Pharmacology Of Pituitary Diseases and thyroid physiology Flashcards
How does neurohypophysis signaling and adenohypophysis signaling differ?
Neuro:
- hypothalamic neurons synthesize and release hormones from the posterior pituitary via vesicles in the
pituitary neurons
Adeno:
- hypothalamic neurons secrete releasing hormones into the portal vessels to the anterior pituitary which causes trophic cells to synthesis and secrete hormones or inhibit them from doing so
Tertiary/secondary/primary endocrine disorders
Tertiary = hypothalamus dysfunction
Secondary = pituitary dysfunction
Primary = target gland/tissue dysfunction
What are the most common types of functional adenomas?
Lactotrope (26%) and somatotropes (14%)
What are the physiological effects of GH?
Growth actions in bones cartilage, body organs and muscles
- does this via IGF-1 signaling
Also does anti-insulin effects:
- increases lipolysis and FFA use in adipose tissue
- increases blood glucose and decreases its use in muscles
Growth hormone axis steps
1) hypothalamus synthesizes and secretes GHRH (ghrelin)
2) GHRH stimulates pituitary gland to synthesis and release growth hormone
3) growth hormone goes to liver and stimulates IGF-1 secretion and synthesis from the liver
- IGF-1 negative feedbacks on GH production and secretion in the anterior pituitary gland
- *somatostatin also is a negative feedback inhibitor of GH**
- is produced by hypothalamus and secreted in response to increased blood glucose/AAs and FAs
Receptors of GH
Belong to thecytokine receptor superfamily
- begin out as monomers and the ligand (in this case GH) binds two monomers and promotes dimerization of the receptor
Dimerization allows for JAK2 to undergo transphosphorylation and autoactivation which induces downstream signaling and does various physiologic responses
- one of theses effects in increased expression of IGF-1
- also regulates Ras/MAPK and PI3K pathways
Why is IGF-1 used as a marker for GH levels?
GH secretion is pulsatile and therefore its concentration is unreliable
Usually use IGF-1 levels clinically instead since they are more constant
the gold standard however for determining levels of GH secretion is the glucose oral tolerance test!
- under normal conditions = give oral glucose and causes release of somatostatin which will lower GH and IGF-1 levels.
- under pathologic conditions = give oral glucose and causes release of somatostatin. However the pathology in the anterior pituitary is resistant to this so GH and IGF-1 levels remain high. This signals a secondary issue not primary
(This includes acromegaly/gigantism)
Causes of GH excess
Anterior pituitary gland tumors
- most common = somatotroph adenoma
GHRH secreting hypothalamus
Ectopic production of GH or GHRH by small cell lung cancer
What are the three classes of GH excess medications used?
Somatostatin (SST) receptor agonists
- octreotide
Dopamine receptor agonists
- bromocriptine
GH receptor antagonists
- pegvisomant
Lab values for primary/secondary and tertiary GH insensitivity
Primary: liver doesn’t respond to GH and doesnt produce a lot of IGF-1
- low IGF-1, normal GHRH, high GH*
- treatment = replace IGF-1
Secondary: pituitary doesnt secrete GH in response to GHRH
- normal GHRH, low IGF-1 and low GH*
- treatment = replace GH
Tertiary: hypothalamus doesnt release any GHRH
- low GH, GHRH and IGF-1*
- treatment = replace GH
Where in the thyroid are thyroid hormones stored?
