Section 3 Flashcards
Another name for hypophysis
pituitary gland
before pituitary was considered a master gland, now it is known that is controlled by hypothalamus, hence what is the system name
hypothalamo-pituitary axis
Weight of the pituitary gland, size, and when in increase by 30%
Weight of the pituitary is 0.5-1.0 g (1 cm diameter about size of a pea) – increases in size (>30 %) during pregnancy
where pituitary gland is found
under hypothalamus and optic chiasma
draw the structure of hypothalamus-pituitary gland
3 parts of anterior, 2 parts of posterior, connection between hypothalamus and pituitary gland and what is find beneath pituitary and where is optic chiasa in all this
pituitary found in what ventricle
3rd ventricle
Hypothalamo-hypophyseal tract is derived from
How hypothalamus is organized
Into discrete nuclei
The interrelation between the hypothalamus and the anterior pituitary
- anterior pituitary is highly vascularized: capillary bed in anterior pituitary is connected to capillary bed in median eminence through portal veins
- Releasing factors are secreted into median eminence that go to pituitary
- Retrograde flow of blood allows for –ve feedback from pit. to hypothalamus
Synthesis , transport and release of hormones of the posterior pituitary
What is halasz knife
Originally used to selectively destroy areas of brain to observe function of nuclei
3 types of hypothalamus neurons
To what types of neurons cells interacting with pituitary are classified
Somatostatin -growth inhibiting hormone
Hypothalamus receives signals from
-the external environment (e.g., light, nociception,
temperature, odorants) and
-internal environment (e.g., blood pressure, blood
osmolality, blood glucose and hormone levels)
where does hypothalamus sends integrated signals from outside and inside
-anterior pituitary gland, posterior pituitary gland,
cerebral cortex, premotor and motor neurons in the
brainstem and spinal cord, and parasympathetic and
sympathetic preganglionic neurons
What are circumventricular organs , the place
in 3 rd and 4th ventricle
Circumventricular organs (CVOs) are structures in the brain characterized by their extensive and highly permeable capillaries, unlike those in the rest of the brain where there exists a blood–brain barrier (BBB) at the capillary level
-Exposed to hormones, metabolites and toxins
Example: OVLT neurons have estrogen
receptors
Name 5 CVOs
-organum vasculosum of the lamina
terminalis (OVLT)
-Subfornical organ (SFO)
-Median eminence (ME)
-Subcommissural organ (SCO)
-Area postrema (AP)
2 types of hypothalamic nuclei
Supraoptic and paraventricular nuclei
Hypothalamic-hypophysiotropic nuclei
Characterize supraoptic and paraventricular nuclei
- Named after the location of the cell bodies of the neurons
-Large neurons (120-200 nm diameter)
-Neuron are specific, producing mainly oxytocin or vasopressin - The hormone granules are visible and can be observed
traveling down the axons (8 mm/h)
Characterization of hypothalamic-hypophysiotropic nuclei (PeVH, PVH, Arc)
What can regulate hypothalamus
Cell types in anterior pituitary, their population, product and tarfet organ
They all have a lot ER, because they produce peptide hormones
name basophils and acidophils in anterior pituitary
Basophils: (take up bases readily)
Thyrotropes →TSH
Gonadotropes → LH or FSH
Corticotropes→ACTH
Acidophils:
Somatotropes →GH
Lactotropes→ PRL
Hypothalamic hormones controlling anterior pituitary ( structure, major functions)
Mechanism of action of hypothalamic hormones affecting the anterior pituitary: half life, feedback, binding , thorugh what receptor they inteact
How hypothalamic hormones are released (time)
vReleased is pulsatile. Pulsatility is important (e.g. treatment
of infertility with GnRH requires administration in pulses
with a defined frequency
Pineal gland, circadian rhythms, day-night cycles, SCN relationship
SCN can regulate itself the secretion of melatonin
Melatonin is sythesized from
Melatonin
When melatonin hits its peak and when it is secreted
at midnight ,during darkness
How melatonin can influence our body and where it is secreted
In pineal gland
-Neural connection with special receptors in the retina.
