the anterior pituitary originates from
Rathke’s pouch which is an embryonic invagination of the pharyngeal epithelium
*ectodermal tissue
the posterior pituitary originates from
a neural tissue outgrowth fro the hypothalamus
*neurally derived
characteristics of hypothalamic releasing hormones (6)
- secreted in pulsatile manner
- Associated w/ plasma membrane receptors and promote increase in intracellular 2nd messengers
- stimulate release of stored hormones of the AP
- stimulate synthesis of AP hormones
- required for maintence of target cells
- has autocrine effects (exhibit trophic influences over cells they regulate)
how does the vascular system of the pituitary contribute its functions
it is highly vascularized (2 capillary networks) which creates a high resistance of blood flow (ie. slow), therefore even though the releasing hormones secreted by the hypothalamus are in low concentrations, they will be concentrated by the slow flow, and will strongly affect the anterior pituitary
examples of hypothalamic releasing hormones
- TRH
- GnRH
- CRH
- GHRH
- GHIH aka Somatostatin
- PIF
- PRF (dopamine)
*all are peptides except PIP which is dopamine
Cell types of the Anterior Pituitary and their products
- Somatotropes- GH
- Corticotropes- ACTH
- Thyrotropes- TSH
- Gonadotropes- LH and FSH
- Mammotroph/Lactotropes- PRL
Hormones secreted by Anterior pituitary
- GH
- ACTH
- TSH
- PRL
- FSH and LH
promotes growth of the entire body by affecting protein formation, cell multiplication and cell differentiation
Growth hormone
Controls the secretion of some of the adrenocortical hormones, which affect the metabolism of glucose, proteins, and fat
Adrenocorticotropin (ACTH)
Controls the rate of secretion of thyroxine T4 and triiodothyronine T3 by the thyroid gland, these hormones control rates of most intracellular chemical reactions in the body
TSH
promotes mammary gland development and milk production
Prolactin
promotes mammary gland development and milk production
FSH and LH
Secretion from the posterior pituitary is controlled by
nerve signals that start in the hypothalamus
Secretion by the anterior pituitary is controlled by
hormones called hypothalamic releasing and hypothalamic inhibitory hormones/factors that are secreted by the hypothalamus and are conducted to the anterior pituitary through small blood vessels called hypothalamic hypophysial portal vessels.
LHRH is secreted in low amounts from hypothalamus –> LH or FSH from the AP are much greater.
How is such a small amount influencing the release?
vasculature!! capillary network–> venous structures –> capillary network –> SERIES resistance –> high R –> sluggish blood flow is why such small amounts of hormone has such a big effect !
Regulation of hormone release from pituitary
- Ultrashort loop inhibition (autocrine inhibition)- hypothalamus releasing hormone has a neg .effect on hypothalamus
- Short loop inhibition- Ant. pituitary secretes a trophic hormone that has a neg. effect on hypothalamus
- Long loop inhibition- trophic hormone effects target cell which releases another hormone that has a neg. effect on hypothalamus and AP hormone
*hypothalamic endocrine axis!
hormones secreted by posterior pituitary
- ADH aka vasopressin
2. oxytocin
controls the rate of water excretion into the urine
ADH
helps express milk from the glands of the breast to the nipples and helps in the delivery of the baby at the end of gestation.
oxytocin
major hormones of the adrenal cortex (types of corticosteroids)
1. Glucocorticoids (cortisol, corticosterone) 2. Mineralocorticoids (aldosterone) 3. Sex steroids (17-keto steroids) (androgens and estrogens)
affect the electrolytes (the minerals) of the ECF, especially sodium and potassium
Mineralocorticoids
affect blood glucose concentration. They also affect protein and fat metabolism
Glucocorticoids
*essential for life
what hormones are secreted from the different parts of the adrenal cortex and medullat
