Endocrine-1 Flashcards
The coupling of the two outer rings of DIT
or of one outer ring of DIT with that of
MIT (each with the net loss of alanine)
leads to the formation of ___ and ___,
respectively.
T4 and T3
____________ (Tg) serves as the matrix for
the synthesis of T4 and T3 and as the
storage form of the hormones and iodide
Thyroglobulin
TRH is ____ amino acids long (_________) secreted by the hypothalamus. Its basic
sequence is pyro-glutamyl-histidine-proline amide
three (tripeptide)
The formation of thyroid hormones involve:
(1) active uptake of _______ by the follicular cells
(2) oxidation of iodide (I-) to hypoiodite (IO-) by H2O2 and ___________ (TPO) and formation of iodotyrosyl residues (MIT and DIT) of thyroglobulin (Tg) through aromatic iodination, (3) formation of iodothyronines from iodotyrosines through ________ reaction catalyzed by TPO and H2O2
(4) _______ of Tg & release of T4 & T3 into blood
(5) conversion of T4 to T3 by the action of _____
iodine
thyroperoxidase
coupling
proteolysis
5’-deiodinase
T4 is a prohormone and its peripheral
metabolism occurs in two ways:
outer ring deiodination -> T3
inner ring deiodination ->T4
conjugation of phenolic hydroxyl group and oxidative deamination of inner tyrosyl ring
Liotrix is a synthetically derived thyroid hormone replacement preparation. It consists of
Levothyroxine sodium and Liothyronine sodium in a __ to __ ratio by weight.
4 to 1
The phenyl-X-phenyl nucleus is essential for thyroid hormonal activities and should
have the following structural features:
Aliphatic Side Chain (R1)
Alanine-Bearing Ring (R3 and R5)
Phenolic Hydroxyl Group (R’4)
Bridging Atom (X)
Phenolic Ring (R’3 and R’5)
Antithyroid Drugs are potent inhibitors of ______________, which is responsible for the iodination of tyrosine residues of thyroglobulin (Tg) and the coupling of iodotyrosine residues to form iodothyronines
thyroperoxidase (TPO)
The most clinically useful thionamides are thioureylenes, which are five- or sixmembered heterocyclic derivatives of thiourea including what
Propylthiouracil (PTU)
1-methyl-2-mercaptoimidazole (Methymazole, MMI)
The grouping R-CS-N- has been referred to as _______, or if R is N, as it is in Thiouracil, PTU, and MMI, it is called a ________
thioamide
thioureylene tautomers (keto or enol)
SARs of the thiouracils and other related compounds as inhibitors of outer ring deiodinase states that the C-2 thioketo/thioenol group and an _________ N-1 position are essential for activity.
unsubstituted
Structural modifications leads to produce inactive ______ inhibitors N1-alkyl or aryl and Thiol alkylation or arylation
TPO
Thyroid Gland
neck surrounding trachea below the larynx
Thyroid Structure: follicles surround the colloid core storing __________, a substrate in thyroid hormone synthesis
thyroglobulin
What two things stimulate the release of T3 and T4 synthesis and release
TRH
TSH
____________ symporter (NIS) transports iodide into follicles
Sodium/Iodide
What is Organification
tyrosine residues are iodinated to form moniodotyrosine (MIT) and diiodotyrosine (DIT)
Thyroidal peroxidase:
inhibition by I-, thioamides
Inhibits T4→T3 conversion
* Methimazole (Tapazole)
* Propylthiouracil (PTU)
T3 not bound to T3 receptor dimer, suppresses what
thyroid hormone response element (TRE)
T3 bound to T3 receptor, activates thyroid
hormone response element promotes heterodimerization with
retinoid X receptor (RXR)
Primary Hypothyroidism:
Deficient thyroid hormone levels
TSH high; T4 low
Secondary (Central) Hypothyroidism:
Deficient TSH
TSH low; T4 low
Peripheral Hypothyroidism:
Deficient transport, metabolism or
action of thyroid hormones
Severe Hypothyroidism symptoms
myxedema (swelling of skin)
myxedema coma (water intox, shock, coma)
Congenital Hypothyroidism
-Initially asymptomatic from maternal T4
-Extended gestation, weight/length normal
-Wide posterior fontanelle
-Extended jaundice
Causes of Hypothyroidism in US
- Hashimoto’s Thyroiditis (autoimmune)
- Drug induced
- Dyshormonogenesis: deficiency of synthetic hormones
- Thyroid Damage: Radiation or surgery
- Congenital: primarily genetic; autoimmune, dietary
- Pituitary or hypothalamic disease (Secondary)
Risk factors for hypothyroidism
pregnancy
age
autoimmune disease
FH
Causes of hyperthyroidism
grave disease
toxic adenoma
plummer’s disease
thyroiditis
Graves disease
Autoimmune Disorder
* TSH receptor antibody stimulates the receptor
* AKA thyroid-stimulating immunoglobulins
tremor, exophthalmoses
