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UNIVERSIDAD CENTRAL DE VENEZUELA
FACULTAD DE MEDICINA
ESCUELA DE MEDICINA “LUIS RAZETTI”
CÁTEDRA DE FISIOLOGIA
Emilia Díaz
1 de marzo 2012
 Glucocorticoides.
 Anatomía de las glándulas suprarrenales.
 Estructura, síntesis, y secreción del cortisol.
 Ritmo circadiano.
 El eje hipotálamo-hipófisis-adrenal: CRH, ACTH.
 Transporte del cortisol en la circulación.
 Productos de degradación del cortisol.
 Mecanismo de acción: receptores nucleares, transducción de la
señal. Efectos genómicos y no genómicos
 Efectos fisiológicos del cortisol. Efectos permisivos. Interacción con
otras hormonas.
CONTENIDO PROGRAMÁTICO
flujo sanguineo 5 ml/min,
© 2005 Elsevier
BIOSÍNTESIS DE CORTISOL
21 C
19 C
ANDRÓGENOS SUPRARRENALES
© 2005 Elsevier
FC: coleterol libre
steroidogenic acute regulatory protein
ACTH
8-25 mg/24horas
ES SECRETADO EN SU TOTALIDAD
NO SE ALMACENA
cytochrome P-450 monooxidase
gene family : CYPs.
Enzyme Name Gene Chromosome
Cholesterol side-chain
cleavage (SCC) (desmolase)
CYP11A1 15q23-q24
3β-Hydroxysteroid
dehydrogenase (3β-HSD)
(type II isozyme)
HSD3B2 1p13.1
17α-Hydroxylase/17,20
lyase
CYP17 10q24.3
21-Hydroxylase CYP21A2 6p21.3
11β-Hydroxylase CYP11B1 8q24.3
Aldosterone synthase CYP11B2 8q24.3
EL EJE HIPOTALÁMICO
HIPOFISIARIO ADRENAL
neuronas parvocelulares
NPV--CRH
Clase 2013 cortisol
Clase 2013 cortisol
Clase 2013 cortisol
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type I CRH receptors
anterior pituitary
V1B receptor
PATRON DE SECRECIÒN
• 41 aa
• Vida media larga:26 min
• Potencian su secreción:ADH y angiotensina II
• Inhiben su secreción: oxitocina y ACTH
• Neuronas CRH:núcleo paraventricular con extensión
a la eminencia media
• También es producida por la placenta
• Sus niveles aumentan al final del embarazo y en el
parto
Clase 2013 cortisol
inhibición de la secreción
de ACTH y cortisol
METABOLISMO
DEL CORTISOL
• Metabolismo disminuido: niños, adultos
mayores
• Depuración reducida: ayuno, gestación
(aumento de CBG)
• Metabolismo de cortisol a 6 b hidroxicortisol
aumentado:neonato, embarazo, estrógenos,
drogas (barbitúricos, mitotane, fenitoina,
rifampicina)
RECEPTORES NUCLEARES (RNs)
ESTRUCTURA DE LOS RECEPTORES NUCLEARES
Structure/function organization of nuclear receptors.
Olefsky J M J. Biol. Chem. 2001;276:36863-36864
©2001 by American Society for Biochemistry and Molecular Biology
http://nrresource.org/general_information/general_information.html
All steroid hormone receptors,
except for the estrogen receptor
(ER), bind to the double-stranded
DNA sequence AGAACA
Structural basis of nuclear receptor (NR)
DNA-binding specificity.
http://nrresource.org/general_information/general_information.html
Clase 2013 cortisol
Clase 2013 cortisol
Efectos genomicos de los glucocorticoides incluyendo la transactivation y la
transrepresion
Stahn C and Buttgereit F (2008)
Clase 2013 cortisol
Clase 2013 cortisol
Regulation of tissue GR activity by distinct signaling pathways
Ann N Y Acad Sci. 2009 October ; 1179: 153–166. doi:10.1111/j.1749-6632.2009.04988.x.
Clase 2013 cortisol
Clase 2013 cortisol
Efectos el metabolismo del cortisol sobre el metabolismo de
los carbohidratos y proteinas en el hìgado
Clase 2013 cortisol
Arthritis specialists (left to right) Dr. C. H. Slocumb,
Dr. Edward C. Kendall, Dr. Philip S. Hench, and Dr. H. F.
