Download Path Chapter 24 p1148-1163 [4-20

Path Chapter 24: The Endocrine System (pages 1148-1163)
The adrenal glands are made of a cortex and medulla, which differ in their development, structure, and
function
The layers of the adrenal cortex from outer to inner are the zona glomerulosa, fasciculata, & reticularis
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The zona fasciculata makes up ¾ of the adrenal cortex
The zona fasciculate makes glucocorticoids
The zona glomerulosa makes mineralocorticoids
The zona reticularis makes sex steroids
The adrenal medulla is made up of chromaffin cells, which make and release catecholamines, mainly
epinephrine
For each of the 3 major corticosteroids, there are 3 hyperadrenal syndromes:
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Cushing syndrome – excess cortisol
Hyperaldosteronism
Adrenogenital or virilizing syndromes - excess androgens
Cushing syndrome (aka hypercortisolism) – excess cortisol
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Cushing syndrome is caused by anything that causes increased glucocorticoids
Most cases of Cushing syndrome are from exogenous glucocorticoids, called iatrogenic
Cushing syndrome
Endogenous causes can be divided into ACTH dependent and ACTH independent
ACTH-secreting pituitary adenomas cause over 2/3 of cases of endogenous hypercortisolism
o This form is called Cushing disease
o Cushing disease affects women way more than men, and happens most often in young
adults
o Most cases of Cushing disease are caused by ACTH-making pituitary microadenomas
o Rarely, the anterior pituitary can have corticotroph hyperplasia without an adenoma
 This can be primary, or happen secondarily from excessive stimulation of ACTH
release by a CRH-releasing tumor in the hypothalamus
o The adrenal glands in Cushing disease are characterized by nodular cortical hyperplasia,
caused by the high ACTH, and the cortical hyperplasia causes the hypercortisolism
Secretion of ectopic ACTH by nonpituitary tumors causes about 1/10 of cases of ACTHdependent Cushing syndrome
o Most of these cases are small-cell carcinomas of the lung
o Other causes include carcinoids, medullary carcinomas of the thyroid, & islet cell tumors
Some neuroendocrine tumors can make ectopic CRH, causing ACTH secretion &
hypercortisolism
o This will also cause bilateral cortical hyperplasia
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o More common in men in their 40’s-50’s
Primary adrenal tumors, like adrenal adenomas (benign epithelial) and carcinomas (malignant
epithelial tumor) are the most common cause for ACTH-independent Cushing syndrome
o In ACTH independent Cushing syndrome, you’ll see high serum cortisol with low ACTH
o Carcinomas cause more hypercortisolism than adenomas or hyperplasia
o In a unilateral tumor of the adrenal cortex, the parts of that cortex, and the cortex of
the other normal adrenal, will atrophy due to suppression of ACTH secretion
By far most hyperplastic adrenals are ACTH-dependent, and primary cortical hyperplasia (aka
ACTH-independent hyperplasia) is uncommon
Macronodular hyperplasia causes nodules in the adrenals, leading to ACTH-independent
hypercortisolism
o The nodules aren’t autonomous though, and instead overexpress receptors to other
hormones like gastric inhibitory peptide (GIP), LH, ADH, and serotonin, which somehow
cause the hypercortisolism
Morphology of Cushing syndrome:
o The main lesions of Cushing syndrome are in the pituitary and adrenals
o The pituitary shows changes regardless of cause
 The most common change is Crooke hyaline change, caused by high
glucocorticoids
 In Crooke hyaline change, the normal granular basophilic cytoplasm of
ACTH making cells in the anterior pituitary turns homogenous & paler,
from accumulation of keratin filaments in the cytoplasm
o Depending on the cause of the hypercortisolism, the adrenals can show one of several
changes:
 Includes cortical atrophy, diffuse hyperplasia, nodular hyperplasia, or cancer
o When exogenous glucocorticoids cause hypercortisolism, endogenous ACTH is
suppressed, causing bilateral cortical atrophy, due to lack of stimulation of the zona
fasciculata and reticularis by ACTH
 Zona glomerulosa is normal sized in this case, because ACTH doesn’t affect it
o Endogenous hypercortisolism means the adrenals will either be hyperplastic or have a
tumor in the cortex
o ACTH-dependent Cushing syndrome shows diffuse hyperplasia
 Both adrenals are enlarged, and the cortex is thickened and nodular
 The hyperplastic cortex shows an expanded “lipid-poor” zona reticularis, with
compact eosinophilic cells surrounded by an outer zone of “lipid rich” cells with
vacuoles that look similar to those in the fasciculata
 The lipid rich cells give the diffusely hyperplastic adrenals a yellow look (p 1149)
o In macronodular hyperplasia, the adrenals are pretty much entirely replaced by nodules
 Unlike diffuse hyperplasia, areas between nodules still contain micronodules
 This micronodular hyperplasia has brown-black micronodules with atrophy in
between them
o Primary adrenocortical tumors that cause Cushing syndrome can be malignant or benign
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Both are more common in women in their 30’s-50’s
Adrenocortical adenomas are yellow tumors surrounded by capsules
Carcinomas are larger an unencapsulated, and anaplastic
In either kind of functional tumor, the adjacent cortex and the entire opposite
gland are atrophic, from suppression of ACTH release by the excess cortisol
Clinical course of Cushing syndrome:
o Cushing’s develops slowly, so early signs can be subtle
o Early stages of Cushings can show hypertension and weight gain
o As time goes, you get more characteristic symptoms like adipose deposition causing
truncal obesity, moon face, and accumulation of fat in the posterior neck and back
(buffalo hump)
o Hypercortisolism causes atrophy of fast-twitch myofibers, causing decreased muscle
mass and proximal limb weakness (protein broken down to release a.a’s in blood)
o Glucocorticoids induce gluconeogenesis, and inhibit glucose uptake by cells, causing
hyperglycemia, glucosura, and polydipsia, together called secondary diabetes
o Catabolism induced in this state causes loss of collagen and resorption of bones, so the
skin is thin, fragile, and easily bruised, with poor healing
 Often there is characteristic cutaneous striae in the abdomen (page 1151)
 Bone resorption leads to osteoporosis, causing backache and easy fracture
o Glucocorticoids suppress the immune system, so people with Cushing’s are prone to
infections
o Cushing’s also causes mental problems, like mood swings, depression, and psychosis
o In women, Cushing’s can cause hirsutism and menstrual abnormalities
o Page 1150 – table on frequency Cushing symptoms are seen
Diagnosing Cushing’s – use 24 hour urine free-cortisol, which will be increased
o 3 patterns of Cushing’s syndrome:
 Pituitary Cushing syndrome – ACTH is high, and can’t be suppressed by low dose
dexamethasone, so urine steroids (17-hydroxycorticosteroids) stay the same
 Higher doses though will cause the pituitary to decrease ACTH relese,
which decreases steroids in the urine
 Most common
 Ectopic ACTH – shows high ACTH that will not respond to any dose of
dexamethasone
 Adrenal tumor – ACTH is low, because the excess cortisol does feedback on the
pituitary, and it won’t respond to any dose of dexamethasone
Primary hyperaldosteronism – chronic excess aldosterone secretion by the adrenals
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Excess aldosterone suppresses renin-angiotensin
High aldosterone will increase blood pressure, which is the main symptom
Causes of hyperaldosteronism:
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Bilateral idiopathic hyperaldosteronism (IHA) – bilateral nodular hyperplasia of the
adrenals
 Most common cause of primary hyperaldosteronism
 Patients are usually older, and have less severe hypertension than adrenal
tumors
o Adrenocortical tumors – can be either an aldosterone-making adenoma or an
adrenocortical carcinoma
 Single aldosterone-secreting tumors are more common, called Conn syndrome
 Happens more often at mid-life, and more common in women
o Glucocorticoid-remediable hyperaldosteronism – caused by a chimera formed by fusion
of genes for CYP11B1 (11-β hydroxylase) and CYP11B2 (aldosterone synthase)
 This leads to making of both cortisol and aldosterone, and then a hybrid steroid
of the two
 Since cortisol is involved, suppressing cortisol with ACTH by giving them
dexamethasone will also suppress aldosterone
 Rare cause of primary hyperaldosteronism
Secondary hyperaldosteronism is excess aldosterone due to excess renin-angiotensin
o Seen in:
 Decreased kidney perfusion – like in arteriolar nephrosclerosis or renal artery
stenosis
 Arterial hypovolemia and edema – like in congestive heart failure, cirrhosis, and
nephrotic syndrome
 Pregnancy – estrogen increases renin
Morphology of high aldosterone:
o Aldosterone-secreting adenomas are almost always single small well circumscribed
lesions, more commonly found on the left adrenal
 Happen most often in 30-40 year old women
