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Life Cycle and Regulatory Systems (LCRS) > Endocrinology > Flashcards

Endocrinology Flashcards

1
Q

Define Endocrine Gland

A

A group of cells which secrete ‘messenger’ molecules directly into the bloodstream

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2
Q

Define Endocrinology

A

The study of endocrine glands and their secretions

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3
Q

Define Hormone

A

The bioactive ‘messenger’ molecule secreted by an endocrine gland into blood i.e. not simply a metabolite or energy substrate

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4
Q

Define Endocrine

A

Relates to a hormone’s action on target cells at a distance from source

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5
Q

Define Paracrine

A

Relates to a hormone’s action on nearby target cells e.g. within the immediate area around the source

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6
Q

Define Autocrine

A

Relates to a hormone having an effect on its own immediate source

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7
Q

Define Cryptocrine

A

Term devised to indicate that a hormone can have an effect within its own cell of production

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8
Q

List the differences between the endocrine and nervous system

A
  • Endocrine releases a chemical into the blood, nervous releases across a synapse
  • Endocrine targets many cells spread throughout the body, nervous only targets areas with nerve cells (innervated)
  • Endocrine can be seconds to days (long term), nervous is generated in milliseconds (short term)
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9
Q

List the ‘classic’ endocrine glands

A
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10
Q

Name the other Endocrine glands which have recently been identified.

A
  • Brain
  • Liver
  • Heart
  • Kidneys
  • Fat (Adipose tissue)
  • Placenta
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11
Q

What are the different hormone classifications?

A
  • Protein/polypeptide hormone
  • Steroid Hormones
  • Miscellaneous
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12
Q

What are the stages of protein/polypeptide hormone synthesis, storage and synthesis?

A
  1. Amino acids are delivered to the cell via the blood
  2. The gene for the hormone is transcribed
  3. The mRNA is translated by ribosomes on RER forming a pro-hormone
  4. The pro-hormone is processed by the Golgi body to form the active hormone.
  5. The active hormone is stored in a vesicle ready to be exocytosed when necessary
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13
Q

Describe the production and secretion of Adrenocorticotropic hormone (ACTH).

A
  • ACTH is produced by pituitary corticotroph cells
  • Translation of the mRNA makes Pro-opiomelanocortin (POMC)
  • POMC is transported to the Golgi body where proteolytic enzymes process it to generate mature active hormone ACTH
  • Mature ACTH is stored in secretory granules within the cell cytoplasm.
  • Released into the blood (capillaries) by exocytosis
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14
Q

What are the stages of steroid hormone synthesis, storage and secretion?

A
  • Low density lipoproteins (LDLs) are taken up by the cell from the blood
  • Cholesterol is broken down into esterified cholesterol and stored in cytoplasmic vacuoles
  • When stimulated, esterase breaks it down into cholesterol
  • A Steroidogenic Acute Regulatory Protein (StAR) controls the transfer of cholesterol from the outer to inner mitochondrial membrane
  • Inside the mitochondria a series of specific enzymatic reactions take place producing the steroid hormone
  • The steroid hormone is lipid soluble so can freely diffuse across the membrane into the blood immediately
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15
Q

Give an example of a steroid hormone and the cell that produces it.

A

Cortisol is produced by adrenal cortical cells.

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16
Q

How are protein/polypeptide and steroid hormones transported around the body?

A
  • Protein/polypeptide is soluble so travels easily in the blood
  • Steroid hormones aren’t lipid soluble so bind to plasma proteins
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17
Q

Explain the binding of steroid hormones and how they access tissues.

A

Hormone + Plasma Protein ⇔ Protein bound hormone

Any hormone bound to protein is biologically inactive.

An equilibrium is set up so that there is always enough free hormones in the blood which can access tissues.

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18
Q

What does the steroid hormone cortisol bind to in the blood?

A
  • Albumin with low affinity and high capacity
  • Binding Globulins (e.g. cortisol binding globulins CBG) with high affinity and low capacity
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19
Q

What happens if there is a decrease in steroid hormone (i.e. it’s taken up by cells)in the blood?

A
  • Equilibrium shifts to increase free hormone initially
  • Then endocrine cells synthesise and release more hormone
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20
Q

How would an increase in plasma protein affect steroid hormone production? Give an example

A
  • Equilibrium shifts so there is more protein bound hormone
  • Endocrine cell synthesises and releases more hormone

Example; during pregnancy CBG (cortisol binding globulin) increases, and therefore so does cortisol to ensure enough free hormones are available.

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21
Q

Describe the mechanism of action of the protein hormone ACTH.

A
  1. ACTH binds to the Gs-protein coupled receptor on adrenal cortical cells
  2. Leads to the dissociation of the α subunit of Gs protein from β, γ subunits
  3. Activates the adenylate cyclase enzyme which converts ATP to cAMP
  4. This binds to cAMP dependent protein kinases
  5. Activates cholesterol esterase and initiates steroid hormone synthesis
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22
Q

What factors affect the biological response of target cells?

A
  • Concentration of hormone in circulation
  • Concentration of number of receptors
  • Affinity of hormone-receptor interaction
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23
Q

What is the general mechanism for the action of protein hormones?

A

Peptide/protein hormone binds to its receptor on the cell surface and activates an effector system resulting in the generation of

  • Intracellular signal and secondary messenger effectors
  • Leads to change in membrane transport, DNA and RNA synthesis, protein synthesis and hormone release
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24
Q

Describe the mechanism of action of the steroid hormone cortisol?

A
  1. Free cortisol enters the cell by passive diffusion
  2. Binds to specific glucocorticoid (GC) receptors in cell cytoplasm
  3. This hormone-receptor complex travels to the nucleus and binds to specific DNA binding sites
  4. Leads to change in transcription rates of specific genes and production of mRNA
  5. Translation of mRNA to protein within ER
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25
Q

What is the negative feedback loop for Cortisol?

A
  • Increased production of ACTH
  • Causes increased cortisol production
  • Increased cortisol production inhibits ACTH production
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26
Q

Why is a feedback loop necessary?

A

To achieve homeostasis and regulate production so there is not excessive hormone production

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27
Q

Define the Negative feedback.

A

Negative feedback -the hormones produced by the peripheral target organ feeds back onto the organ that stimulates it to control its own function

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28
Q

Where is the hypophysis (pituitary gland)?

A

The pituitary gland lies at the base of the brain in the Sella Turcica directly underneath the Hypothalamus

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29
Q

What are the two parts of the hypophysis?

A
  • Anterior lobe/adenohypophysis - glandular
  • Posterior lobe/neurohypophysis - consists of mainly nerve axons and nerve terminals
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30
Q

Describe the development of the hypophysis.

A
  • Anterior lobe - ‘Grows up’ and attaches to the base of the brain
  • Posterior lobe - nervous tissue ‘grows down’ and attaches to the anterior lobe
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31
Q

What is the Region of median eminance?

A

The area between the hypothalamus and the pituitary gland.

One of few areas where there is no blood-brain barrier

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32
Q

Name these parts of the brain and pituitary. (Excluding 6, 8, 10)

A
  1. 3rd ventricle of the brain
  2. Optic chiasma
  3. Region of median eminence
  4. Neurohypophysis
  5. Adenohypophysis
  6. /
  7. Pars tuberalis
  8. /
  9. Pars distalis
  10. /
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33
Q

How do hypothalamic hormones reach their targets in the adenohypophysis?

A
  • The blood supply to the Region of Median Eminence is the Superior hypophysial artery
  • When hypothalamic nuclei are activated neurosecretions are released into the primary capillary plexus of the hypothalamo-hypophysial portal system
  • The neurosecretions travel through the long portal veins to reach the secondary capillary plexus
  • Here they act on the anterior pituitary target cells, which releases Adenohypophysial hormone into the Cavernous sinus and then into general circulation
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34
Q

What are the two types of neurones in Hypothalamus Nuclei?

A
  • Neurones that pass through the region of median eminence and end at the Neurohypophysis within the pituitary gland
  • Neurones that terminate at the region of median eminence
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35
Q

List the 6 Adenohypophysisal hormones released, and their relation to hypothalamic hormones

A
  • Somatrophin (growth hormone) stimulated by Somatotrophin releasing hormone and inhibited by Somatostatin (SS)
  • Prolactin stimulated by Thyrotrophin releasing hormone (TRH) and inhibited by dopamine
  • Thyrotrophin stimulated by Thyrotrophin releasing hormone
  • Luteinizing hormone (LH) and Follicle stimulating hormone (FSH) is stimulated by Gonadotrophin releasing hormone (GnRH) and inhibited by Gonadotrophin inhibitory hormone (GnIH)
  • Corticotrophin (ACTH) stimulated by Corticotrophin releasing homone (CRH) and Vasopressin (VP)
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36
Q

What are the 6 main adenohypophysial hormones and the cells that produce them?

