Endocrine Regulation of Prenatal and Postnatal Growth: GH and IGF

Historical Foundations of Growth Hormone (GH) Research

Early Experiments (1900s): Investigations involved the injection of "bovine pituitary extract" into rodents, which resulted in a notable increase in growth.
Hypophysectomy (Hypox): Researchers found that if a rodent's pituitary gland was surgically removed ( $Hypox$ ), growth was significantly reduced.
Restoration of Growth: When the pituitary extract was back-injected into $Hypox$ rodents, their normal growth patterns were restored (Source: Hossner, $2005$ , Hormonal Regulation of Farm Animal Growth).
Conclusion and Identification: These findings indicated that a substance produced by the pituitary gland had major effects on growth, later identified as Growth Hormone ( $GH$ ).
Species Specificity: GH is mostly species-specific. If GH is injected from a different species, it is generally not bioactive unless there is a high degree of structural similarity in receptor binding (e.g., monkey and human, or certain rat and cow experiment scenarios).

Biochemistry and Secretion of Growth Hormone (GH)

Synthesis: GH is a protein synthesized by the anterior pituitary gland.
Structural Properties: - It consists of approximately $191$ amino acids. - It is a $22\,kd$ protein.
Release Patterns: GH is released at night in $6$ to $8$ pulses per night, heavily associated with sleep.
Regulation and Production: - Hypothalamic Stimulation: Stimulated by Growth Hormone Releasing Hormone ( $GHRH$ ) from the hypothalamus. - Hypothalamic Inhibition: Inhibited by Somatostatin ( $SS$ ). - Genetic Control: The GH gene contains a $5'$ promoter region for transcription factors.

Biological Targets and Effects of Growth Hormone

Primary Target Organ: The Liver is the major target organ for GH, containing the highest number of $GHR$ (Growth Hormone Receptors).
Cellular Targets: Bone, muscle, and fat (adipose) cells also possess Growth Hormone Receptors ( $GHR$ ).
Tissue-Specific Effects: - Muscle: Positive effect ( $+$ , growth stimulation). - Bone: Positive effect ( $+$ , growth stimulation). - Adipose Tissue: Negative effect (, reduction in fat).
Case Study: Recombinant Porcine GH (rPST/Porcine Somatotropin): - In pigs, daily or periodic GH injections for extended periods before slaughter affect pork quality. - Result: Increased muscle mass and decreased fat content.

The Discovery of Somatomedins (IGF-1)

Serum Factors: Research by W. H. Daughaday (Washington University, St. Louis) found an interesting dynamic: GH does not act alone. - Serum from "Normal mice" induced radioactive sulfate incorporation into cartilage, indicating active cell growth. - Serum from $Hypox$ mice (Growth Hormone deficient) failed to induce this incorporation, suggesting a missing "serum factor."
Identification of IGF-1: The factor was identified as Insulin-like Growth Factor $1$ ( $IGF-I$ , formerly called Somatomedin C).
Biochemical Similarity: Insulin, $IGF-I$ , and $IGF-II$ are structurally similar. - $IGF-I$ is a single-chain $70$ amino acid peptide. - It shares $50\%$ homology with insulin.

IGF Receptors and Binding Proteins (IGFBPs)

Receptor Binding: - IGFR1 (IGF Type 1 Receptor): Binds $IGF-I$ and can bind the insulin receptor, though with low affinity. - IGFR2 (IGF Type 2 Receptor): High affinity for $IGF-II$ . - This structural similarity links the effects of $IGF$ and insulin.
GH-IGF Link: $GH$ stimulates the synthesis of both $IGF-1$ and $IGFBP-3$ , primarily in the liver, bone, and muscle.
IGF-Binding Proteins (IGFBPs): These modulate $IGF$ action through the $IGF$ receptor. - Hypoglycemia Prevention: An infusion of pure $IGF-1$ would induce rapid hypoglycemia; $IGFBPs$ prevent this effect. - Production: Produced mostly by the liver; they enter circulation to prolong the half-life of $IGF$ and buffer its activity. - IGFBP-3: The most prevalent binding protein, synthesized by the liver with > 80\% of $IGF-1$ bound to it. It serves as the primary clinical measure in blood to indicate $IGF-1$ levels. - IGFBP Protease: This enzyme separates $IGF$ from the binding protein to make it active.

Endocrine vs. Paracrine / Local IGF Effects

Impact: Local (paracrine) $IGF$ has a greater impact on growth than systemic (endocrine) $IGF$ . Most tissues are capable of producing their own $IGFs$ .
Circulating IGF: Primarily comes from the liver to control pituitary $GH$ release and local tissue $IGF$ production.
Observation: Injecting endocrine $IGF-I$ has relatively little effect on overall growth compared to the stimulation of local production.

