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251 Cards in this Set

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Most common cause of hyperpituitarism?
An adenoma in the anterior lobe (adenohypophysis).
Most common type of mixed pituitary adenoma?
Growth hormone and prolactin mixed adenoma.
A mutation in what gene is responsible for most growth hormome and ACTH secreting adenomas?
GNAS1
This gene codes for the Gsa (stimulatory G protein) subunit. When the ligand is bound, GDP dissociates and GTP binds leading to the activation of an effector (like andenyly cyclase) and a rise in intracellular cAMP.
A mutation in the Gas subunit then, results in constant activation and production of cAMP leading to unchecked cell proliferation
Most common type of hyperfunctioning pituitary adenoma?
Prolactin hormone producing adenoma (prolactinoma)
Symptoms of hyperprolactinemia?
Amenorrhea, galactorrhea, loss of libido and infertility
Name 7 causes of hyperprolactinemia other than a prolactinoma
1. Pregnancy
2. High-dose estrogen therapy
3. Renal failure
4. Hypothyroidism
5. Hypothalamic lesion
6. Dopamine inhibiting drugs
7. Mass in supresellar compartment preventing hypothalamic inhibition of prolactin secretion (stalk effect)
Why would prolactinomas be diagnosed earlier in pre-menopausal females than in men and post-menopausal females?
Because the manifestations are most noticible in pre-menopausal females
Second most common type of hyperfunctioning pituitary adenoma?
Growth hormone producing adenoma
Persistant hypersecretion of growth hormone stimulates what other hormone?
Insulin-like growth factor I or Somatostatin C (from the liver)
- Obese patients have increased IGF-1 levels which inhibits GH secretion.
- In malnourished children, levels of GH are high but the liver cannot produce sufficent IGF-1; this leads to growth failure
Excessive growth hormone secretion in pre-pubertal (before epiphysial closure) children results in?
Gigantism:
characterized by increased body size with disproportionately long arms and legs
Excessive growth hormone secretion in adults (after epiphysial closure) results in?
Acromegaly:
characterized by growth in soft tissues, skin and viscera and in the bones of the face, hands and feet
Most common complication is congestive heart failure.
Patients also at increased risk of breast and colon cancer; high IGF-1 levels may promote tumerogenesis.
Name 7 other symptoms of excess growth hormone
1. Abnormal glucose tolerance
2. Diabetes mellitus
3. Generalized muscle weakness
4. Hypertension
5. Arthritis
6. Osteoporosis
7. Congestive heart failure
What syndrome is caused by excessive ACTH?
Cushing syndrome:
May be caused by a wide variety of conditions in addition to ACTH producing pituitary neoplasms
When the cause of excess ACTH comes directly from overproduction of the pituitary, what is the condition called?
Cushing disease
Describe Nelson syndrome
Large and aggressive corticotroph adenomas that develop after removal of the adrenal glands due to a loss of the inhibitory effect of corticosteroids on a preexisting corticotroph microadenoma
Name a side effect of excess ACTH that can be visually seen on a patient
Hyperpigmentation:
ACTH is synthesized as part of a larger prohormone that includes MSH (melanocyte stimulating hormone)
When are most gonadotroph adenomas found?
In middle aged men and women:
FSH and LH secreting adenomas are usually subclinical and are only diganosed when the adenoma becomes large enough to cause neurological symptoms.
What type of pituitary adenoma is a rare cause of hyperthyroidism?
Thyrotroph adenoma:
Only accounts for about 1% of all pituitary adenomas
Comprising about 25% of all pituitary adenomas, non-functioning pituitary adenomas have what typical presentation?
Mass effects:
Damage to the brain due the bulk of a tumour, the blockage of fluid or excess accumulation of fluid within the skull.
a. pituitary - panhypopituitarism
b. optic chiasm - bitemporal hemianopsia
c. cavernous sinus - cranial nerves 3,4,5,6- palsies
d. Increased CSF → headache, etc
Absence or loss of how much of the anterior pituitary is required before hypofunction is seen?
75%
Name the 2 most common causes of anterior pituitary hypofunction
1. Non-functioning pituitary adenoma
2. Ischemic necrosis of the anterior pituitary
What is postpartum necrosis of the anterior pituitary called?
Sheehan syndrome
How does Sheehan syndrome develop?
During pregnancy the prolactin secreting cells increase in size and number, but the blood flow to the anterior pituitary remains the same. This causes the enlarged gland to be susceptible to ischemic injury - especially in those that develop hemorrhage and hypotension in the peripartum/postpartum period
Patients may present months to years after delivery with a history of failure of post-partum lactation, failure to resume menses, fatigue, and cold intolerance
Clinically significant pituitary necrosis may be caused by five factors other than pregnancy; name them
1. DIC
2. Sickle cell anemia
3. Elevated intracranial pressure
4. Traumatic injury
5. Shock of any origin
A rare mutation in what transcription factor can cause a multi-hormone, congenital hormone deficiency?
Pit-1 (a pituitary transcription factor)
Mutation causes lack of differentiation to somatotrophs, lactotrophs and thyrotrophs.
A GH defiency in children can cause?
Pituitary dwarfism:
different from short stature (i.e. achondroplasia) –patients are systemically under developed -decreased growth of organs and bones-sexual development is decreased- never progresses beyond that of a young child
A GnRH or gonadotropin hormone deficency can lead to what symptoms?
Amenorrhea and infertility in women. Decreased libido, impotence and loss of axillary and pubic hair in men.
