minutes before a meal
  • Intermediate acting - Isophane insulins (Insulatard, Humalin I)
    • Suspension of insulin with protamine
    • Onset is 1-2 hours
    • Maximum effect is 4-12 hours
    • Duration of action is 16-35 hours. 
    • Injected once or twice a day.
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Long acting insulin

  • Insulin zinc suspensions
    • Finely divided amorphous solids or relatively insoluble crystals which are injected as a suspension.
    • Insulin Glargine (Lanctus) is injected once a day
    • Insulin Detemir (Levemir) is injected twice a day
    • They both reach a steady state concentration after 2-4 days.
  • Biphasic insulin
    • Its a mixture of rapid or short acting with intermediate acting.
    • NovoMix30
      • 30% insulin aspart, 70% insulin aspart protamine
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Structure of Insulin and Peptide Analogues

  • Insulin lispro (Humalog)
    • Lysine and Proline are switched.
  • Insulin glargine (Lantus)
    • 2 arginines extend the B chain.
    • Designed to supply a constant basal supply of insulin.
    • It forms a microprecipitate at the pH of subcutaneous tissue, prolonging absorbtion from the injection site.
  • Insulin aspart
    • Proline 28 is substituted for asparagine 
    • This reduces its propensity to form hexamers
    • Gives it a higher rate of absorbtion
  • Insulin has 2 disuphide bridges between the A chain and the B chain, as well as an intrachain disulphide bridge in the A chain.
    • These happen between cysteine molecules
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Type 2 diabetes

  • Commonly diagnosed in middle age but can occur at any age
  • There is a genetic predisposition however environmental factors play a role much more. 
  • It's associated with both insulin resistance and impaired insulin secretion.
    • Resistance occurs initially before symptoms show and often goes undetected.
  • A diet high in sugars and carbs may cause increased insulin levels. 
    • The tissues that insulin exerts its effects on become unresponsive due to downregulation and impaired signalling mechanisms that recruit the transporter GLUT 4.
      • As tissues no longer effectively respond to insulin, glucose can no longer enter the cell, meaning blood glucose continues to rise. 
      • In an attempt to drive glucose into the cell, pancreatic B cells produce more insulin, resuling in hyperinsulinaemia.
      • Gradually, b cells become depleated and impaired insulin secretion occurs. 
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Impaired glucose tolerance

  • A prediabetic state of hyperglycaemia
  • It is associated with insulin resistance and carries an increased risk of cardiac pathology. 
  • It may precede type 2 diabetes by many years and may often go undetected.
    • Detection is difficult because fasting blood glucose and insulin levels can be near normal.
    • After a glucose challenge (a fasting patient given a large quantity of glucose) above noral levels or blood sugar and insulin are observed. 
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Management of type 2

  • A management plan is tailored to meet individual patients needs and their stage of development of the condition.
  • Non pharmacological
    • Dietary modifications (increase complex carbs, high fibre, foods with low glycaemic index, low fat)
    • Weight loss as required
    • Increased physical activity as tolerated
  • Pharmacological
    • Supplementation or promotion of endogenous insulin secretion
    • Antagonism of carbohydrate metabolism/absorption from the GI tracts to reduce resistance.
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Biguanides (Metformin)

  • Reduce hepatic glucose production (glucogenesis), which is usually increased in type 2 diabetes. 
  • Increases glucose uptake and utilisation in skeletal muscle
  • Reduces carbohydrate absorption 
  • Reduces circulating levels of LDL and VLDL.
  • Does not cause hypoglycaemia
  • Can cause dose related side effects 
    • Anorexia, diarrhoeas, nausea and GI related effects.
    • Most serious one is lactic acidosis which is more likely in patients with reduced drug elimination or reduced tissue oxygenation
      • Should not be used in patients with renal or hepatic disease.
  • Can improve outcome for the outcome of heart disease.
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Sulphonylureas (-ide)

