Estrogens

Estrogen Biosynthesis/Metabolism

• Estrogenic activity:
  • many substances
    • steroidal estrogens -- animal sources
    • nonsteroidal estrogens -- synthetic
    • phenols -- estrogenic

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  • Natural Estrogens:
    • Major estrogens:
      • estradiol (estradiol-17 ß, E₂)
      • estrone (E₁)
        • hepatically formed from estradiol
        • formed in peripheral tissues from androstenedione/other androgens
        • small amount: ovarian
      • estriol (E₃)
        • hepatically formed from estradiol
        • formed in peripheral tissues from androstenedione/other androgens

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    • Anatomical sites of estrogen synthesis:
      • initial part eventual cycle: -- theca cells (ovarian follicle)
      • Following ovulation: --estrogens + progesterone: granulosa cells of the corpus luteum
      • During pregnancy:
        • Significant estrogens synthesis: fetoplacental unit
          • Estriol ® maternal circulation; urinary excretion
          • maternal urinary estriol excretion: helpful for fetal condition assessment

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    • Significant source of natural estrogen:
      •  Stallion
      •  Equine estrogens -- recovered from urine; may be used for medical applications
        • equilenin
        • equilenin

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    • Synthetic Estrogens:
      • Chemical modifications of natural estrogens -- Major consequences = enhanced oral effectiveness
      • Examples of nonsteroidal agents with estrogenic activity:
        • dienestrol
        • diethylstilbestrol
        • benzestrol
        • hexestrol
        • methestrol
        • methallenestril
        • chlorotrianisene

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• Pharmacokinetics:Estrogens-- Following release into circulation:
  • Estradiol binds with high affinity to an a₂-globulin (sex hormone-binding globulin, {SHBG})
    • estradiol binds to albumin with lower affinity
    • only free estradiol is physiologically active

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  • Conversion Steps:
    • Estradiol converted to (by the liver/other tissues):
      •   estrone, estriol (low estrogen receptor affinity)
      •   2-hydroxylated derivatives; conjugated metabolites --lipid insoluble ® biliary excretion then conjugates are hydrolyzed in intestine to active, reabsorbable forms
  •  Catechol estrogens: neurotransmitters
    • converted to 2-and 4-methoxy derivatives by catechol-O-methyltransferase
  •  Estrogens: secreted (small amounts) in breast milk

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  • High biliary excretion and intestinal reabsorption (enterohepatic circulation) ® significant hepatic:peripheral effect ratio
    •  Significance: hepatic concentration-- undesirable actions may result:
      • increased clotting factor synthesis
      • increased plasma renin substrate
    •  To minimize enterohepatic effects-- estrogens for peripheral actions (postmenopausal women)-- use routes of administration that avoid first pass effects (vaginal, transdermal, injection)

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Physiological Effects:Estrogens

•  Mechanism:Sequence
  1. sex hormone-binding globulin bind plasma estrogens (plasma)--forms complex
  2. complex dissociation followed by cell entry leading to intracellular estrogen receptor binding
     •   Estrogen Receptors:
       • steroid/thyroid receptor superfamily
       •  Location: mainly nuclear -- associated with stabilizing proteins
       • hormone + receptor interaction causes a conformational change with release of associated, stabilizing proteins (primarily hsp90)

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     •   Estrogen -- estrogen receptor complex
       • forms homodimers
       • homodimers buying to estrogen response elements (EREs) regulating transcription various genes
       • ERE -- receptor dimer interaction involves transcription element proteins
       • receptor complex: does not bind exclusively to gene promoter regions

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     •  Hormone action -- Cellular specificity
       • depends on variety/number of receptors sites & transcription factors

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     • Genomic Effects:estrogen
       • consequence of proteins synthesized in response to gene(s) activation
       • also indirect genomic effects:
         •   paracrine effects of cytokines produced by regional cells under regulation by target cell proteins, induced by estrogen

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  • Membrane Estrogen Receptors:
    • Consequences of estrogen-activation of membrane receptors (no gene activation) include, e.g.:
      • rapid, granulosa cell calcium uptake
      • increased uterine blood flow

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• Female Maturation:estrogen required for normal female maturation
  • Stimulate the development of:
    •  vagina
    •  uterus
    •  uterine tubes
    •  secondary sex characteristics

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  • Stimulation:estrogen-
    •  stromal development
    •  ductal growth in the breast
    •  growth spurt/closing of the epiphyses of long bones (puberty)
    •  axillary & pubic hair; promote redistribution of body fat -- resulting in typical female body contours
    •  skin pigmentation -- particularly in the nipple region, areolae, and genital areas

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• Endometrial Effects:estrogen
  •  Promotes endometrial lining development
  •   Continuous, excessive estrogen exposure ® endometrial hyperplasia (may cause abnormal bleeding)
  •   estrogen & progesterone coordination during normal menstrual cycle:
    • periodic bleeding
    • endometrial lining shedding

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• Metabolic Effects:estrogen
  1. Maintenance of normal skin/blood vessel structure (in women)
  2. Decrease rate of bone resorption (parathyroid hormone antagonism)
  3. Promote intestinal absorption (decrease bowel motility)
  4. Hepatic effects -- metabolic and causes increased circulating concentrations of:
     • transcortin (CBG)
     • thyroxine-binding globulin (TBG)
     • sex hormone-binding globulin (SHBG)
     • renin substrate
     • transferrin
     • fibrinogen
     • These effects tend to increase the circulating concentrations of thyroxine,estrogen, testosterone, iron, copper, other compounds
  5. Plasma Lipid Effects:
     • increased in high-density lipoproteins
     • slight decrease in low-density lipoproteins
     • decreased cholesterol
     • increase plasma triglycerides
       • increased triglycerides synthesis
       • decreased lipid oxidation ketones

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• Blood Coagulation:Estrogen
  • Estrogen: causes enhancement of blood coagulation
    • increased circulating factors II, VII, IX, X. {note hepatic effects}
    • decreased antithrombin III
    • increased plasminogen concentration
    • decreased platelet adhesiveness

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• Miscellaneous Effects: Estrogen
  1. induce progesterone receptor synthesis
  2. affect human libido
  3. promote renal Na/water retention
  4. influence sympathetic nervous system-mediated smooth muscle tone

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