Endocrinology: 8:00-9:00 am Scribe: Maggie Law
Friday, November 6, 200 Proof: Ashley Hollady
Dr. Cotlin Thyroid, Parathyroid, and Adrenal Glands Page 3 of 7
BL=basolateral; ZG= zona glomerulosa; ZF=zona fasciculata; ZR=zona reticularis
I. The Endocrine Systems; Thyroid, Parathyroid and Adrenal Glands [S1]: skipped
II. Thyroid and Parathyroid Glands [S2]
a. Skipped, already covered
III. Blood supply to the thyroid [S3]
a. skipped
IV. The Thyroid Gland [S4]
a. skipped
V. Functional and Structural Unit [S5]
a. Concept of a thyroid follicle—all of them are highly polarized structures so that their apical surface.
b. Pars intermedia is not polarized.
c. The following cells will secrete T3 and T4- colloid; parafollicular will secrete calcitonin.
VI. Follicular Cells [S6]
a. skipped
VII. EM of Thyroid Follicular cell [S7]
a. Basolateral region; lots of active processes going on with mitochondria and rough ER. T3 and t4 made on a scaffold of thyroglobulin.
b. Producing thyroglobulin—specific protein to the thyroid, the follicular cells, they are producing this, up-taking iodine always at the basolateral side of the cell.
c. See iodine receptors as well as receptors for TSH.
d. In the apical region this is essentially colloid—you will see microvilli, little surfaces processes and once they are activated to secrete hormone, these will put out large fillapodia and kind of re-ingest the colloid =Remember this association.
e. The colloid is totally separate from all the tissue around it--surrounded by follicular cells.
f. THIS IS WHERE THE AUDIO PICKED UP AT—ABOVE IT JUST WHAT I HAD TYPED IN CLASS.
VIII. Parafollicular Cells [S8]
a. Parafollicular cells secrete calcitonin in the blood and have the effect of lowering the calcium concentration in the blood.
IX. Thyroid Gland [S9]
a. skipped
X. Synthesis of Thyroid Hormone [S10]
a. 2 things dependent on producing T3 and T4---collectively thyroid hormone.
i. 1. Stimulation by the TSH, which is released from anterior pituitary into circulation; these cells have receptors for TSH at the basolateral and also have iodine transporters. Both things are necessary.
1. First you have stimulation of the cells and then you have to have adequate supply of iodine; this is the primary place in body where you use iodine.
ii. Transport iodine at basolateral surface; it’s actively taken up, transported across the cell in a transcellular process and released at apical surface; on the extracellular side of the apical surface there is thyroid peroxidases that oxidizes iodine and it’s going to be incorporated into thyroglobulin.
iii. Iodine is being taken up, transported, and oxidized at the apical surface; thyroglobulin is being made and secreted at the apical surface as well.
iv. Iodine, colloid, thyroglobulin are in the colloid, thyroglobulin becomes iodinated at the apical membrane on the extracellular side— the thyroglobulin is like a scaffold for making T3 and T4.
1. This results in mono and di-iodo-tyrosine molecules; tyrosine is where the iodine is attached; those are the amino acids that are modified.
v. The colloid is a storage spot for T3 and T4, or in this case, iodinated thyroglobulin—do not actually generate T3 and T4 until it is taken back up into the cell and processed.
vi. In colloid is iodinated thyroglobulin—is just a storage reservoir, have several months supply if you need it—it will just sit there and it’s kind of a resting situation.
vii. These cells are cuboidal in a resting situation, but once they are stimulated they become much more polarized and columnar .
viii. Now you have sufficient iodine and iodinated thyroglobulin.
1. Once you get the signal, the TSH, that binds to the receptors and activates a signaling process—first thing that happens is the cell is activated to take up the colloid; the fillipodia that will engulf these and are capable of taking in large amounts in a pinocytosis-like way.
2. The vesicles fuse with lysosome or late endosome, something with a lower pH—the more acidic vesicles—and that’s where we see digestion of the thyroglobulin molecules.
3. Digestion and cleaving of the mono and di-iodo-tyrosin, you get releasing of the T3 and T4.
ix. T3 and T4 are generated and secreted at the BL surfaces; the cell tries to recycle it’s iodine and thyroglobulin; the iodine is cleaved from the MIT (mono-iodo-tyrosine) and DIT (di-iodo-tyrosine) and can be reused.
x. T3 and T4 are distributed—there is lots of vasculature in this, so they will secreted on the BL side and directly enter the connective tissue of the vasculature into the blood stream.
