ME04 - Adrenal Androgens Flashcards
Central 20% of Adrenal Gland
Neuroectodermal origin
Functionally related to sympathetic nervous system
An enlarged specialized sympathetic ganglion
Adrenal Medulla
What does Adrenal Medulla secretes in response to sympathetic stimulation
CATECHOLAMINES |? Discharge catecholamines into the bloodstream
? Composed of Chromaffin cells
What innervates Adrenal Medulla?
Cholinergic preganglionic sympathetic neurons
Components of Chromaffin cells
Has granules that contains: epinephrine and norepinephrine (20% by weight), adenosine triphosphate and other nucleotides (15%), proteins (35%), and lipids (20%).
Main functions of Adrenal Medulla
Catecholamines are secreted into the blood to act as hormones
? Source of all circulating epinephrine (80%) and ~30% of circulating norepinephrine (20%)
Describe Adrenal Medulla Vascularity
Blood is carried from cortex to medulla ; Few medullary arterioles (oxygen- and nutrient-rich blood)
Numerous cortical sinusoids (rich with cortical hormones)
Flow to the suprarenal vein
Medullary arterioles and cortical sinusoids fuse ? medullary plexus of vessels ? single suprarenal vein
Consequence of the Adrenal Medulla Vascularity
high concentration of cortisol from cortex bathe chromaffin cells
Action of Cortisol to the Adrenal Medulla Vascularity
Cortisol inhibits neuronal differentiation of the medullary cells
Cortisol induces expression of PNMT (converts NE to epinephrine)
? Outer 80% of Adrenal Gland
? Mesodermal in origin
? Secretes corticosteroids which are all synthesized from cholesterol.
Adrenal Cortex
Three Distinct layers of Adrenal Cortex
? Zona glomerulosa: Mineralocorticoids (Aldosterone)
? Zona fasciculata: Glucocorticoids (Cortisol)
? Zona reticularis: Adrenal androgens (Androgen)
Thin layer underneath the capsule of Adrenal Cortex
Zona Glomerulosa
? Secretes ALDOSTERONE because it contains ALDOSTERONE SYNTHASE
? Controlled mainly by ANGIOTENSIN II & POTASSIUM
Both stimulate aldosterone secretion
? Middle and widest of the Adrenal Cortex
? Has Straight cords of large cells with “foamy” cytoplasm
filled with lipid droplets
Zona Fasciculata
? Secretes CORTISOL & CORTICOSTERONE, and small amounts of androgen and estrogen
? Controlled by ACTH (Adrenocorticotropichormone)
Deep layer OF Adrenal Cortex
Zona Reticularis
Hormones secreted by the Zona Reticularis
Secretes DHEA (Dehydroepiandrosteione) and Androstenedione, and small amounts of estrogen and glucocorticoids ? Controlled by ACTH & Cortical androgen stimulating hormone.
What are the 2 principal Corticosteroids?
Aldosterone & Cortisol
Principal Mineralocorticoid
Aldosterone (principal mineralocorticoid)
o Affect the electrolyes (?minerals?) of the ECF ? Sodium & Potassium
Principal Glucocorticoid
Cortisol (principal glucocorticoid)
o Exhibit important effects that increase blood glucose concentration
o Protein and fat metabolism
Formation of Catecholamines
Tyrosine»_space; (Tyrosine Hydroxylase)» DOPA»_space; Dopamine»_space; (Dopamine B-hydroxylase)» NE»_space; (PMNT)»_space; Epinephrine
Rate limiting step in the formation of catecholamines
Tyrosine Hydroxylase
Dopamine B Hydroxylase is induced by what factor?
Sympathetic stimulation
PMNT is done by what type of transport?
Facilitated Diffusion
What are adrenocortical Hormones
Progesterone, Glucocorticoids, Mineralocorticoids
Structure of Adrenocortical Hormone
? All are chemical modifications of CHOLESTEROL -
4 rings with 21 carbons
? Progesterone, GLUCOCORTICOID, and MINERALOCORTICOID are 21-carbon steroids
? ANDROGEN are 19-carbon steroids | ESTROGEN (produced primarily in the ovaries) are 18-carbon steroid
Synthesis of Adrenocortical Hormones
Each layer is specialized to synthesize particular hormones
? Depending on the presence or absence of enzymes
17,20- lyase in zona fasciculata: androgenic steroid
Aldosterone synthase in zona glomerulosa: aldosterone
Rate limiting reaction in the Synthesis of Adrenocortical Hormones
Transfer of cholesterol from the outer to the inner mitochondrial membrane
First step in conversion STAR (stereodogenic acute regulatory protein)
Cholesterol desmolase (CYP 11A1) - first step in conversion STAR (stereodogenic acute regulatory protein) - facilitates entry of free cholesterol
? Principal mineralocorticoid
? Synthesized only by the zona glomerulosa | Due to presence of aldosterone synthase
Cannot synthesize glucocorticoids
Aldosterone
What regulates Aldosterone
Regulated primarily by __________________________
Minimally influenced by ACTH
Transport and Metabolism of Aldosterone
? Only ~60% bind to plasma proteins, 40% in free form
? half-life: ~20 mins
? Almost all inactivated by the liver in one pass
Conjugated especially to glucuronic acid and to a lesser extent sulfates
? Excretion
Bile then feces: ~25%
Urine: remaining
Physiologic Action of Aldosterone on DCT and CD
Three actions on the late distal tubule and collecting ducts of the kidney:
increases Na+ reabsorption (principal cells)
increases K+ secretion (principal cells)
increases H+ secretion (?-intercalated cells)
EFFECTS OF INCREASE IN ALDOSTERONE
??Excess increases ECF Volume and arterial pressure but has only small effect on plasma sodium concentration.