What sign can you visually see on a patient with hypopituitarism?
Pallor:
The anterior pituitary is the source of MSH which is a stimulator of melanocytes
What 2 syndromes involve ADH?
Diabetes insipidus and Syndrome of inappropriate ADH
Diabetes insipidus is characterized by?
Excessive urination (polyuria)
What is the difference between Central and Nephrogenic diabetes insipidus?
Central DI is caused by a deficiency of ADH.
Nephrogenic DI is caused by renal tubular unresponsiveness to ADH.
What are the clinical manifestations of diabetes insipidus?
Polyuria with a low specific gravity, increased serum sodium and osmolality and excessive thirst (polydipsia).
What does syndrome of inappropriate ADH (SIADH) cause?
Resorption of excessive amounts of free water with a resulting hyponatremia
What are the 3 most common causes of SIADH?
1. ADH secreting malignant neoplasms (especially small cell carcinoma of the lung)
2. Non-neoplastic diseases of the lung
3. Local injury to the hypothalamus or neurohypophysis
What are the clinical manifestations of SIADH?
Hyponatremia, cerebral edema and neurological dysfunction.
Peripheral edema DOES NOT develop.
What do the letters "VINDICATE" mean in regards to pathological mechanisms of endocrine disorders?
Vascular hemorrhage/infarction
Infectious
Neoplasm
Drugs
Inflammatory
Congenital
Autoimmune
Trauma
Endocrine
Pituitary adenomas have what microscopic characteristics?
Homogenous cells in sheets or cords with very little stroma.
If an "incidentaloma" is found measuring under 1cm, what is the treatment protocol?
Endocrine evaulation first. If negative, then get an MRI every 6-12 months. If stable after 2 years then no further evaluation is needed
If an "incidentaloma" is found measuring more than 1cm, what is the treatment protocol?
Both endocrine evaluation and treatment of hypersecretion and/or mass effects (medical management and/or surgery)
What is a craniopharygeoma?
A tumor that arises from remnant cells of Rathke’s pouch (along the anterior pituitary migration path from the oral cavity) close to the pituitary.
More common in children and adolescents.
Patients present with mass effects.
Microscopic features of a craniopharygeoma?
Microscopic features- nests or cords of stratified squamous cells edged with a periphery of columnar cells. May see
Keratin, Cholesterol-rich cysts, fibrosis,Calcifications (radiologically visible).
Structures resemble germinal teeth.
In regards to PITUITARY disease and not endocrine disease in general, what does a primary disease mean?
The problem is within the pituitary itself.
A disorder in what hormone causes Kallman syndrome?
GnRH:
If the gene is dysfunctional or absent - leads to hypothalamic hypogonadism and anosmia
Why should IGF-1 levels not be used as a screen for GH levels?
Because 60% of GH deficient patients have normal IGF-1 levels.
What is the biggest health problem in those with GH deficiency?
Cardiovascular disease
Name 5 metabolic causes of hyperprolactinemia:
1. elevated estrogen
2. primary hypothyroidism
3. medications
4. idiopathic
5. stalk disease
What is the primary treatment for almost all patients with hyperprolactinemia?
Bromocriptine; a dopamine agonist
What is the second most common cause of hypopituitarism?
CNS irradiation
What is empty sella syndrome?
Destruction of all or part of the pituitary.
Can be caused by surgery (craniopharygneoma), radiation or a congenital defect leading to absence of the diaphragm allows CSF into the sella (CSF compresses the pituitary)
What is pituitary apoplexy and what are its symptoms?
A sudden expanding hemorrhage (usually in an adenoma) that leads to the destruction of adjacent pituitary cells.
Symptoms include headache, visual disturbance and nausea
What is the cause of the acute lethal form of Sheehans syndrome?
Rapid loss of pituitary tissue leads to loss of corticoid steroid production --> severe hypotension.
Where are the V1 receptors for ADH located and how tightly do they bind?
The V1 receptors are located on vascular smooth muscle and act via IP3 to vasoconstrict and increase BP. ADH binds with low affinity.
Where are the V2 receptors for ADH located and how tightly do they bind?
V2 receptors are located in the kidney act via G-coupled proteins to increase water retention. ADH binds with high affinity.
What does ADH binding to its V3 receptor do?
Stimulates ACTH secretion from the pituitary.
Describe the ADH feedback loop:
Is ADH secretion more sensitive to plasma osmolarity or volume changes?
Osmolarity changes:

Only a 1-2% osmolarity change is needed to increase/decrease ADH; compared to a volume change of 7-10%
At what plasma osmolarity are osmorecepters inactive?
280 mosm/Kg
Where are osmoreceptors located at?
In the anterolateral hypothalamus.
Where are baroreceptors located at?
In the carotid sinus and aortic arch. Baroreceptors measure blood pressure and must be SUPPRESSED to stimulate ADH; as the receptors are no longer "stretched" they cease to fire and no signals are sent.
What chromosome is the gene for ADH located on?
Chromosome 20
What 2 drugs can cause nephrogenic DI?
Lithium
Demeclocyline (reversible)
What placental enzyme can cause gestagenic DI?
placental vasopressinase; degrades ADH in the mother's system.
What are the symptoms and clinical signs of DI?
Polyuria, increased thirst and nocturia.
Plasma hypernatremia with urinary hyponatremia.
What drug is used as a replacement for ADH in a water deprivation test to diagnose DI?
