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Hormone replacement therapy: where are we now?
The number of postmenopausal women is increasingworldwide. Hormone replacement therapy is the standardfirst-line treatment ofmenopausal symptoms, but uncer-tainty about important long-term risks (such as breast can-cer) and benefits (such as the prevention ofcoronary heartdisease) remains. Every week new papers are published,some contradicting previous reports, yet recommenda-tions must be made before definitive answers are available.This paper reviews recent studies of the risks and bene-fits ofhormone replacement therapy.
This review is based on a computer search of the 1990to 1999 literature on MEDLINE using the following keywords: estrogen, hormone replacement therapy, menopause,and women's health. Only recent papers are cited.
hormone agonist treatment) specifically enhanced ver-bal memory but did not enhance visual memory.7 Anxiety,cognitive symptoms, and affective symptoms did not dif-fer by treatment assignment in the PostmenopausalEstrogen/Progestin Interventions Trial trial, but womenwith severe symptoms were not included.!
In a recent meta-analysis of 26 studies of hormonereplacement therapy and depressed mood, Zweifel andO'Brien found that women using hormone replacementtherapy had less depressed mood than women not usingestrogen, that estrogen alone reduced depressed moodmore than the combination of estrogen with proges-terone, and that androgen replacement was associatedwith the greatest benefit.8
Cynthia StuenkelElizabeth Barrett-Connor
Department of Familyand PreventiveMedicineUniversity ofCalifornia, San DiegoLa Jolla, CA92093-0607
Correspondence to:Dr. Barrett-Connor
SYMPTOM RELIEFVasomotor symptomsFor manywomen, the onset ofvasomotor symptoms marksthe onset ofthe menopause transition. Estrogen replacementremains the gold standard for relief of hot flashes. In thePostmenopausal Estrogen/Progestin Intervention trial, therewas no additional benefit of estrogen-progestin combina-tions over estrogen alone in reducing vasomotor symptoms.1
Menopausal symptoms may be useful for identifyingpremenopausal women at higher risk for low bone min-eral density and, perhaps, osteoporosis. In the Women'sHealthy Lifestyle Project, bone mineral density at thespine and hip was significantly lower in women with hotflashes and menstrual cycle irregularities than in asymp-tomatic women.2
Vaginal dryness and urinary symptomsVaginal dryness and urinary symptoms may begin in theperimenopause or later. Topical estrogen is as effective assystemic therapy. In addition to vaginal creams, whichmay increase serum concentrations of estrogen, localestrogen therapy is now available in multiple preparations,including a silastic vaginal ring requiring replacementevery 3 months.3
In a randomized clinical trial, urinary tract infectionswere reduced by the use of vaginal estrogen.4 The effectofhormone replacement therapyon urinary incontinencehas been inconsistent.5,6
COGNITION AND DEPRESSIVE SYMPTOMSPerimenopausal and postmenopausal women often com-plain of"fuzzy thinking," trouble concentrating, ormem-ory loss. In a randomized clinical trial, Sherwin found that"add-back" estrogen therapy in premenopausal womenrendered estrogen-deficient (by gonadotropin-releasing
DISEASE PREVENTIONOsteoporosis preventionEstrogen is the treatment of choice to prevent post-menopausal osteoporosis, and prevention of osteoporo-sis-related fractures currently constitutes the strongestindication for long-term estrogen use.9 In observationalstudies, hormone replacement therapy reduces hip frac-ture by 30% and vertebral fracture by 50%. Two smallclinical trials showed a significantly reduced number ofvertebral fractures in estrogen users, but there was no dif-ference in clinical fractures after 4.1 years in the Heartand Estrogen/Progestin Replacement Study, a random-
* As the standard first-line treatment of menopausal symp-toms, estrogen improves vasomotor symptoms, vaginaldryness, and recurrent urinary tract infections.
* Estrogen should be initiated at the time of menopauseand taken indefinitely for osteoporosis prevention andtreatment; alternatively, benefit can still be achieved ifhormone replacement therapy is not started until age 6oor later.
* Endometrial cancer risk is increased in estrogen usersunless concurrent progestin therapy is added, eithercyclically or continuously.
* Uncertainty remains about the important long-term riskof breast cancer, shown in observational studies to haveincreased by 32% after 5 years of hormone replacementtherapy.
* The risk of venous thromboembolic events is increasedby two- to three-fold.
e Surrogate markers for cardiovascular protection are
improved by estrogen, although the use of hormonessolely for prevention of coronary heart disease shouldnot be recommended until clinical benefit has beendemonstrated in randomized trials.
