Author(s): Arno Kumagai, M.D., Robert Lash, M.D., 2009License: Unless otherwise noted, this material is made available und...
Citation Key                            for more information see: http://open.umich.edu/wiki/CitationPolicyUse + Share + A...
M2 Endocrine Sequence              University of Michigan Medical School                          Directors:              ...
General Information•    Syllabus and Lecture notes•    Required Sessions:     •    Patient presentation: Friday, March 6th...
Feedback loops and                anterior pituitary physiology                     M2- Endocrine Sequence                ...
Optic chiasm                           10 mmAnterior                                          Posterior                   ...
Source Undetermined
Pituitary cell types    Pituitary cell           Pituitary     Clinical syndrome        type                 hormone      ...
Hormonal Feedback Loops
You                  (-)                    (+)   (-)Your thermostat                  (+)  Your furnace R. Lash
Hypothalamus                (-)                    (+)      Pituitary           (-)                  (+)   End organ R. Lash
Adrenal axis                            (-)           CRH                            ACTH           ±AVP                  ...
Hypothalamic-Pituitary-Adrenal Axis                                                CRH = Corticotropin                    ...
Hypothalamic-Pituitary-Adrenal Axis                                                ACTH = Corticotropin                   ...
Post-translational Processing of POMC in theNormal Pituitary       POMC = Pro-opiomelanocortin                            ...
Growthhormone axis           GHRH           GH   (-)     SRIF                      (+)        (-)                         ...
Growth hormone axis                                                 GH ReleasingGHRH              GH(-)     SRIF          ...
Growth hormone axis                                                 Somatostatin (SRIF)                                   ...
Growth hormone - prolactin family •    Significant homology, less so at the protein      level (16%) •    Prl & GH both ac...
Prolactin axis                          Prl       (-)                      Dopamine                  PRF                  ...
Regulation of prolactin = tonically inhibited  !  Prolactin-inhibiting                factors (PIFs)     "    Dopamine, Do...
Thyroid axis           TRH                     SRIF                       (+)   (-)                                       ...
Thyroid axis                           T4 # T3           TRH                        SRIF                       (+)      (-...
Hypothalamic-Pituitary-Thyroid Axis                    T4 # T3                                                    TRH = Th...
The TRH Tripeptide                       O              O                       C   NH   CH    C    NO                N   ...
Hypothalamic-Pituitary-Thyroid Axis                    T4 # T3                                                    TSH = Th...
Thyroid stimulating hormone (TSH) is part  of a family of glycoprotein hormones !  Composed  of noncovalently bound   ! an...
Glycoprotein hormone family                        TSH-"                        FSH-"#       !-subunit            92 aa   ...
Hypothalamic-Pituitary-Gonadal Axis          GnRHO                                  Testo   (-)                       (+) ...
Hypothalamic-Pituitary-Gonadal Axis                         T#E2          GnRHO                                     Testo ...
Hypothalamic-Pituitary-Gonadal AxisO               T#E2        GnRH         •    GnRH = Gonadotropin                      ...
Gonadotropin releasing hormone(GnRH)  !  Pulsatility   and pulse frequency are critical  !  Pulsatile             infusion...
Hypothalamic-Pituitary-Gonadal Axis O            GnRH                        (+)                                       Est...
You                   (-)                    (+)   (-)    Your stereo                  (+)Your roommateR. Lash
Positive feedback loop          You                 (+) That special         (+)  someoneR. Lash
You     (?)                       (?)                             (?)   (?)   That special    someoneSpecial someone s    ...
Female gonadal axis(negative feedback)             GnRH                        (+)            Estrogen                    ...
Female gonadal axis (Positive feedback  during ovulation)             GnRH                        (+)   Estrogen          ...
Let s review the major players    Hypothalamic             Pituitary           Effect of   releasing factor          hormo...
Rhythms in endocrinology  !  Circadian         rhythms    "    Occur over the course of a day, and repeat daily    "    Ch...
Pulsatility in the reproductive axis  !  GnRH    "    Pulsatile infusion at 90 minute intervals can induce ovulation in wo...
Frequency of administration determines                effect of PTH on bone cellsTrabecular Bone Perimeter %              ...
Things to remember if you re just wakingup  !    Generally, hypothalamic hormones       stimulate pituitary hormone releas...
Things to remember if you re just wakingup  !  Pituitary      hormones fall into three groups    "    Glycoprotein hormone...