Other receptors present in the body
-May entrain body’s biological rhythms to the dark-light
cycle eg. Core body temperature
Other functions:
-Induction of sleep
-Depression of reproductive activity, inhibition of ovulation and
semen production in some animals –questionable role in humans
-Seasonal fluctuations may affect the timing of breeding,
migration and hibernation in mammals
Where melatonin receptors are found and what happens with its concentration with age
Decreases
in all body
Other functions of melatonin apart from sleep
-Adjustment of jet-lag (esp. if travelling east > 5 time zones)
-Sleeping aid in the elderly (4 min decrease in time to fall
asleep, 12 min increase in total sleep)
vantioxidant (anti-aging properties?); but supraphysiological
levels
-Enhancement of immunity; evidence is not clear
Adverse side effects of melatonin
- Daytime sleepiness and Hypothermia
- Desensitization of melatonin receptors if doses too high
- Possible adverse events in those with seizure disorders
- Possible interaction with those taking coumadin/warfarin
hormones secreted by anterior pituitary, their structure and and dominant second messenger system
What is the trend of hormone expression in pituitary
- Hormones are co expressed
- No unique TSH cells
- 60-70% GH+ cells express only GH
- 6-16% PRL+ cells express only PRL (sexual dimorphism)
- Both gonadotropins are co-expressed
What are the largest portion of endocrine cells in anterior pituitary
Somatotrophs
How much GH pituitary stores
5-15 mg in granules
Growth hormone is ___ hormone (nature)
Peptide
On what genes and forms GH is expressed
GH locus has GH locus has hGH-N, chorionic somatotropins(hGH-A, B, V and L)
Where hCS can be found (place and period)
hCS’s in placenta; hCG-V increases midgestation
to delivery
Men never express this forms
Major form of GH ( length) and what is the form of GH that contributes to 10% of GH
191 AA, shorter isoform , where 32-46 AAs missing contributes to 10% GH pool
Differences between 2 isoforms of GH
There are subtle differences in the spectrum of bioactivities +
degree of glycosylation
For what diseases GH is used ( what was the problem with the method of extraction before)
Human GH used for treatment of
pituitary dwarfism (60000 cadavers
required) - Problems with prion
contamination (Jacob Kreutzfeld
disease)
- Recombinant GH is now being used.
Start of the biotech industry
(Genentech)
control of growth hormone secretion starts is performed by
Balance between GHRH and somatostatin
GHRH treatment induces ___ secretion and in which sex the repsonse is bigger
Induces secretion
More in women than men
Somatostation ___ GH
inhibits secretion, but not synthesis
How GH is secreted (time), how it changes with age
GH secretion – episodic; 2/3rd in
slow-wave sleep
- Levels fetus > child < adolescent >
adult - Changes in amplitude but not
frequency of pulses
How Gh circulates in circulation
Bounded to extracellular doamin of GHR - GHBP
Growth hormone secretion is stimulated by what events
Suppresion of GH release occurs when
Inhibition of GH interaction with receptors and its action, though the hormone is released, when
Growth hormone signalling though what pathway
How suppresor of cytokine signalling acts on GH signalling
Inhibits
Negative feedback
How growth hormone affects growth
Direct actions:
vPromotion of cell
differentiation
Indirect actions:
vInduction of IGF-I that
promotes cell division
and has insulin-like
effects
When GH via IGF-1 is important
During childhood growth, but less during gestation for neonate
IGF-1 leves are ____ grwoth rate in children until 20s
parallel to
GH and IGF-1 promote
promote growth of long bones at the epiphyseal plates (proliferation of cartilage cells, i.e. chondrocytes).
Epiphyses fuse at the end of puberty and longitudinal
growth ceases
Metabolic effects of GH
In adults: optimizes body
composition, physical function and
substrate metabolism
Interacts with insulin to regulate
Glu, fat and protein metabolism
Enhances lipolysis and FA
oxidation – imp during fasting
Reduces urea synthesis and
excretion – Protein sparing
Increases AA uptake and protein
synthesis
Inhibits insulin stimulated glucose
uptake
Also, GH treatment induces insulin
secretion and glucose uptake
What are 2 types of IGF
insulin like growth factors
1- GH-dependent
2- GH-independent
Structure of IGFs is similar to ___
insulin
Where IGF-1 is secreted
-Produced by the liver and other tissues. IGF-I from the liver is
released into the blood stream.
-Other tissues - local production and paracrine/autocrine.
What is the function of IGF-II
vImportant in fetal development. Role in adults less clear. May
act via IGF-I receptors.
When IGF-binding proteins are secreted and what is their role
Secreted by target cells together with specific proteases.
May regulate bioavailability and turn-over of IGFs
Binding proteins block IGF, when proteases destroy binding protein
How IGFs concentration change with GH flucriations
Remain relatively constant
IGF-1 and IGF-2 are expressed
on 2 genes
compare and contract Gh and IGF receptors (place, what mechanism of action, structure of receptor)
GH-receptor:
-In most tissues.
- Acts via recruitment of tyrosine kinase, JAK2 and activation of
STATs, MAPK or IP3K.
- Extracellular domain circulates and acts as binding protein.