Iodination is inhibited by what kind of mechanism
feedback inhibition
Primary disease of endocrine gland
problem is with the endocrine gland itself
(ex: primary hyperthyroidism, primary hypothyroidism, primary ovarian failure)
Secondary disease of endocrine gland
Problem usually in pituitary
(ex: secondary adrenal insufficiency, hypogonadotropic hypogonadism)
Tertiary disease of endocrine gland
something wrong with hypothalamus (very rare)
What are the three effects of TSH
-stimulate increase thyroid cell growth, increase cell size, and vascularity of gland
-TSH increase all step in synthesis of thyroid hormone
-TSH increase all step in release of thyroid hormone
What is thyroid autoregulation
adaption of thyroid activity based on iodine availability
Results of thyroid autoregulation
independent of TSH activity
sensitivity of thyroid gland to TSH can be altered
rate of synthesis and secretion of thyroid hormones can be altered
Examples with excessive intake of iodine
wolff-chaikoff effect
inhibition of thyroid peroxidase activity
decreased sensitivity of gland to the effects of TSH
Triiodothyronine (selected thyroid function test)
Serum T3 measures the total level of hormone
FT3 measures amount of free hormone
Thyroxine (selected thyroid function test)
Serum T4 measures the total level of hormone
FT4 measures amount of free hormone
Serum TSH (selected thyroid function test)
in patients with primary thyroid disease
-TSH is the most sensitive indicator of overall thyroid function
-primarily used for screening
Euthyroidism
normal thyroid function; TSH and fT4 are both in normal range
Primary hypothyroidism FT4 and TSH levels
FT4: below normal
TSH: above normal
Primary hyperthyroidism FT4 and TSH levels
FT4: above normal
TSH: below normal
Secondary hypothyroidism FT4 and TSH levels
FT4: below normal
TSH: below normal
Secondary hyperthyroidism FT4 and TSH levels
FT4: above normal
TSH: above normal
Subclinical hypothyroidism FT4 and TSH levels
FT4: normal
TSH: above normal
Subclinical hyperthyroidism FT4 and TSH levels
FT4: normal
TSH: below normal
Goiter
any enlargement of thyroid gland
What are the two types of goiters
diffuse: general overall enlargement of gland
nodular: irregular or lumpy enlargement
-single node
-multiple nodules
Endemic goiter
aka iodine deficiency goiter
most occur in developing countries
Examples of antibody testing for thyroid disease
TSH receptor antibodies (TRAb) -> graves
Anti-TPO antibodies (TPOAb) -> hashimotos, antibodies develop in response to inflammation indicating damage
Diagnostic radioactive iodine uptake (RAIU)
pt given I123
indicates how active thyroid gland is at taking up iodine
(high RAIU = graves, low RAIU = thyroiditis)
What is Hashimoto’s thyroiditis
autoimmune disease caused by hypothyroidism
thyroid follicles replaced by lymphocytes and fibrous tissue
What are the 4 etiologies of hypothyroidism
Hashimoto
iodine deficiency
congenital
iatrogenic (thyroidectomy, after RAI, drug-induced mainly amiodarone)
Levothyroxine treatment in hypothyroidism
synthetic T4
bind to plasma proteins
converted to T3 in periphery
ADR of levothyroxine treatment
only develop if a patient is overtreated (hyperthyroid symptoms)
Liothyronine therapy in hypothyroidism
synthetic T3
25 mcg of T3 approx equiv to 100 mcg of T4
not considered appropriate initial therapy
When to use liothyronine in patients
patients on levothyroxine whose thyroid labs are normal but they are still having symptoms despite having levels in normal range
What are the combination drugs of T4/T3
liotrix (thyrolar)
Desiccated thyroid gland (Armour® thyroid, USP, generics)
Levothyroxine replacement therapy what are the two factors that impact the choice of initial dose
age >60 yo
History of coronary heart disease (CHD)
use 25 or 50 mcg once daily
How to calculate healthy adults hypothyroidism dose
1.6 mcg/kg/day
use ideal body weight
What are the 3 weird doses of levothyroxine
88mcg
112 mcg
137 mcg
When to check TSH levels
6-8 weeks
Goals of TSH Initial monitoring & follow-up for primary hypothyroidism
feel better, relief of symptoms
want TSH in a normal range
free T4 in normal range
usual counseling of levothyroxine
Take in the morning with water
Take on an empty stomach…at least 30-60 minutes before eating anything
Drug / Food interactions of levothyroxine
Fiber supplements
Ferrous sulfate
Calcium / Aluminum
Soy
What to do in patients on levothyroxine who become pregnant
Dose increased 30%
-take 2 extra doses per week