A
  • Somatotrophs make Somatotrophin (growth hormone)
  • Lactotrophs make Prolactin
  • Thyrotrophs make Thyrotrophin (Thyrod stimulating hormone TSH)
  • Gonadotrophs make LH and FSH
  • Corticotrophs make Corticotrophin (Adrenocorticotrophic Hormone ACTH)
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37
Q

Describe the synthesis, storage and release of adenohypophysial hormones.

A
  1. Transcription and translation of DNA and RNA results in Pro-hormones
  2. Enzymatic cleavage of the Pro-hormone yields the bioactive hormone
  3. The hormone is stored in secretory granules
  4. When stimulated they are released by exocytosis
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38
Q

Under what classification can secretion of hormones of adenohypophysial cells be?

A
  • Paracrine
  • Autocrine
  • Endocrine
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39
Q

What is the size and makeup of the adenohypophysial hormones?

A
  • Proteins:
    • Somatotrophin - 191 amino acids
    • Prolactin - 199 amino acids
  • Glycoproteins: consist of α and β sub-units (92 amino acid α sub-unit common to all)
    • Thyrotrophin (thyroid stimulating hormone) - β sub-unit 110 amino acids
    • Gonadotrophins LH and FSH - β sub-unit 115 amino acids
  • Polypeptide:
    • Corticotrophin (ACTH) - 39 amino acids
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40
Q

What are the main target cells of Adenohypophysial hormones?

A
  • Somatotrophin - General body tissues, particularly liver
  • Prolactin - Breasts (Lactating women)
  • Thyrotrophin - Thyroid
  • Gonadotrophins (LH and FSH) - Testes (men), Ovaries (women)
  • Corticotrophin - Adrenal cortex
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41
Q

Why does Somatotrophin target the Liver?

A

On stimulation by Somatotrophin the Liver produces Somatomedins (Insulin-like growth factor - IGF 1 and IGF 2) which promote cell growth and division

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42
Q

What are the effects of Somatotrophin (direct and indirect)?

A
  • Stimulates amino acid transport into cells
  • Stimulates protein synthesis
  • Increases cartilaginous growth
  • Stimulates lipid metabolism leading to increased fatty acid production
  • Decreases glucose utilization (more increased resistance) and more gluconeogenesis resulting in increased blood glucose concentration
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43
Q

What inhibits and stimulates the production of Somatotrophin?

A

Inhibits:

  • Negative feedback
    • Somatotrophin inhibits GHRH
    • Somatomedins inhibits both Somatotrophin and GHRH

Stimulates:

  • Sleep (Stages III and IV)
  • Stress (acute)
  • Oestrogens
  • Exercise
  • Fasting (Hypoglycaemia)
  • Amino Acids
  • Ghrelin from stomach (secreted when hungry)
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44
Q

What are the effects of Prolactin?

A
  • Breast Lactogenesis in post-partum women
  • Increased number of LH receptors in Gonads
  • Effects immune system e.g. stimulates T cells
  • Renal Na+/water reabsorption
  • Steroidogenesis

In high circulating levels:

  • Decreased LH release from the pituitary gland
  • Decreased sexual behaviour (involves Hypothalamus)
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45
Q

How is the release of Prolactin controlled?

A

Controlled by the neuroendocrine reflex arc which is made of the Afferent neural pathway and Efferent endocrine pathway.

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46
Q

Describe the Efferent pathway with relation to Prolactin production including inhibitors and stimulators

A

Efferent Endocrine Pathway - Hormone pathway to a target tissues intiating change

  • Dopamine normally inhibits Prolactin
  • Oestrogens and Iodothyronines stimulate TRF and Prolactin
  • Thyrotrophin releasing hormone (TRF) stimulates Prolactin production
  • Prolactin stimulates milk production in the breast
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47
Q

Describe the Afferent Neural pathway in Prolactin production.

A

Suckling stimulates tactile receptors in the breast which through nerve impulses inhibits dopamine production in the hypthalamus. So more prolactin is made for the next feed.

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48
Q

Describe the negative feedback loop in the hypothalamo-adenohypophysial-thyroidal axis.

A
  • Neural stimulus - Cold, stress, fasting
  • Hypothalamus produces thyrotrophin releasing hormone (TRH) causes
  • The Anterior pituitary to make thyroid stimulating hormone (TSH) causes
  • The thyroid gland produces thyroid hormones (thyroxine, triiodothyrinine) causes
  • Effector cells increase metabolic rate, and cell growth and development
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49
Q

What are the principal physiological actions of Corticotrophin (ACTH), thyrotrophin (TSH), LH and FSH?

A
  • ACTH - Stimulates cortisol production in the cortext of the Adrenal gland
  • TSH - Stimulates thyroxine and triiodothyronine production by the thyroid
  • LH - Males: stimulates testosterone production, Females: stimulates oestrogen and progesterone production
  • FSH - Males and Females: Stimulates germ cell production, Females: Stimulates follicular development
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50
Q

Explain why hyperprolactinaemia is associated with a contraceptive effect on the reproductive system.

A

Hyperprolactinaemia is the presence of high levels of prolactin in the blood. This can cause loss of libido which has a contraceptive effect.

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51
Q

How does the neurohypophysial hormone system work?

A

Nerves in the hypothalamus which have their endings in then neurohypophysis produce hormones, and then it enters the blood in the posterior pituitary

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52
Q

Label these features of the neurohypophysial system

A
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53
Q

What are two cell types that originate in the hypothalamus and supply the pituitary?

A
  • Magnocellular - Originate in either the Supraoptic or Paraventricular nuclei and terminate in the neurohypophysis
  • Parvocellular - Originate in the Paraventric nuclei and terminate either in the Region of Median Eminence or in other parts of the brain. Supply the adenohypophysis
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54
Q

What are the hormone properties of Supraoptic and Paraventricular neurones?

A

Either Vasopressinergic or Ocytocinergic

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55
Q

Describe the synthesis of Vasopressin. What are the two differences in Oxytocin synthesis?

A
  1. Pre-provasopressin produced by transcription and translation
  2. Cleavage of the signal peptide
  3. Proteolytically cleaved into Vasopressin, Neurophysin and Copeptin (glycopeptide)

In Oxytocin production;

  • Different neurophysin (carrier from hypothalamus to posterior pituitary)
  • There is no glycopeptide
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56
Q

What is the name of the structure of Vasopressin and Oxytocin? How are they different?

A

Nonapeptides

Differ by two amino acids.

(3 and 8)

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57
Q

What is the principle physiological action of Vasopressin?

A

It has an Antidiuretic effect by stimulating water reabsorption in the Renal collecting ducts

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58
Q

What are the secondary effects of Vasopressin?

A
  • Vasoconstriction - Increases blood pressure
  • Corticotrophin release (with corticotrophin releasing hormone CRH)
  • CNS effects
  • Acts as a neurotransmitter (or hormone) affecting behaviour e.g. mating
  • Synthesis of blood clotting factors (VIII and Von Willbrandt factor)
  • Hepatic glycogenolysis
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59
Q

What are the different Vasopressing receptors and where are they found?

A

V1a:

  • Arterial/arteriolar smooth (vasoconctriction)
  • Hepatocyte (glycogenolysis)
  • CNS neurones (beahavioual and other effects)

V1b/V3:

  • Adenohypophysial corticotrophs (ACTH production)

V2:

  • Collecting duct cells (water reabsorption)
  • Other unidentified cells (e.g. endothelial - vasodilator?)
  • (Factor VIII and Von Willbrandt factor)
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60
Q

How do V1 receptors produce a cellular response?

A
  • Linked via G proteins to phospholipase C
  • Acts on membrane phospholipids to produce Inositol triphosphate IP3 (and diacyl glycerol, DAG)
  • Increases cytoplasmic [Ca2+] and other intracellular mediators
  • Produces cellular response
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61
Q

How do V2 receptors produce a cellular response?

A
  • Linked via G proteins to Adenyl cyclase
  • Acts on ATP to corm cyclic AMP
  • Activates protein kinase A (PKA)
  • Activates other intracellular mediators
  • Produces a cellular response (aquaporins (AQP))
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62
Q

What are the two receptors, stimuli and responses that lead to the production of Vasopressin?

A
  • Increased plasma osmolality is detected by osmoreceptors. Vasopressin is made causing an increase in water absorption
  • Decreased arterial blood pressue is detected by baroreceptors/volume receptors, Vasopressin is made causing an increase in vasocronstriction and therefore blood pressure
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63
Q

What are the actions of Oxytocin?