- GHR is. downregulated by GH or other factors (sex hormones)
IGF-I receptor:
- Similar to insulin receptor. Dimer of two glycoprotein subunits (AB)2
- Acts via intrinsic tyrosine kinase activity, MAPK or IP3K
IGF-II receptor:
- Single-chain spanning the membrane once. Also binds mannose-6-
phosphate. No known signal activity, at least postnatally
- Ultimate action may be via IGF-I receptor (10% less affinity than IGFII
receptor)
Summarize regualtion of GH release
vBalance between GHRH and somatostatin (GH release
inhibiting hormone)
vFeedback control by IGF-I on pituitary and
hypothalamus
vFeedback control by GH
vControl by the nervous system:
v Stress (exercise, excitement , cold, anesthesia, surgery,
hemorrhage) → surge in GH.
v Sleep induces fluctuations in GH. Secretion every 1-2 h.
vMetabolites:
v Increase: Hypoglycemia (e.g. produced by insulin
administration) Amino acids (arginine)
v Decrease: Hyperglycemia (oral glucose), free fatty acids
exercise increase GH and fastign as well
psychological stress decreases GH
Gh released in pulse ____ (time)
1-2 h
Effect of glucose and insulin on GH levels
Prolactin structure
similar to Gh but longer ( 198 vs 191 aa)
how much prolactin in pituitary
0.1 mg
What hormones are essential for milk secretion initiation
Prolactin and cortisol
Hypophysectomy leads to immediate cessation of
milk production,
Adrenalectomy leads to a gradual reduction in milk
production
what does it demonstrate
that both prolactin and cortisol are needed
How many genes are their that code prolactin
1, PRL
In what forms prolactin circulates
Circulates in various sizes – monomeric, dimeric and
polymeric
v Monomeric – most bioactive
Gene expression and release of prolactin are regulated by
Positive- PrRP, EGF,
FGF, VIP, estrogen, TRH, thyroid hormone,
Negative- dopamine,
endothelin, TGFb
Prolactin can be regulated by 2 processes __- and ____
expression and release, because it is also stored in granules
The major type of prolactin release is
Through negative regulation with dopamine
More dopamine receptors on the cell, less prolactin
Prolactitn receptors are found in dopamine neurons in hypothalamus, so if this receptors does not work-> high prolactin, low dopamine
What is the rhytm of prolactin secretion,when the release is the lowest, what happens with age
v Half-life – 25-45 minutes
v Episodic release – 4-14 pulses
v lowest 10:00-12:00
v Levels reduce with age
How estrogen influences prolactin secretion
Estrogen-> positive on prolactin gene expression
But also should be negative (contextual) because needs to go down in the late pregnancy, so prolactin secreated
How prolactin signalling functions
Where prolactin receptors are expressed
PRL receptors are expressed in breast tissue and in many other tissues
prolactin function in breath and oxytocin role
Duct system development:
estrogen, GH, adrenal steroids
v Alveolar growth: estrogen,
progesterone, adrenal
steroids, PRL
v PRL stimulates milk secretion
from alveolar epithelial cells.
v Oxytocin acts on myoepithelial
cells to induce contraction of
the alveoli
Second function of prolactin
Involved in regulation of
the reproductive systems
v hyperprolactinemic
conditions associated
with hypogonadism in
males and females
v e.g. high levels of PRL
associated with breast
feeding associated with
lactational amenorrhea
v common birth control
method in many cultures
3rd function of prolactin
immunomodulation –
v PRLR on both B and T
cells and macrophages
v PRL acts as a mitogen and
promotes survival
v PRL receptors found in
most tissues
v acts synergistically with
many other hormones
ACTH is derived from and what other hormones are derived from this molecule and by what enzyme
ACTh and related peptides
Melanocyte stimulating hormones (MSH)
v Darkening of the skin
v Beta-endorphin - Morphine-like activity
v ACTH - Adrenal steroidogenesis
Molecular pathway of tanning
UV DNA damage – Local production of MSH by keratinocyte
v Stimulate melanocyte (also present in skin) to produce melanin
v Melanin transported back to keratinocyte to reduce UV damage (protective to keratinocyte)
v significance of MSH/endorphin production by human pituitary unclear
v MSH/endorphins produced by POMC neurons and used as
neurotransmitters in brain
Mechanism of action of ACTH
Binds to receptors in the adrenal gland
v Activate Gsα-protein
v Enhanced mobilization of cholesterol.
