Cook - Hypothalamus, Pituitary, Thyroid Rx Flashcards
(41 cards)
1
Q
What is the key difference between injection and natural production of anterior pituitary hormones?
A
- PULSATILE RELEASE: packets of release move down from hypothalamus on a molecular motor
- Very HIGH CONCENTRATION when administered via injection —> this can be a big problem for the administration of some hormones
2
Q
List the hypothalamic releasing hormones.
A
- Growth hormone-releasing hormone (GHRH)
- Gonadotropin-releasing hormone (GnRH)
- Thyrotropin-releasing hormone (TRH)
- Corticotropin-releasing hormone (CRH)
- Inhibitory:
1. Somatostatin: negatively regulates GH, TSH
2. Dopamine: inhibits secretion of Prolactin
3
Q
GH: releasing hormone, target tissues, effects
A
- Releasing hormone: GHRH
- Targets and effects: has both direct effects, and indirect effects via IGF-1
1. IGFs or somatomedins from liver and other tissues -> body tissue, bone, and organ growth, i.e., SOMATIC CELL GROWTH
2. Adipose tissue fat mobilization
3. Liver INC gluconeogenesis
4. Muscle INC protein synthesis
4
Q
TSH: releasing hormone, target tissues, effects
A
- Releasing hormone: TRH
- Targets and effects:
1. Thyroid -> T4, T3 thyroid hormones -> cellular ATP production and INC metabolic rate
5
Q
ACTH: releasing hormone, target tissues, effects
A
- Releasing hormone: CRH
- Targets and effects:
1. Adrenal cortex -> corticosteroids -> Na+ uptake, stress adaptation, anti-inflammatory and immunosuppressive effects
6
Q
PRL: releasing hormone, target tissues, effects
A
- Releasing hormone: PRF (INH by Dopamine)
- Targets and effects:
1. Mammary gland growth and devo -> lactation -> milk proteins
2. Testis -> high levels INH FSH and LH pulsatile secretion, lower testosterone levels, INH spermatogenesis
7
Q
FSH, LH: releasing hormone, target tissues, effects
A
- Releasing hormone: GnRH
- Targets and effects:
1. FSH
a. Testis: growth of seminiferous tubules and spermatogenesis -> sertoli cell production of androgen-binding protein, inhibin, other factors
b. Ovary: devo of follicles -> estradiol
2. LH
a. Testis: interstitial cell devo -> testosterone
b. Ovary: ovulation, corpus luteum -> progesterone
8
Q
What factors stimulate/INH somatotropes?
A
- Somatotropes: all cells that make GH (roughly half of the anterior pituitary)
- Hypothalamus: GHRH +, somatostatin -
1. GH also (-) feedback for GHRH - Anterior pituitary: IGF-1 and somatostatin (from GI, pancreas) INH somatotropes
9
Q
How can you diagnose GH deficiency?
A
- Inject insulin -> DEC glucose, which should encourage GH release
1. Hypoglycemia stimulates GH release (hyper-glycemia INH its release) - Need to be in a setting where you can MONITOR for hypoglycemia
- Simple measurement w/o this provocative test is useless bc GH exhibits pulsatile release (spikes, with overall low concentration)
- THIS IS IMPORTANT
- Note: also used to diagnose with hGHRH admin, but this Rx is no longer on the market for econ reasons
10
Q
What are the actions of GH?
A
- Opposes insulin effects
- Children deficient in GH can have hypoglycemia
-
11
Q
What causes/happens in GH deficiency?
A
- CAUSES: neonatal genetic deficiency, or by breech or traumatic delivery injury to the pituitary
1. May be normal size at birth (GH NOT needed for prenatal growth) - RESULTS: general obesity, DEC muscle mass, reduced cardiac output in adults
12
Q
How is GH used to decrease mortality?
A
- Used in adults to decrease mortality from CV disease and AIDS-associated wasting
13
Q
What is used to tx GH deficiency?
