Introduction to Hormones

Hormones

• Hormones are mobile messages synthesized in one organ and transported by the circulatory system to act on another tissue.
• Hormones can act on adjacent cells (paracrine action) and on the cell in which they were synthesized (autocrine action) without entering the systemic circulation.

Classification of Hormones

• Hormones can be classified according to:
  • Chemical composition
  • Solubility properties
  • Location of receptors
  • The nature of the signal used to mediate hormonal action within the cell

Hormone Synthesis

• Hormones synthesized from:
  • Cholesterol (e.g. glucocorticoids, mineralocorticoids, androgens, estrogens, progestins)
  • Amino acids (e.g. thyroxine, triiodothyronine)

Androgen Synthesis

• Dehydroepiandrosterone (DHEA) is the major androgen precursor produced in the adrenal cortex.
• DHEA is converted into androstenedione, which is then reduced to form testosterone.

Testosterone

• Testosterone is converted into dihydrotestosterone (DHT) in tissues outside the testes.
• Some estradiol is formed from the peripheral aromatization of testosterone.

Ovarian Steroidogenesis

• 17β-Estradiol is the primary estrogen of ovarian origin.
• Estrogens are formed by the aromatization of androgens in the ovary.
• Progesterone is produced and secreted by the corpus luteum.

1,25(OH)2-D3 (Calcitriol)

• 1,25(OH)2-D3 is synthesized from 7-dehydrocholesterol in the skin and transported to other organs.
• Hydroxylation at position C1 produces 1,25(OH)2-D3 in the kidney.

Tyrosine Derivatives

• Catecholamines (dopamine, norepinephrine, and epinephrine) are synthesized from tyrosine in the chromaffin cells of the adrenal medulla.
• Thyroid hormones (T3 and T4) are synthesized from tyrosine in the thyroid gland.

Thyroid Hormone Synthesis

• Thyroglobulin is iodinated and then glycosylated to form T4 and T3.
• The coupling of two DIT molecules forms T4, or of an MIT and DIT forms T3.
• T3 synthesis occurs in the thyroid gland and in peripheral tissues.

Angiotensin II

• Angiotensin-converting enzyme (ACE) forms angiotensin II from angiotensin I.
• Angiotensin II inhibits renin release and stimulates aldosterone production.

Variations in Storage and Secretion of Hormones

• Steroid hormones and 1,25(OH)2-D3 are synthesized in their final active form and secreted as they are made.
• Catecholamines are synthesized in active form, stored in granules, and released in response to neural stimulation.
• PTH is stored in vesicles and secreted when Ca2+ levels are low in the parathyroid cells.
• Insulin is stored in the β cells of the pancreas and secreted in response to stimuli such as glucose.

Hormone Signaling

• Hormones that bind to surface receptors communicate with intracellular metabolic processes through second messengers, which are generated as a consequence of the ligand-receptor interaction.
• The ligand-receptor complex is the intracellular messenger in this group.

Hormone Classification

• Polypeptide/protein hormones and catecholamines bind to receptors located on the plasma membrane, generating a secondary messenger or signal that regulates various intracellular functions.
• Lipophilic steroid, retinoid, and thyroid hormones interact with intracellular receptors, directly providing a signal that affects the transcription rate of specific genes.

Hormone Synthesis and Modification

• Hormones derived from cholesterol are synthesized in final form and secreted immediately.
• Catecholamines are synthesized in final form and stored in the producing cells.
• Hormones like insulin are synthesized as precursor molecules in the producing cell, processed, and secreted upon a physiologic cue (plasma glucose concentrations).
• T3 and DHT are converted to their active forms from precursor molecules in peripheral tissues.

Adrenal Steroidogenesis

• The adrenal gland has two different parts.
• Cleavage of the side chain involves sequential hydroxylations, followed by side chain cleavage to give the 21-carbon steroid.
• All mammalian steroid hormones are formed from cholesterol via pregnenolone through a series of reactions that occur in either the mitochondria or endoplasmic reticulum of the producing cell.
• Aldosterone is the most potent natural mineralocorticoid in humans, stimulating Na+ reabsorption and K+ excretion in the kidneys.
• Cortisol is the most potent natural glucocorticoid hormone in humans, stimulating gluconeogenesis and inhibiting the immune response.

Steroid Transport

• Glycocorticoid transport: The main plasma binding protein is transcortin, or corticosteroid-binding globulin (CBG).
• Gonadal Steroid Transport: Testosterone is carried in the circulation by sex hormone–binding globulin (SHBG) or testosterone-estrogen–binding globulin (TEBG), and estrogens are bound to SHBG and progestins to CBG.

Androgen Synthesis

• The major androgen or androgen precursor the adrenal cortex produces is dehydroepiandrosterone (DHEA).
• DHEA is converted into the more potent androstenedione, which is then reduced to form testosterone, the most potent adrenal androgen.

Testosterone

• Testosterone can be considered a prohormone and is metabolized by two pathways.
• It is converted into its more potent metabolic compound Dihydrotestosterone (DHT), and some estradiol is formed from the peripheral aromatization of testosterone, particularly in males.

Ovarian Steroidogenesis

• 17β-Estradiol is the primary estrogen of ovarian origin.
• Estrogens are formed by the aromatization of androgens, catalyzed by the P450 monooxygenase.

Thyroid Hormone Synthesis

• DIT, diiodotyrosine, and MIT, monoiodotyrosine, are precursors to T3 and T4 hormones.
• Thyroglobulin (prohormone) is iodinated and then glycosylated to form T4 and T3.
• The coupling of two DIT molecules to form T4—or of an MIT and DIT to form T3—occurs within the thyroglobulin molecule.

Tryptophan Derivatives

• Serotonin and melatonin are synthesized from tryptophan derivatives.

Protein/Peptide Hormones

• Several hormones are made from larger peptide precursors, such as insulin, parathyroid hormone (PTH), angiotensin II, and pro-opiomelanocortin (POMC) protein.
• These hormones are produced in pre-prohormone structure in ribosomes.

Insulin

• Insulin is synthesized as a preprohormone in the pancreatic beta cells.
• Pro-insulin is the inactive form, which undergoes site-specific peptide cleavages in the Golgi apparatus to form equimolar amounts of mature insulin and C-peptide.