Endocrine Hypothalamus and Anterior Pituitary Chapters 5 and

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), Gn. RH, 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 IP 3, 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 PIT 1=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 prepro. SRIF • 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 (T 3 > T 4) – 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 IP 3 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 (D 2)

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 H 2 receptors

Gonadotropin Releasing Hormone FSH, LH • Mammalian decapeptide; well conserved – Chromosome 8 p 21 -8 p 11. 2 • Gn. RH 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)

• Gn. RH neurons (cont’d) – Intrinsic rhythmic activity pulsatile release – Stim input via • Neuropeptide Y • Noradrenergic neurons @ a 1 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

• Gn. RH target cells: gonadotrophs • Gn. RH receptors – Encoded by chromosome 4 q 13. 2 -13. 3 – Contains response elements that regulate its expression • For glucocorticoid, progesterone, thyroid hormones, CREB – G-prot linked heptahelical transmembr • Gaq PLC pathway • IP 3 -Ca, DAG-PKC-MAP kinase expression of a subunit common to FSH/LH

• Gn. RH 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) Gn. RH – Upregulated w/ high pulses Gn. RH • FSH, LH – Glyocprot’s sim to TSH, h. CG – 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 • Gn. RH 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 Gn. RH pulses received by gonadotrophs • Gn. RH pulses @ higher freq suppression FSH b subunit • Continuous Gn. RH absolute inhib’n FSH b subunit – Activins (sim to inhibins) incr’d FSH b m. RNA (autocrine) • High Gn. RH pulses prod’n follistatin w/in pit • Follistatin binds activins prevent FSH-stim’ng activity

• LH b subunit – Chromosome 19 (homologous w/ h. CG b subunit genes) – Required for receptor specificity – Stim’d w/ • Gn. RH applied @ higher freq’s, amp’s – Suppressed w/ • Androgens (male), progesterone (female) inhib freq Gn. RH pulses • Estrogens (directly @ pit) • Testosterone estradiol in pit (via aromatase)

• FSHH/LH b subunit reg’n – Higher Gn. RH pulses upreg’n Gn. RH 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) • • • Emotional; hypoxia; hypercapnia Decr’d bp; depl’n ECF vol Infections (w/ incr’d IL 1 b) 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 CRH 1 R) – G-prot coupled heptahelical receptors – Binding ad cyclase synth, release ACTH – Neg feedback control by cortisol • Glucocorticoids suppress CRH 1 R m. RNA

• 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 • • 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 – – Human intermed ant pit in fetal life Skin keratinocytes w/ UVB eumelanin Monocytes – antiinflammatory Some neurons – appetite suppr’n, decr body temp