A
  • Release of oxytocin causes uterus to be at parturition (about to give birth)
  • Effects Myometrial cells (muscle in uterus)
  • Causes it to contract
  • Leads to delivery of baby
  • Release of oxytocin to the breast during lactation
  • Effects Myoepithelial cells
  • Causes it to contract
  • Leads to milk ejection
  • Central effects (e.g. behaviour)
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64
Q

Describe the Neuroendocrine reflex arc of Oxytocin

A
  • Stimulus: suckling
  • Receptors around nipple send impulse to hypothalamus
  • Oxytocin is produced in the hypothalamus and secreted by the posterior pituitary
  • Causes contraction and milk ejection in the breast
  • If stimulus stops (no suckling) then oxytocin and therefore milk ejection with stop
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65
Q

Name some clinical conditions associated with Vasopressin.

A
  • Diabetes Insipidus: causes polyuria (excess urine) and polydipsia (thirst)
    • Central - no vasopressin produced
    • Nephrogenic - tissue insensitivity
  • Syndrome of Inappropriate ADH (SIADH): when ADH is produced somewhere other than the neurohypophysis
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66
Q

Why is blood glucose concentration closely regulated? What are the hormones involved in controlling it?

A

Glucose is a very immportant energy substrate, particularly for the CNS so if it falls much lower than 4-5mM (hypoglycaemia) brain function is impaired and it can lead to a coma and ultimately death

Hormones: Insulin, Glucagon, Catecholamines (adrenalin), Somatotrophin and Cortisol

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67
Q

Describe the features of the Islets of Langerhans.

A
  • 2% of the pancreas is made up of the islets of Langerhans
  • Cells have many gap junctions allowing smal molecules to pass between them
  • Cells have tight junctions forming small intercellular spaces
  • Contain α, β and δ cells
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68
Q

What are the hormones produced by the cells of the islets of Langerhans? What are their main roles?

A
  • α cells produce Glucagon increases blood glucose
  • β cells produce Insulin decreases blood glucose and stimulates growth and developmentin utero and in children
  • δ cells produce Somatostatin inhibits both Insulin and Glucagon
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69
Q

Describe the synthesis of Insulin?

A
  • Transcription and translation of gene forms Pro-insulin; single amino acid chain joined by many disulphide bridges
  • Processed by β cell before release;
    • Cleaved at amino acid 64 and 32
    • Produces C-Peptide and α and β chains of insulin
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70
Q

Describe the mechanism of secretion of Insulin in β cells.

A
  1. Glucose enters the β cell through Glut 2 (glucose transporter)
  2. Glucose is converted to glucose-6-phosphate using enzyme Glucokinase/Hexokinase IV and enters the metabolic pathway
  3. ATP is made
  4. This stops the ATP sensitive K+ channel
  5. Due to change in potential, voltage dependent Ca2+ channels open
  6. This stimulates a release of preformed Insulin and synthesis of new insulin
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71
Q

What is the difference in reaction to oral and IV glucose?

A

The production of Insulin is greater for oral glucose than for IV.

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72
Q

What are the effects of Insulin?

A
  • Decrease Blood glucose
  • Increase Glycogenesis
  • Increased Glycolysis
  • Increased glucose transport into cells via GLUT4
  • Increased amino acid transport
  • Increased protein synthesis
  • Decreased Lipolysis
  • Increased Lipogenesis
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73
Q

What stimulates β cells to produce Insulin?

A
  • Increased blood glucose
  • α cells secrete glucagon
  • Certain gastrointestinal hormones
  • Certain amino acids
  • Parasympathetic nervous activity (β-receptors)
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74
Q

What inhibits β cells from producing Insulin?

A
  • Sympathetic nervous activity e.g. norepinephrine and epinephrine (α receptors)
  • Somatostatin
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75
Q

What stimulates α cells to release Glucagon?

A
  • Decreased blood glucose
  • Certain gastrointestinal hormones
  • Certain amino acids (Alanine and argenine)
  • Sympathetic activity e.g. epinephrine
  • Parasympathetic activity
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76
Q

What inhibits α cells from producing glucagon?

A
  • β cells secrete insulin
  • Somatostatin
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77
Q

What are the effects of Glucagon produced by α cells?

A
  • Increases blood glucose
  • Increased Hepatic Glycogenolysis
  • Increased amino acid transport into Liver → Increased Gluconeogenesis
  • Increased Lipolysis → Increased Gluconeogenesis
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78
Q

Describe the properties and function of Glucagon like peptide-1.

A
  • Gut hormone
  • Secreted in response to nutrients in the gut
  • Transcription product of Pro-glucagon gene mostly from L-cells in the intestines
  • Stimulates insulin, suppresses glucagon
  • Increases satiety
  • Short half life due to rapid degredation from Dipeptidyl peptidase-4
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79
Q

Describe the way that Insulin is secreted.

A

Secretion is Biphasic.

First phase: Stored insulin is released directly after a meal

Second phase: Newly synthesised insulin released over a couple of hours, and increases food storage

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80
Q

Decribe how Insulin induces a change in cells of the body.

A
  1. Insulin binds to the α-subunits of the insulin receptor
  2. Causes a conformational change
  3. Tyrosine kinase domains in the β-subunits phosphorylates cell protein substrates. Autophosphorylation and cross-phosphorylation of receptors occurs
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81
Q

List the actions of Insulin.

A
  • Glucose
    • Decrease Hepatic glucose output
    • Increase muscle intake of glucose
  • Protein
    • Decrease proteolysis
  • Lipid
    • Decrease lipolysis
    • Decrease ketogenesis
  • Growth
  • Vascular
  • Ovarian
  • Clotting
    • PAI-1
  • Energy Expenditure
    • relation to Leptin
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82
Q

Describe the features and functions of the GLUT-4 channel.

A
  • Found in the membranes of Muscle and Adipose cells
  • Insulin responsive
  • Lies in Vesicles
  • Recruited and enhances by Insulin
  • 7 times increase glucose uptake
  • Consists of a hydrophylic core and hydrophobic outer layer
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83
Q

What is the relationship between Insulin and proetiens?

A
  • Insulin (growth hormone and IGF1) increases protein synthesis
  • Insulin decreases proteolysis (cortisol increases it)
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84
Q

Decribe the process of gluconeogenesis and the hormones involved.

A

Gluconeogenesis is the synthesis of glucose from non carbohydrate carbon substrates.

  1. Pyruvate, lactate or gluconeogenic amino acids are taken up into the liver or kidney. Stimulated by GLUCAGON.
  2. Proteolysis is stimulated by protein deficiency and glucagon. Inhibited by Insulin.
  3. Gluconeogenesis is stimulated by glucagon, catecholamines (e.g. epinephrine) and Cortisol. Inhibited by Insulin.
  4. This results in increased hepatic glucose output into the blood and increased blood glucose.
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85
Q

What are the processes that happen in fat metabolism and what are the hormones that effect them?

A
  • Insulin and Lipoprotein Lipase causes the breakdown of triglycerides into glycerol and non-esterified fatty acids
  • Insulin stimulates the uptake of glucose into adipose tissue via GLUT-4 transporter
  • In adipose tissue glucose
    • stimulates the formation of triglycerides from glycerol-3-phosphate and non-esterified fatty acids
    • inhibits the breakdown of triglycerides
  • Catecholamines, cortisol and growth hormone stimulates the breakdown of triglycerides and release of glycerol and non-esterified fatty acids
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86
Q

What are the different fuel stores and their properties?

A
  • Carbohydrates
    • Liver and muscle cells: glycogen to glucose
    • Short term source - 16 houts
  • Protein
    • Longer term - 15 days
  • Fat
    • Highest enery released per gram
    • 30-40 days
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87
Q

Describe omental circulation. Why is gut fat important?

A
  • Circulates from the
    • Heart to
    • Gastrointestinal tract to
    • Liver back to heart
  • Adipocytes in GI tract are highly metabolically active
  • Increased number of adipocytes in the GI tract leads to an increased risk of ischaemic heart disease and death
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88
Q

If a person fasts for 10 hours what happens in the liver?

A
  • Gluconeogenesis
  • Glycerol is taken up into the hepatocytes
  • Forms Glycerol-3-phosphate
  • Glycerol-3-phosphate can be readily interconverted to triglycerides
  • Glycerol-3-phosphate is converted to glucose
  • Glucose is released by the hepatic glucose output
  • Accounts for 25% of glucose output when fasting
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89
Q

What does the brain use as an energy source?

A

Can use glucose or ketone bodies.

Not fatty acids.

