Somatotropic axis. Growth hormone Pituitary protein hormone –191 amino acids 22 kDa –Non-glycosylated –Two disulfide bridges Shares homology with prolactin,

Somatotropic axis

Growth hormone

• Pituitary protein hormone– 191 amino acids

• 22 kDa

– Non-glycosylated– Two disulfide bridges

• Shares homology with prolactin, placental lactogen, and GH-variant– 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