Endocrinology - Science Flashcards
What are the 4 layers of the adrenal gland from outer to inner and what do they secrete?
1) Zona glomerulosa - mineralocorticoid (aldosterone)
2) Zona fasciculata - glucocorticoid (cortisol)
3) Zona reticularis - androgens (testosterone)
4) Medulla - adrenaline
What enzyme does the zona glomerulosa lack?
17 alpha hydroxylase
What enzyme does the zona fasciculata lack?
Aldosterone synthase
What enzyme does the zona reticularis lack?
Aldosterone synthase
Describe the control of synthesis and release of cortisol
1) Hypothalamus released CRH
2) CRH stimulates corticotrophs in the anterior pituitary to produce ACTH derived from POMC
3) ACTH stimulates the adrenal cortex to synthesise and release cortisol
4) Cortisol feeds back on the corticotrophs and the hypothalamus to decrease ACTH and CRH release
Describe the synthesis of cortisol (steroid)
(All derived from cholesterol)
1) ACTH acts on GPCR (melanocortin 2 receptor - MC2R)
2) This activates PKA which activates cholesteryl ester hydrolase (CEH) which liberates cholesterol from lipid droplets
3) There is also stimulation of cholesterol 20,22-hydroxylase (desmolase) which is the first enzyme in the pathway and is the rate limiting step
4) This leads to increased synthesis of cortisol
Describe the action sequence of ACTH on cortical cells (adrenal cortex)
ACTH → receptor → cAMP → PKA → CEH which breaks down cholesteryl esters → cholesterol → pregnanolone → cortisol
Which hormone has a higher total plasma concentration (is produced more) - aldosterone or cortisol?
Cortisol
What is CBG?
Cholesterol Binding Globulin - a steroid hormone binding protein
What % of cortisol is free, bound to CBG and bound to albumin?
Free - 10%
CBG - 75%
Albumin - 15%
What % of aldosterone is free, bound to CBG and bound to albumin?
Free - 40%
CBG - 20%
Albumin - 40%
What is the half life of cortisol?
90 min
What is the half life of aldosterone?
15 min
Why does aldosterone have a shorter half life than aldosterone?
Because it has a higher % of free hormone
Describe how steroid hormones interact with nuclear receptors
1) Hormone enters cell by diffusion and binds to cytoplasmic receptor
2) This leads to dissociation of hsp90 from the receptor
3) The hormone-receptor complex dimerises and is translocated to the nucleus
4) The complex binds to hormone responsive element (HRE) on DNA
5) This leads to an increase in mRNA production and therefore to increased protein synthesis
What are the 4 metabolic effects of cortisol?
1) Hyperglycaemia → decrease cell glucose uptake and use and increase gluconeogenesis
2) Muscle wasting → decrease protein synthesis and increase protein breakdown
3) Lowers calcium → decreases absorption in the gut and increases excretion in the kidney
4) Osteoporosis → decrease activity of osteoblasts and increase activity of osteoclasts
What are early phase anti-inflammatory effects of cortisol?
Reduce redness, heat, pain and swelling
What are late phase anti-inflammatory effects of cortisol?
Reduce wound healing, repair and proliferation
In what ways does cortisol have anti-inflammatory effects?
It decreases... 1) Expression of COX2 2) Cytokine production 3) Complement in plasma 4) NO production 5) Histamine release 6) IgG production It increases... 1) Annexin-1 which inhibits phospholipase A2 2) Increases sodium and water retention 3) Increases potassium excretion
Why does cortisol activation of the mineralocorticoid receptor need to be prevented?
Cortisol has a higher affinity for the mineralocorticoid receptor than the glucocorticoid receptor
How is cortisol activation of the mineralocorticoid receptor prevented?
1) Cortisol is interconverted between its active (cortisol) and inactive (cortisone) form by 11β-HSD
2) 11β-HSD2 isoform expressed in aldosterone sensitive tissues converts cortisol to cortisone
3) 11β-HSD1 isoform expressed in the liver, adipose and muscle converts cortisone to cortisol
What are adverse effects of (exogenous) glucocorticoids?
1) Suppression of response to infection
2) Suppression of endogenous glucocorticoid production
3) Metabolic effects
4) Osteoporosis
5) Iatrogenic Cushing’s syndrome
Describe the effects of aldosterone in the kidney
- Effects in distal tubule and collecting duct
1) Increased number of sodium channels (ENaC) in apical membrane
2) Increase in Na/K-ATPase in the basolateral membrane (increased Na/K exchange)
What two weak androgens are secreted by the adrenal gland?
1) Dehydroepiandrosterone
2) Androstenedione
What happens to androstenedione in the pre-menopausal woman?
50% of androstenedione is derived from the adrenal gland and is converted in peripheral tissue to oestrogen and testosterone
What happens to androgens in the post-menopausal woman?
- With the regression of the ovary, the main oestrogen is oestrone
- As peripheral conversion takes place in adipose tissue, the production of oestrone is higher in the obese post-menopausal woman
Describe the structure of the thyroid
- Sits on trachea, two lobes joined by isthmus
- Adult gland weighs 10-20g
- Blood supply from superior and inferior thyroid arteries
- Highly vascular
When is the thyroid enlarged?
1) Adolescence
2) Pregnancy
3) Lactation
4) Later portion of the menstrual cycle
What hormone do the parathyroid glands produce?
Parathyroid hormone - increases calcium
What are the 2 types of cells in the thyroid gland and which hormone do they produce?
1) Follicular cells → thyroid hormones (T4 and T3)
2) Parafollicular (C) cells → calcitonin (reduces calcium)
What are the two functions of thyroid hormones?