 Aldosterone-secreting adenomas are buried in the adrenal and won’t cause
visible enlargement
 Weirdly, they’re filled with lipid filled cortical cells more similar to a fasciculata
tumor (aldosterone is made in the glomerulosa)
 A characteristic feature of aldosterone-releasing tumors is eosinophilic,
laminated inclusions in the cytoplasm called spironolactone bodies, that are
seen after treatment with antihypertensive drug spironolactone (diuretic)
 There’s no atrophy in the rest of the gland or opposite adrenal
o Bilateral idiopathic hyperplasia – shows both diffuse and focal hyperplasia with cells
resembling the glomerulosa
 More common in kids and young adults, and surgery won’t help, so you give
them an aldosterone agonist like spironolactone
Primary hyperaldosteronism may be the most common cause of secondary hypertension
o The more severe the hypertension is, the more likely it is from primary
hyperaldosteronism
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o 1/5 of cases of treatment-resistant hypertension are from primary hyperaldosteronism
Aldosterone targets the kidney mineralocorticoid receptor, to promote sodium reabsorption,
which then increases reabsorption of water, increasing ECF volume and cardiac output
Sodium reabsorption causes potassium secretion, causing hypokalemia
o This can cause muscle weakness, paresthesia, vision problems, and tetany
(involuntary muscle contractions)
Aldosterone also causes endothelial dysfunction by decreasing glucose-6-phosphate
dehydrogenase levels, which decreases endothelial NO making and causes oxidative stress
Long-term effects of hyperaldosteronism are related to chronic high blood pressure
o This can cause left ventricular hypertrophy, decreased diastolic volume, stroke, and MI
To diagnose primary hyperaldosteronism, there is high aldosterone with lower renin
Aldosterone secreting tumors can be removed well by surgery
Androgenital syndromes:
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The adrenal cortex secretes dehydroepiandrosterone (DHEA) and androstenedione, which get
converted to testosterone in peripheral tissues
Unlike gonad androgens, ACTH regulates adrenal androgen making
o So excess androgens can either be a “pure” syndrome, or happen in Cushing disease
Causes of excess androgens are adrenocortical tumors, & congenital adrenal hyperplasia (CAH)
Adrenocortical tumors that cause virlization are more likely to be androgen-secreting adrenal
carcinomas, which also cause hypercortisolism, so it’s a “mixed syndrome”
Congenital adrenal hyperplasia is a name for a group of autosomal-recessive metabolic errors
characterized by deficiency or lack of an enzyme needed to make a cortical steroid, usually
cortisol
o So the block shunts supplies to make steroids towards the pathways for steroids that
are still open, causing excess of those steroids, usually androgens
o If aldosterone making is also impaired, it’s called salt-wasting
o The excess androgens cause virilization, and the lack of cortisol causes ACTH release,
leading to adrenal hyperplasia
o Page 1153 – steroid making pathways
o 21-hydroxylase deficiency – the defective conversion of progesterone to 11deoxycorticosterone by 21-hydroxylase causes over 90% of CAH
 The mutation is to the CYP21A2 gene, and can cause mild or total loss
 CYP21A2 is inactivated by recombination with a neighboring
pseudogene called CYP21A1
o A pseudogene is an inactive homologous gene created by
ancestral duplication in a localized part of a genome
 In most cases of CAH, parts of CYP21A1 pseudogene replace all or part
of the active CYP21A2
 The effect of taking nonfunctional sequences from CYP21A1 and putting
them into CYP21A2 is the same as inactivating CYP21A2
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3 forms of CAH:
 Salt-wasting (classic) adrenogenitalism
 Simple virlizing adrenogenitalism
 Nonclassic adrenogenitalism – mild form
 Simple virlizing and nonclassic have a higher carrier frequency
 21-hydroxylase deficiency is most common in Hispanics and Ashkenazi jews
 Salt-wasting (classic) adrenogenitalism – lack of 21-hydroxylase causes:
 Block of progesterone11-deoxycorticosterone – so no aldosterone
 Block of 17-hydroxyprogesterone11-deoxycortisol – so no cortisol
 Usually see problems soon after birth, because in uterus the
electrolytes and fluid can be regulated by mom’s kidneys
 Salt wasting CAH shows salt loss, hyponatremia, and hyperkalemia,
which cause acidosis, hypotension, and cardiovascular collapse that can
lead to death
 The block in cortisol leads to excess androgens, which causes
virlization
o Females this is obvious in, but guys you probably won’t notice
until some salt-wasting crisis happens
 Simple virilizing adrenogenitalism - only cortisol making is blocked, so you can
reabsorb sodium fine, & the block shunts to make excess androgens, causing
virlization
 Nonclassic or late-onset adrenal virlism – most common form of 21hydroxylase deficiency
 There’s only a partial deficiency to 21-hydroxylase, which is why it’s
late onset
 Can be asymptomatic or show mild symptoms, like hirsutism, acne, and
menstrual problems (effect of androgens)
In all cases of CAH the adrenals are bilaterally hyperplastic from excess ACTH
 The cortex is thick and nodular, and looks brown from lack of lipid
Most people with CAH have hyperplasia of corticotrophs (ACTH-making cells) in the
anterior pituitary
The main problems in CAH is androgen excess, with or without aldosterone or cortisol
deficiency
CAH also affects the medulla
 High levels of cortisol in the adrenals are needed for the adrenal medulla to
make catecholamines epinephrine and norepinephrine
 In people with salt wasting, the loss of water along with the low cortisol levels
causing adrenomedullary dysplasia (medulla developmental defects) decreases
catecholamine making
 This makes hypotension more likely and can lead to circulatory
collapse
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Depending how severe CAH is, onset of symptoms can be noticed anywhere from in
utero to rarely in adulthood
21-hydroxylase deficiency causes excessive androgens to masculinize females
 Shows clitoral hypertrophy and pseudohermaphroditism in infants, and
oligomenorrhea, hirsutism, and acne in post puberty girls
In males, excess androgens enlarges the external genitalia and causes precocious
(early) puberty, and oligospermia in older males
CAH should be suspected in any newborn with ambiguous genitalia
Treat CAH with exogenous glucocorticoids, which replaces them and suppresses ACTH
to decrease excessive making of androgens
 If salt-wasting, need to give them mineralocorticoids
Adrenocortical insufficiency (aka hypofunction) – can be primary or from decreased stimulation of the
adrenals by decreased ACTH (secondary)
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Primary acute adrenocortical insufficiency – adrenal crisis
o Can happen in people with chronic adrenocortical insufficiency, when any stress
happens that needs increased steroids, and the adrenals can’t make them
o Can also happen when you’re maintaining someone with exogenous corticosteroids, and
then you take them away rapidly, or don’t increase them enough when a stress happens
o Can also happen in a massive adrenal hemorrhage that damages the cortex enough
that it’s insufficient
 Happens in newborns after prolonged and difficult delivery with lots of trauma
and hypoxia
 Newborns also lack prothrombin until days after birth
 This also happens in people on anticoagulants, and in postsurgical patients who
develop disseminated intravascular coagulation leading to hemorrhagic
infarction of the adrenals
 DIC – lots of little clots take up all the clotting factors, allowing easy
bleeding
 Can also happen in bacteremic infection, called Waterhouse-Friderichsen
syndrome
 Waterhouse-Friderichsen syndrome shows:
o Overwhelming bacterial infection – classically Neisseria
meningitides
 Can also be pseudomonas, pneumococci, H. influenza,
or staph
o Rapidly progressive hypotension leading to shock
o DIC with widespread purpura, especially in the skin
o Rapid adrenocortical insufficiency with massive bilateral adrenal
hemorrhage
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Waterhouse-Friderichsen is rare, but catastrophic, and can happen at
any age but is more common in kids
 The adrenals are converted to sacs of clotted blood, which obscures
any underlying detail when you look at it
 Death follows within hrs to days unless you treat it early with antibiotics
Primary chronic adrenocortical insufficiency – called Addison disease
o Rare, caused by progressive destruction of the adrenal cortex
o Symptoms of insufficiency won’t show up until 90% of the adrenal cortex is damaged
o Autoimmune causes of Addison’s is more common in whites and women
o Most cases of damage to the adrenal cortex are either from autoimmunity, tuberculosis,
AIDS, or metastatic cancers
o Autoimmune adrenalitis causes most cases of Addison’s disease
 There is autoimmune destruction of steroid making cells
 Includes antibodies to 21 and 17 hydroxylase
 Two types of autoimmune adrenalitis:
