Steroid Hormones

• all steroids are cholesterol derivatives. they only differ in ring structure and added side chains
• 6 classes of steroid hormones:

  1. estrogens
  2. androgens
  3. progestins
  4. glucocorticoids
  5. mineralocorticoids
  6. vitamin d steroids
• What is a precursor to 5/6 steroid hormones?

  pregnenolone
• control of steroidogenesis:

  1. synthesis of cholesterol
  2. tissue-specific conversion of cholesterol to steroid hormones
• cholesterol synthesis:

  acetate (n=3) -> mevalonate (n=6 molecules) -> cholesterol

  • acetate -> mevalonate step uses HMG-CoA reductase - this is the RATE LIMITING STEP
  • increase cholesterol -> decreased reductase
  • eating a lot of cholesterol causes the liver to reduce cholesterol production
• primary sites of steroidogenesis

  • adrenal gland
  • gonads (ovary, testis)
• secondary sites of steroidogenesis

  • placenta
  • skin
  • liver
  • kidney
  • brain
• sites of cholesterol synthesis

  • liver
  • intestine
  • skin
  • adrenal gland
  • ovary, testis, placenta
  • brain
  • accounts for 60% of cholesterol synthesis
• cholesterol transport in blood

  • lipids have to be escorted around the blood (packaged) by lipoproteins
  • lipoproteins are not molecules, not particles made up of thousands of molecules
  • contain triacylglycerol, phospholipids and cholesterol and amphipathic proteins called apolipoproteins
  • lipoproteins differentiated on basis of density and kind of apolipoprotein they contain
  • VLDL, LDL, HDL, chylomicrons
• • the function of LDL is to deliver cholesterol to cells, where it is used in membranes, or for the synthesis of steroid hormones
  • as VLDL particles are stripped of triacylglycerol, they become more dense
  • these particles are remodeled at the liver and transformed into LDL
• cells take up cholesterol by receptor-mediated endocytosis
• LDL binds to a specific LDL receptor and is internalized in the endocytic vesicle
• either:

  1. cells make own cholesterol
  2. cells take up LDL and converts that into free cholesterol
• negative regulation:

  1. reduce cholesterol production, if necessary
  2. increase acyl CoA cholesterol acyl transferase
  3. ACAT esterifies cholesterol
  4. esterified cholesterol is the form that is stored inside the cells
  5. esterification requires coupling of cholesterol to a fatty acid (monounsaturated; oleic acid)
  6. decrease LDL receptors
  7. decrease uptake of LDL and, therefore, more cholesterol
• cholesterol transport: within the cell

  • StAR: steroid acute regulatory protein
  • inside of cell is aqueous
  • StAR helps cholesterol get across between outer and inner mitochondrial membrane
  • exact mechanisms unclear
  • StAR independent processes exist
  • placental steroidogenesis is StAR independent
  • no crossing, no steroid hormone production
• synthesis of pregnenolone

  • 1st step in steroid hormone synthesis (ignoring all vitamin d derivatives)
  • Enzyme: cholesterol side chain cleavage enzyme (P450scc)
  • occurs in the mitochondria
  • required for synthesizing 5/6 classes of steroid hormones
  • availability of cholesterol via StAR is RATE LIMITING
• P450 enzymes

  • cytochrome P450 (pigment 450) is a generic term for a group of oxidative enzymes. they absorb light at 450 nm in their reduced states complexed with carbon monoxide
  • activity:
  • NADPH-dependent oxidation of steroids
  • associated with mitochondria or smooth ER
• four possible actions of P450 enzymes:

  1. introduce an oxygen atom to form a hydroxyl group
  2. oxidize hydroxyl groups to form an aldehyde
  3. cleave hydrogen bonds
  4. aromatization
• HSD (hydroxysteroid dehydrogenases) steps are generally reversible
• what else regulates steroid hormone production?