Polley examining a patient at the Mayo Clinic.
“In 1950, Philip S. Hench
and his co-workers
Edward Kendall and
Tadeus Reichstein
received the Nobel Prize
for medicine for their
landmark discovery of
glucocorticoids and the
beneficial effects in
rheumatoid arthritis ”.
http://www.the-rheumatologist.org/details/article/984173/Chronotherapy_with_Glucorticoids_in_Rheumatoid_Arthritis.ht
CELL TYPE FACTOR COMMENTS
Macrophages and
monocytes
Arachidonic acid and its metabolites
(prostaglandins and leukotrienes)
Mediated by glucocorticoid inhibition of
cyclooxygenase-2 and phospholipase A2.
Cytokines, including: interleukin (IL)-1, IL-
6, and tumor necrosis factor-α (TNF-α)
Production and release are blocked. The cytokines
exert multiple effects on inflammation (e.g.,
activation of T cells, stimulation of fibroblast
proliferation).
Acute phase reactants These include the third component of complement.
Endothelial cells Endothelial leukocyte adhesion molecule-1
(ELAM-1) and intracellular adhesion
molecule-1 (ICAM-1)
ELAM-1 and ICAM-1 are intracellular adhesion
molecules that are critical for leukocyte localization.
Acute phase reactants Same as above, for macrophages and monocytes.
Cytokines (e.g., IL-1) Same as above, for macrophages and monocytes.
Arachidonic acid derivatives Same as above, for macrophages and monocytes.
Basophils Histamine, leukotriene C4 IgE-dependent release inhibited by glucocorticoids.
Fibroblasts Arachidonic acid metabolites Same as above for macrophages and monocytes.
Glucocorticoids also suppress growth factor-induced
DNA synthesis and fibroblast proliferation.
Lymphocytes Cytokines (IL-1, IL-2, IL-3, IL-6, TNF-α, GM-
CSF, interferon-γ)
Same as above for macrophages and monocytes.
Goodman & Gilman's The Pharmacologic Basis of Therapeutics - 11th Ed. (2006
Effects of Glucocorticoids on Components of Inflammatory/Immune Responses
Clase 2013 cortisol
1. Inhibición de fibroblastos, colágeno y tejido
Conectivo
2. Inhibición de formación ósea
3. Estimulación de resorción ósea (aumenta excreción
de hidroxiprolina)
4. Potencia acción de PTH y Vitamina D3 en el hueso
5. Reduce absorción intestinal de calcio
6. Aumenta excreción urinaria de calcio
Clase 2013 cortisol
Clase 2013 cortisol
1. Inhibición farmacológica de TRH, TSH y T4
2. Inhibición farmacológica de LH y rpta de LH a
GnRH
3. Incrementa tono intraocular (dosis
farmacológica)
Edwards and Burnham , 2001
Clase 2013 cortisol
Clase 2013 cortisol
Table 59-1. Normal Daily Production Rates
and Circulating Levels of the Predominant
Corticosteroids
CORTISOLALDOSTERONE
Rate of secretion under optimal conditions
10 mg/day 0.125 mg/day
Concentration in peripheral plasma:
8 A.M. 16 ug/100 ml 0.01 ug/100 ml
4 P.M. 4 ug/100 ml 0.01 ug/100 ml
Respuesta
genómica
androstrenedione
andro
GLOMERULOSA
RETICULADA
FASCICULADA
Clase 2013 cortisol
The episodic, pulsatile pattern of ACTH secretion and its concordance with cortisol secretion in
a healthy human subject during the early morning.
(Reproduced, with permission, from Gallagher TF et al: ACTH and cortisol secretory patterns in
man. J Clin Endocrinol Metab 1973;36:1058.)
Secretion
The physiologic
secretion of ACTH
Clase 2013 cortisol
Clase 2013 cortisol
Clase 2013 cortisol
Figure 42-16 Steroidogenic pathways in the zona glomerulosa. The first common reaction in the pathway, conversion of cholesterol to pregnenolone by CYP11A1, is not shown. Note that
the last three reactions are catalyzed by CYP11B2. (Modified from Porterfield SP, White BA: Endocrine Physiology, 3rd ed. Philadelphia, Mosby, 2007.)
