anterior pituitary hormones
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Anterior pituitary hormones. Five secretory cells producing 6 different hormones Cortocotroph ACTH Gonadotroph LH and FSH Somatotroph GH Lactotroph Prolactin Thyrotroph TSH. ACTH. Part of larger protein Pro-opiomelanocortin One gene (8kb, three exons and two introns)

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Presentation Transcript
slide2
Five secretory cells producing 6 different hormones
    • Cortocotroph
      • ACTH
    • Gonadotroph
      • LH and FSH
    • Somatotroph
      • GH
    • Lactotroph
      • Prolactin
    • Thyrotroph
      • TSH
slide3
ACTH
  • Part of larger protein
    • Pro-opiomelanocortin
      • One gene (8kb, three exons and two introns)
        • Codes for one large protein
      • Transcription of gene
        • Activated by CRH, arginine vasopressin, cytokines
        • Inhibted by glucocorticoids
slide4
Transcription of POMC gene
    • CRH type 1 receptor
      • Production of cAMP and activation of protein kinase A pathway
        • Activation of CREB transcription factor
      • Activation of MAP-Kinase pathway
    • Cytokine receptor (LIF)
      • Activation of JAK/Stat pathway
        • Interaction with CRH signaling pathway
slide5
Pro-opiomelanocortin
    • 266 amino acids
    • Proteolytically cleaved to produce corticotrophic, opioid, and melanotrophic peptides
slide6
Secretion of ACTH
    • Complex regulation through HPA (hypothalamus-pituitary-adrenal) axis
    • Circadian and ultradian rhythm
      • Hypothalamic control (CRH)
        • Activity of nuclei regulated by glucocorticoids
      • Pulse amplitude rather than frequency determines circadian rhythm
regulation of acth secretion
Regulation of ACTH secretion
  • Exercise (short and exhausting)
    • Increased secretion of ACTH
      • Hypercortisolism in athletes
  • Stress
    • Increased production of cortisol
      • Integration of information received by the CNS
      • Constrain the inflammation
action of acth
Action of ACTH
  • Primary function
    • Proper maintenance of adrenal gland
    • Adrenal steroidogenesis
      • Cholesterol transport
      • Conversion to pregnenolone
      • Inhibited by glucocorticoids
gonadotropins
Gonadotropins
  • Two hormones from one type of cells
    • LH and FSH
  • Glycoprotein hormones
    • Two subunits
      • Alpha
        • Universal among all glycoprotein hormones
      • Beta
        • Hormone specific
      • Combination of alpha and beta subunits
        • Essential for biological activity
synthesis of gonadotropins
Synthesis of gonadotropins
  • Alpha subunit
    • Generated from different gene
      • Chromosome 6
    • Increased synthesis by GnRH and TRH
  • Beta subunits
    • Determinant of biological activity
      • LH beta on chromosome 19
      • FSH beta on chromosome 11
slide11
Transcription of LH beta subunit mRNA
    • GnRH
    • SF-1
    • Estrogen
  • Transcription of FSH beta
    • Role of GnRH and steroids
      • Unclear
      • Different promoter structure from LH
regulation of gonadotropin secretion
Regulation of gonadotropin secretion
  • Pulsatile secretion
    • Mirror image of GnRH pulses
      • Frequency and amplitude
      • LH more sensitive to changes in GnRH
  • Gonadal steroid hormones
    • Testosterone
      • Inhibits secretion
      • Enhances FSH beta subunit mRNA transcription
    • Estrogens
      • Dual function (stimulatory/inhibitory)
      • Cyclic changes in female during reproductive cycle
slide13
Gonadal peptides
    • Inhibins
      • Inhibits secretion of FSH
    • Activins
      • Stimulates FSH secretion and action
    • Follistatin
      • Inhibits FSH secretion and action
function of gonadotropins
Function of gonadotropins
  • Receptors for LH and FSH
    • Highly homologous
      • 50 % of extracellular domain
      • 80 % of transmembrane domain
  • Steroidogenesis in male and female
    • cAMP production
      • Increased cholesterol availability via increased production of steroidogenic acute regular protein (StAR)
      • Increased enzyme activity
function of gonadotropins1
Function of gonadotropins
  • Receptors for LH and FSH
  • Steroidogenesis in male and female