-monitor every 4 weeks
Congenital Hypothyroidism babies testing
Mandatory testing in newborn babies in most developed nations to identify it
Goal of Congenital Hypothyroidism
start thyroid replacement by 14 days old
Causes of thyrotoxicosis (hyperthyroidism)
-Primary hyperthyroidism – the problem is with the thyroid gland
-Secondary hyperthyroidism – the problem is with the pituitary (rare)
-Exogenous / Iatrogenic / Drug induced
Goals of treating thyrotoxicosis
-To relieve symptoms IF they are present
-To stop thyrotoxicosis (and restore euthyroidism if possible)
-IF possible - cause a “remission” (remaining euthyroid for 1 year after stopping drug therapy)
Radioactive iodine I131 (drug in thyrotoxicosis) MOA
slow destruction from radiation
methimazole (Tapazole) and propylthiouracil (drugs in thyrotoxicosis) MOA
inhibition of thyroid hormone synthesis
-Inhibition of the enzyme thyroid peroxidase
-Inhibition of enzyme 5’deiodinase – ONLY propylthiouracil does this, decrease peripheral conversion of T4 to T3
methimazole ADR
are dose related; rare if dose is < 30mg/day
propylthiouracil ADR
idiosyncratic
Major side effects of concern of methimazole and propylthiouracil
Agranulocytosis
Vasculitis
Hepatotoxicity
What is the preferred hyperthyroidism drug in most patients
methimazole
(except for 1st trimester then you use propylthiouracil)
Monitoring for hyperthyroidism
TSH, fT4, & fT3 periodically
-Most patients will improve or normalize thyroid function in 4-12 weeks
-Decrease dose to lowest effective dose to avoid adverse effects
symptoms of methimazole and propylthiouracil
mainly fever and sore throat
(fatigue, joint pain, bruising, jaundice)
Clinical use of Beta Blockers in hyperthyroidism
For the symptomatic relief of tachycardia/palpitations, heat intolerance/sweating, and nervousness/anxiety/tremor that occur during thyrotoxicosis; target to a pulse <90
What is the special consideration of propranolol in thyroid use
stop conversion of T4 to T3
Iodide use in hyperthyroidism MOA
-induce the Wolff-Chaikoff block
Makes the gland firmer, decrease size and decrease vascularity of the thyroid gland
etiology of graves disease
-An autoimmune disorder
-Antibodies develop to the TSH receptors of the thyroid gland. (TSH-R-Ab)
Diagnosis of graves disease
Goiter
Thyrotoxic symptoms may be present
IF a RAIU with I123 is done, uptake is elevated; entire gland will be overactive
Unique features of Grave’s disease (Orbitopathy)
Immune reaction causes soft tissue swelling/edema behind the eyes
-Protrusion of the eyes
-may lead to double vision
-smoking is a risk factor for eye involvement
Unique features of Grave’s disease (Infiltrative dermopathy)
-Front of the shins
-Hard, non-pitting edema
-occasional raised hyperpigmented papules or “bark-like” appearance
Adult patients should receive the anti-thyroid drug therapy for ___ to ___ months in treatment of graves disease
12-18 months
(Patients whose TSH-R-Ab remained at higher levels are at > risk of relapse)
Follow-up / Monitoring of using I123 in graves disease
-Hypothyroidism
-function will normalize within 2-6 months
-Hypothyroidism generally occurs within 4-12 months
Thyroidectomy treatment for graves disease
Anti-thyroid drug
Might give Iodide to ↓ vascularity of the gland & make removal easier
Nodular thyroid disease
autonomously functioning nodules secrete thyroid hormone
Types of Nodular thyroid disease
Toxic multi-nodular goiter (at least 2 nodules present)
Solitary toxic thyroid nodule (1 unilateral nodule)
Clinical diagnosis of toxic nodular goiter
-hyrotoxic symptoms may be present
-Nodular goiter is present
-RAIU with I123 will reveal the presence of active nodules; uptake is elevated
Treatment options for Nodular thyroid disease
Beta-blocker
Radioactive iodide
Surgery
Nodular thyroid disease surgery antithyroid drugs
methimazole (dont use longterm therapy)
Nodular thyroid disease surgery iodide drugs
never use in toxic nodules
Thyroiditis
an inflammatory condition of the thyroid gland
Etiology of Thyroiditis
Autoimmune (i.e. Hashimoto’s)
Radiation
Drug induced
Infectious
Thyroiditis Inflammation → follicle cell damage → ________ of already formed thyroid hormone
leaking
Subacute thyroiditis
symptom is pain
often occurs after viral URI
Autoimmune lymphocytic inflammation
painless thyroiditis (variant of Hashimoto’s thyroiditis)
Postpartum thyroiditis (occurs after pregnancy)
Treatment of thyroiditis in subacute and painless
subacute treat pain (NSAIDs or prednisone)
