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

• 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 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

CREB=Cyclic AMP Response Element Binding Protein

CRE=Cyclic AMP Response Element

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 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 @ 1 adrenergic receptors

– Inhib input via• GABAergic neurons (impt prior to puberty)

• Some NPY neurons-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• Gq PLC pathway IP3-Ca, DAG-PKC-MAP kinase expression

of 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- subunit

– Downregulated when continuous (not pulsatile) GnRH

– Upregulated w/ high pulses GnRH

• FSH, LH– Glyocprot’s sim to TSH, hCG– Share common subunit– Hormone specific subunits

• FSH/LH subunit– Chromosome 6– Required for receptor binding– Expression controlled by sev hormones

• Coordinated w/ expression subunit genes

– In gonadotrophs, stim’d by• GnRH via DAG-PKC-MAP kinase pathway

– Inhib’d by • Estrogens

– Unaffected by thyroid hormones

• FSH subunit– Chromosome 11– Required for receptor specificity– Highest when low freq GnRH pulses received

by gonadotrophs• GnRH pulses @ higher freq suppression FSH

subunit• Continuous GnRH absolute inhib’n FSH

subunit

– Activins (sim to inhibins) incr’d FSH mRNA (autocrine)

• High GnRH pulses prod’n follistatin w/in pit• Follistatin binds activins prevent FSH-stim’ng

activity

• LH subunit– Chromosome 19 (homologous w/ hCG

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 subunit reg’n– Higher GnRH pulses upreg’n GnRH

receptors favors LH prod’n– Sertoli cell inhibin B inhib’n FSH @

gonadotrophs• Inhibin B stim’d by FSH

– Testosterone/DHT suppress FSH • 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)

• Emotional; hypoxia; hypercapnia• Decr’d bp; depl’n ECF vol• Infections (w/ incr’d IL 1)• 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, -LPH, -MSH

-MSH not physio active– w/ -LPH: -endorphin, met enkephalin (neurohormones)

• Proprotein convertase 3 catalyzes POMC ACTH + -LPH

– Cleaved -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

• 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

-MSH prod’d in– Human intermed ant pit in fetal life

– Skin keratinocytes w/ UVB eumelanin

– Monocytes – antiinflammatory

– Some neurons – appetite suppr’n, decr body temp