DDAVP (Desamino-D-arginine AVP)
Graph showing effect of DDAVP administration on a normal patient and those with DI
What syndrome presents with hyponatremia and hypoosmolarity of body fluids coupled with increased urine osmolarity?
SIADH
What are the 4 possible causes of SIADH?
1. Unregulated AVP – unregulated secretion of vasopressin
2. Elevated basal AVP- elevated basal secretion of
vasopressin despite normal regulation by osmolality
3. “Reset Osmostat” -The reset osmostat syndrome
occurs when the threshold for AVP secretion is reset
downward. Patients with this condition have normal
water-load excretion and intact urine-diluting ability after
water deprivation test
4. Undetectable vasopressin-these patients may have a gain of function mutation of the V2 receptor
What are some of the clinical signs of SIADH?
Water intoxication” – headache, loss of appetite, lethargy, nausea, hyponatremia (135 mEq/L severe = 125 mEq/L)

Confusion and personality changes

Seizures from “water intoxication”
What are the treatment options for SIADH?
Treatment of underlying cause: fluid restriction

If severe, with CNS symptoms-cautious infusion of hypertonic (3%) saline and furosemide. If the sodium is corrected too rapidly, there is a risk of central pontine myelinolysis (CPM) destruction of the myelin sheath covering nerve cells in the brainstem

If no CNS symptoms: Fluid restriction

V2 receptor-antagonists- More recent- Anti-antidiuretic hormones (“Aquaretics”)
The diagnosis of Cushing's requires?
Evidence of increased cortisol production with loss of suppression of cortisol synthesis
Or loss of cortisol diurnal variation.
What is the #1 cause of Cushing's in the US?
Exogenous steroids
What are the screening test protocols for Cushings?
screen with cortisol and ACTH levels:
24hr urinary free cortisol (UFC) or salivary cortisol

If normal repeat 2 times
If normal three times then repeat in 6 months if signs/symptoms persist

If cortisol (above test) is abnormally elevated on 2 occasions the patient has Cushing’s syndrome
What are the effects of low and high dose dexamethasone administration on the pituitary, adrenal or ectopic cause of Cushings?
What is the effect on cortisol levels in a normal person given low dose dexamethasone?
Cortisol levels would be decreased.
What enzymatic reaction does metyrapone inhibit?
Conversion of 11-deoxycortisol to cortisol.
A person with a normal CSH-ACTH-cortisol axis would have what response to metyrapone?
A rise in CRH and ACTH levels and, increased steroid precursors (11-deoxy-cortisol) in the pathway
A person with adrenal insuffienciecy would have what response to metyrapone?
If 11-deoxycortisol levels do not rise and ACTH rises it is highly suggestive of impaired adrenal insufficiency.
A person with pituitary or hypothalamus disfunction would have what response to metyrapone?
If neither 11-deoxycortisol nor ACTH rise it is highly suggestive of an impaired HPA axis at either the pituitary or hypothalamus.
Where is the best location to sample blood coming from the pituitary?
The petrosal sinus
What drug is used to diagnose acute adrenal insufficiency?
Cosyntropin (an ACTH analogue)
What is the effect on a normal patient vs a patient with adrenal insuffiency when given cosyntropin?
A normal person would show an increase in cortisol.

A person with adrenal insufficiency would not show an increase in cortisol.

If cortisol doesn't rise at least 20 mcg/dL then the diagnosis is made of adrenal insufficiency
What levels of ACTH and cortisol would be expected in a patient with Addison's?
High ACTH and low cortisol
Congenital adrenal hyperplasia shows what kind of inheritance pattern?
Autosomal recessive
What defect(s) are characteristic of congenital adrenal hyperplasias?
A defect in cortisol synthesis enzymes leading to a buildup of androgen precursors and an increased ACTH.
Impaired aldosterone production is also possible - leads to "salt wasting"
80-90% of congenital adrenal hyperplasias are due to a defect in what enzyme?
21-hydroxylase
What is the best screening test for pheochromocytoma?
Plasma free metanephrines
Name 3 hyperadrenal clinical syndromes:
1. Cushing syndrome (cortisol)
2. Hyperaldosteronism
3. Adrenogenital (virilizing)
When the pituitary is responsible for an increase in ACTH what is the condition called?
Cushing's Disease
(most cases caused by a microadenoma)
What do the adrenal glands look like in Cushing's Disease?
The glands have bilateral nodular cortical hyperplasia caused by elevated levels of ACTH
Most common tumor responsible for secretion of ectopic ACTH?
Small cell carcinoma of the lung
What are some signs and symptoms of Cushing syndrome?
hypertension, weight gain, abnormal adipose distribution to face, abdomen and back, decreased muscle mass and proximal limb weakness, hyperglycemia, glucosuria, polydipsia, cutaneous striae on the abdomen, hirsutism and mestrual abnormalities
What might be a visible sign of Cushing syndrome?
Increased skin pigmentation due to increased MSH (b/c of increased ACTH)
Excess of what hormone can cause hypertension and hypokalemia?
Hyperaldosteronism
Secondary hyperaldosteronism would show what levels of plasma renin?
Increased renin
Primary hyperaldosteronism would show what levels of plasma renin?
Decreased renin
What are some causes of secondary hyperaldosteronism?
1. Decreased renal perfusion
2. Arterial hypovolemia and edema (CHF, cirrhosis and nephrotic syndrome)
3. Pregnancy
What gene may be responsible for primary hyperaldosteronism by stimulating overactivity of the aldosterone synthase enzyme?
