HORMONE REPLACEMENT THERAPY

See also Botanical treatments for Menopausal Symptoms and Hormonal Contraception

Estrogen preparations for HRT

Progestin preparations for HRT

Studies on the effects of HRT on clinical outcomes:

The Women's Health Initiative Study

I. The Women's Health Initiative Study--Note: Since this study looked at multiple clinical outcomes and is the largest RCT of HRT done to date, I have included it in its own section here:

  1. Combined estrogen-progestin arm (JAMA 288:321, 2002; other separately-published analyses are cited below)

    1. 16,608 postmenopausal women age 50-79y with an intact uterus randomized to combined HRT (conjugated equine estrogen 0.625mg/d + medroxyprogesterone acetate 2.5mg/d) vs. placebo. After avg. 5.2y f/u, the study was halter b/c of the findings regarding risks of the following outcomes:

*--"Summarizing the balance of risks and benefits included the 2 primary outcomes plus stroke, pulmonary embolism (PE), endometrial cancer, colorectal cancer, hip fracture, and death due to other causes."

  1. Concluded that "The risk-benefit profile found in this trial is not consistent with the requirements for a viable intervention for primary prevention of chronic diseases"

  2. The reduction in fracture risk was seen in subgroups stratified by age, body mass index, smoking status, history of falls, calcium intake, BMD, or past use of HRT (JAMA 290:1729, 2003--abst)

  3. Over mean 4y f/u, HRT group vs. placebo group had sig. higher incidence of dementia (hazard ratio 2.05; sig.) (JAMA 289:2651, 2003--JW) and sig. higher incidence of sig. decline on mini-mental state exam (6.7% vs. 4.8%; sig.) ( JAMA 289:2663, 2003--JW)

  4. Incidence of invasive ovarian Ca, cervical Ca, and endometrial Ca were not sig. different between active-treatment and placebo groups (JAMA 290:1739, 2003--abst)

  5. Various quality-of-life scores showed a small but statistically sig. improvement at 1y but no diff. at 3y (NEJM 348:1839, 2003--JW)

  1. Estrogen-only arm

    1. 10,739 postmenopausal women 50-79yo with h/o prior hysterectomy randomized to conjugated equine estrogen 0.625mg PO QD vs. placebo 

    2. Over mean 6.8y f/u, incidence of coronary heart disease was no diff. but estrogen group had sig. higher incidence of CVA, sig. reduced risk for hip fx, nonsig. lower breast Ca incidence, and nonsig. higher incidence of venous thromboembolism (JAMA 291:1701, 2004)

    3. In a separately-published report on 2,947 members of this cohort > 65yo with no probable dementia at baseline, over mean 5.4y f/u, mini-mental status exam scores were sig. lower in estrogen group compared with placebo group (JAMA 291:2959, 2004--abst)

    4. Urinary incontinence--RR 2.15 for 1y incidence of stress incontinence and 1.79 for mixed incontinence (JAMA 293:935, 2005-abst)

    5. No sig. differences in various quality-of-life measures in a published report from the WHI estrogen-only arm in 2005 (don't have reference)

II. Studies of HRT's effect on overall mortality

  1. Nonrandomized studies have suggested reduced mortality--Click HERE for details
  2. In a meta-analysis of 30 randomized trials of > 6mos duration comparing HRT vs. placebo or no treatment, with total 26,708 participants, found no sig. diff. in total mortality overall or in women > 60yo at baseline, but sig. reduced mortality in women < 60yo at baseline (OR 0.61) (J. Gen. Int. Med. 19:791, 2004--abst)