painless thyroiditis (beta blocker, maybe low dose levothyroxine)
Levothyroxine suppressive therapy
TSH is a trophic hormone – it may influence some nodules to “grow”
Thyroid axis suppression – can be induced by giving excessive levothyroxine
Treatment of nodules
-High index of suspicion for carcinoma = surgical removal of the nodule
-Low index of suspicion = 6-12 month trial of suppressive levothyroxine therapy to see if the
nodule regresses
Epithelial cells
the cells that make thyroid hormones
Rationale for suppressive levothyroxine after surgery
To reduce the risk of future thyroid cell development that might be stimulated by TSH
Levothyroxine suppressive therapy (TSH suppression) goals
To intentionally “over treat” with levothyroxine
To intentionally suppress the TSH below normal
To cause an asymptomatic subclinical hyperthyroidism
Risks of Levothyroxine suppressive therapy
Development of overt clinical hyperthyroidism
Cardiac arrhythmias
Osteoporosis
Dosing / Monitoring of Levothyroxine suppressive therapy
Usually give 100-150mcg levothyroxine initially
Usually requires a dose > 2mcg/kg/day
Subclinical hypothyroidism what might happen
Progression to overt hypothyroidism
TSH will become normal within a year
Who should be treated for subclinical hypothyroidism
TSH >10mIU/L treat always
TSH <10 treat if pregnant or planning to become pregnant, symptoms consistent w/hypothyroidism
Iatrogenic subclinical hypothyroidism
adherence must be assessed
(labs indicate they might be “undertreated”)
Subclinical hyperthyroidism what might happen
Early multi-nodular goiter
Early Grave’s disease
What are the risks of NOT treating Subclinical hyperthyroidism
Increased risk of atrial fibrillation
Increased risk of bone loss / osteoporosis
Iatrogenic subclinical hyperthyroidism
Patients receiving levothyroxine (labs indicate they might be “over-treated”)
Patients receiving levothyroxine replacement therapy for hypothyroidism in Iatrogenic subclinical hyperthyroidism
being overtreated (need to decrease dose)
Patients receiving levothyroxine suppressive therapy for thyroid nodules or cancer in Iatrogenic subclinical hyperthyroidism
leave dose where it is
Assessment of “subclinical” lab values
screening
diagnose
monitoring therapy
ACTH stimulates the release of what
cortisol
ACTH synthesis: prohormone convertase 1
proteolytic cleavage enzyme for POMC hormones
ACTH synthesis: Pro-opiomelanocortin (POMC)
precursor for ACTH (and other hormones)
ACTH stimulates de novo cortisol synthesis via ____-Protein Kinase A pathway
MC2R
Adrenocorticosteroids
steroid hormones secreted by the adrenal cortex
Glucocorticoids
metabolic regulation
Mineralocorticoids
electrolyte regulation
Adrenal gland: Adrenal Cortex and Adrenal Medulla
Adrenal Cortex: outer portion
Adrenal Medulla: inner portion
Zona Glomerulosa: angiotensin II (Ang II) and K+ stimulate _________________ release
mineralocorticoid
Zona Fasciculata
ACTH stimulates cortisol release
Zona Reticularis
ACTH stimulates dehydroepiadrosterone (DHEA) and DHEA-S - androgen precursors
Where do you get endogenous cholesterol from
de novo biosynthesis
Glucocorticoid Receptors: Expressed in almost every cell (cytosol) – ____ _________ of development, metabolism, and immune response.
gene regulation
Cortisol (S) bound in plasma corticosteroid-binding globulin (CBG) interacts with intracellular _______________ __________ and binds to glucocorticoid response element
glucocorticoid receptor
Certain cells (kidney, colon, salivary gland) contain 11β-hydroxysteroid dehydrogenase
Type II (11βHSD2), which metabolizes ___________ to an inactive form
glucocorticoids
(11β-HSD1 which does the opposite)
Metabolic effect of cortisol in glucose, fat, and proteins
glucose: increase
fat: decrease
protein: decrease
Synthetic Steroids
Cortisone, prednisone
Tissues with low 11βHSD1 what steroids are preferred
hydrocortisone and prednisolone
Treatment of hypercortisolism
Ketoconazole and Metyrapone
Drugs that are used for Growth Hormone Excess
Octreotide: somatostatin agonist
Pegvisomant: GH receptor antagonist
Hyperprolactinemia drugs
Bromocriptine: partially-selective dopamine receptor 2 (DRD2) agonist
Cabergoline: “more” selective and potent DRD2 agonist
A ________________ (rings A, B, and C) is the completely saturated derivative of phenanthrene
perhydrophenanthrene
The polycyclic hydrocarbon known as _________ refers to a steroid with 27 carbons that includes a side chain of eight carbons at position 17.