 Autoimmune polyendocrine syndrome type 1 (APS1) – characterized by
chronic mucocutaneous candidiasis and problems of the skin, tooth
enamel, and nails, along with autoimmune destruction of certain organs
o APS1 is caused by mutation to autoimmune regulateor (AIRE)
gene
 AIRE is expressed mainly in the thymus, and acts as a
transcription factor to promote expression of
peripheral tissue antigens
 Self reactive T cells that respond to these antigens are
destroyed
 Autoimmune polyendocrine syndrome type 2 (APS2) – shows a combo
of adrenal insufficiency and autoimmune thyroiditis or type 1 diabetes
in early adulthood
 Primary autoimmune adrenalitits is characterized by shrunken adrenals, with
scattered remaining cortex cells in a network of connective tissue
o Infections, especially tuberculosis and fungi, can cause Addison’s
 TB adrenalitis also affects the lungs and GU
 Histoplasma capsulatusm and coccidiodes immitis are fungi that can cause
addison’s
 People with AIDS are at risk for developing adrenal insufficiency from infectious
or noninfectious (like Kaposi sarcoma) complications
 Infectious adrenalitis shows granulomatous inflammation in the adrenals
o The adrenals are a common site for metastasis of cancer
 Most of the time adrenal function is fine, but sometimes the tumor causes
adrenal insufficiency
 The most common tumors that spread to the adrenals are the lungs and breast
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 Metastatic carcinoma causes the adrenals to enlarge
o Addison’s starts insidiously (not acute) and won’t be noticed till circulating steroids are
very decreased
 The initial signs are progressive weakness and easy fatigue
 GI problems are common and include anorexia, nausea, vomiting, weight loss,
and diarrhea
 In primary addison’s, a characteristic finding is hyperpigmentation of the skin,
especially the sun-exposed areas and at pressure pints, like the neck, elbows,
knees, and knuckles
 This is from increased pro-opiomelanocortin (POMC), a precursor to
both ACTH and melanocyte stimulating hormone (MSH)
 When adrenal insufficiency is caused by the pituitary or hypothalamus,
you will not see hyperpigmentation
 Decreased mineralocorticoids causes potassium retention and sodium loss,
leading to hypotension
 Decreased glucocorticoids can cause hypoglycemia
 Stresses in Addison’s can cause acute adrenal crisis, seen as vomiting,
abdominal pain, hypotension, and vascular collapse leading to death unless you
get them corticosteroids fast
Secondary adrenocortical insufficiency – caused by any problem in the hypothalamus or
pituitary that decrease ACTH, leading to hypoadrenalism
o Can be caused by infection, cancer, infarct, irradiation, and prolonged exogenous
glucocorticoids
o Won’t show hyperpigmentation, because MSH isn’t increased!
o Also unlike Addison’s, secondary will decrease cortisol and androgens, but keep
aldosterone normal, so you won’t see hyponatremia or hyperkalemia
o Secondary can be differentiated form Addison’s by seeing low plasma ACTH
 In secondary, giving them ACTH will raise plasma cortisol, while in Addison’s it
will not
o The adrenals will be smaller
Adrenocortical tumors:
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Adrenal carcinomas are more common in kids, while carcinomas and adenomas are about equal
in adults
Most adrenal cortex tumors are sporadic
Li-fraumeni syndrome (germline p53 mutation) and Beckwith-Widemann syndrome are familial
causes of adrenal tumors
Functional adrenal tumors most often cause hyperaldosteronism and Cushing syndrome
Virilizing tumors are more likely to be a carcinoma
Functional and nonfunctional (nonhormone-making) adrenal tumors look the same
Most adrenocortical adenomas are silent, and is a well circumscribed nodular lesion
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o Unlike functional adenomas, there is no atrophy of adjacent cortex
o They look yellow from lipids, & are made of cells that look like the normal adrenal cortex
Adrenocortical carcionmas are rare, and are more likely to be functional and cause virilism
o They’re large, invasive, poorly demarcated with areas of necrosis & hemorrhage & cystic
change
o Adrenal cancers tend to invade the adrenal vein, vena cava, and lymphatics, and
spread to regional and periaoritic nodes, and the lungs
o Average survival is about 2 years
o Carcinomas that spread to the adrenals are more common than primary adrenal
carciomas
Adrenal incidentalomas are asymptomatic adrenal masses seen in about 4% of people, but most are
small and don’t secrete anything and don’t cause any damage
The adrenal medulla is developmentally, functionally, and structurally different from the adrenal cortex
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The adrenal medulla is made of neuroendocrine cells (neural crest) called chromaffin cells,
and supporting (sustentacular) cells
The adrenal medulla is the major source of catecholamines (epinephrine and norepinephrine)
Outside the adrenals are clusters of neuroendocrine cells similar to chromaffin cells, and the
adrenal medulla and these cells together make up the paraganglion system
o The paraganglion system works with the autonomics, and is divided into 3 groups
based on anatomy: Branchiomeric, Intravagal, and aorticosympathetic
o The branchiomeric and intravagal paraganglia of the parasymps are found near major
arteries and cranial nerves, and include the carotid bodies
o Intravagal paraganglia are distributed along the vagus nerve
o The aoritcosympathetic chain is found at the symp segmental ganglia, so it’s distributed
along the abdominal aorta
Pheochromocytoma – cancers of chromaffin cells, causing excess catecholamines
o Pheochromocytomas are rare causes of surgically correctable hypertension
o Pheochromocytomas follow the rule of 10’s:
 10% of pheochromocytomas are extra-adrenal, happening at organs of
Zuckerkandl (aorticosymps) and the carotid body
 These are called paragangliomas
 10% of sporadic adrenal pheochromocytomas are bilateral
 If it’s familial, half are sporadic
 10% of adrenal pheochromocytomas are malignant
 10% of adrenal pheochromocytomas don’t cause hypertension
 Those that do cause hypertension, most are paroxysmal with episodes
of sudden rise in BP and palpitations, which can be fatal
o ¼ of pheochromocytomas and paragangliomas have germline mutations
 These people usually have symptoms at a younger age, & more often bilateral
 Malignancy is more common in tumors from germline SDHB mutations
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The 3 succinate dehydrogenase complex genes are SDHB, SDHC, &
SDHD, and they encode proteins for electron transport and oxygen
sensing in the mitochondria
 Loss of function of one of these genes stabilizes transcription of the
oncogene for hypoxia-inducible factor 1α (HIF-1α), causing tumors
In many pheochromocytomas you will see remnants of the adrenals
If you incubate pheochromocytomas with potassium dichromate, the tumor turns dark
brown from oxidation of stored catecholamines, which is why they’re called chromaffin
cells
The chromaffin cells can look polygonal or spindle shaped, and their clustered with chief
cells and sustentacular cells into small nests called zellballen, surrounded by a vascular
network (page 1160)
The nuclei of pheochromocytomas have stippled “salt and pepper” chromatin
characteristic of neuroendocrine tumors
There is no histologic feature that reliably predicts clinical behavior of a
pheochromocytoma
 Those with benign features can metastasize, and those with malignant features
may not be
 So you only diagnose whether a pheochromocytoma is malignant or not, by
whether it has metastasized
The main symptom of a pheochromocytoma is hypertension, seen in 90% of patients
 About 2/3 have paroxysmal episodes of hypertension, with sudden big increase
in BP, along with tachycardia, palpitations, headache, sweating, tremor, and a
sense of apprehension (anxiety)
 These episodes can also include abdominal pain, chest pain, nausea, and
vomiting
 Most often these patients have chronic increased BP, and then have episodes
that raise it higher
 The episodes can be precipitated by emotional stress, exercise, posture
changes, and palpation of the area with the tumor
 Those with bladder paragangliomas can cause an episode during peeing
The increase in catecholamines can also cause congestive heart failure, pulmonary
edema, MI, ventricular fibrillation, or cerebrovascular events
 The heart ones are called catecholamine cardiomyopathy
Pheochromocytomas show increased urinary excretion of free catecholamines and
their metabolites, like vanillylmandelic acid and metanephrines
Multiple endocrine neoplasia (MEN) syndromes – inherited diseases causing proliferative lesions of
multiple endocrine organs
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These tumors happen at a younger age than sporadic, happen in many organs, and in each
organ they are multifocal, and preceded by asymptomatic endocrine hyperplasia, and reoccur
more than sporadic
MEN 1 (aka Werner syndrome) – rare, characterized by problems with the parathyroid,
pancreas, and pituitary (the 3 P’s!)