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ized clinical trial of hormone replacement therapy ver-sus placebo in nearly 3000 postmenopausal women.10
Though estrogen reduces bone loss at the hip andspine in postmenopausal women of all ages, timing ofhormone replacement therapy may be important. In theRancho Bernardo Study, women who had taken estro-gen for only 5 to 10 years immediately after menopausehad no discernable benefit by age 75, while bone densi-ty was nearly as good in women who initiated therapyafter age 60 as in women who had used estrogen con-tinuously since menopause.1" Accordingly, the NationalOsteoporosis Foundation has recently recommendedstarting replacement therapy after age 60.
An estrogen dose equivalent to 0.625 mg ofconjugatedequine estrogen has been the standard for the preventionofbone loss, but recent studies suggest that a lower dose(0.3 mg) of esterified estrogen12, 0.5 mg of micronizedestradiol13, or 0.3 mg of conjugated equine estrogens isadequate to prevent bone loss in most women. The addi-tion of androgens to the standard regimen of hormonereplacement therapy may increase bone formation; com-bination therapy with the most commonly used prog-estins provides no added benefit to estrogen alone.14
Calcium supplementation potentiates the effect ofestrogen on bone.15 Calcium alone or with vitamin Dhas been shown in clinical trials to prevent hip fracturesin elderly women.
In the past 10 years 3 new modalities-alendronate,raloxifene, and calcitonin-have been approved for pre-vention or treatment of osteoporosis, or both.
Alendronate has been approved for prevention andtreatment of osteoporosis. Results from the FractureIntervention Trial of6450 postmenopausal women aged55 to 81 years showed that treatment with alendronate,10 mg daily, substantially reduced the risk of vertebral,hip, and wrist fractures in older postmenopausal womenwho had osteoporotic bone mineral densities 6 or exist-ing vertebral fractures at baseline.17
Raloxifene, a selective estrogen receptor modulator,has also been approved for prevention of osteoporosis.In the Multiple Outcomes of Raloxifene Experiencestudy, a randomized clinical trial involving 7705 osteo-porotic women, the relative risk of vertebral fracturesafter 24 months was significantly reduced by 44% inthe women treated with 60 mg/day of raloxifene com-pared to placebo.18
Calcitonin has also been approved for treatment ofosteoporosis. In the Prevent Recurrence ofOsteoporoticFracture (PROOF) Study, 200 IU/day intranasalsalmon calcitonin over 5 years resulted in a 39%decrease in the rate ofnew and/or worsening vertebralfractures.19 Calcitonin is usually used for only a few yearsand is most effective in reducing pain in women withvertebral fractures.
At the present time, estrogen remains the usual first-linepreventive or therapeutic agent for women with osteo-porosis. Alendronate is chosen forwomen with severe dis-ease and particularly those most at risk for hip fracture.Raloxifene may prove to be the drug of choice for long-term use in women with or at risk of vertebral fracturesbecause it has fewer side effects and risks than estrogen.
Coronary heart disease preventionBecause coronary heart disease is the commonest cause ofdeath in postmenopausal women, its prevention would bethe strongest indication for universal use of hormonereplacement therapy. Most ofmore than 30 observationalstudies have reported a 30% to 50% reduced risk ofcoro-nary heart disease in women using estrogen alone or withprogestin.20 Women who take hormones tend to be edu-cated and affluent, to have more favorable risk factors, andto be unusually compliant-all factors that could spuri-ously elevate the apparent benefit ofestrogen.20 Therefore,randomized trials that equalize the distribution of bothknown and unknown determinants ofmedication use arerequired to confirm findings in observational studies.
