PHCY 507: Endocrine Test 1
Study online at https://quizlet.com/_emdhu4
major endocrine organs
1.Pituitary gland
2.Thyroid gland
3.Parathyroid gland
4.Adrenal gland
5.Pancreas
6.Thymus
7.Gonads: Testes and ovaries
endocrine system
Organs that secrete hormones by diffusion into nearby blood
vessels
endocrine system glands
pituitary (anterior), pineal, thyroid, parathyroid, adrenal glands
endocrine stimuli types
humoral
neural
hormonal
humoral stimuli
Altered levels of certain critical ions
Or nutrients cause hormone release
neural stimuli
neural input stimulate hormone release
hormonal stimuli
Another hormone (a tropic hormone) cause
hormone release
pituitary gland is divided into
-Adenohypophysis (anterior lobe)
-Neurohypophysis (posterior lobe)
pituitary gland is connected to the brain via
hypothalamus, which controls release of hormones from the pituitary gland in two different ways.
anterior pituitary secretes
TSH (tropic)
ACTH (tropic)
FSH (tropic)
LH (tropic)
GH (direct)
PRL (direct)
TSH
tropic, stimulates production of thyroid hormones in thyroid gland
ACTH
adrenocorticotropic hormone, tropic, stimulates production of glucocorticoids & androgens in adrenal gland
FSH
follicle-stimulating hormone, tropic, stimulates ovaries to produce
estrogens & follicle maturation/testes to produce sperm
LH
luteinizing hormone, tropic, stimulates ovaries to produce estrogens & progesterone/testes to produce testosterone
GH
direct acting, stimulates growth in muscle, bone, cartilage...
PRL
direct acting, stimulates milk production in breast secretory tissue
posterior pituitary hormones
does not produce them just stores them
oxytocin
ADH
oxytocin
labor and milk ejection, produced in PVN
ADH
fluid retention in kidneys, produced in supraoptic nucleus
thyroid gland
largest purley endocrine gland
produces TH and calcitonin
thyroxine
T4, most abundant in circulation
trilodothyronine
T3, more potent that t$
function mof thyroid
essential for normal growth and development, body temperature
and energy levels
thyroid hormones increase
basal metabolic rate (BMR): affect growth and overall metabolism
Hashimoto's
•Hypothyroidism due to autoimmunity
endemic goiter
•Hypothyroidism due to lack of iodine (TSH is increased)
1 / 16
PHCY 507: Endocrine Test 1
Study online at https://quizlet.com/_emdhu4
grave's disease
Most common type of hyperthyroidism
Immune system makes abnormal antibodies that mimic TSH:
oversecretion of TH
Sx: nervousness, weight loss, sweating, rapid HR, ...
parathyroid glands
small pea-like organs that regulate calcium and phosphate balance in blood, bones, and other tissues
parathyroid hormone
increases blood calcium levels
oxyphil cells
increase in # as body ages, unknown function
adrenal glands
adrenal cortex and adrenal medulla
adrenal cortex
secretes corticosteroids (mineralocorticoids, glucocorticoids, androgens)
adrenal medulla
-stores & releases epinephrine and norepinephrine (upon sympathetic stimulation)
3 zones of adrenal cortex
•Zona glomerulosa: tufts of cells; mineralocorticoids (aldosterone)
•Zona fasciculata: cords of cells; glucocorticoids (cortisol)
•Zona reticularis: abundant reticular fibers (boundary between
medulla and cortex) (dehydroepiandrosterone)
glucocorticoids
influence function of most cells in the body
Part of stress response
Modulates immune response
stimulate gluconeogenesis and release of insulin
net increase of fat deposition in certain areas
Cushing's syndrome
hyper secretion of glucocorticoid hormones (usually a pituitary
tumor)
Mineralocorticoids (Aldosterone)
Na and fluid retention in kidney ’ ‘ blood volume ’ ‘ BP
aldosterone secretion is subject to
•ACTH
•Angiotensin
pancrease
exocrine gland: secrete digestive enzyme and endocrine gland:
islets secrete hormones
endocrine pancrease
controls blood glucose homeostasis, secrete glucagon and insulin
alpha cells of pancreas
secrete glucagon
glucagon
Signal liver to metabolize glycogen into glucose, and the adipose
tissue to metabolize triglycerides into glucose ’ raise blood sugar
beta cells of pancrease
secrete insulin
insulin
Signal most body cells to take up glucose from the blood after a
meal ’ lower blood sugar
delta cells of pancrease
secrete somatostatin: Inhibit secretion of insulin and glucagon
F (PP) cells of pancreas
secrete pancreatic polypeptide: May inhibit exocrine activity of the
pancreas
thymus
•Located in the lower neck and anterior thorax. Superior to heart,
within mediastinum
•Important immune organ: site of T cell maturation after release
from bone marrow, stimulated by thymic hormones (thymopoietin
and thymosin)
testes
•Interior divided into lobules containing seminiferous tubules
•FSH & LH from anterior pituitary
secrete androgens (testosterone)
ovaries
•Interior divided into cortex (follicles) and medulla (blood supply)
•FSH, LH from anterior pituitary stimulate follicle development
ovaries secrete
-Estrogen à maintain reproductive organs, secondary sex characteristics
-Progesterone à preparation of uterus for pregnancy