o Primary hyperparathyroidism is the most common manifestation – seen by age 40-50
 Show hyperplasia or adenomas
o Pancreas tumors are the leading cause of death in MEN 1
 Usually aggressive and mestasize, often causing many microadenomas in the
pancreas along with one or two dominant lesions
 They’re often functional, and usually secrete pancreatic polypeptide
o The most common anterior pituitary tumor in MEN 1 is a prolactinoma
o The duodenum is also a common site of tumors
o MEN 1 is caused by a germline mutation to the MEN1 tumor suppressor gene, which
codes for menin
 Menin works in gene regulation, and both promotes and inhibits parts of the
cell cycle
o Symptoms of MEN 1 include hypoglycemia from insulinomas of the pancreas, peptic
ulcers in Zollinger-Ellision syndrome, kidney stones from hypercalcemia from excess
PTH, or prolactin excess
MEN 2- there’s 3 types:
o MEN-2A (aka Sipple syndrome) – characterized by pheochromocytoma, medullary
carcinoma of the thyroid, and parathyroid hyperplasia
 Medullary carcinoma of the thyroid happens in every case, is multifocal, and
causes C-cell hyperplasia of the adjacent thyroid
 They’re aggressive and secrete calcitonin
 MEN-2A is caused by mutations to the RET proto-oncogene
 The RET proto-oncogene codes for a receptor tyrosine kinase that binds
glial-derived neurotrophic factor (GDNF), transmitting growth and
differentiation signals
 This is a gain of function mutation that continuously activates the
receptor
o MEN-2B – has more aggressive medullary thyroid carcinomas, but no
hyperparathyroidism, and leads to neuromas of the skin, oral mucosa, eyes, respiratory
and GI tracts
 Shows marfanoid habitus – long axial skeletal features & hyperextensible joints
 Caused by a single amino acid change in RET, which affects the catalyzing
domain of the tyrosine kinase, leading to continuous activation
o Familial medullary thyroid cancer – only affects thyroid, and happens at a later age than
the other 2
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All people with germline RET mutations are advised to have prophylactic thyroidectomy
to prevent inevitable development of medullary carcinomas
Pineal gland – made of pineocytes with photosensory and neuroendocrine function
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The pineal gland secretes melatonin, which helps control circadian rhythm, including the sleepwake cycle
Tumors of the pineal gland are rare
Most come from embryonic germ cells, and form germinomas
Pharm Chapter 26: Pharm of the Hypothalamus and Pituitary Gland
The hypothalamus and the pituitary gland are the main regulators of the endocrine system
The pituitary gland consists of:
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Anterior pituitary- aka the adenohypophysis, derived from ectoderm
o “adeno”- oral ectoderm
Posterior pituitary- aka neurohphysis, a neural structure derived from the ventral diencephalon
ectoderm
The hypothalamus controls the pituitaries, by taking neural signals form the brain, and converting
them into chemical messages to regulate secretion of pituitary hormones
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The hypothalamus controls the anterior pituitary by secreting hormones into the hypothalamicpituitary portal vascular system
o Page 466- it starts at the superior hypophyseal artery and capillaries at the
hypothalamus, and has fenestrations to release hormones into the veins and carry the
hormones to the pituitary
The hypothalamus controls the posterior pituitary through a direct neural connection
o Cell bodies of neurons of the supraoptic and paraventricular nuclei of the hypothalamus,
make hormones that are transported down axons to be stored in the posterior pituitary
Both pituitaries have capillaries then to get hormones to the system
During development, transcription factors Pit-1, T-Pit, and Prop-1 cause anterior pituitary cells to
differentiate into somatotrophs, lactotrophs, thyrotrophs, corticotrophs, and gonadotrophs
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Page 467
Except for dopamaine, all hypothalamic releasing factors are peptides
All anterior pituitary hormones are proteins and glycoproteins
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Since ingested proteins get digested in the intestines and absorbed as a.a.’s, treatment with
these or for these must be done nonorally
Anterior pituitary hormones are grouped as:
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Somatotropic hormones- GH and prolactin
Glycoprotein hormones- LH, FSH, and TSH
o They each have the same α subunit, as does human chorionic gonadotropin (hCG), but
each has a unique β subunit that’s part of its specificity
Adrenocorticotropin (ACTH)- its own class, made from proteolysis of a larger precursor
Hypothalamic factors bind to G protein coupled receptors on anterior pituitary cell membranes
-
Most of the receptors then alter levels of intracellular cAMP or IP3, and calcium
Ex: GHRH binds to its receptor on somatotrophs, ↑ intracellular cAMP and calcium, while
somatostatin binds its receptor on somatotrophs, and ↓ cAMP and calcium
Most hypothalamic releasing factors are secreted in a cyclical or pulsatile manner
-
Ex: GnRH is released every few hours, and how often and how much is secreted determines how
much FSH and LH is released
o If you continuously release GnRH though, it inhibits FSH and LH release
Endocrine axis- endocrine pathways involving the hypothalamic factor, pituitary target cell, and the
ultimate target cell
Usually for hypothalamic-pituitary axes, the target organ makes a hormone that does negative feedback
on the hypothalamus and pituitary, in order to maintain homeostasis
Primary disorders are caused by the target cell, secondary by the pituitary, and tertiary by the
hypothalamus
The hypothalamic-pituitary-GH axis regulates processes that promote growth
-
GH is made by somatotrophs
GH is first expressed in high amounts at puberty, and is secreted in a pulsatile manner, with the
largest pulse coming during sleep
Most of the anabolic effects of GH are mediated by insulin-like growth factors, especially IGF-1,
which is released into blood from hepatocytes in response to GH
GH has a short half-life and has pulsatile release, while IGF-1 is protein bound and in the
circulation for a long time
So IGF-1 levels can tell you about GH activity, and are more appropriate to screen for
acromegaly
Environmental factors like hypoglycemia, sleep, exercise, & good nutrition can all ↑ GH release
Endogenous things that ↑GH are GHRH, sex steroids, dopamine, and ghrelin
o Most ghrelin is secreted by gastric fundal cells during fasting
Environmental factors that inhibit GH are hyperglycemia, no sleep, and poor nutrition
Endogenous things that inhibit GH are somatostatin, IGF-1, and GH
Failure to secrete GH, or to enhance IGF-1 release, during puberty, stunts growth
o GH deficiency is most commonly from defective release of GHRH (tertiary)
o
-
Laron dwarfism- primary deficiency that’s a failure of IGF-1 release in response to GH,
and can’t be treated with GH
o Sermorelin- synthetic GHRH, can be used to determine primary, secondary, or tertiary
 Tesamorelin- GHRH analogue that can also check for etiology
 If the problem is the hypothalamus, then giving them GHRH should increase
their GH release
 Glucagon, arginine, clonidine, and hypoglycemia can also trigger GH release
o Most cases of GH caused stunted growth are treated with somatropin, which is
recombinant human GH (hGH), taken subcutaneous or intramuscular
 Because it’s co$tly, somatropin needs confirmed GH deficiency or
panhypopituitarism, to be approved
 Unapproved use in sports is a problem
 Somatropin is also used for children with shortness, chronic kidney disease, and
Turner’s and Prader-Willi syndromes
o Mecasermin- recombinant IGF-1, and is used for GH insensitivity, like in Laron dwarfism
 Also approved for GH deficiency and autoantibodies against GH
 Adverse effects are hypoglycemia and rare intracranial hypertension
GH excess usually happens from a somatotroph adenoma, but can also happen from ectopic
making of GH or GHRH
o Gigantism happens if the GH excess is before closure of the epiphyses
 The increased IGF-1 increases bone growth
o Acromegaly happens if the GH excess is after closure of the epiphyses
 The IGF-1 promotes growth of organs and cartilage