(Lipolytic enzymes aren’t present)

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90
Q

How are ketone bodies produced?

A
  • Non-esterified fatty acids are taken up by hepatocytes and converted to fatty acyl CoA
  • Fatty acyl CoA is then converted to
    • Acetyl CoA → Acetoacetate → Acetone and 3 Hydroxybutarate
  • Released as ketone bodies

Process is stimulated by Glucagon and inhibited by Insulin

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91
Q

What is an indication of Insulin deficiency?

A
  • Ketones present in the urine AND elevated glucose
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92
Q

Outline Hepatic glycogenesis and glycogenolysis.

A
  • Glucose taken up by the liver is converted to glucose-6-phosphate and stored as glycogen.
  • Insulin stimulates conversion of glucose-6-phosphate into glycogen
  • Glucagon and catecholamines inhibit this but stimulate the reverse
  • Glucose-6-phosphate can be re-converted into glucose released via hepatic glucose output to increase blood glucose levels
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93
Q

What do muscle cells use as an energy source? What hormones are related to uptake?

A
  • Fatty acids are taken up and converted to acetyl CoA (which enters Krebs cycle)
  • Glucose is taken up
    • Via GLUT-4
    • Stimulated by Insulin
    • Inhibited by growth hormones, catecholamines and cortisol
  • Glucose is either stored as glycogen or converted to acetyl-CoA
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94
Q

What changes takes place in the Fasted state?

A
  • Low insulin to glucagon ratio
  • [glucose] 3.0 - 5.5mmol/L
  • [Non-esterified fatty acids] increases
  • [amino acid] decreases when prolonged
  • Increased proteolysis
  • Increased Lipolysis
  • Increased hepatic glucose output from glycogenolysis and gluconeogenesis
  • Muscle uses lipids (fatty acids)
  • Brain uses glucose, and later ketones
  • Increases Ketogenesis when prolonged
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95
Q

What changes take place in the Fed state?

A
  • Stored Insulin released, then 2nd phase of synthesised Insulin
  • High [Insulin} to [Glucagon] ratio
  • Stop Hepatic glucose output
  • Increased Glycogen
  • Decreased Gluconeogenesis
  • Increased Protein synthesis
  • Decreased Proteolysis
  • Increased Lipogenesis
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96
Q

What are the two types of Diabetes Mellitus?

A
  • Type-1 Diabetes: Insulin deficiency
    • Presents with: weight loss due to proteolysis, Hyperglycaemia, Glycosuria with osmotic symptoms (e.g. thirst and polyuria), Ketonuria
  • Type-2 Diabetes: Insulin resistant
    • Presents with: Hypertension (BP>135/80), Large waist circumference (men>102, women>8), Fasting glucose >6.0mmol/L, High [triglyceride] low [HDL} (heart disease), Increased Adipocytokines
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97
Q

Explain Insulin induced hypoglycaemia.

A

Treatment induced complication - i.e. Type-1 diabetic who has injected too much insulin

  • Increased glucose uptake into muscle SO low blood glucose concentration
  • Causes increased levels of glucagon → Increased hepatic glucose output due to glycogenolysis, gluconeogenesis and increased lipolysis → increased blood glucose
  • Catecholamines, cortisol and growth hormones increase too
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98
Q

Where is the Insulin restistance in Type-2 Diabetes?

A

Liver, muscle and adipose tissue.

BUT there’s enough Insulin to suppress Ketogenesis and Proteolysis.

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99
Q

What are the two pathways initiated by the binding of Insulin to its receptor? What do the pathways cause?

A
  • MAPK Pathway
    • Shc on receptor stimulated, leads to ras activating the MAPK pathway
    • Stimulates growth and proliferation.
  • ​PI3K-Akt Pathway
    • ​IRS (Insulin receptor substrate) initiates the pathway
    • Stimulate metabolic actions, involved in lipid, protein and glycogen synthesis
100
Q

What is the effect of Insulin resistance on the pathways stimulated by Insulin?

A

Insulin resitance leads to compensatory hyperinsulinaemia (high [insulin]).

Insulin resistance inhibits the Pi3K-Akt pathway, and increases the MAPK pathway.

  • Increased lipoproteins
  • Smooth muscle hypertrophy
  • Interferes with ovarian function
  • Increased clotting risk
  • Decreased energy expenditure
101
Q

What is the diet recommended for poeple with diabetes?

A
  • Total calories control
  • Reduce calories as fat
  • Reduce calories as refined carbohydrates
  • Increased calories as complex carbohydrates
  • Increased soluble fibre
  • Decreased sodium
102
Q

Label the parts of the Thyroid.

A
103
Q

Label the cells in the thyroid.

A
104
Q

List the main hormones produced by the follicular and parafollicular cells of the thyroid.

A
  • Follicular cells produce THYROXINE and TRIIODOTHYRININE
  • Parafollicular cells produce CALCITONIN
105
Q

Describe the steps of the synthesis and secretion of iodothyronine.

A
  1. Iodide is taken up into the follicular cell by co-transport with Na+ and transported to the Colloid
  2. Thyrotrophin/Thyroid stimulating hormone stimulates the nucleus to synthesise thyroglobulin
  3. Thyroglobulin moves into the colloid and stimulates thyroidal peroxidase to convert Iodine into reactive iodine (Iodination)
  4. Iodine reacts with tyrosyl residues in thyroglobulin forming Di-iodyltyrosyl (DIT) and monoiodotyrosyl (MIT)
  5. Thyroidal peroxidase then catalyses the coupling of DIT and MIT forming T3 (3,5,5-triiodothyronine) and T4 (3,5,3,5-tetraiodothyronine) which are attached to the thyroglobulin
  6. T3 and T4 is taken up by lysosomes (endocytosis) where the thyroglobulin in broken down and T3 and T4 is secreted into the bloodstream
106
Q

What are the two hormones released by the follicular cells of the thyroid?

A

3,5,3’-tri-iodothyronine T3

3,5,3’,5’-tetra-iodothyronine T4 or Thyroxine

107
Q

What are the three proteins that can transport Iodothyronines?

A

Thyroxine/Thyroid-binding globulin (TBG)

Albumin

Prealbumin/Transthyretin

108
Q

To which protein do Iodothyronines bind to the most?

A

Thyroxine/thyroid-binding globulin (TBG)

T4 - 70%

T3 - 80%

109
Q

What are the Latent periods of each Iodothyronine?

A

T3 - 12 hours

T4 - 72 hours

110
Q

What are the Biological half-lives of the Iodothyronines?

A

T3 - 2 days

T4 - 7-9 days

111
Q

What is the main hormone produced by the thyroid?

A

T4/Thyroxine

112
Q

Which is the most bioactive Iodothyronine? How do other cells use this?

A
  • T3 is the most bioactive
  • T4 is deiodinated to T3 in target tissues

Can also be deiodinated in a different position to produce the biologically inactive molecule reverse T3 (rT3)

113
Q

What are the physiological effects of Iodothyronines?

A
  • Increases basal metabolic rate - in most peripheral tissues (except brain) resulting in calorigenesis (secondary increase in heat)
  • Increase protein, carbohydrate and fat metabolism - important for growth and development (especially in fetal growth, lack of iodothyronines can result in Cretinism)
  • Potentiate (increase) some actions of Catecholamines (e.g. tachycardia, glycogenolysis, lipolysis)
  • Interact with other endocrine systems (e.g. oestrogen)
  • Have an effect on the CNS
  • Increase Vitamin A (and retinal) synthesis
114
Q

What are the possible mechanisms of action of Iodothyrinines?

A
  • Enters cell (T4 deiodinated to T3)
  • Binds to (iodo) thyronine receptor
    • on mitochondria - Stimulates metabolic activity, increased ATP production
    • on nucleus - Increases protein synthesis, acts as a transcription factor and increases rate of transcription etc
115
Q

List all of the hormones involved in the hormone production in the thyroid.

A

Hypothalamus - Thyrotrophin releasing hormone

Anterior pituitary - Thyrotrophin/thyroid stimulating hormone

Thyroid gland - Iodothyronines (T3 and T4)

116
Q

What is involved in the feedback loop of Iodithyronine production?

A

Indirect -ve: affects hypothalamus

  • T4 and T3 inhibit production of Thyrotrophin releasing hormone

Direct -ve: affects adenohypophysis

  • T4 and T3 inhibit production of Thyrotrophin
  • Somatostatin inhibits Thyrotrophin

Auto -ve: affects hypothalamus

  • Thyrothrophin inhibits thyrotrophin releasing hormone

Other - Inorganic iodide presence inhibits iodothyronine production

117
Q

What is thyrostimulin?