2 / 16
PHCY 507: Endocrine Test 1
Study online at https://quizlet.com/_emdhu4
thyroid function
•Responsible for the formation and secretion of three thyroid hormones as well as iodine homeostasis within the body
three hormones that thyroid produce in the body
•Triiodothyronine (T3)
•Thyroxine (Tetraiodothyronine) (T4)
•Calcitonin
calcitonin
hormone that regulates circulating levels of calcium
1. hypothalamus releases thyroid-releasing hormone (TRH)
2. Tells the anterior pituitary to
synthesize and release TSH
Thyroid function controlled by thyroid-releasing hormone and thy3. Tells thyroid to make two iodine-containing hormones: Thyroxine
roid-stimulating hormone (TSH)
(T4) and Triiodothyronine (T3)
4. Enzymatic reactions lead to incorporation of iodide
into active T3 and T4
Thyroid hormone production negatively regulates TRH & TSH
release through a
negative feedback loop
iodine organification
•DIT + DIT’ thyroxine (T4)
•DIT + MIT ’ triiodothyronine (T3)
Thyroxine and T3 in plasma are reversibly bound to protein, primarily
thyroxine-binding globulin (TBG)
Most thyroid hormone in blood is
T4
normal range for total T4
5-12
normal range for total T3
82-180
normal range for free thyroxine
0.8-1.9
normal range for TSH
0.4-4.0
hypothyroidism
Defined as the clinical and biochemical syndrome resulting from
decreased thyroid hormone production
primary hypothyroidism
Hashimoto's thyroiditis
hashimoto's disease is also called
autoimmune thyroiditis
Hashimoto disease presentation
Patients may present either with goitrous thyroid gland enlargement and mild hypothyroidism or with thyroid gland atrophy and
more severe thyroid hormone deficiency.
goiter
“T3/T4 ’ ‘‘TSH secretion (feedback) ’ trophic stimulation of thyroid
Common Signs & Symptoms of Hypothyroid Disease
•S leepiness, fatigue, lethargy
•L oss of memory
•U nusually dry, coarse skin
•G oiter
•G radual personality changes
•I ncrease of weight, or puffiness
•S ensitivity to cold
•H air loss, sparseness of hair
hypothyroidism clinical presentation
slowing down of all body functions
•In infants and children ’ striking retardation of growth and development, e.g. dwarfism and mental retardation (cretinism)
extreme case of hypothyroidism
myxedema coma
myxedema coma
•Early symptoms of myxedema:
•Increased sensitivity to cold
•Fatigue
•Heavier menstruation
•Depression
•Weight gain
•Late symptoms
•Slow speech
•Decreased taste/smell
3 / 16
PHCY 507: Endocrine Test 1
Study online at https://quizlet.com/_emdhu4
•Puffy extremities
•Coma ’ Death
Subclinical Hypothyroidism
•Increased TSH WITHOUT specific symptoms
•Highest incidence in the elderly
•Often progresses to diagnosed hypothyroidism
highest risk for subclinical hypothyroidism
•Initial TSH > 20 mIU/mL
•High initial antibody titers
Pharmaceutical (Generic) Equivalence
•Products with same active ingredient, and identical dosage form,
strength, and route of administration
bioequivalence
Generic equivalents with similar Cmax, Tmax and AUC (80-125%
of the standard)
Therapeutic Equivalence
Pharmaceutical equivalents meeting FDA, USP, and Current Good
Manufacturing Practices (Presumed similar E/S profiles)
drugs with a narrow therapeutic index
extended phentyoin, digoxin, lithium carbonate, conjugated estrogens, carbamazepine, warfarin, levothyroxine
•95% of hypothyroid patients are hyperlipidemic
Correlation of Serum TSH and Cholesterol in Hypothyroid Patients •Correction of hypothyroidism normalizes cholesterol in majority
of patients
hyperthyroidism
Defined as a syndrome with EXCESS thyroid hormone production
Causes of Hyperthyroidism
•Graves' Disease
•Toxic Uninodular Goiter
•Multinodular Goiter
•Jod-Basedow
•Factitious
•Drugs
•Thyroiditis
•Tumor
graves disease
An autoimmune syndrome that usually includes:
•Hyperthyroidism
•Diffuse thyroid enlargement
•Exophthalmos
•Pretibial myxedema (less common)
•Thyroid acropachy
graves disease patho
1. Antibodies bind to and stimulate TSH-R
2. Stimulate growth and biosynthetic activity of the thyroid cell
3. Excessive amounts of thyroid hormone synthesis
Toxic Uninodular Goiter
•Discrete thyroid mass whose function is independent of pituitary
and TSH control.
Arises from gain-of-function somatic mutations of the TSH receptor, the Gs±
prote
multinodular goiter
•Follicles with autonomous function coexist with normal or even
nonfunctioning follicles
•Diffuse hyperplasia caused by goitrogenic stimuli, leading to mutations and clonal expansion of benign neoplasms
Common Signs & Symptoms of Hyperthyroid Disease
•Flushed, Moist Skin
•Thinning of hair
•Proptosis, lid lag
•Pretibial myxedema
•Palmar erythema
•Brisk DTR's
•Goiter
Tremor
•Weakness, fatigue
•Nervousness
•Muscle aches
•Weight Loss
•Heat Intolerance
4 / 16
PHCY 507: Endocrine Test 1
Study online at https://quizlet.com/_emdhu4
•Palpitations
•Amenorrhea
•Diarrhea
Hyperthyroidism Clinical Presentation
Excess levels of thyroid hormone
•Symptoms include high temperature, high metabolic rate, excessive alertness, etc.