Fetal and Neonatal IGF Dynamics

Late Gestation: $IGF-I$ levels in fetal circulation (umbilical, amnion) correlate ( $r$ ) with fetal size.
Primary Sources: - Placenta: The primary source of $IGF-I$ for the fetus through most of gestation; it affects nutrient transfer by the placenta. - Fetal Liver: Becomes the major source of $IGF-1$ during late gestation.
Post-natal Transition: $IGF-1$ increases in the blood soon after birth as $GH$ begins to take effect on the liver.
IGF-II characteristics: - Levels are greater in the fetus but are not related to size differences. - Levels decline after birth.
Genomic Imprinting: $IGF-II$ and $IGF2R$ are imprinted genes expressed monoallelically by parentage. - Example (Mouse Fetus): Only the paternal $IGF-II$ gene is expressed; only the maternal $IGF-2R$ is expressed.
Nutritional Influence: Gestational limits on nutrition reduce fetal and adult size because local tissue growth is produced in response to nutritional factors from the placenta.
Fetal GH independence: Fetal $GH$ is not required for growth. - Evidence: Fetal $Hypox$ or fetal decapitation (in pigs, rats, and sheep) has minimal effects on birth weight. These fetuses survive and grow in utero for a time because placental nutritional factors drive $IGF$ production.

Metabolic Regulation of Post-natal Growth

Post-natal Dependence: Growth depends on pituitary $GH$ and Liver-derived endocrine $IGF$ .
Positive Stimulators for GH Release: Sleep, nutrition, exercise, and sex steroids.
Negative Inhibitors for GH Release: Stress and glucocorticoids.
The Gut Link: An empty stomach produces Ghrelin (a $28$ amino acid peptide), which acts as a $GH$ -releasing peptide.
Physiologic Conditions Required for Growth (Positive): - Low blood glucose. - High ( $+$ ) insulin. - High ( $+$ ) amino acids. - High ( $+$ ) $GH$ .
Physiologic Conditions for Growth Inhibition (Negative): - High ( $+$ ) $IGF-1$ (provides negative feedback on $GH$ ). - High ( $+$ ) Free Fatty Acids ( $FFA$ ). - Low () $GH$ .

Tissue-Specific Metabolic Effects of GH and IGF

Liver Effects: - $GH$ increases liver $IGF-1$ production. - Reduces amino acid oxidation (sparing amino acids). - Increases glucose release via glycogen breakdown. - Reduces insulin responsiveness and gluconeogenesis.
Muscle Effects: - Increases amino acid uptake resulting in protein synthesis. - Mobilizes muscle glycogen stores. - Increases glucose uptake.
Adipose Effects: - Reduces lipogenesis (lowers insulin sensitivity). - Increases lipolysis (fat breakdown).
Insulin Synergy: - $IGF$ and Insulin mediate glucose and amino acid uptake into insulin-dependent tissues. - Many amino acid and glucose transporters are insulin-dependent. - Insulin-Dependent Tissues: Muscle (uses fatty acids and glucose; stores glycogen) and Adipose (induces glucose uptake and releases fatty acids). - Non-Insulin-Dependent Tissues: Brain (glucose fuel, no glycogen storage) and Liver (stores glycogen; uptake depends on glucose concentration; fuel is ketoacids from amino acid degradation).

Bone Growth and Clinical Disorders

Normal Bone Growth: $GH$ induces normal long bone growth before puberty.
Growth Phase Termination: At puberty, high levels of sex steroids (specifically estrogen) end long bone growth.
Correlates of Growth: - Dogs: Body weight and size in different breeds (Toy, Miniature, Standard) are highly correlated with $IGF-1$ levels (P < .01, r = 0.88). - Humans: $IGF-1$ levels associate with height at puberty; this is also true for rodents, livestock, and cats. - Genetics: Even breed size in dogs is associated with a specific $IGF-1$ allele.
Excess GH Before Puberty (Gigantism): - Results in excessive elongation of bones and organ growth. - Often caused by a pituitary tumor. - Example: Robert Wadlow ( $1918-1940$ ) reached $8'11"$ .
Excess GH After Puberty (Acromegaly): - Occurs when the epiphyseal plate is closed, so no additional height is gained. - Bone growth continues in width/size, leading to enlarged hands, feet, nose, and jaw. - Example: Andre the Giant ( $7'4", 520\,pounds$ ).
Deficiency in GH Before Puberty (Dwarfism): - Low GH: Results in abnormal proportions (disproportional dwarfism) from limited long bone growth. - GH/IGF Binding Failure: Results in a miniature body size with normal proportions (e.g., miniature Brahman cattle at $70\%$ of normal height). - Causes: Pituitary tumors, cell trauma (radiation), or gene mutations.