Downloaded from: StudentConsult (on 26 February 2011 05:10 PM)
© 2005 Elsevier
Downloaded from: StudentConsult (on 26 February 2011 05:10 PM)
© 2005 Elsevier
Clase 2013 cortisol
Figure 1 One gene encodes different receptor variants
Stahn C and Buttgereit F (2008) Genomic and nongenomic effects of glucocorticoids
Nat Clin Pract Rheumatol doi:10.1038/ncprheum0898
Nature Reviews Neuroscience 5, 917- (December 2004) | doi:10.1038/nrn1555
http://www.sabiosciences.com/
pathway.php?sn=Glucocorticoid_Receptor_Signaling
NEFAs: non-esterified (or free) fatty acids are a major source of fuel for
oxidative metabolism
Musculo cardíaco y esquelético
período postabsortivo
TAG:
triacylglycerides

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Clase 2013 cortisol

  • 1. UNIVERSIDAD CENTRAL DE VENEZUELA FACULTAD DE MEDICINA ESCUELA DE MEDICINA “LUIS RAZETTI” CÁTEDRA DE FISIOLOGIA Emilia Díaz 1 de marzo 2012
  • 2.  Glucocorticoides.  Anatomía de las glándulas suprarrenales.  Estructura, síntesis, y secreción del cortisol.  Ritmo circadiano.  El eje hipotálamo-hipófisis-adrenal: CRH, ACTH.  Transporte del cortisol en la circulación.  Productos de degradación del cortisol.  Mecanismo de acción: receptores nucleares, transducción de la señal. Efectos genómicos y no genómicos  Efectos fisiológicos del cortisol. Efectos permisivos. Interacción con otras hormonas. CONTENIDO PROGRAMÁTICO
  • 7. © 2005 Elsevier FC: coleterol libre
  • 9. 8-25 mg/24horas ES SECRETADO EN SU TOTALIDAD NO SE ALMACENA cytochrome P-450 monooxidase gene family : CYPs.
  • 10. Enzyme Name Gene Chromosome Cholesterol side-chain cleavage (SCC) (desmolase) CYP11A1 15q23-q24 3β-Hydroxysteroid dehydrogenase (3β-HSD) (type II isozyme) HSD3B2 1p13.1 17α-Hydroxylase/17,20 lyase CYP17 10q24.3 21-Hydroxylase CYP21A2 6p21.3 11β-Hydroxylase CYP11B1 8q24.3 Aldosterone synthase CYP11B2 8q24.3
  • 11. EL EJE HIPOTALÁMICO HIPOFISIARIO ADRENAL neuronas parvocelulares NPV--CRH
  • 16. type I CRH receptors anterior pituitary V1B receptor
  • 18. • 41 aa • Vida media larga:26 min • Potencian su secreción:ADH y angiotensina II • Inhiben su secreción: oxitocina y ACTH • Neuronas CRH:núcleo paraventricular con extensión a la eminencia media • También es producida por la placenta • Sus niveles aumentan al final del embarazo y en el parto
  • 20. inhibición de la secreción de ACTH y cortisol
  • 22. • Metabolismo disminuido: niños, adultos mayores • Depuración reducida: ayuno, gestación (aumento de CBG) • Metabolismo de cortisol a 6 b hidroxicortisol aumentado:neonato, embarazo, estrógenos, drogas (barbitúricos, mitotane, fenitoina, rifampicina)
  • 24. ESTRUCTURA DE LOS RECEPTORES NUCLEARES
  • 25. Structure/function organization of nuclear receptors. Olefsky J M J. Biol. Chem. 2001;276:36863-36864 ©2001 by American Society for Biochemistry and Molecular Biology
  • 27. All steroid hormone receptors, except for the estrogen receptor (ER), bind to the double-stranded DNA sequence AGAACA Structural basis of nuclear receptor (NR) DNA-binding specificity.
  • 31. Efectos genomicos de los glucocorticoides incluyendo la transactivation y la transrepresion Stahn C and Buttgereit F (2008)
  • 34. Regulation of tissue GR activity by distinct signaling pathways Ann N Y Acad Sci. 2009 October ; 1179: 153–166. doi:10.1111/j.1749-6632.2009.04988.x.