III. Other studies of effects of HRT on specific outcomes:

  1. Relief of "vasomotor" symptoms associated with menopause, e.g. hot flashes
    1. Effect depends on dose; click link for details
    2. Overall beneficial effect on quality of life was limited to women who had hot flashes at baseline in one randomized trial of combined estrogen-progestin HRT in 2763 postmenopausal women with CAD ("HERS" Study; JAMA 287:591, 2002--abst)
  1. Osteoporosis and osteoporotic fractures
  1. Fracture prevention
    1. A meta-analysis of 22 clinical trials (some of them uncontrolled) concluded that HRT was ass'd with RR for non-vertebral fx of 0.73 and for hip or wrist fx of 0.60; for > 60yo, risk reduction was not significant (JAMA 285:2909, 2001--JW)
    2. See also data from the Women's Health Initiative above
  2. Issues of timing
    1. May get most protection in first 5 years of treatment, but discontinuation of tx is followed by rapid resumption of bone loss & increase in fx risk (BMJ 316:1858, 1998--JW)
    2. Bone density (tested at 4 sites) in women who started postmenopausal HRT after age 60 was just as good as those who had started at menopause; both had increased bone density c/w never-users or past users (JAMA 277:543, 1997-JW)
  3. Issues of dosing
    1. 0.625mg/d and 0.45mg/d of conjugated equine estrogens did NOT differ significantly in effect on bone mineral density, though 0.3mg/d dose was ass'd with significantly lower increases in BMD, in a randomized trial of 694 women 40-65yo who were < 4y s/p their last menstrual period (JAMA 287:2668, 2002--JW)
    2. Low-dose estrogen replacement (0.25mg micronized 17-beta-estradiol PO QD vs. placebo x 3y in 167 postmenopausal women; those with a uterus also got cyclic micronized progesterone) was ass'd with significant increases in BMD (JAMA 290:1042, 2003--JW)
  4. Transdermal estrogen for maintenance of bone mass
    1. As effective at reduction in risk of hip fx as oral in a case-control study done in 4,640 Swedish women (BMJ 316:1585, 1998--AFP)
    2. Dose-dependent sig. advantage over placebo in a randomized trial of 97 postmenopausal women (transdermal estradiol 0.025-0.1mg/d) (Obs. Gyn. 94:330, 1999--AFP)
    3. 417 postmenopausal women 60-80yo randomized to transdermal estradiol 0.014mg QD vs. placebo; all received Ca & vitamin D; none were on progestins. At 2y f/u, estradiol group had sig. higher mean lumbar-spine BMD (by 2.1%) (Obs. Gyn. 104:443, 2004--JW)
  1. Blood lipids
  1. Unopposed estrogen decreases LDL by about 15%; increases HDL up to 15%; may increase TG's (NCEP report); also reduce Lipoprotein (a) by 20-50%
  2. Non-oral routes probably don't have this effect to the same degree
    1. Randomized study of transdermal 17-beta-estradiol vs. Premarin 0.625mg/d; both with cyclic progestin, found slight advantage to Premarin in improvement of Lipoprotein (a) and HDL, but none in LDL (e.g. Menopause 5:157, 1998--AFP)
  3. PEPI Trial (JAMA 273:199, 1995)
  1. 3-year multicenter randomized double-blind trial of placebo, unopposed Premarin 0.625/d, cyclic Premarin/Provera (10mg/d, 12d/mo), cyclic Premarin/micronized progesterone (200mg/d for 12d/mo), or continuous Premarin/Provera (2.5 QD)
  2. 875 healthy postmenopausal women 45-64yo
  3. Measured HDL, fibrinogen, BP, and insulin
  4. Unopposed estrogen raised HDL by 5.6 mg/dl
  5. Premarin/micronized progesterone raised HDL by 4.1 mg/dl
  6. Premarin/Provera (cyclic or continuous) raised HDL by 1.2 to 1.6 mg/dl
  7. All tx regimens decreased LDL and fibrinogen without sig. diff between tx groups
  8. No sig. changes with any treatment of BP or insulin
  9. Another report of PEPI trial (Circ 97:979, 1998--JW) found that levels of Lipoprotein (a) were sig. decreased in all the HRT regimens w/o sig. differences among the regimens
  1. Raloxifene--Click on link for details
  1. Cardiovascular disease
  1. Nonrandomized studies have shown neutral to beneficial effects--click HERE for detail
  1. Randomized trials have shown neutral to harmful effects
    1. See data from the Women's Health Initiative above
    2. HERS study ("Heart and Estrogen/progestin Replacement Study," JAMA 280:605, 1998)