 Symptoms are large face, hands, feet, organomegaly, fatigue, hyperhidrosis
(excessive sweating), and macroglossia (big tongue)
 If a pituitary adenoma caused it, you can also get headache, loss of other
pituitary hormones, and visual field loss
o Treatment for the adenoma are surgery, medicine, and radiation
 Usually do a trans-sphenoidal surgery
 Medical options are somatostatin receptor agonists (aka somatostatin receptor
ligands (SRLs) or somatostatin analogues), dopamine analogues, and GH
receptor antagonists
o Somatostatin receptor agonists (SRLs) are the mainstay of medical therapy
 Somatostatin inhibits GH release, and but only has a half life of a few minutes,
so it’s not used to treat much
 Octreotide and lanreotide-synthetic, longer lasting somatostatin analogues
 Since GH receptors are used for lots of things, octreotide can also be
used for esophageal varices and hormone-secreting tumors
 Adverse effects of SRL’s are nausea, diarrhea, gallstones, and lightheadedness
 SRLs can normalize GH and IGF-1 levels, and ↓ size of pituitary tumors
o Dopamine mainly acts on lactotrophs to inhibit prolactin release, but also can
stimulate somatotrophs to release GH
o
 For some reason though, dopamine can ↓GH in people with acromegaly
 Bromocriptine and cabergoline are dopamine analogues used
 Dopamine receptor agonists are cheaper, but less effective than SRLs
A GH molecule has two binding sites, each of which can bind one GH receptor
 After it binds, GH causes dimerization of the receptor to trigger receptor
activation and intracellular signaling
 Pegvisomant- GH analogue that’s been modified so that one of its binding sites
has higher affinity to bind the receptor, and the other binding site is inactive
 Pegvisomant binds the receptor and prevents dimerization, so it’s a
competitive antagonist of GH activity
 It also has lots of polyethylene glycol, which prolongs its half life so that
it can be taken once a day
 Pegvisomant is the most potent at inhibiting IGF-1, but then it therefore
↑GH since there’s less IGF-1 to inhibit it
 Issues with it are it’s expensive, it’s new, and causes liver issues
Lactotrophs of the anterior pituitary make and release prolactin
-
-
-
-
Dopamine from the hypothalamus inhibits this
TRH not only stimulates thyrotrophs, but also increases prolactin release
Estrogen and breast feeding increase prolactin release
Unlike other anterior pituitary cells, lactotrophs are continually inhibited by the hypothalamus
through dopamine
o So a disease that interrupts the hypothalamic-pituitary portal would decrease release of
most anterior pituitary hormones, but increase release of prolactin
o Dopamine receptor antagonists phenothiazine and metoclopramide can cause excess
prolactin
Prolactin doesn’t have any negative feedback system
Prolactin regulates mammary gland development and milk protein making and release
Prolactin levels are usually low in men and nonpregnant women
Increased estrogen during pregnancy stimulates lactotrophs to release more prolactin
o During pregnancy though, estrogen antagonizes prolactin action at the breasts, so there
is no lactation until after parturition
o Suckling provides a powerful neural stimulus for prolactin release, and breast feeding
causes positive feedback of prolactin release to replenish milk
o If mom doesn’t breast feed, prolactin levels go down within a couple weeks
Increased prolactin levels suppress estrogen making, by antagonizing GnRH at the
hypothalamus, and by decreasing gonadotroph sensitivity to GnRH
o This decreases LH and FSH, in order to prevent ovulation during breast feeding
o Prolactinemia will also suppress this hypothalamic-pituitary-gonadal axis
Bromocriptine-synthetic dopamine receptor agonist that inhibits lactotroph cell growth
o Used to treat prolactinemia, and is taken orally
o
-
Adverse effects are nausea and vomiting, because the area postrema of the medulla,
which controls vomiting, has dopamine receptors
Cabergoline and quinagolide- other synthetic dopamines for prolactinemia
o Cabergoline can be taken once a week or two weeks, and has less GI problems
o Both cabergoline and bromocriptine are safe for pregnancy
o Higher doses of cabergoline may cause valve heart disease
The hypothalamus secretes TRH, which stimulates thyrotrophs in the anterior pituitary to make and
release TSH, which promotes making of TH by the thyroid gland
-
-
TH regulates body energy homeostasis, and has negative feedback on TSH and TRH
TRH and TSH are used to diagnose the etiology
o If the problem is primary at the thyroid, TSH levels will be ↑from decreased TH
o So serum TSH is the main test used in screening for primary thyroid disease
o If it were secondary at the pituitary, TSH would be low despite TH levels
 In this case, if you gave them TRH, TSH would still be low
o Recombinant TSH (thyrotropin) is often used during radioactive iodine treatment
 Allows you to use least amount of radiation possible, to localize its effects to the
thyroid
TH is used to treat hypothyroidism
Neurons from the paraventricular nucleus of the hypothalamus make and release corticotropinreleasing hormone (CRH)
-
-
-
CRH binds to corticotrophs of the anterior pituitary, and triggers release of adrenocorticotropinreleasing hormone (ACTH)
ACTH is made as part of proopiomelanocortin (POMC) precursor that gets cleaved into
melanocyte-stimulating hormone (MSH), lipotropin, and β-endorphin as well
Since ACTH is similar to MSH, it can also bind to MSH receptors, and cause enhanced skin
pigmentation in hypoadrenalism
ACTH stimulates the making and release of adrenocortical steroids glucocorticoids, androgens,
and mineralocorticoids (just for their release, not levels)
o Mineralocorticoid making is also regulated by potassium balance and blood volume,
which are way more potent to it than ACTH
Excessive ACTH causes hypertrophy of the zona fasciculata and reticularis of the adrenal cortex,
while deficiency causes atrophy
The main product from ACTH release is cortisol, which is the main feedback inhibitor of ACTH
o Cortisol is a stress hormone that works in vascular tone, electrolyte balance, and
glucose homeostasis
o Cortisol deficiency can cause illness or death, and excess can cause Cushing’s syndrome
Cosyntropin-synthetic ACTH, used to diagnose primary/secondary adrenal insufficiency
o If it’s primary and you give them cosyntropin, cortisol won’t increase, but if it’s
secondary cortisol will increase
-
Glucocorticoid deficiency is usually treated with cortisol analogues
CRH can be used to look for Cushing’s disease (a pituitary corticotroph adenoma)
o If it’s Cushing’s disease, CRH will increase ACTH
Gonadotrophs secrete LH and FSH, called gonadorotopins
-
-
-
Gonadotropins promote making of androgens and estrogens by the gonads
In males, testosterone does negative feedback on gonadotropes
In females, estrogen can both excite and inhibit gonadotropes, depending on stage of menstrual
cycle
Inhibin is made by the gonads, and inhibits FSH release, and somewhat LH
Activin is a paracrine factor to cause FSH release
GnRH has a short half-life, and can be given in a pulsatile way to trigger gonadotropin release
GnRH analogues with longer half-lives can be giver to suppress making of sex hormones, by
desensitizing the pituitary gland to the stimulating effects of the releasing factor
Leuprolide- most commonly used GnRH agonist, given as a daily subcutaneous injection, or as a
monthly depot injection
o Osmotic pump implants can also be used to deliver leuprolide for 12 months
Long lasting agonists are used to suppress gonadotropins, but will initially cause several days of
increase in sex hormone levels, followed by the lasting suppression
FSH is used to stimulate ovulation for in vitro fertilization
o Urofollitropin-purified FSH taken from urine of postmenopausal women
o Follitropin-recombinant FSH
o Both work, but can cause ovarian hyperstimulation syndrome
GnRH antagonists cetrorelix and ganirelix are sometimes used in assisted reproduction
o They suppress premature surges in LH in early to mid-follicular phase of the menstrual
cycle, helping implantation and pregnancy
Antidiuretic hormone (ADH, aka vasopressin) is made by magnocellular cells of the hypothalamus
-
-
Magnocellular cells have osmoreceptors that sense changes in extracellular osmolality
Increased osmolality (plasma osmotic pressure) stimulates ADH release from the posterior
