Estrogens: Clinical Uses

• Primary Hypogonadism:
  • Estrogens for estrogen replacement therapy
  • Estrogen deficiency due to:
    1. castration
    2. primary failure of ovarian development
    3. menopause
  • Treatment of primary hypogonadism:
    •  initiation time -- 11-13 years of age
      • Rationale:
        1. stimulation of secondary sex characteristics, menses
        2. stimulation of growth
        3. avoiding psychological effects of the delayed puberty
    •  Agents used:
      • conjugated estrogens
      • ethinyl estradiol
  • Following growth completion® transition to chronic therapy (estrogen + progestins)

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•  Postmenopausal Hormonal Treatment:estrogens
  •  Longer-lasting changes associated with menopause: those that may influence health/well-being of postmenopausal women:
    •  accelerated bone loss --predisposing to:
      • wrist, vertebral, hip fractures
    • Osteoporosis: close correlation between estrogen loss and osteoporosis development
      • Frequency of vertebral/hip fractures between ages of 60 -90 years of age: women -- 25%; men-- 10%
      • Highest hip fracture frequency: elderly, white women
      • major cause of morbidity/death; death frequency -- 30% or more in patients over eighty years of age.
      • Other factors influencing osteoporosis development:
        • smoking, diet, physical activity, general health, estrogen deprivation
    •  lipid changes: increasing risk of cardiovascular disease

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  • Bone:estrogen replacement effective
    • Factors influencing osteoporosis development:
      • amount of initial bone present
      • calcium intake
      • physical activity
      •  Risk Highest:
        • thin, Caucasian, inactive women with low calcium intake + strong family history
    • Estrogen replacement:
      • Conjugated Estrogen or ethinyl estradiol effective
        • in preventing decrease in bone density recurring menopause
        • insuring adequate daily calcium intake is also important

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  • Cardiovascular Issues:
    •  Following oophorectomy or menopause -- estrogen levels fall:
      • increase in plasma cholesterol + LDL
      • decrease in LDL receptors
      • +/-HDL
    • Following estrogen replacement:
      •  decrease in total cholesterol
      •  decrease in LDL cholesterol
      •  increase in HDL cholesterol
      •  50% reduction in myocardial infarction frequency
      •  as much as 40% reduction in fatal stroke frequency

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  • Management of hot flushes:
    • symptomatic relief -- use lowest estrogen does possible
      • limited period of treatment to reduce breast cancer risk
    • Following hysterectomy: estrogens alone {frequency-five days per week or continuously; progestins are not required to reduce endometrial hyperplasia or cancer risk}
    • Symptoms relieved by estrogen replacement:
      • hot flushes
      • sweating
      • insomnia
      • atrophic vaginitis
    •  Symptoms which may not be relieved by estrogen replacement:
      • psychopathological conditions, including depression

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  •  Atrophic vaginitis:
    •  Post menopausal symptoms limited to atrophic vaginitis & limited osteoporosis risk:
      •  topical treatment:
        • locally administered estrogens not subject to first-pass effect (negative hepatic consequences minimized)

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  • Cancer:
    •  estrogen monotherapy: increased risk of endometrial carcinoma
    •  progestational agent + estrogen: prevents endometrial hyperplasia; markedly reduced cancer risk
      • Combinations: estrogen + progestin medroxyprogesterone: reduced risk (protocol: -- estrogen, first 25 days of the month; progestin medroxyprogesterone added during last 10-14 days of month)
        •  cyclic bleeding may occur
        •  cyclic bleeding eliminated with treatment combining conjugated equine estrogens + medroxyprogesterone:
          • this combination will also:
            • control vasomotor symptoms
            • prevent genital atrophy
            • maintained bone density
            • promote favorable lipid profiles
          • associated with endometrial atrophy
            • some breakthrough bleeding
            • continues therapy: disadvantage -- periodic biopsy if bleeding occurs after first few months

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  •  Therapeutic approach if estrogen replacement therapy: contraindicated --
    • progestational drugs
    • clonidine

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  • Other Uses:
    • Estrogen + progestins:
      • ovulation suppression for treating intractable dysmenorrhea
      • ovarian suppression used to manage hirsuitism and amenorrhea due to excessive ovarian androgen secretion
    • Estrogen:
      • stop excessive uterine bleeding -- caused by endometrial hyperplasia
      • may stop blood loss (temporarily)

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•  Adverse Effects:estrogen
  • Use smallest dose possible to minimize adverse effects
  • Estrogen therapy -- major cause of Postmenopausal bleeding
    •  other cause: endometrial carcinoma
    • endometrial hyperplasia: prevented by a progestational agent along with estrogen in each cycle
  • Nausea-- common (minimized by smallest effective estrogen dose)
  • Breast tenderness-- common (minimized by smallest effective estrogen dose)
  • Hyperpigmentation
  • Increased frequency of:
    •  gallbladder disease
    •  hypertension
    • cholestasis
    • migraine headaches
  •  Cancer:estrogens
    • chronic estrogen use:
      •  small increase in breast cancer risk
      •  following unilateral breast cancer surgery:
        •  tamoxifen treatment reduces by 35% breast cancer risk on contralateral side
        •  tamoxifen: well tolerated --
          • positive, estrogen-like changes in plasma lipids
          • stabilizes bone loss
      • increase risk of endometrial cancer with estrogen monotherapy
        • could dependent on estrogen dosage and duration-contraversial
      • decreased risk of endometrial cancer with estrogen combined with progestin.
    • Diethylstilbestrol:
      •  vaginal carcinoma in young women whose mothers received diethylstilbestrol early pregnancy
      • low incidence (1 per 1000) has been considered to low to establish cause-and-effect relationship with complete certitude:
        • in the same population, increased risk for:
          •  infertility
          •  premature delivery
          •  ectopic pregnancy
      • No role of diethylstilbestrol during pregnancy
        • may be used in management of prostatic cancer
        • alternative use: "morning-after" contraceptive
•  Contraindications:estrogen--patients:
  • with estrogen-dependent neoplasm (e.g. endometrial carcinoma)
  • at higher risk for or with breast carcinoma
  • with undiagnosed genital bleeding
  • with liver disease
  • predisposed to thromboembolic disease