CYP11B2
What is Conn's syndrome?
Primary hyperaldosteronism caused by an aldosterone secreting adenoma in one adrenal gland.
(about 80% of all cases)
Spironolactone bodies are characteristic of what type of adenoma?
aldosterone producing adenoma
(from the aldosterone agonist drug spironolactone)
Adrenocortical neoplasma associated with androgen excess are likely to be what type?
Carcinoma; as opposed to an adenoma
Which gene encodes the 21-hydroxylase enzyme involved in CAH?
CYP21B
What do the adrenal glands look like in all cases of CAH?
The adrenals are hyperplastic bilaterally due to sustained elevation in ACTH
What are the 3 types of adrenocortical insufficiency?
1. Primary acute (adrenal crisis)
2. Primary chronic (Addison disease)
3. Seondary
Waterhouse-Friderichsen syndrome, a cause of acute adrenal insufficiency, is frequently caused by septicemia from what organisms?
Most common is N. meningitidis. Also Psuedomonas, pneumococci and H. influenza
More than 90% of cases of Addison's disease are caused by what 4 causes?
1. Autoimmune adrenalitis
2. Tuberculosis
3. AIDS
4. metastatic cancers
Carcinomas of the _____ and _____ are the source of most metastases in the adrenals:
Lung and breast
Hyperpigmentation is absent in secondary adrenocortical insufficiency because?
The pituitary or hypothalamus is involved - leading to decreased production of ACTH and MSH
What is the aldosterone level in patient's with Addison's?
Normal or near-normal
What are some syptoms and signs of adrenocortical insufficiency?
weakness and fatigability, GI disturbances (anorexia, nausea, vomiting, diarrhea).
*In patients with primary disease - will also see hyperkalemia and hyponatremia resulting in hypotension.
What is the embryologic origin of the adrenal medulla?
Made up of cells from the neural crest (chromaffin cells)
What are the symptoms/signs of a pheochromocytoma?
Abrupt episodes of hypertension. Tachycardia, palpitations, headache, sweating, tremor and a sense of apprehension.
The laboratory diagnosis of pheochromocytoma NOT associated with high-risk groups is based on what?
Increased urinary excretion of free catecholamines and their metabolites; such as VMA and metanephrine
The laboratory diagnosis of pheochromocytoma associated with high-risk groups (MEN or previous tumor) is based on what?
Serum free metanephrines and normetanephrines
This drug must be given before operating to remove a pheochromocytoma
Adrenergic-blocking agent
Signs of MEN syndrome
Tumors occur at a younger age, arise in multiple endocrine organs, tumors are often multifocal and are more aggressive and recur.
What inheritance pattern and what gene is associated with MEN1?
Autosomal dominant.
MEN1 gene is located at 11q13; a tumor suppressor gene.
Parathyroid, Pancreas and Pituitary commonly affected.
What inheritance pattern and what gene is associated with MEN2?
Autosomal dominant.
RET protooncogene located at 10q11.2
What type of tumors are characteristic of MEN2A?
Pheochromocytoma and parathyroid (hyperparathyroidism)
What kind of tumors are characteristic of MEN2B?
Pheochromocytoma
(patients also develop ganglioneuromas of mucosal sites and marfanoid habitus)
Why does a deficiency of ACTH not necessarily lead to a deficiency of aldosterone?
ACTH stimulates both cortisol and aldosterone production; BUT, it only stimulates aldosterone about 1/2….aldosterone production is mostly under control of the renin-angiotensin system. This is why a deficiency of ACTH does not always lead to a deficiency of aldosterone.
When cortisol binds to a GRE and prevents transcription of inflammatory cytokines, what is this called?
Transrepression
When cortisol binds to a GRE and induces transcription of Lipocortin-1 and other anti-inflammatory molecules, what is this called?
Transactivation
What does Lipocortin-1 do?
It inhibits phospholipase A2 to prevent production of arachidonic acid.
What 2 substances can inhibit phospholipase A2 to prevent arachidonic acid production?
Lipocortin-1 and glucocorticoids
What drug inhibits cyclooxygenase to prevent conversion of arachidonic acid to prostaglandins and thromboxanes
NSAID's
What are the metabolic effects of glucocorticoids?
Name 3 short acting glucocortiocoids in order of increasing selectivity:
Predisone (oral)
Predinisolone
Methylprednisolone (IV)
Name 3 long acting glucocorticoids in order of increasing selectivity:
Betamethasone (for lung maturation)
Dexamethasone
Beclomethasone
Corticosteroid property table:
Why are calcium supplements not effective at preventing osteoporosis in those taking glucocorticoids?
Because steroids inhibit the production of Vitamin D - which leads to decreased calcium absorption
What conditions can corticosteroids be used for?
When are the peak times of ACTH secretion?
It is highest when waking in the morning and also peaks after meals
How does cortisol bind to its receptor?
Cortisol diffuses into the cell where it binds with cytoplasmic receptor-Heat shock protein complexes. The HSP dissociate and the receptor-ligand complex is transported to the nucleus. It binds to DNA as a homodimer.
Why is cortisol not as effective at stimulating aldosterone receptors even though it binds with similar affinity?
Due to the expression of 11B-hydroxysteroid dehydrogenase; an enzyme in some tissues that converts cortisol to cortisone.
Glucocorticoids simulate what enzymes necessary for gluconeogenesis and glycogen synthesis in the fasting state?