  • 37. Efectos el metabolismo del cortisol sobre el metabolismo de los carbohidratos y proteinas en el hìgado
  • 39. Arthritis specialists (left to right) Dr. C. H. Slocumb, Dr. Edward C. Kendall, Dr. Philip S. Hench, and Dr. H. F. Polley examining a patient at the Mayo Clinic. “In 1950, Philip S. Hench and his co-workers Edward Kendall and Tadeus Reichstein received the Nobel Prize for medicine for their landmark discovery of glucocorticoids and the beneficial effects in rheumatoid arthritis ”. http://www.the-rheumatologist.org/details/article/984173/Chronotherapy_with_Glucorticoids_in_Rheumatoid_Arthritis.ht
  • 40. CELL TYPE FACTOR COMMENTS Macrophages and monocytes Arachidonic acid and its metabolites (prostaglandins and leukotrienes) Mediated by glucocorticoid inhibition of cyclooxygenase-2 and phospholipase A2. Cytokines, including: interleukin (IL)-1, IL- 6, and tumor necrosis factor-α (TNF-α) Production and release are blocked. The cytokines exert multiple effects on inflammation (e.g., activation of T cells, stimulation of fibroblast proliferation). Acute phase reactants These include the third component of complement. Endothelial cells Endothelial leukocyte adhesion molecule-1 (ELAM-1) and intracellular adhesion molecule-1 (ICAM-1) ELAM-1 and ICAM-1 are intracellular adhesion molecules that are critical for leukocyte localization. Acute phase reactants Same as above, for macrophages and monocytes. Cytokines (e.g., IL-1) Same as above, for macrophages and monocytes. Arachidonic acid derivatives Same as above, for macrophages and monocytes. Basophils Histamine, leukotriene C4 IgE-dependent release inhibited by glucocorticoids. Fibroblasts Arachidonic acid metabolites Same as above for macrophages and monocytes. Glucocorticoids also suppress growth factor-induced DNA synthesis and fibroblast proliferation. Lymphocytes Cytokines (IL-1, IL-2, IL-3, IL-6, TNF-α, GM- CSF, interferon-γ) Same as above for macrophages and monocytes. Goodman & Gilman's The Pharmacologic Basis of Therapeutics - 11th Ed. (2006 Effects of Glucocorticoids on Components of Inflammatory/Immune Responses
  • 42. 1. Inhibición de fibroblastos, colágeno y tejido Conectivo 2. Inhibición de formación ósea 3. Estimulación de resorción ósea (aumenta excreción de hidroxiprolina) 4. Potencia acción de PTH y Vitamina D3 en el hueso 5. Reduce absorción intestinal de calcio 6. Aumenta excreción urinaria de calcio
  • 45. 1. Inhibición farmacológica de TRH, TSH y T4 2. Inhibición farmacológica de LH y rpta de LH a GnRH 3. Incrementa tono intraocular (dosis farmacológica)
  • 49. Table 59-1. Normal Daily Production Rates and Circulating Levels of the Predominant Corticosteroids CORTISOLALDOSTERONE Rate of secretion under optimal conditions 10 mg/day 0.125 mg/day Concentration in peripheral plasma: 8 A.M. 16 ug/100 ml 0.01 ug/100 ml 4 P.M. 4 ug/100 ml 0.01 ug/100 ml
  • 53. The episodic, pulsatile pattern of ACTH secretion and its concordance with cortisol secretion in a healthy human subject during the early morning. (Reproduced, with permission, from Gallagher TF et al: ACTH and cortisol secretory patterns in man. J Clin Endocrinol Metab 1973;36:1058.)
  • 58. Figure 42-16 Steroidogenic pathways in the zona glomerulosa. The first common reaction in the pathway, conversion of cholesterol to pregnenolone by CYP11A1, is not shown. Note that the last three reactions are catalyzed by CYP11B2. (Modified from Porterfield SP, White BA: Endocrine Physiology, 3rd ed. Philadelphia, Mosby, 2007.) Downloaded from: StudentConsult (on 26 February 2011 05:10 PM) © 2005 Elsevier
  • 59. Downloaded from: StudentConsult (on 26 February 2011 05:10 PM) © 2005 Elsevier
  • 61. Figure 1 One gene encodes different receptor variants Stahn C and Buttgereit F (2008) Genomic and nongenomic effects of glucocorticoids Nat Clin Pract Rheumatol doi:10.1038/ncprheum0898
  • 62. Nature Reviews Neuroscience 5, 917- (December 2004) | doi:10.1038/nrn1555
  • 64. NEFAs: non-esterified (or free) fatty acids are a major source of fuel for oxidative metabolism Musculo cardíaco y esquelético período postabsortivo TAG: triacylglycerides