The Postmenopausal Estrogen/Progestin InterventionsTrial, a 3-year randomized clinical trial in 874 healthy post-menopausal women, provided 3-year placebo-controlledevidence ofimprovement in cardiac risk factors. Womenassigned to hormone replacement therapy had 12%lower low-density lipoprotein cholesterol and 12% high-er high-density lipoprotein cholesterol levels withoutsignificant changes in weight, blood pressure, or glucosemetabolism.21 Others have shown that estrogen caninduce favorable changes in apolipoproteins, fibrinogen,Lp(a), PAI-1, antithrombin III, homocysteine, endothe-lial function, vascular reactivity, and blood flow. Studieshave also shown estrogen's antioxidant and calcium chan-nel blocking activity.22
The first large randomized double-blind clinical trialto question whether changed coronary heart disease riskfactors translate into reduced coronary heart disease eventswas reported recently. The Heart and Estrogen/progestinReplacement Study, a secondary prevention trial, evalu-ated hormone replacement therapy versus placebo in2763 women with coronary heart disease at baseline andfound no significant difference between the 2 treatmentgroups after an average of 4.1 years.10 A significant timetrend was reported, however, with a 50% increase in car-diac morbidity and mortality in the first year after ran-domization to the hormone replacement therapy groupand fewer events in the last 2 years. Given these findings,hormone replacement therapy should not be initiated toprevent new events in women with preexisting coronaryheart disease. On the other hand, if a woman with coro-nary heart disease has tolerated hormone replacementtherapy for 2 years, then it might be beneficial to continue.
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Results from several other clinical trials are expectedwithin the next decade. Meanwhile, all women can ben-efit from not smoking, regular exercise, and a healthydiet. For women with established coronary heart diseaseor with high low-density lipoprotein cholesterol or lowhigh-density lipoprotein cholesterol, HMG Co-A reduc-tase inhibitors (statins) have been shown in clinical trialsto reduce coronary heart disease events.
Dementia reductionA meta-analysis of 10 observational studies of post-menopausal estrogen use and risk ofdementia23 suggest-ed a 29% decreased risk, but the findings of the studieswere heterogeneous and probably subject to the influ-ence of self-selection because healthier, more educatedwomen tend to choose hormone replacement therapy.Clinical trials of estrogen therapy in women withAlzheimer's disease are too small, too short, and too lit-tle controlled to draw any conclusions. In spite of plau-sible biological mechanisms by which estrogen mightreduce the risk for or severity of dementia, randomizedplacebo-controlled trials, now in progress, are necessary toestablish benefit.
Colon cancer risk reductionSeveral studies have found that current or recent users ofeither estrogen or combined hormone replacement ther-apy had a significantly reduced relative risk ofcolon can-cer.24 This association is now being studied in ongoingclinical trials.
RISKS OF HORMONE REPLACEMENT THERAPYEndometrial cancerAll studies show an increased risk of endometrial cancerinwomen taking unopposed estrogen, although endome-trial cancer is rare in women taking combined therapy.25In the Postmenopausal Estrogen/Progestin InterventionsTrial, unopposed estrogen therapy increased the risk ofatypical or complex endometrial hyperplasia, a prema-lignant lesion, by 10% per year.21 No such hyperplasiaor endometrial cancer was seen in wonien when cyclicor continuous medroxyprogesterone acetate was addedto estrogen. Therefore, combination therapy should berecommended to all women who have not had a hys-terectomy. Micronized progesterone, now FDA-approvedand available in the United States, was shown in the trialto be equally effective, yet with a better cardiovascularrisk profile.2'
Breast cancerBreast cancer is the risk most dreaded by women. A 1997reanalysis of 51 observational studies showed a 32%increased risk of breast cancer among women who hadusedhormone replacement therapy for 5 years or longer.26
While this risk has yet to be confirmed in randomizedclinical trials, the possibility is sobering and points tothe desirability oflimiting exposure to hormone replace-ment therapy to 5 years or less. The selective estrogenreceptor modulators like tamoxifen and raloxifene mayprevent breast cancer and preserve bone in post-menopausal women.
Other risksIn clinical trials, estrogen therapy has been shown toincrease the risk of gall bladder disease by 40% and toincrease the risk of venous thromboembolic events two-to three-fold.'0 A recent review27 ofother conditions pos-sibly caused or prevented by hormone therapy showed noconsistent association of hormone replacement therapywith osteoarthritis or rheumatoid arthritis, a nearly three-fold increased risk of systemic lupus erythematosus, anincreased risk ofasthma, and an increased risk ofRaynaud'ssyndrome (only with unopposed estrogen). Pancreatitisis seen rarely in women with hypertriglyceridemia.
INDICATIONS FOR HORMONE REPLACEMENTTHERAPYOn the basis of current knowledge, the following rec-ommendations seem reasonable:
1. Anywoman who has troublesome menopausal symp-toms and does not have contraindications to hormonereplacement therapy (liver disease, undiagnosed vaginalbleeding, or a history of deep vein thrombosis, pulmonaryembolus, or estrogen-dependent cancer) should be offeredhormone replacement therapy for symptom relief
2. Ifhormone replacement therapy is used for preven-tion of osteoporosis, it must be continued indefinitelyafter menopause. In many women, if not most, estrogencan be initiated at age 60 or 65, because most fracturesoccur after age 65. Reducing the duration oftreatment byhalfwould be expected to offer protection at reduced costand possibly to decrease the risk ofany breast cancer asso-ciated with hormone replacement therapy.
