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