•Resembles sympathetic nervous system overactivity (esp. on CV
system)
extreme case of hyperthyroidism
thyroid storm
Acute exacerbation of all symptoms:
•Agitation, alertness, confusion, rapid heart rate, increased systole, shaking, sweating
•Can develop CHF and Pulmonary edema ’ death
treatment of hyperthyroidism
surgery
radioactive iodine
drug therapy
Clinical and laboratory evaluations should be performed for thyroid hormone
•~6-week intervals at initiation and dose adjustments
•Annually once a euthyroid state is established
under replacement of thyroid hormone risks
•Continued hypothyroid state
•Hyperlipidemia
•Decreased heart rate and ventricular contractility
•Increased peripheral resistance and diastolic pressure
•Memory loss
•Fatigue
Depression
over replacement of thyroid hormone risk
•Induced hyperthyroid state
•Increased heart rate and myocardial contractility
•For cardiac patients, increased risk of angina and myocardial
infarction
•Reduced bone density (osteoporosis)
thyroid hormone in pregnancy
•Treat even mildly elevated TSH
•Increase T4 replacement by 30% with 1st detection of pregnancy
•Monitor TSH and adjust dose accordingly
•Routine screening suggested
Inappropriate Uses of THR Therapy
•Obesity
•Chronic Fatigue
•Short Stature
•Infertility
Parathyroid Glands
•Small endocrine glands located on the back of the thyroid in
variable locations
•Responsible for production and secretion of parathyroid hormone
in response to a low blood calcium
Parathyroid Hormone (PTH)
•The most important endocrine regulator of calcium and phosphorus concentration in extracellular fluid
•Secreted from the parathyroid glands
Major targets: bone and kidney
synthetic TH drugs
•Levothyroxine: T4 - preparation of choice
•Liothyronine: T3
•Liotrix: Levothyroxine + Liothyronine (4:1)
TH drugs boxed warning
DO NOT use to treat obesity if levels are normal (not effective/detrimental).
levothyroxine
•Synthetic version of endogenous T4 (thyroxine)
levothyroxine MOA
activation of all receptors for T4, converted to T3 and activates
T3-R
•Preparation of choice for thyroid replacement and suppression
therapy
levothyroxine
5 / 16
PHCY 507: Endocrine Test 1
Study online at https://quizlet.com/_emdhu4
levothyroxine AE
hyperthyroid-related due to therapeutic overdosing (‘HR, palpitations, sweating, weight loss, arrhythmias, irritability)
Liothyronine
T3, cytomel
liothyronine cons
shorter half life
expensive
liothyronine pros
3-4x more potent than levothyroxine
liothyronine AE
hyperthyroidism with OD
liothyronine CI
patients with cardiac disease
liotrix
•Levothyroxine + Liothyronine (4:1)
•Tablet
•No advantage over levothyroxine alone
•Available, but almost never indicated (cost)
dessiccated USP thyroid
armour thyroid
•Animal origin (porcine)
•~100 mg of desiccated thyroid = 100 mcg levothyroxine + 37.5
mcg of liothyronine
•NOT recommended
•protein antigenicity
•variable potency and stability
•difficulty in lab monitoring
If a woman with hypothyroidism becomes pregnant, her dose of
levothyroxine will need to be:
increased
Antithyroid drug therapy
1.Thioamides
2.Iodides
3.Anion Inhibitors
adjunctive therapy for hyperthyroidism
Adrenoreceptor-blocking agents
radioactive iodine
•Preferred for most patients over 21 (easy, effective, cheap, painless).
•Antithyroid therapy prior to administration.
•80% develop hypothyroidism afterwards.
thioamides MOA
1.Prevent hormone synthesis by inhibiting thyroid peroxidase and
interfering with the incorporation of iodine into tyrosyl residues of
thyroglobulin
2.Block coupling of MIT and DIT
3.PTU also partially inhibits peripheral deiodination of T4 à T3
methimazole
•Drug of choice for Graves' disease , 10x more potent than PTU
propylthiouracil
•Class prototype, but Black box warning for severe liver injury &
acute liver failure ’ only used if:
•Cannot tolerate methimazole, and radioactive iodine/surgery are
not appropriate
•Thyroid storm
First trimester pregnancy
thioamides adverse events
•Nausea, GI upset, skin rash (4-6%), +/- fever. Other rare reactions
(vasculitis, lupus-like reactions)
•Propylthiouracil: black box warning for severe liver damage
Methimazole AE
most severe (very rare) event is agranulocytosis = potentially fatal,
rapidly reversible with D/C of drug and CSFs
propylthiouracil black box warning
severe liver damage
Iodides MOA
•Excessive iodide in thyroid temporarily inhibits iodide organification and hormone release
•Decrease size and vascularity of hyperplastic thyroid gland
iodides AE
•Rare & mostly reversible: rash, swollen salivary glands and risk of
mucous membrane ulcerations, conjunctivitis, rhinorrhea, metallic
6 / 16
PHCY 507: Endocrine Test 1
Study online at https://quizlet.com/_emdhu4
taste, bleeding disorder
•GI upset (take with food to decrease )
Anion Inhibitors MOA
Competitively block iodide uptake through NIS
Anion Inhibitors
thiocyanate, no longer used
Adrenoreceptor Blockers
Symptomatic therapy, no effect on the thyroid itself
Adrenoreceptor Blockers drugs
B-blockers: metoprolol, propranolol, atenolol
adrenoreceptor blockers CI
•Decompensated HF
•If non-cardioselective selective, care must be taken in asthmatics
and with COPD!