A

2-unit glycoprotein found in the anterior pituitary (and other tissues) which binds to thryotrophin receptors. May act as a paracrine regulator.

118
Q

Where is the adrenal gland?

A

The two adrenal glands are situated in the abdomen, above the kidney and below the diaphragm.

119
Q

Label the parts of the Adrenal gland.

A
120
Q

What are the two types of hormones produced by the the adrenal gland? Where are they produced?

A

CATECHOLAMINES are produced by the Medulla

CORTICOSTEROIDS are produced by the Cortex

121
Q

What are the two ways that blood is transported through the different cortical zones to the medulla?

A
  • Blood perfuses through cells till it reaches the Tributary of Central vein in the centre of the medulla
  • Through clearly defined Arterioles it flows from the outer capsule to the medulla
122
Q

What makes up the Adrenal Cortex?

A

Zona Glomerulosa

Zona Fasciculata

Zona Reticularis

123
Q

What type of cells is the Adrenal Medulla made up of?

A

Chromaffin Cells

124
Q

What proportions of hormones does the Adrenal Medulla produce?

A

Produces Cetecholamines:

Adrenaline 80%

Noradrenaline 20%

Dompamine (small)

125
Q

What are the three types of Corticosteroids produced by the Adrenal Cortex?

A
  • Mineralocorticoids e.g. Aldosterone (Zona Glomerulosa only)
  • Glucocorticoids e.g. Cortisol
  • Sex steroids e.g. Androgens, Oestrogens
126
Q

What is the molecule used to make all of the Corticoids in the Adrenal gland, and the hormones in the Gonads?

A

Cholseterol

127
Q

What are the intermediates in the synthesis of Aldosterone?

A
  1. Cholesterol
  2. Pregnenolone
  3. Progesterone
  4. Deoxyxcorticosterone
  5. Corticosterone
  6. Aldesterone
128
Q

What are the intermediates of synthesis of Cortisol?

A
  1. Cholesterol
  2. Pregnenolone → 17α-hydroxypregnenolone → 17α-hydroxyprogesterone
  3. OR Pregnenolone → Progesterone → 17α-hydroxyprogesterone
  4. 11β-deoxycortisol
  5. Cortisol
129
Q

What are the intermediates in the synthesis of Androgens?

A
  1. Cholesterol
  2. Pregnenolone
  3. 17α-hydroxypregnenolone → dehydroepiandrosterone → androstenedione
  4. OR Pregnenolone → 17α-hydroxypregnenolone → 17α-hydroxyprogesterone → androstenedione
  5. OR Pregnenolone → Progesterone → 17α-hydroxyprogesterone → androstenedione
  6. androstenedione → Androgens (in peripheral tissues)
130
Q

How is Cortisol transported in the blood?

A

75% bound to Cortisol/Corticosteroid binding globulin (CBG or Transcortin)

15% bound to Albumin

10% free (bioactive)

131
Q

How is Aldosterone transported in the blood?

A

60% bound to cortisol binding globulin

40% free (bioactive)

132
Q

What is the difference between Cortisol and Aldosterone concentrations?

A

MUCH smaller concentrations of Aldosterone

Cortisol: 80-690 nmol/L

Aldosterone: 140-560 pmol/L

133
Q

Summarise the actions of Aldosterone.

A
  • Stimulates Na+ reabsorption in distal convoluted tubule and cortical collecting duct (and sweat glands, gastric glands and colon)
  • Stimulates K+ and H+ secretion in distal convoluted tubule and cortical collecting duct
134
Q

What is the mechanism of action of Aldosterone on cells in the distal convoluted tubule?

A
  1. Aldosterone in the blood enters the cell (lipid soluble)
  2. Binds to an intracellular receptor (mineralocorticoid), and enters the nucleus
  3. The receptor-hormone complex is transported into the nucleus, where it binds to specific DNA
  4. This activates transcription, translation and synthesis of specific proteins
  5. The proteins produced either act as:
    • ION CHANNELS: in the apical membrane. Allows Na+ to be reabsorbed into the distal convoluted tubule, and K+ and H+ to be removed through the basolateral
    • ION PUMPS/ENZYMES: in the basolateral membrane. Pumps Na+ into the blood from the distal convoluted tubule
135
Q

Label the Juxtaglomerular Apparatus.

A
136
Q

What cells produce Renin?

A

Juxtaglomerular cells in the Kidney

137
Q

What stimulates the production of Renin?

A
  • Decreased renal perfusion pressure (normally associated with decreased arteriole blood pressure)
  • Increased renal sympathetic activity (direct to juxtaglomerula cells)
  • Decreased Na+ load to the top of the loop of Henle (macula densa cells detect this)
138
Q

Describe the Renin-Angiotensin-Aldosterone system.

A
  1. When stimulated juxtaglomerular cells produce Renin
  2. Renin activates Angiotensinogen which is always circulating (produced by liver) into Angiotensin I by cleaving it
  3. Angiotensin converting enzyme (ACE) produced by the lungs cleaves Angiotensin I further producing Angiotensin II
  4. Angiotensin II stimulated the Zona glomerulaosa in the adrenal cortex to produce Aldosterone which increases Na+ uptake in the kidneys and increases output of K+ and H+ (increases blood pressure)
  5. Angiotensin II causes vasoconstricton of the arteries (increases blood pressure)
139
Q

What stimulates the production of Aldosterone?

A

Renin-Angiotensin-Aldosterone system (Low Na+, dehydration = low blood pressure)

Increased K+ in extracellular fluid

Corticotrophin

140
Q

What are the metabolic effects of the physiological actions of Cortisol in a normal stress response?

A

Metabolic effects:

  • Peripheral protein catabolism (break down)
  • Hepatic gluconeogenesis
  • Fat metabolism (lipolysis in adipose tissue)
  • Increased blood [glucose]
  • Enhanced effects of Glucagon and catecholamines
141
Q

What are the other physiological actions of Cortisol in the normal stress response? (I.e. not metabolic)

A
  • Effect on mineralocorticoid (stimulates Aldosterone production)
  • Renal and Cardiovascular effects e.g. excretion of water load, increased vascular permeability
  • Other effects e.g. on bone, CNS, growth etc
142
Q

What are the pharmacological uses of large amounts of Cortisol?

A
  • Anti-inflammatory action
  • Immunosuppressive action
  • Anti-allergic action

These processes involve decreased production of molecules such as prostaglandins, leukotrienes, histamine etc. Affects the movement and function of leukocytes and the production of interleukins.

143
Q

What are the fates of Corticosteroids?

A
  • Bind to Glucocorticoid receptor (GR)
  • Bind to Aldosterone receptor (MR)
  • Inactivated by 11β-hydroxysteroid
144
Q

What is the mechanism of action of Cortisol?

A
  1. Cortisol diffuses into the cell and binds to the receptor
  2. The complex translocates to the nuceus where it binds to specific DNA and initiate transcription and translation
  3. The new proteins then go on to perform a function: e.g. production of Annexin 1 which is secreted and then acts on the same cell and neighbouring cells, binding to the Annexin 1 receptor. This stimulates the production of Arachidonic acid in the cell which inhibits Prostaglandin syntheis. (inhibit inflammation)
145
Q

How is ACTH produced?

A
  • POMC is a precursor molecule
  • Formed in the Anterior pituitary
  • POMC is cleaved to produce Pro-ACTH, then cleaved again making Pro-γ-MSH and ACTH
146
Q

Describe the Negative feedback of Cortisol.

A
  • Corticotrophin (ACTH) stimulates cortisol production, but INHIBITS Corticotrophin releasing hormone (CRH) by the hypothalamus
  • Cortisol inhibits Corticotrophin (ACTH) directly and indirectly by inhibiting Corticotrophin releasing hormone (CRH)

CIRCADIAN Rhythm controls the release of Cortisol.

147
Q

How does Circadian Rhythm affect Cortisol?

A

At night (20:00 - 08:00) ACTH and Cortisol levels are higher than during the day

148
Q

What is Dehydroepiandrosterone (DHEA)? What is its importance?

A
  • Precursor for androgens and oestrogens which are converted to active hormones by the target cells (which have the optimum enzymes)
  • Serum levels peak at 20-30 years, then decrease steadily with age
  • Important in postmenopausal women as a precursor for oestrogen and androgen synthesis by target tissues, in the absence of ovarian steroids
149
Q

What is the origin of the Thyroid gland?

A
  • The back/base of the tongue
  • Migrates downward forming the thyroglossal duct
  • Disappears leaving the foramen caecum (dimple in tongue)
150
Q

What is the weight of the adult thyroid weight?