      1. 2763 postmenopausal women < 80yo with established CAD, avg. age 67y, randomized to Premarin 0.625/Provera 2.5 QD vs. placebo.
      2. Over avg. 4.1y f/u, no sig. diff. in incidence of: combined outcome of nonfatal MI or CAD death (RR 0.99 w/HRT), nonfatal MI (RR 0.91 w/HRT), TIA or CVA (RR 1.13 w/HRT), or total mortality (RR 1.08)
      3. A significantly increased risk of DVT or PE was observer; click on the link for details
      4. In a followup study observing 93% of the original cohort an additional 2.7y after the initial 4.1y f/u, there were still no sig. differences in incidence of the above outcomes with the exception that the sig. differences in risk of gallbladder disease and DVT or PE did still persist (JAMA 288:49, 2002, JAMA 288:58, 2002--abst)
    3. 664 postmenopausal women, mean age 71y, with h/o TIA or nondisabling CVA, randomized to 17-beta-estradiol 1mg/d vs. placebo; over avg. 33mo f/u, no sig. diff. in endpoint of (death or nonfatal CVA); 6mo incidence of CVA was sig. higher in HRT group than placebo group (RR 2.5) but this disappeared by 3y (NEJM 345:1243, 2001--JW)
    4. 309 postmenopausal women (mean age 66yo) with CAD (1 or more coronary vessels w/>30% stenosis on angiography) randomized to Premarin 0.625/Provera 2.5mg QD vs. placebo; over avg. 3.2y f/u, no diff. in changes in coronary stenosis (NEJM 343:522, 2000--JW)
    5. In a randomized trial of 423 postmenopausal women (mean age 65yo) with angiographically-proven CAD of at least one vessel randomized to (conjugated equine estrogens 0.625mg QD + medroxyprogesterone acetate 2.5mg/d, the latter not given if s/p hysterectomy) vs. placebo, over mean 2.8y f/u, incidence of angiographic progression was nonsig. higher in the HRT group ("WAVE" trial; JAMA 288:2432, 2002--abst)
  1. Risk of Dementia
  1. Nonrandomized studies have shown neutral to beneficial effects--click HERE for details
  2. Randomized trials have shown neutral to harmful effects
    1. 62 healthy postmenopausal women with previous hysterectomy randomized to transdermal estrogen vs. placebo in a crossover study (tx x 3mos, 1mo washout, then tx x 3mos)--no difference in performance on several cognitive tests (Obs. Gyncol 91:459, 1998--JW)
    2. In a randomized trial of conjugated equine estrogens 0.625mg/d or 1.25mg/d vs. placebo in 120 postmenopausal comen (avg. age 75yo) with mild-mod Alzheimer's; there were no diff. in change in cognitive function over 12mo f/u (JAMA 283: 1007, 2000--JW)
    3. See also data from the Women's Health Initiative above
  1. Colorectal Cancer
    1. 59,000 postmenopausal women in Nurse's Health Study followed prospectively x 14y. Current use of HRT (75% on estrogen-only) ass'd with RR 0.65 for development of colorectal Ca; duration of use didn't affect (Ann. Int. Med 128:705, 1998--JW)
    2. Both estrogen-only and combined HRT ass'd with RR 0.54 for colon Ca in a case-control study; J. Natl. Ca Inst. 87:1067, 1995
    3. See also data from the Women's Health Initiative above
  1. Endometrial Neoplasms
  1. RR 8.0 for unopposed estrogen-only HRT; Tend to be less invasive than sporadically occurring endometrial Ca
  2. Risk of endometrial Ca with combined estrogen-progestin HRT
    1. Use of HRT with or without progestin was not ass'd with increased risk of endometrial cancer recurrence in a non-randomized prospective study of 150 women s/p hysterectomy for endometrial cancer followed for mean 83mos (Obs. Gyn. 97:555, 2001--JW)
    2. Case-control study of 832 women 45-72yo with endometrial Ca vs. 1114 age-maatched controls. Relative to women who had never used postmenopausal HRT, ever use of unopposed estrogen ass'd with RR 4 for endometrial Ca, and use of estrogen with cyclic progestin ass'd with RR of 1.4 (3.1 for <10d/mo progestin; 1.3 for 10-21 d/mo progestin). Use of combined with cyclic progestin x 5y or more ass'd with RR 3.7 for <10d/mo progestin; 2.5 for 10-21d/mo progestin (Lancet 349:458, 1997)
    3. See also data from the Women's Health Initiative above
  1. Venous thromboembolism--May significantly increase risk; though absolute risk increase is small
  1. Nonrandomized studies have shown increased risk--Click HERE for details
  2. Data from randomized trials