A
- Somatotropin: generic name of all GH that is identical with hGH (all of these are exactly the same peptide)
- NOTE: can NOT use animal GH in humans (with the possible exception of some primate GH)
14
Q
When is hGH (somatotropin) tx most effective? AEs?
A
- Therapy most effective in kids in first 2 years, and continues until growth stops
1. Few AEs in kids: intracranial HTN, vision changes, papilledema, headache, N/V
2. Leukemia has also been reported, so not used w/in 1-2 yrs of treating peds tumors - Men treated w/hGH have INC muscle/bone, and DEC fat
- AEs in adults: peripheral edema, carpal tunnel syndrome, arthralgia, and myalgia
15
Q
How are GH and GHRH abused? Why?
A
- Injections in adults INC muscle mass and DEC adipose tissue mass (NOT approved for this use)
1. Athletes may use both of these drugs; GHRH may escape detection in drug testing - No evidence that either drug improves athletic performance
16
Q
IGF-1 deficiency? Treatment?
A
- RARE -> these children do NOT respond to hGH
-
Mecasermin: complex of hIGF-1 and hIGFBP-3 (the binding protein is necessary to produce longer 1/2 life)
1. Children w/this deficiency usually deficient in IGFBP too
17
Q
What are the 2 key manifestations of GH excess? Txs (3)?
A
- Gigantism: die fairly early
- Somatostatin analogs are best tx when pituitary sx is not possible
1. OCTREOTIDE: inject 3x/day (short 1/2 life)
a. GI AEs: diarrhea, nausea, abdominal pain
2. LANREOTIDE: long-acting, slow-release form (injected once every 4 weeks) -
Acromegaly: usually takes long time to show, and pts usually dx themselves (can’t take off rings)
1. Overproduction of pituitary hormones often a consequence of hyperplasia -
PEGVISOMANT: GH receptor antagonist -> DEC IGF-1
1. PEG (polyethylene glycol) covalently bound, DEC renal clearance and INC 1/2 life
18
Q
What is prolactin? Prolactinemia causes/results? Txs?
A
- Rises during pregnancy, and remains elevated until birth; falls thereafter, unless mom breastfeeds
1. NO therapeutic uses - Hyperprolactinemia is fairly common: caused by pituitary adenomas or diseases that interfere with dopamine signaling
1. Galactorrhea, amenorrhea, infertility in F; loss of libido, impotence, infertility in M - TX: surgery, radiation, dopamine-receptor (D2) agonists
1. CABERGOLINE: higher affinity for D2 receptors, longer 1/2 life, better tolerated
2. BROMOCRIPTINE: not well tolerated
19
Q
What are the TRH and hTRH drugs? Used for?
A
- Protirelin: TRH -> stimulates TSH release from pituitary; used to test thyroid function
- Thyrotropin alpha hTRH: used in diagnostics for thyroglobulin levels -> can be used to diagnose where the problem is
20
Q
What is thyroid hormone?
A
- Synthesized in the thyroid gland as T4 (90%) and T3 (10%)
- Metabolized to active form (T3) mostly in the liver and brain (via deiodinase)
21
Q
What are the actions of thyroid hormone?
A
-
Growth and devo: esp. important in the brain -> hypothyroidism is leading cause of mental retardation worldwide
1. Important for devo of bones and teeth - Calorigenic: INC oxygen consumption (heart, sk m, liver, kidney); not caused by uncoupling
- CV: INC heart rate and force of contraction (heart can’t beat w/o thyroid hormone, so fetuses need this from mom in order for heart to start beating)
- Metabolic: maintains metabolic homeostasis in many organs
22
Q
Describe the synthesis and release of thyroid hormone (image).
A
- Active transport of iodide via Na/I symporter
- Iodide into colloid via apical pendrin, then oxidized by thyroid peroxidase to iodine
- Thyroid peroxidase inserted into apical membrane as part of vesicle transporting thyroglobulin to colloid
- Thryoglobulin iodinated, endocytosed -> fusion with lysosome, and release of T3 (10%), T4 (90%) into circulatory system
23
Q
Describe the interconversion of the thyroid hormone forms.
