chapter 4 organization of the mammalian hypothalamus—pituitary axes copyright © 2013 elsevier...

Chapter 4Chapter 4

Organization of the Mammalian Organization of the Mammalian Hypothalamus—Pituitary AxesHypothalamus—Pituitary Axes

Copyright © 2013 Elsevier Inc. All rights reserved.

Figure 4-1 The vertebrate neuroendocrine system. The hypothalamus secretes RHs and RIHs, stores them in the median eminence, and releases them to the pars distalis and pars intermedia where they regulate release of tropic hormones. The activity of the hypothalamus is influenced by a variety of exogenous environmental factors via the central nervous system. The tropic hormones affect some non-endocrine targets, but most have endocrine targets that in turn release hormones that have specific effects on target cells and feedback at the hypothalamus or adenophypophysis (pars distalis). The hypothalamus also secretes the nonapeptides oxytocin (OXY) and vasopressin (AVP), which are stored in the pars nervosa and released into the blood through which they travel to nonendocrine targets. Only one type of long feedback is shown, but short (tropic hormone feedback) and ultrashort feedback (neuropeptides) may also influence hypothalamic function.

2Copyright © 2013 Elsevier Inc. All rights reserved.

Figure 4-2 Pathways for classical neurotransmitter innervation of the hypothalamus. Nomenclature for (A) dopamine, (B), epinephrine, (C) norepinephrine, (D) acetylcholine, and (E) serotonin pathways is based upon Dahlstrom and Fuxe (1964). Abbreviations: BF, basal forebrain; LC, locus coeruleus; PPT, pedunculopontine tegmental nucleus. (Adapted with permission from Cooper, J.R. et al., “The Biochemical Basis of Neuropharmacology,” Oxford University Press, New York, 2002.)


Figure 4-3 A generalized mammalian hypothalamus–pituitary axis. The hypothalamus contains several neurosecretory centers including the arcuate (ARC) nucleus, dorsomedial nucleus (DMN), paraventricular nucleus (PVN), preoptic area (POA), supraoptic nucleus (SON), and the ventromedial nucleus (VMN). The median eminence (ME) and pars nervosa are separate neurohemal areas. The superior hypophysial artery supplies blood to the capillaries in the ME. The ME is connected by hypothalamic portal blood vessels passing through the pars tuberalis to the pars distalis where releasing hormones from the hypothalamus stimulate tropic hormone release. The pars nervosa stores nonapeptides and has a separate blood supply. OC, optic chiasm.


Figure 4-4 Pituitary gland development. Early understanding of development of the stomatodeal epidermis into the adenohypophysis from Rathke’s pouch and the neurohypophysis from the neural infundibulum. The pars intermedia developed at the point of contact between the neuroinfundibulum and Rathke’s pouch. (Adapted from Dubois, P.M. and El Amraouci, A., Trends in Endocrinology and Metabolism, 6, 1–7, 1995. © Elsevier Science, Inc.)


Figure 4-5 Anterior neural ridge origin of the hypothalamic and pituitary endocrine cells. (A) Dorsal view of neurula stage of anuran embryo showing close proximity for origins of hypothalamic neurons (H), pituitary endocrine cells (A), and the olfactory placodes (O). GnRH cells of the hypothalamus originate from the olfactory placodes. (B) Similar origins are shown for an avian embryo. (Redrawn from several sources.)


Figure 4-6 Gonadotrope (left) and corticotrope (right) cell types. Note the differences in abundance and size of electron dense granules. Compare to the lactotrope and somatotrope in Figure 4-7. (Adapted with permission from Norman, A.W. and Litwack, G., “Hormones,” 2nd ed., Academic Press, San Diego, CA, 1997.)