1) Development → neural development in fetus, growth in young child
2) Metabolism → controls BMR
What does the gland do to produce thyroid hormones?
It concentrates iodine for incorporation into thyroid hormones - contains 60-65% of body iodine
Describe the regulation of thyroid hormone synthesis
1) Hypothalamus releases TRH
2) TRH stimulates thyrotrophs in the anterior pituitary to produce TSH which goes into blood
3) TSH stimulates thyroid gland to synthesise and release thyroid hormones
4) Main hormone is T4, which is converted to T3 in the periphery
5) T3 acts on the thyrotrophs to decrease release of TSH and TRH
Can you make T4 from T3?
No, only reverse T3 which is inactive
Describe the synthesis of thyroid hormones
1) Active uptake of iodine
2) Synthesis of thyroglobulin (made of tyrosine residues)
3) Organification of iodine by thyroid peroxidase in the presence of H2O2
4) Addition of (1/2) iodine to tyrosine → Mono/di-iodotyrosine (MIT/DIT)
5) Coupling - MIT + DIT → T3, DIT + DIT → T4
When is more T3 produced than T4?
When there is less iodine
Why does it take a while for thyroid problems to appear?
Due to the high storage levels of T4 (10x more than T3)
Which thyroid hormone is more highly protein bound?
T4
Which thyroid hormone is more active at stimulating thyroid receptors?
T3
What are reference values for thyroid hormones?
No absolute values, different for everyone
What are the two thyroid hormone binding proteins?
1) TBG - thyroxine binding globulin
2) TBPA - thyroxine binding pre-albumin
Why can only free thyroid hormones produce a response?
Because the receptors are intracellular
How do thyroid hormones bind with thyroid receptors?
1) Thyroid hormone enters cell by diffusion or transporter
2) T3 enters nucleus and binds to thyroid receptor
3) Thyroid receptor dimerises with retinoid X receptor
4) Hormone-receptor complex binds to thyroid hormone receptive element (TRE) on DNA
What are the cell level effects of the thyroid hormone-receptor complex binding to TRE?
Increased…
1) mRNA production
2) protein synthesis
3) Na/K-ATPase levels
4) ATP turnover
5) O2 consumption
6) number of adrenoreceptors esp. beta receptors
What are the 10 effects of thyroid hormones?
Increased…
1) O2 consumption and heat production
2) Cardiac muscle contractility
3) Sensitivity to adrenaline
4) Gut motility
5) Erythropoiesis
6) Bone turnover
7) Protein turnover - decrease in muscle mass
8) Cholesterol degradation
9) Metabolic turnover of hormones and drugs
10) Maintenance of hypoxic and hypercapnic drive in respiratory centre
Describe the structure of the pituitary gland
1) Anterior lobe (adenohypophysis) - pars distalis and pars tuberalis
2) Posterior lobe (neurohypophysis) - pars nervosa and infundibulum
What are the 5 cells types in the anterior pituitary and what hormones do they release?
1) Corticotroph → ACTH
2) Gonadotroph → FSH, LH
3) Lactotroph → Prolactin (PRL)
4) Somatotroph → GH
5) Thyrotroph → TSH
What hormones are released by the hypothalamus?
1) CRH
2) GnRH
3) Dopamine (prolactin inhibitory factor)
4) GHRH
5) Somatostatin (inhibits GH release)
6) TRH (also causes release of PRL?)
What is the action of inhibin released by the gonads?
Inhibits FSH secretion
Which female hormone(s) inhibit release of GnRH?
Progesterone
Which female hormone(s) inhibit release of LH and FSH?
Oestrogen and progesterone
When is there increased PRL secretion?
During pregnancy and lactation
Which hypothalamic hormones control PRL release?
1) Prolactin inhibitory factor (PIF) and dopamine
2) Prolactin released factor (PRF)
3) TRH
What are the actions of prolactin?
1) Pregnancy → promotes additional breast development
2) Postpartum → stimulates milk production in lactating mother and suppresses menstrual cycle so that mother doesn’t become pregnant when suckling first child
What controls release of GH?
1) GHRH and somatostatin
2) GH negative feedback to hypothalamus
3) Insulin-like growth factor (IGF) negative feedback to hypothalamus and pituitary
What are the actions of GH?
1) Growth of long bones until fusion of epiphyses
2) Increase in size of viscera
3) Anti-insulin effects
4) Metabolic effects related to growth - anabolic for protein, catabolic for fats and carbs
What factors stimulate GH secretion?
1) Physiological - episodic release, exercise, stress, sleep, postprandial glucose decline
2) Pharmacological - drug-induced hypoglycaemia, amino acid infusions, small peptide hormones, monoaminergic stimuli
How are posterior pituitary hormones synthesised?
- Synthesised in cell bodies in supraoptic nucleus (SON) and paraventricular nucleus (PVN) of hypothalamus
- Precursor = neurophysin 1 (oxytocin) or neurophysin 2 (ADH)
When is ADH secreted?
When there is a decrease in total body water or low BP
1) Hyperosmolarity - hypothalamic osmoreceptors
2) Low plasma volume - baroreceptors
3) Angiotensin II
4) Other stimuli not directly related to fluid balance
What is the action of ADH?
Maintains BP via actions on:
1) Fluid balance - increased water reabsorption (V2 receptors)
2) Blood vessels - vasoconstriction (V1 receptors)
When is oxytocin secreted?
Labour and lactation
What are the actions of oxytocin?
1) Contractions in the uterus
2) Milk ejection in mammary gland
3) Social behaviour in the brain
What is the sella turcica?
The bony cavity in the sphenoid bone where the pituitary sits
