Week 3 The endocrine system II

Question 1

What is the Hypothalamo-Pituitary Complex?

Answer 1

• Hypothalamus = part of diencephalon below thalamus
• The hypothalamus is conntected to the pituitary by the Infundibulum
• Hypothalamus communicates with anterior pituitary lobe (adenohypophysis) via hypothalamic-hypophyseal portal circulation
• Adenohypophsis = glandular epithelium - grows up from buccal cavity

Question 2

What are Hypothalamic Hormones?

Answer 2

• 7 hypophysiotropic hormones (peptides)
• “Hypophysis” = pituitary*
• “Tropic” = nourishing / directing*
• Endocrine axis commonly involves 3 hormones in a hierarchical chain (“H-P-gland” axis): HPA, HPG & HPT axes
• Hypophysiotropic hormone = direct pituitary, 1st member in chain. However…
  
  • Primary endocrine disorder = defect in final endocrine gland in hierarchy (e.g. thyroid)
  • Secondary endocrine disorder = AP defect (e.g. TSH)
  • Tertiary endocrine disorder = defect in hypothalamus (e.g. TRH)

Question 3

Hypothalamic Hormones: What are the 7 hypophysiotropic hormones?

Answer 3

7 hypophysiotropic hormones (generally peptides – median eminence – 3o ventricle):

1. PRH = prolactin-releasing hormone (unknown how large it is, not seen even tho inhibiting hormone is present)
2. PIH = prolactin-inhibiting hormone
3. TRH = thyrotropin-releasing hormone (3 a.a.)
4. CRH = corticotropin-releasing hormone (41 a.a.)
5. GHRH = growth hormone-releasing hormone (44 a.a.)
6. GHIH = growth hormone-inhibiting hormone (somatostatin) (28 a.a.)
7. GnRH = gonadotropin-releasing hormone (10 a.a.)

Hypothalamus influenced by neural & hormonal inputs

Question 5

Answer 5

Question 6

What are the AP Hormones?

Answer 6

6 AP hormones synthesised within the AP by 5 different cell populations:

1. TSH (thyroid-stimulating hormone) / thyrotropin
2. GH (growth hormone) / somatotropin
3. ACTH (adrenocorticotropic hormone) / corticotropin
4. FSH (follicle-stimulating hormone) / follitropin
5. LH (luteinising hormone) / luteotropin
6. PRL (prolactin)

Of these six hormones, not all are tropic hormones

Question 7

AP Hormone: TSH (thyroid-stimulating hormone) / thyrotropin

Answer 7

• synthesised by AP thyrotropes
• synthesis & secretion of TSH stimulated by TRH
• TSH stimulates growth & function of thyroid gland (increased synthesis & secretion of T₄ and T₃)
• indirect effects on BMR

Question 8

AP Hormone: GH (growth hormone) / somatotropin

Answer 8

• synthesised by AP somatotropes
• synthesis/secretion of GH stimulated by GHRH; inhibited by GHIH / somatostatin
• GH stimulates growth & metabolism
• Some direct effects; some indirect effects (via hepatic IGF1 = somatomedin)

Question 9

AP Hormone: ACTH (adrenocorticotropic hormone) /corticotropin

Answer 9

• synthesised by AP corticotropes
• synthesis/secretion of ACTH stimulated by CRH
• ACTH stimulates growth and function of adrenal cortex (increased synthesis of cortisol + DHEA)
• indirect effects on metabolism (plasma [glucose]) and development

Question 10

AP Hormone: FSH (follicle-stimulating hormone) / follitropin

Answer 10

• synthesised by AP gonadotropes
• one of 2 (or 3) gonadotropins (each a heterodimeric glycoprotein: common α-subunit plus specific β-subunit)
• synthesis/secretion of FSH stimulated by GnRH
• FSH stimulates growth and function of gonads (germ cell maturation and release)
  
  • in ovary, stimulates growth of ovarian follicles and synthesis of estradiol (via granulosa cells of ovarian follicles)
  • in testis, stimulates spermatogenesis (via Sertoli cells of testis)