3. Until clinical trial data showing benefits are avail-able, hormone replacement therapy should not be rec-ommended for prevention of coronary heart disease.Statin therapy is a reasonable alternative.
4. Careful monitoring must accompany the commit-ment to hormone replacement therapy. Unscheduledbleeding must be investigated to rule out endometrialpathology. Annual mammography for breast cancer sur-veillance is necessary as well.
CONCLUSIONSThe menopausal transition is important both from thestandpoint ofsymptoms and as a risk factor for bone lossand possibly other chronic diseases. The optimal para-digm for menopausal health will depend upon each indi-
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vidual woman's desires, perceived and actual risks, andanticipated benefits.28 As stated during the CanadianConsensus Conference on Menopause and Osteoporosis,"Recommendations for practice must be based on scien-tific evidence with ongoing research to determine the mosteffective interventions."29 The only clear-cut indicationsfor hormone replacement therapy are to relieve symptomsand prevent or treat vertebral fracture. The most impor-tant challenge is to keep abreast ofnew findings as resultsof more randomized clinical trials of hormone replace-ment therapy become available.
References1 Greendale GA, Reboussin BA, Hogan P, et al. Symptom relief and side
effects of postmenopausal hormones: results from the PostmenopausalEstrogen/Progestin Interventions Trial. Obstet Gynecol 1998;92:982-988.
2 Salamone LM, Gregg E, Wolf RL, et al. Are menopausal symptomsassociated with bone mineral density and changes in bone mineral den-sity in premenopausal women? Maturitas 1998;29:179-187.
3 Henriksson L, Stjernquist M, Boquist L, et al. A one-year multicenterstudy of efficacy and safety of a continuous, low-dose, estradiol-releas-ing vaginal ring (Estring) in postmenopausal women with symptomsand signs of urogenital aging. Am J Obstet Gynecol 1996;174:85-92.
4 Raz R, Stamm WE. A controlled trial of intravaginal estriol in post-menopausal women with recurrent urinary tract infections. N Engl JMed 1993;329:753-760.
5 Cardozo L, Bachmann G, McClish D, et al. Meta-analysis of estrogentherapy in the management of urogenital atrophy in postmenopausalwomen: second report of the hormones and urogenital therapy com-mittee. Obstet Gynecol 1998;92:722-777.
6 Thom DH, Brown JS. Reproductive and hormonal risk factors for uri-nary incontinence in later life: a review of the clinical and epidemiolog-ic literature. J Am Geriatr Soc 1998;46:1411-1417.
7 Sherwin BB, Tulandi T "Add-back" estrogen reverses cognitive deficitsinduced by a gonadotropin-releasing hormone agonist in women withleiomyomata uteri. J Clin Endocrinol Metab 1996;81:2545-2549.
8 Zweifel JE, O'Brien WH. A meta-analysis of the effect of hormonereplacement therapy upon depressed mood. Psychoneuroendocrinology1997;22:189-2 12.
9 Eastell R. Treatment of postmenopausal osteoporosis. N Engl J Med1998;338:736-746.
10 Hulley S, Grady D, Bush T, et al. Randomized trial of estrogen plusprogestin for secondary prevention of coronary heart disease in post-menopausal women. Heart and Estrogen/progestin Replacement Study(HERS) Research Group. JAMA 1998;280:605-613.
11 Schneider DL, Barrett-Connor EL, Morton DJ. Timing of post-menopausal estrogen for optimal bone mineral density. The RanchoBernardo Study. JAMA 1997;277:543-547.
12 Genant HK, Lucas J, Weiss S, et al. Low-dose esterified estrogen thera-py: effects on bone plasma estradiol concentrations, endometrium, and
lipid levels. Estratab/Osteoporosis Study Group. Arch Intern Med1997; 157:2609-2615.
13 Ettinger B. Use of low-dosage 17 beta-estradiol for the prevention ofosteoporosis. Clin Ther 1993; 15:950-962.
14 The Writing Group for the PEPI Trial. Effects of hormone therapy onbone mineral density: results from the Postmenopausal Estrogen/Prog-estin Interventions (PEPI) Trial. JAMA 1996;276:1389-1396.
