adrenal hu Flashcards
layers of adrenal cortex
-from mesoderm
-zona glomerulosa: mineralcorticoids (aldosterone)
-zona fasciculata and reticularis : glucocorticoids and androgens
-adrenal cortex is essentail for life, loss of function is fatal
adrenal medulla: from neural crest. epi, norepi, dopa, and dopamine. derived from neural crest. total loss isn’t life threatening.
acetate to 27 carbon cholesterol to pregnenolone to progesterone to everything else
- first step is cholesterol side chain cleavage by p450 desmolase side chain cleavage enzyme to make pregnenolone. is the RATE limiting step.
- most of the enzymes are cytochrome p450 oxidases, exception is the cytoslic 3beta hydroylsteroid dehydrogenase.
glomerulosa layer of adrenal cotex makes aldosterone
- does not have 17 alpha hydroxylase so cant make cortisol or androgens.
- has aldosterone synthase, so can make aldosterone.
- aldosterone is a steroid hormone so it isnt pooled, its synthesized on demand. limited by the rate at which glomerulosa cells can synthesize it.
- once made, 37% is free in plasma, rest is bound weakly to CBG(corticosteroid binding protein) and albumin
- aldosterone is for kdney reabsorption of sodium and water to enhance potassium secretion. similar action in colon, salivary and sweat glands
- aldosterone: increases NaCl reabsorption from distal nephron and potassium secretion from distan nephron
cortisol and androgens get made in fasciculata and reticularis layers
- the fasciculata and reticularis dont have aldosterone synthase, so cant make aldosterone. do have 17 alpha hydroxylase though so they can make androgens and cortisol.
- cortisol in blood: 90% bound to cortisol binding protein, 7% bound to albumin, 3% free
- you use 17 alpha hydroxylase to make androgens and cortisol. androgens amde are: DHEA and androstenedione. Androstenedione can be converted to testosterone in peripheral tissue.
- DHEA reaches peak production in your 20s. DHEA related to aging.
cortisol mechanism of action
cortisol crosses cell membrane, binds receptor in cytosol, goes to nucleus, and modulate gene transcription.
- feedsback and inhibits the expression of CRH receptor and ACTH in the cortocotrophs of the anterior pituitary.
- Cortisol also inhibits POMC
effects of cortisol action
-metabolic:
stimulates gluconeogenesis in liver. enhances protein breakdown in muscle to give aa for gluconeogenesis. stimulates lipolysis in adipose tissue for fuel. fat gets deposited centrally for some reason.
-interferes with calcium absorption in gut and decreases osteoblast activity.
-anti inflammatory effects:
inhibits cytokine production. inhibits production of chemoattractants. vasoconstriction and decrease capillary permeability.
immunosuppressive:
decreases lymphocyte proliferation. inhibits hypersensitivity rxn.
causes emotional instability bc you have receptors in the brain.
overall: anti inflammatory and suppresses the immune system. causes muscle breakdown and lipid lipolysis. block glucose uptake, except in brain. just puts glucose in blood.
cortisol is a glucocorticoid but has a little bit of mineral corticoid activity.
certain drugs can mimic activity of cortisol and can have greater or less and every combo of mineral and gluco corticoid activites.
cellular actions of ACTH and CRH
- CRH from the hypothalamus acts on corticotroph in anterior pituitary. binds to a gprotein coupled receptor that increases cAMP, PKA, calcium in and ACTH from vesicles in the corticotroph are released.
- ACTH binds to adrenal cortex melanocortin receptor. g rprotein linked receptor, cAMP, to pka, to increasing activit of desmolase and synthesis of several enzymes.
- ACTH is made by post translational modification of of the precursor protein POMC.
- ACTH increases activity of desmolase.
- feedback: circulating cortisol inhibits ACTH and CRH release. in anterior pituitary, cortisol inhibits POMC and inhbits release of ACTH vesicles. in hypothalamus, cortisol decreases mRNA and peptide levels of CRH and inhibits release of CRH.
diurnal variations in ACTH and cortisol production
- before every cortisol peak, you have an ACTH peak. both are under diurnal control.
- highest level of cortisol in early morning and lower in the evening.
- physical, psychological, and biochemical stress enhance CRH secretion and ACTH secretion which increases cortisol. Ex is hypoglycemia increases CRH and ACTH which increases cortisol and raise blood glucose level
21-alpha hydroxylase deficiency
-causes congenital adrenal hyperplasia. decreased cortisol and aldosterone production. you have increased ACTH production, bc there is no cortisol to feedback and stop it. ACTH is a trophic factor, so it causes the adrenal zona glomerula to hypertrophy.
-end up with increased androgen production and female genitalia.
-hormone replacement therapy: you can use other glucocorticoids to substitute cortisol and reduce ACTH levels. this will also reduce the hyperplasia and overproduction of androgens. mineralcorticoids for aldosterone are also available.
consequences of 21-alpha hydroxylase deficency:
–decrease aldosterone synthesis, hypotension, loss of salt, dehydration
–decreased cortisol synthesis, hypoglycemia, hyperplasia of adrenal gland
–increased androgen synthesis, weird sex organ
17 alpha hydroxylase deficiency
reduced or no synthesis of cortisol or androgens.
- increased aldosterone. hypertension, hypokalemia, sexual infantilism
- the hypertension and mineralcorticoid excess is treated with glucocorticoid replacement.
- estrogen treatment for women and surgery and testosterone for men
- you have decreased cortisol but same amt of ACTH so you end up with adrenal hyperplasa.
Cushings syndrome
- hyperadrenal function. can be hypercortisolism or hyperadrenocorticism.
- happens when tissues are exposed to excessive cortisol for a long time. often caused by prolonged imunosupression drugs, adrenal tumors, and turmors that increase ACTH like pituitary adenomas, ectopic ACTH syndromes, etc.
- Cushings SYNDROME is excess cortisol of any etiology
- Cushings DISEASE is only hypercortisolism secondary to excess production of adrenocorticotropin from a pituitary gland adenoma.
- moon face, buffalo hump, body fat, emotioal issue, muscle wasting, hypokalema, hypertension
diagnosis of Cushings
urinary or salivary cortisol measurement
-dexamethasone supression test. dexamethasone provides negative feedback to pituitary to supress ACTH release.
-normal results of test: cortisol low and ACTH low
adrenal tumor: cortisol high and ACTH low
ACTH producing tumor: ACTH high and cortisl high
treatment: surgery to remove adrenal adenoma or ACTH adenoma. if you remove both adrenals, you have to give hormone replacement of hydrocortisone or prednisolone. alternative therapy is inhibit cortisol synthesis.
Addison’s disease
hypoadrenal function.
- can be autoimmune, TB, infection.
- lack of aldosteorne synthesis. hypotension. hypokalemia.
- lack of cortisol: hypoglycemia, weakness, weight loss, weakness, poor stress tolerance
- faiulre of adrenal glands to make enough cortisol.
- can be bc of antibodies against 21-alpha hydroxylase which makes cortisol and aldosterone