Radioactive Iodine (131I)
•Oral administration (solution/capsule)
•Rapidly absorbed, concentrated in the thyroid, incorporated into
colloid of follicles without endangering other tissues
Radioactive Iodine (131I) MOA
•emits beta-rays with effective t1/2 = 5-8 days. Within weeks, thyroid parenchyma is destroyed with epithelial swelling and necrosis,
edema, leukocyte infiltration.
•Patients should be euthyroid before RAI (antithyroid drugs first)
Radioactive Iodine (131I) advantages
ease of administration, efficacy, low expense, painless
Radioactive Iodine (131I) CI
pregnant women or nursing mothers (fetal thyroid will concentrate
the isotope)
levothyroxine med chem
T4 widely used
prohormone
antacids and cations reduce absorption
t3/t4 mixture
armour thyroid
liothyronine med chem
T3 hormone
bypasses bodys control of metabolism
shorter half life than T4
propylthiouracil med chem
inhibit thyroid peroxidase
prevent formation of T3 and T4
use gloves when handeling
methimazole med chem
inhibit thyroid peroxidase
prevent formation of T3 and T4
use gloves when handeling
cincacalcet med chem
Increases sensitivity of calcium-sensing receptor of parathyroid
gland
Lowers parathyroid hormone and serum levels of calcium
etelcalcetide med chem
Allosteric activator of the calcium-sensing receptor of the parathyroid gland
somatostatin
•Growth hormone inhibiting hormone
ØInhibits the release of growth hormone
ØInhibits the release of thyroid stimulating hormone
•Produced by pancreas
•Peptide hormone (pre-hormone)
Half-life is 2-3 minutes
octreotide med chem
cyclic peptide (prevent metabolism)
inhibits growth hormone secretion
lanreotide med chem
cyclic peptide (prevent metabolism)
inhibits growth hormone secretion
pasireotide med chem
cyclic peptide (prevent metabolism)
inhibits growth hormone secretion
40 fold more potent than octreotide
two necessary parts of clinical guidelines
systematic review and set of recommendations
rigorously conducted systematic reviews should use
meta-analysis
7 / 16
PHCY 507: Endocrine Test 1
Study online at https://quizlet.com/_emdhu4
PRISMA
outlines the minimum set of items required for a systemic review
or meta analysis
systematic reviews contain
a focused questions
a methods section with defined inclusion and exclusion criterai
and predefined literature search strategy
key questions in study should define the following
type of population
type of exposure/intervention
comparator of interest
outcome of interest
GRADE assessment
evaluating the strength of evidence for each major outcome and
for each comparison made
hypothyroidism treatment for pt 15-50 year old treatment
levothyroxine 50-100, FU in 6 weeks
hypothyroidism treatment for pt >50 or heart disease
levothyroxine 25-50 mg, FU in 6 weeks
liothyroxine half life
short, require multiple daily dosing
liothyroxine greater risk of
cardiac toxicity
liothyroxine indication treatment of
myxedema coma
•NOT recommended for routine replacement therapy
•Best used for the short-term suppression of TSH
liothyroxine CI
•Uncorrected adrenal cortical insufficiency
•Untreated thyrotoxicosis
liothyroxine AE
•Cardiac dysrhythmia
•Myocardial infarction
•Tachycardia
Hyperthyroidism
liothyroxine DI
•Oral anticoagulants and vasopressors
liotrix components
•Combination therapy of T3 and T4
•Physiologic ratio of 4:1
•1 grain (65mg) equivalent to approximately 60 ¼
g of T4
Preparation of choice for thyroid replacement and suppression
therapy
levothyroxine
levothyroxine CI
acute myocardial infarction, thyrotoxicosis, uncorrected adrenal
insufficiency
levothyroxine administration
on empty stomach for best absorption
Six populations of thyroid hormone replacement patients especially at risk with inconsistent T4 dosing:
•Pregnant women
•Infants
•Thyroid cancer patients
•Patients with preexisting cardiac disease
•Older persons
•Patients with preexisting skeletal disease
treating hypothyroidism in pregnancy
•Treat even mildly elevated TSH
•Monitor TSH monthly and adjust dose accordingly
goal TSH in pregnancy
goal 0.1-3.0 mIU/L
treating hypothyroidism in thyroid cancer
•Goal: inhibit TSH secretion (0.1-0.2 mIU/mL), which will inhibit
growth of thyroid cells, without causing overt HTR
•Post thyroidectomy use higher T4 doses
treating thyroid issues in patients with preexisting cardiac disease
Start low (12.5 mcg) and go slow (12.5-mcg increments every 6-8
weeks).
treating thyroid issues in patients with osteopenia/osteoporosis
watch for over-replacement
treating thyroid issues in older patients
•Start low (12.5 mcg) and go slow (12.5-mcg increments every 6-8
weeks).
