Physiology 3 Flashcards
Zona Glomerulosa
Adrenal Cortex
-make mineralcorticoids (aldosterone)
15%
Zona Fasciculata
Adrenal Cortex
75%
Glucocorticoids (Cortisol)
some androgens, estrogen
Zona Reticularis
Adrenal Cortex 10% Androgens Estrogens some cortisol
Adrenal Medulla
Catecholamines
Epi/Norepi
(Adrenaline and noradrenaline)
Function of Mineralocorticoids
(aldosterone)
-increase Na adsorption and K secretion to maintain body fluid volume
Function of Glucocorticoids
(cortisol)
- provede sustained energy source (glucose, FAs, AAs)
- enhance gluconeogenesis in liver
- increase fatty acids as an alternative energy source
- raise blood glucose
Catecholamines
(epinephrine & norepinephrin)
-rapid response to stress: fuel availability (glucose, fatty acids) to increase CV function and performance (heart, lung, muscle)
Adrenal Sex Hormones
-growth developmental control in men and women
The transport of adrenocortical hormones in blood
- steroid hormone-binding serum proteins
1) globulins
2) albumin
3) cortisol
4) aldosterone
Globulins
- high-affinity reversible binding:
- corticosteroid-binding globulin (CBP, transcortin)
- aldosterone-binding globulin
- sex-steroid-binding protein (SSB)
- progesterone-binding globulin (PBG)
Albumin
-low affinity reversible binding
Cortisol
~90% bound to transcortin (majority) and albumin (less)
- 10% is in plasma is free
- t1/2 60-90 min
Aldosterone
~60% is bound to transcortin, aldosterone-binding globulin and albumin
- 40% is free
- t1/2 is 20min
Purposes of hormone protein-binding?
1) suppresses biological activity of steroid hormones (inactive pool)
2) protect hormone from structural alterations
3) to extend the life-time of hormones in the plasma
4) provide active hormone to target tissue rapidly when needed
Cholesterol
-source for synthesis of all steroid hormones
LDL
-main provider of cholesterol
~80% cholesterol for steroid synthesis
~20% cholesterol is synthesized in adrenal gland
Transport of Cholesterol to Adrenal Cells
- LDL binding to LDL receptors on plasma membranes of adrenal cortical cells
- LDL transported into cell by endocytosis in clathrin-coated pits
- formation of endosomes (early and late) and lysosomes (cholesterol is released from receptors)
- LDL receptors are recycled to plasma membranes
Cholesterol Storage
-esterified and stored in cytoplasmic vesicles until it is needed for synthesis of corticosteroid hormones
Adrenal Corticosteroid Synthesis
-mitochondrial rate limiting step: cholesterol to pregnenolone
Enzyme is CYP11A1 (P450) (cholesterol desmolase)
Neuroendocrine control of steroidogenesis
- ACTH (hypothalamus-pituitary axis)
- stimulates the activity of CYP11A1
- increases cholesterol uptake (by upregulating LDL receptors)
Mineralocortiocoids
-Aldosterone (most potent) ~90% of all activity
-Deoxycorticosterone (DOC, aldosterone precursor)
1/30 aldosterone potency
-9alpha-Fluorocortisol: synthetic potent aldosterone analogue, slightly more than aldosterone
Key Enzymes in Mineralocorticoid Biosynthesis
-CYP11A1 (cholesterol desmolatse) upregulated by ACTH
-Aldosterone Synthase (upreg by ACTH)
corticosterone to aldosterone (final step of synthesis)
Organs that have Mineralocorticoid Receptors
target organs for aldosterone
- kidney
- brain
- lungs
- heart
- vascular tissues
Specific ligand of MR - Aldosterone
- high receptor affinity
- low blood level
Non-specific activation of MRs by glucocorticoids
Cortisol -high receptor affinity -high blood level -active ligand Cortisone -low receptor affinity -inactive ligand
Mineralocorticoid Effects of Gene Expression
UP REGULATION
1) aldosterone binds MRs in cytoplasm
2) hormone-receptor complex translocated to nucleus
3) binding to promoter area of specific genes
4) upregulating of gene expression (Na+/K+ ATPase, Na+, K+ transporters)
- NON-GENOMIC effects - cAMP, IP3, Ca2+ dep regulation, protein phosphorylation mediated cell signaling pathways (SGK-1, ERK1/2, JNK)
Corticosterone
-aldosterone precursor
Cortisol
