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Author(s): Arno Kumagai, M.D., Robert Lash, M.D., 2009 License: Unless otherwise noted, this material is made available under the terms of the Creative.

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Presentation on theme: "Author(s): Arno Kumagai, M.D., Robert Lash, M.D., 2009 License: Unless otherwise noted, this material is made available under the terms of the Creative."— Presentation transcript:

1 Author(s): Arno Kumagai, M.D., Robert Lash, M.D., 2009 License: Unless otherwise noted, this material is made available under the terms of the Creative 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, and adapt 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, or clarification 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 for medical evaluation, advice, diagnosis or treatment by a healthcare professional. Please speak to your physician if you have questions about your medical condition. Viewer discretion is advised: Some medical content is graphic and may not be suitable for all viewers.

2 Citation Key for more information see: http://open.umich.edu/wiki/CitationPolicy Use + Share + Adapt Make Your Own Assessment 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 License Creative Commons – Zero Waiver Public Domain – Ineligible: Works that are ineligible for copyright protection in the U.S. (17 USC § 102(b)) *laws in your jurisdiction may differ Public Domain – Expired: Works that are no longer protected due to an expired copyright term. Public Domain – Government: Works that are produced by the U.S. Government. (17 USC § 105) Public Domain – Self Dedicated: Works that a copyright holder has dedicated to the public domain. 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. { Content the copyright holder, author, or law permits you to use, share and adapt. } { Content Open.Michigan believes can be used, shared, and adapted because it is ineligible for copyright. } { Content Open.Michigan has used under a Fair Use determination. }

3 M2 Endocrine Sequence University of Michigan Medical School Directors: Arno K. Kumagai, M.D. Thomas Giordano, M.D., Ph.D. Winter 2009

4 General Information Syllabus and Lecture notes Required Sessions: Patient presentation: Friday, March 6 th Endocrine Small Groups: Thurs-Fri, March 5-6 th Longitudinal Case Endocrine Photo Gallery

5 Feedback loops and anterior pituitary physiology M2- Endocrine Sequence Arno K. Kumagai, M.D. Division of Metabolism, Endocrinology & Diabetes Winter 2009

6 AnteriorPosterior Optic chiasm Anterior pituitary Posterior pituitary 10 mm Pituitary Bright Spot Source Undetermined

7

8 Pituitary cell types Source Undetermined

9 Hormonal Feedback Loops Source Undetermined

10 You Your thermostat Your furnace (+) (-) Source Undetermined R. Lash

11 Hypothalamus Pituitary End organ (+) (-) R. Lash

12 (+) (-) CRH  AVP ACTH (-) ACTH Cortisol Adrenal axis R. Lash

13 (+) (-) CRH  AVP ACTH (-) ACTH Cortisol Hypothalamic-Pituitary-Adrenal Axis CRH = Corticotropin Releasing Hormone 41 amino acids long Ovine form is more potent than human form A trophic factor and a releasing hormone R. Lash

14 (+) (-) CRH  AVP ACTH (-) ACTH Cortisol Hypothalamic-Pituitary-Adrenal Axis ACTH = Corticotropin Derived from a large molecule (POMC) 39 amino acids long, first 24 are the same in multiple species Synthetic ACTH (aa 1- 24) used clinically 250  g in the pituitary - about 50  g secreted daily R. Lash

15 Post-translational Processing of POMC in the Normal Pituitary POMC = Pro-opiomelanocortin ACTH MSH = Melanocyte stimulating hormone Source Undetermined

16 Growth hormone axis (+) (-) GHRH GH (-) SRIF IGF-I GH (-) R. Lash

17 Growth hormone axis (+) (-) GHRH GH (-) SRIF IGF-I GH (-) GH Releasing Hormone (GHRH) About 44 amino acids long Discovered in pancreatic tumors Men over 40 have little response to GHRH R. Lash

18 Growth hormone axis (+) (-) GHRH GH (-) SRIF IGF-I GH (-) Somatostatin (SRIF) Inhibits secretion of GH and TSH Also inhibits GI hormones and functions Octreotide is a clinically useful analogue R. Lash

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 (+) ‘PRF’ Prl (-) Dopamine Neural Stimulus Prolactin axis Prl (-) IMPORTANT Prolactin release is tonically inhibited by DOPAMINE Janine Chedid, Wikimedia Commons R. Lash

21 Regulation of prolactin = tonically inhibited n Prolactin-inhibiting factors (PIFs) l Dopamine, Dopamine, Dopamine, maybe GABA l Bromocriptine is a dopamine agonist l Block multiple aspects of lactotrope function n Prolactin-releasing factors (PRFs) l TRH - but probably not physiologically important l Other candidates: AVP, VIP, Oxytocin, PHI-27

22 (+) (-) TRH TSH (-) SRIF T 3 /T 4 Thyroid axis R. Lash

23 (+) (-) TRH TSH (-) SRIF T 3 /T 4 Thyroid axis T4T3T4T3 T 4  T 3 R. Lash

24 Hypothalamic-Pituitary-Thyroid Axis (+) (-) TRH TSH (-) SRIF T 3 /T 4 T4T3T4T3 T 4  T 3 TRH = Thyrotropin Releasing Hormone Tripeptide (3 amino acids) Also a potent stimulator of prolactin release Synthesized as a prohormone with six copies of the TRH molecule R. Lash