A
- Thyroid hormone (both T4 and T3) released into the blood (in a ~10:1 ratio) from the thyroid gland in response to thyroid stimulating hormone (TSH)
- Ratio in tissues is not the same as the synthesis ratio because of the action of the deiodinases
1. Type 1: T4 -> T3
2. Type 2: T4 -> feedback inhibition of TSH release (in brain, CNS, placenta)
3. Type 3: T4 -> rT3 - Ratio of T4 to T3 synthesized in the thyroid gland drops from 4:1 to 1:3 during iodine deficiency
24
Q
How does the fetus get thyroid hormone?
A
- Adequate amounts of thyroid hormone essential for normal fetal BRAIN DEVO
- In the first trimester of pregnancy, the fetus relies on thyroid hormone derived from maternal circulation
- This image seems confusing -> probably disregard it
25
How are thyroid hormones "metabolized?" Why is this important?
- Both metabolized in the liver via biotransformation through **glucuronide** and **sulfate conjugation** pathways that allow excretion of these hormones through the BILE
1. Important pathways for DEC T3, T4 levels
- Subject to **enterohepatic cycling** bc glucuronidases secreted by microorgs in lower intestine hydrolyze the glucuronide conjugates, and release the free hormones to be reabsorbed
1. Efficient recycling of thyroid hormones bc critical for development/metabolism
26
How are thyroid hormones transported in the circulation?
- **Thyroxine binding globulin** (TBG; binds 1:1): major carrier -\> T4 bound tighter than T3 (longer 1/2 life: 8d vs 1d)
- **Transthyretin** (TTR; binds 2:1): formerly called pre-albumin -\> higher levels in blood for TTR than TBG (also transports T4 in CSF)
- **Albumin**: binds T3 and T4
1. Familial dysalbuminemic hyperthyroxinemia: INC T4 (bc higher bonding affinity for it; often confused w/hyperthyroidism)
27
What is the free hormone concept?
- Thyroid hormones are very highly bound to protein in the blood -\> changes in protein levels or amount of binding to these proteins can cause large changes in total serum hormone levels
- **Hormone signal is unbound hormone, NOT the total amount**
- Pituitary senses only "free," unbound hormone, and maintains free level via INC or DEC synthesis
- Total loss of any one carrier protein does not affect the euthyroid state
28
What regulators are involved in the control of thyroid hormone production?
- Pharmacologic glucocorticoids, somatostatin, and dopamine INH TRH release
- Catecholamines stimulate TRH release
29
What are the effects of TSH on the thyroid gland?
- _Immediate effect_: INC secretion (minutes)
- _Later effects_: iodide uptake, hormone synthesis, and proteolysis
- _Last effects_: hypertrophy and hyperplasia
30
How does TSH act on the thyroid gland (at a molecular level)? Mutations?
- Acts via TSH receptors: **G-protein** coupled receptor that stimulates adenylyl cyclase (and **cAMP**)
1. At higher TSH levels, phospholipase C stimulated, resulting in INC PIs that INC cytosolic Ca2+
- Mutations in the TSH receptor can result in continuous activation (as in thyroid adenomas) or decreased function (one cause of hypothyroidism)
31
What happens to the thyroid in iodine deficiency? How is this prevented?
- DEC iodine in the diet = INC TSH, leading to **thyroid hypertrophy**
- Severe deficiency can lead to hypothyroidism and cretinism in adults, or retarded growth and development in children
- Iodized **salt** is the preferred method of preventing iodine deficiency
32
What is the MOA of thyroid hormone?
- Act primarily via binding to **nuclear receptors**
- T3 binds to specific receptor proteins TRα1, TRβ1, and TRβ2 that bind to specific DNA sequences (**thyroid hormone response elements**, TRE's) to INC and/or DEC DNA transcription
1. Although T4 can bind to these receptors, it cannot regulate transcription
2. Activities of T3 modulated by coactivators or corepressors
- T3 also binds avidly to mito mems, and activates the **mitochondrial adenine nucleotide transporter**
- **RXR** is *always required* for thyroid hormone action (heterodimer)
33
What are the CV effects of hypo- and hyperthryoidism?