-hydrocortisone; mineralocorticoid activity
Cortisone
-slight mineralocorticoid activity
Enzymatic inactivation of cortisol
(adrenal cortex, liver)
-11 beta hydroxysteroid dehydrogenase (11betaHSD) converts cortisol to cortisone
casuse increase selectivity of MRs to aldosterone
Aldosterone-Regulated Genes
1) Na,K ATPase -transport Na out and K in
2) Epitheilial sodium channel (ENaC)
3) Serum and GLucocorticoid - regulated Kinase 1
4) Renal Outer Medullary K channel (ROMK) an ATP-dependent K channel that transports K out of cells
Sgk1 activated Na/K ATPase, ENaC, and ROMK to maintain:
low intracellular Na
high intracellular K
Renal Effects of Mineralocorticoids
- Na+ reabsorption to increase total body Na
- K+ secretion to decrease plasma K
- H+ secretion - metabolic alkalosis
- HCO3- production - metabolic alkalosis
- H2O reabsorption for volume expansion
Cortisol
Glucocorticoids
-(hydrocortisone) most potent
~95% of total glucocorticoid activity
Corticosterone
-cortisol precursor, modest potency
~4% of total glucocorticoid activity
Synthetic Glucocorticoids
- more potent than natural
- Dexamethasone (30X cortisol)
- Methylprednisone (5X)
- Prednisone (4X)
Key Enzymes in Cortisol Biosynthesis
- CYP11A1 (MX) cholesterol desmolase inhibited by: Ketoconazole
- 17alpha-hydroxylase
- 3beta-hydroxylase
- 21betahydroxylase
- 11beta-hydrolylase (mx) inhibited by metyrapone; etomidate
Genomic Effects of Glucocorticoids
- Glucocorticoids are cell-permeable
- Binding to glucocortiocid receptors in cytoplasm
- The hormone-receptor complex translocates into the nucleus
- Binding to promoter regions of target genes (5-25% of genome)
- Stimulation or repression of gene expression (transactivation)
- Suppression of genes via transcriptional factors (NFkappaB) (transrepression)
Glucocorticoids on Liver
- promotes gluconeogenesis from amino acids
- upregulate key enzymes
- mobilization of amino acids from muscle into blood
- enhanced glycogen formation to store glucose in liver
Glucocorticoids on Pancreas
- increase insulin production
- increase plasma insulin
Glucocorticoids on Other organs
-insulin resistance increases (insulin-sensitive glucose uptake is not enhances)
Glucocorticoids on glucose uptake and utilization by most cells
decrease
-via inhibiting insulin sensitive glucose transporters and enzymes involved in glucose catabolism
Glucocorticoids on Blood
glucose level increase (up to 50%)
-protection against hypoglycemia
Glucocorticoids on Brain
-enhanced glucose supply increase (insulin-independent)
Glucocorticoids & Protein Metabolism
-various organs (except liver)
Stimulate protein catabolism
-increase protein degradation to amino acids
-amino acids in blood increase
-amino acid transport to tissues decrease
-decrease protein synthesis (muscle, lymphoid tissue) decrease
-body weight decrease
-muscle weakening
-immune functions suppressed, deccreased involution of thymus
Glucocorticoids and Liver
- increased protein synthesis (upregulation of key enzymes)
- increase gluconeogenesis (convert amino acids to glucose)
Overall purpose
-mobilize protein from the peripheral tissues to provide glucose supply to the brain and other tissues
Glucocorticoids on Adipose Tissue
- promote lipolysis
- enhance mobilization & oxidation of fatty acids as an alternative energy source at time of starvation
- fat degradation to fatty acids in the cells
- fatty acids in blood increase
- oxidation of fatty acids in cells increase
Glucocorticoids with Food
- increase food uptake
- redistribution of body fat
- paradoxical fat deposits in the body
Cushing’s Syndrome
- high doses of Glucocorticoids
- fat in chest, head, fat lump between shoulders, purple stretch marks on skin, rounded face
- HTN, diabetes, bone loss
Effects of Cortisol on Immunity and Inflammation
main targets are macrophages and T-lymphs
- dec. production of inflammatory cytokines
- function on inflammatory cells dec
- apoptosis increase
- atrophy of lymphoid tissue
Suppression of inflammation?
