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

• Hormones are chemical messengers that circulate in body fluids and produce specific effects on cells that are far from the source of the hormones.
• Growth hormone, prolactin, estrogen, and other hormones are examples.
• Hormonal action is classified into two types based on the mechanism of hormonal action. i. Peptide Hormone Mechanism and ii. Steroidal Hormone Mechanism PEPTIDE HORMONE MECHANISM

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

• Growth hormone, GHRH, and somatostatin preparations such as ‘Mecasermin’ are used in the diagnosis and treatment of growth problems caused by excessive or insufficient growth hormone secretion.
• Mecasermin is a human IGF- 1 recombinant.
• Escherichia coli bacteria that have been transfected with the human IGF- 1 gene, produce it.
• Mecasermin is approved to treat growth failure in children with severe IGF- 1 insufficiency who are insensitive to growth hormone administration, including those with a growth hormone receptor mutation and those who have generated growth hormone neutralizing antibodies.

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)

• GHRH, a 44 - amino acid peptide generated by hypothalamic neurons, increases GH secretion by binding to a particular GPCR on anterior pituitary somatotrophs.
• When the GHRH receptor is triggered, it binds to Gs, raising intracellular levels of cAMP and Ca 2 + and therefore increasing Growth Hormone production and secretion.

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

THE SEX HORMONES

• Sex hormones, also referred to as sex steroids, are steroid hormones that interact with sex hormone receptors.
• These hormones include estrogen and androgens, which are generated predominantly by the ovaries and testes.

MECHANISM OF ACTION OF TESTOSTERONE

Testosterone hormone is bound to the SHBG (sex hormone binding globulin) and remains inactive. The free testosterone passes through the plasma membrane and reaches the cytoplasm and binds with the Androgen Receptor (AR) (which remains inactive when it is bounded to the heat shock protein). HSP gets displaced by the testosterone and testosterone- androgen receptor complex formed and undergo dimerization. The dimer translocates itself into the nucleus. 12

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.

MECHANISM OF ACTION OF ESTROGEN The estrogen receptor (ER) is in inactive form as they are bound with HSP. Estrogen enters the into the cell across plasma membrane and binds with ER and displaces the HSP. It forms a complex of estrogen and estrogen receptor and undergo dimerization. It interacts with the specific DNA sequence called as estrogen response element (ERE). This causes the activation and formation of desired target gene expression. This undergo transcription and forms mRNA. The formed specified mRNA interacts with the Ribosomes to form specified proteins that are directed by the Estrogen