In the thyroid follicles
Are surrounded by C-cells which are calcitonin induced cells to help the follicles release appropriate amounts of thyroid hormone
2 main types of thyroid hormones
BOTH are derived from the analog tyrosine
T3: (triiodothyronine)
T4: (Thyroxine)
Steps of thyroid hormone synthesis
1) thyroid requires iodide anions from the blood via a I/Na+ symporters seen on the basal surfaces of follicular cells
- known as “iodide trapping”
- inhibited by thiocyanate and perchlorate anions
2) thyroglobulin is a large glycoprotein produced by the thyroid and plays a role as a precursor to Thyroid hormones and also a storage form of thyroid hormone
- is synthesized from tyrosine residues*
- is synthesized by thyroid follicular cells and secreted across apical membrane
3) Intracellular iodide rapidly diffuses across the apical membranes of follicular cells and into the colloidal lumen. Iodide then binds to tyrosine residues on thyroglobulin
- in order to bind to thyroglobulin, the enzyme thyroid perioxidase is required which promotes oxidation of iodide (I-) to organic Iodide (I2) and conjugation of tyrosine into free radicals capable of binding to thyroglobulin*
4) organification of thyroglobulin+ iodide occurs to bind Monoiodotyrosine (MIT) or diiodotyrosine (DIT) molecules to the complex
- this also controlled by peroxidase enzymes
5) coupling reaction occurs between MIT and DIT complexes to form either T3 (MIT + DIT) or T4 (DIT + DIT)
- these remain attached to thyroglobulin until TSH induces secretion
6) when TSH binds to surface receptors on thyroid epithelial cells, results in pinocytosis of luminal thyroglobulin bound to T3/T4 hormones from lumen -> inside cells
7) lysosomes fuse with thyroglobulin and break down thyroglobulin with proteases, releasing the T3/T4 hormones
- these hormones then leave the thyroid cells into the blood
8) T3/T4 then go to peripheral tissues and can be interchanged into either via 5-deiodinase enzymes
9) excess MIT/DIT is recycled via thyroid cell specific 5-Deiodinase enzymes back into iodide for future use as needed
What anti thyroid medications inhbit Thyroid peroxidase (TPO) enzymes from working
Propylthiouriacil (PTU) and methimazole
How does T3/T4 levels regulate thyroid hormones?
Increased levels of free T3/T4 inhibit anterior pituitary from releasing TSH and inhibit hypothalamus from releasing TRH
- classic negative feedback
also somatostatin can also inhibit anterior pituitary from releasing TSH
Graves’ disease
Caused by autoimmune antibodies called Thyroid stimulating immunoglobulins
- in addition to being autoantibodies and attack things, they also bind to the same receptors as TSH does on the thyroid, inducing hyperthyroidism (excessive T3/T4)
Other regulation of thyroid hormones
Dopamine inhibits anterior pituitary from secreting TSH
How do TRH receptors work?
Are PLC Gq-proteins
- when stimulated via TRH, upregulate IP3/DAG levels
This increases intracellular calcium sand causes exocytosis of TSH
**also has phospholipase A2 receptors which upregulate arachidonic acid metabolites
How do TSH receptors work?
Are Gs proteins bound to AC
- when stimulated upregulates cAMP levels which increases gene transcription as well as increases the following 7 actions:
- iodide uptake
- iodination of thyroglobulin
- conjugation of iodinated tyrosine
- endocytosis of iodinated thyroglobulin into follicular cells from thyroid colloid
- proteolysis of iodinated thyroglobulin in follicular cells
- secretion of T3/T4 into the circulation
- hyperplasia of thyroid gland
What is the form of thyroid hormone that actually conducts systemic functions?
Free T4
Bound thyroid cannot do any actions!!
What protein conducts 99% of protein bound T4 in the blood stream (NOT in thyroid gland)
Thyroxine binding globulin (TBG)
- binds to thyroxine and triiodothyronine molecules
- concentration increases with estrogen levels, pregnancy and oral contraceptive use
- note that increase in TBG DOESNT change levels of FREE thyroid hormone. (Remain euthyroid)
serum albumin can also bind some T3/T4 but not a lot
Inhibitory factors to hyoid hormone secretion
Iodine Deficiencies
Deiodinase enzyme Deficency
Excessive iodine intake (Wolff-chaikoff effect)
- thyroid gland intuitively turns off secretion in the presence of excess iodine
Presence of perchlorate or thiocyanate anions
- inhibits Na/I cotransporter
Propylthiouracil presence
- inhibits peroxidase enzyme activity
Decreased TBG levels in blood
Stimulation factors for Thyroid hormone secretion
TSH levels high
TSI levels high (Graves’ disease)
Pregnancy and other causes of TBG increases
- causes the anterior pituitary to secrete more TSH since the pituitary assumes there is not enough being produced (since TBG is binding T3/T4)
Effects of thyroid hormones
T3 is the only format hat does any action on the body!
