What are the two distinct endocrine gland regions found in the adrenal glands?
Cortex and the medulla
What are the three steroid hormones that the adrenal glands secrete?
Glucocorticoids Mineral corticoids androgens
What are the catecholamines that are secreted by the adrenal glands?
Epinephrine and norepinephrine
What are the three layers of the adrenal cortex going from superficial to deep?
zona glomerulosa, zona fasciculata, and zona reticularis
What does the adrenal cortex synthesize?
What are the two chemicals that regulate aldosterone synthesis?
Angiotensin II, and K
What are the two glucocorticoids that the zona fasciculata and the zona reticularis secrete?
Cortisol and corticosterone
What are the two androgens that the zona fasciculata and the zona reticularis secrete?
dehydroepiandosterone (DHEA) and androstenedione
What are the cells in the inner layer of the adrenal glands that synthesize and secrete epi/norepi?
What is the zona glomerulosa responsible for synthesizing?
What is the zona fasciculata responsible for synthesizing?
What is the zona reticularis responsible for synthesizing?
What is the main function of cortisol?
Restoring homeostasis after exposure to stresses
The production of glucocorticoids is controlled by multiple hormones that are synthesized and secreted from where?
The HPA axis
What are the components of the HPA axis?
Hypothalamus, the anterior pituitary, and the adrenocortical
What is the hormone that causes the release of glucocorticoids in the hypothalamus?
Corticotropin-releasing hormone (CRH)
What is the function of CRH? (what does it bind to, what does it cause x2)
Binds to, and activates a G-protein on corticotropic cells of the anterior pituitary, causing ACTH secretion and increase production of POMC
What is the function of ACTH once released from the pituitary?
Binds to a melanocortin 2 receptor on adrenal cortical cells, to increase steroidogenic enzyme expression and secretion
What type of G protein is found on the corticotroph cells that cause the release of ACTH? What is the pathway associated with this?
G-alpha, causes PKA and Ca increase, causing preformed ACTH release
ACTH is a proteolytic cleavage product of what?
the larger precursor protein called pro-opiomelanocortin (POMC)
What is the receptor that ACTH binds to on the surface of adrenal cortex? What G protein?
When ACTH binds to MC2R on the adrenal cortex, what does this cause? (2)
PKA to increase, which activates cholesterol side chain cleavage enzyme, and increases cholesterol transport into the cell
What is the first step of steroid production? What is the protein needed for this?
Transport of cholesterol into the mito STAR protein
What is the protein that converts cholesterol in the mitochondria to pregnenolone?
What is the first, and rate limiting step of steroid synthesis? (substrate, enzyme, and product)
Cholesterol conversion to pregnenolone via the p450scc enzyme
Draw out the mineralocorticoid, glucocorticoids, and androgen synthesis pathways.
A defect in the 17alpha enzyme leads to a build up of what product?
A defect in the 21-hydroxylase enzyme leads to a build up of what products?
What is the major enzyme found in the glomerulosa of the adrenal cortex? What is the enzyme found in the lowest amount?
Aldosterone synthase Little 17alpha-hydroxylase
What are the androgens? Where are these produced?
DHEA and androstenedione In the reticularis part of the adrenal cortex
What are the two components of aldosterone synthase?
What is the effect of ACTH on the growth of the adrenal cortex?
Increased ACTH causes hypertrophy.
Cortisol and ACTH are released into the blood in what sort of pattern?
Pulsatile with fluctuations based on the circadian cycle
When is the highest level of cortisol? Lowest?
Highest = when waking Lowest = at bed time
What is the biggest cause of increased ACTH/cortisol?
Free cortisol can freely traverse the cell membrane since it is lipophilic. What happen once it does?
Binds to the GR receptor, causing the receptor to dissociate from HSPs.
Where does the GR receptor/cortisol complex go once bound together? What does it then bind to?
To the nucleus, dimerizes, and binds to the glucocorticoid response element on DNA
What is the overall effect of the binding of the GR receptor/cortisol complex to the GRE?
Either activate or inhibit gene transcription
What is the effect of cortisol on blood glucose levels?
What is the effect of cortisol on the immune system?
What is the effect of cortisol on fibroblast proliferation?
Decreased, leading to decrease CT
What is the effect of cortisol on bone matrix reabsorption and Ca excretion?
What is the effect of cort on muscles?
Breaks down into AAs to feed into gluconeogenesis pathway
What are the two ways that cort increases blood glucose levels through the liver?
Increases gluconeogenesis and glycogenolysis
What are the three major effects of cort on skeletal muscle
1. Decreases glucose uptake 2. increases glycogenolysis 3. Increases protein catabolism
What is the effect of cort on adipose tissue?
Decreases glucose uptake Increases lipolysis
What are the two enzymes that cortisol affects to increase glycogenolysis?
Increases expression of glycogen synthase Inhibits glycogen phosphorylase
How does cort increase cardiac output and blood pressure?
Induces expression of receptors for epi and norepi
How does cortisol increase the conversion of norepi into epi in the adrenal medulla?
Increases expression of the enzyme that does the conversion in the chromaffin cells
How does cortisol decrease the production of prostaglandins, leukotrienes, PAF etc?