pituitary
ADH can also be released when baroreceptors in the atria and carotids sense decreased blood
pressure
Hypervolemia and increased atrial distention inhibit ADH release
ADH binds to two types of receptors: V1 and V2
o V1 receptors in systemic arterioles mediate vasoconstriction
o V2 receptors in the kidneys, stimulate expression of water channels to increase water
reabsorption
o So ADH increases blood pressure and increases water reabsorption
Excessive ADH causes syndrome of inappropriate ADH (SIADH)
o Cancer, drugs, pulmonary processes, CNS issues, or pituitary issues can cause it
o
o
-
Causes hypertension and excessive water retention with decreased sodium
Treat with vasopressin receptor antagonists, hypertonic saline, and restricting water
 Conivaptan and tolvaptan- vasopressin receptor antagonists
 Tolvaptan is specific for V2 receptors
Decreased ADH or ADH resistance causes diabetes insipidus
o Shows thirst, polydipsia, and polyuria, from an inability to concentrate urine and retain
water in te kidneys
o Neurogenic diabetes insipidus results from hypothalamus neurons not being able to
make ADH
 In this case, exogenous ADH called desmopressin can stimulate V2 receptors
and fix the symptoms
o Nephrogenic diabetes insipidus results when the kidneys don’t respond to ADH
 Can be caused by mutation to the V2, or by drugs like lithium
 Desmopressin won’t help, so you treat with amiloride or hydrochlorothiazide
diuretics
Oxytocin is made by paraventricular cells of the hypothalamus, and cause muscle contractions of milk
release during lactation, and uterine contraction
-
Oxytocin causes contraction of myoepithelial cells surrounding mammary gland alveoli
Oxytocin release is probably not the stimulus for labor during pregnancy, but it’s used as a drug
to artificially induce labor
Page 477-479
Pharm Chapter 28: Pharm of the Adrenal Cortex
The adrenal gland is made of 2 organs fused together during embryo
-
The outer adrenal cortex forms from mesoderm – makes steroids for salt balance, metabolism,
and androgens
The inner adrenal medulla forms from neural crest cells – makes epinephrine, which is
important for maintaining symp tone
Glucorticoids are important for use as anti-inflammatory agents
-
Long term use though has adverse effects
The adrenal cortex makes mineralocorticoids, glucocorticoids, and androgens
In histo, the adrenal cortex is divided into 3 zones – page 490 (pic of zones)
-
Zona glomerulosa – outermost, makes mineralocortiocoids
o Controlled by angiotensin 2, blood potassium, and a little bit by ACTH
Zona fasciculata – makes glucocorticoids
-
Zona reticularis – makes androgens
Both the zona fasciculata and reticularis are controlled by ACTH, which itself is controlled by
corticotropin releasing hormone (CRH), vasopressin, and cortisol
Glucocorticoids:
-
-
-
-
Cortisol is the endogenous glucocorticoid, and made from cholesterol
Page 491 – pathway to making steroids from cholesterol
o It all starts with the rate-limiting step of converting cholesterol to pregnalone with a
side chain cleavage enzyme (cholesterol desmolase)
o Pregnalone can then be converted into any of the steroids
o Each rxn is catalyzed by oxidase enzymes that are mitochondrial cytochromes
o Each zone has the specific cytochrome oxidase enzymes needed to make its specific
product (ex: fasciculata makes cortisol, but not the other 2, because it has only the
enzymes to make cortisol, and not the enzymes for the other 2)
90% of circulating cortisol is bound to plasma proteins, the main ones being corticosteroidbinding globulin (CBG, aka transcortin) and albumin
o CBG (transcortin) has high affinity for cortisol but low capacity, albumin is not high
affinity, but has high capacity
o Only unbound (free) cortisol is bioavailable and can diffuse through plasma
membranes into cells
 So affinity and capacity of plasma binding proteins regulates availability of
active hormone and therefore hormone activity
The liver and kidney are the main sites of peripheral cortisol metabolism
o The liver inactivates cortisol by conjugating it with glucoronic acid, making cortisol more
water soluble so that the kidneys can excrete it
o The liver and kidney have 2 different isoforms of 11-β hydroxysteroid dehydrogenase
 In the kidney distal collecting ducts, 11-β hydroxysteroid dehydrogenase type
2 (11β-HSD 2) converts cortisol to the inactive cortisone, which can’t bind the
mineralocorticoid receptor, unlike cortisol (aka hydrocortisone)
 The liver has 11β-HSD 1, which can convert cortisone back into cortisol
Cortisol is a steroid that diffuses through the cell plasma membrane into the cytoplasm and
binds to a receptor in the cytoplasm
o 2 types of glucocorticoid receptors:
 Type 1 glucocorticoid receptor – found in organs of excretion (kidney, colon,
salivary glands, sweat glands) and the hippocampus, blood vessels, heart,
adipose, and blood cells
 The type 1 glucocorticoid receptor acts the same as a mineralocorticoid
receptor, so it’s often called the mineralocorticoid receptor
 Type 2 glucocorticoid receptor – found in even more tissues
-
-
-
-
-
-
-
Once cortisol binds its receptor, the hormone-receptor complex dimerizes with another
hormone-receptor complex, and is internalized to the nucleus, where it binds to glucocorticoid
response elements (GRE’s), which are a promoter gene for cortisol
o A lot of genes (1/10 of them) have GRE’s, so cortisol works on most tissues, and either
has a metabolic effect or an anti-inflammatory effect
Metabolic effects of cortisol increase nutrient availability by increasing blood glucose, amino
acids, and triglycerides
o It increases blood glucose by antagonizing insulin action and promoting gluconeogenesis
in the fasting state
o Cortisol also increases protein catabolism, releasing a.a’s to be used by the liver for
gluconeogenesis
o Cortisol helps GH activity in the adipocytes, increasing activity of hormone-sensitive
lipase, causing lipolysis to break down triglycerides & release free fatty acids into blood
 Free fatty acids further increase insulin resistance
Cortisol levels increase in the stress response to many stressors, like vigorous exercise,
psychological stress, acute trauma, surgery, fear, severe infection, hypoglycemia, and pain
o By raising blood glucose, cortisol ensures that the organs will have all the fuel they
need to fight during the stress response
Cortisol as an anti-inflammatory:
o Cortisol inhibits NF-kB, which causes inhibition of cytokine release
o Cytokines like Il-1, Il-2, Il-6, and TNF-α, can stimulate the hypothalamus to release
CRH, which stimulates ACTH and cortisol release
 See there’s a feedback loop for inflammation
In response to circadian rhythm and stress, neurons in the paraventricular nucleus of the
hypothalamus make and release corticotropin-releasing hormone (CRH)
o CRH then travels through the hypothalamic-pituitary portal system to bind G protein
receptors on corticotroph cells of the anterior pituitary
o This stimulates corticotrophs to make pro-opiomelanocotin (POMC), a precursor to
ACTH
The neurons in paraventricular nuclei can also respond to stress by making and releasing
vasopressin (ADH) , which works with CRH to increase release of ACTH
Cleavage of POMC will give you ACTH, melanocyte-stimulating hormone (MSH), lipotropin, and
β-endorphin
o MSH binds receptors on skin melanocytes, causing melanin making to increase skin
pigmentation
o ACTH and MSH are similar in structure, so excess ACTH can bind and activate MSH
receptors, causing increased skin pigmentation
o β-endorphin works in pain regulation and reproduction
ACTH causes cortisol making in the adrenal gland
ACTH also has a trophic effect on the fasciciulata and reticularis of the cortex, so chronic excess
ACTH can cause hypertrophy of the adrenal cortex
Cortisol will cause feedback on the hypothalamus and anterior pituitary
o
o
-
-
-
High cortisol decreases making and release of CRH and ACTH
Chronic decreased ACTH will cause atrophy of the fasciculate and reticularis, but leave
the glomerulosa ok, because blood potassium and angiotensin continue to stimulate it
to make aldosterone
Adrenal insufficiency:
o Addison’s disease – primary adrenal insufficiency where the adrenal cortex is destroyed
due to T cell autoimmune rxns most often, but also from infection, cancer, or
hemorrhage