simultaneous osmotic absorption of almost equivalent amounts of water
stimulate thirst and increased water intake
??Excess causes hypokalemia and muscle weakness; Too Little causes hyperkalemia and cardiac toxicity.
Stimulates transport of potassium into ICF
Alters the electrical excitability of the nerve and muscle fiber membranes
weakness of heart contraction, development of arrhythmia, heart failure
EFFECT OF ALDOSTERONE IN SALIVARY AND SWEAT GLANDS
Effect on salivary glands: for conservation of salt when excessive quantities of saliva are lost
Effect on sweat glands: for conservation of salt in hot environments
Aldosterone has a proinflammatory, profibrotic effect on the cardiovascular system, causes LVH and remodeling. True or False?
True. Aldosterone binds to mineralocorticoid receptor, an intracellular receptor. Similar to cortisol that alters gene expression
What is the Cellular mechanism of Aldosterone
? Aldosterone diffuses readily to the interior of the tubular epithelial cells.
? Combines with __________________________
Has a stereomolecular configuration that allows only aldosterone or very similar compounds to combine with it.
? Aldosterone-receptor complex diffuses into the nucleus
? mRNA, in conjunction with the ribosomes, causes protein formation.
one or more enzymes
membrane transport proteins required for sodium, potassium, and hydrogen transport through the cell membrane
Aldosterone is almost entirely independent of regulation of cortisol and androgens by zona fasciculata and reticularis. True or False?
True.
Major stimuli for aldosterone production
INC Angiotensin and Serum potassium
INC Na ion concentration very slightly decreases aldosterone secretion. True or False?
True.
ACTH is necessary for aldosterone secretion. True or false?
True, but has little effect in controlling the rate of secretion in most physiological conditions
Major actions of angiotensin II on the adrenal cortex
Specifically increase output of ALDOSTERONE
increased growth (HYPERTROPHY) and Vascularity of the zona glomerulosa;
NO EFFECT on other two zones
increased StAR and ALDOSTERONE SYNTHASE activity
? Major glucocorticoid (STRESS HORMONE)
? Synthesized in zona fasciculata/ reticularis
? ? 95% of glucocorticoid activity of the adrenocortical secretions
CORTISOL
Small but significant portion of Cortisol
Corticosterone
Transport and Metabolism of Cortisol
? Cortisol is bound predominantly (>90%) when in circulation
cortisol-binding globulin (i.e. transcortin)
Albumin (5-7%)
? Circulating half-life of cortisol: 60-90 minutes
? Liver - predominant site of steroid inactivation inactivates cortisol and conjugates them so that they can be excreted more readily by the kidney
Mechanism of Action of Cortisol
??Acts through glucocorticoid receptor (GR)
??Increased gene transcription:
- Rapid translocation of the cortisol-GR complex into the nucleus
- Cortisol-GR complex interacts with glucocorticoid response elements (GREs) in the DNA
- Recruitment of coactivator proteins
- Assembly of general transcription factors
??Reduced gene transcription
- Rapid translocation of the cortisol-GR complex into the nucleus
- Interaction with negative glucocorticoid response elements (GREs)
- Recruitment of corepressor proteins; OR interference with ability of transcription factors to activate gene expression
Cortisol’s Effect on Metabolism
o Catabolic and diabetogenic
o ? blood glucose
??Stimulates GLUCONEOGENESIS in liver
??Inhibit PROTEIN SYNTHESIS, ? proteolysis in muscle
??INCREASE lipolysis
o Promotes glucose sparing
??Decreases glucose utilization by tissues
??Decreases insulin sensitivity of adipose tissue
??? Glut4-mediated glucose uptake
??Potentiates effects of catecholamines on lipolysis
Cortisol’s Cardiovascular Actions
o Permissive actions on Catecholamines
o Good cardiac output and blood pressure
o Stimulates EPO synthesis
Cortisol’s Anti-inflammatory and immunosuppressive actions
o DECREASE production of proinflammatory cytokines
o INCREASE production of anti-inflammatory cytokines
Cortisol results to Decrease or Inhibition as Anti-Inflammatory and Immunosuppressive Actions
o INHIBIT leucocyte migration to site
o INHIBIT phagocytic activity of neutrophils
o ? circulating T-lymphocytes
o ? ability of T-lymphocytes to migrate to site of antigenic stimulation
