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PITUITARY GLAND (Posterior Pituitary Gland (. (dropped image link), ADH,…
PITUITARY GLAND
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Hypothalamus
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CTRH
- corticotrophin releasing
hormone
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Delta Cells
- also found in the pyloric antrum,
duodenum, Islet of Langerhans
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TRH
- Thyroproin releasing
hormone
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HORMONES:ghrelin
- peptide hormone
- fundus of the stomach --> Hypothalemus
- stimulates hunger
- released when the fundus is not stretched, inhibited when fundus is stretched
leptin
- peptide hormone
- released from adipose cells
- inhibits hunger and promotes satiety = full
- obese people have high leptin, but either it is either mutated or their body downregulates receptors due to high leptin levels (similar to type 2 diabetes)
somatostatin
- inhibits all hypo-APG axes, as well as BOTH insulin and glucagon
Hypothalemic - Anterior Pituitary - Gonadal Axis:
- all gonadotropin sex hormones LH, FSH and thyroid stimulating hormone = TSH have the same alpha unit
--> it is their beta unit that defines them
Gonadotropin Releasing Hormone
- released in pulsatile manner
- 5 regulators:
--> Puberty - high levels of GnRH
--> negative feedback
--> stress - lowers GnRH
--> lactation - prolactin decreases GnRH
--> pheramones (+/-)
Porlactin hyprsecretion & Amenorrhea
- shut down of GnRH completely
- caused by over secretion of prolactin
- prolactin decreases GnRH
- Dopamine D2 receptors are opposite to D1 receptors
- Dopamine D2 receptors decrease prolactin and indirectly increase GnRH
LH
- biphasic --> (2 letters)
- both LH and FSH are diurnal = daily circadian release
- females: LH surges at day 13 of woman's mestrual cycle
--> LH surge causes estrogen spike and release of egg
- males: LH constantly pulsatile --> continuous production of testosterone
- LH directly inhibited by gonadal sex hormones, where FSH is NOT
FSH
- uniphasic release
- both LH and FSH are diurnal = daily circadian release
- beta subunit is regulated by the specific proteins made by the gonads --> inhibin and activin
LH and Ovulation
- estrogen normally has a negative feedback loop on LH, but at high sustained levels, causes release of LH
- females: LH surges at day 13 of woman's mestrual cycle
--> LH surge causes estrogen spike and release of egg
- progesterone inhibits LH release
--> most oral contraceptives have progesterone to stop LH surge (and estrogen spike and release of egg)
Puberty
- recall that LH is low amplitude and high frequency
- puberty is marked by higher frequency in GnRH levels, with nocturnal LH peaks
--> higher frequency means higher ratio of Lh compared to FSH
- low body weight --> will hit puberty at a later age
- have a "mini-puberty" where at infancy you have a surge in GnRH, then plateaus at childhood before 2nd surge at actual puberty
- increase in E2 for females is more "step-wise"
- for males, testosterone increase is exponential
Changes to outside Regulators of GnRH at Puberty
- Glutamate neurons and leptin = main stimulators of GnRH
--> both increased at puberty
- GABA neurons = GnRH inhibitor
--> decreased at puberty
- melatonin = GnRH inhibitor
--> decreased at puberty
GH and IGF-1 Permissive effect on Gonad development
- 3 major factors
- Gh and IGF-1 both increase gonads to release Testosterone and E2
- IGF-1 increases release of GnRH
- testosterone and E2 both increase GH production in a feddforward loop
Menopause and Andropause
- menopause
--> occurs usually at 50
--> occurs more suddenly and total loss of estrogen and progesterone production
- andropause
--> men slowly start to lose testosterone, not sudden and complete loss like for females
- lower levels of gonadal steroids makes sexual organs start to atrophy
--> less negative feedback
Hypothalemic - Anterior Pituitary - Thyroid Axis:Notes
- diurnal circadian rhythm
--> diurnal = of the day, opposite to nocturnal
--> circadian = recurring naturally in 24 cycles
- stress can effect it, but not as much as the hypo-ant pit - adrenal axis