    1. HERS study suggests increased risk--2763 postmenopausal women < 80yo with established CAD, avg. age 67y, randomized to Premarin 0.625/Provera 2.5 QD vs. placebo; Over avg. 4.1y f/u, RR of DVT or PE was 2.7 for users of HRT (sig.) (Ann. Int. Med. 132:689, 2000--JW)
    2. See also data from the Women's Health Initiative above
    3. Esterified estrogens were associated with lower risk of VTE than conjugated equine estrogens in one case-control study (JAMA 292:1581, 2004--AFP) 
    4. Raloxifene--Click on link for details
  1. Breast Cancer
  1. Nonrandomized studies have shown neutral to detrimental effects of both estrogen-only HRT and combined estrogen-progestin HRT--Click HERE for details
    1. Note the findings in these studies that risk elevation may be greater for women of average- or above-average BMI and in women on combined estrogen-progestin HRT
  2. See also data from the Women's Health Initiative above
  3. HRT in women with history of breast cancer
    1. 319 postmenopausal women with h/o localized breast Ca (median disease free duration 9.5y) followed prospectively for median 40mo; the 39 who elected to start HRT risk of new dx of breast Ca was no diff. between the 2 groups (3% in HRT vs. 5% in non-HRT groups) (J. Clin. Oncol. 17: 1482, 1999--JW)
    2. In a nonrandomized retrospective trial comparing 174 women who used HRT after treatment for breast Ca and 695 women with h/o brast Ca who didn't use HRT, breast Ca recurrence was sig. less in women who used HRT (RR 0.52) and breast Ca mortality was sig. less (RR 0.33) (J. Nat. Ca. Inst. 93:754, 2001--JW)
    3. In a trial of 434 symptomatic postmenopausal women with h/o breast Ca randomized to HRT (summary doesn't specify regimen) vs. placebo, over median 2y f/u, RR of new breast Ca dx was 3.3 (Hormonal Replacement Therapy After Breast Cancer-Is It Safe? "HABITS" trial; Lancet 363:410, 2004--JW)
  4. In women with h/o previous benign breast disease
    1. In an observational study of 5.813 postmenopausal women who had undergone previous breast bx showing either normal breast tissue or fibroadenoma were followed for mean 20y. There was no increase risk of invasive breast Ca in those women who received HRT during the f/u period (Cancer 85:1277, 1999--AFP)
  5. In women with a family h/o breast Ca
    1. An 8y prospective cohort study of breast Ca, mortality, and HRT use in 35,900 women examined the subgroup with a family h/o breast Ca (sis, mom, or daughter) (Ann. Int. Med. 127:973, 1997--JW). They found that within this subgroup, after adjusting for known breast Ca risk factors, former or current use of HRT was ass'd with:
  1. Nonsig. increased risk for breast Ca (RR 1.17-1.37 increased depending on duration of use)
  2. Sig. decrease in total mortality (RR 0.67)
  1. Breast Ca ass'd with HRT may be largely limited to the more benign histologic types
  1. 433 postmenopausal women with invasive breast Ca; HRT users (25% of pts) were sig. more likely to have well-differentiated, grade I tumors; no sig. diffrence in tumor size, receptor status, pos. nodes in women who underwent ax. node removal; or recurrence rates in median f/u of 45 mos. (BMJ 312:1646, 1996-JW)
  2. Iowa Women's Health Study showed an association of HRT with "favorable histologic subtypes" of breast Ca (medullary, papillary, tubular, and mucinous) but not with "less favorable" ones in a prospective study of 37,105 postmenopausal women (JAMA 281:2091, 1999)
  3. In a study of 1113 women with breast Ca, 15% of which had been using HRT at the time of Dx, there were no sig. diff. between HRT users & non-users in histologic type, size, or grade of tumors, or in prevalence of positive axillary nodes (BMJ 320:238, 2000--JW)
  1. Ovarian Cancer
    1. Ovarian cancer was NOT associated with HRT use in a case-control study of 491 pts with epithelial ovarian Ca and 741 controls (Obs. Gyn. 89:1012, 1997-JW)
    2. In a prospective cohort study of 211,581 postmenopausal women followed x 14y, used of HRT at baseline was ass'd with sig. higher risk of death from Ovarian Ca (1.51) vs. never-users; former users had very little increase in risk.  An association was found with duration of use and risk of ovarian Ca mortality (JAMA 285:1460, 2001--JW)
