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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

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Endocrine Hypothalamus and Anterior Pituitary

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  1. Endocrine Hypothalamus and Anterior Pituitary Chapters 5 and 6

  2. 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

  3. Nonhypophysiotrophic functions • Thirst • Hunger/satiety • Thermoregulation • Regulatory systems of emotions (behavior) • Sex hormones assoc’d

  4. 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

  5. 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

  6. 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

  7. CRE=Cyclic AMP Response Element CREB=Cyclic AMP Response Element Binding Protein FOS=prot that regulates sev genes PIT1=Pituitary specific transcription factor

  8. 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

  9. 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

  10. 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

  11. 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

  12. 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

  13. 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

  14. 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)

  15. 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

  16. 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

  17. 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)

  18. 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

  19. 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

  20. 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

  21. 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

  22. 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

  23. 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)

  24. 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

  25. 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

  26. 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 1b) • Env. temp changes; fever • Ethanol consumption

  27. 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

  28. 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

  29. 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

  30. 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

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