  • They work on pancreatic b cells and stimulate insulin secretion, reducing plasma glucose.
    • Therefore they are only effective if there are functional B cells available. 
  • Not used in type 1 or late stage type 2.
    • Intracellular levels of insulin have already been severely depleted. 
  • SUR1 receptors are present on the potassium ion channel
    • Antagonising these receptors blocks the efflux of potassium
    • This triggers the activation of the calcium ion channels
      • Causing calcium ion entry and the releasing of vesicles.
  • They are usually well tolerated
  • Most common side effect is hypoglycaemia.
  • Long acting formulations are best avoided in the elderly as they have reduced renal function.
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  • Pioglitazone
    • Indicated an increased incidence of heart failure and a risk of bladder cancer.
  • Rosiglitazone
  • Slow onset with a maximal effect after 1-2 months.
  • Reduce hepatic glucose output and increase glucose uptake into muscle.
    • Enhances the effects of endogenous insulin 
  • They reduce the amount of exogenous insulin required for maintennance by around 30%.
  • They also reduce insulin, small dense LDL and free fatty acid concentrations.
  • Side effects are weight gain and fluid retention
      • Due to an increase in plasma volume and a reduction in haemoglobin concentration.
  • Bind to PPAR gamma
    • PPARs then form heterodimers with RXR alpha
      • This facilitates their binding to the PPRE in the enhancer regions of target genes
        • They are important in insulin signalling, fat metabolism and fluid volume.
      • This results in differentiation of adipocytes and an increase in lipogenesis (weight gain).
      • It enhances the uptake of fatty acids and glucose into cells
      • Promotes amiloride sensitive sodium ion reapsorbtion into renal collecting ducts. 
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Glucosidase inhibitors

  • Acarbose
  • Inhibits the intestinal enzyme glycoside hydrolase.
    • This leads to delays in carbohydrate absorbtion, reducing the postprandial increase in blood glucose. 
  • Side effects
    • Flatulance 
    • Loose stools
    • Diarrhoea
    • Abdominal pain/bloating.
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  • Sitagliptin
  • Vildagliptin 
  • Synthetic DDP4 inhibitors
  • They potentiate endogenous incretins as DDP4 usually breaks them down.
  • They are usually added to other orally activated drugs to improve control in patients with type 2 diabetes.
  • Generally well tolerated as well as weight neutral.
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Incretin mimetics

  • Exenatide
    • Synthetic version of extendin-4 which is a peptide isolated from the saliva of the Gila monster which is a lizard which disables pray by inducing hypoglycaemia
  • Endogenous GI peptides that stimulate insulin secretion
  • Include glucagon-like peptide 1 and gastric inhibitory peptide. 
  • They also inhibit pancreatic glucagon secretion from alpha cells.
  • They slow the rate of absorbtion of digested foods by decreasing gastric emptying.
  • Must be subcutaneously administered as it is a peptide.
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The female reproductive system

  • Main female steroid hormones are oestrogens and progesterone
    • They are steroid hormones which act by influencing gene transcription.
    • They passively diffuse into the cell and bind to their cognate receptors in the cytoplasm or the nucleus.
      • These receptors are associated with heat shock proteins (HSPs) when in their unbound state. 
        • HSPs dissociate when the hormone binds to the receptor and the receptor forms dimers which translocate to the nucleus.
          • They induce transcription of target genes. 
  • The steroid-receptor complex associates with hormone-response elements of numeous responsive genes.
  • Oestrogen binds to ER alpha and ER beta, which have different tissue distributions.
  • Progesterone binds to PR-A and PR-B
  • Steroid hormones are responsible for some non-genomic actions by binding to extra-nuclear steroid receptors.
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Menstruation and The Follicular Phase

  • Endocrine control of the cycle relies on the hypothalamic-pituitary-gonadal (HPG) axis as well as associated hormonal fluctuations. 
  • Menstruation usually lasts from 3-6 days and marks the beginning of the menstrual cycle
    • During this the superficial layer of the endometrium is shed.
  • During the follicular phase, the endometrium regenerates and gonadotrophin releasing hormone (GnRH) is secreted from the hypothalamus
    • This stimulates the anterior pituitary to release follicle stimulating hormone (FSH) and lutenising hormone (LH)
      • These act upon the ovaries to promote the development of small groups of follicles, which each contains an ovum.
      • One follicle will develop more rapidly than others to form the Graafian follicle (GF), which proceeds to secrete oestrogen.
        • The remainder of the ova degenerate.
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The Proliferative Phase and The Luteal Phase