PEPCK, G6P and glycogen synthase and stimulate the release of amino acids.
Why do glucocorticoids increase fat deposition and increase fatty acids and glycerol in the circulation?
Glucocorticoids increase glucose levels --> insulin release and inhibition of glucose uptake by muscle. They also stimulate hormone sensitive lipase --> lipolysis.
Insulin stimulates lipogenesis and to a lesser degree inhibits lipolysis --> a net increase in fat deposition combined with increased fatty acid and glycerol in the circulation.
Describe some of the ways that glucocorticoids exhibit anti-inflammatory and immunosuppresive effects:
1. Prevents extravasation of neutrophils to site of irritation
2. Inhibit functions of tissue macrophages and other antigen presenting cells.
3. Reduce prostaglandins and leukotrienes that come from phospholipase A2
4. Reduce the expression of cyclooxygenase --> reduced prostaglandins
5. Cause vasoconstriction when applied directly to skin
What pituitary hormones can chronic glucocorticoid therapy suppress?
ACTH, GH, TSH and LH
Hypokalemia may cause what metabolic disturbance?
alkalosis; due to loss of H+ along with K+ from the kidney
Glucocorticoid therapy can reactive a dormant infection of what bacteria?
Tuberculosis
What kind of dietary recommendations should you give to a patient on corticosteroids?
High protein and potassium enriched diet.
At what parts of the kidney do mineralocorticoids stimulate reabsorption of sodium?
From the distal part of the distal convoluted tubule and from the collecting duct
Expression of what 2 "pumps" are increased through the action of aldosterone?
Na+/K+ ATPase
Epithelial sodium channel
From what embryonic tissue is the adrenal cortex derived from?
The coelemic epithelium adjacent to the gonadal ridge
Histology of the adrenal cortex:
Source, functions and regulation of cortisol:
Source: Adrenal Zona Fasciculata
Bound: Corticosteroid binding globulin (CBG)
Functions:
Blood pressure maintenance through α1 receptors
Suppress bone formation
Anti-Inflammatory
Suppress immune function
Increases gluconeogenesis, lipolysis and proteolysis
Regulation:
1. CRH (hypothalamus) → ACTH (pituitary) → cortisol (z.fasciculata)
2. Chronic stress induces prolonged secretion
What would the serum renin level be in Conn's syndrome?
Low
Renin-Angiotenin-Aldosterone system:
Why is the adrenal cortex depleted of lipids in CAH?
Because of an enzyme defect there is a lack of negative feedback to the pituitary --> constant ACTH stimulation and the using up of all lipids as the adrenals try to make cortisol and aldosterone
Why is there no salt wasting in 11-B-hydroxylase CAH?
Because the precursor to aldosterone, deoxycorticosterone, is still made and has some aldosterone-like function
In autoimmune adrenalitis, is the medulla spared or not?
It is spared - the autoantibodies only target the cortex
What type of cancer is the earliest manifestation of MEN syndrome?
Thyroid cancer
What is autoimmune polyendocrinopathy syndrome?
Subgroup of patients in whom Hashimoto’s thyroiditis, pernicious anemia, DM I, idiopathic hypoparathyroidism and adrenal insufficiency may coexist; associated with mutations in AIRE1 gene on chromosome 21q22.
Which receptor does epinephrine and norepinephrine act on in the vasculature?
Alpha receptors
Which one can stimulate B-receptors? NE or Epi?
Epinephrine
What is the most common solid extracranial tumor in children under 5?
Neuroblastoma
What lab test can you do to check for neuroblastoma?
What gene is neuroblastoma associated with?
The patient will usually have elevated HVA in the urine (breakdown of dopamine) and the tumors are associated with N-myc oncogene.
Ketoconazole
Used to treat Cushing's
Mechanism: Inhibits several steroid synthesis enzymes – decrease cortisol production
17a hydroxylase (predominant)
11B-hydroxylase
CYP450 inhibitor –Major 3A4 inhibitor (infamous)
PK: complicated hepatic metabolism
Adverse effects:
Hepatotoxicity major concern
Reduces androgen levels
Rare –cardiovascular
Metyrapone
Only drug approved to treat Cushing's in pregnant women:
MAO: Competitive inhibitor of 11-B-hydroxylase enzyme.
- Decrease cortisol synthesis
- 11-deoxycortisol precursor increases
Adverse-hypertension due to
precursor build-up
Adverse – androgenic due to the shift in synthesis to other pathway
- Offset by aminoglutethimide
Aminoglutathimide
MAO: competitive inhibition of desmolase & aromatase.
- Blocks rate-limiting conversion of cholesterol to pregnenolone.
- Decreases ALL adrenal steroids
- Cholesterol builds up
- Often used with metyrapone
- Increases adrenal steroid clearance
Adverse side effects: Decreases thyroxine synthesis
Common side effects-nausea, dizziness, orthostatic hypotension
Spironolactone
MOA: competitive antagonist at the aldosterone receptor.
- It is non-selective and can also antagonize androgen receptors
- Considered a potassium-sparing diuretic
- Can develop metabolic acidosis on high doses
Why do males on spironolactone develop gynecomastia?
Because it is a competitive agonist at androgen receptors.
Eplerenone
Selective aldosterone antagonist:
Lowers serum Na+
Increases K+
Lowers BP
Similar effect reduces BP in Primary Aldosteronism
*No gynecomastia in males
Phenoxybenzamine
Irreversible non-competitive inhibitor of alpha adrenergic receptors:
Prevents adrenal tumor catecholamines from activating α adrenergic receptors.
