fri, april 20th.

hypothyroidism continued...
causes:
1) failure of thyroid gland to make enough TH (primary hypothyroidism is most common)
... in developing countries with insuff iodine hypothyroidism due to deficiency of iodine in diet. When iodine deficient you can't produce T3/T4, so loss of feedback control of TRH/TSH (negative feedback loop missing) which leads to increased secretion of TSH and thyroid gland grow to compensate. ( only sometimes do they get goiter). the thyroid gland is unusual in that it is able to store colloid. the thyroid evolved to protect individual where iodine is not plentiful. colloid can supply TH for weeks.
tx for hypothyroidism: thyroxine pills (T4) which is metabolically converted to T3, and over time would reinstate negative feedback look, and decrease TSH/TRH and hopefully decrease goiter. T4 suppliment because it has a much longer half life so it is easier to maintain steady levels with.

2) thyroid follicles are destroyed (hashimoto's disease): autoimmune disease .
the body can compensate by growing non-attacked follicles but eventually lose function.
tx-thyroxine

3)inactivation of TSH receptors: due to muation of inactiavtion by antibodies blocking receptors.
the thyroid gland is not stimulated to produce T3 and T4. Have raised TRH/TSH secretion but no enlargement of thyroid b/c receptor is inactive. only have growth of goiter if TSH receptoer is overactive.

second degree hypothyroidism: problem at hypothalamic or pit level.
1. decreased TRH secretion
and
2. decreased TSH secretion
both are much less common, and are potentially caused by tumor growth.

can determine if pit/hypoth cause of illness by measuring TSH levels in the blood if TSH is low that it is pit/hypoth NOT thyroid. if give bolus of TRH and TSH levels rise, then the issue is hypoth. if give bolus TRH and TSH still low, the its the pit.

Thyroid hormone resistant: TH made but cells not recognizing it.
1. loss of function mutation in 1+ TH receptor
2. loss of function mut in transporter in plasma membrane of target cells.

loss of TBG would decrease half life of TH but body would generally be able to compensate.

HYPERTHYROIDISM: cells recieve too much TH stimulation.
signs/symptoms: weight loss, feel warm/hot, jittery/nervous/anxious, rapid heart rate, muscle wasting (proteolysis>protein synth), weakness, fatigue, reproductive tract issue.
Causes:
1. tumors that secrete TRH/TSH/T3/T4 (rare)
2. injest thyroid supplements (sometimes for weight loss) (ie: exsessive use of kelp tabs)
3. Graves Disease (most common and tends in families): autoimmune disease that produces antibodies that activate the TSH receptors (antibodies = thyroid stimulating immunoglobulins TSIs)
TSH-R on thyr activated by TSI -> produces too much T3/T4 -> signals pit to reduce TSH production even though it is low already (negative feedback loop fails to mediate levels).

tx: initially attempt to limit T3/T4 production with TX, and next step is radioactive iodine which incorporates to colloid and helps to destroy thyroid gland. This makes the person hypothyroid, but that can be treated with TX (thyroxine).

The antibodies additionally tend to attack muscle tissue surrounding the eyes.

TSI can also cause goiter... goiter is not only a symptom of hypo/hyper thyroidism.

GROWTH HORMONE (see handout) (GH)
It is important because:
1) absolutely nec for post natal growth... no GH = stunted growth.
2) regulates a lot of metabolic pathways.
GHRH (Growth Hormone Releasing Hormone) + somatostatin control GH secretion.
... both act on ant.pit. (GHRH is positive control, and somatostatin is negative control) stimulates somatotropes.
1. GH binds target tissue and causes reaction
2. GH acts on liver and other tissues and stimulates them to produce insulin like growth factor (IGF1) .... binds target tissue and cause reaction.
>> both 1 and 2 needed together to cause the effect.
Approach: structure GH, structure IGF, biological activities, reglulation/secretion, GH-R, pathologies.

GROWTH HORMONE STRUCTURE:
-non-glycosylated single chain polypeptide (191aa, mw=20K)
-structurally, aa seq conserved between GH and prolactin
... structural similarity extends to placental lactogens as well.
......similarity makes them 'family':: GH-PRL-PL gene hormone family
-important of structural similarity>> get lot of info about mech action within family because mech of action is much the same.
-GH=large protein>> unusual binding (~40%) circulates bound to GH-BP in the blood
Half-life is roughly 30 mins (but that half life is increase by being bound to the BP.

INSULIN-LIKE-GROWTH-FACTORS
two types: IGF1 and IGF2 (or IGF-II)
IGF1 - major part of regulation via GH but not all regulation is by GH
IGF2 - regulated by lots of things
.. single chain polypeptide (mw ~ 7K)
.. circulates bound to BP
.. structure is similar to insulin
.. most IGF1 in the blood is from liver under regulation by GH, but IGF1 is also made in numerous other target tissues, and those are also regulated by GH, and others.
When IGF-1 is made in other tissues, they mostly act in situ, although some will get into circulation (autocrine/paracrine effect)

Somatomedan hypothesis: GH effects to raise IGF1 production by the liver and IGF1 then mediates ALL actions of GH (but that is a far oversimplification)

Current view (much more like handout): GH effects to raise IGF1 secretion in many tissues, and some systems require both GH & IGF1 to get biological effect.

In other systems GH can act independantly of IGF1 but you must look at specific systems to see that.