Additional Source Information                                for more information see: http://open.umich.edu/wiki/Citation...
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02.25.09: Introduction to Pituitary Physiology

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02.25.09: Introduction to Pituitary Physiology

  1. 1. Author(s): Arno Kumagai, M.D., Robert Lash, M.D., 2009License: Unless otherwise noted, this material is made available under the terms of theCreative Commons Attribution–Noncommercial–Share Alike 3.0 License:http://creativecommons.org/licenses/by-nc-sa/3.0/We have reviewed this material in accordance with U.S. Copyright Law and have tried to maximize your ability to use, share, andadapt it. The citation key on the following slide provides information about how you may share and adapt this material.Copyright holders of content included in this material should contact open.michigan@umich.edu with any questions, corrections, orclarification regarding the use of content.For more information about how to cite these materials visit http://open.umich.edu/education/about/terms-of-use.Any medical information in this material is intended to inform and educate and is not a tool for self-diagnosis or a replacement formedical evaluation, advice, diagnosis or treatment by a healthcare professional. Please speak to your physician if you have questions aboutyour medical condition.Viewer discretion is advised: Some medical content is graphic and may not be suitable for all viewers.
  2. 2. Citation Key for more information see: http://open.umich.edu/wiki/CitationPolicyUse + Share + Adapt { Content the copyright holder, author, or law permits you to use, share and adapt. } Public Domain – Government: Works that are produced by the U.S. Government. (17 USC § 105) Public Domain – Expired: Works that are no longer protected due to an expired copyright term. Public Domain – Self Dedicated: Works that a copyright holder has dedicated to the public domain. Creative Commons – Zero Waiver Creative Commons – Attribution License Creative Commons – Attribution Share Alike License Creative Commons – Attribution Noncommercial License Creative Commons – Attribution Noncommercial Share Alike License GNU – Free Documentation LicenseMake Your Own Assessment { Content Open.Michigan believes can be used, shared, and adapted because it is ineligible for copyright. } Public Domain – Ineligible: Works that are ineligible for copyright protection in the U.S. (17 USC § 102(b)) *laws in your jurisdiction may differ { Content Open.Michigan has used under a Fair Use determination. } Fair Use: Use of works that is determined to be Fair consistent with the U.S. Copyright Act. (17 USC § 107) *laws in your jurisdiction may differ Our determination DOES NOT mean that all uses of this 3rd-party content are Fair Uses and we DO NOT guarantee that your use of the content is Fair. To use this content you should do your own independent analysis to determine whether or not your use will be Fair.
  3. 3. M2 Endocrine Sequence University of Michigan Medical School Directors: Arno K. Kumagai, M.D. Thomas Giordano, M.D., Ph.D.Winter 2009
  4. 4. General Information•  Syllabus and Lecture notes•  Required Sessions: •  Patient presentation: Friday, March 6th •  Endocrine Small Groups: Thurs-Fri, March 5-6th •  Longitudinal Case•  Endocrine Photo Gallery
  5. 5. Feedback loops and anterior pituitary physiology M2- Endocrine Sequence Arno K. Kumagai, M.D. Division of Metabolism, Endocrinology & DiabetesWinter 2009
  6. 6. Optic chiasm 10 mmAnterior Posterior Pituitary Bright Spot Posterior pituitary Anterior pituitary Source Undetermined
  7. 7. Source Undetermined
  8. 8. Pituitary cell types Pituitary cell Pituitary Clinical syndrome type hormone associated w/ tumor Corticotrope ACTH Cushingʼs disease Somatotrope GH Acromegaly Gonadotrope FSH and LH None Lactotrope Prl Prolactinoma Thyrotrope TSH Hyperthyroidism Source Undetermined
