Growth Hormone and IGF-1

Introduction: Human growth hormone (hGH) plays a pivotal role in postnatal growth and development. Growth hormone helps to maintain lean body mass and bone density in adults. During fasting situations, growth hormone helps to raise blood glucose and stimulates lipolysis and fat utilization. Many of the effects of growth hormone are indirect and are stimulated by the Liver secretion of IGF-1 (insulin-like-growth-factor) also known as Somatomedin. (The most common Somatomedin is Somatomedin C which is also called IGF-1.) Some other tissues also secrete somatomedins in response to GH stimulation.

Synthesis and Secretion of hGH Growth hormone is synthesized in anterior pituitary cells called somatotrophs. The somatotrophs make up 40-50% of the cells of the anterior pituitary. The hormone is stored in large granules within the somatotrophic cells. Two hypothalamic hormones regulate the synthesis and secretion of growth hormone. Growth hormone releasing hormone (GHRH) induces synthesis and stimulates the secretion of growth hormone; whereas, Somatostatin inhibits synthesis and secretion. Pulsatile release of GHRH causes a similar pulsatile release of GH. Somatostatin inhibits the effect of GHRH on the somatotrophic cells.

In addition the secretion of GH is affected by many other stimuli including:

Stimulation
GHRH
Protein Nutritional Deficiency
Decrease in FFA, glucose
Fasting, caloric restriction
Puberty
Exercise
Stage IV sleep
Physiologic Stress (i.e. trauma, surgery, infection, fever)
Estrogens and Androgens

Inhibition
Somatostatins
Increased blood glucose
Increased blood FFA
Obesity
Senescence
Somatomedins
GH (exogenous)

Variations in Secretion

• Life Span: Plasma levels of GH are greatest in children and peak during puberty. GH levels are the lowest in senescence
• Circadian Rhythm: GH secretion varies within the 24 hour sleep-wake cycle See peak secretion about 1 hour after the onset of deep sleep
• Sex differences: GH secretion is greater in females than males Estradiol stimulates GH secretion with a peak just before ovulation. Testosterone stimulates GH secretion in males

Is GH the magic pill, the "Fountain of Youth"? GH supplements to middle aged males (66y/o) did not enhance muscle mass and strength gains over placebo effect when both groups performed weight training exercises. [Zachwieja, JJ and Yarasheski KE, Does growth hormone therapy in conjunction with resistance exercise increase muscle force production and muscle mass in men and women aged 60 years or older? Phys Ther. 1999 Jan;79(1):76-82. Review.]

Actions of GH & IGF-1 (Somatomedins)
The GH receptor is a member of a large class of receptors, the cytokine receptors, which do not encode enzymatic activity but rather couple noncovalently to JAK (janus) kinases. Mechanism of action of GH: schematic overview GH receptor signal mechanism

The IGF-1 receptor is a cell surface receptor that is a member of the IGF receptor family. IGF-1 receptor is a transmembrane receptor tyrosine kinase. Mechanism of action of IGF-1: schematic overview of IGF-1 receptor signal mechanisms

Metabolic Effects of activating pituitary secretion of GH (effects include GH + IGF-1 effects)
1. Increase protein synthesis (synergistic action with Insulin)

• Increased amino acid transport into cells
• Stimulation of transcription and translation
  
• Inhibit protein catabolism

2. Mobilization of fatty acids and utilization of fatty acids

• Stimulates release of fatty acids from adipose cells therefore see an increase in plasma FFA and ketoacids
  Increases oxidation of fatty acids by the body's cells

3. Overall effect on Carbohydrate (CHO) metabolism is to decrease utilization of glucose, therefore elevate blood glucose

• Elevated GH causes decreased entry of glucose into cells
• GH is a diabetogenic hormone because it increases insulin resistance, excess GH can cause metabolic disturbances similar to what is observed in type 2 Diabetes Mellitus
• Stimulates glucose production by the liver

Growth promoting Effects
The growth promoting effects of hGH requires normal levels of insulin and adequate diet of CHO and protein.
GH stimulates linear growth in bone by stimulating all aspects of chondrocyte function.

• Increased amino acid uptake
• Increased protein synthesis
  
• Increased collagen
• Increased chondroitin sulfate
• Increase cell size and number
• Total bone mass and mineral content of bone are increased by GH
  
• GH is a potent stimulator of osteoblastic activity
• Hypertrophy and hyperplasia of visceral organs
  
• See increased growth of heart, lung, liver, pancreas, GI tract, adrenal glands, etc.
  
• GH sensitizes the gonads to LH and FSH during puberty

Growth Failure: Postulate various possibilities for disruptions in normal growth

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