WHAT IS GROWTH HORMONE AND HOW IT WORKS

Growth and Metabolic Effects of Growth Hormone

Growth hormone (GH) exerts significant effects on both growth and metabolism. These effects can be categorized as follows:

1. Growth Effects:
   • GH stimulates the production of insulin-like growth factor-1 (IGF-1), primarily in the liver, which mediates many of its growth-promoting actions.
   • IGF-1 promotes linear bone growth by stimulating chondrocyte proliferation and differentiation in the epiphyseal growth plates during childhood and adolescence.
   • GH enhances protein synthesis in various tissues, contributing to increased muscle mass and organ size.

2. Metabolic Effects:
   • GH has anabolic effects on protein metabolism, increasing amino acid uptake and protein synthesis while reducing protein breakdown.
   • It has lipolytic effects, promoting the breakdown of triglycerides into free fatty acids (FFA) in adipose tissue, thereby increasing circulating FFA levels.
   • GH induces insulin resistance, reducing glucose uptake in peripheral tissues such as skeletal muscle and adipose tissue. This leads to increased hepatic gluconeogenesis and elevated blood glucose levels.

Principal Insulin-Like Growth Factors and Their Relationship to Growth Hormone Actions

The principal insulin-like growth factors are:

1. Insulin-Like Growth Factor-1 (IGF-1):
   • IGF-1 is the primary mediator of GH’s anabolic effects.
   • It is produced mainly by the liver in response to GH stimulation but is also synthesized locally in tissues where it acts in an autocrine or paracrine manner.
   • IGF-1 promotes cell proliferation, differentiation, and survival, particularly in bone, cartilage, and muscle.

2. Insulin-Like Growth Factor-2 (IGF-2):
   • IGF-2 plays a more prominent role during fetal development than postnatal life.
   • Its actions are less dependent on GH compared to IGF-1.

Relationship with GH: GH stimulates hepatic production of IGF-1 by binding to growth hormone receptors (GHRs) on hepatocytes. The resulting increase in circulating IGF-1 provides negative feedback to suppress further GH secretion at both the hypothalamic (via somatostatin release) and pituitary levels. Additionally, IGF-binding proteins (e.g., IGFBP-3) regulate the bioavailability of IGFs by prolonging their half-life.

Regulation of Growth Hormone Secretion

GH secretion is tightly regulated by a complex interplay between stimulatory and inhibitory signals from the hypothalamus:

Role of Hypothalamus:

The hypothalamus controls GH secretion through two key hormones:

1. Growth Hormone-Releasing Hormone (GHRH):
   • GHRH is secreted from the hypothalamus into the hypophyseal portal system.
   • It binds to receptors on somatotroph cells in the anterior pituitary gland, stimulating pulsatile secretion of GH.

2. Somatostatin:
   • Also known as growth hormone-inhibiting hormone (GHIH), somatostatin inhibits GH release from somatotrophs by suppressing cAMP production within these cells.

Feedback Regulation:

Circulating levels of IGF-1 provide negative feedback at both the hypothalamic level (increasing somatostatin release) and pituitary level (directly inhibiting somatotrophs).

Factors Stimulating Growth Hormone Secretion

Several physiological factors stimulate GH secretion:

1. Hypoglycemia or fasting states.
2. Exercise or physical activity.
3. Sleep—particularly during slow-wave sleep stages.
4. Stress via catecholamine release.
5. High-protein meals or amino acid infusion (e.g., arginine).
6. Ghrelin—a gastric peptide that acts synergistically with GHRH to enhance pituitary GH release.

Factors Inhibiting Growth Hormone Secretion

Conversely, certain factors inhibit GH secretion:

1. Hyperglycemia or elevated blood glucose levels.
2. Elevated free fatty acids in circulation due to lipolysis suppression.
3. Aging—GH secretion declines significantly with age.
4. Obesity—associated with reduced pulsatility of GH secretion due to high intra-abdominal fat content.
5. Exogenous glucocorticoids or chronic stress leading to increased cortisol levels.

Role of Hypothalamus, GHRH, and Somatostatin

The hypothalamus plays a central role in regulating pituitary function through its release of GHRH and somatostatin:

1. Hypothalamus:

The hypothalamus integrates signals from peripheral metabolic cues such as nutrient availability, stress hormones, ghrelin levels, and circadian rhythms.

2. Growth Hormone-Releasing Hormone (GHRH):

GHRH stimulates cyclic AMP production within anterior pituitary somatotrophs via binding to its receptor—a G-protein coupled receptor—thereby enhancing transcriptional activation for GH synthesis and pulsatile release.

3. Somatostatin:

Somatostatin counteracts GHRH action by inhibiting adenylate cyclase activity within somatotrophs through Gi-protein signaling pathways.

Together, these hormones ensure that appropriate amounts of GH are secreted based on physiological needs while preventing excessive or insufficient production.