Figure 4-7 Somatotrope (GH), lactotrope (PRL), and follicostellate cells (SC). All three cell types are located near a capillary (CAP). The GH and PRL cells are distinguished by the different size and relative abundance of secretion granules, whereas the SC are not granulated and show a tendency to form a follicular structure (F) where they contact one another. Compare to gonadotropes and corticotropes in Figure 4-6. (Adapted from Baker, B.L., Yu, Y. U. Cell and Tissue Research 156, 443–449, 1975.)


Figure 4-8 Projections from the hypothalamus to the median eminence. Cells in the paraventricular nucleus (left) and arcuate nucleus (ARC) (right) are stained with wheat germ agglutinin after injection of the tracer into the median eminence (ME). Abbreviations: III, third ventricle; DP, dorsal parvocellular subdivision of the paraventricular nucleus; MP, medial dorsal parvocellular subdivision of the paraventricular nucleus; PM, magnocellular paraventricular nucleus; VMN, ventromedial nucleus. (Reprinted with permission from Lechan, R.M. et al., Brain Research, 245, 1–15, 1982.)


Figure 4-9 The rat median eminence. In this photograph, immunoreactive cytokine (stromal cell-derived factor 1, in green) and AVP (in red) are co-localized (yellow) in nerve fibers innervating the internal layer of the rat median eminence. (Reprinted with permission from Callewaere, C. et al., Journal of Molecular Endocrinology, 38, 355–363, 2007.)


Figure 4-10 Projections from the hypothalamus to the pars nervosa. Magnocellular neurons in the paraventricular nucleus (PVN) project (arrows) ventrally to the supraoptic nucleus (SON) where they join (arrowheads at bottom of figure) fibers innervating the pars nervosa. (Reprinted with permission from Lechan, R.M. and Toni, R., Functional anatomy of the hypothalamus and pituitary, Chapter 3B, www.endotext.org, 2012.)


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Figure 4-11 Hypothalamic neurosecretory centers. (A) Sagittal section of brain showing nuclei on one side. (B) Cross-section of brain showing paired nature of nuclei. The nuclei depicted here are as follows: AH, anterior hypothalamic; ARC, arcuate; DMN, dorsomedial; PH, posterior hypothalamic, POA, preoptic area; paraventricular, PVN; suprachiasmatic, SC; ventromedial, VMN. Abbreviations: ADENO, adenohypophysis; MB, mammillary body; ME, median eminence; OC, optic chiasm; OT, optic tract; PN, pars nervosa.


Figure 4-12 Origin and targets for some hypothalamic-releasing and release-inhibiting hormones. Note that each hypothalamic hormone travels through the portal system and binds to receptors on different pars distalis cell types, evoking tropic hormone release. Abbreviations: ACTH, corticotropin; ARC, arcuate nucleus; CRH, corticotropin-releasing hormone; DA, dopamine (prolactin release-inhibiting hormone); FSH, follicle-stimulating hormone; GnRH, gonadotropin-releasing hormone; LH, luteinizing hormone; PRL, prolactin; PVN, paraventricular nucleus; TSH, thyrotropin; TRH, thyrotropinreleasing hormone.


Figure 4-13 Human genes for the secretin-glucagon family of peptides. SP, signal peptide; see Appendix A or text for other abbreviations. (Adapted with permission from Sherwood, N.M., Krueckl, S.L., McRort, J.E. Endocrine Reviews 21, 619–670, 2000.)


Figure 4-14 Generalized structures of pituitary glycoprotein hormones. The -subunit is common to all three hormones but the -subunit coded for by a different gene is unique to each hormone and is responsible for the type of biological activity shown by the mature heterodimer.


Figure 4-15 Comparison of growth hormone (GH) and prolactin (PRL). Both hormones are of comparable size, exhibit considerable overlap in amino acid sequence, and may have similar actions in some systems. GH typically has two disulfide bonds, whereas PRL typically has three.


