Estrogen Replacement

Aka: Estrogen Replacement, Hormone Replacement, Estrogen Replacement Therapy, Hormone Replacement Therapy

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II. Indications

  1. Premature Ovarian Failure
  2. Menopause
    1. Bothersome menopausal symptoms (e.g. Vasomotor Symptoms of Menopause) AND
    2. First 10 years after last Menses or age <60 years in otherwise healthy women without contraindication

III. Contraindications: Estrogen Replacement

  1. Absolute Contraindications
    1. Unexplained Vaginal Bleeding
    2. Acute Liver Disease or severe liver disease
    3. Breast Cancer (Hormone-sensitive)
    4. Active Thrombophlebitis
    5. Thromboembolic disorder including past history of Venous Thromboembolism
    6. Pregnancy
  2. Relative Contraindications
    1. Chronic Liver Disease
    2. Heart disease
    3. Endometrial Cancer
    4. Hypertension
    5. Familial Hyperlipidemia
      1. Consider Transdermal Estrogen
    6. Seizure Disorder
    7. Migraine Headaches
    8. History of Thrombophlebitis
    9. Endometriosis
    10. Gall Bladder disease

IV. Precautions

  1. Estrogen Replacement is recommended only for symptom control (e.g. Hot Flushes), not for chronic disease prevention
    1. Risks and benefits of Estrogen with or without Progesterone are complex
    2. ACOG and AAFP do not recommend Hormone Replacement for chronic disease prevention
    3. Use the lowest effective dose for the shortest duration needed
    4. (2013) Obstet Gynecol 121(6): 1407-10 [PubMed]
    5. Manson (2013) 310(13): 1353-68 +PMID:24084921 [PubMed]
  2. Consider for women under age 60 years old or within 10 years of Last Menstrual Period
    1. Avoid when contraindicated (see below)
    2. All cause mortality (including CAD risk) is not increased with HRT
      1. Manson (2017) JAMA 318(10): 927-38 [PubMed]
    3. Over age 60 years, HRT risks of CVA, MI, Dementia outweigh benefits
  3. Different Estrogen types are equivalent in efficacy
    1. Adverse effects and safety are also equivalent
    2. No evidence for superiority of bioidentical synthetic Estradiol over other Estrogen preparations
    3. References
      1. Gaudard (2016) Cochrane Database Syst Rev (8):CD010407 +PMID: 27479272 [PubMed]
      2. Nelson (2004) JAMA 291:1610-20 [PubMed]
  4. Combination therapy (with Progesterone) differ in their risks compared with Estrogen alone
    1. Outside of SERM use (e.g. Bazedoxifene in Duavee), HRT with intact Uterus requires combination therapy
    2. Invasive Breast Cancer and CAD risks are increased with combination therapy but not Estrogen alone
    3. Colorectal Cancer risk is decreased with combination therapy but increased with Estrogen alone

V. Advantages: Benefits of Estrogen Replacement

  1. All cause mortality (including CAD risk) is not increased with HRT
    1. Manson (2017) JAMA 318(10): 927-38 [PubMed]
  2. Osteoporosis
    1. Estrogen increases bone density by 20-30%
    2. Increases Bone Mineral Density 5-15% in 3 years
    3. Benefit even if started late postmenopausal
    4. Benefit also seen with Transdermal Estrogen
    5. Hazard Ratio for Hip Fracture: 0.66
    6. (2002) JAMA 288:321-333 [PubMed]
  3. Endocrine Effects
    1. Reduces Type II Diabetes Mellitus Risk by 20% (PEPI)
    2. Improves Glucose Metabolism
    3. Improves Insulin sensitivity
    4. Decreases Fasting Glucose levels
  4. Relief of perimenopausal Major Depression symptoms
    1. Transdermal Estrogen effective Antidepressant
    2. Soares (2001) Arch Gen Psychiatry 58:529-34 [PubMed]
  5. Relief of Genitourinary symptoms
    1. See adverse effects below regarding Incontinence
    2. Vaginal Dryness
    3. Dyspareunia
    4. Urethritis
  6. Relief of perimenonpausal vasomotor symptoms
    1. Hot Flashes
    2. Insomnia
    3. Irritability
    4. Anxiety
  7. Reduces tooth loss
  8. Protective against Colorectal Cancer
    1. Colorectal Cancer risk is decreased with combination therapy but increased with Estrogen alone
    2. Combination HRT decreases cumulative Colon Cancer risk
    3. Hazard Ratio for Colorectal Cancer 0.63
    4. (2002) JAMA 288:321-333 [PubMed]
    5. Gartlehner (2022) JAMA 328(17):1747-65 +PMID: 36318128 [PubMed]