•Cholestyramine
•Colestipol
•Aluminum Antacids
8 / 16
PHCY 507: Endocrine Test 1
Study online at https://quizlet.com/_emdhu4
drugs the decrease absorption of thyroid hormone
•Ferrous Sulfate
•Sucralfate
•Raloxifene
•Di- and Tri-valent Cations
drugs that increase metabolism of thyroid hormone
•Traditional anti-epileptic drugs (PB, PHT, CBM)
•Rifampin
subclinical hypothyroidism
•Increased TSH without specific symptoms
•Highest incidence in the elderly
highest risk patients for subclinical hypothyroidism
•Initial TSH > 20 mIU/mL
•High initial antibody titers
myxedema coma treatment
•Treat underlying disorder
•IV Glucocorticoids (HC 100 mg )
•High-dose IV levothyroxine or triiodothyronine
•CV/Respiratory support
•Treatment of hypothermia, hypoglycemia, hyponatremia
hyperthyroidism In young patients/small glands/mild disease
treatment
antithyroid drug therapy
thioamides
anion inhibitors
iodines
hyperthyroidism treatment in most patients over 21
radioactive iodine
thioamides
Methimazole
Propylthiouracil
methimazole in treatment of hyperthyroidism
Drug of choice in adults & children
10x more potent than PTU
patient should report fever, sore throat, and flu like symptoms
t1/2 = 6 h
propylthiouracil in treatment of hyperthyroidism
Indicated only in:
•First trimester pregnancy
•Thyroid storm
•Adverse reaction to methimazole
potassium iodine brand names
•SSKI (38 mg/drop) - better palatability
•Lugol's Solution (6 mg/drop)
•Thyro-Block (potassium iodide 130 mg)
potassium iodine MOA
•Block thyroid hormone release
•Inhibit organification
•Inhibit peripheral T4 conversion
•Decrease gland size/vascularity
iodines advantages
•Prompt effectiveness, useful for thyroid storm
•Effective adjunct for surgery
iodines disadvantages
•Can't use alone
•May delay onset of thioamide therapy or delay treatment with
radioactive iodine (‘intraglandular stores of iodine)
•CI's: pregnancy; pts with nodular goiter or adenomas; prior to RAI
•Allergic reactions
"Escape phenomenon"
iodines AEs
•Rare & mostly reversible: rash, swollen salivary glands and risk of
mucous membrane ulcerations, conjunctivitis, rhinorrhea, metallic
taste, bleeding disorder
•May induce hyperthyroidism in susceptible patients (make it
worse)
adrenoreceptor blockers in hyperthyroidism
Provide symptomatic improvement, with no change in the etiology
of the disease
treatment of choice for hyperthyroidism in pregnancy
Low-dose PTU (MMI in 2nd and 3rd trimester)
Maintain FT4 in high-normal range
9 / 16
PHCY 507: Endocrine Test 1
Study online at https://quizlet.com/_emdhu4
treatment of choice for toxic nodular goiter
RAI therapy
Surgery
Avoid Iodides!
treatment of choice for thyroiditis
Usually self-limited
Inflammatory in nature
Treat symptomatically with NSAID (or steroid) and BB as needed
Look for subsequent transient hypothyroidism
neonatal thyrotoxicosis treatment of choice
Treat with thioamides and/or beta blockers
treatment of choice for iodine induced HTR disease
Due to excessive iodine ingestion (Jod-Basedow)
Discontinue source of iodine
Usually self-limited
treatment of choice for thyrotoxicosis factitia
Due to excessive thyroid hormone administration
Discontinue or decrease dose of thyroid hormone
treatment of choice for pituitary adenoma
Rare cause of HTR
Requires neurosurgical resection
treatment of choice for subclinical hyperthyroidism
> 65 years old
Concerns of CVD (angina, arrhythmias)
Concerns of Osteoporosis
Concerns of symptomatic HTR
treatment of choice for thyroid storm
Supportive Therapy
Fluids, Fever, Nutrition
Treat precipitating event
High dose PTU
Iodide Therapy
Beta blocker Therapy
IV Glucocorticoids
adrenocorticosteroids
glucocorticoids
mineralcorticoids
androgen, estrogen, and progesterone
glucocorticoids function
intermediary metabolism and immune function, cortisol
mineralcorticoids function
salt retaining activity
aldosterone
cortisol is also know as
hydrocortisone
cortisol function
•Regulates intermediary metabolism (intracellular conversion of
nutrients to cellular components), CV function, growth, immunity
•Tightly regulated synthesis and secretion, tight negative feedback
loop
cortisol responds to
physio/psychological stress to maintain homeostasis (stress can
override negative feedback control)
cortisol MOA
Glucocorticoid receptor agonist
Regulates gene transcription
cortisol physiologic effects
•Extensive - influence the function of most cells in the body,
generally via direct intracellular actions
•Important permissive effects: Deficiency of physiological levels of
cortisol attenuates physiological response to other hormones (e.g.
catecholamines)
cortisol metabolic effects
•Stimulate gluconeogenesis
•Increase serum glucose levels à release of insulin.
