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)
