Adrenal Gland Physiology Flashcards
Steroid hormone biosynthesis
First step in steroid hormone synthesis is the release of cholesterol (from LDL originally) from lipid droplets by removal of the esters.
The subsequent steps in steroid hormone synthesis occur within either the mitochondria or endoplasmic reticulum. The rate-limiting step requires mitochondrial enzymes - the cytochrome P-450 enzymes or 20, 22 desmolase. Pregnenolone is the product of this reaction.
Transport of glucocorticoids in the plasma
Cortisol circulates primarily (90%) bound to proteins. Only 10% circulates in a free form.
Of the 90% that is bound, 75% is bound to cortisol binding globulin (CBG) and 15% is bound to albumin.
The free form of hormones is the active form, although it is in equilibrium with the bound form.
Protein binding increases the plasma concentration of hormone, prevents its excretion by the kidney, prolongs its half-life and serves as a reservoir of extra hormone. If the binding protein is elevated, the total concentration of hormone in the plasma is elevated but the biological activity of the hormone is unchanged, because it is the concentration of free hormone (set point) that is regulated.
Actions of cortisol
- Stimulation of gluconeogenesis in the liver
- Increased proteolysis in muscle and other soft tissues providing amino acid substrates for gluconeogenesis.
- Facilitate lipolysis (in normal doses)
- Facilitation of excretion of a water load (this occurs due to cortisol’s ability to inhibit ADH function)
- Increased gastric acid secretion
- Paracrine effect on the adrenal medulla and stimulates the synthesis and activity of phenyl-N-methyl Transferase (PNMT) thus increasing the production of epinephrine from norepinephrine
Great significance in maintaining or elevating blood glucose in times of stress
Regulation of ACTH production and release
Hypothalamus secretes CRH, which acts on the anterior pituitary to stimulate the release of ACTH
CRH binds to receptors on corticotrophs, thereby activating adenylate cyclase. Secretion of ACTH occurs in a calcium-dependent manner; POMC gene transcription is also activated.
ACTH in turn interacts with receptors on the cells of the Zona fasciculata and reticularis to promote secretion of cortisol
Plasma free cortisol feeds back on the hypothalamus and the pituitary to inhibit CRH and ACTH secretion, completing the negative feedback loop. There is also evidence that ACTH can inhibit its own secretion.
Stress of various forms stimulates secretion of CRH and thus ACTH and cortisol
Actions of ACTH
ACTH has several actions, which lead to increased cortisol secretion.
In the cortex, ACTH leads to elevated cAMP levels, which in turn increase the rate of synthesis of pregnenolone.
LDL uptake is also enhanced, as is hydrolysis of stored cholesterol esters and transport of cholesterol into mitochondria.
Epinephrine release
Perception or even anticipation of danger, trauma, pain, and other physiological stressors like hypovolemia, hypotension, hypoglycemia, and exercise all trigger the rapid secretion of epinephrine.
Responses are initiated at the hypothalamus and brainstem. The final common pathway is the activation of the cholinergic fibers in the greater splanchnic nerve.
ACh is released on cholinergic receptors on chromaffin cells to release epinephrine (and to a lesser extent, norepinephrine (NE)).
The release occurs from secretory granules of chromaffin cell by calcium-dependent exocytosis.
Body’s integrated response to stress
Major stressors activate CRH, ADH and NE neurons in the hypothalamus.
NE release in the brain acts as a molecular switch for mediating arousal, aggressiveness and sharpening a number of sensory behaviors.
CRH activates the ACTH-cortisol axis.
At the same time, stimulation of sympathetic neurons in the hypothalamus leads to stimulation of the splanchnic nerve and release of epinephrine from the adrenal medulla.
Both epinephrine and cortisol lead to rapid energy mobilization and redistribution as well as changes in cardiac responsiveness.
At the same time, these hormones lead to inhibition of a number of non-essential (as far as stress response is concerned) physiological responses leading to rapid mobilization of resources towards combating stress.
There is a negative feedback of this response
Actions of epinephrine
Increased: Glycogenolysis Gluconeogenesis Lipolysis Calorigenesis Insulin Secretion Glucagon Secretion Muscle K+ uptake Cardiac contractility Heart rate Conduction velocity Arteriolar dialtion GI, urinary, and bronchial muscle relaxation
Decreased:
BP
Glucose utilisation
Mechanisms of adrenergic receptor action
G-protein coupled receptors.
β-adrenergic receptors stimulate adenylate cyclase and thus cAMP is the second messenger that mediates their effects.
The α2-adrenergic receptor is coupled to the G-protein Gi and inhibits cAMP production.
On the other hand, the α1 adrenergic receptors activate the Phospholipase C signaling pathway.
What is the most common congenital defect of an adrenal enzyme?
21-hydroxylase
Required for conversion of 17-hydroxyprogesterone and progesterone to the precursors of cortisol and aldosterone (11-deoxycortisol and 11-deoxycorticosterone)
Neither cortisol nor ALDO are synthesized; levels of adrenal androgens are increased
Adverse effects of too much cortisol for too long
Detrimental effects in situations where they are maintained at high levels for prolonged periods:
Muscle weakness
Thinning of the skin (decreased fibroblasts and collagen syn)
Increased capillary fragility and easy bruising
Interference with calcium absorption and/or bone formation (osteoporosis and bone fractures) due to Vit D antagonism actions
Deposition of adipose tissue on the trunk, abdomen, face, and mobilization from the extremities (HIGH DOSES ONLY)
Anti-inflammatory (can be therapeutic!) by inhibiting Phospholipase A2
Immunosuppressive (decreased T-cell numbers and activation)
Polycythemia and Beta-adrenergic effects
When is the rate-limiting step in epinephrine and NE synthesis
Tyrosine hydroxylase converts tyrosine to dihydroxyphenylalanine. RATE LIMITING
This compound in turn is converted to dopamine in the cytosol.
Dopamine is then taken up in the secretory granules where it is converted to norepinephrine and then epinephrine.
Which receptors do NE and Epi affect more?
Epinephrine activates the β-adrenergic receptors with greater efficacy
Norepinephrine activates the α-adrenergic receptors better.
What is the major mediator of cholinergic control?
Activation of nicotinic acetylcholine receptors (nAChRs)- ligand gated
And to a lesser extent: calcium increases by the activation of muscarinic acetylcholine receptors (mAChRs)- g-protein coupled
What’s more important for regulation or hormone levels: free hormone or bound hormone levels?
Free hormone levels!