cholestane
5a-cholestane is said to have a _____________________ backbone
trans-anti-trans-anti-trans
(5 beta is cis-anti-trans-anti-trans)
Cholestane contains ___ carbon atoms
Pregnanes are steroids with __carbon atoms
Androstanes contain ___ carbon atoms
Estranes contain ___ carbon atoms, with the C19 angular methyl group at C10 replaced by hydrogen
27
21
19
18
This C21 steroid is converted via enzymatic oxidations and isomerization of the double bond to a number of physiologically active C21 steroids, including the female sex hormone progesterone and the adrenocorticoids cortisol, corticosterone, and aldosterone
Pregnenolone
_______ is metabolized by the liver and is mainly
excreted in the urine as inactive O-glucuronide
conjugates at 3 and 21 positions and minor O-sulfate conjugates of urocortisol, 5b-dihydrocortisol, and urocortisone
cortisol
All of the biologically active __________ contain a ketone at the 3-position and a double bond in the 4,5-position
adrenocorticoids
The conserved structural features of glucocorticoids like Hydrocortisone include: Δ4-keto, an a,b-unsaturated carbonyl system, which means the presence of double bond at position 4 and ____ group at position 3, _____ at position 20 and hydroxyl alcoholic group at position 21
keto
ketone
The 17b-ketol side chain and the Δ4-3-ketone contribute to the _________ of adrenocorticoids
potency
The ________ _______ donating 11b-OH group of Hydrocortisone (active) is essential for drug-receptor interaction
hydrogen bond
Structural Modifications on Hydrocortisone purpose is to produce glucocorticoids with ________ potency enhancement and/or to _______ selectivity over MR
greater
increase
Glucocorticoids: Insertion of a ______ _____ between positions 1 and 2 in Hydrocortisone increases binding affinity
double bond
Glucocorticoids: Insertion of an a-CH3 group at position 6 provides ______ selectivity, prevents the metabolism at the 3-keto, and increases glucocorticoid activity
greater
Glucocorticoids: Insertion of a-OH groups into positions (e.g., 6, 7, and 16) or reduction of the 20-ketone decreases
glucocorticoid activity due to increased __________
hydrophilicity
Glucocorticoids: 16a-OH to the 16a-methyl increases GR binding affinity due to favorable _______ contacts of the 16a-methyl group within a hydrophobic pocket of GR that is not available in MR
hydrophobic
Glucocorticoids: Replacement of the 21-OH group with _________ increases glucocorticoid and sodium-retaining activities
fluorine
In C: Rigidity of A-ring is increased. Flattening of
A-ring enhances GR affinity binding, increases
potency and half-life and producing ______ active
agents.
orally
lack of substituents on Aldosterone’s ______ face explains higher affinity for MR over GR.
alpha
The 21-esters are __________. Hydrolysis provides the 21-OH active derivatives
prodrugs
The extremely water-soluble 21-sodium succinate and 21-sodium phosphate _______ are used for IV or IM injection in the management of emergency conditions
esters
Increased lipophilicity improves penetration through the ________ ________. accomplished by introducing 6a, 7a, and/ or 9a halogens, removing the 17a-hydroxy group, masking 16a-,17a-,or 21 hydroxy groups using cyclic ketals esters, or replacing the 21-hydroxy group with a halogen
stratum corneum
The topical glucocorticoids can be classified based on their 16-position substitution into derivatives of
triamcinolone (16a-hydroxyl)
dexamethasone (16a-methyl
betamethasone (16b-methyl)
prednisolone (no 16-substituted).
The new inhaled/ intranasal glucocorticoids are more lipophilic than those used in oral and systemic therapy and have greater affinity for the ______
GR
_________ is a highly potent nonhalogenated
glucocorticoid composed of a 1: 1 mixture of epimers of the 16,17-butylacetal, which creates a chiral center. The 22Repimer binds to the GR with higher affinity than does the 22S-epimer
Budesonide
__________ is a third-generation nonhalogenated Prednisolone analog. It is the 21-isobutyrate ester and the 16a, 17a-acetal of the cyclohexane carboxaldehyde analog of Prednisolone
ciclesonide
__________ ____________ is a trifluorinated thiester
glucocorticoid with the 17a-propionoxy group
Fluticasone propionate
The intact furoate side chain occupies a discrete
pocket, conferring ________ _______ with higher GR affinity and higher nasal and lung tissue affinity compared to Fluticasone propionate
Fluticasone furoate
What are the two functions of prolactin
stress hormone (help regulate metabolism)
stimulates proliferation of breast tissue in preparation for lactation
What are the two synthesis steps of prolactin
-prolactin is produced by the lactotroph cells of the anterior pituitary
-synthesis is under tonic inhibition by dopamine from the hypothalamus
What are the normal serum prolactin levels for women and men
women: <20mcg/L
men: <15mcg/L
What are the three things that can override the tonic inhibition by dopamine
certain types of nerve impulses
estrogen
TRH
What is the prolactin mechanism when a baby suckles
prolactin continues to increase causing milk production
stimulates oxytocin release form the posterior pituitary which ejects milk from breast
Pathologic hyperprolactinemia
abnormal state of continuously elevated prolactin levels
High levels of TRH stimulate the anterior pituitary what occurs in the thyrotroph cells and lactotroph cells
thyrotroph cells: increase TSH production
lactotroph cells: increase prolactin production
What are typical antipsychotics
potent D2 antagonists and disassociate slowly from the receptor
increase prolactin levels and may cause sustained hyperprolactinemia
What are atypical antipsychotics
they have a variety of structures and receptor activity
most are prolactin-sparing
(exception: risperidone increase prolactin)
What is prolactinoma
a pituitary adenoma that secretes prolactin
Pathophysiology of prolactin: most are due to ________________ _______________
hypogonadotropic hypogonadism (secondary hypogonadism)
Increase of prolactin causes a decrease in GnRH which decreases FSH/LH secretion causing a decrease in what
gonad hormones (causes disorders in reproductive function)
treatment of prolactinomas
medical management of dopamine agonists
(drug therapy is preferred)
MOA of prolactinomas
agonist drug binds to D2 receptors on lactotroph cells of the anterior pituitary restoring tonic inhibition of prolactin secretion
What are the two prolactinoma drugs
bromocriptine
cabergoline
(monitor prolactin levels)
Goals of prolactinoma drug treatment
reduce prolactin levels
improve symptoms
reduce adenoma size
restore fertility
decrease long-term risk of osteoporosis
ADH MOA
When ADH is present, the renal collecting ducts become permeable to water (increase urine concentration)
When ADH is absent, the renal collecting ducts become almost impermeable to water
What is ADHs relation to plasma osmolality
is the most important determinant of ADH secretion
Osmoreceptors in the hypothalamus monitor osmolality
thirst is backup mechanism
Diabetes insipidus (DI)
A condition of abnormal water regulation/conservation.