Zona Glomerulosa- Aldosterone
Zona fasciculata- glucocorticoids and sex steroids
Zona reticularis- sex steroids
medulla- epi and norepi
**All Cortex parts are stimulated by ACTH!
describe how Cortical atrophy and hypertrophy occur
atrophy- caused by hypophysectomy bc it loses ACTH
Hypertrophy- caused by increase in ACTH. ( stress–> hypothalamus stimulated ==> + CRH –> + pituitary–> increase in ACTH release
*ACTH regulates adrenal cortex maintenance
ACTH and cortisol levels increase on a diurnal rhythm, when are levels highest
rise at 4 am and peak around 7-8AM
*as you approach sleep/wake cycle, ACT and correspondingly cortisol increases
all steroids are derived from
cholesterol
describe the synthesis of steroids
ACTH binds to Gs receptor–> + PKA–> phosphrorylation–> + CEH **RLS
LDL mediates receptor mediated endocytosis –> LDLs are made of 50% cholesterol in ester form –> + CEH breaks down cholesterol esters to yield free cholesterol **RLS –> enters ER–> synthesis of steroid hormones in mito
**ACTH is literally driving the availability of free cholesterol to engage in biosynthetic activity!!!!
describe congenital adrenal hyperplasia (CAH)
it is a consequence of an enzyme in the cortisol production pathway being almost non-existant. So the person lacks the enzyme machinery to engage in cortisol production. This leads to a back up of ACTH and a hyperplastic adrenal gland
what is the dexamethasone suppression test
This test evaluates the integrity of the hypothalamus, pituitary, adrenal gland axis.
-Dexa is a powerful glucocorticoid given orally at night that raises glucocorticoid levels in the system. This negatively influences ACTH release and ultimately the release of cortisol
ACTH impacts all aspects of steroid hormone synthesis. What are its impacts
Immediate: (via phosphorylation of CEH via PKA)–> increase cholesterol transport to mito and more bind to p450= enhanced production of steriods by a number of hydroxylases
Subsequent: increase in LDL receptors and gene transcription
Longterm: (via insluin like growth factors)–> increases the size and number of cells in the adrenal cortex
what stimulates aldosterone secretion
angiotensin II
decrease in ECF volume (decrease BP)–> renin release from kidneys–> cleaves angiotensinogen from liver–> angiotensin I–> cleaved by ACE from lungs–> angiotensin II–> stimulates aldosterone release from zona glomerulosa
how is cortisol transported to its target
- binds primarily to transcortin- 80% (has the highest affinity for cortisol)
- overflow cortisol binds to albumin (15%) (lower affinity for cortisol)
- Free cortisol in ECF that can associate with receptors
This is our most important mineralocorticoid it is a K+ secretor Na+ keeper- lipophilic substance so it crosses membrane! Receptor is in cytoplasm or in nucleus
aldosterone
aldosterone is regulated by
angiotensin II
Plasma Na+ reduction (causes increase in aldosterone)
Plasma K+ increase (cause increase in aldosterone)
ACTH - weak but still promotes
our most important glucocorticoid
cortisol
what are the effects of increased AA in the ECF due to increased cortisol?
AA undergo transamination (utilization) in the liver to produce TCA cycle intermediates (can then be used to promote gluconeogensis, glycogen synthesis, and urea cycle activity–> see an increase in BUN via deamination)
cortisols diabetogenic results
- hyperglycemic, ketogenic, lypolytic
- increase in FFA
- increase in plasma AA–> increase in BUN
How does cortisol effect insulin
- shifts the curve to the right
- requires more insulin to drive the same level activity bc cortisol desensitized cells to insulin
how does cortisol affect the immune system and inflammation
- blocks NO production = decreased vasodilation
- blocks platelet activation factors= decreased permeability
- inhibits phospholipase which produces Arachidonic acid= decreased inflammation
- blocks interleukin production of T and B cells
- Blocks macrophage production of interleukins= increased fever
what are the effects of aldosterone
- increase Na+ reabsorption and passive movement of water with it (increase in [Na+] in plasma)
- increase in K+ secretion
- increase in ECF volume
- increase in BP
*results in more concentrated urine
describe the biosynthesis of catecholamines
-occurs in adrenal medulla
Tyrosine–>Dopa (via tyrosine hydroxylase **RLS)–> Dopamine–> norepi (via dopamine beta-hydroxylase)–> Epi (via PMNT)
Tyrosine hydroxylase and dopamine beta-hydroxylase are (+) by ACTH and sympathetic stimulation
PMNT is stimulated by cortisol
Cushing’s can be caused by
- Adenomas of the anterior pituitary that secrete large amounts of ACTH which then causes adrenal hyperplasia and excess cortisol.