  9. 9. Hormonal Feedback Loops
  10. 10. You (-) (+) (-)Your thermostat (+) Your furnace R. Lash
  11. 11. Hypothalamus (-) (+) Pituitary (-) (+) End organ R. Lash
  12. 12. Adrenal axis (-) CRH ACTH ±AVP (+) (-) Cortisol ACTH (-) (+) R. Lash
  13. 13. Hypothalamic-Pituitary-Adrenal Axis CRH = Corticotropin (-) Releasing HormoneCRH±AVP ACTH •  41 amino acids (+) long (-) Cortisol •  Ovine form is more potent than ACTH (-) human form •  A trophic factor (+) and a releasing hormone R. Lash
  14. 14. Hypothalamic-Pituitary-Adrenal Axis ACTH = Corticotropin (-) •  Derived from a largeCRH molecule (POMC) ACTH±AVP (+) •  39 amino acids long, (-) first 24 are the same Cortisol in multiple species !  Synthetic ACTH (aa ACTH (-) 1-24) used clinically •  250 µg in the pituitary - about 50 µg (+) secreted daily R. Lash
  15. 15. Post-translational Processing of POMC in theNormal Pituitary POMC = Pro-opiomelanocortin ACTH Source Undetermined MSH = Melanocyte stimulating hormone
  16. 16. Growthhormone axis GHRH GH (-) SRIF (+) (-) (-) IGF-I GH (-) (+) R. Lash
  17. 17. Growth hormone axis GH ReleasingGHRH GH(-) SRIF Hormone (GHRH) (+) (-) •  About 44 amino (-) acids long IGF-I •  Discovered in GH (-) pancreatic tumors •  Men over 40 have little response to (+) GHRH R. Lash
  18. 18. Growth hormone axis Somatostatin (SRIF) •  Inhibits secretionGHRH GH(-) SRIF of GH and TSH (+) (-) •  Also inhibits GI (-) hormones and IGF-I functions GH (-) •  Octreotide is a clinically useful analogue (+) R. Lash
  19. 19. Growth hormone - prolactin family •  Significant homology, less so at the protein level (16%) •  Prl & GH both activate the prolactin receptor •  Family also includes placental lactogen (PL)
  20. 20. Prolactin axis Prl (-) Dopamine PRF (-) (+) NeuralStimulus (+) Prl (+) IMPORTANT Prolactin release is tonically inhibited by DOPAMINE Janine Chedid, Wikimedia Commons R. Lash
  21. 21. Regulation of prolactin = tonically inhibited !  Prolactin-inhibiting factors (PIFs) "  Dopamine, Dopamine, Dopamine, maybe GABA "  Bromocriptine is a dopamine agonist "  Block multiple aspects of lactotrope function !  Prolactin-releasing factors (PRFs) "  TRH - but probably not physiologically important "  Other candidates: AVP, VIP, Oxytocin, PHI-27
  22. 22. Thyroid axis TRH SRIF (+) (-) (-) T3/T4 TSH (-) (+) R. Lash
  23. 23. Thyroid axis T4 # T3 TRH SRIF (+) (-) (-) T4#T3 T3/T4 TSH (-) (+) R. Lash
  24. 24. Hypothalamic-Pituitary-Thyroid Axis T4 # T3 TRH = Thyrotropin Releasing HormoneTRH SRIF •  Tripeptide (3 amino (+) (-) acids) (-) •  Also a potent T4#T3 stimulator of T3/T4 prolactin release TSH (-) •  Synthesized as a prohormone with six copies of the TRH (+) molecule R. Lash
  25. 25. The TRH Tripeptide O O C NH CH C NO N CH2 C O NH2 N N HSource Undetermined
  26. 26. Hypothalamic-Pituitary-Thyroid Axis T4 # T3 TSH = Thyroid Stimulating HormoneTRH SRIF •  AKA Thyrotropin (+) (-) •  Binds to receptors on (-) T4#T3 thyroid to stimulate T3/T4 synthesis and release TSH (-) of thyroid hormones T4 (and some T3). •  Part of a glycoprotein (+) hormone family R. Lash
  27. 27. Thyroid stimulating hormone (TSH) is part of a family of glycoprotein hormones !  Composed of noncovalently bound ! and " subunits !  Both subunits are glycosylated !  ! subunit is common !  "subunits are unique - confer biologic and immunologic specificity
  28. 28. Glycoprotein hormone family TSH-" FSH-"# !-subunit 92 aa LH-"# CG-"# 112-147 aa R. Lash
  29. 29. Hypothalamic-Pituitary-Gonadal Axis GnRHO Testo (-) (+) (LH) LH & (-) Inhibin FSH (FSH) (+)R. Lash
  30. 30. Hypothalamic-Pituitary-Gonadal Axis T#E2 GnRHO Testo (-) (+) (LH) LH & (-) Inhibin FSH (FSH) (+)R. Lash