A

20g

151
Q

How many lobes are there in the thyroid? Which one is the largest? What are the glands found embedded in the thyroid?

A
  • 4 lobes
  • Right lobe, Left lobe, Isthmus and Pyrimidal lobe
  • Parathyroid glands
152
Q

What nerve runs close to the thyroid gland?

A

Left recurrent laryngeal nerve which supplies the vocal cord (larynx)

Damage (e.g. in surgery) can result in a change in the voice or difficulty talking

153
Q

List three problems that can occur with the development of the thyroid.

A
  • Agenesis - Complete absence of the thyroid gland
  • Lingual Thyroid - Incomplete Descent i.e. it’s betwen the base of the tongue and trachea
  • Thyroglossal cyst - Segment of the thyroglossal duct remains, persists and presents as a lump years later
154
Q

What is the result of a thyroxine deficiency during development? What is the current procedure in detecting this?

A

Thyroxine is ESSENTIAL for normal brain development.

There is irreversible brain damage resulting in ‘Cretinism’.

  • Prevention - Heel prick test measuring Thyroid stimulating hormone at 5-10 days
  • If high, thyroxine is given immediately
  • If given early enough Cretinism can be prevented
155
Q

What is the site of thyroxine synthesis?

A

Thyroid follicular cells

156
Q

Generally speaking, what are the functions of the thyroid hormones?

A

Regulate:

Growth

Development

Metabolic rate

157
Q

What is the prevalence of thyroid disease?

A
  • Affects 5% of the population
  • Female:Male ratio = 4:1 (more common in females)
  • Overactive : Underactive = 1:1
158
Q

What is Primary Hypothyroidism? What are the indicators for it?

A

Thyroxine deficiency caused by autoimmune damage to the thyroid (or operation)

Indicators - Thyroxine levels low, Thyroid stimulating hormone high

159
Q

What are the features of Primary Hypothyroidism?

A
  • Deepening voice
  • Depression and tiredness
  • Cold intolerance
  • Weight gain with reduced appetite
  • Constipation
  • Bracycardia
  • Eventual myxoedema coma
160
Q

What happens if hypothyroidism is not treated?

A

Death is likely if untreated.

Their quality of life (and performance) will be poor.

Cholesterol increases - increased risk of heart attacks and strokes

161
Q

What is the treatment for Hypothyroidism?

A

Replace thyroxine with a tablet.

Monitor the thyroid stimulating hormone and adjust dose until TSH is normal.

162
Q

What is Hyperthyroidism/thyrotoxicosis? What is the indicator of it?

A

Over production of thyroxine.

Indicator - Thyroid stimulating hormone falls to zero

163
Q

What are the effects of an overactive thyroid gland?

A

Too much thyroxine means -

  • Raised basal metabolic rate
  • Raised temperature
  • Burn up calories (lose weight)
  • Increased heart rate
  • Every cell in the body speeds up
164
Q

What are the features of Hyperthyroidism?

A
  • Myopathy (muscle weakness)
  • Mood swings
  • Heat intolerance
  • Diarrhoea
  • Increased appetite but weight loss
  • Tremor of hands
  • Palpitations (noticible heart beat)
  • Sore eyes, goitre
165
Q

What is the main cause of Hyperthyroidism?

A

Graves’ disease -

An autoimmune disease where antibodies bind to and stimulate the thyroid stimulating hormone receptor in the thyroid. It increase thyroxine levels and causes the whole gland to be smoothly enlarged.

166
Q

What are two specific symptoms of Graves’ disease and how are they caused?

A
  • Exophthalmos (protrusion of the eye/eyeball) caused by antibodies binding to muscles behind the eye
  • Pretibial Myxoedema (hypertrophy (growth) of the shins) caused by the stimulation of antibodies. Swelling of shins, but non-pitting.
167
Q

What are the gonads?

A

Develops as the Testes in Males

Develops as the Ovaries in Females

168
Q

What are the functions of the Gonads?

A
  • Production of Gametes for reproduction (gametogenesis)
    • In Males - Spermatogenesis (production of male spermatozoa)
    • In Females - Oogenesis (production of ripe ova)
  • Production of Steroid hormones (steroidogenesis)
    • In Males - Androgens (and oestrogens, progestogens)
    • In Females - Oestrogens, Progestogens (and Androgens)
169
Q

Decribe the pattern of the activation of germ cells from birth onwards.

A

In both Males and Females the number of activated germ cells is very high before birth ( ~ 6x106)

  • In Males - the levels of Spermatogonia stays roughly the same after birth and through life
  • In Females - the levels of Oogonia decrease drastically before birth, and again before puberty. It continues to fall until it reaches 0 at menopause (around 50)
170
Q

Describe the process of Spermatogenesis.

A
  • Diplod Germ cell (44 chromosomes + XY)
    • Activates to become
  • Spermatogonia (44 chromosomes + XY)
    • Undergoes mitotic division
  • Primary Spermatocytes (44 chromosomes + XY)
    • Undergo first meiotic division at puberty
  • Secondary Spermatocytes (22X or 22Y)
    • Second Meiotic division
  • Spermatids (22X or 22Y)
    • Undergo maturation (spermiogenesis)
  • Spermatozoa
171
Q

Describe the production of Gametes in Males.

A
  • Gametogenesis begins at puberty
  • Spermatogonia undergo either differentiation or self-renewal
  • A constant pool of spermatogonia remains available for subsequent spermatogenic cycles throughout life
  • Therefore males retain some spermatogenic capability throughout life producing 300-600 sperm/gm testis/second
172
Q

Describe the process of Oogenesis.

A
  • Germ cell (44 chromosomes + XX)
  • Oogonia (44 chromosomes + XX)
    • Mitotic division
  • Primary Oocytes (44 chromosomes + XX)
    • First Meiotic division - halted at prophase till puberty
  • Secondary Oocytes (22X and 22X in first polar body)
    • Second meiotic division
  • Ovum (22X and 22X in second polar body)
173
Q

Describe the production of Gametes in Females.

A
  • Initial number of Oogonia in primordial follicles (in fetus) is about 6 million, all halted in prophase of Meiosis
  • These primordial follicules are arrested in development and enter process of atresia (degredation)
  • By birth there is approx. 2 million left, and at puberty approx. 0.5 million
174
Q

Label the parts of the Testes

A
175
Q

Label the cross section of the Seminiferous Tubule.

A
176
Q

What are the differences between Sertoli and Leydig cells?

A
  • Sertoli - form seminiferous tubules. Leydig - lie outside seminiferous tubules
  • Sertoli - synthisise FSH and androgen receptors. Leydig - synthesise LH receptors
  • Sertoli - in response to FSH produce various molecules including inhibin. Leydig - in response to LH are the principle source of testicular androgens (mainly testosterone)
  • Sertoli - intimately associated with developing spermatocytes etc.
177
Q

Label the parts of Graffian follicle.

A
178
Q

What are the different stages of follicles found in the ovaries?

A
  • Follicles undergoing atresia (degeneration)
  • Graffian follicle
  • Remnants of last Corpus luteum
179
Q

What are the hormones produced from cholesterol?

A

Adrenals;

  • Mineralocorticoids
  • Glucocorticoids
  • Androgens

Gonads;

  • Progestogens
  • Androgens
  • Oestrogens
180
Q

Outline the the reactions that produce Dihydrotestosterone and 17β-Oestradiol.

A

Adrenals and Gonads:

Cholesterol → Pregnenolone → Progesterone → 17-OH Progesterone → Androstenedione →

Gonads normally:

→ Testosterone → Dihydrotestosterone

OR

→ Testosterone → Oestrone → 17β-Oestradiol

181
Q

What is the Menstrual cycle?

A
  • Approximately 28 days (can be 20 to 35+)
  • Day 1 is first day of menstruation
  • Ovulation at day 14
182
Q

Define Menstruation.

A

Loss of blood and cellular debris from necrotic uterine epithelium.

183
Q

What does the menstrual cycle consist of?

A

Ovarian cycle: Ovary

Follicular Phase

(Ovulation)

Luteal Phase

Endometrial Cycle: Uterus

Proliferative Phase

-

Secretory Phase

184
Q

How does the Ovarian cycle effect the endrometrial cycle?

A

In the follicular phase Oestrogen (17β-Oestradiol) stimulates the Proliferative phase.

In the Luteal phase Progesterone and 17β-Oestradiol stimulates the Secretory Phase.

185
Q

Describe the patterns of LH, FSH, 17β-Oestradiol and Progesterone in a typical mentrual cycle. What happens to the basal temperature?

