2 Endocrinology

• The survival of multicellular organisms depends on their ability to adapt to a constantly changing environment
• Intercellular communication mechanisms are necessary requirements for this adaptation
• The nervous system and the endocrine system provide this intercellular, organism-wide communication
• Hormone


  A substance that is synthesized in one organ and transported by the circulatory system to act on another tissue
• Target cell


  Any cell in which the hormone (ligand) binds to its receptor, whether or not a biochemical or physiologic response has yet been determined

  
• Factors that determine the response of a target cell to a hormone

  • Factors that affect the concentration of the hormone at the target cell
  • Factors that affect the actual response of the target cell to the hormone

  
• Hormone receptors


  • They discriminate precisely between hormones and other similar molecules
  • They have a recognition domain that binds the hormone ligand and a coupling domain that generates a signal to regulate intracellular functions

  
• Receptors are proteins that can be classified into different groups based on their mechanism of action
• Classification of hormones by mechanism of action

  • Lipophilic hormones that bind to intracellular receptors
  • Water-soluble hormones that bind to cell surface receptors and use second messengers to mediate their effects

  
• Hormones are synthesized in a variety of cellular arrangements, including discrete organs, specialized cells within organs, and requiring multiple organs
• Hormones are chemically diverse, with many derived from cholesterol and some acting as precursors for other hormones

  
• The testes produce mature spermatozoa and testosterone
• Organs that produce hormones

  • Small intestine (glucagon-like peptide)
  • Thyroid (calcitonin)
  • Kidney (angiotensin II)
• The synthesis of some hormones requires the parenchymal cells of more than one organ, e.g. the skin, liver, and kidney are required for the production of 1,25(OH)2-D3 (calcitriol)

  
• Chemical building blocks for hormones

  • Cholesterol
  • Tyrosine

  
• Steroid hormones


  Derived from cholesterol

  
• Catecholamines and thyroid hormones

  Derived from the amino acid tyrosine

  
• Types of hormones


  • Polypeptides
  • Glycoproteins

  
• Polypeptide hormones


  • Thyrotropin-releasing hormone (TRH, tripeptide)
  • Adrenocorticotropic hormone (ACTH, 39 amino acids)
  • Parathyroid hormone (PTH, 84 amino acids)
  • Growth hormone (GH, 191 amino acids)
  • Insulin (A-B chain heterodimer, 21 and 30 amino acids)

  
• Glycoprotein hormones


  Have a common α subunit and unique β subunits, molecular mass 25-30 kDa

  
• Ways hormones are synthesized and modified

  • Synthesized in final form and secreted immediately
  • Synthesized in final form and stored in producing cells
  • Synthesized as precursor molecules, then processed and secreted
  • Converted to active forms from precursor molecules in peripheral tissues

  
• Adrenal steroidogenesis


  1. Cholesterol derived from plasma and synthesized in situ

  2. Cholesterol transported into mitochondria

  3. Cholesterol converted to pregnenolone by P450scc enzyme

  4. Pregnenolone converted to steroid hormones through series of reactions

  
• Adrenal steroidogenesis


  • Cellular specificity - some enzymes only in certain adrenal zones
  • Shuttling of substrates between mitochondria and endoplasmic reticulum

  
• Mineralocorticoid synthesis


  1. Pregnenolone converted to progesterone

  2. Progesterone hydroxylated to 11-deoxycorticosterone

  3. 11-Deoxycorticosterone hydroxylated to corticosterone

  4. Corticosterone converted to aldosterone by 18-hydroxylase

  
• Glucocorticoid synthesis


  1. Pregnenolone or progesterone hydroxylated at C17

  2. 17α-Hydroxyprogesterone hydroxylated at C21 to form 11-deoxycortisol

  3. 11-Deoxycortisol hydroxylated at C11 to form cortisol

  
• Androgen synthesis


  1. 17-Hydroxypregnenolone converted to dehydroepiandrosterone (DHEA) by 17,20-lyase

  2. DHEA converted to androstenedione

  3. Androstenedione converted to testosterone

  
• Adrenal androgen production


  Increases if glucocorticoid biosynthesis is impeded

  
• DHEA


  A prohormone that is converted to more potent androgens

  
• Testicular steroidogenesis


  1. Cholesterol transported into mitochondria by StAR protein

  2. Cholesterol converted to pregnenolone by P450scc

  3. Pregnenolone converted to testosterone via Δ4 or Δ5 pathways

  
• Dihydrotestosterone (DHT) formation


  1. Testosterone metabolized by 5α-reductase to form DHT in peripheral tissues

  2. DHT is a more potent metabolite of testosterone

  
• Dihydrotestosterone (DHT)


  The active metabolite of testosterone, produced in target tissues

  
• Testosterone metabolism


  Conversion to DHT by 5α-reductase enzyme

  
• DHT is a much more potent metabolite than the parent compound testosterone

  
• Metabolism by the less efficient second pathway occurs primarily in target tissues and produces the potent metabolite DHT

  
• The most significant metabolic product of testosterone is DHT
• In many tissues, including prostate, external genitalia, and some areas of the skin, DHT is the active form of the hormone

  
• The plasma content of DHT in the adult male is about one-tenth that of testosterone
• About 400 μg of DHT is produced daily as compared with about 5 mg of testosterone
• About 50 to 100 μg of DHT are secreted by the testes, the rest is produced peripherally from testosterone by the 5α-reductase enzyme

  
• Testosterone can be considered a prohormone since it is converted into the much more potent compound DHT, and most of this conversion occurs outside the testes