VI. Disadvantages: Mixed Risks and Benefits

  1. Cardiovascular disease
    1. Post-stoppage study suggested cardiovascular benefit in early Menopause
      1. Manson (2013) JAMA 10(13): 1353-68 +PMID:24084921 [PubMed]
    2. NIH Women's Health Initiative Results
      1. Combined HRT Study stopped early
        1. Increased coronary risk by 7 per 10,000 patients
        2. Hazard Ratio for coronary events: 1.29
        3. Slight risk, but definately no CAD benefit
      2. Estrogen alone post-Hysterectomy
        1. Associated with slight decrease in CAD risk
      3. References
        1. (2002) JAMA 288:321-333 [PubMed]
        2. Gartlehner (2022) JAMA 328(17):1747-65 +PMID: 36318128 [PubMed]
    3. Earlier studies questioned cardiovascular benefit
      1. Increased coronary event risk in first year of ERT
      2. Protective effect after first year
      3. Grodstein (2001) Ann Intern Med 135:1-8 [PubMed]
      4. Herrington (2001) N Engl J Med 343:522-9 [PubMed]
    4. Improved survival in Congestive Heart Failure
      1. Reis (2000) J Am Coll Cardiol 36:529-33 [PubMed]
    5. Lowers systolic Blood Pressure (no diastolic effect)
      1. More pronounced effect in Obesity and advanced age
      2. Scuteri (2001) Ann Intern Med 135:229-38 [PubMed]
    6. Lipid effects (Estrogen alone without Prosterone)
      1. Increases HDL
      2. Decreases LDL
  2. Cerebrovascular Disease Risk
    1. Initial studies showed increased CVA risk
      1. Grodstein (2000) Ann Intern Med 133:933-41 [PubMed]
    2. NIH Women's Health Initiative also had increased risk
      1. Increased Incidence by 8 per 10,000 patients
      2. Hazard Ratio for Cerebrovascular Accident: 1.41
      3. (2002) JAMA 288:321-333 [PubMed]
    3. Large prospective Cohort study with no increased risk
      1. No HRT increased ischemic or Hemorrhagic CVA risk
      2. Angeja (2001) J Am Coll Cardiol 38:1297-301 [PubMed]
  3. Cognitive effects
    1. Initial studies showed decreased Alzheimer's Risk
      1. Appeared to protect against cognitive decline
      2. Paganini (1996) Arch Intern Med 156:2213-7 [PubMed]
      3. Yaffe (2000) Lancet 356:708-12 [PubMed]
    2. Recent studies have shown no benefit
      1. No benefit
        1. Buckwalter (2004) J Am Geriatr Soc 52:182-6 [PubMed]
        2. Viscoli (2005) Am J Obstet Gynecol 192:387-93 [PubMed]
      2. May adversely affect global cognitive function
        1. Espeland (2004) JAMA 291:2959-68 [PubMed]

VII. Disadvantages: Risks of Estrogen Replacement

  1. Invasive Breast Cancer
    1. See Breast Cancer Risk Factors
    2. Risk appears to be associated with replacement type
      1. Combination therapy increases risk
        1. Estrogen only therapy: 3-7 additional cases/1000
        2. Combination therapy: 18-20 additional cases/1000
        3. (2003) Lancet 362:419-27 [PubMed]
        4. Lytinen (2006) Obstet Gynecol 108:1354-60 [PubMed]
      2. Associated with Continuous Estrogen Replacement
        1. Less associated with Estrogen alone
        2. Less associated with Sequential Replacement
        3. Weiss (2002) Obstet Gynecol 100:1148-58 [PubMed]
  2. Endometrial Cancer
    1. Occurs with Unopposed Estrogen (without Progesterone)
      1. Atypical Hyperplasia in 30% on Unopposed Estrogen
      2. Risk remains 10 years after Unopposed Estrogen use
    2. Women with intact Uterus must use combination HRT
    3. Evaluate Postmenopausal Abnormal Uterine Bleeding
      1. Anticipate uterine bleeding for first 4-6 months
      2. Evaluate bleeding >6 months after starting HRT
        1. Endometrial Biopsy
        2. Uterine Ultrasound
  3. Ovarian Cancer
    1. Associated with Estrogen use without Progestin
    2. Relative Risk of Ovarian Cancer in ERT: 1.6
    3. Relative Risk if ERT use >20 years: 3.2
    4. Lacey (2002) JAMA 288:334-41 [PubMed]
  4. Venous Thrombosis risk
    1. Higher risk with Estrogen dose over 2.5 mg/day
    2. Higher risk when used with Progesterone (combination therapy)
      1. Smith (2004) JAMA 292:1581-7 [PubMed]
    3. NIH Women's Initiative
      1. Hazard Ratio for Pulmonary Embolism: 2.13
      2. (2002) JAMA 288:321-333 [PubMed]
    4. Risk if prior Venous thrombosis occurred
      1. Trauma-related: no increased risk
      2. Oral Contraceptive related: possible increased risk
    5. Esterified Estrogen (Menest) not assoc. with thrombus
      1. May be preferred form for Estrogen Replacement
      2. Smith (2004) JAMA 292:1581-7 [PubMed]
  5. Genitourinary
    1. Urinary Incontinence risk increases with Estrogen Replacement
    2. Grodstein (2004) Obstet Gynecol 103:254-60 [PubMed]
  6. Special considerations
    1. Gall Bladder disease risk
      1. Relative Risk: 1.5 to 2.0
      2. Risk persists for 5 years after Estrogen stopped
    2. Increased Triglycerides
      1. Baseline Triglycerides: 250 to 750
        1. Start Estrogen Replacement
        2. Recheck Triglycerides in 4 weeks
      2. Baseline Triglycerides: over 500
        1. Consider transdermal Estrogen Replacement
      3. Baseline Triglycerides: over 750
        1. Avoid Estrogen Replacement
        2. Risk of Pancreatitis

