Adrenal glands, parathyroid hormone and calcium homeostasis

Describe the structure of adrenal glands

Describe the synthesis of steroid hormones

Cholesterol is converted to pregnenolone by Desmolase

and can we further converted by

hydrogenase enzyme to progesterone and

after a few steps to aldosterone, cortisol

and Testosterone, which can be converted

to Oestradiol by Aromatase enzyme

Describe the physiological action of mineralcorticosteroid aka aldosterone

control of electrolyte homeostasis

Increases sodium reabsorption and potassium excretion in kidney

- Regulated by renin-angiotensin

system

- Increases blood volume and

pressure

Describe the physiological action of glucocorticoids aka cortisol

response to "stress"

metabolism:hyperglycemia, gluconeogenesis and decrease in glucose uptake into cells

muscle: protein catabolism and reduced synthesis

bones: osetoporosis due to reduced Ca absorption and osteoblast activity

Inflammatory & immune systems to:

- inhibition of inflammatory responses, reduce wound healing, repair and proliferation long term and short term reduce redness, pain, swelling

reduce COX2, cytokines, complement, NO, histamine and IgG

increase annexin-1, which inhibits PLA2 that produces Arachidonic acid

Describe the physiological actions of androgens aka testosterone

involved in the development of secondary sexual characteristics at puberty

• role in preventing degenerative changes in ageing

How do you regulate mineralocorticoid function

Renin released by kidney

nephrons in response to

reduced plasma volume

- Renin converts

angiotensinogen into

angiotensin I

- Angiotensin 1 is converted

to angiotensin II (ATII) in

tissues

- ATII acts on glomerulosa

cells to stimulate

aldosterone production

- Aldosterone increases Na+

reabsorption and so

increases plasma volume

How do you regulate glucocorticoid function

stimuli such as pain, stress etc release CRH in hypothalamus, which causes the release of ACTH in anterior pituitary, which stimulates the release of glucocorticoids and androgens in the adrenal cortex

glucocorticoids inhibit CRH and ACTH via negative feedback

Describe Addison's disease

primary adrenal insufficiency due to adrenal cortex or secondary due to lack of ACTH

- Severe illness with hypotension, tiredness,

weakness, anorexia, hyperpigmentation, GI effects, salt craving

- Treated by Fludrocortisone replacement

Describe Cushing's syndrome

ACTH dependant-pituitary tumour producing excess

ACTH independant= adrenal adenoma, hyperplasia, carcinoma

Weight gain, redistribution of fat to abdomen,

face & posterior neck, diabetes, glucose resistance

acne, hirsutism, more likely to get infections and bruising, osteoporosis, skin thinnening, high blood pressure

Describe the anatomy of the parathyroid gland

Chief cells produce parathyroid hormone

What is the function of Ca in the body

1-2kg calcium in the adult human body

- 99% resides in bone and teeth as hydroxyapatite crystals, providing structural integrity

of skeleton and teeth

- Calcium ions in intracellular (0.9%) and extracellular (0.1%) fluids play key roles in :

- Bone growth and remodelling

- Blood coagulation (enzyme co-factor)

- Muscle contraction (required for actin:myosin interactions)

- Neuronal function(regulates excitability)

- Enzyme action

- Exocytosis of hormones and neurotransmitters (triggered by Ca2+ influx)

- Intracellular signalling (second messenger)

Describe parathyroid hormone synthesis PTH

Produced by parathyroid Chief cells :

- Synthesized from the precursor molecule pre-pro-PTH (115 amino acids)

- Precursor (pre-pro-PTH ) is subsequently cleaved to pro-PTH (90 amino acids)

- PTH is a biologically active 84 amino acid peptide (the first 34aa are fully active)

How is PTH secreted and inhibited

• Inhibited by Vitamin D Secondary mechanism-negative feedback

inhibited by high Ca levels

• Low Ca2+-> detected by calcium-sensing receptor (CaSR) on the surface of chief cells PTH binds to the G-protein coupled receptor PTH-R -> Activation of PTH-R causes increases in cAMP and release of Ca2+ from intracellular stores

Describe the physiological action of PTH

- promote bone resorption and increase Ca2+

concentration in blood

- PTH inhibits PO4 reabsorption in kidneys, so more free plasma

Ca2 and PTH Stimulates Ca2+ reabsorption on distal convoluted tubule, so more in plasma

- PTH stimulates Ca2+ reabsorption via activation of vitamin D through stimulating renal 1α-hydroxylase