A
  • LH and FSH decreases leading to day 14 due to negative feedback from oestrogen. Then increases and peaks at ovulation before decreasing due to negative feedback from progesterone
  • 17β-Oestradiol slowly increases and peaks just before ovulation. It then decreases rapidly before increasing again around day 20
  • Progesterone remains low increasing slightly before ovulation and then rapidly increasing after ovulation
  • Basal temperature increases after ovulation
186
Q

What are the development stages of the follicle? How do they progress?

A

FSH binds to FSH receptors on Granulosa cells, stimulating it to get bigger and become an antral follicle, then Graffian follicle. The dominant follicle continues development, but others undergo atresia.

A surge in LH causes the follicle to rupture and the egg to be released.

187
Q

Describe how Gonadotrophin hormones and cells in the ovaries interact.

A

Thecal cells - LH receptors (when activated) will stimulate steroid hormone synthesis of Androgens. (But they do not have the aromatase enzyme)

Granulosa cells - FSH receptors (when activated) will stimulate the activity of Aromatase to convert androgens to 17β-Oestradiol and Progesterone.

188
Q

What are the dominant hormones in the Endometrial cycle?

A
  • Proliferative Phase - dominant oestrogen influence
  • Secretory Phase - dominant progesterone influence (plus oestrogen)
189
Q

Describe the properties of the endometrium and glands in the Proliferative phase of the endometrial cycle.

A

Endometrium - Thin in early phase.

Thickens (due to mitosis) in late phase

Glands - Straight in early phase.

Enlarged, coil; Increased blood supply in late phase

190
Q

Describe the properties of the endometrium and glands in the Secretory phase of the endometrial cycle.

A

Endometrium - Becomes secretory

Day 1 - Becomes necrotic and is shed

Glands - Secrete (glycogen, mucopolysaccharide, etc); mucosa engorged with blood

191
Q

What are the two fates of testosterone? Where do the occur?

A

Reduction (5a-reductase) to the the more potent androgen (but same receptors) Dihydrotestosterone (DHT). Occurs in the prostate, testes, seminal vesicles, skin, brain and adenohypophysis.

Aromatisation (aromatase) to oestrogen e.g. 17β-Oestradiol. Occurs in the adrenals, testes, liver, skin and brain.

192
Q

How are testosterone and DHT transported?

A

In blood: (mainly)

Sex hormone binding globulin (SHBG) 60%

Albumin 38%

Free 2% (BIOACTIVE)

Seminiferous fluid:

Androgen binding globulin (ABG)

193
Q

What are the principal actions of Androgens in a Fetus?

A
  • Development of male internal and external genitalia
  • General growth (acting with other hormones)
  • Behavioural effects (development)
194
Q

What are the principle actions of Androgens in Adults?

A
  • Spermatogenesis
  • Growth and development of
    • Male genitalia
    • Secondary (accessory) sex glands
    • Secondary sex characteristics
  • Protein anabolism
  • Pubertal growth spurt (with GH)
  • Behavioural (CNS) effects
  • Feebback regulation

Note - some of these effects are mediated by conversion to oestrogen

195
Q

Define Oestrogens. Give examples.

A

Any substance (natural or synthetic) which induced mitosis in the endometrium.

17β-Oestradiol (main one during menstrual cycle, mot potent)

Ostrone (precursor)

Oestriol (main one during pregnancy)

196
Q

What are the principle actions of Oestrogens?

A
  • Stimulate proliferation (mitosis) of the endometrium
  • Final maturation of follicle during follicular phase of menstruation
  • Positive feedback on LH resulting in ovulation
  • Effects on vagina and cervix
  • Stimulates growth of ductile system of breast
  • Decreases sebaceous gland secretion
  • Increases salt (and water) reabsorption
  • Increases plasma protein synthesis (hepatic effect)
  • Metabolic actions (e.g. on lipids)
  • Stimulates osteoblasts
  • Influences release of other hormones (e.g. prolactin, thyrotrophin)
  • Behavioural effects
  • Feedback regulation (negative and positive)
197
Q

Define Progestogens. Give examples.

A

Any substance (natural or synthetic) which induces secretory changes in the endometrium.

E.g. Progesterones,

17α-hydroxyprogesterone

198
Q

What are the principal actions of Progesterones?

A
  • Stimulates secretory activity in endometrium and cervix
  • Stimulates growth of alveolar system in breast
  • Decreases renal NaCl re-absorption (competitive inhibition of aldosterone)
  • Associated with increase in basal body temperature
  • Negative feedback regulation
199
Q

What is the general mechanism of action of steroid hormones?

A
  1. Hormone diffuses into the cell
  2. Binds to an intracellular receptor
  3. Enters the nucleus
  4. Binds to the DNA
  5. Stimulates transcription and translation of mRNA and synthesis of new proteins
  6. These proteins will have further actions
200
Q

Outline the Hypothalamo-pituitary-testicular axis.

A

Gonadotrophin releasing hormone release is pulsatile so inhibitio would slow the pulse generator.

High levels of Testosterone cause virilisation (development of male characteristics in females).

201
Q

Outline the hypothalamo-pituitary-ovarian axis during the early follilcular phase.

A

Low Oestrogen and Progesterone levels (i.e. no negative feedback) = increase in Gonadotrophin pulses and so increase in LH and FSH

Increase in LH and FSH causes a number of follicles to begin developing.

Small rise in 17β-oestradiol

202
Q

Outline the hypothalamo-pituitary-ovarian axis during the Early-mid follicular phase.

A

Local positive feedback loop in the developing follicles in the ovary enhances oestradiol production. 17β-oestradiol binds to oestrogen receptors in the same cell and stimulate aromatase more, as well as cell proliferation (more cells means more oestrogen). This is AUTOCRINE

203
Q

Outline the hypothalamo-pituitary-ovarian axis in the mid-follicular phase.

A

Selective negative feedback loop by oestrogen and inhibin on the GnRH-FSH system results in atresia (regression) of all follicles that are still FSH dependent. The Graafian follicle survives. Oestrogen levels increase.

The rising concentration of 17β-oestradiol in the absence of progesterone, for a minimum of 36hrs at a certain level results in the positive feedback swith on the hypothalamo-adenohypophysial system.

204
Q

Outline the hypothalamo-pituitary-ovarian axis during the Late follicular phase.

A

The positive feedback loop of Oestradiol triggers an LH surge (and a smaller FSH surge).

205
Q

Outline the hypothalamo-pituitary-ovarian axis during the Luteal phase.

A

If fertilization does not occur - progesterone, oestradiol and inhibin exert a negative feedback on LH and FSH release. leading to luteolysis (degredation of corpum luteus) and mentruation.

206
Q

Define Amenorrhoea.

A

Absence of menstrual cycles

  • Primary - Never happened
  • Secondary - Happened but stopped (may be physiological, e.g. pregnancy)
207
Q

Define Oligomenorrhoea.

A

Infrequent cycles - has various causes but can be due to absence of LH surge (e.g. due to insufficient oestrogenic effect as end of follicular phase) etc.

208
Q

What are some causes of Infertility?

A

Infertility - unable to get pregnant or impregnate

Various causes e.g. physical, psychological, emotional and endocrine problems.

E.g. excess prolactin (e.g. from a prolactinoma)

209
Q

What are the roles of Calcium in the body?

A
  • Neuromuscular excitability
  • Muscle contraction
  • Strength in bones
  • Intracellular second messenger
  • Intracellular co-enzyme
  • Hormone/neurotransmitter stimulus-secretion coupling
  • Blood coagulation (factor IV)

Etc.

210
Q

Where and in what form is calcium found in the body?

A
  • Most calcium is present as calcium salts
  • Mainly in bone (99%) as complex hydrated calcium salt (hydroxyapatite crystals)
  • In blood, some is present as ions, some bound to protein and a small amount left as soluble salts
  • ONLY FREE (unbound) Ca2+ is bioactive
211
Q

List the principle organs involved in calcium metabolism.

A

Parathyroid glands

Kidneys

Bone

Small Intenstine

212
Q

List the bone cells and their functions.

A
  • Osteoblast - Cuboidal cell involved bone formation
  • Osteoclast - Involved in bone resorption
213
Q

What are principal hormones which regulate blood calcium ion concentration and their sites of synthesis.

A

[Ca2+} increased by:

  • Parathyroid hormone (PTH) produced by parathyroid glands
  • Calcitonin/1,25-dihydroxy-cholecalciferol (Vitamin D3)

[Ca2+] decreased by:

  • Calcitonin produced parafollicular cells
214
Q

Describe the synthesis of Parathyroid hormone (PTH).

A
  • Initially synthesized as protein pre-proPTH
  • PTH is polypetide of 84 amino acids
215
Q

Describe the synthesis of 1,25-dihydroxy-cholecalciferol/calcitriol synthesis.