- Abnormal function of the hypothalamus that causes high levels of corticotropin releasing hormone CRH which stimulates excess ACTH
- Ectopic secretion of ACTH by a tumor elsewhere in the body like an abdominal carcinoma
- Adenoma of the adrenal cortex
whats the difference between Cushing’s disease and Cushings syndrome
When Cushing’s syndrome is secondary to excess secretion of ACTH by the anterior pituitary this is called Cushing’s disease
why do we see muscle wasting in Cushing’s?
protein is being broken down into AA so that it can be used in gluconeogenesis
Most common adrenal disorder of infancy and childhood
congenital adrenal hyperplasia
causes of congential adrenal hyperplasia
Secondary to defect in steroid synthesis
- due to partial/complete lack of one or more ezymes that is responsible for making glucocortisol. Absence of the end product will not suppress the ACTH levels and this drives the hypertrophic response
effects of deficient C21 hydroxylase in CAH
*95% of cases
- Partial loss of activity = simple virilizing → don’t have complete loss, back up by-products and so shift toward the android steroid
- Severe (salt losing)- serious deficiencies in cortisol and aldosterone → can lose 5-10% of Na loss in the DCT without aldosterone
*this enzyme is crucial for glucocorticoid and mineralicoid production
effects of deficient C11 hydroxylase in CAH
serious deficiences in cortisol and aldosterone.
-Hypertension is present
why does deficient C11 hydroxylase in CAH cause hypertension
- Progressive adrenal hyperplasia due to persistent ACTH (no cortisol to inhibit it) results in an extreme overproduction of 11-deoxycorticosterone (DOC)
- DOC is a weak mineralocorticoid, but when it reaches high enough levels it causes mineralocorticoid excess: HTN, Salt retention, and Volume expansion
*too much DOC will cause increased Na+ reabsorption in tubular cells in kidneys= increase water reabsorption= increase ECF volume=increase in BP
why are there virilizing effects associated with C21 hydroxylase deficiency in CAH?
blocking C21 causes increase in 17-alpha-hydroxypregnenolone–> increase in testosterone pathway
*too much testosterone can cause increase in estradiol
but you see more increase in testosterone because most estrogen is produce in the ovaries
what is a major source of T3
deiodidination of T4
what happens with MIT and DIT get deiodinated
they get recycled and they contribute to the iodide pool
what inhibits iodide transport into the thyroid follicular cell?
ClO4-
SCN-
what transports T3 and T4?
TBG and TBPA in plasma
*TBG has a higher affinity for T3 and T4
What coupling Rxns form T3 and T4
DIT + DIT (via ester linkage)= T4
DIT + MIT (via ester linkage) = T3
what are the functional units of thyroid
follicles
*They are secretory cells that surround/synthesize the cells with colloid
how is the thyroid gland able to store hormones and later use it
- it stores large amounts of hormone in its colloid areas bound to thyroglobulin
- In order to get these hormones out for use, the follicular cell must take in colloid via endocytosis and break it down into free T3 and T4.
is T3 or T4 more potent
T3
*but present in much smaller quantities
why is TSH low is hyperthyroidism?