 Destroying the adrenal cortex decreases making of all adrenocortical hormones
o Secondary adrenal insufficiency, unlike Addison’s, is caused by hypothalamus or
pituitary problems or chronic exogenous glucocorticoid
 The decreased ACTH released causes ↓ making of cortisol & sex steroids
o Whatever the cause, adrenal insufficiency causes fatigue, loss of appetite, weight loss,
dizziness on standing, and nausea
o In primary adrenal insufficiency, you also see hyperkalemia cause aldosterone is lost
o With chronic exogenous glucocorticoids, it can take up to a year for the hypothalamicpituitary axis to start working again
Cushing syndrome – excess glucocorticoids
o Cushing disease – increased cortisol from ACTH-secreting pituitary adenomas
o Ectopic secretion of ACTH is most commonly caused by small cell carcinoma from the
lung
o The most common cause of Cushing syndrome is secondary iatrogenic Cushing’s from
exogenous glucocorticoids
o Symptoms of Cushing syndrome include more central fat, hypertension, proximal limb
myopathy, osteoporosis, immunosuppression, and diabetes mellitus
o In endogenous Cushing syndrome, the cortisol activates mineralocorticoid receptors
to cause increased blood volume, hypertension, and hypokalemia
Cortisol and glucocorticoid drug analogues
o Drug therapy with glucocorticoids is done for 2 reasons:
 Replace glucocorticoids in adrenal insufficiency
 Suppress inflammation and immune responses – most often in asthma,
rheumatoid arthritis, and transplants
 Asthma glucocorticoids are inhaled
 Arthritis glucocorticoids are injected into the joint
 Topical glucocorticoids are used for skin inflammation
o To avoid adverse effects, you try to deliver the glucocorticoids right to the area affected,
limiting systemic exposure
o Glucocorticoids are divided into 2 classes based on what’s happening at the 11 carbon
 If it has a hydroxyl (OH), like cortisol, it has intrinsic glucocorticoid activity
 If it has a carbonyl (c=o), like cortisone, it’s inactive
 11β-HSD 1 has to reduce the carbonyl to a hydroxyl to activate the steroid

o
o
o
o
o
So cortisone is an inactive prodrug until it’s converted by the liver to the active
drug cortisol
 The skin doesn’t have much 11β-HSD 1, so the drug needs to be active
 Also, if they have a liver problem, you would prefer the active drug so the liver
doesn’t have to do anything
All glucocorticoid drugs are made from the original endogenous cortisol “backbone”
 Page 495 – structural analogues of cortisol
 Adding a double bond between C1 and C2 makes prednisolone, which is a more
potent anti-inflammatory than cortisol
 Adding an α-methyl to C6 of prednisolone forms methylprednisolone, which is
even more potent than prednisolone
 Both prednisolone and methylprednisolone have lower potency at the
mineralocorticoid receptor than cortisol
 Adding an α-fluorine to C9 of cortisol makes fludrocortisone, which then has
increased both glucocorticoid and mineralocorticoid potencies
 Dexamethasone adds both the C1=C2 double bond and the 9α-fluorine, and
adds an α-methyl to C16
 Dexamethasone is more potent than any of those as a glucocorticoid,
but has pretty much no mineralocorticoid activity
 What’s clinically important is knowing how potent each version of cortisol is
 In general, glucocorticoids used as drugs should have minimal
mineralocorticoid activity so that you don’t cause hypertension and↑ blood
volume
Prednisone is an inactive analogue of cortisone
Duration of action of glucocorticoid drugs depends on:
 Fraction of drug bound to plasma proteins – analogues usually bind to CBG
with lower affinity than cortisol, and most circulate in plasma bound to
albumin, while the rest is free steroid
 Since only free steroid is metabolized, how much is bound to plasma
proteins will determine the drug’s duration of action
 Affinity of the drug for 11β-HSD 2 – those with lower affinity for it will have a
longer half-life cause they won’t be inactivated as fast
 How lipophilic the drug is – the more lipophilic it is, the more that gets sent to
adipose stores, which decreases drug metabolism & excretion & ↑ half-life
 Affinity of the drug for the glucocorticoid receptor – increased affinity will
increase the duration of action, because it will stick to the receptor longer
 In general, glucocorticoid drugs with higher anti-inflammatory potency have a
longer duration of action
Page 496 – table summing up the cortisol analogues
Oral hydrocortisone is the drug of choice for replacing steroids in adrenal insufficiency
 This therapy must done for life, so you want to give the smallest possible
effective dose of cortisol to minimize adverse effects of excess glucocorticoids

-
Those with secondary adrenal insufficiency won’t need mineralocorticoids,
while those with primary will need them
o Glucocorticoid drugs inhibit cytokine release, blocking WBC recruitment and activation
o Glucocorticoids also block the making of arachidonic acid metabolites like
thromboxanes, prostaglandins, and leukotrienes, which work to cause vascular
permeability, platelet aggregation, and vasoconstriction
o Glucocorticoids as anti-inflammatories do not cure underlying disorders, they just
inhibit the inflammation caused by them
 So if you quit taking the glucocorticoids, you get inflammatory symptoms again
o Adverse effects of glucocorticoids:
 You’re suppressing the immune system, so you’re prone to infection
 Diabetes mellitus – since glucocorticoids raise plasma glucose and cause insulin
resistance, making the pancreatic β cells release more insulin
 Secondary hyperparathyroidism – glucocorticoids inhibit vitamin D-mediated
absorption of calcium, increasing bone resorption
 Osteoporosis – the bone resorption plus glucocorticoids directly suppress
osteoblasts, causing bone loss
 Can prevent this with bisphosphonate drugs, which inhibit osteoclasts
to slow bone loss
 In kids, growth can be stopped in retarded by glucocorticoids, making
them short
 Weakness and catabolism of proximal muscles – glucocorticoids cause atrophy
of fast-twitch muscle fibers
 Characteristic central obesity and wasting of peripheral fat – excessive fat
deposits on the back of the neck (called buffalo hump) and face (moon face)
o Chronic use of exogenous glucocorticoids will suppress CRH and ACTH, causing
atrophy of the adrenal cortex
 If you then abruptly stop taking the glucocorticoids, it can cause acute adrenal
insufficiency, because it takes months for the hypothalamus and pituitary to get
working again, and even more time may be needed to secrete enough hormone
as it’s supposed to
o Also, when stopping chronic glucocorticoid use, the inflammation you were inhibiting
can come back
o So when you want to stop glucocorticoid therapy, you do it gradually and slowly,
allowing the hypothalamus, pituitary, and adrenals to gradually get back to normal and
avoid insufficiency
Ways to take glucocorticoids:
o Glucocorticoids can be given locally at much higher than normal plasma concentrations,
while minimizing systemic adverse effects
o Inhaled glucocorticoids – treatment of choice for chronic asthma
 They inhibit airway inflammation by eosinophils

o
o
o
o
Since inhaled glucocorticoids are sent right to the lungs, less dose is needed
than oral glucocorticoids, so they have less toxicity, especially in kids
 Inhaled glucocorticoids include fluticasone, beclomethasone, flunisolide, and
triamcinolone
 If you’re switching from systemic glucocorticoid to inhaled, you should not stop
the systemic dose abruptly, or you can get adrenal insufficiency
 About 20% of inhaled glucocorticoid is taken to the lung, and 80% is swallowed
 But inhaled glucocorticoids have significant first pass liver metabolism,
so most of the swallowed part is converted to inactive forms in the liver
 An adverse effect of inhaled glucocorticoids is oropharyngeal candidiasis
 Some of the drug gets to the oral and pharyngeal mucosa and
suppresses the immune system, allowing opportunistic infection
 Can avoid this by rinsing mouth with water after every dose, or with
antifungal mouthwash
Cutaneous glucocorticoids – used topically
 Topical glucocorticoids have an extremely low dose go systemic, so you can
give much higher doses
 The skin has very little 11β-HSD 1, so the glucocorticoid must be active
 Cutaneous glucocorticoids include hydrocortisone (cortisol),
methylprednisolone, and dexamethasone