- free T4 survives longer in the blood stream and is more prominent but is converted into T3 via 5-iodinase enzymes into T3 to induce functions. Does this via removing 5’iodine from T4*
T3 binds to retinoid nuclear receptors (RXR) which then induces transcription of DNA and synthesis fo new proteins which do the following effects:
1) growth of bone and tissues
2) maturation of CNS
3) increases basal metabolic rates, O2 consumption and heat production
4) increases lipolysis/gluconeogenesis/ glycogenolysis/ glucose absorption, protein catabolic effects
5) increases cardiac output and upregulation of B1 receptors
** note that caloric starvation inhibit 5-iodinase enzymes from converting T4 -> T3 in order to store fuel and not burn it up (via BMR)
What is cretinism
Hypothyroidism in newborns
Result in mental retardation, short stature, coarse features, jaundice, hearing loss and umbilical hernias
- bone age grows much faster than height and mental ages
Is caused by any of the following:
- failure of thyroid gland formation
- inability to synthesize T3/T4
- lack of iodine while in utero
- radioiodine taken in by pregnant mother
- untreated hypothyroidism in pregnant mother
Treatments for hyperthyroidism
Propylthiouracil
Thyroidectomy
B-adrenergic blocking agents as adjuvant
Treatments for hypothyroidism
Thyroid replacement therapy only
Symptoms of thyrotoxicosis
Symptoms of hyperthyroidism
- weight loss with excess hunger
(Increases BMR)
- heat intolerance
(Increased consumption of O2 generates heat) - Tremors
- nervousness
- sleeplessness
(Increased B1 receptors leads to epinephrine levels) - heart palpitations and hyperthyroidism
(TH increases B1 upregulation, especially in heart which produces positive chronotropic effects) - irregular menstration
(Thyroid hormones cause inhibition of GnRH)
How to rule out thyroid overactivity possibilities
Radioactive Iodide level test
Exogenous/endogenous consumption = no increased Iodide uptake in the thyroid or even a decrease (since levels of free T4/T3 are elevated already)
Primary hyperactivity (tumor or Graves’ disease) = increased iodide uptake in thyroid
What does a T3 resin uptake test show?
The purpose of the T3 resin test is to add radioactive iodide to the system. Radioactive iodide has a high binding affinity to TBG. Therefore if TBG levels or binding sites are decreased then T3 resin uptake is increased.
Hyperthyroidism/ increased free T3/T4 = high T3 resin
Hypothyroidism/ decreased free T3/T4/ increased TBG (pregnancy) = low T3 resin
Treatments for thyrotoxicosis
In no order
1) use of propylthiouracil (PTU)
- Inhibtors perioxidase enzymes in thyroid which both helps make T3/T4 by conjugation inside the thyroid and also helps convert free T4 into T3
- decreases synthesis of T3/T4
2) use of thiocyanate
- competitive inhibitor of the Na/I symporter in the thyroid gland
- decreases synthesis of T3/T4
3) thyroidectomy or use of radioactive iodide in high doses
4) can use propranolol or BB-blockers to inhibit cardiac and HTN effects (these are the lethal effects)
Why does treatment of thyrotoxicosis sometimes cause hypocalcemia?
Only when treatment of thyroectomy results in accidental removal of paratrhyroid glands(s)
Results in lowered serum calcium and ionized calcium
Results in severe muscle crumps, tingling and numbness in the face and extremities
- hypocalcemia tetany
- *also results in the following signs:**
- Chvostek sign: uncontrolled facial spams when tapping on facial nerve exit (2 cm anterior to the external auditory meatus)
- trousseau sign: carpopedal spasms when using a blood pressure cuff and inflating it above normal systolic (120 mmHg)
How do you treat hypoparathyroidism?
High calcium diets as well as oral activated vitamin D
must be active already (1,25-dihydroxycholecalciferol) since PTH directly controls renal activation of inactive vitamin D
What do thyroid antimicrosomal antibodies found in hashimoto thyroiditis actually target?
The perioxidase enzymes in they thyroid gland
Why is T3 resin uptake decreased in hashimoto thyroiditis?
There is decreased free floating T3/T4 in the blood
Remember the resin test puts radioactive T3 with a synthetic binding resin and puts it in with patient blood
- decreased T3 resin = less free radioactive T3 in patient blood since it is bound to patient TBG (more TBG is free since endogenous T3/T4 levels are decreased)
- increased T3 resin = more free radioactive T3 is in patient blood since endogenous T3 is more bound to TBG and inactivated
In hashimoto = decreased T3 resin test
- this is because low T3/T4 endogenous levels
In hyper thryrodism (thyrotoxicosis) = increased T3 resin test
- due to high T3/T4 endogenous levels
Why can hypothyroidism causes goiter?
Even though there is less production of the thyroid gland, as long as the anterior pituitary is secreting TSH in high levels, there will by hypertrophy and hyperplasia of the thyroid gland
Hyperthyroidism is more likely though since the activity of the thyroid being increased leads to hyperplasia also