Reduces hypertension/other sympathomimetic effects
Concern – side effect - orthostatic hypotension/ severe hypotension (if combined other antihypertensives)
Long duration effect – stabilizes BP prior to surgery
Why is phenoxybenzamine administered before propanalol before pheochromocytoma removal?
To vasodilate before beta-blocking the heart; if not done could cause a hypertensive crisis.
- Normally both alpha and beta receptors in vessels are activated by Epi and NE with alpha (vasoconstriction) being dominant.
- phenoxybenzamine will block the alpha receptors in vessels to cause vasodilation; if you beta block first, then even though the heart rate will go down, you will now have unopposed alpha vasoconstrictor activity in the vessels which will lead to a hypertensive crisis (b/c the resistance of the vessels is more important than the heart rate/preload in determining BP)
Propanolol
Propranolol: non-selective competitive beta adrenergic antagonist:
B1 adrenergic antagonist blocks catecholamines effects on heart.
Tachycardia (“racing heart”) is reduced by preventing activation of B1 adrenergic receptors.
Sequence: Critical to give propranolol AFTER alpha block stabilizes BP!
Beta block antagonizes B2-mediated vasodilation.
Hypertensive crisis is possible if propranolol administered BEFORE alpha adrenergic block.
Why is spironolactone considered a potassium sparing diuretic?
Lowers Na+/K+ countertransport
Vitamin D2 comes from which source?
Vitamin D3 comes from which source?
Vitamin D2 is dietary (cereals, milk, orange juice, supplements)
Vitamin D3 comes from oily fish and skin synthesis
What are the recommendations for adequate dietary intake of vitamin D?
0-12 months - 400 IU
1-70 years - 600 IU
Over 70 - 800 IU
The best indicator of vitamin D status?
25 hydroxyvitamin D; best indicator of dietary and skin formed sources
Vitamin D levels:
Vitamin D deficiency and hypertension effect?
Increase risk of cardiovascular events
Why are the obese more likely to have vitamin D deficiency?
Because vitamin D gets trapped in adipose tissue.
How might vitamin D increase insulin sensitivity?
Vitamin D may aid insulin action by the regulation of insulin receptor gene expression, and hence increase insulin sensitivity
What is the normal range of vitamin D levels?
30-50 ng/mL
Describe the MOA of GH at its receptor:
GH acts at JAK-kinase receptors.
STAT molecules get phosphorylated by the kinase.
STAT alters transcription of somatomedins.
- insulin-like growth factor -1 (IGF-1) – major effects
- insulin-like growth factor -2 (IGF-2)
What type of receptor does IGF-1 act at?
A tyrosine kinase receptor
Somatotropin:
-A recombinant human GH that acts at GH receptors like endogenous GH.
- IGF-1 levels are measured to determine if GH is working as it should.
- Some adverse effects are: slipped femoral epiphysis, carpal tunnel syndrome and hyperglycemia in diabetics
- Used for: short stature in GH deficient children, pediatric renal failure, Turners syndrome, catabolic syndromes and short bowel syndrome
Mecasermin:
- An agonist directly at the IGF-1 receptor; used if somatotropin fails
- adverse effects: increased intracranial pressure and hypoglycemia (need food at injection time)
Desmopressin:
MOA: acts as a selective agonist at V2 ADH receptors in the kidney with little activity at V1 receptors in blood vessels.
- Can be administered orally
- used for diabetes insipidus
- reverses water loss and corrects hypernatremia with minimal effects on BP
Adverse effects: headache and hyponatremia
What happens when ADH binds to its receptor in the kidney?
ADH-receptor binding activates a G-protein/adenlyl cyclase. Production of cAMP activates a kinase. Activation of the kinase results in phosporylation of aquaporin and its insertion into the cell membrane. This increases water reabsorption.
Vasopressin (arginine vasopressine)
MOA: a non-selective agonist at both V1 and V2 receptors in kidney and vessels.
- A potent vasoconstrictor and antidiuretic.
- reverses severe hypotension in DI
- Administered IM or IV only; rapid acting
Adverse effects: hyponatremia, seizures, CNS toxicity
- Use with care in alcoholics and pregnant women.
Octreotide:
An analog of somatostatin. It acts at somatostatin receptors in the pituitary to reduce production of GH. Effectiveness is determined by measuring IGF-1 levels.
- Given via injection
- can also be used to control esophageal bleeding
- Adverse effects: Gallstones, GI disturbance, hyperglycemia and lowered insulin levels
Pegvisomant:
An antagonist at the GH receptor in the liver --> reduced levels of IGF-1.
- Used when octreotide fails
- GH levels will still be high
Adverse effects: changes in liver enzymes (monitoring needed)
Conivaptan:
A non-selective vasopressin V1 & V2 receptor antagonist
- Used for SIADH
- Blocks effects of excessive ADH
- Reduces hypertension specifically caused by high ADH
- Increases free water excretion, reduces hyponatremia
Tolvaptan:
An oral V2 antagonist
- Used for SIADH
- Blocks effects of excessive ADH
- Reduces hypertension specifically caused by high ADH
- Increases free water excretion, reduces hyponatremia
Drugs which inhibit the neurotransmitter ______ are most likely to disrupt prolactin levels:
Dopamine
What two diseases can disrupt dopamine levels and cause hyperprolactinemia?