Patients urinate a very large amount
Diabetes insipidus (DI) symptoms
Polyuria
Polydipsia
Central Diabetes insipidus (CDI) etiology
lack of ADH
What are the 4 causes of ADH deficiency
Can be a total loss or a partial loss
Can be inherited genetically
Can be acquired… through trauma, surgery, tumors, and infections
Can be idiopathic
Symptoms of Central Diabetes insipidus (CDI)
Occur when ~80% of ADH producing cells have been lost (are severe when >95% lost)
Severity is variable; it depends on the cause of loss and the speed of the loss
Treatment of Central Diabetes Insipidus (CDI)
Desmopressin acetate (synthetic ADH agonist with V2 receptor specificity)
goals of treatment for CDI
Improve the patient’s quality of life
(more tolerable water intake, prevent nocturia and sleep deprivation)
Maintain Safety
Educate Patients (must not drink water unless they are thirsty)
Nephrogenic Diabetes Insipidus (NDI) etiology
V2 receptor resistance
Syndrome of Inappropriate ADH (SIADH)
SIADH a condition of excessive ADH….which causes hyponatremia….without edema
(hyponatremia)
Syndrome of Inappropriate ADH (SIADH) etiology
↑ADH from the posterior pituitary due to trauma, surgery, brain tumors
An “ectopic” source of ADH production exists somewhere
Iatrogenic / Drug induced – may ↑ the amount of ADH released or ↑sensitivity to ADH
Symptoms of hyponatremia
Depend on the rate of sodium loss
Depend on how low the level of serum sodium is
(Na level < 120meq /L, Nausea /Vomiting / Headache)
(Na level < 110meq /L,seizures, coma, death)
Treatment of SIADH
FLUID RESTRICTION
Nocturnal enuresis / “Bedwetting” treatment
NON-DRUG therapy
(is have to use drugs use desmopressin)
Nocturnal polyuria treatment
Nocdurna® (desmopressin) sublingual tablets
GH secretion is under dual control what are they
Somatostatin – provides a tonic inhibition of GH secretion (it sets the basal rate)
GHRH – is released: in pulses – which stimulates GH release: in pulses.
Direct and indirection physiologic action of growth hormone
Direct action – GH itself acts on certain tissue surface receptors (such as adipose tissue)
Indirect action – GH stimulates production of IGF-1 (insulin-like growth factor)
(majority growth due to IGF-1
Major functions of GH: metabolism
Stimulates lipolysis
Promotes protein synthesis & retention of nitrogen
Increases gluconeogenesis in the liver
Promotes glycogen storage in the liver
Decreases glucose uptake by extrahepatic tissues
Major functions of GH: growth
Bones and cartilage
Soft tissues, organs (mainly adults)
Evaluation of Grown Hormone levels
Taking a random sample of GH is NOT a reliable way to determine GH status
GH levels decline with age; GH levels are also suppressed in obese patients
Proactive testing of growth hormone levels
GH Stimulation Tests – may be used to confirm GH deficiency
-Insulin Tolerance Test
-Intravenous infusion of arginine
GH Suppression Test of growth hormone levels
Oral Glucose Tolerance Test
Growth Hormone deficiency etiology
Congenital disorders – GHRH deficiency, GH gene deletion, pituitary aplasia/hypoplasia…
Acquired disorders – due to hypothalamic or pituitary disease, surgery, radiation, trauma…
Growth Hormone Deficiency in children
Delayed sexual development associated with normal mental function
Poorly developed muscles (decreased protein synthesis)
Tendency toward hypoglycemia (no GH to respond to low glucose levels)
↑subcutaneous fat (b/c no GH to promote lipolysis)
Diagnostic parameters of growth hormone deficiency
↓ linear growth (growth charts)
decrease “Bone Age” (patient’s bone x-rays are compared to standardized bone x-rays)
decrease IGF-I levels
Growth Hormone Deficiency in adults
Depression, reduced energy, ↓ QoL
↓ BMD (bone mineral density) – increases risk for osteoporosis and fractures
Change in body composition (↑abdominal obesity, ↓ muscle mass)
Hyperlipidemia; increased markers of atherosclerosis
Examples of Non-Deficient indications to receive GH therapy
Certain genetic syndromes
Idiopathic Short Stature
Small for Gestational Age
Growth failure in children with Chronic Kidney Disease
HIV associated wasting/cachexia; HIV associated lipodystrophy
Growth Hormone Therapy goals for children and adults
For children: ↑growth and height; ↑bone age, ↑muscle tone, etc…
For adults: to improve their QoL, decrease the risk of bone fractures
Growth hormone therapy somatropin administration
injection
given in evening
Dosing of somatropin
Children - is always Weight Based
Adults - 0.2mg/day (range 0.15 – 0.3mg)
Monitoring of somatropin in children
growth measurements
x-rays to monitor bone age
IGF-1
Growth Hormone Excess
A condition of excessive GH secretion that occurs after the closure of the epiphyses
Cause of Growth Hormone Excess