•
•Stimulate hormone-sensitive lipase and thus lipolysis
•However, insulin à lipogenesis
too much cortisol can lead to
decreased muscle mass, skin thinning and osteoporosis
cortisol anti-inflammatory and immune suppressing effects
Dramatic decrease in inflammation
modulation of leukocyte function, suppressing inflammatory cytokines and chemokines
10 / 16
PHCY 507: Endocrine Test 1
Study online at https://quizlet.com/_emdhu4
cortisol effects in CNS
•Too low à apathy, depression, irritability, and even psychosis
•Too much à behavioral disturbances like insomnia and euphoria
followed later by depression
cortisol effect in GI tract
•Large amounts associated with peptic ulcers
aldosterone secretion in subject to
•Angiotensin II
•ACTH
aldosterone MOA
Gene transcription upon binding to mineralocorticoid receptor
aldosterone effects
•Renal reabsorption of sodium & potassium excretion in the kidney
•Reabsorption of sodium in sweat, salivary glands, GI mucosa,
across cell membranes
aldosterone AE
•Increased plasma volume
•Hypertension
•Hypokalemia
•Metabolic alkalosis
disease with too much cortisol
cushings syndrome
disease with too much aldosterone
hyperaldosteronism
disease with too little cortisol and aldosteron
adrenal insufficiency (Addison's disease)
cushing's syndrome
Constellation of clinical features that result from chronic exposure
to excess glucocorticoids of any etiology (hypercortisolism)
ACTH-producing pituitary adenoma ("Cushing disease")
cushing's syndrome treatment
•Surgical removal of tumor is the treatment of choice, but not
always effective
•Adjuvant therapy with pharmacological inhibitors:
•Inhibitors of ACTH secretion
•Inhibitors of adrenal steroidogenesis
•Inhibitors of glucocorticoid receptors
primary aldosteronism
excess production of aldosterone by the adrenal zona glomerulosa, most common cause of mineralcorticoid excess
hyperaldosteronism can cause
resistent hypertension
peripheral edema
severe hypokalemia
metabolic alkalosis
Aldosterone excess may cause direct damage to
the myocardium and the kidney glomeruli
Patients with primary aldosteronism (AKA Conn's syndrome)
show increased rates of
osteoporosis, type 2 diabetes, and cognitive dysfunction
hyperaldosteronism treatment
•surgery
•Pharmacological treatment for not surgical candidates: MR antagonists
Primary adrenal insufficiency
Addison's disease, structural or functional lesions of the adrenal
cortex (autoimmune)
Secondary adrenal insufficiency
structural or functional lesions of the anterior pituitary or hypothalamus
Addison's disease symptoms
•weakness, fatigue, weight loss, hyperpigmentation, inability to
maintain blood glucose level while fasting.
hypotension, circulatory shock and death
Addison's disease treatment
DAILY glucocorticoid (hydrocortisone) and mineralocorticoid (fludrocortisone) replacement, increased during periods of stress
acute adrenal crisis
•Life-threatening, emergency presentation
•Requires large doses of GCs (parenteral hydrocortisone), fluid
and electrolyte correction, and tx of underlying cause
•Characterized by GI symptoms (N/V, abdominal pain), dehydration, hyponatremia, hyperkalemia, hypoglycemia, weakness,
lethargy, and hypotension.
•Usually associated with disorders of the adrenal rather than the
11 / 16
PHCY 507: Endocrine Test 1
Study online at https://quizlet.com/_emdhu4
pituitary or hypothalamus and sometimes follows abrupt withdrawal of GCs used at high doses or for prolonged periods.
synthetic corticosteroids MOA
GR agonists, mimicking cortisol
short acting glucocorticoids
DOA <12 h
hydrocortisone
cortisone
intermediate acting glucocorticoids
DoA = 12-36h
prednisone
prednisolone
methylprednisolone
triamcinolone
long acting glucocorticoids
DOA: 1.5 - >2 days
highest potency
more anti-inflammatory action
betamethasone
dexamethasone
hydrocortisone
•Equally efficacious anti-inflammatory and salt-retaining properties
•Used in wide array of applications, including dermatological (topical), ulcerative colitis, hemorrhoids, Addison's disease (chronic
and acute presentations), general immune suppression
•PO, IM, IV, SC
cortisone
•Prodrug of hydrocortisone
•No topical activity, but equi-active at anti-inflammation and
salt-retention
•PO
intermediate acting glucocorticoids are used for
Used to treat skin conditions (psoriasis, eczema - topical), immune
disorders (arthritis, ulcerative colitis, lupus - oral), asthma prevention (inhaled), keloids (injectable)
predinsone
prodrug of prednisolone, hepatic activation, only PO
betamethasone is used for
skin (eczema, psoriasis), fetal lung development (crosses placenta)
dexamethasone use
•Anti-inflammatory - RA, bronchospasm/asthma, idiopathic
thrombocytopenia purpura, allergic rhinitis, anaphylaxis, bacterial
meningitis where bacterial "clean-up" can be problematic;
•Oncological - anti-emetic and decreases post-surgical inflammation (ie. brain tumor removal), also directly toxic to some "liquid"
tumors;
•Fetal lung development
agents of choice for adrenal insufficiency
•hydrocortisone or cortisone acetate BID (mimic morning cortisol)
•prednisolone (once daily, or alternate-day is appropriate response.)