T4 is increased due to hyperactive thyroid
-T4 feeds back to inihibit ant. pituitary and hypothalamus and inhibits TSH secretion
how do you get hypertrophy of the thyroid gland?
overstimulation by TSH
what are the actions of TSH
- increase metabolic activity
- increase cell size
- increase cell number
- increase follicular formation
- driving of the iodide pump
- increase intracellular Ca2+
*driving hyperplastic response
describe the half lives of T3 and T4
T4 (Thyroxine) has a higher affinity for its carrier protein so it has a longer half life
T3 has less affinity for its carrier protein so it falls off easily and is degraded more quickly
*there is a long latent period before T4 activity begins. Note- almost all of the T4 is converted to T3 before the hormone acts on the cell. Only about 10% of hormone is still T4 at this point
Pharmacology- these inhibit peroxidase enzyme, thus reducing thyroid hormone synthesis via inhibiting iodine formation and coupling reaction of tyrosine residues to make our T4 and T3
Thioamide compounds
GH release is mediated by:
hormones/stress
Neurogenic
Metabolic (ex. hypoglycemia)
what is secreted by the liver in response to GH
somatomedins (act as GH)
*Small proteins that have similarities to the effects of insulin on growth. So somatomedins are also called insulin like growth facts IGFs.
what is the biggest inhibitor of GH
somatostatin
*released by the hypothalamus and inhibits ant. pituitary (decrease GH release)
metabolic triggers are used to promote what hormones
cortisol
GH
*both hormones are diabetogenic!! (increases resistance to insulin and can cause diabetes!)
direct effects of GH
- Adipose tissue: decrease adiposity by decrease glucose uptake and increased lipolysis
- Muscle: increase LBM by increased protein synthesis, increase AA uptake, and decreased glucose uptake
- Liver: increase RNA/protein synthesis, increase gluconeognesis, increase somatomedins
how does GH promote increase in LBM
GH is enhancing the conversion of FFA to Acetyl CoA in tissues throughout the body for energy.
- So under the influence of GH fat is used for NRG instead of carbs and proteins.
- So GH causes an increase in lean body mass
explain the Ketogenic effect of GH:
under the influence of excessive growth hormone, fat mobilization from adipose tissue sometimes becomes so great that large quantities of acetoacetic acid are formed by the liver and released into body fluids causing ketosis.
*This excessive mobilization of fat from the adipose tissue also causes fatty liver.
GH ____ glucose up take in skeletal muscle and fat cells
decreases
GH _____ glucose production by the liver and GH _____ insulin secretion.
increases
increases
what factors are necessary for GH and promotion of normal growth
TH
glucocorticoids
insulin
gonadal steroids
**must have an intact endocrine system for GH to be released
roles of prolactin in regards to lactation
- regulation of gene expression for milk
2. mammary gland differentiation during pregnancy
what is unique of prolactin compared to other anterior pituitary hormones?
because it is the ONLY one under tonic inhibition. This term means that the hypothalamus mainly inhibits prolactin production by secreting prolactin inhibiting factor (AKA dopamine- catecholamine)
what do somatastatins do?
inihibit GH and prolactin from ant. pituitary
*released from hypothalamus
what hormones are responsible for ductal breast growth and lobulo-aveolar growth
- estrogen
- GH
- adrenal steriods
= Ductal growth
+ progesterone + prolactin = LA growth
how does prolactin activate its pathway
acts through JAK-STAT pathway–> increase in mRNA that drives milk synthesis (increase in enzyems)–> increase in lipid, protein, and lactose synthesis
what is the main protein in cows milk and humans milk
Cows- Casein (Casein 80%, Whey 20%)
Humans- Whey (Casein 34%, Whey 66%, Alpha lactalbumin 3.6g/L)
what is the role of alpha lactalbumin?
this protein is important for lactose synthase enzyme to make lactose from UDP-galactose
lactose synthase = alpha lactalbumin + galactosyltransferase)
what hormones act through the JAK-STAT pathway?
prolactin
what are calciums 6 roles
- Membrane potential and stabilization
- Cellular excitability
- Muscle contraction
- Regulation of enzymatic activity*
- Exocytosis* (ex. insulin release)
- Cellular adhesion
sx of hypercalcemia
- Neurologic signs (Fatigue, depression, mental confusion, anorexia, coma)
- CV signs (ECG changes, arrhythmias)
- GI/renal (BONES, STONES, and GRONE)
describe what bones, stones, and grones means
bone degradation happens kidney stones (come from calcium plus phosphate) and constipation
sx of hypocalcemia
- muscle spasms → carpopedal spasm, laryngeal spasm
- convulsions, respiratory arrest, increased intracranial pressure, irritability, depression, psychosis.