Question 11

AP Hormone: LH (luteinising hormone) / luteotropin

Answer 11

• synthesised by AP gonadotropes
• one of 2 (or 3) gonadotropins (each a heterodimeric glycoprotein: common α-subunit plus specific β-subunit)
• synthesis/secretion of LH stimulated by GnRH
• LH stimulates growth and function of gonads
  
  • in ovary, stimulates release of oocyte at ovulation, synthesis of androgens (in theca cells of ovarian follicles) and progesterone (in cells of corpus luteum)
  • in testis, stimulates synthesis of testosterone (in Leydig cells)

Question 12

AP Hormone: PRL (prolactin)

Answer 12

• synthesised by AP lactotropes
• under dominant negative control of PIH (dopamine)
• PRL stimulates lactation (mammary glands) – sex-specific endocrine action (function unknown in healthy males)
• Second order feedback loop to hypothalamus; no downstream endocrine gland to exert third order feedback

Question 13

Hypothalamo-Pituitary Complex: What does the hypothalamus communicate with (& via) to produce oxytocin (OT) & vasopressin (AVP)?

Answer 13

posterior pituitary lobe (neurohypophysis) via neural tract

(cell bodies of magnocellular neurones in hypothalamus – terminate in posterior lobe – secrete oxytocin (OT) & vasopressin (AVP))

Question 14

What are the PP hormones?

Answer 14

oxytocin (OT) & vasopressin (AVP)

Question 15

PP hormones: what does OT stimulate?

Answer 15

• stimulates contraction of smooth muscle
  
  • mammary glands [suckling reflex]
  • myometrium [Fergusson reflex])
• behavioural / emotional actions
  
  • bonding + hugs

Question 16

PP hormones: what does AVP stimulate?

Answer 16

1. stimulates contraction of blood vessels to increase blood pressure (vasopressor)
2. facilitates water resorption in renal collecting ducts

Question 17

In fish, amphibians and birds – vasotocin does what?

Answer 17

Vasotocin combines OT and AVP actions

Question 18

What are the cells present in the ardenal coretx and adrenal medulla, and what do they synthesis?

Answer 18

• Adrenocortical cells - synthesise corticosteroid hormones
• Adrenomedullary chromaffin cells – synthesis and secrete catecholamines

Question 19

The structure of Adrenal Glands:

Answer 19

Question 20

Corticosteroids: What do Mineralocorticoids (e.g. aldosterone) do?

Answer 20

influence salt and water balances (electrolyte balance and fluid balance)

• increases resorption of Na⁺ ions (in distal nephron, colon and salivary glands) / anti-natriuresis, then drives water resorption to increase plasma volume / BP
• increases secretion of K⁺ ions (into urine) in distal nephron / kaliuresis (hypokalemia can cause tetani)

Question 21

Corticosteroids: How are Mineralocorticoids (e.g. aldosterone) synthesised?

Answer 21

• synthesised in ZG (zona glomerulosa)
• synthesis stimulated by electrolytes:
  • directly by increased plasma [K⁺]
  • indirectly by decreased plasma [Na⁺]
• (fall in BP increases secretion of renin - converts*

angiotensinogen to angiotensin I, metabolised to

angiotensin II by ACE; activates AT₂ receptors in ZG)

Question 22

Point of clinical interest: What are the clinical therapies for hypertension?

Answer 22

1. ACE inhibitors (e.g. ramipril) decrease conversion of Ang I to Ang II
2. AT₂R antagonists (e.g. losartan) – inhibit stimulation of aldosterone synthesis by Ang II
3. Aldosterone synthase (CYP11B1) inhibitors (e.g. metyrapone) inhibit conversion of corticosterone to aldosterone
4. Mineralocorticoid receptor antagonists (e.g. spironolactone) prevent aldosterone from increasing renal and colonic Na+ resorption

Question 23

Corticosteroids: What do Glucocorticoids (e.g. cortisol) do?