•Might also need mineralocorticoid replacement
glucocorticoids in non-adrenal disorders
•Mostly used for their ability to suppress inflammatory & immune
responses (where host response is the problem).
•Assess Risk / benefit
•Immune response might be important to control pathological
problem
•Might also cause irreparable damage
•Only symptomatic. Not specific or curative
Best medium- to intermediate-acting glucocorticoids. If possible,
alternate day therapy
non-adrenal disorders that use glucocorticoids
allergic reactions
hematologic disorders
systemic inflammation
inflammatory condition of bones and joints
nausea and vomiting
12 / 16
PHCY 507: Endocrine Test 1
Study online at https://quizlet.com/_emdhu4
organ transplants
skin diseases
dexamethasone suppression test
blood analysis for cortisol levels after administration of synthetic
glucocorticoid, used to detect cushing's syndrome
short period of corticosteroids (<2 weeks) AE
•Insomnia, behavioral changes, acute peptic ulcers (acute pancreatitis with high doses, rare but serious)
long term use of corticosteroids metabolic AE
•100 mg/day for >2 weeks à iatrogenic Cushing's syndrome
•rounding puffy face (moon face), fat deposition and redistribution,
hair growth, acne, insomnia and increased appetite
•Increased glucose production and diabetes
•Weight gain, visceral fat added, myopathy, muscle wasting, thinning skin and osteoporosis, impaired wound healing
long term use of corticosteroids AE
kids --> growth arrest
hypertension: sodium and fluid retention
glucocorticoid withdrawal
adrenal suppression
flare up of underlying disease
Steroidogenesis inhibitors drugs
Metyrapone
Ketoconazole
Etomidate
adenolytic drugs
mitotane
glucocorticoid receptor antagonist
Mifepristone
Neuromodulators of ACTH Release
pasireotide and cabergoline
metyrapone MOA
Inhibits 11²-hydroxylase ’ blocks cortisol and aldosterone production (not androgens)
metyrapone AE
significant androgenic AE (hirsutism, acne, etc)
’ not ideal for women... but safest choice during pregnancy.
•BP and electrolyte abnormalities.
metyrapone DDI
inducer of CYP3A4
ketoconazole
•Antifungal agent
•At higher doses, non-selective & potent inhibitor of adrenal and
gonadal steroid synthesis.
•MOA: inhibition of multiple enzymes (including 11²-hydroxylase
and 17±hydroxylase)
ketoconazole AE
•Antiandrogenic activity (gynecomastia and hypogonadism in
men).
•Hepatotoxic (CI in hepatic disease), reversible elevation of hepatic transaminases in 10% pts
•GI upset, dermatologic reactions.
ketoconazole DDI
strong inhibitor of CYP3A4
etomidate MOA
inhibits 11²-hydroxylase, aldosterone synthase
•For acute hypercortisolemia requiring emergency tx or in preparation for surgery (IV only)
mitotane effect on adrenal cortex
Cytotoxic effects to the adrenal cortex
mitotane use
•non-operable adrenal carcinoma
•Cushing's only off-label (compassionate basis only)
mitotane AE
•GI upset, nausea, diarrhea (up to 80% pts)
Lethargy, somnolence, CNS disturbances
mifepristone MOA
Binds GR with high affinity ’ stabilization of the hsp-GR complex;
blocks cortisol binding via competition; and changes the interaction with co-regulators (no effect on steroid synthesis).
mifepristone use
Treatment Cushing's syndrome (hyperglycemia) in inoperable patients with ectopic ACTH secretion or adrenal carcinoma who
didn't respond to other therapies
13 / 16
PHCY 507: Endocrine Test 1
Study online at https://quizlet.com/_emdhu4
mifepristone AE
Hypokalemia, nausea, fatigue, headache, peripheral edema,
dizziness, endometrial hyperplasia
mifepristone CI
pregnancy and severe hepatic impairment
Pasireotide (Signifor)
•Somatostatin analog: agonizes somatostatin receptors ’ inhibit
ACTH secretion ’ “cortisol secretion.
cabergoline
•D2-receptor agonist
•Sustained response in only 30-40% pts
aldosterone effect in body
Na+ and fluid retention in kidney ’ ‘ blood volume ’ ‘ BP
fludrocortisone
•Aldosterone receptor agonist
•CA: adrenal insufficiency associated with mineralocorticoid deficiency to modulate salt retention
•250-fold more salt-retention than cortisol
Mineralocorticoid Antagonists
Spironolactone
Eplerenone
Steroids that compete with aldosterone for its receptor
Mineralocorticoid Antagonists clinical applications
•Aldosteronism
•Excessive aldosterone production, usually by adrenal adenoma
or another tumor.