Explain Ca2+ binding in ECF
Ca2+ binds to albumin
in acidic environment: albumin knocks off Ca2+ and binds H+ to decrease ECF [H+] and increase pH
in basic environment: albumin knocks off H+ and binds Ca2+ to increase ECF [H+] and decrease pH
*albumin acts as a buffer
what is being liberated from bone via PTH
*mineralized bone contains a lot of this!
hydorxy-appatite= (Ca2)10(PO4)6(OH)2
What regulates ParaThyroid Hormone (PTH) release?
FREE calium
- When FREE calcium levels are too low, PTH is secreted
- When FREE calcium levels get too high, PTH drops
these are young cells that are responsible for making soft bone that is part of the rapidly exchangeable pool (osteoid). Lays down osteoid= non-mineralized bone = rapidly exchangeable pool of Ca and PO4.
Osteoblasts
These are responsible for both bone mineralization and bone degradation. Switch Hitters.
osteocytes
breaking down and eroding away of mineralization
Osteocytiocsteolysis
Bone degradation/removal or resources in bone. These are the most influential to bone loss. Responsible for lysosomal activity to demineralize cortical bone
osteoclasts
PTHs actions on osteoblasts/cytes/clasts
PTH inhibits osteoblastic activity and new bone deposition.
PTH stimulates osteolysis in osteoctyes
PTH stimulates osteoclasts to dissolve mineralized bone.
the transfer of substances across an epithelium by passing through the intercellular space between the cells
paracellular
ex. Ca2+ in PCT
a marker for osteoclast and osteocyte activity. These are driving the bone demineralization to mobilize calcium and phosphate
hydroxyproline
*urine hydroxyproline increases with PTH administration
why do we see Ca2+ and (PO4)2-increase in urine with PTH administration
This is simply because we have mobilized stores of Ca++ and phosphate. More in the ECF means more is filtered, means more is secreted even though we are actively trying to re-absorb the calcium with PTH!!!
-increase free Ca2+ –> increased filter load of Ca2+
what are the effects of PTH administration
- increase free Ca2+, decrease in free phosphate
- increase in filtered load = increase in Ca2+ and phosphate in the urine (bc of more mobilized stores of calcium and phosphate)
- increase in hydroxyproline (increase in bone demineralization to mobilize Ca2+ and phosphate)
- Decrease in TRP (tubular reabsorption of phosphate)
Long term regulator of Ca & PO4 concentrations
Vit. D3
what inhibits prostaglandins
aspirin
NSAIDs
Thromboxane A2 causes
vasoconstriction and platelet aggregation
Prostacyclins do what
counteract thromboxane A2s actions
thromboxane A2–> vasoconstriction and platelet aggregation
essentail FA
linoleic acid, linolenic acid Omega 6 and 3
- expression is stimulated by growth factors, cytokines, and endotoxins
- levels increase in inflammatory diseases such as arthritis
COX2
- constitutively expressed in virtually all tissues
- essential for thromboxane formation in platelets, and for maintaining integrity of the gastrointestinal epithelium
COX1
competitive inhibitor of COX1 and 2
acetaminophen
irreverislbe inhibitor of COX 1 and 2
*covalent modifer at active site
aspirin
physiological effects of LTs (5)
- Potent chemotactic agent – LTB4
- Promoter of leukocyte adhesion to endothelial cells
- Cause vascular smooth muscle contraction – cysteinyl LTs
(Slow reacting substances of anaphylaxis) - Cause bronchiolar SM contraction
- Alter vascular permeability → diminish the ability of PLPA2