XI. Release of Thyroid Hormones [S11]
a. skipped
XII. Images [S12]
a. Here a tyrosine molecule with a hydroxyl group.
b. There are certain positions on the benzene ring that are going to iodinated.
c. Mono would have one iodine molecule attached. Di-iodo-tyrosine has 2.
d. If you put the mono and the di-iodo together, you will get a molecule of T3.
e. If you put 2 di-iodo’s together , you can get T4 molecules.
f. Have the thyroglobulin with all the tyrosines, that are scaffolded and iodinated are all over the place, it can be taken up and processed and the result is these two molecules.
g. Active molecules-The T3 is a molecule with 3 iodine’s; T4 has 4 iodine’s; any extra iodine molecules are just recycled.
h. These are bulky and hydrophobic but that have reactive groups on end; in circulation they are bound to thyroid hormone binding protein.
i. That’s true for most hormones; they are not circulating freely but are usually bound to some accessory molecules.
XIII. Physiological Effects of T3 and T4 [S13]
a. Bind to proteins in the plasma and slowly be released; they are bound to intracellular proteins and slowly diffuse over days.
b. Both of them have nuclear hormones—they can get through plasma membrane, get to nucleus and stimulate many genes involved in metabolism.
c. These are slow acting and don’t cause an immediate reaction in the cell; you do something by turning on gene expression—a slower effect, but a more long lasting effect.
d. Circulating in blood stream is mostly T4; T3 has a much shorter half life (less than a day) whereas T4 has a longer half life of almost a week.
e. Cell can take T4 and cells can convert it to T3; T4 is more stable and it can be used to generate T3.
f. T3 has a much more potent activity and can bind with higher affinity to most cells. Cells will preferentially use T3.
XIV. T3 and T4 Functions [S14]
a. Overview—T3 and T4 functions—these control most of your resting metabolic activities—increase metabolic rate, promote the use of energies and protein synthesis, normal cardiac function, normal neuronal development, promotes body growth. If you don’t have normal levels, you will decrease all of these things.
i. T3 and T4 are used all over your body for resting and normal metabolic functions.
XV. Clinical Correlations [S15]
a. Graves’ Disease
i. Autoimmune disease in which the thyroid is constantly stimulated
1. Person affected would have hyperplasia and hyper stimulation all the time.
2. These patients have heart arrhythmias, muscle fatigue because they are always activating things when they are not supposed to.
b. Hypothyroidism—not producing enough T3 and T4.
i. More prone to infection, metabolic functions slow, lethargy, etc.
ii. Goiter-when you have insufficient dietary iodine—you need it to build all the stuff but can’t make the hormone because you don’t have iodine.
XVI. The Parathyroid Glands [S16]
a. Very small glands imbedded and encapsulated in the thyroid tissue—have a thin connective tissue coating
b. They produce PTH, which acts to increase calcium levels in blood.
XVII. Histology of Parathyroid Glands [S17]
XVIII. Histology [18]
a. Two types of cells
i. Oxyphil—not sure what they produce on a functional level as far as their secretions
ii. Chief cells—primary secretory cell of the parathyroid gland and these release parathyroid hormone
XIX. Thyroid and Parathyroid Glands [S18]
a. You can see the non-uniformity of all the follicles—not all the same size and shape.
XX. Parathyroid glands of an adult [S19]
a. Tends to accumulate fat as adult gets older—see the dark cells vs. the light cells.
i. The dark and grainy cells are the chief cells producing the PTH.
ii. The lighter ones are oxyphils.
XXI. Histology Slide [S20]
a. Small, encapsulated with lots of blood vessel around them; embedded right in the thyroid tissue itself.
XXII. Effects of Parathyroid Hormone [S21]
a. Calcitonin—toning something down, so you are lowering calcium.
b. PTH is the reverse--increases calcium.
i. Need calcium stores for a lot of things—action potentials, at the nerve terminals.
ii. Many of the secretory, regulatory secretions require an influx of Calcium.
iii. Always need Ca high outside the cell, low inside the cell, and high in the ER because Ca is used for muscle contraction and basic signal transduction pathways all over the body.
c. Want to increase Ca and release stores of it in our body there are a few places to go.
i. PTH’s most active sites are osteoclasts. These are macrophage cells in the bone that digest bone; acts on the osteoclasts to active them and acts on this lineage to produce more osteoclasts by stimulating the progenitors.
ii. Absorption of Ca in the intestine—take up more from food sources
iii. Conservation of Ca by the kidney--acts on the tubules and the collecting ducts to retain Ca so you don’t loss it in the urine.
iv. Also stimulates the conversion of active vitamin D; active vitamin D can be a cofactor for increased Ca uptake .
v. All these things together have one goal—to increase Ca in the blood stream!
vi. Lose the high extracellular Ca; blood is just the extracellular media, lots of bad things can happen.
vii. Muscles and nerves require Ca.