Answer 23

• increase plasma [glucose] for brain
• increase plasma [NEFA] and amino-acids
• mediate chronic stress response - suppress all “non-essential” body functions (e.g. reproduction) and immune system (anti-inflammatory steroids)
• circulate in association with albumen and CBG (transcortin)
• exert negative feedback on CRH and ACTH

Question 24

Corticosteroids: How are Glucocorticoids (e.g. cortisol) synthesised?

Answer 24

• synthesised in ZF (zona fasciculata)
• stimulated by ACTH in HPA axis

Question 25

Point of clinical interest: “Mineralocorticoid” receptor (MR) = type 1 corticosteroid receptor is **non-specific** – **equal affinities** for glucocorticoids & mineralocorticoids

Answer 25

* **Cortisol** acts as MR ligand * Cortisol present at **100 to 1000X higher concentrations** than aldosterone * **Cortisol** has to be **inactivated** (by **11βHSD2**) to **confer specificity** for aldosterone on MR * Enzymatic inactivation of cortisol defective in patients with **HSD11B2 *mutations*** or following intoxication with **liquorice**

Question 26

Corticosteroids: What do **Adrenal androgens** (e.g. dehydroepiandrosterone / DHEA) do?

Answer 26

* adrenal DHEA **metabolised** in **peripheral** tissues (e.g. skin, adipose tissue and bone) to more potent androgens (e.g. androstenedione and testosterone) and estrogens (e.g. estradiol) – implicated in **pubertal development & ageing** * DHEA circulates in association with **albumen** and **SHBG** * **DHEA-S (sulphate)** has no affinity for SHBG

Question 27

Corticosteroids: How are **Adrenal androgens** (e.g. dehydroepiandrosterone / DHEA) synthesised?

Answer 27

* synthesised in **ZF & ZR** (zona reticularis) * stimulated by **ACTH** in HPA axis

Question 28

What is the Adrenal Medulla?

Answer 28

Modified part of **sympathetic** autonomic nervous system (ANS) – **chromaffin** cells = modified post-ganglionic neurones (lack axons)

Question 29

What does the Adrenal Medulla synthesis and secrete?

Answer 29

* Synthesises and secretes **catecholamines – 80%:20% adrenaline:noradrenaline** (epinephrine:norepinephrine) * **methylation** of noradrenaline to adrenaline catalysed by **PNMT** enzyme – upregulated by **glucocorticoids** from overlying adrenal cortex * secretion of adrenaline (**chromaffin granules**) triggered **SOLELY** by **sympathetic innervation** (NOT under endocrine control!)

Question 30

Adrenal Medulla: What do Catecholamines act via?

Answer 30

Catecholamines act via **GPCR’s**: * **α₁AR** and **α₂AR** (modulate [**Ca**²⁺]i) * **β₁AR** and **β₂AR** (modulate [**cAMP**]i; activate PKA)

Question 31

What response does the adrenal medulla mediate?

Answer 31

Mediate **acute stress** response – *aspects of the “fight or flight response”* • e.g. vasoconstriction / increased peripheral resistance plus increased heart rate increases blood pressure / flow * e.g. increase plasma [glucose] and [NEFA] * e.g. sensitise the CNS and exert autonomic functions (sweating and dilation of the pupils)

Question 32

What is are the features of the pancreas?

Answer 32

Question 33

What are the features of the pancreas: duct and acinar cells?

Answer 33

Question 34

The features of the pancreas: What does the **Exocrine** pancreas do?

Answer 34

pancreatic **acini** secrete “**pancreatic juice**” (amylase, lipase, nuclease and protease enzymes plus HCO₃- ions) via **ducts** into GI tract

Question 35

The features of the pancreas: What does the **Endocrine** pancreas do?

Answer 35

_Regulate plasma [glucose]_ * ​**endocrine** glands * account for **1-2%** of pancreas (by mass) * secrete **hormones directly** into **plasma**: * **glucagon** - raises plasma [**glucose**] * **insulin** - lowers plasma [**glucose**] * **somatostatin** - inhibits secretion of **pancreatic hormones** * **pancreactic polypeptide** (PP) - **appetite** control

Question 36

What are the Islets of Langerhans?