Depot glucocorticoids – intramuscular injections that are alternatives to oral doses
 They can last for days to weeks, so you don’t have to take them every day
 Depot methylprednisolone in polyethylene glycol can be used to inject into
joints, like for rheumatoid arthritis or gout
 Intra-articular injections need to be active cause they lack 11β-HSD 1
Pregnancy – the placenta forms a metabolic barrier from mom to fetus, so mom can
take prednisone during pregnancy with no fetal side effects
 Mom liver activates the prednisone to prednisolone, but the placenta has 11βHSD 2 to convert it back to prednisone
 The liver doesn’t function during fetal life, so the baby can’t convert the
prednisone to active prednisolone
 Also, glucocorticoids promote lung development in the fetus
 So you can give the mom dexamethasone, which is a poor substrate for
placental 11β-HSD 2, and therefore crosses the placenta in an active
form
Inhibitors of adrenocortical hormone making
 It’s not generally possible to change production of a single adrenal hormone and
not affect the other ones
 The enzymes to make adrenal hormones are P450 enzymes, so inhibitors can
also effect liver P450 enzymes

o
They can be divided into those affecting early steps, which have broad effects,
and those affecting later steps, which are more selective
 Early step inhibitors are mitotane, aminoglutethimide, & ketoconazole (p. 499)
 Mitotane is an analogue of DDT, a potent insecticide toxic to
adrenocortical mitochondria
o Used rarely for removing the adrenals in severe Cushing’s or
adrenal carcinoma
o Mitotane also inhibits cholesterol oxidase, so it causes
hypercholesterolemia
 Aminoglutethimide inhibits side chain cleavage enzyme and aromatase
 Ketoconazole is an antifungal that inhibits fungal p450 enzymes, and
high doses can also suppress steroid making by adrenals and gonads
o Ketoconazole inhibits mainly 17, 20-lyase, which is needed to
make adrenal androgens
o Ketoconazole also inhibits side chain cleavage enzyme
(cholesterol desmolase), which converts cholesterol to
pregnenolone, so it can inhibit making of all adrenal steroids
 Metyrapone inhibits 11β hydroxylation, blocking cortisol and aldosterone
making
 Metyrapone is used to test hypothalamic and pituitary response to
decreased circulating cortisol
Mifepristone is a progesterone receptor antagonist used to induce abortion early in
pregnancy
 At higher doses it will block the glucocorticoid receptor
Mineralocorticoids:
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The zona glomerulosa makes aldosterone in response to angiotensin 2, blood potassium, and
ACTH
Circulating aldosterone binds with low affinity to transcrotin, albumin, and a specific
mineralocorticoid binding protein
o Only 50-60% of circulating aldosterone is bound to transport proteins, and aldosterone
has a short elimination half-life of 20 minutes
Oral aldosterone also has a high first pass liver metabolism, with ¾ inactivated on first pass
o So oral aldosterone is not a good replacement for adrenal insufficiency
Mineralocorticoids are important in regulating sodium reabsorption in the kidney, colon, and
sweat and salivary glands
Circulating aldosterone diffuses across the plasma membrane and binds to mineralocorticoid
receptor in the cytoplasm
o The receptor-aldosterone complex then goes to the nucleus, where it adjusts
transcriptions of genes by binding hormone-response-element domains on specific gene
promoters
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In the kidney, aldosterone increases sodium/potassium ATPase activity
o This increases sodium reabsorption and potassium secretion across the lumen
o So aldosterone increases sodium retention, potassium excretion, and proton excretion
o Sodium retention causes water retention, leading to increased volume
o So excess aldosterone can cause hypokalemic alkalosis and hypertension, and too little
aldosterone causes hyperkalemic acidosis and hypotension
The mineralocorticoid receptor is also found in endothelial cells, vascular smooth muscle, the
heart, adipose, neurons, and inflammatory cells
o It works in vascular injury, atherosclerosis, heart disease, kidney disease, and stroke
o Activating the mineralocorticoid receptor increases oxidative stress, promotes
inflammation, regulates adipocyte differentiation, and decreases insulin sensitivity
o Antagonists of aldosterone at the mineralocorticoid receptor help prevent heart failure,
improve vascular function, decrease heart hypertrophy, and decrease albuminuria
3 things regulate aldosterone making: renin-angiotensin, blood potassium, and ACTH
o Renin-angiotensin-aldosterone system is the main regulator of ECF volume
 Decrease in ECF volume decreases perfusion pressure at the afferent arteriole in
the renal glomerulus
 This stimulates the juxtaglomerular cells to secrete renin, which cleaves
angiotensinogen to angiotensin 1, which is quickly converted to angiotensin 2 by
angiotensin converting enzyme (ACE) in the lungs
 Angiotensin 2 binds and activates a G protein receptor in zona glomerulosa cells
of the adrenal cortex, causing making of aldosterone
o Aldosterone does not exert negative feedback on ACTH
Hypoaldosteronism can be primary or secondary
o Most cases of hypoaldosteronism are from primary decreased aldosterone making
 Defects in 21-hydroxylase block cortisol and aldosterone making, leading to CAH
and salt wasting
o Addison’s is primary adrenal insufficiency, and causes hypoaldosteronism secondary to
destruction of the zona glomerulosa
 Most cases of Addison’s are caused by autoimmune adrenalitits
 Symptoms include salt wasting, low blood volume, hyperkalemia, and acidosis
o Low renin can cause hypoaldosteronism, called hyporeninemic hypoaldosteronism, and
is common in diabetic renal insufficiency
o Both the mineralocorticoid receptor not listening to aldosterone, and inactivating
mutation of the aldosterone-regulated epithelial sodium channel (ENaC) will cause
hypoaldosteronism, despite normal to increased aldosterone in the blood
Primary hyperaldosteornism happens from excess aldosterone making by the adrenal cortex
o The 2 most common causes are bilateral zona glomerulosa adrenal hyperplasia and an
aldosterone-making adenoma
o Excess aldosterone causes hypertension, decreased renin, and hypokalemia
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Primary hyperaldosteronism also causes adverse cardiovascular effects like endothelial
dysfunction, increased intima and media thickness, vascular stiffness,a nd thickened left
ventricular wall, and insulin resistance
You can’t give someone mienralocorticoids, because the liver inactivates ¾ of oral aldosterone
o So instead if they need mineralocorticoids, you give them the cortisol analogue
fludrocortisone, which has a low first pass metabolism and a high mineralocorticoidto-glucocorticoid ratio
o Adverse effects are all from excess mineralocorticoids
Mineralocorticoid receptor antagonists:
o Spironolactone – competitive antagonist of the mineralocorticoid receptor
 It also binds and inhibits androgen and progesterone receptors
 This can cause gynecomastia in males, so that limits its use
o Eplerenone – mineralocorticoid receptor antagonist that binds it selectively, so it
doesn’t have the adverse effects spironolactone does
o Both can be used as antihyeprtensives and for heart failure
o Watch potassium levels, since these antagonists can cause hyperkalemia (potassium
sparing diuretics)
Adrenal androgens:
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The adrenal cortex makes DHEA, which acts as a prohormone that’s converted to more potent
androgens, mainly testosterone (DHEAtest happens in the liver)
Adrenal androgens are important for making test in females to develop pubic hair at puberty,
which is when adrenal androgen release is activated, called adrenarche
The most common form of congenital adrenal hyperplasia is 21 hydroxylase deficiency, which
blocks aldosterone and cortisol
o Since cortisol is the main feedback regulator of pituitary ACTH release, decreased
cortisol making will lead to increased ACTH
o The high ACTH causes shunting of precursor to pathways that still work, like androgen
making
o In females, they’re masculinized, but in males, you may not notice symptoms
o Treat by replacing glucocorticoids and mineralocorticoids
DHEA is over the counter and commonly abused for its anabolic effects