n.b. naturally occurring human estrogens = estrone, estradiol, estriol

I Oral--Extensive first-pass, so liver is exposed to higher levels than peripheral blood; this may be a reason for pro-coagulant and lipid-altering effects
  1. Conjugated equine estrogens (Premarin) 0.3 -1.25mg PO QD
  1. Has most long-term data available
  2. 50% estrone, 25% equiline, and others
  3. Dosing
    1. In estrogen-only (no progestin) HRT, reduction in vasomotor symptoms was sig. better with 0.625mg CEE than with lower doses but in combined estrogen-progestin HRT, all doses were equally good (0.3-0.625mg/d) in a randomized trial in 2673 postmenopausal women.  Lower doses of CEE were ass'd with higher rates of amenorrhea in both estrogen-only and combined HRT regimens (Fertil. Steril. 75:1080, 2001--JW)
  1. Esterified estrogents (Estratab, Menest)
  2. Conjugated estrogen, synthetic (Cenestin, Enjuvia) 0.625-1.25mg PO QD
  1. Estradiol valerate (Estrace) 1-2mg PO QD
    1. Metabolized to estrone
  1. Estropipate 0.625-5mg PO QD
  1. Estradiol/estrone/estriol mixture (used mostly in Europe)
  1. "Selective Estrogen Receptor Modulators"--designed to act on lipids & bone but not breast or uterus
    1. Tamoxifen--has significant action on uterus in addition to bone & lipids; acts as an estrogen antagonist in breast tissue
    2. Raloxifene (Evista) 60mg QD
      1. Acts as estrogen agonist bone & lipids but antagonist on breast & endometrium
      2. Increases bone density and decreases risk of vertebral fx
        1. Greater increase c/w placebo in postmenopausal but less in historical comparisons than Premarin (NEJM 337:1641, 1997)
        2. 7705 women 31-80yo, 37% with existing vertebral fx, all at least 2y post menopause, with osteoporosis, randomized to Raloxifene 120mg/d, 60mg/d, or placebo; all got Ca & vit. D. Over 3y f/u, RR of vertebral fx c/w placebo was 0.7 for 60mg group and 0.5 for 120mg group (both sig.); no sig. effect on risk of nonvertebral fracture ("MORE" study, JAMA 282:637, 1999--abst)
      3. Effects on endometrium
        1. No diff. in endometrial thickness between raloxifene and placebo group (NEJM 337:1641, 1997)
        2. No diff. in incidence of endometrial Ca in 40mo trial c/w placebo (JAMA 281:2189, 1999)...
        3. ...or in a 3.3y study of Raloxifene 60-120mg/d vs. placebo (Multiple Outcomes of Raloxifene Evaluation ("MORE") Trial; Obs. Gyn. 104:837, 2004--JW)
      4. Effects on cardiovascular disease & risk factors
        1. Raloxifene ass'd with decrease in total and LDL cholesterol c/w placebo but no change in HDL (NEJM 337:1641, 1997)
        2. 390 women assigned to raloxifene, combined HRT, or placebo x 6mos. Raloxifene and HRT groups showed similar reductions in LDL; raloxifene ass'd with sig. less improvement in HDL and lipoprotein (a) c/w HRT (JAMA 279:1445, 1998)
        3. In a secondary analysis of the MORE study data (done primarily to assess effects of Raloxifene in breast Ca reduction), pts receiving Raloxifene 60mg QD vs. placebo had similar risk for fatal or nonfatal cardiovascular events; in subgroup of 1035 women with high CV risk (prior coronary event or DM + one other cardiac risk factor), Raloxifene was ass'd with sig. lower risk (8% vs. 13% over 4y f/u) (JAMA 287:847, 2002--JW)
        4. 390 healthy postmenopausal women randomized to: a. Raloxifene 60mg/d; b. Raloxifene 120mg/d; c. premarin 0.625 + provera 2.5/d; d. placebo. After 6mos f/u, LDL levels were down 12% in both raloxifene groups c/w 14% in standard HRT group. Lipoprotein (a) was down 7-8% with raloxifene c/w 19% with standard HRT. HDL-2 was up 15-17% with raloxifene c/w 33% with standard HRT. No sig. change in total HDL, TG, or plasminogran activator inhibitor-1 with raloxifene, while standard HRT increased HDL by 11%, TG 20%, and PAI-1 by 29%. Fibrinogen was down 12-14% with raloxifene; no effect with standard HRT (JAMA 279:1445, 1998--abst)
        5. In a study in 10,101 postmenopausal women at high risk for CAD randomized to raloxifene 60mg/d vs. placebo, after median 5.6y f/u, incidence of (cardiovascular death, MI, or hospitalization for acute coronary syndrome) was not sig. diff. between the two groups (for overall cohort + various subgroups). Raloxifene recipients had sig. lower incidence of breast Ca. (0.20% vs. 0.29%) and fewer vertebral fractures ("Raloxifene Use for The Heart" ("RUTH") Trial NEJM 355:125, 2006--JW)
      5. Prevention of Breast Cancer--Click link for details
      6. Venous thromboembolism--ass'd with increased risk
        1. RR 3.0 in one study (JAMA 281:2189, 1999)
        2. RR 3.1 (sig.) in the first MORE trial (see above)
        3. In a trial in 7,705 postmenopausal women (31-80yo) with osteoporosis randomized to raloxifene 60-120mg/d vs. placebo, over mean 3.3y f/u, raloxifene was ass'd with RR 2.1 (sig.) for venous thromboembolism (absolute risk increase 1.8 events per 1,000 person-years of use); no sig. diff. in risk for gallbladder disease, endometrial Ca, or cataracts (Multiple Outcomes of Raloxifene Evaluation ("MORE") Trial; Obs. Gyn. 104:837, 2004--JW)
        4. The Factor V Leiden mutation was associated with sig. increase in risk (OR 4.7) of venous thromboembolism in a case-control study women with breast Ca on tamoxifen (J. Nat. Ca. Inst. 102:942, 2010-JW)
      7. Overall risk of Cancer: No increase seen in studies w/up to 3y f/u (Med. Letter 40:30, 1998)
      8. Other adverse effects:
        1. Hot flashes
        2. Flu-like syndrome
        3. Left cramps
        4. Peripheral edema
        5. Diabetes Mellitus (RR 2.2 for new or worsening DM in 40mo f/u, although there was no diff. in median changes in fasting plasma glucose or HbA1c--JAMA 281:2189, 1999)
      9. May decrease effect of warfarin
      10. Does not cause resumption of menses as does estrogen therapy
    3. Bazedoxifene
      1. Associated with no sig. diff. in changes in endometrial thickness or incidence of breast Ca compared with both raloxifene and placebo in several randomized trials with durations of up to 2 years (Menopause 16:1102, 2009; Menopause 16:1116, 2009-JW)
II. Parenteral
  1. Advantages over oral
  1. Less effect on thrombotic state because of no "first-pass" effect--See below for details
  2. Better in pts with stable liver disease
  1. Available preparations:
  1. Transdermal estradiol 0.05-0.1mg 2x/wk
  2. Subcutaneous estradiol pellets (not good; fluctuating absorption as of 1994)
  3. Estradiol vaginal pessaries or rings
III. Topical-Used primarily to relieve symptoms due to urogenital atrophy