Week 3 The endocrine system II Flashcards
What is the Hypothalamo-Pituitary Complex?
- 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
What are Hypothalamic Hormones?
- 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)
Hypothalamic Hormones: What are the 7 hypophysiotropic hormones?
7 hypophysiotropic hormones (generally peptides – median eminence – 3o ventricle):
- PRH = prolactin-releasing hormone (unknown how large it is, not seen even tho inhibiting hormone is present)
- PIH = prolactin-inhibiting hormone
- TRH = thyrotropin-releasing hormone (3 a.a.)
- CRH = corticotropin-releasing hormone (41 a.a.)
- GHRH = growth hormone-releasing hormone (44 a.a.)
- GHIH = growth hormone-inhibiting hormone (somatostatin) (28 a.a.)
- GnRH = gonadotropin-releasing hormone (10 a.a.)
Hypothalamus influenced by neural & hormonal inputs
What are the AP Hormones?
6 AP hormones synthesised within the AP by 5 different cell populations:
- TSH (thyroid-stimulating hormone) / thyrotropin
- GH (growth hormone) / somatotropin
- ACTH (adrenocorticotropic hormone) / corticotropin
- FSH (follicle-stimulating hormone) / follitropin
- LH (luteinising hormone) / luteotropin
- PRL (prolactin)
Of these six hormones, not all are tropic hormones
AP Hormone: TSH (thyroid-stimulating hormone) / thyrotropin
- 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
AP Hormone: GH (growth hormone) / somatotropin
- 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)
AP Hormone: ACTH (adrenocorticotropic hormone) /corticotropin
- 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
AP Hormone: FSH (follicle-stimulating hormone) / follitropin
- 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)
AP Hormone: LH (luteinising hormone) / luteotropin
- 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)
AP Hormone: PRL (prolactin)
- 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
Hypothalamo-Pituitary Complex: What does the hypothalamus communicate with (& via) to produce oxytocin (OT) & vasopressin (AVP)?
posterior pituitary lobe (neurohypophysis) via neural tract
(cell bodies of magnocellular neurones in hypothalamus – terminate in posterior lobe – secrete oxytocin (OT) & vasopressin (AVP))
What are the PP hormones?
oxytocin (OT) & vasopressin (AVP)
PP hormones: what does OT stimulate?
- stimulates contraction of smooth muscle
- mammary glands [suckling reflex]
- myometrium [Fergusson reflex])
-
behavioural / emotional actions
- bonding + hugs
PP hormones: what does AVP stimulate?
- stimulates contraction of blood vessels to increase blood pressure (vasopressor)
- facilitates water resorption in renal collecting ducts
In fish, amphibians and birds – vasotocin does what?
Vasotocin combines OT and AVP actions
What are the cells present in the ardenal coretx and adrenal medulla, and what do they synthesis?
- Adrenocortical cells - synthesise corticosteroid hormones
- Adrenomedullary chromaffin cells – synthesis and secrete catecholamines
The structure of Adrenal Glands:
Corticosteroids: What do Mineralocorticoids (e.g. aldosterone) do?
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)
Corticosteroids: How are Mineralocorticoids (e.g. aldosterone) synthesised?
- 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)
Point of clinical interest: What are the clinical therapies for hypertension?
- ACE inhibitors (e.g. ramipril) decrease conversion of Ang I to Ang II
- AT2R antagonists (e.g. losartan) – inhibit stimulation of aldosterone synthesis by Ang II
- Aldosterone synthase (CYP11B1) inhibitors (e.g. metyrapone) inhibit conversion of corticosterone to aldosterone
- Mineralocorticoid receptor antagonists (e.g. spironolactone) prevent aldosterone from increasing renal and colonic Na+ resorption
Corticosteroids: What do Glucocorticoids (e.g. cortisol) do?
- 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
Corticosteroids: How are Glucocorticoids (e.g. cortisol) synthesised?
- synthesised in ZF (zona fasciculata)
- stimulated by ACTH in HPA axis
Point of clinical interest:
“Mineralocorticoid” receptor (MR) = type 1 corticosteroid receptor is non-specific – equal affinities for glucocorticoids & mineralocorticoids
- 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
Corticosteroids: What do Adrenal androgens (e.g. dehydroepiandrosterone / DHEA) do?
- 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
Corticosteroids: How are Adrenal androgens (e.g. dehydroepiandrosterone / DHEA) synthesised?
- synthesised in ZF & ZR (zona reticularis)
- stimulated by ACTH in HPA axis
What is the Adrenal Medulla?
Modified part of sympathetic autonomic nervous system (ANS) – chromaffin cells = modified post-ganglionic neurones (lack axons)
What does the Adrenal Medulla synthesis and secrete?
- 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!)
Adrenal Medulla: What do Catecholamines act via?
Catecholamines act via GPCR’s:
- α1AR and α2AR (modulate [Ca<b>2+</b>]i)
- β1AR and β2AR (modulate [cAMP]i; activate PKA)
What response does the adrenal medulla mediate?
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)
What is are the features of the pancreas?
What are the features of the pancreas: duct and acinar cells?
The features of the pancreas: What does the Exocrine pancreas do?
pancreatic acini secrete “pancreatic juice” (amylase, lipase, nuclease and protease enzymes plus HCO3- ions) via ducts into GI tract
The features of the pancreas: What does the Endocrine pancreas do?
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
What are the Islets of Langerhans?
- α cells – glucagon
- β cells – insulin
- δ cells – somatostatin
- PP cells – PP!
Point of Clinical Interest: Plasma [glucose] has to be kept between 4 and 8 mmol L-1 (typically 5 mmol L-1) in humans
- 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
Glucose Homeostasis: Insulin and glucagon serve as _____ _____ to control _____ (glucose, NEFA & a.a.) usage and storage
Insulin and glucagon serve as antagonistic pair to control metabolic fuel (glucose, NEFA & a.a.) usage and storage
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?
- 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)
Glucose homeostasis: What is the Absorptive state?
Absorptive state – raised [glucose] 3-4 hours post-feeding (anabolic) (elevates insulin)
Glucose homeostasis: What is the Post-Absorptive state?
Post-absorptive state – decreased [glucose] between meals (catabolic) (elevates glucagon + …)
What is the Antagonistic Control in glucose homeostasis?
Anatagonistic Control in the Endocrine Pancreas:
How is Insulin Secretion controlled?
- β cells respond directly to plasma [glucose]
- Mechanism of excitation-secretion coupling for insulin relies on 2 types of plasma membrane ion channel:
- ATP-sensitive K+ channel (closed by ATP binding) (drug target for sulphonylureas)
- Voltage-gated Ca2+ channel (closed at resting potential but opened by depolarisation of β cell)
What are the 2 types of channel in the beta cell?
2 types of channel in the beta cell:
- ATP sensitive K+ channel (remains open unless ATP binds to it)
- Voltage gated Ca2+ channel (closed at resting potential)
* Relevant in relation to the mechanism of excitation-secretion coupling of insulin*
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 _____
- 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