Answer 36

* α cells – **glucagon** * β cells – **insulin** * δ cells – **somatostatin** * PP cells – **PP!**

Question 37

Point of Clinical Interest: Plasma [**glucose**] has to be kept between **4 and 8 mmol L^-1** (typically 5 mmol L^-1) in humans

Answer 37

* **hypoglycaemia** (**\<4mmol** L^-1) – insufficient glucose to support brain function (**coma**) * **hyperglycaemia** (**\>8mmol** L^-1) – excess glucose causes: * disturbance to **osmolarity** * damage to membrane proteins and lipids (**advanced glycation end-products**) culminating in diabetic nephropathy, neuropathy and retinopathy

Question 38

Glucose Homeostasis: Insulin and glucagon serve as _____ \_\_\_\_\_ to control _____ (glucose, NEFA & a.a.) usage and storage

Answer 38

Insulin and glucagon serve as **antagonistic pair** to control **metabolic fuel** (glucose, NEFA & a.a.) usage and storage

Question 39

Glucose homeostasis: Insulin and glucagon serve as antagonistic pairto control metabolic fuel (glucose, NEFA & a.a.) usage and storage What is an **anabolic** state? What is an **catabolic** state?

Answer 39

* **anabolic** state (polymer synthesis – excess energy stored as glycogen {liver and skeletal muscle} and triglyceride {adipose tissue}) * **catabolic** state (polymer breakdown – energy stores mobilised through glycogenolysis and/or lipolysis)

Question 40

Glucose homeostasis: What is the Absorptive state?

Answer 40

Absorptive state – raised [glucose] 3-4 hours post-feeding (anabolic) (**elevates insulin**)

Question 41

Glucose homeostasis: What is the **Post-Absorptive** state?

Answer 41

Post-absorptive state – decreased [glucose] between meals (catabolic) (**elevates glucagon + …**)

Question 42

What is the Antagonistic Control in glucose homeostasis?

Answer 42

Question 43

Anatagonistic Control in the Endocrine Pancreas:

Answer 43

Question 44

How is Insulin Secretion controlled?

Answer 44

* β cells respond **directly** to plasma [**glucose**] * Mechanism of excitation-secretion coupling for insulin relies on 2 types of plasma membrane **ion channel**: 1. **ATP-sensitive K⁺ channel** **​****​​​​​​**(closed by ATP binding) (drug target for sulphonylureas) 2. **Voltage-gated Ca²⁺ channel** (closed at resting potential but opened by depolarisation of β cell)

Question 45

What are the 2 types of channel in the beta cell?

Answer 45

2 types of channel in the beta cell: 1. ATP sensitive K+ channel (remains open unless ATP binds to it) 2. Voltage gated Ca2+ channel (closed at resting potential) * Relevant in relation to the mechanism of excitation-secretion coupling of insulin*

Question 46

What is Excitation-Secretion Coupling? * Increase plasma [glucose] --\> **\_\_\_\_\_** * Glucose phosphorylated to**\_\_\_\_\_** by **\_\_\_\_\_** – committed to glycolysis * Increased ATP:ADP ratio closes **\_\_\_\_\_** * Decreased efflux of K+ **\_\_\_\_\_** * Opens **\_\_\_\_\_** – facilitates **\_\_\_\_\_** * Increased [Ca2+]_i triggers **\_\_\_\_\_**

Answer 46

* Increase plasma [glucose] --\> **More glucose admitted to β-cell via GLUT2** * Glucose phosphorylated to **glucose-6phosphate** by **glucokinase** – committed to glycolysis * Increased ATP:ADP ratio closes **K+ channels** * Decreased efflux of K+ **depolarises cell** * Opens **voltage-gated Ca2+ channel** – facilitates **Ca2+ influx** * Increased [Ca2+]_i triggers **exocytosis of secretory**

Question 47

Answer 47