- Initial stages of inflammation (lysosomal disruption)
- prevents edema (decreased permeability of blood capillaries)
- decreases leukocyte migration to the inflamed area
- suppresses immune system (T lymphocytes)
- attenuates fever (IL-1 release)
- prevents immunological rejection of transplanted organs and tissues
Glucocorticoids in Skin
-collagen syntheses dec.
Glucocorticoids in Intestine
-Ca2+ absorption dec.
Glucocorticoids in Kidney
-Ca2+ reabsorption dec.
Glucocorticoids in blood
Ca2+ level dec.
-blood clotting reduced, resulting in bruising
Glucocorticoids in bones
- Ca2+ mobilization inc. leads to bone demineralization (osteoporosis)
- growth suppression
Glucocorticoids in blood vessels
-vasoconstrictioin, promotes hypertension
Glucocorticoids in GI
-stimulate GI function, gastric acid and enzyme production
Glucocorticoids in Nervous System
- suppress hypothalamic-pituitary-adrenal axis
- increase appetite, influence sleep and mood
Adrenal Sex Hormones
-androgen precursors and androgens
(dehydroepiandrosterone DHEA, androstenedione, testosterone) - moderately active male sex hormones
Function: developmental regulation of reproductive organs
Adrenal Sex Hormones: Adult males
-weak effects
Adrenal Sex Hormones: Adult females
- the major androgens
- excess leads to suppression of gonadal function and masculinization - adrenogenital syndrome
- Progesterone and estorgen
- important during post-menopausal period
Epinephrine
Adrenal Medulla (80%) -adrenaline -secreted to blood -amino acids derivatives (catecholamines) from Tyrosine
Norepinephrine
Adrenal Medulla (20%)
- noradrenaline
- amino acids derivatives (catecholamines)
Hormones of Adrenal Medulla Target
- heart
- lungs
- muscles
- vessels
Functions of Adrenal Medulla Hormones
- inc. heart rate, breathing, BP, glucose release from liver, blood glucose level, metabolic rate, vasodilation of blood vessels, blood flow to skeletal muscle, fat metabolism, free fatty acids
- dec. digestive processes, urine production
Neural Control (sympathetic nervous system)
Hypothalamic-pituitary-adrenal-axis
-regulates stress response, energy usage, immune response, digestion
CRH
-Hypothalamus - Pituitary
-corticotropin-releasing hormone (CRH) stimulates the pituitary gland to secrete Adrenocorticotropic Hormones (ACTH)
Pituitary - Adrenal
ACTH stimulates adrenal cortex (production of glucocorticoids, mineralocorticoids, sex hormones)
-ACTH also stimulates adrenal medulla to produce adrenalin
Feedback Regulation of Hypothalmic-Pituitary-Adrenal axis
-cortisol, via glucocorticoid receptors (GluRs), initiates a neg. feedback reg by inhibiting the hippocampus, hypothalamus, and pituitary gland
-negative feedback loop
suppression of inhibitory input of hippocamous
suppression of CRH release by hypothalamus
suppression of ACTH production by pituitary gland
Long Term Treatment with Dexamethasone
- cortisol production dec
- functional atrophy of the hypothalamic-pituitary-adrenal axis
Stress
- non-specific response of body to any demand
- stress causes: starvation, infection, trauma, debilitating disease, psychological stress, anxiety, depression
Moderate Stress
-activates hypothalamic - pituitary - adrenal axis while maintaining negative feedback
Acute Stress
- Heart rate inc
- Breathing rate inc
- Blood glucose inc
- Glucose utilization inc
- Energy productioin inc
Effects of Sustained Severe Stress on Hypothalamic-Pituitary-Adrenal Axis
-excessive activation and dysregulation of hypothalamic-pituitary-adrenal axis (overriding negative feedback)
-continuous stimulation of adrenal steroid hormones
-enlargement of adrenal glands, adrenocortical hyperfunction
Major Health Problems:
-Heart disease, immunosuppression, digestive problems, sleep disorders, anxiety, depression