A pituitary adenoma that secretes GH
Results in sustained high levels of GH…and therefore high levels of IGF-I
signs and symptoms of growth hormone excess
Coarsening of facial features
Joints / Soft tissue enlargement
Cardiovascular effects
Excessive sweating
Hypertension
Sleep apnea
Glucose intolerance
Increase in colon polyps
Diagnosis of growth hormone excess
Clinical suspicion
Biochemical confirmation
(random IGF-1 measurement)
(glucose suppressed GH measurement)
Treatment options of growth hormone excess
Surgery to remove adenoma – is the treatment of choice
Medical Management (Drug Therapy)
Radiation – last line
Drugs for growth hormone excess
Somatostatin analogs
-octreotide
GH receptor antagonist
-pegvisomant
Gigantism
is due to GH excess in children before the closure of the epiphyses
Gigantism cause
a pituitary adenoma that secretes GH
Gigantism symptoms
Symmetric growth of stature, sometimes reaching 8-9 feet
Cardiac hypertrophy & mild HTN that may proceed to heart failure
Osteoporosis and muscle weakness in later stages (bone growth > Ca intake)
Symptoms of acromegaly may also occur if the excess growth stimulus continues
beyond the closure of the epiphyses
Gigantism Diagnosis & Treatment
identical to acromegaly
The circadian rhythm
ACTH release – is controlled by CRH, free cortisol levels, & the sleep cycle
ACTH is released in pulses – the largest pulse occurs in early morning
The “stress” response of Neuroendocrine control
Stress increases the output of ACTH
Up to 10x of the normal cortisol may be released if necessary
Stress response can override the circadian rhythm
Glucocorticoids: Metabolic homeostasis / supports ↑energy needs during stress, hypoglycemia
Permits lipolysis to happen
Inhibits protein synthesis
Stimulates the process of gluconeogenesis
Short term and long term of glucocorticoids
Short term - excessive GC production or GC drug therapy ↑glucose levels
Long term - hyperglycemia …↑ insulin secretion …↑ fat storage/weight gain
Glucocorticoids CNS deficiency
apathy, fatigue, depressed mood may occur
Glucocorticoids CNS excess
Common - initial euphoria (feeling good, energy) ↑appetite
- INSOMNIA
Less common– irritability, confusion, mania, and overt psychosis
Glucocorticoids Connective tissue
Excessive GC inhibits fibroblasts…↓ collagen synthesis & connective tissue
Thin skin, easy bruising, striae (stretch marks), and poor wound healing may occur
Glucocorticoids bone
GC delays linear bone growth: growth may catch up if discontinued before puberty
GC inhibit bone formation by inhibiting osteoblasts
GC effects Ca/P processes which promote bone resorption
Glucocorticoids eyes
↑ development of cataracts
↑ intraocular pressure…↑ risk for glaucoma
Mineralocorticoids: Things that regulate aldosterone secretion
↓ intravascular blood volume or effective circulating volume
K+ levels
Na+ levels
Physiologic actions of aldosterone
Aldosterone causes Na+ reabsorption and K+ excretion
water follows the sodium
H+ follows the potassium
Aldosterone excess results in
Hypertension
Hypokalemia
Metabolic alkalosis
Aldosterone deficiency results in
Hypotension
Hyperkalemia
Metabolic acidosis
Adrenal androgens: primarily (DHEA)
Have little physiologic androgen activity themselves
They are precursors for peripheral conversion to testosterone & dihydrotestosterone
Adrenal androgens: in adult females and adult males
In adult males: they account for ~5% of testosterone production
In adult females: DHEA / androstenedione significantly contributes to androgen production
Primary Adrenal Insufficiency
Addison’s disease
Etiology of Addison’s disease
Autoimmune disease (~90% cases)
Infectious
Other - adrenal hemorrhage, metastatic cancer, genetic disorders
All 3 zones of the cortex are destroyed = deficiency of cortisol, aldosterone in what disease
addisons disease
Signs/Symptoms of Addison’s disease
Muscle weakness
Hyperpigmentation
Weight loss
Hypotension
Lab abnormalities (hypoglycemia, hyponatremia, hyperkalemia)
Diagnosis / Initial lab tests of addisons disease
Basal morning cortisol (should be high)
Cosyntropin stimulation test
HC doses of ~50mg also have mineralocorticoid activity equivalent to ______ fludrocortisone
~0.1mg
Dexamethasone does NOT interfere (cross react) with the measurement of _______ levels
cortisol
Management of Addison’s disease goals
Improve symptoms / ↑ QoL / less fatigue
Avoid excessive GC replacement / do not over treat / minimize side effects
Prevent adrenal crisis
Glucocorticoid replacement
hydrocortisone (drug of choice)
~2/3 in morning
~1/3 about 6-8 hours later
Mineralocorticoid replacement
fludrocortisone
Monitoring of fludrocortisone
BP
edema
K+/Na+
With glucocorticoids does the patient need to receive an extra “stress dose” of fludrocortisone?