XXIII. PTH Synthesis and Action [S22]
a. PTH is secreted as prohormone;
b. Traffics through the ER and the Golgi like any other secreted protein; pro-sequence is removed in the Golgi and the mature hormone is secreted, so there are a couple of different processing steps to go through.
c. What stimulates its release? Unlike the a lot of the other things that have a hormone from the anterior pituitary that binds and actives, this is NOT under the control of TSH.
d. It simply responds to Ca levels; there are Calcium sensors in the chief cells with receptors on the surface; when these things are triggered by low Ca concentrations, that stimulates the cell directly to release PTH.
e. Not under any kind of pituitary control—simply responds to Ca levels; when Ca levels are sufficiently high, this process of synthesis and secretion is down regulated.
f. The receptor signals through a G-protein receptor, adenylate cyclase, to produce cAMP—as you except the receptors are on osteoclasts primarily and also tubular epithelial cells in the kidneys.
g. Release calcium through bone digestion and conserve Ca through the urine production process.
XXIV. PTH and Calcitonin [S23]
a. Both are controlled by circulating Ca; They work in opposing fashions
XXV. Clinical Correlations [S24]
a. Can have hypo or hyper parathyroid.
XXVI. The Suprarenal Glands [S25]
a. Suprarenal Glands and Adrenal Glands are the same thing; suprarenal because of where they sit on top of the kidneys.
b. Small little glands (3 to 5 cm by 1 cm) sitting on top of the kidney; totally encapsulated with its own little connective tissue surrounding it; usually has some adipose tissue sitting around it.
c. 2 basic classes of molecules made here—lots of our steroids are manufactured and secreted in the adrenal glands as well as catchacholamines (epi and NE).
d. 2 different regions
i. Cortex—responsible for steroid synthesis
ii. Medulla-catchacholamines
e. Both are from very different embryonic origins similar to what we saw with the pituitary (part from ectoderm and part was nerve tissue).
XXVII. Blood Supply [S26]
a. Very vascular tissue—has superior, medial and inferior suprarenal arteries; set so the blood will enter all over like little cones; the arterial supply is around the periphery and will all leave by a central vein.
b. There are lots of arterial branches that supply the adrenal gland, but one adrenal vein drains the entire contents of the gland.
XXVIII. Development [S27]
a. Cortex, all three layers, derived from from mesoderm.
b. Medulla derives from neural crest cells.
c. As the medulla is developing, the fetal cortex only has two layers; the third layer won’t develop until after birth.
XXIX. Structure of the Adrenal Gland [S28]
a. Surrounded by a capsule w/ 3 layers
b. Three layers of the cortex
i. Glomerulosa
ii. Fasciculata
iii. Reticularis
c. In a circular pattern—underneath the cortex, the immediate layer surrounding the entire gland is the ZG which is very thin.
d. The ZF is shown in light purple. The ZR is the light green.
e. These three layers make of the cortex from mesodermal origin.
f. Medulla is in the central region and derives from neural crest cells.
g. See a situation where you have direct and physical contract of the nerve system in endocrine tissue, similar to the pituitary gland.
XXX. Organization of cells in the Adrenal glands [S29-30]
a. Have capsular arteries; all the branches--superior, medial, inferior will insert into the capsule and then we will see a plexus and branching throughout.
i. Glomerulosa cells— primarily secrete mineralcorticoids.
ii. Fasciculata, the largest, will produce glucocorticoids.
iii. Reticularis—produces androgens—sex hormones.
iv. Medulla—two types of cells secreting epi and NE.
XXXI. Blood Supply to adrenal Glands [S31]
a. See branches that will penetrate the cortex and from sinusoids around all of the cells and have some arteries that will go directly through the cortex to the medulla.
b. Plexus with capillaries—secrete contents directly into the vasculature.
c. Along the fasciculata, see these longitudinal sinusoids with a fenestrated epithelium; see these cells with spaces inside of them that are sinusoid cavities; they capillarize again in the reticularis and then in the medulla.