Figure 4-16 Fates of proopiomelanocortin (POMC) in pituitary cells. The convertase enzyme PC1 (=PC3, PC1/PC3) hydrolyzes POMC in corticotropes of the pars distalis to yield mainly corticotropin (ACTH) and β-lipotropin (β-LPH). Corticotropes may also release β-endorphin (β-END) and γ-LPH from the β-LPH fraction, perhaps through action of PC1 or presence of PC2 in some cells. In some melanotropes within the pars intermedia, PC2 separates the major fragment of ACTH into α-MSH (melanotropin), a major inactive fragment consisting of part of ACTH and γ-LPH, and releases β-END. If PC1 and PC2 are both active in the melanotrope, the result is α-melanotropin (α-MSH), corticotropin-like peptide (CLIP), γ-LPH, and β-END. The 16K-peptide is inactive but in some groups contains the sequence known as γ-MSH. (Adapted with permission from Tanaka, S., Zoological Science, 20, 1183–1198, 2003.)


Figure 4-17 Role of accessory proteins in the function of the MSH (MC1R) and ACTH (MC2R) receptors. There are two ligands for the MC1R (A): MSH which promotes dark (eumelanin) synthesis and agouti signaling protein (Agouti), which promotes light (pheomelanin) production. Agouti protein interaction with the MC1R requires a separate accessory protein, attractin. MC1R signaling is inhibited by the cytosolic protein mahogunin ring finger-1 (MGRN1). MSH receptors can be sent to the plasma membrane without the accessory protein (melanocortin receptor accessory protein, MRAP), but when MRAP is coupled with the MSH receptor the potency of MSH is actually reduced. In contrast, MRAP is required for transfer of the ACTH receptor to the plasma membrane (B). (Adapted with permission from Cooray, S.N. and Clark, A.J., Molecular and Cellular Endocrinology, 331, 215–221, 2011.)


Figure 4-18 Chemical structures of opiate and opiate receptor antagonist (naloxone) drugs. Three common opiates (morphine, heroin, codeine) and the opiate receptor antagonist naloxone differ according to the groups (red) attached to the carbon rings.


Figure 4-19 Endogenous opioid peptides (EOPs) as neuromodulators. EOPs affect hormone release in at least three ways as exemplified with specific examples here. They can (A) increase PRL release by blocking the release of dopamine (DA) which normally blocks PRL release; (B) inhibit norepinephrine (NE) stimulation of GnRH release; or (C) prevent oxytocin (OXY) release when arginine vasopressin (AVP) is being released from the pars nervosa. Dyn, dynorphin. (Adapted from Brown R.E. “An Introduction to Neuroendocrinology,” Cambridge University Press, 1994.)


Figure 4-20 Hypothalamic factors affecting tropic hormone release. (A) Identification of principle sources for hypothalamic hormones. (B) Control of LH and FSH release. (C) Control of TSH release. (D) Control of ACTH release. (E) Control of GH release. (F) Control of PRL release. (G) Control of α-MSH release. See Appendix A or text for explanation of abbreviations and text for descriptions of regulation.


Figure 4-20 cont’d. Hypothalamic factors affecting tropic hormone release. (A) Identification of principle sources for hypothalamic hormones. (B) Control of LH and FSH release. (C) Control of TSH release. (D) Control of ACTH release. (E) Control of GH release. (F) Control of PRL release. (G) Control of α-MSH release. See Appendix A or text for explanation of abbreviations and text for descriptions of regulation.


Figure 4-21 Distribution of the forms of GnRH in the mouse brain. See text for explanation of abbreviations. (Adapted with permission from Whitlock, K.E., Trends in Endocrinology and Metabolism, 16, 145–151, 2005. © Elsevier Science, Inc.)


Figure 4-22 Structure of endothelins and the related sarafotoxin from snake venom. The colored circles represent amino acids not present in the sequence of endothelin-1. Amino acid abbreviations are explained in Appendix C. (Adapted with permission from Masaki, T., Endocrine Reviews, 14, 256–268, 1993. © The Endocrine Society.)