Parkinson's
Acromegaly
Drugs for what neurological disorders can cause hyperprolactinemia?
Bipolar disorder
Schizophrenia
Bromocriptine:
A non-selective D1 and D2 ergot dopamine agonist.
- Activates pituitary D2 receptors to reduce prolactin secretion.
- Given orally
Adverse effects: nausea, orthostatic hypertension (D1 receptor activity), cardiovascular risk (DA receptors in heart) and CNS issues (delusions, hallucinations, psychosis)
Drugs which inhibit the neurotransmitter ______ are most likely to disrupt prolactin levels:
Dopamine
Cabergoline:
A selective D2 non-ergot dopamine agonist.
- Activates pituitary D2 receptors to reduce prolactin secretion.
- Given orally or vaginally (longer 1/2 life)
Adverse effects: nausea, cardiovascular risk (DA receptors in heart) and CNS issues (delusions, hallucinations, psychosis)
What two diseases can disrupt dopamine levels and cause hyperprolactinemia?
Parkinson's
Acromegaly
Oxytocin:
Oxytocin:
G-protein coupled receptor increases influx of Ca+2 ions into myometrial smooth muscle.
-Causes uterine contractions
-Alveoli contraction = milk ejection
Used for induction of labor and to decrease uterine hemorrhage.
Adverse effects: sustained tetanic contractions, edema and water intoxication (drug has similar structure to vasopressin and can activate vasopressin receptors)
Drugs which inhibit the neurotransmitter ______ are most likely to disrupt prolactin levels:
Dopamine
How is T3 and T4 produced in the thyroid?
After TSH binds to its receptor, activation of a G-protein increases cAMP levels leading to stimulation of thyroid hormone synthesis via cAMP dependant protein kinases.
Thyroid follicular cells convert thyroglobulin into T3 and T4
What is contained within thyroid follicles?
Thyroglobulin
Which thyroid hormone is more biologically active?
T3
What is thyrotoxicosis?
A hypermetabolic state caused by elevated circulating levels of T3 and T4.
What is the most useful lab test for detecting hyperthyroidism?
TSH; because levels are decreased even at the earliest stages when the disease may still be subclinical
Radioactive iodine uptake patterns can help differentiate between causes of hyperthyroidism how?
Graves disease: diffusely increased uptake in the whole gland
Toxic adenoma: increased uptake in a solitary nodule
Thyroiditis: decreased uptake
In regards to hypothyroidism, myxedema means what?
A "cretinoid" state in adults.
Manifestations include sluggishness, depression, cold intolerance, obesity, enlargement of the tongue and deepening of the voice and constipation
What lab test is the most effective screening test for hypothyroidism?
TSH
What is the most common cause of hypothyroidism in areas of the world where iodine levels are sufficient?
Hashimoto's thyroiditis
What is the pathogenesis of Hashimoto's thyroiditis?
An autoimmune disease in which there is progresive destruction of thyroid epithelial cells; the cells are replaced by mononuclear cell infiltration and fibrosis.
Common presenting clinical features of Hashimoto's thyroiditis?
Painless enlargement of the thryoid, usually associated with hypothyroidism in middle aged women.
What is de Quervain thyroiditis?
Also called subacute granulomatous thyroiditis; believed to be caused by a viral infection. The majority of patients report an upper respiratory infection just before onset. Usually self-limiting
How does de Quervain thryoiditis present?
Acute, painful thryoid with fever, malaise and variable swelling of the thyroid. Transient hyperthyroidism may occur as a result of disruption of the follicles and release of excessive hormone
After injection of radioactive iodine, a "cold nodule" is discovered on a thyroid; is this more likely to be malignant or benign?
Malignant; most malignant adenomas take up iodine less avidly than normal thyroid tissue.
What are the two more common types of thryoid carcinoma?
Papillary (most common) and follicular
What two mutations are common in papillary thyroid carcinoma?
RET and BRAF
What mutation is most common in follicular thyroid carcinoma?
RAS
What cell type does medullary thyroid carcinoma arise from? What is it's common mutation?
parfollicular C cells.
RET.
What is the most common subtype of pancreatic endocrine neoplasm?
Insulinoma
What are the clinical signs of an insulinoma?
1. Attacks of hypoglycemia with glucose below 50 mg/dL
2. Attacks occur with confusion, stupor and loss of consciousness
3. Attacks are precipitated by fasting or exercise and are relieved by administration of glucose
What causes Zollinger-Ellison syndrome?
A gastrinoma of the pancreas or duodenum
What are the manifestations of a gastrinoma?
Excessive gastrin stimulates gastric acid secretion leading to peptic ulceration. There are usually multiple ulcers and they are not helped by usual therapies.
Most patients will also present with diarrhea.
What would be the effect on T4 levels if a patient is administered a drug that affects protein binding?
Bioavailability would increase or decrease depending on whether binding increased or decreased.
Levothyroxine:
- Is an analogue of T4 and is the first line treatment for hypothyroidism.
- Adverse effects: syptoms of thyrotoxicosis
What happens at the thyroid response element in the nucleus when T3 enters?
Co-suppressor proteins dissociate and Coactivators associate --> transcription
What enzyme converts T4 to T3?
5-deiodinase
Name 4 drugs that inhibit 5-deiodinase and therefore reduce conversion of T4 to T3:
1. Propanolol (b-blockers)
2. Corticosteroids
3. Aminogluthemide
4. Amiodarone (antidiuretic)
Liothyronine:
- A T3 analogue
- Rapid onset with potent short duration; ideal for emergencies
- May need to give this along with Levothyroxine due to inability to convert T4 to T3 or for severe hypothyroidism.