Thyroid Axis response to cold weather
- in animal and in babies ONLY (not adults)
- in cold weather, TSH increases
TSH= thyrotropin stimulating hormone - tyrosine derivative
Thyroid Hormones and Productiontri-iodothyronine = T3
- has 2 tyrosine molecules
- 3 iodine molecules
diiodothyronine = T4
- has 2 tyrosine molecules
- 4 iodine molecules
- precursor to T3
- in blood, 80% bound to thyroxine binding globulin (TBG), 10% bound to thyroxine binding prealbumin, 9% albumin
- ONLY 1% of blood thyroxine is free thyroxine
Follicles (Soup)
- the thyroid gland is arranged into follicles
- follicles contain thyroglobulin, tyrosine and iodine as the main precursors to making two main thyroid hormones t3 and t4
Iodine and t3 and t4 formation
- iodine must be taken in the diet, cannot be made
1 - iodine reduced to iodide- first is reduced to iodide = I- before it can be absorbed in the small intestine
2 - iodine trapped by cotrasnporter - iodine is trapped at the basolateral membrane of the parafollicle cells
--> it is secondary actively pumped in by sodium iodine cotransporter
--> uses gradient of sodium potassium ATPase pump
3 - iodine oxidized back to iodine in Follicle - it is then trapped in the lumen of the follicles by being oxidized to iodine again I0--> forming I2
4 - Iodination or Organification - iodine is organified or joined to the tyrosine residues, that are branches of the thyorglobulin molecule
--> done by TPO = thyroid peroxidase enzymes
--> 1 iodine bound to tyrosine = monoiodotyrosine = MIT
--> 2 iodines bound to tyrosine = di-iodotyrosine = DIT
--> Wolf-Chaikoff Effect - is counter intuitive --> the more I- iodide there is in the follicle they inhibit organification and hence production of t3 d t4
--> OrganificationDefect - where iodine cannot be conjugated to tyrosine and no t3 or t4 can be made
5 - Conjugation - coming together of the iodinized tyrosines while they are still attached to the thyroglobulin molecules
--> MIT + DIT = 3 iodines --> t3
--> DIT x 2 = 4 iodines --> t4
6 - Thyroglobulin Colloid endocytosis - the thyroglobulin with the t3 and t4 attached to them are endocytosed from the follicles back into the follicle cells to merge with lysozomes
7 - Proteolysis - the t3 and t4 are cleaved form the thyroglobulin molecules
8 - t3 and t4 passively diffuse out of cell - thy are lipophlic so enter blood easily
Thyroid hormones in the blood
- most thyroid hormone released is thyroxine = t4
- small amount of t3 is released into the blood
--> all t4 must be changed into t3 at the peripheral cells to give their action
- t4 binds to binding/buffering proteins
--> about 80% thyroxine binding globulin
--> 10% prealbumin
--> remaining albumin
- only free thyroid hormones giver their action
--> 0.1% of t4 is free
--> 1% of t3 is free
Wolff- Chaikoff Effect
- when there is excess iodide
- this inhibits organification of iodide into iodine
--> lasts for 2-3 days
--> ends with "escape phenomenon" --> t3 and t4 levels return to normal
--> escape phenomenon happens due to reduced expression of the sodium iodine cotransporter that brings the iodine in and lowers levels back to normal in the cell
- Clinical relevance - iodine is injected to reduce the size of the thyroid gland and also reduce the blood supply to the gland
--> this can be done to hyperactive thyroid simply to reduce it's size
- lower t3 and t4 production automatically does this
Hypothalemic - Anterior Pituitary - Growth Hormone Axis:Sleep-Waake cycle release
- GH is released on a sleep-wake cycle, NOT a day/night circadian cycle
- largest pulse at first 2 hrs sleep
- pulses every sleep cycle, except at the REM cycle --> no release
Life Cycle GH and IGF-1
- both increase at birth
- plateau during childhood
- peak highest at puberty
- plateau again
--> height gain at puberty due to both GH and IGF-1
--> height gain at birth due to IGF2
--> IGF-2 is the main growth factor for fetus
Short and Long Negative feedback Loops
- IGF-1 liver long feedback to hypothal
--> main feedback loop
- GH (somatotropin) short feedback
--> neg feedback from APG to Hypothal
GH = Growth Hormone = somatostatin
- classified as a stress hormone --> BUT physical and exercise stress, not psych, etc.