Figure 4-23 Gonadotropin-releasing hormone (GnRH) migration in the mouse embryo. Immunostaining of GnRH sagittal section of the head on embryo day 13.5. Arrow indicates GnRH neurons already located in the brain, whereas the arrow heads designate migrating GnRH neurons still in the nasal compartment. Abbreviations: nc, nasal cavity; oc, oral cavity; vno, vomeronasal organ. The dotted line designates the cribiform plate separating the nasal region from the brain. (Courtesy of Drs. John Gill and Pei-San Tsai, University of Colorado.)


Figure 4-24 Distribution of kiss1 and GnRH neurons in mammal brains. (Adapted with permission from Colledge,W.H., Trends in Endocrinology and Metabolism, 20, 115–121, 2009.)


Figure 4-25 Kiss1 and control of gonadotropin secretion. E2 binds to ERs (yellow) in kiss1 neurons, resulting in activation (positive feedback) in the AVPV and inactivation (negative feedback) in the arcuate nucleus. These kiss1 neurons innervate and may activate secretion of GnRH from GnRH neurons in the POA and/or ARC via kisspeptin (Kp) acting through the GPR54 receptor (purple), thus increasing gonadotropin secretion (FSH/ LH) from the gonadotropes in the pars distalis of the pituitary. (Adapted with permission from Smith, J.T. et al., Reproduction, 131, 623–630, 2006.)


Figure 4-26 Action of Kisspeptin on GnRH release via GPR54 receptors. Kisspeptin enhances GnRH secretion by binding to the GPR54 receptor and increasing the inositol triphosphate (IP3) second-messenger pathway. As a result, diacylglycerol activates (+) non-selective cation channels and inactivates (–) membrane potassium channels, leading to depolarization of the GnRH neuron. These channels also may be modulated directly by phosphatidylinositol bisphosphate (PIP2) or calmodulin-dependent protein kinases. (Adapted with permission from Colledge, W.H., Trends in Endocrinology and Metabolism, 20, 115–121, 2009.)


Figure 4-27 Melatonin released from the pineal gland stimulates GnIH secretion from neurons in the PVN. See text for explanation. (Adapted with permission from Tsutsui, K. et al., General and Comparative Endocrinology, 153, 365–370, 2007.)


Figure 4-28 Diurnal patterns of human GH and PRL release. (Adapted with permission from Baulieu, E. and Kelly, P., “Hormones: From Molecules to Disease,” Chapman & Hall, London, 1990, p. 206.)


Figure 4-29 Multireceptor regulation of GH secretion. GHRH, ghrelin, and somatostatin (SST). GHRH and ghrelin each act independently to increase GH secretion through the GHRH receptor and growth hormone secretagogue receptor (GHS), respectively. In addition, there are synergistic effects on GH release when both GHRH and ghrelin activate their receptors. Ghrelin also acts within the hypothalamus to stimulate GHRH secretion and inhibit SST secretion. SST also may act within the somatotrope to blunt GHRH and ghrelin action through Gi activation (see Chapter 3). (Adapted with permission from Lengyel, A.M.J., Arquivos Brasileiros de Endocrinologia & Metabologia, 50, 17–24, 2006.)


Figure 4-30 Response of perifused rat pituitary lactotropes to dopamine (DA). Additions of DA immediately depresses the spontaneous secretion of PRL normally seen in vitro. (Adapted with permission from Martini, L. and Besser, G.M., “Clinical Neuroendocrinology,” Academic Press, New York, 1977.)


Figure 4-31 Actions and interactions of corticotropin-releasing hormone (CRH) and urocortins (Ucn). Two CRH receptors have been identified, CRH-R1 and CRH-R2. CRH has a higher affinity for the CRH-R1 receptor and greater affect on ACTH release than does Ucn-I. Similarly, Ucns all have a much greater affinity for the CRH-R2 receptor.