no, since you are giving a high dose already
Androgen replacement
men do not need it
women its not required (improves libido)
Symptoms of Adrenal crisis
Severe weakness/fatigue
Nausea/Vomiting
Hypoglycemia
Hypovolemia / dehydration leading to hypotension/shock
Treatment of Adrenal Crisis
Identify and treat the underlying cause of the “stress”
Intravenous fluid replacement to maintain blood pressure & glucose
Intravenous hydrocortisone injection (high dose / stress dosing)
Controversy in Critically Ill patients: If adrenal insufficiency is suspected and is not corrected…the patient may not recover
Option 1 – treat first and then assess the outcome
Option 2 – assess the HPA axis to decide if treatment might be needed
What is the problem with secondary adrenal insufficiency
lack of ACTH
What are the causes of secondary adrenal insufficiency
Any pituitary disease that results in a loss of ACTH production
HPA axis suppression – from glucocorticoid drug therapy
Symptoms of secondary adrenal insufficiency
-Muscle weakness, fatigue, anorexia, weight loss, N/V/D, hypoglycemia
-Acute Adrenal Insufficiency
(NO Hyperpigmentation or low BP, Na+, K+)
Management of SECONDARY adrenal insufficiency
-IF due to pituitary disease: pts need chronic GC replacement therapy + stress doses prn
-For patients with medical conditions receiving chronic GC therapy: Only stress doses need sick day plan
Key point for secondary adrenal insufficiency management
MC replacement (fludrocortisone) is NOT needed – aldosterone secretion is normal
What is “Cushing’s syndrome” (hypercortisolism)
The physiologic changes that occur from prolonged excessive levels of glucocorticoids
General signs and symptoms of cushing’s syndrome (hypercortisolism)
central obesity
facial rounding
fat accummulation
hypertension
edema
Metabolic signs and symptoms of cushing’s syndrome (hypercortisolism)
glucose intolerance
Type 2 DM
Musculoskeletal signs and symptoms of cushing’s syndrome (hypercortisolism)
Muscle weakness
Osteoporosis
Skin signs and symptoms of cushing’s syndrome (hypercortisolism)
striae (stretch marks)
Causes of Cushing’s syndrome: A source of excessive ACTH exists somewhere
pituitary ACTH-secreting adenoma
Ectopic ACTH syndrome
Causes of Cushing’s syndrome: A source of Cortisol or GC drug exists somewhere
Primary adrenal tumor/neoplasm
Iatrogenic / Drug induced: chronic administration of GC drugs
Diagnosis of Cushing’s syndrome
Medical history
Physical exam
Laboratory tests
Selected tests for the evaluation of patients with Cushing’s syndrome
Late-night serum cortisol (should be low)
24-hour urine free cortisol
Overnight LOW DOSE dexamethasone SUPPRESSION test
Treatment of Cushing’s syndrome
-Evaluation for ANY possible source of exogenous glucocorticoid
-IF the cause is an adenoma or tumor – SURGERY to remove
-Pharmacologic therapy
May be used if the patient is not a surgical candidate or as an adjunct to surgery if needed
Steroidogenic inhibitors –drugs that inhibit the synthesis of cortisol
ketoconazole (drug of choice - inhibits CYP450 enzymes)
mitotane
metrapone
aminoglutethimide
Suppression of HPA axis with GC administration: Degree of adrenal suppression depends on what factors
dose
duration
route of administration
the patient
In general: GC doses < prednisone 7.5mg/day (or equivalent) for ____ weeks is not expected to suppress HPA axis
<3 (want to taper doses)
Definition of Conn’s syndrome aldosterone adenoma (primary aldosteronism)
describes a group of conditions of excess aldosterone production by the zona glomerulosa
Primary Aldosteronism clinical manifestations
HTN
hypokalemia
metabolic alkalosis
Treatment of primary aldosteronism
surgery
spironolactone
amiloride
Pheochromocytoma
syndrome of catecholamine excess
Etiology of Pheochromocytoma
catecholamine producing tumor of the adrenal medulla
Dominant clinical feature of pheochromocytoma
hypertension
Diagnosis of pheochromocytoma
S/S of pheochromocytoma
24h urine measurement of catecholamines and their metanephrine metabolites
MRI or CT to localize tumor
Treatment of pheochromocytoma
SURGERY
Medical management - BP must be stabilized before surgery can occur
phenoxybenzamine
