Download Endocrine Hypothalamus and Anterior Pituitary

Endocrine Hypothalamus and
Anterior Pituitary
Chapters 5 and 6
Medial Basal Hypothalamus
• Hypophysiotropic
• Median eminence to suprachiasmatic region
• Parvocellular neurosecretory system
– CNS input via synaptic contact
– Synthesis of hypophysiotropic factors
– Release  hypophysial portal system
• Via neuronal impingement
• Peptide hormones
Nonhypophysiotrophic functions
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Thirst
Hunger/satiety
Thermoregulation
Regulatory systems of emotions (behavior)
Sex hormones assoc’d
Anterior Pituitary
• Embryonic origin
– Through roof of mouth
– Differs from post pit
• 2 lobes of 3 regions
• Pars distalis
– Posteriolateral – gonadotrophs, somatotrophs
– Anteriomedial – corticotrophs, thyrotrophs
• Pars intermedia – melanotrophs
– Fetal humans, lower animals
• Lactotrophs throughout
Pituitary Hormones
• Hypophysiotropic hormones
– GHRH, SST (GHIH), TRH, PIH (da), GnRH,
CRH
• Three main families of anterior pituitary
hormones
– Proopiomelanocortin (POMC)  ACTH, MSH
– Glycoproteins sharing common a subunit:
TSH, FSH, LH
– Somatomammotropic (lactogenic): GH, PRL
Growth Hormone Releasing
Hormone  Growth Hormone
• GHRH: 44 aa, simple peptide (Fig 6.8)
– First 29 residues highly conserved
– Expressed in arcuate and ventromedial nuclei
• Target cells: ant pit somatotrophs
– Heptahelical G-prot coupled receptor
– Stim’n ad cyclase
• PKA through act’n plasma Ca channels
• PLC through IP3, incr’d intracell Ca
–  Synth GH + discharge stored GH
– Cortisol, thyroid hormones required
CRE=Cyclic AMP Response Element
CREB=Cyclic AMP Response Element Binding Protein
FOS=prot that regulates sev genes
PIT1=Pituitary specific transcription factor
• Amt GH discharged
– Amt GHRH
– Somatotroph GHRH receptor status
– Amt stored GH
• Episodic GHRH  episodic GH release
• Termination GH burst w/ negative feedback
on brain neurons
– Neurons prod SST
– Somatotrophs have SST receptors
• Cortisol  GHRH receptor expression +
GH expression
Somatostatin  Inhib’n GH
Release
• SST, GHIH
• 14 aa’s; 2 cys  intrachain disulfide bond
cyclization
• SRIF gene on chromosome 3  116 aa
preproSRIF
• Convertase  14 aa brain peptide
– Also pancreas, gi tract SST’s
• SRIF’s
– Heptahelical receptors
– G-prot coupled
– Inhibit ad cyclase
• Somatotrophs: turn off GH secr’n
• Widespread effects
– Inhibits calcitonin, PTH, renin, gastric HCl,
ACh, adrenergic neurotransmitters
– Lowers serum [glucose]
– TRH antagonist
– Antagonizes messengers impt to cell prolif’n
Thyrotropin Releasing Hormone
 Thyroid Stimulating Hormone
• Gene for TRH on chromosome 3
– Inhib’n expression by glucocorticoids
• Precursor prot; posttranslational cleavage
– 255 aa’s
– TRH tripeptide duplicated 5 times in seq (Fig
6.6)
• Most impt regulator of synth TRH=thyroid
hormones (T3 > T4)
– Long-loop neg feedback
• Episodic secr’n  portal system
–  Circadian rhythm of TSH secr’n
– Stim’d by a adrenergic receptor agonists
– Inhib’d by da agonists, endorphins, SST
• Target cells: ant pit thyrotrophs
– Heptahelical receptor
– Coupled to G prot
– Activates IP3 pathway
• PLC and PKC activity
–  Synth, secr’n TSH
• Gene for TRH receptor on chromosome 8
• TRH cleaved by membr-bound enz
– Synth enz controlled by ant pit
– Regulates signal strength (w/ receptor control)
• TRH found in most vertebrates
– Can  PRL release
– Not restricted to CNS in lower animals
Prolactin Inhibiting Hormone
• Basal PRL release unless interrupted w/
hypothal signal
• PIH=dopamine (da)
– Also prod’d by tuberoinfundibular,
tuberohypophyseal da neurons
• Da receptor (D2)
Signals to Advance PRL Synth
• Estrogens stim PRL gene expression
– Inhibit tuberohypophyseal DA neurons
– Induce lactotroph hyperplasia
• TRH stim’s PRL secr’n
– Not physio release factor during lactation
• Oxytocin stim’s PRL secr’n (?)
• Angiotensin II stim’s PRL secr’n
• Prolactin Releasing Hormone??
– VIP (from GHRH family) stim’s PRL secr’n in
vitro
• Acts through ad cyclase
• Prod’d by lactotrophs (autocrine?)