Inhibits phospholipase A2 activity
How does cortisol decrease prostaglandin production?
How does cortisol decrease NO production?
Inhibits NO synthase
How does cortisol suppress cell mediated immunity?
Inhibits cytokine production
How does cortisol decrease levels of mast cell inflammatory mediators (e.g. histamine and 5HT)?
Inhibits mast cell activity and reduction of mast cell numbers
What is the effect of cortisol on blood vessels?
What are the three primary androgens? What can they all be converted into?
DHEA, DHEA-S, and androstenedione Converted into Testosterone/estrogens
What is the relative contribution of testosterone from the adrenal cortex in the male?
What is the importance of androgen derived testosterone in women?
Maintenance of pubic and axillary hair
Excess adrenal androgens cause what in men and women?
Men = precocious puberty Women = hirsutism
How does aldosterone increase BP?
Increases volume by decreasing Na secretion and increased K excretion
Renin is released by what? What does it do?
Release by juxtaglomerular cells. Cleaves angiotensinogen to angiotensin I...aldosterone
What is the rxn that ACE catalyzes?
Angiotensin I to II
What does aldosterone bind to when it enters a renal epithelial cell? What what does this then bind to?
Mineralocorticoid receptor (MR) This complex travels to the nucleus, to bind to GRE on DNA
What does the MR/aldosterone complex increase the transcription of?
ENaC transporter Na/K ATPase
What is the function of ENaC transporter?
Transports Na from the tubular lumen of the nephron to the lumen of the renal epithelial cell
What is the function of the Na/K transporter in the nephron tubule epithelial cell? How does this increase water in the blood?
Transports Na into the interstitial fluid in exchange for K. Water follows Na
What is the inactive form of cortisol?
What is the enzyme that converts cortisone to cortisol? What is the enzyme for the reverse reaction?
11beta-HSD1 goes to cortisol 11beta-HSD2 goes to cortisone
Cortisol can bind to the GRE element of the renal tubule epithelial cell's DNA just as well as aldosterone can. How does the tubule cell get around this issue?
Converts cortisol into cortisone
What happens to 11beta-HSD2 in cushing's syndrome? What does this eventually cause?
It becomes saturated, eventually causing HTN
Is the adrenal medulla innervated by the parasympathetic or sympathetic nervous system? What is the neurotransmitter used in this? What does this neurotransmitter bind to
Sympathetic--Ach--binds to chromaffin cells
What are the cells in the renal medulla that synthesize and secrete epi/norepi?
What is the rate limiting step of catecholamine synthesis? What is the enzyme that is involved?
Y to DOPA, catalyzed by Tyrosine hydroxylase
What is the substance that can inhibit tyrosine hydroxylase?
What is the enzyme that converts Epinephrine to Norepinephrine?
What is epinephrine metabolized to? Norepi?
Epi = Metanephrine Norepi = Normetanephrine
What are the receptors of epi/norepi? What are they coupled to?
Adrenergic receptors (alpha and beta) G protein coupled
What are the subtypes of the alpha and beta adrenergic receptors that epi and norepi use?
a1, a2, B1, B2, B3
Which are more strongly activated by norepi, alpha or beta adrenergic receptors?
What is the chemical that mediates the short term stress response? Long term?
Short = epi/norepi Long = ACTH (mineralocorticoids and glucocorticoids)
Moon facies + thick neck + growth retardation + fat trunk + abdo and thin extremities = what disease?
Why can hypercortisolism cause hypokaleemia and HTN?
Increases aldosterone, (which leads to increase in Na/K pumps on renal epithelial cells, as well as ENaC pores).
What is Cushing's "disease"?
Pituitary hypersecretion of ACTH
What happens to ACTH levels if you have an adrenal adenoma? What does this adenoma cause?
Lowers ACTH but causes cushing's syndrome
What are the four ways Cushing's syndrome can result?
1. Pituitary hyper ACTH secretion 2. Adrenal adenoma 3. Ectopic ACTH production 4. Iatrogenic glucocorticoid administration
What happens to [ACTH] with iatrogenic cushing's?
What is the underlying cause of Addison's disease?
Destruction of the adrenal cortex via autoimmune. This decreases cort and glucocorticoids
What happens to [ACTH] in primary adrenal insufficiency or Addison's disease? Why?
increases since there is no Cort to feed back
Why do you get hypoglycemia in Addison's disease?
Why do you get hypotension in Addison's disease?
Why do you get hyperkalemia with Addison's disease?
Less cort means less aldosterone means less K excretion
Why is hyperpigmentation seen in Addisons?
What are the two possible causes of secondary adrenal insufficiency?
Pituitary disease or hypothalamus disease
What is the [CRH] for hypothalamic causes of adrenal insufficiency? [ACTH]?
What is the [CRH] for pituitary causes of adrenal insufficiency? [ACTH]?
increased CRH lower ACTH
What is the one function that is mostly preserved with secondary adrenal insufficiency?
What is the enzymatic deficiency of congential adrenal hyperplasia? What does this lower the [c] of?
21-hydroxylase, leading to decreased aldosterone