Growth Hormone and Its Effects on Growth

Growth Hormone (GH) Experiments

  • Early 1900s experiments demonstrated that injecting "bovine pituitary extract" into rodents resulted in increased growth (postnatal).

  • It was observed that:

    • Removing the pituitary from rodents (hypophysectomy, abbreviated as Hypox) reduced their growth.

    • Injecting pituitary extract into Hypox rodents restored their growth.

    • Reference: Hossner 2005 "Hormonal Regulation of Farm Animal Growth".

Significance of Findings

  • The results indicated that a substance produced by the pituitary gland has major effects on growth.

  • This substance was later identified as Growth Hormone (GH):

    • GH is mostly species-specific; injection from other species generally lacks bioactivity.

    • Exceptions exist if there is a similar structure allowing receptor binding, as seen in monkey and human interactions, and rat and cow experiments.

Characteristics of Growth Hormone (GH)

  • GH is a protein synthesized by the anterior pituitary gland.

  • Structural Information:

    • Composed of approximately 191 amino acids; has a molecular weight of 22 kilodaltons (kd).

  • Release Patterns:

    • Released at night in 6-8 pulses, particularly during sleep.

  • Regulation of Production/Release:

    • Stimulated by the hypothalamic hormone GHRH (Growth Hormone-Releasing Hormone).

    • Inhibited by somatostatin (SS).

    • The GH gene possesses a 5' promoter region for transcription factors.

Major Target Organs for GH

  • The primary target organ for GH action is the liver, which has a higher number of GH receptors (GHR).

  • Other target cells include bone, muscle, and adipose tissues, which are also equipped with GHRs.

  • GH has significant positive effects on muscle and bone tissues, while having a negative effect on adipose tissue.

Effects of GH in Pigs

  • Recombinant Porcine GH (commercially known as porcine somatotropin, rPST) is utilized:

    • Administered daily or periodically prior to slaughter.

    • Results in improved pork quality:

    • Increased muscle mass.

    • Decreased fat content.

Interaction of GH and Other Factors

  • GH does not operate in isolation.

  • Serum from normal mice can induce radioactive sulfate incorporation into cartilage, indicating cell growth, while serum from Hypox mice cannot.

  • This implies a missing serum factor that GH interacts with for effective growth.

Discovery of IGF Activity

  • Insulin-like Growth Factor 1 (IGF-1) discovered as an important component in GH action.

  • Research by W. H. Daughaday at Washington University, St. Louis.

  • Function demonstrated by radioactive sulfate incorporation as a marker for growth.

Characteristics of IGF-1

  • GH exerts its effects through IGF-1.

  • Comparison with Insulin:

    • IGF-1 is a single chain peptide consisting of 70 amino acids.

    • It shares about 50% homology with insulin.

IGF Receptors

  • IGF-1 binds to its own receptor, creating biological effects, and also binds to the insulin receptor albeit with low affinity.

  • IGF-II also has a receptor (IGFR2R) with high binding affinity.

  • The effects of IGF and insulin are interconnected and significant.

Regulation of IGF Effects

  • The action of IGF is regulated by IGF Binding Proteins (IGFBP-1 through IGFBP-3).

  • GH stimulates the synthesis of both IGF-1 and IGFBP-3 primarily in the liver, bone, and muscle.

Role of IGF-Binding Proteins (IGFBPs)

  • IGFBPs modulate the action of IGF via its receptor (IGFR).

  • Infusion of IGF-1 can induce rapid hypoglycemia, but the presence of IGFBP can mitigate this effect.

  • IGFBPs are primarily produced in the liver and bind 99% of circulating IGF.

  • The most prevalent IGFBP, IGFBP3, is synthesized by the liver with over 80% bound to IGF-1, serving as a clinical indicator of IGF-1 activity.

Systemic and Local IGF Effects

  • The systemic effects of IGF differ from paracrine/autocrine actions.

  • Paracrine/autocrine IGF generally has a more significant growth impact than endocrine IGF.

  • Circulating IGF from the liver controls pituitary GH release and regulates local IGF production.

Fetal and Neonate IGF Activity

  • In late gestation, IGF-1 levels in fetal circulation are correlated with fetal size.

  • The placenta is the primary source of IGF-1 for the fetus during most of gestation, influencing nutrient transfer.

  • The fetal liver becomes the major source of IGF-1 in late gestation, and postnatally, IGF-1 levels spike due to GH effects on the liver.

IGF-II Dynamics

  • IGF-II levels are higher in the fetus, but are not directly related to size; they decline post-birth.