v Increased conversion of cholesterol to pregnenolone
Control of ACTH secretion
v Controlled by the hypothalamic hormone CRH
v CRH induced by stress (pain, fear, fever, hypoglycemia)
v Lowest around midnight, morning peak and then declines
v CRH action is potentiated by other hormones (vasopressin)
v Subject to feedback control by cortisol
Cortisol can give negative feedback to
Hypothalamus and pituitary
TSH , the other name is
Thyrotropin
Structure of TSH , where secreted
vSecreted by the thyrotrophs
vTwo protein chains (⍺ and β) Glycosylated.
vUnique β-chain; Common ⍺-chain with FSH/LH
Actions of TSH
vRegulator of thyroid gland. Receptor signaling via Gproteins
(cAMP).
vMajor factor controlling the formation of thyroid
hormones
vStimulates metabolism of thyroid follicular cells
Control pathway of release of thyrotropin
Actions of FSH in males and females
Females: Development of ovarian follicles and estradiol secretion
v Males: Spermatogenesis, production of sex-hormone binding
globulin
v Both sexes: Secretion of inhibin (negative feedback on FSH)
Actions of LH
Females: Steroidogenesis in follicles, induction of ovulation,
maintenance of steroidogenesis by the corpus luteum
v Males: Stimulation of testosterone production in the Leydig cells
How LH and FSH secreted (time)
LH and FSH secretion is pulsatile:
v about every 60 min in response to GnRH pulses
Pusle of gH and then pulse of LH , faithfully respond to eahc GH pulse
FSH is also regulated by GH, but in general, not as LH
the hypothalamo-pituitaru-gonadal axis in men
The hypothalamo-pituitary -gonadal axis in female
Most commonly disorders of pituitary are die to
Benign tumors (adenomas)
What are microadenomas and macroadenomas, temp of growing and from what cells they arise
Microadenomas < 10mm
Macroadenomas > 10mm
Typically slow growing
Arise from the
adenohypophyseal cells
Functional tumors are more common at ___ and how they are deleted
at younger age
surgical fixation through the nose
Most common adenomas are on what types of cell
prolactin
Tumors secreting PRL, GH or ACTH are most common.
Pituitary adenomas- signs and symptoms
Usually due to hypofunction, hyperfunction, or mass effect
v Impingement on optic chiasm – visual field defects
v Lateral extension to cavernous sinuses – diplopia (double
vision), ptosis (drooping eyelids), altered facial sensation
Gh deficiency: signs
decreased muscle strength and exercise
tolerance, diminished libido, increased body fat
Gonadotropin deficiency will result in what symptoms
oligo/amenorrhea, diminished
libido, infertility, hot flashes, impotence (clinically like
primary hypothyroidism)
ACTH deficiency : signs
malaise, fatigue, anorexia,
hypoglycemia
TSH deficiency : signs
malaise, leg cramps, fatigue, dry skin,
cold intolerance
Tumors may arise because
may arise de novo or because of the lack of
feed-back control
v Example: Cushing disease → primary defect in negative
feedback control of CRH and ACTH secretion by cortisol →
ACTH-producing cells are continuously stimulated by CRH →
tumor formation
Oversecretion of prolactin will lead to
what population is the most vulnerable
vProlactinoma: oligo/amenorrhea, galactorrhea,
infertility, *decreased libido, *headaches, *visual
field defects
v*often the presentation in men and postmenopausal
women
Growth hormone disorders
Gigantism , dwarfism, gigantism
Effects of GH-secreting tumors
How GH then is produced
How it is treated
Effects of GH-secreting tumors:
vGigantism and acromegaly
vGH produced at a high level without pulsatility.
vIGFs elevated as a consequence
vTreated with long-acting somatostatin analogues
vBest is surgical removal
Administration of Gh to dwarf child will lead to
Catch up of growth, but can be side effects
How GH disfunction is diagnosed, and what will bedone if there are already visual field defects
vUsually delayed due to non-specific nature of
many symptoms
vMRI is imaging
vTests can reveal whether adenoma is hypo- or
hyperfunctional
vVisual field defects often require resection of
pituitary gland
What lab tests are done for GH deficiency
insulin tolerance test, GHRH/arginine test,
IGF-1 levels
Lab tests for gonado tropins deficiencies
sexual history, menstrual
history, FSH/LH/estradiol/prolactin/testosterone
levels
ACTH deficiency lab tests
AM cortisol, cosyntropin test (ACTH)- Injecting acth and measuring aldosteron-> less functional adrenal glnad, because it shrinked due to hypofunction of ACTH,
insulin tolerance test
TSH -lab diagnosis of deficiency
T4 and TSH levels
Diagnosis of prolactonomia
prolactin level, drug history,
clinical setting (e.g. pregnancy, breast
stimulation, stress, hypoglycemia)
Acromegaly diagnosis in lab
IGF-1 level, oral glucose tolerance
test
TSH overproduction: lab diagnosis
free T4, T3, TSH levels
Treatment of over production diseases and what is the exception
and what is the treatment for deficiency states
vTypically requires surgical resection of adenoma
vException: prolactinoma in which 1st line
treatment is dopamine agonist therapy
vTreatment with bromocriptine: Binds and activates
dopamine receptors → inhibition of PRL secretion
vSomatostatin analogs are used for acromegaly
vDeficiency states require replacement of the
indicated hormone
What is posterior pituitary?