VIII. Safety

  1. Recent data suggests HRT is safe for 4-5 years of use
  2. All cause mortality (including CAD risk) is not increased with HRT
    1. Consider for women under age 60 years old or within 10 years of LMP, without contraindications
    2. Manson (2017) JAMA 318(10): 927-38 [PubMed]
  3. NIH Women's Health Initiative did not study age <50
    1. Consider continuing Estrogen in these patients
    2. (2002) JAMA 288:321-333 [PubMed]
  4. Meta-analysis 4000 patients, 29 studies
    1. Initially irregular bleeding for 6 months
    2. Amenorrhea in 75% after 6 months
    3. Atrophic Endometrium in 90% of patients
    4. Endometrial Hyperplasia in 1% of patients
    5. Adenocarcinoma in 0.05% of patients (2 cases)
    6. Udoff (1995) Obstet Gynecol 86:306-16 [PubMed]

IX. Medications

  1. Vasomotor Symptoms of Menopause
    1. Continuous Estrogen Replacement
      1. Preferred over sequential due to lower risk of Endometrial Hyperplasia
        1. Jaakkola (2009) Obstet Gynecol 114(6): 1197-1204 [PubMed]
    2. Sequential Estrogen Replacement
    3. Transdermal Estrogen
  2. Genitourinary Syndrome of Menopause (e.g. Atrophic Vaginitis)
    1. Vaginal Estrogen

X. Management: Algorithm for choice of replacement method

  1. Use the lowest effective dose of replacement that controls symptoms
  2. Age under 40 years, Ovaries removed, or Perimenopause (see Menopause for strategy)
    1. Sequential Estrogen Replacement OR
    2. Oral Contraceptive
  3. Menopause
    1. Continuous Estrogen Replacement (preferred) OR
    2. Sequential Estrogen Replacement
  4. Late Postmenopausal
    1. Vaginal Estrogen for atrophic vagina OR
    2. Continuous Estrogen Replacement
      1. Avoid after age 60 years as risk of CVA, MI, Dementia increase

XI. Management: Protocol to stop Hormone Replacement

  1. Timing of Estrogen Replacement discontinuation
    1. Premature Menopause
      1. Re-evaluate continued Estrogen use at age 51
    2. Estrogen Replacement with Progesterone
      1. Consider stopping Estrogen Replacement after 3-5 years of use
    3. Estrogen Replacement without Progesterone
      1. Consider stopping Estrogen Replacement after 7 years of use
  2. Decrease dose as able to lowest effective dose
  3. Slow taper over 2-3 months reduces withdrawal affects
  4. Estrogen withdrawal effects to anticipate
    1. Irregular Vaginal Bleeding or spotting
    2. Hot Flushes
  5. Taper protocol
    1. First: HRT only monday to friday for 1-3 months
    2. Next: HRT only monday, wednesday, friday x1-3 months

XII. Management: Consider alternatives to Estrogen Replacement

  1. See Hot Flushes
  2. See Atrophic Vaginitis
  3. See Cardiac Risk Management
  4. See Osteoporosis Management
  5. Local Estrogen sources (Vaginal Estrogen)
    1. Vagifem tablets
    2. Estring vaginal ring

XIII. References

  1. (2022) Presc Lett 29(11): 66
  2. Chang (2023) Am Fam Physician 108(1): 28-39 [PubMed]
  3. Gartlehner (2022) JAMA 328(17):1747-65 +PMID: 36318128 [PubMed]
  4. Hill (2016) Am Fam Physician 94(11): 884-9 [PubMed]

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