  31. 31. Hypothalamic-Pituitary-Gonadal AxisO T#E2 GnRH •  GnRH = Gonadotropin Releasing Hormone Testo (-) (+) (LH) •  10 amino acids in lengthLH & (-) Inhibin •  GnRH # LH & FSHFSH (FSH) # Sex steroids •  Regulates both LH (+) and FSH R. Lash
  32. 32. Gonadotropin releasing hormone(GnRH) !  Pulsatility and pulse frequency are critical !  Pulsatile infusion stimulates LH and FSH secretion !  Constant infusion inhibits LH and FSH secretion !  GnRH can be used to induce fertility and suppress gonadal function
  33. 33. Hypothalamic-Pituitary-Gonadal Axis O GnRH (+) Estrogen (±) LH & (-) InhibinThis is where FSH (FSH) things getcomplicated… (+) R. Lash
  34. 34. You (-) (+) (-) Your stereo (+)Your roommateR. Lash
  35. 35. Positive feedback loop You (+) That special (+) someoneR. Lash
  36. 36. You (?) (?) (?) (?) That special someoneSpecial someone s (?) significant other (?) R. Lash
  37. 37. Female gonadal axis(negative feedback) GnRH (+) Estrogen (±) LH & (-) Inhibin FSH (FSH) (+) R. Lash
  38. 38. Female gonadal axis (Positive feedback during ovulation) GnRH (+) Estrogen (+) LH & FSH (+) R. Lash
  39. 39. Let s review the major players Hypothalamic Pituitary Effect of releasing factor hormone hypothalamic factor TRH TSH (and Prl) Stimulatory CRH ACTH Stimulatory GHRH GH Stimulatory Somatostatin (SRIF) GH and TSH Inhibitory Dopamine Prl Inhibitory GnRH FSH and LH Stimulatory Source Undetermined
  40. 40. Rhythms in endocrinology !  Circadian rhythms "  Occur over the course of a day, and repeat daily "  Characteristic of most endocrine functions "  Examples: Cortisol secretion !  Ultradian rhythms "  Bursts (spikes) of hormone secretion "  Can be superimposed on circadian rhythms "  Physiologically important, particularly in reproduction
  41. 41. Pulsatility in the reproductive axis !  GnRH "  Pulsatile infusion at 90 minute intervals can induce ovulation in women with hypothalamic disease "  Continuous infusion is used to suppress LH/FSH in preparation for in vitro fertilization !  LH and FSH "  Puberty is associated with pulses of greater frequency and amplitude
  42. 42. Frequency of administration determines effect of PTH on bone cellsTrabecular Bone Perimeter % 35 Vehicle † 30 SC 1 h/day 25 2 h/day ‡ Continuous 20 * 15 10 5 0 Osteoblast Osteoclast P<0.05, †P<0.01, ‡P<0.001 vs VehicleDobnig and Turner. Endocrinology 1997;138:4607-4612
  43. 43. Things to remember if you re just wakingup !  Generally, hypothalamic hormones stimulate pituitary hormone release !  Prolactin regulation, in contrast, is primarily inhibitory !  The inhibitory hypothalamic factors worth remembering are somatostatin and dopamine
  44. 44. Things to remember if you re just wakingup !  Pituitary hormones fall into three groups "  Glycoprotein hormones (TSH, LH, and FSH) "  ACTH "  Growth hormone and prolactin !  Negative feedback is the usual state of affairs, but not the only one !  Hormone activity depends on both the quantity present, and its mode of release
  45. 45. Additional Source Information for more information see: http://open.umich.edu/wiki/CitationPolicySlide 6: Source UndeterminedSlide 7: Source UndeterminedSlide 8: Source UndeterminedSlide 10: Robert LashSlide 11: Robert LashSlide 12: Robert LashSlide 13: Robert LashSlide 14: Robert LashSlide 15: Source UndeterminedSlide 16: Robert LashSlide 17: Robert LashSlide 18: Robert LashSlide 20: Robert Lash; GFDL, Janine Chedid, Wikimedia Commons, http://en.wikipedia.org/wiki/GNU_Free_Documentation_LicenseSlide 22: Robert LashSlide 23: Robert LashSlide 24: Robert LashSlide 25: Source UndeterminedSlide 26: Robert LashSlide 28: Robert LashSlide 29: Robert LashSlide 30: Robert LashSlide 31: Robert LashSlide 33: Robert LashSlide 34: Robert LashSlide 35: Robert LashSlide 36: Robert LashSlide 37: Robert LashSlide 38: Robert LashSlide 39: Source UndeterminedSlide 42: Dobnig and Turner. Endocrinology 1997;138:4607-4612

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