- Adverse effects: cardiotoxicity, arythmias, insomnia and anxiety
- Contraindicated in those with heart disease
- Use with care in the elderly; higher risk of CV problems
Liotrix/Armour:
Mixtures of T3/T4
Not considered first line
Pregnancy would affect dosing for hypothryoidism how? Why?
Dose should be increased. Low maternal thyroid hormone can cause cretinism in babies.
*Also should avoid drugs that prevent conversion of T4 to T3!
Radioactive iodine (131I) is used to treat what?
Hyperthyroidism; the radioactive iodine destroys the thryoid tissue via beta radiation
What does a high dose of iodine salt do to production of thyroid hormone?
It actually decreases it temporarily
Propylthiouracil and
Methimazole
- Are both thioamides given to treat hypothyroidism.
- PTU is short acting with a slow onset.
- Methimazole is highly potent with a longer duration
- MOA: inhibit peroxidase and inhibit organification, block coupling of iodotyrosines, inhibit 5-deiodonase
- Adverse effects: GI upset and macropapular rash
- Black box warnings: Jaundice, hepatitis, lupus-like syndrome, vasculitis and agranulocytosis
- Avoid PTU use in children due to hepatisis
- Greater risk of agranulocytosis with methimazole
What treatment would be good for thryoid storm?
Propranolol: A beta blocker to reduce CV symptoms and reduce T4 to T3 conversion
IV PTU: to rapidly inhibit T4 and T3 production
Hydrocortisone: to inhibit T4 to T3 conversion
What type of thyroid cancer is associated with ionizing radiation?
Papillary carcinoma
Papillary carcinoma histology
Medullary carcinoma of the thyroid
Amyloid deposits are common
Anaplastic carcinoma of the thyroid histology
Giant cells and spindle cells
Bethesda system for reporting thryoid cytopathology:
I- Nondiagnostic or Unsatisfactory
II- Benign
III- Atypia (or follicular lesion) of Undetermined Significance
IV- Follicular Neoplasm or Suspicious for Follicular Neoplasm
V- Suspicious for Malignancy (Specify)
VI- Malignant (Specify)
Causes of hypothyroidism?
Hashimoto thyroiditis
Surgical or radiation ablation
Inherited defect in hormone synthesis
Iodine deficiency (endemic goiter)
Drugs (Amiodarone, Lithium, antithyroid Rx)
Pituitary disease (like a tumor)
Useful laboratory tests for hypothyroidism:
TSH – most sensitive test to diagnose primary disease
Ultrasound – best test for determining cause
Thyroid (TPO) antibody* – to confirm Hashimoto disease
T4 – to access severity of hypothyroidism
Causes of thyrotoxicosis:
Graves’ Disease
Toxic adenoma (hot nodules)
Toxic multinodular goiter (same as above/multiples)
DeQuervain’s subacute thyroiditis
Silent and postpartum thyroiditis (usually self limiting – but can progress)
Iodine-induced hyperthyroidism (the drug amiodarone)
Excess TSH (pituitary or placenta)
Excessive ingestion of thyroid hormone
Is menorraghia associated with hyper or hypothyroidism?
Hypo
Pretibial myxedema, lid lag and eye changes are associated with?
Graves disease
Pathogenesis of Graves disease:
- Autoimmune disorder
- Antibodies to TSH receptor which is central to disease
- Thyroid-stimulating immunoglobulin (TSI) relatively specific for Graves’ Disease
- Also antibodies to thyroid peroxisomes and thyroglobulin (not specific)
- Labs: increased T4 and T3, decreased TSH, increased radioactive uptake
Scalloped colloid is a histologic characteristic of Grave's disease
Toxic nodular goiter:
- Due to single or multiple benign nodules
- Account for 15% of hyperthyroidism
- Most patients’ age > 40
- Radioactive iodine uptake shows only the “hot nodules” taking up excessive iodine.
- Thyroid stimulating Ig (TSI) negative
- No ophthalmopathy or dermopathy
- Treated with RAI or surgery
Hashimoto's thyroiditis:
- Also known as chronic lymphocytic thyroiditis
- Painless enlargement: diffuse, symmetric
- Hypothyroidism but may be preceded by thyrotoxicosis (hashitoxicosis; T4, T3 ↑)
Gross appearance of thyroid in Hashimoto's thyroiditis:
Tissue appears yellow due to lymphoid infiltrates
Histology of Hashimoto's thyroiditis:
Pathology shows lymphoid follicles and infiltrate of lymphocytes and plasma cells. Follicles appear
atrophic with less colloid and cells have abundant granular pink cytoplasm called Hurthle or oxyphil cells.
Histology of subacute thyroiditis (de Quervains):
There is destruction of thyroid follicles with extravasated colloid causing inflammatory response including foreign body giant cells.
Follicular adenoma histology:
Follicular adenomas tend to be hypercellular with small acini compared to normal.
What do islet cells in the pancreas produce?
They produce Insulin (beta cell), glucagon (alpha), somatostatin (delta) and
Vasoactive intestinal peptide (Pancreatic polypeptide cells)
Pancreas histology showing normal and tumor
Pheochromocytoma histology:
Note nests of cells and prominent vessels
Symptoms of a glucagonoma:
(An alpha-cell tumor of the pancreas)
Diabetes, skin rash and anemia