25 N CH 2 CH NH O C O N N H C O N C O NH 2 The TRH Tripeptide Source Undetermined

26 Hypothalamic-Pituitary-Thyroid Axis (+) (-) TRH TSH (-) SRIF T 3 /T 4 T4T3T4T3 T 4  T 3 TSH = Thyroid Stimulating Hormone AKA “Thyrotropin” Binds to receptors on thyroid to stimulate synthesis and release of thyroid hormones T4 (and some T3). Part of a glycoprotein hormone family R. Lash

27 Thyroid stimulating hormone (TSH) is part of a family of glycoprotein hormones Composed of noncovalently bound  and  subunits n Both subunits are glycosylated  subunit is common  subunits are unique - confer biologic and immunologic specificity

28 Glycoprotein hormone family  -subunit LH-  FSH-  TSH-  CG-  92 aa 112-147 aa R. Lash

29 GnRH (+) (-) LH & FSH Testo (LH) Inhibin (FSH) Hypothalamic-Pituitary-Gonadal Axis O R. Lash

30 GnRH (+) (-) LH & FSH Testo (LH) Inhibin (FSH) Hypothalamic-Pituitary-Gonadal Axis O T  E2 R. Lash

31 GnRH Hypothalamic-Pituitary-Gonadal Axis GnRH = Gonadotropin Releasing Hormone 10 amino acids in length GnRH  LH & FSH  Sex steroids Regulates both LH and FSH O (+) (-) LH & FSH Testo (LH) Inhibin (FSH) T  E2 R. Lash

32 Gonadotropin releasing hormone (GnRH) n Pulsatility and pulse frequency are critical n Pulsatile infusion stimulates LH and FSH secretion n Constant infusion inhibits LH and FSH secretion n GnRH can be used to induce fertility and suppress gonadal function

33 (+) (-) GnRH LH & FSH Estrogen (  ) Inhibin (FSH) Hypothalamic-Pituitary-Gonadal Axis O This is where things get complicated… R. Lash

34 You Your stereo Your roommate (+) (-) R. Lash

35 You That special someone (+) Positive feedback loop R. Lash

36 You That special someone Special someone’s significant other (?) R. Lash

37 (+) (-) GnRH LH & FSH Estrogen (  ) Female gonadal axis (negative feedback) Inhibin (FSH) R. Lash

38 (+) GnRH LH & FSH Estrogen (+) Female gonadal axis (Positive feedback during ovulation) R. Lash

39 Let’s review the major players Source Undetermined

40 Rhythms in endocrinology n Circadian rhythms l Occur over the course of a day, and repeat daily l Characteristic of most endocrine functions l Examples: Cortisol secretion n Ultradian rhythms l Bursts (spikes) of hormone secretion l Can be superimposed on circadian rhythms l Physiologically important, particularly in reproduction

41 Pulsatility in the reproductive axis n GnRH l Pulsatile infusion at 90 minute intervals can induce ovulation in women with hypothalamic disease l Continuous infusion is used to suppress LH/FSH in preparation for in vitro fertilization n LH and FSH l Puberty is associated with pulses of greater frequency and amplitude

42 Frequency of administration determines effect of PTH on bone cells OsteoblastOsteoclast P<0.05, † P<0.01, ‡ P<0.001 vs Vehicle Dobnig and Turner. Endocrinology 1997;138:4607-4612 Trabecular Bone Perimeter % Vehicle SC 1 h/day 2 h/day Continuous 0 5 10 15 20 25 30 35 * † ‡

43 Things to remember if you’re just waking up n Generally, hypothalamic hormones stimulate pituitary hormone release n Prolactin regulation, in contrast, is primarily inhibitory n The inhibitory hypothalamic factors worth remembering are somatostatin and dopamine

44 Things to remember if you’re just waking up n Pituitary hormones fall into three groups l Glycoprotein hormones (TSH, LH, and FSH) l ACTH l Growth hormone and prolactin n Negative feedback is the usual state of affairs, but not the only one n Hormone activity depends on both the quantity present, and its mode of release

45 Additional Source Information for more information see: http://open.umich.edu/wiki/CitationPolicy Slide 6: Source Undetermined Slide 7: Source Undetermined Slide 8: Source Undetermined Slide 10: Robert Lash Slide 11: Robert Lash Slide 12: Robert Lash Slide 13: Robert Lash Slide 14: Robert Lash Slide 15: Source Undetermined Slide 16: Robert Lash Slide 17: Robert Lash Slide 18: Robert Lash Slide 20: Robert Lash; GFDL, Janine Chedid, Wikimedia Commons, http://en.wikipedia.org/wiki/GNU_Free_Documentation_Licensehttp://en.wikipedia.org/wiki/GNU_Free_Documentation_License Slide 22: Robert Lash Slide 23: Robert Lash Slide 24: Robert Lash Slide 25: Source Undetermined Slide 26: Robert Lash Slide 28: Robert Lash Slide 29: Robert Lash Slide 30: Robert Lash Slide 31: Robert Lash Slide 33: Robert Lash Slide 34: Robert Lash Slide 35: Robert Lash Slide 36: Robert Lash Slide 37: Robert Lash Slide 38: Robert Lash Slide 39: Source Undetermined Slide 42: Dobnig and Turner. Endocrinology 1997;138:4607-4612

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