o Promote atrophy of thymus and other lymphoid tissue
o Inhibit cell-mediated immunity
When CORTISOL stabilizes lysozomal membranes, it results to:
Stabilizes lysozomal membranes ? ? release of proteolytic enzymes that augment local swelling
Cortisol’s action on Reproductive System
dampen reproductive behavior and function
? ? the function of the reproductive axis at the hypothalamic, pituitary and gonadal levels
Cortisol’s action on the bone
o ? bone resorption
? ?intestinal Ca+2 absorption
? ? renal Ca+2 reabsorption
o Inhibit osteoblast bone-forming functions
Cortisol’s action on the kidney
o Inhibit secretion and action of ADH
o ? GFR by increasing cardiac output and acting directly on the kidney
? Vasodilation of the afferent arteriole
Cortisol’s action on the CNS
Glucocorticoid receptor in the limbic system
? Decreases REM sleep
? Increases slow-wave sleep
? Increases awake time
Cortisol’s action on FETAL DEVELOPMENT
o Required for normal development of CNS, retina, skin, GI tract and lungs
o In the lungs, induces differentiation and maturation of TYPE II Alveolar Cells
Other actions of Cortisol
? Connective tissue:
Inhibit fibroblast proliferation and collagen formation
? Gastrointestinal tract:
Trophic effect on GI mucosa
Stimulates appetite
Stimulates gastric acid and pepsin secretion
How is the Secretion of Cortisol regulated
? Regulated by hypothalamus-pituitary-adrenal axis
Hypothalamus: CORTICOTROPIN RELEASING HORMONE (CRH)
Pituitary gland: ADRENOCORTICOTROPIC HORMONE
? Almost entirely controlled by ACTH from anterior pituitary
? Norigenic and systemic stress
Strong diurnal rhythmic regulation from suprachiasmatic nucleus. True or False?
True, Cortisol surges early predawn and morning hours then decline continually throughout the day and night
CRH chronically increases _______________________________ gene expression
Prooplomelanocortin (POMC)
precursor of ACTH and other peptides such as melanocyte-stimulating hormone (MSH)
POMC
What does Adrenal Androgen produces
? Produces DHEAS & DHEA and androstenedione
? Only small amounts of potent androgens are normally produced by adrenal cortex
In females, adrenal androgens are major androgens:
For pubic and axillary hair
For libido
What is the main product of Adrenal Androgen?
DHEAS: main product
Become detectable at ~6 years old: adrenarche
Continually increase, peak during mid-twenties and progressively decline with age (DHEA exhibit same pattern)
Most abundant circulating hormone in young adults
Formation of DHEAS and DHEA
? Zona reticularis expresses cofactors or conditions that enhance the 17,20-lyase function, generating DHEA from 17-hydroxypregnenolone
? Expresses DHEA SULFOTRANSFERASE (SULT2A1 gene), which converts DHEA into DHEAS
? 3?-HSD is expressed at much lower levels
? Androstenedione is a minor product compared to DHEAS and DHEA
Metabolism of DHEAS and DHEA
? DHEAS can be converted back to DHEA by peripheral sulfatases
? DHEA and androstenedione can be converted to active androgens (testosterone and dihydrotestosterone) peripherally in both sexes
? DHEA binds to albumin and other globulins in blood with LOW affinity.
? half-life: 15-30 mins
? DHEAS binds to albumin with high affinity
? half-life: 7-10 hours
Physiologic Actions OF Adrenal Androgens
? Contribution of adrenal androgens to active androgens
Men: negligible
Women: for the growth of axillary and pubic hair and for libido
Regulation of Secretion OF ADRENAL ANDROGEN
??ACTH: primary regulator
zona reticularis shows the same atrophic changes as the zona fasciculata in conditions with little or no ACTH
DHEA and androstenedione display same diurnal pattern as cortisol
DHEA: does not follow diurnal pattern because of long half-life
Other unknown factors regulate zona reticularis function
Adrenarche occurs in the face of constant ACTH and cortisol levels
Rise and decline of DHEAS is not associated with a similar pattern of ACTH and cortisol production
SUMMARY:
The adrenal cortex secretes an entirely different group of hormones, called corticosteroids. These hormones are all synthesized from the steroid cholesterol, and they all have similar chemical formulas. However, slight differences in their molecular structures give them several different but very important functions.
