Day 9.2 Endocrine Flashcards
Layers of the Adrenal Cortex
GFR:
Zona glomerulosa
Zona fasciculata
Zona reticularis
What controls the Zona Glomerulosa? What does it produce?
Renin-Ang –> ZG –> Aldosterone
“salt”
What controls the Zona Fasiculata? What does it produce?
ACTH, CRH –> ZF –> Cortisol and sex hormones
“sugar” (glucocorticoids)
What controls the Zona Reticularis? What does it produce?
ACTH, CRH –> ZR –> Sex hormones (e.g. androgens)
“sex”
What kind of cells are located in the adrenal medulla? From where are they embryologically derived?
Chromaffin cells
Come from neural crest.
What controls the adrenal medulla? What does it produce?
Preganglionic sympathetic fibers signal the adrenal medulla, it makes catecholamines (epi, NE)
Embryo: where does the cortex derive from? the medulla?
Cortex is from mesoderm
Medulla (chromaffin cells) is from neural crest
How do the adrenal hormones get into cells?
They diffuse in, where they act on intracellular receptors, which regulate DNA transcription.
What is the most common tumor of the adrenal medulla (medulla specifically!) in adults? in kids?
Adults: pheochromocytoma
Kids: adrenal neuroblastoma
Pheochromocytoma causes episodic HTN; neuroblastoma does not.
What adrenal tumor is most common in adults?
Benign adrenal adenoma.
For medulla specifically, pheochromocytoma is most common
Where and how do the adrenal glands drain?
Left adrenal —> L adrenal vein —> L renal vein —> IVC
Right adrenal —> R adrenal vein —> IVC
This is the same as L and R gonadal- R testes is higher than left bc R vein drains directly to IVC, so neg prs draws testicle upwards.
How is cholesterol converted to Aldosterone? Where does this take place?
Happens in ZG of cortex: Cholesterol (Desmolase) Pregnenolone (3B-hydroxysteriod dehydrogenase) Progesterone (21a hydroxylase) 11-Deoxycorticosterone (11B hydroxylase) Corticosterone (aldosterone synthase) Aldosterone
What converts cholesterol to pregnenolone? How is it stimulated? How is it suppressed?
Desmolase is the enz
ACTH stimulates desmolase
Ketoconazole (anti-fungal) inhibits it.
What is the precursor to cholesterol?
Acetate
How is Cortocosterone converted to Aldosterone? What stimulates this conversion?
Aldosterone synthase is the enz
Angiotension II stimulates aldo synthase.
How is cholesterol converted to Cortisol (glucocorticoids)? Where does this take place?
Happens in ZF of cortex Cholesterol (Desmolase) Pregnenolone (17a-hydroxylase) 17-hydroxypregnenolone (3B- hydroxysteroid dehydrogenase) 17-hydroxyprogesterone (21a hydroxylase) 11-Deoxycortisol (11B hydroxylase) Cortisol
How is cholesterol converted to androgens? where does this happen?
Happens in ZR of cortex Cholesterol (Desmolase) Pregnenolone (17a-hydroxylase) 17-hydroxypregnenolone (17, 20 lyase) Dehydroepiandrosterone DHEA (3B- hydroxysteroid dehydrogenase) Androstenedione (17B) Testosterone
In the periphery, Testosterone can be converted to DHT (more potent form by 5a-reductase)
How is cholesterol converted to estrogens? Where does this occur?
1st part of pathway is same is androgens, so occurs in the ZR.
But, actual conversion to estrogens rather than androgens occurs in the periphery.
Androstenedione (+Aromatase) –> Estrone
Testosterone (+Aromatase) –> Estradiol
Testosterone is also converted to DHT (more potent form) in the periphery- this is catalyzed by 5a-reductase.
Action of finasteride
Drug that inhibits 5a-reductase, therefore it doesn’t allow conversion of testosterone to DHT.
What are the 3 things that cause congenital bilateral adrenal hyperplasia? Why are the adrenals hyperplastic?
17a-hydroxylase deficiency
21-hydroxylase deficiency
11B-hydroxylase deficiency
All congenital adrenal enz defects cause enlgmt of the adrenals since cortisol is decreased. Decreased cortisol causes increased ACTH, and the increased ACTH is what causes the enlgmt.