Describe vitamin D synthesis

Synthesised in skin keratinocytes from 7-dehydrocholesterol via action of ultraviolet light

• Ingested in food and absorbed into blood stream

• Metabolised in liver to 25-hydroxycholecalciferol and in kidneys to activated form: 1,25-

dihydroxyvitamin D3 /Calcitriol by 1α-hydroxylase

Describe the action of Vit D

Calcitriol acts on nuclear receptors (VDR) in the small intestines, which increases gene transcription

• Increases in Ca2+ transport proteins→ increased rate of Ca2+ absorption; rapid uptake of Ca2+ from the gut

• Increases bone resorption and reduces urinary Ca2+ loss at the kidney

Describe calcitonin

Peptide hormone produced by parafollicular cells ( C-cells) in the thyroid gland

Released in directly response to increased Ca2+ in extracellular fluid

Describe the action of calcitonin

Inhibits osteoclasts (release Ca2+ from bone)→protective effect on bone Ca2+

• Stimulates Ca2+ release from kidneys (opposite effects of PTH)

• No significant effect on Ca homeostasis, PTH and D3 are main

What could be the causes of hypocalcemia

Vitamin D Deficiency: lack of sunlight/dietary sources

- Chronic Renal Failure: reduced hydroxylation of vitamin D

- Pseudohypoparathyroidism: tissue resistance to PTH

- Iatrogenic: damaged or removed during thyroid surgery

- Autoimmune disorders: auto-antibodies destroy tissue

What are the symptoms of hypocalcaemia

tetanic muscle contractions: spasms laryngeal muscle (laryngeal stridor)

- seizures (brain)

- cardiac effect (repolarization is delayed with prolonged QT

interval)

- cataract (protein accumulation)

- dry & flaky skin; brittle nails

- tetany in the hand (Trousseau sign of latent tetany)

- Osteoporosis ( fragile& brittle bones)

- Rickets ( bones bended inwards)

What can cause hypercalcemia

Adenoma (90%) or hyperplasia, more common in

women(benign tumour)

Chronically elevated plasma PTH

What are the symptoms of hypercalcemia

Psychic Moans - depression of nervous system; slow reflex;

depression

- Abdominal Groans - decreased appetite; anorexia;

constipation; vomiting

- Bones - osteitis fibrosa/arthritis; cystic area in bone, may

contain fibrous tissue; marrow fibrosis.

- Stones - calcium phosphate crystals throughout body; kidney stones (deposit in kidney

What are the treatments for Cushing syndrome

Inhibit steroid biosynthesis:

- Metyrapone-11b-hydroxylase inhibitor

- Ketoconazone -17a-hydroxylase & 11b-hydroxylase

inhibitor

Inhibit ACTH release:

- Pasireotide-SSTR5 agonist (somatostatin analogue,

inhibits release from anterior pituitary)

- Cabergoline- dopamine D2 agonist( can supress

secretion of ACTH)

Inhibition of glucocorticoid receptor :

-Mifeprestone (also progestogen receptor antagonist)

Describe the release of cortisol

Pro-opiomelanocortin (POMC) is the archetypal polypeptide precursor of ACTH, this

allows to save energy (4 for 1) and allows to have better regulation of ACTH

- ACTH acts on a G-protein coupled receptor (melanocortin 2 receptor, MC2R) to activate

adenyl cyclase which leads to an increase in cAMP levels and the activation of protein

kinase A (PKA), this leads to:

- Activation of cholesteryl ester hydrolase (CEH) which liberates cholesterol from lipid

droplets.

- Uptake of cholesterol into the mitochondria.

- Stimulation of cholesterol desmolase/CYP11A1 (rate limiting step in steroid hormone

biosynthesis) which results in increased synthesis of cortisol.

- ACTH has little effect on aldosterone synthesis, which is driven primarily by angiotensin

II

Describe how cortisol binds to affects gene transcription

Inactive Glucocorticoid receptor molecule is kept in the cytosol through binding to

HSP90 Heat shock proteins, HSP bind to a region on the receptor that binds DNA

- Transcription activation domain (once receptor is sitting on DNA it recruits proteins to

synthesise mRNA), DNA binding domain (recognises and binds to DNA), ligand binding

domain (hormone binds to receptor)

- Once hormone binds there is a conformational change in receptor, it will kick off HSP90

and transport receptor from cytosol to nucleus, which will allow it to bind hormone

response elements, which recruit transcription factors (co-activator/ suppressors) and

promote/supress genes