Hypothalamic nuclei with neurosecretory neurons
-Extend axons to posterior pituitary gland
What nuclei produce oxytocin and vasopressin
- Oxytocin (OT) - PVN
- Vasopressin/ADH - SON
Structure of posterior pituitary hormones
Nonapeptides - 9 AAs
v Formation of ring via disulfide
bridge (Between 1 and 6 th, ring structure in both hormones)
v Highly conserved amino acid
sequences
Pigs have lysine-vasopressin
v Structurally similar
function of oxytocin in 2 phrases
Contraction of smooth muscle cells:
vMyoepithelial cells of the alveoli
vSmooth muscle cells of the
uterus during labour
Function of ADH in 2 phrases
v H2O retention by the kidney
v Contraction of blood vessels
(arterioles)->
All that regulate blood pressure
receptors for ADH, their forms and role
Functions of vasopressin and how it is achieved
Function: regulation of water retention and thirst –
primary regulator of blood osmolality
Regulation of osmolality – involves osmostat in
hypothalamus
vControl/conservation of water
vRegulation of Na concentrations in plasma
vPressure-volume (involves baroreceptors)
Regulation of thirst
vInvolves renin-angiotensin system and aldosterone
How osmolality is detected in our body
Homeostatic repsonses to conserve sodium balance and water balance
How low blood pressure is corrected with vasopressin
molecular pathway how low blood pressure is corrected with vasopressin
In distal tubule
Name sections of nephron
Do you pee when you not drinking?
Replacement of water in the body
vUrine production can be minimized but cannot be
terminated
vInsensible water loss (Basal urine formation, as long as your blood pumps, even if you drink no water)
What is thirst, to what physiological changes it is the response, and do generally people meet their fluid requirement?
v Defense mechanism
v Triggered by changes in osmolality or volume
v Strongly triggered by hypovolemia and decrease
in blood pressure
v Generally people ingest excess fluid
Draw the strucutre , how vasopressin and thirst restore osmolality and blood volume
vasopressin and thirst during pregnancy
What happens to vasopressin and thirst with age ( in elderly)
v By age 80 total body water declines to as low as 50 % of adult
v decrease in kidney filtration rate
v collecting duct less responsive to Vasopressin
v decreased response to dehydration
v reduced ability to excrete water load
v elderly susceptible to both hypo and hypernatremia
What is diabetes insipidus
excretion of a large volume of urine (diabetes)
that is hypotonic, dilute and tasteless (insipid)
Causes of diabetes insipidus
lack of vasopressin (trauma, tumour etc)
v lack of response to vasopressin in kidney
v receptor defect or aquaporin defect
v Rapid metabolism of vasopressin
v Pregnancy i.e. transient diabetes insipidus
What is polydipsia
Polydipsia – ie. individual drinks too much
Leads to Polyurea
Where baroreceptors are found in the body
When arginine vasopressin is released what decrease in volume and pressure
8% decrease in volume
5% decrease in pressure
What is vasocontriction and vasodilation
How vasoconstriction and vasodilation can be caused
Where oxytocin is produced
Hypothalamus
Extrapituitary synthesis of oxytocin
vOvaries (corpus luteum) – involved in luteolysis
vUterus in some species
Oxytocin is regulated by what stimuli
Regulated by suckling stimuli
vClassical regulatory mechanism
Function of oxytocin
v Lactation - milk let-down
Oxytocin receptors
Contraction of myoepithelial
layer
v Secretion stimulated by
suckling or Tactile response
What is usual state of uterine myometrium and why and what happens to it closer to labor
Relaxed during pregnancy
vProgesterone (placenta/corpus luteum) and relaxin
(hormone from cervix)
vBecome responsive to oxytocin as parturition
approaches
Increased number of receptors
Formation of gap junctions (synchronous contraction)
For the labor oxytocin works in concert with
Prostaglandin F2a
How oxytocin may influence behevior?
Oxytocin receptor makes people monogamous
Reduced bonding , if knocked out oxytocin
Female bonding with new born and mate potential through oxytocin