- **HyperTH**: _tachycardia, INC stroke volume, cardiac hypertrophy_, DEC peripheral vascular resistance, INC pulse pressure
- **HypoTH**: _bradycardia_, DEC cardiac index, pericardial effusion, INC peripheral vascular resistance, DEC pulse pressure, and _elevation of mean arterial pressure_ (MAP)
34
What are the 3 types of hypothyroidism? List some causes.
- Types:
1. Adult myxedema (simple goiter)
2. Juvenile myxedema: usually diagnosed by dentists due to slow development, and decreased eruption of teeth
3. Infant -\> **cretinism**
- Causes:
1. _Hashimoto's thyroiditis_: autoimmune destruction of thyroid gland
2. _Drug-induced_
3. _Congenital hypothyroidism_ (no, or ectopic gland): pituitary disease (TSH deficit, radiation-induced)
35
What are the tx options for hypothyroidism?
- Exogenous admin of thyroid hormone (T3 or T4)
- **Levothyroxine** (T4): higher doses required for kids
1. May take several weeks for steady state level
2. MONITOR T3 and T4 levels: small differences are important
- **Lyothyronine sodium** (T3: tablets or injectable)
- **Liotrix**: T3 and T4 mixture
36
What thyroid disorders cause hyperthyroidism? General tx categories?
- Graves disease: auto-Abs against TSH receptors, INC hormone production
- Toxic nodular goiter: carcinoma
- TX more complex than that for hypothyroidism, and may consist of:
1. Surgery
2. Radioactive iodine
3. Drugs
37
What are the antithyroid drugs?
- THIOUREYLENES: inhibit iodine organification (the peroxidase catalyzed rxns: iodination and coupling)
- **Propylthiouracil** (PTU): also INH peripheral conversion of T4 to T3
1. Rapidly absorbed, but shorter plasma 1/2 life than Methimazole
2. Preferred in pregnant pts bc less placental transfer and limited excretion in milk
- **Methimazole**: 10x more potent than PTU
1. Better for most pts, but NOT PREGNANT WOMEN bc crosses placenta, and gets concentrated in fetal thyroid
- **Carbimazole**
- _Minimal AEs_ (3-12%): agranulocytosis (vulnerability to infection), skin rash
38
How can Propranolol be used to tx hyperthyroid?
- Preferred in some pts (Graves disease and thyrotoxicosis/thyroid storm) because T3 has potent effects on the HEART
- Blocks conversion of T3 to T4: want to give this to patients in thyrotoxic crisis (can also use high conc of iodine some pts -\> will stop EVERY PART of processing of thyroid hormone)
- SHORT-TERM TREATMENT
39
What is iodinated contrast media used for? AEs?
- Used for improved contrast in CT scans, cardiac catheterizations, etc.
- Can cause INCIDENT HYPERTHYROIDISM in euthyroid pts
1. For short period of time (temporary)
- Can also cause THYROID STORM in hyperthyroid pts
-
40
How is iodine used to treat hyperthyroidism?
- Large doses of iodine **INH all aspects of iodine metabolism** by the thyroid gland, RAPIDLY blocking release of thyroid hormone
- Used in TX of THYROID STORM (some patients)
- DEC size, vascularity, fragility of the hyperplastic gland, so valuable for pre-operative treatment
1. Works best for preoperative treatment or with other antithyroid drugs
- NOT to be used prior to radioactive iodide treatment (dilution)
- Long-term treatment usually fails
41
What is radioactive iodine used for?
- Na131I is administered orally
- Concentrated in thyroid gland, where β-radiation will **destroy all or part of the parenchymal cells in several weeks**, but not surrounding tissue of thyroid gland
- No evidence of radiation-induced damage to any other tissues
- Adults 35 years or older, but NOT women of child-bearing age