  peptide/protein hormones frequently regulate the production of steroid hormones. the complement of peptide/protein hormone receptors on the cell dictates what kinds of responses and hormone production will occur
• • generally, steroid hormones are not stores in tissues
  • steroid hormones are released into the circulation after their synthesis
• plasma transport of steroids

  • vitamin d binding protein (DBP)
  • corticosteroid binding globulin (CBG)
  • cortisol, progesterone
  • sex hormone binding globulin (SHBG)
  • testosterone, estrogen
  • thyroxine binding globulin (TBG)
  • thyroxine (not a steroid hormone)
  • retinol binding protein (RBP)
  • retinol (vitamin a) (not a steroid hormone)
• plasma transport of steroids

  • all of the major steroid binding proteins are made in the liver
  • very little sequence homology between them
  • very little homology between the ligand binding domains of these proteins, the steroid receptors, and the substrate binding domains of P450 enzymes
• freeing the steroids:

  • there are fenestrations in the capillary walls
  • the fenestrations allow the steroid to cross through with the steroid binding protein
  • the binding protein goes along with the steroid to the target cell membrane, at which point it releases it
  • hormone is free to diffuse through the cell membrane to find a receptor
• hormone concentrations at target

  1. signaling at producing cell
  2. rate of synthesis
  3. most highly regulated aspect
  4. positive and negative feedback
  5. rate of delivery
  6. high, low blood flow regions
  7. rate of degradation
  8. half life, excretion
• factors influencing steroid hormone concentrations in blood

  1. rate of synthesis
  2. rate of catabolism
  3. excretion by kidney, inactivation by liver
  4. tightness of binding to carrier proteins (effects tests of hormones)
• hormone half life

  time required to reduce the circulating plasma concentrations of a hormone by one half in the absence of new hormone secretion
• catabolism

  • occurs primarily in the liver
  • increases water solubility - easier to excrete
  • conjugation with sulfate and/or glucuronides
• steroid hormone receptors:

  • found:
  • in the plasma membrane
  • in the cytosol
  • most common
  • in the nucleus
  • on the ER?
  • main function of steroid hormone receptors is to induce gene transcription
  • zinc-finger transcription factors (nuclear receptors)
  • most dimerize and bind to a matching hormone response element
• hormone response elements

  • hormone response elements are in the promotor region of genes
  • can either enhance or repress the transcription of the gene product
  • class III nuclear hormone receptors (except ER): AGAACA
  • all other members (class I) + ER: AGGTCA
  • most nuclear receptors bind as dimers so the hexameric motif is repeated twice to form a hormone response element
• for a steroid hormone to regulate (turn on or off) gene transcription, its receptor must:

  • bind to the hormone
  • bind to a second copy of itself to form a homodimer or another similar receptor to form a heterodimer
  • be in the nucleus, moving from the cytosol if necessary
  • bind to its response element
  • bind to other protein cofactors
• • when the stress hormone cortisol - bound to its receptor - enters the nucleus of a liver cell, the complex binds to:
  • the positive response elements of the many genes needed for gluconeogenesis - the conversion of protein and fat into glucose resulting in a rise in the level of blood sugar
  • the negative response element of the insulin receptor gene thus diminishing the ability of the cells to uptake/store glucose from the blood
• nuclear receptor superfamily

  • the receptors consists of at least three functional modules or domains. From n-terminal to c-terminal, these are:
  • a domain needed for the receptor to activate the promotors of the genes being controlled
  • the zinc-finger domain needed for DNA binding (to the response element)
  • the domain responsible for binding the particular hormone as well as the second unit of the dimer
• the domain structure of the protein of members of the nuclear receptor superfamily:

  • AF-1: constitutive transactivation domain; hypervariable
  • hinge: linker, nuclear localization signals, coR interactions
  • DNA binding domain: also dimerization
  • AF-2: ligand binding, coA and coR binding, interaction with heat shock proteins in the cytosol, dimerisation
  • F: present in some members of this superfamily; unknown function