15 Nieves JW, Komar L, Cosman F, Lindsay R. Calcium potentiates theeffect of estrogen and calcitonin on bone mass: review and analysis. AmJ Clin Nutr 1998; 67:18-24.
16 Cummings SR, Black DM, Thompson DE, et al. Effect of alendronateon risk of fracture in women with low bone density but without verte-bral fractures: results from the Fracture Intervention Trial. JANIA 1998;280:2077-2082.
17 Black DM, Cummings SR, Karpf DB, et al. Randomised trial of effectof alendronate on risk of fracture in women with existing vertebral frac-tures: Fracture Intervention Trial Research Group. Lancet 1996;348:1535-1541.
18 Ettinger B, Black D, Cummings S, et al. Raloxifene reduces the risk ofincident vertebral fractures: 24-month interim analyisis. The MOREStudy Group. Osteoporos Int 1998;8(Suppl 3):0R23.
19 Silverman SL, Chesnut C, Andriano K Salmon calcitonin nasal spray (NS-CT) reduces risk ofvertebral fracture(s) (VF) in established osteoporosisand has continuous efficacy with prolonged treatment: accrued 5 yearworldwide data of the PROOF Study [abstract 1108]. In: 1998 Programand Abstacts of the Second Joint Meeting of the American Society forBone Mineral Research and the Intemational Bone and Mineral Society,1999 Dec 1-6; San Francisco, CA.
20 Barrett-Connor E, Grady D. Hormone replacement therapy, heart dis-ease, and other considerations. Ann Rev Public Health 1998; 19:55-72.
21 The Writing Group for the PEPI Trial. Effects of estrogen orestrogen/progestin regimens on heart disease risk factors in post-menopausal women: the Postmenopausal Estrogen/Progestin Interven-tions (PEPI) Trial. JAMA 1995; 273:199-208.
22 Mendelsohn ME, Karas RH. The protective effects of estrogen on thecardiovascular system. N Engl J Med 1999;340:1801-181 1.
23 Yaffe K, Sawaya G, Lieberburg I, Grady D. Estrogen therapy in post-menopausal women: effects on cognitive function and dementia.JAMA 1998;279:688-695.
24 Grodstein F, Martinez ME, Platz EA, et al. Postmenopausal hormoneuse and risk for colorectal cancer and adenoma. Ann Intern Med 1998;128:705-712.
25 Beresford SAA, Weiss NS, Voight LF, McKnight B. Risk of endometri-al cancer in relation to use of oestrogen combined with cyclic progesta-gen therapy in postmenopausal women. Lancet 1997;349:458-461.
26 Collaborative Group on Hormonal Factors in Breast Cancer. Breastcancer and hormone replacement therapy: collaborative reanalysis ofdata from 51 epidemiological studies of 52,705 women with breastcancer and 108,411 women without breast cancer. Lancet 1997;350:1047-1059.
27 Barrett-Connor E. Postmenopausal estrogen therapy and selected (less-often-considered) disease outcomes. Menopause 1999;6:14-20.
28 Greendale GA, Lee NP, Arriola ER The menopause. Lancet1999;353:571-580.
29 The Canadian Consensus Conference on Menopause and Osteoporo-sis. Introduction. Journal SOGC 1998;20:5-8.
The pill is safe for women with Crohn's disease Oral contraceptives have little impact on the severity of Crohn's disease, French researchershave found, although many women with the disease are advised to avoid them (Gut 1999;45:218-222). In a study of over 300 women withstable disease, women who used oral contraceptives did not have more flare ups during follow up than the rest. Smoking, on the otherhand, emerged as a clear risk factor. Women with Crohn's disease should be allowed the same choice of contraceptives as everyone else,the researchers conclude.
Kinder colonoscopy for screening Radiologists at the Mayo Clinic are convinced that virtual colonoscopy is the coming technique forscreening for colorectal cancer-although they betieve more evaluation is needed (Gut 1999;44:301-3o5). Data obtained using a spiralcomputed tomographic scanner are processed off-line to produce two- and three-dimensional images. The patient's colon must be dis-tended with gas or air, but the procedure takes only two minutes and the exposure to radiation is about the same as a barium enema. Aprospective trial of 70 patients found that for lesions of 0.4 inches or more, the sensitivity was 75% and the specificity was 90%.
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