• Serotonin, adrenaline stim PRL secr’n
• Histamine may inhibit PRL via H2
receptors
Gonadotropin Releasing
Hormone  FSH, LH
• Mammalian decapeptide; well conserved
– Chromosome 8p21-8p11.2
• GnRH neurons
– Human dev in olfactory placode
• Migrate via olfactory bulb guided by anosmin (neural cell
adhesion mol)
• Anosmin also reg’s migration olfactory epith (incl those
from vomeronasal organ)
• GnRH neurons (cont’d)
– Intrinsic rhythmic activity  pulsatile release
– Stim input via
• Neuropeptide Y
• Noradrenergic neurons @ a1 adrenergic receptors
– Inhib input via
• GABAergic neurons (impt prior to puberty)
• Some NPY neurons
 b-endorphin neurons
– Implicated in stress; negative feedback of androgens, progesterone
• Dopaminergic neurons
• GnRH target cells: gonadotrophs
• GnRH receptors
– Encoded by chromosome 4q13.2-13.3
– Contains response elements that regulate its
expression
• For glucocorticoid, progesterone, thyroid hormones,
CREB
– G-prot linked heptahelical transmembr
• Gaq  PLC pathway
•  IP3-Ca, DAG-PKC-MAP kinase  expression of
a subunit common to FSH/LH
• GnRH receptors (cont’d)
– Also  opening of voltage gated Ca channels 
Ca influx
• Impt to release gonadotropins
•  selective expression LH-b subunit
– Downregulated when continuous (not pulsatile)
GnRH
– Upregulated w/ high pulses GnRH
• FSH, LH
– Glyocprot’s sim to TSH, hCG
– Share common a subunit
– Hormone specific b subunits
• FSH/LH a subunit
– Chromosome 6
– Required for receptor binding
– Expression controlled by sev hormones
• Coordinated w/ expression b subunit genes
– In gonadotrophs, stim’d by
• GnRH via DAG-PKC-MAP kinase pathway
– Inhib’d by
• Estrogens
– Unaffected by thyroid hormones
• FSH b subunit
– Chromosome 11
– Required for receptor specificity
– Highest when low freq GnRH pulses received
by gonadotrophs
• GnRH pulses @ higher freq  suppression FSH b
subunit
• Continuous GnRH  absolute inhib’n FSH b
subunit
– Activins (sim to inhibins)  incr’d FSH b
mRNA (autocrine)
• High GnRH pulses  prod’n follistatin w/in pit
• Follistatin binds activins  prevent FSH-stim’ng
activity
• LH b subunit
– Chromosome 19 (homologous w/ hCG b
subunit genes)
– Required for receptor specificity
– Stim’d w/
• GnRH applied @ higher freq’s, amp’s
– Suppressed w/
• Androgens (male), progesterone (female) inhib freq
GnRH pulses
• Estrogens (directly @ pit)
• Testosterone  estradiol in pit (via aromatase)
• FSHH/LH b subunit reg’n
– Higher GnRH pulses  upreg’n GnRH
receptors  favors LH b prod’n
– Sertoli cell inhibin B  inhib’n FSH b @
gonadotrophs
• Inhibin B stim’d by FSH
– Testosterone/DHT suppress FSH b
• Via gonadotroph androgen receptors
• FSH/LH secr’n pulsatile
– LH high amp fluctuations
– FSH rel stable amp’s
Corticotropin Releasing Hormone 
ACTH
• 41 aa’s; highly conserved
• Synth’d in parvocellular region of hypothal
paraventricular nucleus
– Sensitive to glucocorticoids (neg feedback)
– Coexpress AVP
• Widely expressed in CNS
– Mediate stress-related psych’l anxiety
– Overprod’n or incr’d CRH
• In csf correlates w/ major depression, anorexia nervosa
• Mediates sleep/appetite disturbances of depression
• CRH outside CNS
– May be proinflamm signal
• Stim’s synth PG’s
– From placenta, parturition initiation
• Induction release w/ central catecholamines
into portal cap plexus
– Probably w/ stress
– Stress  ACTH release (through CRH)
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Emotional; hypoxia; hypercapnia
Decr’d bp; depl’n ECF vol
Infections (w/ incr’d IL 1b)
Env. temp changes; fever
Ethanol consumption
• CRH has binding prot (CRH-BP)
– CRH “sink”
• Assoc’d w/ membr’s near CRH brain target cells
• Another form secr’d by liver, placenta
• Target cells: corticotrophs
• Two CRH receptors (CRH ligand of
CRH1R)
– G-prot coupled heptahelical receptors
– Binding  ad cyclase   synth, release
ACTH
– Neg feedback control by cortisol
• Glucocorticoids suppress CRH1R mRNA
• ACTH
– Synth’d in pars distalis
– Precursor = POMC (proopiomelanocortin)
• 241 aa’s
• Holds ACTH, b-LPH, b-MSH
 b-MSH not physio active
– w/ b-LPH: b-endorphin, met enkephalin (neurohormones)
• Proprotein convertase 3 catalyzes POMC  ACTH
+ b-LPH
– Cleaved  a-MSH in pars distalis
• Sim seq’s
• ACTH melanotropic activity
– Circadian adrenocortical rhythm
• ACTH (cont’d)
– Smallest ant pit peptide hormone
• 39 aa chain; highly conserved
– Bio activity in invariant 1-24 aa N-terminal seq
– Syth, secr’n stim’d
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CRH
ADH (AVP)
CCK (sometimes)
ACh  CNS cholinergic structures  ACTH
release)
– Suppr’d
• Glucocorticoids
– Hypothal membr receptor non-genomic mech, then @ ant
pit
• CRH-BP
• ACTH (cont’d)
– Target = adrenal steroidogenic tissue
• Stim’s glucocort biosynth
– Cortisol, corticosterone
– Impt in carb metab
– Glucocort’s feedback inhibit @ hypothal, ant pit
a-MSH prod’d in
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Human intermed ant pit in fetal life
Skin keratinocytes w/ UVB  eumelanin
Monocytes – antiinflammatory
Some neurons – appetite suppr’n, decr body temp