    3. In a retrospective cohort study of data from the Breast Cancer Detection Demonstration Project, following 44,241 postemenopausal women for avg. 13y, multivariate analysis found that estrogen-only HRT was ass'd with RR 1.6 for ovarian Ca (sig.); a duration-dependent association was noted; combined estrogen-progestin HRT was not ass'd with increased risk of ovarian Ca except when there was a prior h/o estrogen-only HRT (JAMA 288:334, 2002--JW)
    4. In a prospecttive study of 98,000 women age 50-71 at the start, over mean 4.2y f/u, use of unopposed estrogen HRT for > 10y was associated with sig. increased risk of ovarian Ca (RR 1.89) (J. Nat. Ca. Inst. 98:1397, 2006--JW)
    5. In a prospective cohort study of 950,000 postmenopausal women, current hormone replacement therapy use > 5y was associated with sig. increase in incidence of ovarian Ca dx (RR 1.20) and ovarian Ca death (RR 1.23), though use for < 5y was not associated with sig. increase in incidence of either outcome. No diff. between use of estrogen-only or combined estrogen-progestin HRT. (Lancet 369:1703, 2007--JW)
    6. In a prospective study of over 900,000 women 50-79yo, over mean 8y f/u, risk of a new diagnosis of epithelial ovarian Ca was sig. associated with use of hormone replacement therapy, even after adjustment for potential confounders-RR 1.44 for any use, RR 1.15 for former use.  Risk approached baseline 2y after cessation of HRT.  No difference in results with combined vs. estrogen-only HRT.  (JAMA 302:298, 2009-JW).
    7. See also data from the Women's Health Initiative above
  1. Urinary Incontinence
    1. In a retrospective analysis of data from the Nurses' Health Study, incidence of urinary incontinence in this cohort of postmenopausal women was sig. higher in women using HRT (RR 1.54; no diff. between combined estrogen-progestin and estrogen-only regimens) (Obs. Gyn. 103:254, 2004--AFP)
    2. In analysis of data from the HERS Study (click on link for details) combined HRT was associated, over mean 4y of treatment, with sig. greater incidence of urinary incontinence (64% vs. 49%; both urge & stres incontinence had highed incidence than placebo) (Obs. Gyn. 106:940, 2005--JW)
    3. See also WHI data above
  2. May have higher (RR 2.0) risk of Systemic Lupus Erythematosus (Ann Int. Med. 122:430, 1995-ML)
  3. May worsen endometriosis, if present
  4. May worsen gallbladder disease
    1. In the HERS Study (click on link for details), in which 2,763 postmenopausal women were randomized to Premarin 0.625/Provera 2.5 QD vs. placebo, over avg. 4.1y f/u, RR of gallbladder disease was 1.38 (sig.); in a followup study observing 93% of the original cohort an additional 2.7y after the initial 4.1y f/u, there was still sig. higher incidence of gallbladder disease in hormone recipients
    2. In a study combining data from two randomized trials with total 22,579 postmenopausal women 50-79yo who had not had prior cholecystectomy, randomized to (equine estrogens 0.625mg/d and (if had not had hysterectomy) medroxyprogesterone acetate 2.5mg/d) vs. placebo, over mean 5.6y f/u (for estrogen-only group) or 7.1y f/u (for combined HRT group), incidence of (hospitalization for gallbladder disease or gallbladder-related procedure) was sig. higher in both estrogen groups c/w placebo (HR 1.67 for estrogen-only and 1.59 for combined HRT).  Absolute risk increase was 3.1 cases per 1,000 person-years of tx for estrogen-only and 2 cases per 1,000 person-years of tx for combined HRT (JAMA 293:330, 2005--abst)
  5. May increase size of leiomyomata, if present
  6. May worsen migraine, especially if pt had migraines linked to menstrual cycle earlier in life
  7. May increase risk of dry eye syndrome (data from a retrospective cohort study--JAMA 286:2114, 2001--JW)
  8. Nausea
  9. Mastalgia
  10. Hypertension has NOT been clearly associated with HRT
  11. May reduce risk of Diabetes Mellitus
    1. In a secondary analysis of the HERS study, 4y incidence of DM was sig. lower w/HRT vs. placebo (6% vs. 10%) (Ann. Int. Med. 138:1, 2003--JW)
  12. May be associated with improvement of Depression--see link for details
  13. May reduce tooth loss (Am. J. Med 102:536, 1997-JW)

