Download Somatotropic axis

Somatotropic axis
Growth hormone
• Pituitary protein
hormone
– 191 amino acids
• 22 kDa
– Non-glycosylated
– Two disulfide bridges
• Shares homology with
prolactin, placental
lactogen, and GHvariant
– Gene duplication
• 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
Secretion pattern
• Pulsatile manner
– Interplay between GHRH
and SS
– Other GH secretagogues
– Release of GH in response
to GHRH
• Elevation of cAMP
• GHRH
– Critical for development
and maintenance of
somatotrophs
• Hypersecretion results in
pituitary tumor
development
• Role of SS
– Affects timing and amplitude of pulsatile GH secretion
• Pulsatile GH
– Diminished secretion of SS coupled with increased GHRH
secretion
• Trough GH
– Diminished secretion of GHRH coupled with increased SS
secretion
• Nature of GHRH/SS regulation of GH secretion
– Somewhat unclear
• Involvement of numerous neurotransmitters
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
• 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
Effects of growth hormone
• Growth of epiphyseal plate in the long
bones
– Incorporation of sulfur into the epiphyseal
cartilage
• Sulfation factor
• Indirect action of GH (delayed response)
– Requirement of mediator(s)
• Somatomedins
Action of GH
• Mediated by Insulin-like growth factors
(IGFs)
– Two types
• IGF-I
• IGF-II
– Structurally similar to preinsulin
• Interact with insulin receptor when in high
concentrations
• IGF-II
– Developmentally important
– Declines with age
– Secretion independent of GH in many species
• IGF-I
– Mediation of growth
– Endocrine
• Liver
– Local (autocrine/paracrine) IGF-I
– Secretion depends on GH
• Importance of IGF-I
– Total deletion (knockout)
• Postnatal lethality
– 32-95 % die within 24 hr postpartum
– Muscular dystrophy and premature lung development
• Growth retardation
– Embryonic
– Postnatal (35 % less than that of normal)
• Infertility
– Impaired steroidogenesis
• Endocrine IGF-I
– Potent inhibitor of GH synthesis and secretion
– May not be essential for normal growth
• Local IGF-I
– Important for normal growth and development
– Important for ovarian function
• Steroidogenesis
– Synergizes with gonadotropins
• Cell proliferation