What does 17a-hydroxylase do?
Converts pregenolone (ZG) to 17-hydroxypregnenolone (ZF) Converts Progesterone (ZG) to 17-hydroxyprogesterone (ZF)
Once converted, the ZF hormones follow the pathway to make glucocorticoids (cholesterol)
17a-hydroxylase deficiency
Decreased sex hormones and decreased cholesterol, bc can’t get from the ZG to the ZF and ZR. Mineralocortocoids (aldosterone) are increased, bc everything stays in the ZG.
Sx: HYPERtension, hypokalemia
The HTN is bc there is excess mineralocorticoids, so increased Na+ and fluid retention.
XY: decreased DHT causes pseudohermaphroditism (externally phenotypic female, no internal reproductive structures)
XX: Externally phenotypic female w normal sex organs, but lacking secondary sex char (sexual infantilism)
What does 21-hydroxylase do?
Converts Progesterone (ZG) to 11-deoxycortisone (ZG) --> > > mineralocorticoids Converts 17-hydroxyprogesterone (ZF) to 11-deoxycortisol (ZF) --> > > Glucocorticoids
21-hydroxylase deficiency
Most common adrenal hormone deficiency.
Bc ZG and ZF pathways are blocked, there is decreased cortisol (and therefore increased ACTH) and also decreased mineralocorticoids (aldo)
Everything is shunted to the ZR, so there are increased sex hormones. (more testosterone is made)
Sx: HYPOtension, hyperkalemia, increased plasma renin acitivity and vol depletion. Salt wasting can lead to hypo-vol shock in a newborn
Masculinization and female pseudohermaphroditism
The hypotension is bc you can’t make mineralocorticoids
What does 11B-hydroxylase do?
Converts 11-deoxycorticosterone (ZG) to Corticosterone (ZG) –> > mineralocorticoids
Converts 11-deoxycortisol (ZF) to Cortisol (ZF) -so makes glucocorticoids
11B-hydroxylase deficiency
Decreased corticosterone and aldosterone (from ZG), decreased cortisol ZF), and eveything is shunted to the ZR, so increased sex hormones.
11B- hydroxylase converts 11-dexoxycorticosterone to corticosterone (and that goes to aldo), so when there is no enz, the 11-deoxycorticosterone builds up in the ZG- and since it’s part of the mineralocorticoid pathway, it’s also a mineralocorticoid (altho a weaker one).
So: deficiency causes HYPERtension (due to the excess 11-deoxycorticosterone which acts as a mineralocorticoid)
Other Sx include masculinization from the increased sex hormones.
Which adrenal hormone deficiencies cause masculinization?
11B-hydroxylase
21a-hydroxylase
(masculinization has a 1 in the 2nd digit)
Which adrenal hormone deficiencies cause HTN?
11B-hydroxylase
17a-hydroxylase
(HTN has a 1 in the 1st digit)
3B-hydroxylase deficiency
Can’t make anything! No mineralocorticoids, glucocorticoids, androgens or estrogens.
Results in excess salt in urine
Early death.
Where is cortisol made?
Adrenal zona fasiculata
Function of cortisol
- Maintains BP by up-regulating alpha-1 receptors in arterioles (doesn’t stimulate them, just puts them there. Has a “permissive effect” on Epi. Alpha-1 is responsible for vasoconstriction- in septic shock can give cortisol to incrse BP)
- Decreases bone formation (will get osteoporosis if you take steroids too long)
- Anti-inflammatory
- Decreases immune fn
- Increases gluconeogenesis, lipolysis, proteolysis (counter-reg hormone. more likely to get diabetes if you take it.)
How is cortisol regulated?
By ACTH.
CRH from hypothal stim’s ant pit to rls ACTH, which stim’s ZF to make cortisol.
What effect does excess cortisol have on the hormones that regulate cortisol?
Neg fdbk:
Decreased CRH, decreased ACTH, and decreased cortisol secretion.
What are the ways to have primary, secondary, and tertiary cortisol deficiency?
Primary: no adrenals
Secondary: no ACTH from ant pit
Tertiary: no CRH from hypothal
What hormone is affected in Cushing’s syndrome?
Cortisol (increased)
What is the #1 cause of Cushing’s syndrome?