A
  1. Two sources of the precursor for vitamin D3, cholecalciferol:
    1. from your diet
    2. 7-dehydrocholesterol in skin converted to cholecalciferol by UV light
  2. Converted to 25-hydroxy-cholecalciferol in the liver and stored
  3. When stimulated by PTH, 1a-hydroxylase converts it to 1,25-dihydroxycolecalciferol in the kidney
216
Q

What are the principal effects of PTH on bone, the kidneys and the intestinal tract.

A

Overall - Increased blood calcium concentration

Bone - (increased bone resorption)

  • Osteoclasts stimulated
  • Osteoblasts inhibited

Kidneys -

  • Increased Ca2+ reabsorption
  • Increased PO43-
  • Stimulates 1a hydroxylase activity → increased Vitamin D3 synthesis

Small Intestine -

  • Increased Ca2+ absorption
  • Increased PO43- absorption
217
Q

What is the effect of PTH on the bone?

A

Binds to PTH receptor and stimulates the release of Osteoclast activating factors e.g. RANKL - receptor activator of nuclear factor κ-B ligand

When activated Osteoclasts increase bone resorption

218
Q

What are the principle effects of Vitamin D3?

A
  • Increased osteoblast activity in bone
  • Increased Ca2+ and PO43- absorption in the small intestine
  • Increased Ca2+, decreased PO43- reabsorption in the kidneys
219
Q

What are the principal actions of calcitonin?

A
  • Inhibits osteoclasts activity in bone (less resorption)
  • Increases urinary excretion of Ca2+ (Na+ and PO43-)

Ultimately leads to reduced [Ca2+] in plasma

220
Q

Outline the control mechanism of PTH.

A
  • Stimulated by decreased [Ca2+] in plasma, and catecholamines
  • Negative feedback:
    • PTH production leads to vitamin D3 synthesis which inhibits more PTH
    • Increased plasma [Ca2+] inhibits PTH production
221
Q

Outline the feedback mechanisms for Calcitonin.

A
  • Stimulated by Increased [Ca2+] in plasma and Gastrin
  • After its actions the decreased [Ca2+] in plasma inhibits further calcitonin production
222
Q

How is vitamin D3 stimulated?

A

By release of parathyroid hormone.

223
Q

How does PTH and Calcitriol affect phosphate rebsorption?

A
  • PTH reduce the number of Na+/PO43- cotransporters in membranes of the proximal tube of the kidney
  • Calcitriol stimulates fibroblast growth factor 23 (from osteocytes) which in turn reduces the number of Na+/PO43- cotransporters and stimulated breakdown of calcitriol
224
Q

Explain how Calcitonin is synthesised and how it works.

A
  • Synthesised as pre-procalcitonin
  • Calcitonin is 32 amino acid polypeptide
  • Binds to transmembrane G-protein linked receptor
  • Activates adenyl cyclase or phospholipase C as second messenger systems
225
Q

List the endocrine causes of hypocalcaemia.

A

Hypoparathyroidism

Pseudohypoparathyroidism

Vitamin D deficiency

226
Q

List the other causes of Hypothyroidism.

A

Idiopathic (unknown cause)

Hypomagnesaemia (magnesium deficiency)

Suppression by raised plasma Ca concentration

227
Q

Define tetany and describe its main cause.

A

Tetany - Condition marked by intermittent muscle spasms

Hypocalcaemia is the most common cause.

228
Q

What are two diagnostic methods used for tetany?

A

Trousseau’s sign - blood pressure cuff on arm with its pressure increased to higer than systolic pressure which blocks the brachial artery. If hypocalcaemic there will be muslce spasms in hand and forearm

Chvostek’s sign - facial nerve on edge of jaw is tapped causing contraction in facial muscles on the same side momentarily

229
Q

What is Pseudohypoparathyroidism? What are its features?

A

(AKA Allbright hereditary osteodystophy)

Target organ resistance to PTH believed to be due to defective Gs protein.

Features:

  • Physical - short stature, round face
  • Low IQ
  • Subcutaneous calcification and bone abnormalities (e.g. shortening metacarpals)
  • Associated endocrine disorder (e.g. hypothyroidism, hypogonadism)
230
Q

What is the medical term for vitamin D deficiency? What are the features?

A
  • Rickets in children
  • Osteomalacia in adults

Features:

  • decreased calcification of bone matrix
  • softening of bone
  • bowing of bones in children
  • fractures in adults
231
Q

List the principle causes of Hypercalcaemia.

A
  • Adenoma - PRIMARY HYPERPARATHYROIDISM
    • tumour overproducing PTH causing increased [Ca2+]
  • Low plasma [Ca] - SECONDARY HYPERTHYROIDISM
    • ​e.g. renal failure
    • high PTH concentration to compensate for low calcium
  • Initial chronic low plasma [Ca] - TERTIARY HYPERTHYROIDISM
    • Autonomous (unregulated) PTH release after low [Ca]
    • No negative feedback from high [Ca}
  • Vitamin D toxicosis - too much vitamin D (leads to high [Ca] in plasma)
232
Q

What are the effects of excess Parathyroid hormone on the kidneys?

A
  • Increased calcium reabsorption
  • Increased PO4 excretion
  • Polyuria
  • Renal stones
  • Nephrocalcinosis (calcium deposits in kidney)
  • Increased synthesis of calcitriol
233
Q

What are the effects of excess parathyroid hormone on the gastro-intestinal tract and bone?

A

Gastro-intestinal tract

  • Gastric acid
  • Duodenal ulcers (ulcer in part of the small intestine)

Bone

  • Bone lesions
  • Bone rarefaction (reduced density)
  • Fractures
234
Q

What are two features of Primary Hyperthyroidism?

A

Clubbing of fingers

Marked periosteal bone erosion in the terminal phalanges

235
Q

What are the two diseases caused abnormal function of the Adrenal gland?

A

Adrenal failure - Addison’s

Excess cortisol - Cushing’s

236
Q

How does circulation work in the Adrenal gland?

A
  • Left adrenal vein drains into the renal vein
  • Right adrenal vein drain directly into the inferior vena cava
  • Both adrenals have many arteries but only on vein
237
Q

What is the relevance of POMC to Addison’s disease?

A

Addison’s is the failure to produce cortisol (and Aldosterone) so ACTH remains high to compensate.

More ACTH means more POMC with more bi-product melanocyte stimulating hormone (MSH) being produced.

This causes pigmentation (tan) a sign of Addison’s.

238
Q

What is primary adrenal failure? What are its causes?

A

The failure of the Adrenal gland to produce cortisol.

Causes:

  • Destruction of the adrenal cortex by the immune system (autoimmune)
  • Tuberculosis of the adrenal glands (most common worldwide)
239
Q

What are the features of Addison’s disease?

A
  • Pigmentation (due to MSH)
  • Hypotension (due to lack of aldosterone and so salt loss)
  • Weight loss
  • Autoimmune vitiligo (loss of skin colour in blotches)

Can lead to death

240
Q

What is the urgent treatment of an Addisonian crisis?

A
  • Rehydrate with normal saline
  • Give dextrose to prevent hypoglycaemia which could be due to glucocorticoid deficiency
  • Give hydrocortisone or another glucocorticoid
241
Q

What are the biological actions/symptoms of excess cortisol?

A
  • Impaired glucose intolerance (diabetes)
  • Weight gain (increase fat, loss of protein)
  • Thin skin and easy bruising
  • Striae (red stretch marks)
  • Proximal myopathy (muscle weakness)
  • Mental changes (depression)
  • Hypertension
  • Fat redistribution (mostly around middle)
  • ‘Moon’ face
  • Buffalo hump (Interscapular fat pad)
  • Hirutism
242
Q

What is Cushing’s syndrome? What are the causes of Cushing’s?

A

Excess of cortisol (or other glucocorticoid)

Causes:

  • Taking steroids orally (common)
  • Pituitary dependent Cushing’s disease (pituitary adenoma producing excess ACTH)
  • Ectopic ACTH (lung cancer producing ACTH)
  • Adrenal adenoma (cancer producing cortisol)
243
Q

What is Conn’s syndrome? What is a cause of primary hyperaldosternism? What are the features of it?

A

Excess production of Aldosterone by the adrenal gland.

Cause can be an aldosterone producing adenoma.

Features: Oedema, low potassium

244
Q

What is a risk of left adrenalectomy? What is a precaution taken?

A

Accidental loss of spleen (due to its proximity).

Vaccination before operation with HIB and pneumovax

245
Q
A

Life Cycle and Regulatory Systems (LCRS) (2 decks)

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