  • The IGF-II and IGF2R genes are imprinted, expressed monoallelically based on parentage.

  • For example, in mouse fetuses, only the paternal IGF-II gene is expressed, while only the maternal IGF2R is expressed.

Placental and Fetal IGF Role

  • IGF is crucial for tissue growth and is produced in response to maternal nutritional factors.

  • Restrictions during gestation limit fetal and subsequently adult size.

  • Fetal GH is not necessary for growth, even in the presence of maternal influence.

  • Example: Fetal hypophysectomy has minimal effect on birth weight in pigs, rats, and sheep.

  • The placenta provides critical nutritional factors driving fetal IGF production.

Maternal GH-IGF Relationships

  • Maternal growth is dependent on GH, which is essential for IGF-1 production.

  • However, maternal GH and IGF do not pass through the placenta to the fetus.

Postnatal Growth Requirements

  • Postnatal growth hinges on GH from the pituitary and IGF from the liver:

    • The liver produces IGF due to its high receptor density (GHR).

    • IGF has major impacts on bone, muscle, and adipose tissues, with these tissues also showcasing GHRs.

Factors Influencing GH Release

  • GH is released in response to various metabolic and hormonal cues:

    • Positive Influences: Sleep, nutrition, exercise, and sex hormones.

    • Negative Influences: Stress and glucocorticoids.

    • Connection to the gut: When the stomach is empty, it produces Ghrelin, a peptide that stimulates GH release.

Physiological Conditions for Growth

  • Positive conditions for growth:

    • Blood glucose levels positive, Insulin positive, Amino acids positive, and GH positive.

  • Negative conditions for growth include elevated IGF-1 levels, free fatty acids, and suppressed GH.

Mechanisms of Growth Regulation

  • In the liver, GH enhances IGF-1 production, reduces amino acid oxidation, increases glucose release, and diminishes insulin responsiveness and gluconeogenesis.

  • In muscle, GH promotes amino acid uptake (enhancing protein synthesis), mobilizes muscle glycogen reserves, and boosts glucose uptake.

  • In adipose tissues, GH reduces lipogenesis (lowering insulin sensitivity) and promotes lipolysis.

Synergy of IGF and Insulin

  • Together, IGF and insulin mediate glucose and amino acid uptake into muscle, adipose, and bone tissues via their receptors.

  • Insulin-dependent transporters for amino acids and glucose become more available on cell surfaces as insulin levels rise.

Insulin's Role in Tissue Metabolism

  • Insulin is crucial for specific tissues:

    • Muscle: Utilizes fatty acids and glucose as main fuels; insulin promotes glucose uptake and glycogen storage.

    • Adipose: Insulin also promotes glucose uptake and fatty acid release.

    • Brain: Glucose acts as the main fuel (lacks glycogen storage).

    • Liver: Responsible for glycogen storage and glucose release; uptake is dictated by glucose concentration.

GH and IGF's Effects on Bone Growth

  • GH before puberty encourages normal long bone growth.

  • Increased levels of sex steroids (such as estrogen) at puberty halt long bone growth, concluding the growth phase.

Postnatal IGF Observations in Dogs

  • Studies have shown dogs' postnatal growth in body weight and size parallels IGF-1 levels, with significant findings from Eigenmann, 1984, Acta Endocrinol.

IGF-1 and Height Association in Humans

  • In humans (both males and females), IGF-1 levels positively correlate with height up until puberty.

  • This pattern is also observed in rodents, livestock, and domestic cats.

  • Additionally, breed size in dogs associates with specific IGF-1 alleles.

Implications of Excess GH

  • In humans and animals before puberty, excess GH can lead to gigantism:

    • Example: Robert Wadlow (1918-1940), who measured 8'11" due to excessive elongation of bones and continued organ growth, often caused by pituitary tumors.

Consequences of Excess GH After Puberty

  • Post-puberty excess GH can cause acromegaly:

    • Example: Andre the Giant, measuring 7'4" and weighing 520 pounds, exhibited enlarged extremities and facial features due to continued bone growth without height increase.

    • This condition typically relates to pituitary tumors causing elevated GH and IGF-1.

Consequences of Low GH Before Puberty

  • Insufficient GH results in dwarfism characterized by abnormal proportions due to restricted long bone growth.

  • The inability to produce or bind GH or IGF can result in a miniature body size, while maintaining normal proportions.

  • An example includes miniature Brahman cattle that are 70% of expected height, often attributed to pituitary tumors, cellular trauma (such as radiation), or genetic mutations affecting growth pathways.