Adrenal Physiology Flashcards
Adrenal Gland Architecture
Cortex composed of 3 zones
1. Outer - zona glomerulosa (mineralocorticoids)
2. Middle - zona fasciculata (glucocorticoids)
3. Inner - zona reticularis (androgens)
Medulla derived from neural crest cells (considered modified sympathetic ganglion -> directly release catecholamines)
Cortiocotropin Releasing Hormone/Factor
mature polypeptide, short half-life ~9 min
- synthesized in hypothalamus
- anterior pituitary corticotrophs have CRFR 1 receptor (Gs protein coupled receptor)
- proinflammatory cytokines and chronic stress promotes release of CRF
CRFR1 receptor
Gs adenylyl cyclase activity
- increased synthesis of pro-opiomelanocortin
- cleavage of POMC –> MSH, ACTH, lipotropin
ACTH
39 AA polypeptide -> synthesized in corticotrophs as part of larger 241 AA precursor
- binds Melanocortin-2-recptor in adrenal cortical cells -> Gs alpha -> cAMP -> signal transduction
- rapidly promotes side-chain cleavage enzyme (CYP11A) synthesis in adrenal cortex (required for cholesterol conversion to pregnenolone) –> Rate Limiting Step in adrenal synthesis
Melanocortin receptor
MC1-R => principal melanocortin receptor in skin -> pigmentation
- excess POMC levels cause increase of MSH and ACTH both which can stimulate hyperpigmentation
MCR-2 => primary ACTH receptor
- expressed predominantly in adrenal cortex (also present in skin, adipocytes)
Glucocorticoids
recognized early to cause rise in circulating glucose levels
- cortisol mobilizes AA from proteins, deficiency can cause hypoglycemia
- cortisol is primary active glucocorticoid
10% circulate free
60% circulate with CBG (transcortin)
30% circulate with albumin
Mineralocorticoids
promotes salt and water retention by kidney = aldosterone
- binds mineralocorticoid receptors
Sex steroids
dehydroepiandosterone (DHEA), androstenedione, some testosterone
- binds androgen receptors
Glucocorticoid Receptors
belongs to nuclear receptor super family
- cortisol has highest affinity and potency
- cytoplasmic location of receptors
- homodimers act as transcription factors -> bind genes with GRE, recruits transcriptional cofactors and initiates or inhibits transcription
- regulates development, metabolism, and immune response
Mineralocorticoid Receptor
- aldosterone receptor*
- found in kidney, colon, sweat glands, heart, hippocampus
- equaly affinity for aldosterone and cortisol (cortisol has no effect tho)
Glucocorticoid metabolism
- intracellular conversion of active glucocorticoid to inactive steroid (11-beta hydroxylase type 2)
- Inactive steroid cannot activate receptor
- Inactive steroids can be converted back to active steroid (11-beta hydroxylase type 1)
- Tissue location of 11b hydroxyalse defines net result in that tissue
* most metabolism occurs in liver where cortisone and cortisol can be rapidly conjugated to form tetrahydrocortisone
Glucocorticoids affects of glucose
- increase gluconeogenesis, decrease glucose uptake, increase plasma glucose, increase hepatic glycogen synthesis
- increase peripheral lipolysis, increase plasma FFA
- increase proteolysis, increase urinary nitrogen excretion
Effects of Mineralocorticoids (Aldosterone)
- stimulates kidney reabsorption of Na and water
- stimulates Na and water reabsorption in colon, salivary glands, and sweat glands
- enhances kidney K+ excretion
- hypersecretion of aldosterone can cause hypertension
Glucocorticoid Axis
CRH –> ACTH –> Cortisol (negatively feedbacks to previous two to decrease secretion)
- cortisol –> supresses immunity, increases gluconeogenesis, increases protein catabolism, increases lipolysis
Adrenocorticoid Synthesis
- All steroids are synthesized from cholesterol
- CYP11A1 –> side chain cleavage –> rate limiting step
- CYP17 –> 17alpha-hydroxylase
- CYP21A –> 21-hydroxylase
- CYP11B1 –> 11beta-hydroxylase
Pregnenolone synthesis
synthesized from 27-carbon cholesterol into 21 carbon
- catalyzed by CYP11A1 –> rate limiting step
Aldosterone Synthesis
zona glomerulosa lacks 17alpha-hydroxylase but expresses aldosterone synthase
Cortisol Synthesis
Pregnenolone into progesterone –(21 hydroxylase)-> 11-deoxycortisol -(CYP11B1)-> cortisol
Androgen Synthesis
Pregnenolone and Progesterone turn into androstenediol and testosterone respectively via 17, 20 desmolase
Mineralocorticoid axis
Normal ACTH is tonic and at high levels ACTH is stimulatory
- angiotensin II is stimulatory
- -> ang II and ACTH increase BP
Secondary hypersecretion due to hypothalamic problem?
increase CRH –> increase ACTH –> increase cortisol
Secondary hypersecretion due to pituitary problem
increased ACTH –> increased cortisol –> feedback (decreased CRH)
Primary hypersecretion due to problem with adrenal cortex
increase cortisol –> feedback (decreases both ACTH and CRH)
Cushing Syndrome/Disease
increased ACTH, increased cortisol, +/- of aldosterone
