Growth Hormone and Sex Hormone, Summaries of Pharmacology

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MOLECULAR & CELLULAR

MECHANISM

OF ACTION OF HORMONES

Growth Hormone & Sex Hormone

CONTENTS

• Basic Hormone Mechanism
• The Growth Hormone (GH)
• Growth Hormone Preparation
• Mechanism of action of growth hormone
• The Sex Hormone

BASIC HORMONE MECHANISM

STEROIDAL HORMONE MECHANISM

• The steroidal hormone penetrates the target cell's cytoplasm and attaches to a specific high- affinity receptor protein.
• The generated receptor protein-hormone complex then diffuses into the nucleolus and interacts with nuclear chromatin.
• This causes the targeted gene to produce mRNA in the nucleolus.
• In the cytoplasm, mRNA interacts with ribosomes to produce new protein.

THE GROWTH HORMONE

• Somatotropin (growth hormone) is a long peptide with 191 amino acids.
• The anterior pituitary gland produces it, and it has both direct and indirect effects on target organs.
• Growth hormone stimulates lipolysis while antagonizing insulin to raise blood glucose levels.
• The majority of growth hormone's effects are mediated by insulin-like growth factor- 1 (IGF- 1 ), a protein made in the liver.
• Skeletal growth, amino acid transport, protein synthesis, nucleic acid synthesis, and cell proliferation are all stimulated by IGF-I.GHRH stimulates growth hormone secretion while somatostatin inhibits it.

THE GROWTH HORMONE

Adverse Effect

• The main adverse effect is hypoglycemia, which is controlled by eating a meal or snack before or soon after the time of the injection GROWTH HORMONE-INHIBITING HORMONE PREPARATIONS.
• Somatostatin (SST) (growth hormone-inhibiting hormone) is a 14 - amino acid peptide that inhibits growth hormone release as well as pituitary hormone secretion. It has a relatively short half- life of 1 to 3 minutes.
• Octreotide is an 8 - amino acid somatostatin derivative that is 45 times more effective at inhibiting growth hormone secretion.
• It has an 80 - minute half-life.

THE GROWTH HORMONE

Regulation of Secretion

• GH secretion fluctuates throughout life. GH secretion is high in children, peaks at puberty, and subsequently declines with aging in adulthood.
• At night, the amplitude of secretory pulses is greatest.
• GHRH and ghrelin promote GH secretion, which is inhibited by GH itself, SST, and IGF- 1.

Growth Hormone-Releasing Hormone (GHRH)

Feedback Control of GH Secretion-IGF 1

• Growth hormone and its principal peripheral effector, IGF- 1 , inhibit GH release via negative feedback loops.
• IGF- 1 has a deleterious effect on the anterior pituitary gland primarily through direct actions, but it also has an effect on the hypothalamus via stimulation of SST secretion.
• SST helps to moderate GH's negative feedback action.
• IGF- 1 interacts with cell surface receptors that mediate its biological activity when it is synthesised and released.

MECHANISM OF ACTION-GROWTH HORMONE

Growth hormone receptor activation. Results in the binding of a single GH to two receptor monomers to form GH-[GH] 2 complex or dimer. It further induces a conformational change that activates downstream signaling. GHR dimer provides docking sites for 2 molecules of JAK 2 (Janus kinase family). The juxtaposition of the JAK 2 molecule leads to the trans- phosphorylation and autoactivation of JAK2. The consequent tyrosine phosphorylation of docking site on cytoplasmic segment of the GHR mediate downstream signaling event. These include STAT proteins, SHC (regulator of Ras/MAPK pathway) and IRS-1 and IRS-2 proteins that activate PI3K pathway. A specific STAT5 protein get phosphorylated and regulates the gene encoding for IGF-1 (the mediator of the effects of GH) 11

MECHANISM OF ACTION OF TESTOSTERONE

The dimer inside the nucleus binds with the coactivator and reacts with the specific DNA sequence called as Androgen Response Element (ARE). This causes the activation of the target gene and mRNA produced which has been specified by the Androgen Response Element. The mRNA then synthesizes specific proteins directed by the Androgen and this leads to specific biological activity.