Exogenous (iatrogenic) steroids.
Causes decreased CRH and ACTH d/t neg fdbk.
What are the 3 endogenous causes of Cushing’s syndrome?
- Cushing’s dz (70%)
- Ectopic ACTH
- Adrenal
What is Cushing’s Dz?
Pituitary adenoma that produces ACTH. (and therefore increases cortisol levels)
(So ACTH is elevated- but only mildly)
What’s the difference b/t Cushing’s Syndrome and Cushing’s Dz?
Cushing’s Syndrome = increased cortisol, can be for any reason (eg taking steroids)
Cushing’s Dz is one of the possible reasons for Cushing’s Syndrome. The Dz is a Pit Tumor that secretes ACTH (thereby increasing cortisol).
When is Cushing’s d/t ACTH that’s produced ectopically?
Non-pituitary tsu makes ACTH:
Sml cell lung cancer, bronchial carcinoids
ACTH is majorly increased ^^^, and so cortisol is increased (Cushing’s Syndr)
When is Cushing’s d/t an adrenal cause?
Adrenal adenoma, Adrenal carcinoma, or Nodular adrenal hyperplasia.
This causes the adrenals to secrete cortisol on their own, w/o any signal.
ACTH is decreased/undetectable, since all of the cortisol is causing neg fdbk. The cortisol doesn’t need ACTH to be produced- the adrenals are just producing it on their own.
Findings in Cushing’s Syndrome (increased cortisol)
HTN Weight gain Buffalo hump, Truncal obesity, Moon facies Hyperglycemia (insulin resistance) Skin chgs (thinning, purple striae) Osteoporosis Amennorhea Immune suppression
How to Dx Cushing’s Syndrome
Dexamethasone suppression test
Dex is a synthestic glucocorticoid. So basically, it’s like giving cortisol.
How will a dose of dexamethasone affect a healthy pt?
Dex is like cortisol.
So, after a dose of dex, cortisol will decrease. This is bc there will be neg fdbk from the dex on ACTH. Decreased ACTH means decreased cortisol.
How will a dose of dexamethasone affect an ACTH-producing tumor?
Dex is like giving cortisol.
After a low dose of Dex, nothing will happen- the tumor is producing ACTH, so cortisol will remain high (increased ACTH means increased cortisol)
However
After a high dose of dex, the ACTH secretion from the tumor will be suppressed (neg fdbk, on the tumor)- so there will be less cortisol, since there is less ACTH.
How will a dose of dexamethasone affect an Ectopic ACTH-producing tumor
The ACTH from a non-pituitary source will not be suppressed, no matter what kind of dose you give.
Since ACTH is high, cortisol will remain high.
The dex has no effect.
How will a dose of dexamethasone affect a cortisol-producing tumor?
There is no effect.
Cortisol stays high no matter what the dose.
The ACTH will be suppressed (regardless of the dex or not) bc the cortisol is high.
Dex has no effect.
Which is the only tumor that is suppressible with Dexamethasone
An ACTH-producing tumor of the pituitary (must be in the pit). Only suppressed by high doses tho.
List the glucocorticoids (drugs)
Hydrocortisone Prednisone Triamcinolone Dexamethasone Beclomethasone
How do glucocorticoid drugs work?
Inhibit Phospholipase A2- so no arachnidonic acid, and therefore no leukotrienes and no prostaglandins.
They also inhibit expression of COX-2 (so no prostaglandins)
So overall, they inhibit inflam.
Clinical use for glucocortiocoid drugs
Inflammation (they reduce it)- arthritis Immune suppression Asthma Addison's dz Keloids (they decrease collagen synthesis, so decrease excess scarring)
Toxicity of glucocorticoid drugs
Iatrogenic Cushing's Syndrome (increased cortisol) and all Cushing's Sx. Adrenocortical atrophy Peptic ulcers Diabetes (if chronic use) Psychosis Insomnia Glaucoma Acne
Where is aldosterone made?
Zona Glomerulosa of adrenal corex
When is aldosterone secreted, and what does it do?
Aldo is secreted when there is low blood volume (via AT II) and when there is increased K+.
Keeps Na+, dumps K+ and H+
Aldo increases Na+ channel insertion and Na+/K+ ATPase insertion in principle cells.