- 3 main stimulators for GH release
1 - physical stress and exercise
2 - stress from low glucose levels (fasting and hypoglycemia)
3 - increase in certain AAs
- 2 main inhibitors for GH release
- somatostatin - general inhibitor
- psychological or emotional stress
--> cortisol release will inhibit GH directly
GH receptors
- tyrosine kinase receptors, similar to thyroid hormone receptors (also tyrosine receptors)
GH Effects on Bone Growth
- Direct effects:
--> increases chondrocyte differentiation, so more cartilage production in the bone
--> increases osteoblast production and more laying down of bone
- Indirect Effects:
--> permissive effects with IGF-1
--> makes bones more open to IGF-1 effects
--> IGF-1 increases the effects of PTH = parathyroid hormone also to increase bone remodelling --> releasing of calcium
Main Goal of GH by Lipids, increases glucose levels only secondary
- increase metabolic short term by:
--> increase in FA lipolysis and AA uptake
--> use these to increase protein production
- increase protein synthesis long term by RNA, DNA and cell growth
GH effects on insulin release
- GH primarily increases blood FAs, secondarily increases glucose
--> increased glucose increases insulin release
--> GH inhibits insulin function POST-RECEPTOR by reducing Insulin receptor response to insulin
--> also, raised FAs in blood decreases the effects of insulin
- high GH levels can also induce diabetes as to respond to effect as Ins receptors, more insulin must be released
- opposite for low GH --> low level so f insulin released
Hypothalemic - Anterior Pituitary - Growth Hormone Axis 2:Different eating states --> GH and insulin
- high AAs (protein)
--> both high insulin and GH
--> recall AAs stimulate both GH and insulin
- high glucose (carbs)
--> high insulin and low GH
- fasting
--> high GH and low insulin
IGF-1,2
- GH is dependent on insulin in order to produce IGF-1
- if there is no pancreas --> GH will not work
- IGF-1,2 very similar to proinsulin, alpha and beta chain with the C-peptide --> can decrease glucose
- IGF-1,2 Main Effect::
increases protein production through long term paths (RNA,DNA, cell growth)
- IGF-1,2 Secondary Effect::
IGF-1,2 since it is similar to proinsulin, can bind to insulin receptors and decrease glucose levels
--> counterintuitive since GH post receptor blocks effects of insulin and increases glucose levels
- IGF-2 is the main growth factor for fetus
- PTH, GH and sex steroids all regulate IGF-1 from the liver
Diseases:
- Dwarfism
--> defect in GH receptor stops GH from acting on the liver to release IGF-1
--> also deficiency in GH release
--> stunted growth
- Gigantism
--> excess GH release
--> over production of GH receptor
--> increase IGF-1
--> more growth after borth and fetus years (IGF-2 responsible for high growth as fetus and baby)
- Acromegaly
--> excess GH release AFTER PUBERTY
--> increase in growth, not of long bones, but other bones, heart, muscle, GIT and accessory organs
all gonadotropins - same alpha subunit,
unique beta subunit
NOTESKey Principals of
Signal Transduction
- Specificity for receptors
- Amplification
--> at each level signal amplified
- Adaptation and Dessensitization
- Integration of different signals
Types of Hormones
- amino acid/ peptide horomes
--> insulin, IGF-1,2
--> glucagon
- protein hormones
--> catecholeamines (epinephrine and norepinephrine)
- steroid hormones (3 basic cholesterol based classes)
--> androgens (testosterone)
--> estrogens (E2 = estradiol) and progesterones
--> cortisol and aldosterone
Steroid Hormone Regulation
- note all steroid hormone synthesis is regulated by peptide hormones
- testosterone and estrogens
--> LH and FSH (peptide hormones)
- Corticosteroids (cortisol)
--> Adrenocorticotropic Releasing hormone
Steroid Hormone Transport in the blood
- 4 major steroid binding proteins
- Albumin
- 2 binding proteins for sex hormones
--> Androgen Binding Proteins
- Sex-Hormone Binding Proteins
- Transcortin
Nuclear vs. Membrane Receptors
- 3-4 thousand membrane receptors
- ONLY about 48 nuclear receptors
- steroid hormones activate nuclear receptors since they are lipophilic and can easily cross the cell membrane
--> activate either negative or positive transcription factors
- effects of steroid hormones re delayed becasue they require transcription and translation
--> response is stronger though
Glucocorticoids
- recall that flagella of bacteria activate TLRs = toll like receptors
--> there are many different kinds of Toll-like receptors
- glucocorticoids (cortisol) are anti-inflammatory steroid hormones
--> slow, but long lasting and powerful effect
- shut down major inflammatory factors
--> TNF-Alpha Cytokine - releases cytokines to promote inflammation
- NF Kappa B --> NF means nuclear factor
--> transcription factor
--> transcribes TNF-Alpha to get cytokine release and inflammation
- I Kappa B alpha
--> I means Inhibitor of Kappa B
--> inhibits Nuclear factor kappa B
--> shuts down the NF kappa B --> TNF-alpha cytokine --> inflammatory pathway
--> can also inject with iodine 2-3 weeks prior to a thyroidectomy (removal of thyroid gland) to reduce the size and hence removal and also reuce the blood flow to reduce the bleeeding during surgery
Adrenal Cortex Axis:CRH = corticotropic releasing hormone
- released from the hypothalamus
- binds to receptors of corticotropic cells in the anterior pituitary gland
--> causes corticotropes to release ACTH
ACTH = adrenocorticotropic hormone
- released from corticotropic cells in the anterior pituitary gland
- bind to receptors in adrenal glands for them to release cortisol
"That's Soma Go Corting Thy Loves"
- somatotropin = GH
- Gonadotropes = LH and FSH
- Corticotropes = ACTH
- thyrotropes = TSH
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