Figure 4-32 Nonapeptide preprohormones and products. (A) Prepropressophysin undergoes posttranslational processing to yield three peptides: vasopressin, neurophysin II, and a glycopeptide called copeptin. (B) Preprooxyphysin gives rise to two peptides: oxytocin and neurophysin I. (Adapted with permission from Baulieu, E. and Kelly, P., “Hormones: From Molecules to Disease,” Chapman & Hall, London, 1990, p. 206.)


Figure 4-33 Vasopressin actions on aquaporins and water transport. Vasopressin binds to the V2-receptor and via a cAMP second-messenger system stimulates synthesis of aquaporin-2. cAMP also activates protein kinase A that through phosphorylation directs the movements of newly synthesized aquaporin-2 molecules to the cell surface where they can participate in water transport. (Adapted with permission from Sasaki, S. et al., Annual Review of Physiology, 60, 199–220, 1998.)


Figure 4-34 Natriuretic peptides. (Adapted from Samson, W.K., Trends in Endocrinology and Metabolism, 3, 86–90, 1992. © Elsevier Science, Inc.)


Figure 4-35 Epithalamic structures. Among the evaginations that develop from the roof of the epithalamus are the epiphysis cerebri or pineal, the parietal or parapineal organ, the dorsal sac, and the paraphysis.


Figure 4-36 Serotonin and melatonin levels related to photoperiod and activity. Both the quantity of melatonin and activity of the ratelimiting enzyme N-acetyl transferase (NAT) in the pineal gland of chickens increases during the photophase. Similar observations have been made in mammals. HIOMT, hydroxyindole- M-transferase. (Adapted with permission from Binkley, S.A., “The Clockwork Sparrow: Time, Clocks, and Calendars in Biological Organisms,” Prentice-Hall, Englewood Cliffs, NJ, 1990.)


Figure 4-37 Patterns of melatonin secretion. Three distinct nocturnal secretory patterns are shown. (A) Increased secretion observed only during the second half of the photoperiod (house mouse, Syrian hamster). (B) Most common pattern where secretion begins soon after darkness, peaks at midphotophase, and decreases prior to onset of photophase. (C) Maximal secretion reached immediately as soon as scotophase begins and continues to secrete at a more or less constant rate until the lights go on (Siberian hamster, domestic sheep). (Adapted with permission from Reiter, R.J., Endocrine Reviews, 12, 151–180, 1991. © The Endocrine Society.)


Figure 4-38 Light and melatonin secretion. Melatonin secretion is regulated by ambient light and the sympathetic nervous system (both inhibitory) as well as hormonal signals from the periphery. RHT, retino-hypothalamic tract.


Figure 4-39 Neuropeptide Y (NPY) and its interactions with norepinephrine (NE). Activation of the release of melatonin is accomplished by NE secreted by sympathetic postgangionic neurons from the superior cervical ganglion. NPYacts as a local inhibitor via Y1 receptors to shut off the response to NE and via Y2 receptors to prevent additional NE release.


Figure 4-40 Melatonin regulates hypothalamic functions. The pineal receives input from hormones as well as sympathetic neural innervation that affects melatonin secretion. Melatonin in turn can block secretion of hypothalamic-releasing hormones (GnRH, TRH, CRH/AVP) as well as stimulate DA release, the PRL release-inhibiting hormone. Gonadal, thyroid, and adrenal hormones may provide negative feedback input through the pineal.


Box Figure 4B-1 Discovery of the chemical structure of TRH. Roger Guillemin (left) and Roger Burgus examining the structure of thyrotropin-releasing factor ([pyro]Glu-His-Pro-NH2) as deduced by mass spectrometry, June 9, 1969, in their laboratory at the Baylor College of Medicine in Houston, Texas. (Reprinted with permission from Guillemin, R.J., Journal of Endocrinology, 184, 11–28, 2005.)


chapter 4 organization of the mammalian hypothalamus—pituitary axes copyright © 2013 elsevier...

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