Therefore
Aldo causes increased Na+ reabs (and therefore more water reabs to raise blood vol).
It also increases indirect K+ secretion and increases H+ secretion. And by secretion, it means secretion into the urine (excretion)- bc it also upreg’s principle cells K+ chnls and intercalated cell H+ chnls.
Aldo keeps Na+ and gets rid of K+ and H+.
What is primary hyperaldosteronism?
Aka Conn’s. High aldo d/t an aldo-secreting tumor.
Aldo normally keeps Na+ and gets rid of K+ and H+, so this effect is amplified:
HTN, hypokalemia, metabolic alkalosis.
All of this happens w LOW renin tho, bc the aldo is coming from the tumor. High renin feeds back to suppress renin
What is secondary hyperaldosteronism?
Hyperaldo is d/t overactive renin-ang system.
Kidney thinks there is low blood volume, and so induces the renin-ang system to fix it.
Reasons kidney thinks there is low vol:
Renal artery stenosis
Chronic renal failure
CHF (low LV ejection fraction –> poor renal perfusion)
Cirrhosis (low protein state, so lose fluid from blood vessels)
Nephrotic syndrome (also low protein state)
In secondary, the renin level is high (that’s what causing the aldo!)
Rx for Hyperaldosteronism
If primary- remove the tumor!
Also:
Spironolactone (K+ sparing diuretic)- acts as an aldo antagonist
Aldo keeps Na+ and dumps K+ and H+.
Spironolactone gets rid of the water that Aldo brought in, but also keeps the K+ that aldo is trying to dump.
Primary adrenal insufficiency
Addison’s dz.
D/t adrenal atrophy, or destruction of adrenals by dz (autoimm, TB, mets)
Have deficiency of both Aldo (mineralocorticoid) and Cortisol (glucocorticoid).
Causes hypotension (d/t hyponatremic volume contraction- no aldo means no Na+ and water retention) Causes hyperpigmentation. (d/t MSH. Increased ACTH production (trying to increase cortisol) also means increased MSH, since they both come from the POMC.)
Addison’s = Adrenal Atrophy in Absence of hormone production; involves All 3 cortical divisions.
Secondary adrenal insufficiency
Secondary is at level of pituitary.
Decreased pit ACTH production, so decreased cortisol. But, adrenals still make aldo, so don’t have hyperkalemia, bc aldo is dumping the K+.
Also, don’t see skin hyperpigmentation as in primary, since the ACTH is decreased (so MSH is not overproduced)
Tertiary adrenal insufficiency
Tertiary is from hypothalamus (CRH)
Usu d/t the abrupt withdrawal of corticosteroids.
If a pt is on long-term corticosteroids, they are neg’ly feeding back on CRH. No CRH -> no ACTH -> no endogenous cortisol is being made. (But, there is still aldo, so K+ is normal)
If you take pt off of corticosteroids abruptly, there will be no CRH right away.
Waterhouse-Friedrichsen syndrome
Acute primary adrenocortical insufficiency d/t adrenal hemorrhage.
The adrenal hemorrhage can be from N. meningitidis septicemia, from DIC (CV collapse causes hemorrhage, see petechial rash), and from endotoxic shock (gram neg)
Multiple Endocrine Neoplasias- what are the types?
MEN 1 - Wermer’s Syndrome (PPP)
MEN 2A - Sipple’s Syndrome (MPP)
MEN 2B (MOP)
2A and 2B are a/w Ret gene
MEN 1 (Werner’s syndrome)
MEN 1 = PPP Parathyroid tumors Pituitary tumors (prolactin or GH) Pancreatic endocrine tumors (Zol-Ellison, insulinomas, VIPomas, glucagonomas-rare)
MEN 1 commonly presents w kidney stones and stomach ulcers.
MEN 2A (Sipple’s Syndrome)
MEN 2A = MPP
Medullary thyroid carcinoma (secretes calcitonin- get amyloidosis)
Pheochromocytoma
Parathyroid tumors
MEN 2B
MOP
Medullary thyroid carcinoma (secretes calcitonin- get amyloidosis)
Oral/Intestinal ganglioneuromas (a/w marfanoid habitus) aka mucosal neuroma
Pheochromocytoma
Which MENs have pheochromocytoma?
MEN 2A and 2B