  • In the proliferative phase the endometrium increases in thickness and vascularity 
    • At peak oestrogen levels there is a prolific cervical secretion of mucus that has a pH of 8-9.
      • It is rich in protein and carbohydrates which facilitates the entry of the sperm to the ovum.
    • High endogenous oestrogen secretion sensitises the LH releasing cells in the anterior pituitary to the action of GnRH
      • This leads to a mid-cycle surge in LH secretion, causing rapid swelling and rupture of the Graafian follicule, which results in ovulation.
        • If fertilisation occurs the fertilised ovum passes down the fallopian tube to the uterus.
  • In the luteal phase, the ruptured Graafian follicle proliferates and develops into the corpus luteum which starts to secrete progesterone.
    • Progesterone acts on the endometrium to render it stable for implantation of the fertilised ovum.
    • The cervical mucus becomes thicker to hinder any sperm.
    • Progesterone exerts a negative feedback on the hypothalamus, decresing synthesis and release of LH.
    • If fertilisation and implantation do not occur progesterone secretion stops at the end of the cycle, triggering menstruation.
    • If fertilisation does occur, the corpus luteum continues to secrete progesterone
      • The causes negative feedback to the hypothalamus and pituitary that prevents further ovulation.
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The combined pill

  • Contains synthetic oestrogen and synthetic progesterone.
  • Second generation have a lower concentration than first generation, which are no longer used due to unwanted side effects. 
  • Third generation contain modified progestogens which have less androgenic activity
    • Desogestrel and gestodene are more potent but are likely to cause a greater risk of thromboembolism than second generation.
  • The prodominant oestrogen is ethinylestrafdiol
    • Altered to slow its metabolism
    • Some contain mestranol
      • This is metabolised to ethinylestradiol in the liver.
  • The progesterone may be levonorgestrel or norethisterone.
  • It is taken cyclically in order to mimic the natural menstrual cycle.
    • Active pill for 21 days followed by a pill free period or placebo of 7 days, to enable a withdrawal menstrual bleed.
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Combined pill mode of action

  • The exogenous oestrogen inhibits the release of FSH, inhibiting the develpoment of follicle development
  • The exogenous progesterone inhibits the release of LH.
  • The lack of follicular development combined with the inhibitory effects of progesterone prevents ovulation whilst also making mucus inhospitable to sperm.
  • Can cause weight gain, nausea, mood changes and skin pigmentation.
    • Some women develop reversible hypertension
    • There is also a risk of thromboembolism with third generation medications.
    • Conflicting evidence both for and against an increased risk of breast cancer. 
  • Benefits include
    • Decreasing irregular periods and inter-menstrual bleeding.
    • Reduces heavy menstrual bleeding (menorrhagia)
    • Reduces pain associated with mensis (dysmenorrhoea)
    • Can reduce pre-menstrual tension.
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Progesterone only pill

  • Norethisterone, levonorgestrel or ethynodiol.
  • Taken every day without a cyclical break.
  • Make mucus thicker, less copious and more hostile to sperm 
  • Also produces an asynchronous development of the endometrium
    • Less receptive to implantation of a fertilised ovum.
  • Less reliable than the combined pill.
    • Low dose progesterone only inhibits ovulation in 50% of cycles
  • This is an option for women affected by side effects of oestrogen.
  • Irregular bleeding is a common occurance. 
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Pharmacokinetics of female sex hormones.

  • Oestrogen and progesterone are highly lipid soluble.
    • They are rapidly and completely absorbed from the gut following oral administration.
    • Synthetic versions are metabolised more slowly and are less susceptible to first pass metabolism.
      • This causes them to have a greater bioavailability and longer half lifes.
  • Metabolised by CYP450 enzymes.
  • Each pill contains around 30mg of ethinylestradiol
    • A low dose is possible because of enterohepatic circulation where metabolised conjugates get sent back to the GI tract from the liver. 
  • An increase in clearance whilst taking a low dose can decrease effectiveness.
    • Care must be taken when administering enzyme inducing drugs such as carbamazepine, barbituates and phenytoin
      • Also anti-retrovirals such as nelfinavir, nevirapine and ritonavir, as well as antibiotics such as rifampicin and rifabutin.
  • General antibiotics aren't confirmed to reduce effectiveness, but they can induce vomiting, nausea and diarrhoea which will reduce effectiveness. 
    • Barrier method is always reccomended while on antibiotics and often for the rest of the cycle of the pill.
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Unwanted effects of oestrogens and progesterones