IV. Combined estrogen-progestin HRT

  1. Involves the addition to the estrogen regimen of progestin administered either cyclically, i.e. daily only during certain days of the month, or or continuously, i.e. every day
  2. Lowers risk of endometrial cancer and hyperplasia compared with estrogen-only HRT, though may still be increased risk c/w women not using HRT! (see above)
  3. Unclear whether alters reduction of risk for osteoporosis; one study on progestins alone in postmenopausal women showed improvement in bone density (Clin. Sci. Mol. Med 54:193, 1978-ref'd in NEJM rvw)
  4. Vaginal bleeding
  1. With continuous progestin regimen, 40% get unpredictable breakthrough bleeding for about 6 mos; 75-90% become amenorrheic within 1y
  2. With cyclic progestin regimens, predictable withdrawal bleeding can continue for years
  3. Dose of progestin when used continuously doesn't affect risk of bleeding
    1. 557 postmenopausal pts randomized to 2.5, 5, or 10mg/d of medroxyprogesterone acetate x 2y; all received 1.25mg/d of estrone sulfate. 42% of all women had some vaginal bleeding at 3mos. At 6mos, % of women with bleeding was 19-24% depending on dose; at 2%, 6-10%; no sig. diff among doses of medroxyprogesterone (Obs. Gyn 91:678, 1998--AFP)
  4. Dose of estrogen does affect risk of bleeding--Click link for details
  1. Per anectodal reports, combined HRT is associated with more breast tenderness, headache, fluid retention, and depression than estrogen-only HRT, though less so with norethindrone than with medroxyprogesterone acetate (Med. Letter; anecdotal).
  2. See above for more data on effects of combined HRT on various clinical outcomes

V. Testosterone for menopausal women

  1. May improve sexual function; long-term safety not studied
  2. In a crossover study of 75 healthy women 31-56yo s/p oophorectomy (1-10 previously) with circulating testosterone levels below normal range for premenupasual women, all on estrogen, all with decreased sexual desire, activity, or pleasure, all receiving placebo, transdermal testosterone 150ug/d, and 300ug/d, in random order.  Active tx was ass'd with sig. greater improvements in sexual function and mood in a dose-dependent fashion (NEJM 343:682, 2000--JW)
  3. In a study in 417 surgically menopausal women on estrogen HRT with hypoactive sexual desire randomized to testosterone 300ug transdermal QD vs. placebo x 24wks. At 24wks, increase in satisfying sexual activity was sig. greater in the testosterone group (mean change from baseline 1.56 vs. 0.73 episodes/4wks). The testosterone group had sig. increased incidence of androgenic side f/x (acne, oily skin, hirsutism, voice change) (Obs. Gyn. 105:944, 2005--JW)