•Diuresis (HTN, HF)
The two classes of steroids are
corticosteroids and sex hormones
topical corticosteroids med chem
•Usually highly potent agents
•Display many halogens to enhance potency and/or block metabolism
1st line for management of cushings
surgical resection of ACTH of cortisol producing tumors
2nd line for management of cushings
oPituitary irradiation
oMedical therapy
oRepeat transphenoidal surgery or bilateral adrenalectomy
ketoconazole response
seen after several weks
ketoconazole benefits
cholesterol and blood pressure
levoketoconazole
new agent recently approved in January 2022 for Cushing's syndrome; has led to sustained improvements of urinary free cortisol
in 31% of 94 patients after 6 months of treatment; ADE: QT prolongation and ALT increase (SONICS Trial: http://bit.ly/2lbLBFJ)
metyrapone response
•Response seen within hours (short t ½ à requires multiple doses/day)
osilodrostat
•Oral cortisol synthesis inhibitor (inhibits 11²-hydroxylase ~
metyrapone)
•Dose 2-7 mg twice daily
•Has longer t½ and is more potent against 11²-hydroxylase >
metyrapone (twice daily dosing vs QID for metyrapone)
•ADE: GI, fatigue, headache, edema, adrenal insufficiency
etomidate
•Only comes as an injection
•Monitor serum cortisol
mifepristone FDA approval
FDA approved for patients who have T2DM or glucose intolerance
and who are not eligible for or who have had poor response to
surgery
mifepristone has ___________ due to anti-progestin activity and
risk of early termination
abortive effects
mitodane response time
•Takes weeks to months (~6 months) for beneficial effects to be
seen
pasireotide FDA approval
Only approved for adults with Cushing whom pituitary surgery is
not an option
pasireotide AE
diarrhea, nausea, QTc prolongation
14 / 16
PHCY 507: Endocrine Test 1
Study online at https://quizlet.com/_emdhu4
vaccinations for Cushing's syndrome
Flu, Shingrix, Prevnar
cortisol-dependent comorbidities
psychiatric disorders, DM, HTN, hypokalemia, infections, DLD,
osteoporosis, poor physical fitness
goals of therapy for primary hyperaldosteronism
normalize aldosterone levels
normalize serum potassium and reduce BP
1st line treatment of primary hyperaldosteronism
unilateral adrenalectomy
2nd line treatment of primary hyperaldosteronism
medical therapy: MR antagonists
spironolactone CI
•Addison's disease (hyperkalemia), hyperkalemia (>5.5 mEq/L),
anuria, CrCl <30 mL/min, co-administration with other potassium-sparing diuretics or potassium supplements (eplerenone,
amiloride)
Preferred drug during pregnancy, preferred for children due to little
anti-androgen effects for hyperaldosteronism
eplerenone
Monitoring for Primary Hyperaldosteronism
education
titrate medical therapy every 4-8 weeks
goals of therapy for Addison's
•Limit morbidity and mortality and return the patient to a normal
functional state
•Ensure patients are aware of treatment complications, expected
outcomes and consequences of missed doses
•Educate patient on long-term steroid therapy and emergency
procedures for adrenal crisis
pharmacotherapy for Addison's
glucocorticoids and mineralocorticoids
glucocorticoids replaces
cortisol
hydrocortisone and cortisone dose adjustment by
weight or BSA
glucocorticoid better for nonadherence but not for pregnant patients
prednisolone
glucocorticoids CI
live vaccines, serious systemic infections (fungal infections)
glucocorticoids ADE
•HPA suppression
•Psychiatric disturbances
Worsen other conditions
pharmacotherapy monitoring for glucocorticoids
•Measurement of plasma ACTH is not recommended
•Monitor replacement and adjust treatment based on clinical assessment of s/s
•signs of glucocortiocid insufficiency and excess
signs of glucocorticoid insufficiency
nausea, poor appetite, weight loss, lethargy, hyperpigmentation
(Addison's)
signs of glucocorticoid excess
weight gain, insomnia, peripheral edema
fludrocortisone ADE
edema
hypokalemia
mineralcorticoid pharmacotherapy monitoring
•Monitor based off clinical assessment of s/s
•Avoid licorice and grapefruit juice à potentiate effects
•Monitor for HTN
steroids taper is necessary when
taking steroid for >14 days
ACTH test for monitoring steroid discontinuation
•Ideally, would want to check HPA integrity using ACTH test or a
serum cortisol (@ 8:00 AM)
•A normal morning serum cortisol (>20µg/dL) or normal ACTH test
indicates therapy may be discontinued
If cortisol is <3µg/dL, axis is suppressed and continued replacement is required; suppression can persist for up to a year in some
patients
addisonian crisis
•Acute adrenal insufficiency mainly from HPA axis suppression =
endocrine emergency (fatal!)
•Occurs with abrupt withdrawal of chronic glucocorticoid use or
15 / 16
PHCY 507: Endocrine Test 1
Study online at https://quizlet.com/_emdhu4
lack dose adjustments during stressful situations (surgery, infection, trauma)
signs and symptoms of addisonian crisis
•weakness, myalgias, malaise, vomiting, fever, hypotension and
shock
treatment of addisonian crisis
•immediate parenteral injection of 100 mg hydrocortisone + fluid
resuscitation, then 200 mg Q24 hrs (continuous infusion or split).
After the initial 24 hrs, may taper dose gradually and resume
normal oral dosing once patient is stable.
addisonian crisis prevention
•add 5-10 mg hydrocortisone to normal daily regimen before
strenuous activities or double dose during times of severe physical
stress (illness)
management of addisons
•Educate about stress dosing for intercurrent illnesses and/or
provide injectable emergency steroids
•Offer a medical alert tag indicating adrenal insufficiency/ glucocorticoid replacement are essential
•Annual visits to an endocrinologist
16 / 16