  • Thromboembolism
    • Risk also increases with age, smoking, obesity and thrombophillic tendency.
    • Baseline risk is 5 in 100,000.
      • Risk with second generation is 15 in 100,000
      • Risk with third generation is 25 in 100,000
      • Context: risk during pregnancy is 60 in 100,000
  • Ischaemic heart disease/stroke
    • Risk also increases with age (>35), smoking and presence of hypertension
  • Increase in blood pressure
    • Common with oestrogen not progesterone.
    • Significant rise can occur in 5% of women with previously normal BP and 15% of women with pre-existing hypertension.
    • Regular BP monitoring is suggested, treatment should be stopped if BP rises above 160/95
  • Cancer risk slightly increased after 5 years of use (cervical)
  • Increased skin pigmentation
  • Can aggravate hirsutism, acne or cause weight gain.
  • Nausea, mastalgia, mood changes, headache, weight gain and provocation of migrane
    • Can prescribe lower concentration of oestrogen or try a different progesterone.
    • Women with migrane with aura are at an increased risk of stroke on combined hormonal contraceptives.
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Menopause and Perimenopause

  • Menopause/climacteric 
    • Thought to occur once she has not had a period for 1 year
    • Usually happens around 50, although some women stop having periods in their mid-40s.
  • Perimenopause
    • Process of change that leads to menopause
    • Can start as early as late 30s or as late as early 50s
    • Usually lasts from 2-8 years
    • Key sign is the decline in oestrogen levels as a consequence of the natural depletion of follicles.
    • Progesterone levels also fall when ovulation does not occur.
      • Due to the lack of negative feedback, levels of LH anf FSH are elevated, which can be used as an indicator for menopause.
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Hormone replacement therapy

  • When menopause causes ovarian function to decrease and oestrogen levels to fall there can be some unpleasant symptoms
    • Hot flushes and night sweats
    • Atrophy of urogenital organs (dryness)
    • Osteoporosis
    • Sleep disturbance
    • Memory loss and brain fogging
    • Development of cardiovascular disease
  • HRT involves the cyclic or continuous administration of low doses of one or more oestrogens with or without progesterone
    • The progesterone is to counteract the possible risks of endometrial and ovarian cancer associated with HRT.
  • Its thought to be beneficial short term for most of the above issues, other than osteoporosis. 
  • HRT does not protect against CHD and it doesnt reduce any occurance of cognitive function.
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Hormone replacement therapy 2

  • Due to the risk of cancer of the ovaries and endometrium, oestrogen only HRT should only be used in women that are post hysterectomy.
    • While a combined oestrogen progesterone preparation may protect against developing these cancers, there may be a small increased risk of developing breast cancer.
  • Tibolone is a synthetic compound with weakly oestrogenic, progestrogenic and androgenic properties.
    • It activates progestogenic and androgenic effects in the endometrium 
    • Can prevent post menopausal symptoms and bone loss.
    • Can cause vaginal bleeding so is not used within 1 year of the last period.
  • Raloxifene is a selective oestrogen receptor modulator (SERM) with anti oestrogenic effects on breast tissue and the uterus.
    • It is pro-oestrogenic on bone and lipid metabolism 
    • Useful for preventing post menopausal osteoperosis
    • Does not effect vasomotor symptoms
    • May have beneficial effects in reducing oestrogen receptor positive breast cancer. 
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HRT Pros and cons

  • HRT helps with
    • Hot flushes/night sweats
    • Atrophy of urogenital organs
    • Osteoporosis 
  • Risk of endometrial and ovarian cancer in users of osetrogen only.
    • Oestrogen causes endometrial hyperplasia within these tissues.
    • Only used in post hysterectomy women with lower levels of circulating oestrogen.
  • Progesterone inhibits endometrial hyperplasia, decreasing the risk of endometrial cancer
    • There is an increased risk of breast cancer.
  • Tibolone
    • Effects are predominantly oestrogenic, however in the endometrium it activates progesterone and androgen receptors, meaning the effects here are mostly progesteronic, and therefore less likely to cause endometrial hyperplasia.
  • Raloxifene
    • Has anti-oestrogenic effects on breast tissue and the uterus.
    • Pro-oestrogenic effects on bone, lipid metabolism and blood coagulation
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Vaginal oestrogen

  • Oestrogen cream (estradiol) or pessaries can be used to treat vaginal atrophy, painful sexual intercourse and relieve urinary frequency and painful/difficult urination.
  • Some formulations may cause significant systemic absorbtion 
    • An oral progesterone may be warranted to prevent endometrial hyperplasia.
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  • Sterility
  • Stability
    • Often possible to overcome issues by using a different solvent or to formulate the product as powder for reconstruction.
  • Isotonicity
    • A related factor is API/excipient concentration
  • pH
    • May elicit pH changes at the site of administration that lead to irritation.
  • Local effects
    • Eg vasoconstriction slowing distribution.
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