    • cAMP production
      • Increased cholesterol availability via increased production of steroidogenic acute regular protein (StAR)
      • Increased enzyme activity
      • Development and function of gonadal cells and gametes
        • FSH
growth hormone
Growth hormone
  • Human GH gene
    • Located in chromosome 17
      • 66 kb in length
      • Cluster of genes that encode closely related genes
        • GH-V
        • Placental lactogen/chorionic somatotropins
    • Transcription of GH mRNA
      • POUF1 transcription factor
        • Pituitary specificity
        • Interacts with protein kinase A pathway
slide17
Large polypeptide hormone
    • 191 amino acids
      • Four alpha helices looped together
  • Interacts with binding protein (GHBP)
    • Extends half-life of GH
    • Found in rodents, rabbits, and humans
      • Extracellular domain of GH receptor in human and rabbit
      • Product of alternative transcription in rodents
regulation of gh secretion
Regulation of GH secretion
  • Major GH pulses (70 % of total daily output)
    • Slow sleep (deep sleep)
    • Age-related loss of GH
      • Decrease quality of sleep
  • Obesity and diabetes
    • Decreased GH release
    • Nutritional status
      • One of the major regulatory factor of GH secretion
slide19
Hormones
    • Steroids
      • Acute elevation in glucocorticoids (+)
      • Chronic elevation in glucocorticoids (-)
      • Gonadal steroids (+)
    • Thyroid hormones
      • Inhibitory
action of gh
Action of GH
  • Growth and metabolism
    • Action mediated by IGF-I
      • Mediation of growth
      • Endocrine IGF-I
        • Liver
      • Local (autocrine/paracrine) IGF-I
slide21
Gender-specific pattern of GH secretion
    • Affects amount of steroidogenic enzymes
      • Gender-specific pattern of steroidogenesis
    • Gender-specific pattern of liver enzyme expression
    • Gender-specific action of GH
      • Mediated by STAT 5b activity
slide22
TSH
  • Glycoprotein hormone
    • Alpha and beta subunits
      • Alpha is identical to that of gonadotropins
      • Thyrotroph-specific expression
        • Different region of gene promoter
    • Gene for TSH beta subunit
      • Located on chromosome 1
      • Transcription regulated by Pit-1
slide23
Post-translational modification
    • Glycosylation
      • Affects proper molecular folding
      • Combination of alpha and beta subunits
      • Regulated by TRH (+) and T3 (-)
secretion of tsh
Secretion of TSH
  • Bioactivity of TSH
    • Glycosylation
      • Clearance rate
  • Pulsatile secretion
    • Not as pronoused as gonadotropins or GH
      • Low variation in concentrations
    • Circadian pattern
      • Increased secretion during night
        • Independent of sleep
slide25
Hormonal regulation
    • Major factor of TSH secretion
      • Thyroid hormone concentrations
        • Extremely important
      • TRH
      • Dopamine (-)
      • Glucocorticoids (-)
      • SS (-)
action of tsh
Action of TSH
  • Thyroid hormone production
    • G-protein coupled receptor
  • Thyroid cell integrity maintenance
prolactin
Prolactin
  • Structurally similar to GH
    • Common ancestry
      • Chromosome 6
  • Prolactin gene expression
    • Estrogen
    • Dopamine
    • TRH
    • Thyroid hormones
slide28
Exits as monomer or polymer in circulation
    • 23 kDa (monomer)
      • Most bioactive
    • 48-56 kDa (dimer)
    • > 100 kDa (polymer)
    • Glycosylated
      • Less active
  • Binds to prolactin binding protein
regulation of prolactin secretion
Regulation of prolactin secretion
  • Inhibitory
    • Hypothalamic
      • Dopamine
      • Calcitonin
    • Paracrine factors
      • Endothelin-1
      • TGF-beta 1
slide30
Stimulatory
    • Growth factors
      • bFGF
      • EGF
    • Gut hormone
      • VIP
    • Estrogen
function of prolactin
Function of prolactin
  • Essential for survival
    • Lactation
      • Prolactin surge during labor
        • Essential for initiation of lactation
      • Not required for maintenance of lactation
    • Immune function
      • Stimulates lymphocyte development
    • Reproduction
      • Essential for rodents
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