dynamed plus_ hormonal replacement therapy (hrt)

20122015 DynaMed Plus Hormonal replacement therapy (HRT)

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Hormonal replacement therapy (HRT)Related Summaries

Hormonal replacement therapy (HRT) and cardiovascular diseaseHormonal replacement therapy (HRT) and osteoporosisHormonal replacement therapy (HRT) and venous thromboembolismHormonal replacement therapy (HRT) and breast cancerMenopause

Overview

also called estrogen replacement therapy (ERT) sometimes HRT used to imply addition ofprogestinssee Menopause for estrogen treatment of menopausal symptomslongshyterm use of combined estrogenprogestin (HRT) has more risks than benefits in healthypostmenopausal women including

breast cancervenous thromboembolismcardiovascular diseasedeath due to lung cancerother risksbenefits include prevention of osteoporotic fractures and colorectal cancerno differences in overall mortality or quality of life

longshyterm use of estrogen alone has benefits that do not outweigh risks overallrisks include stroke and possibly deep vein thrombosisbenefits include prevention of osteoporotic fractures and possibly lower risk of invasivebreast cancerno differences in overall mortality cardiovascular disease colorectal cancer or quality of life

discontinuation of HRT associated with recurrence or onset of menopausal symptoms

Recommendations

United States Preventive Services Task Force (USPSTF) recommendationsroutine use of combined estrogen and progestin not recommended for prevention of chronicconditions in postmenopausal women (USPSTF Grade D)routine use of estrogen alone not recommended for prevention of chronic conditions inpostmenopausal women who have had a hysterectomy (USPSTF Grade D)Reference shy USPSTF recommendation statement on menopausal hormone therapy forprimary prevention of chronic conditions (Ann Intern Med 2013 Jan 1158(1)47 editorialcan be found in Ann Intern Med 2013 Jan 1158(1)69 or at USPSTF 2012 Oct 23 fullshytext)supporting systematic review for updated recommendations can be found in Ann Intern Med


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2012 Jul 17157(2)104 fullshytext

Canadian Task Force on Preventive Health Care (CTFPHC) recommendationsHRT for primary prevention of chronic diseases

use of combined estrogenshyprogestin therapy and estrogenshyonly therapy notrecommended for primary prevention of chronic diseases in menopausal women(CTFPHC Grade D)discuss risks and benefits of HRT for alleviating menopausal symptoms withindividual patientsReference shy CMAJ 2004 May 11170(10)1535 fullshytext

postmenopausal HRT for primary prevention of cardiovascular and cerebrovascular diseaseuse of HRT not recommended for primary prevention of myocardial infarction andcardiovascular death in perimenopausal women without coronary artery disease(CTFPHC Grade D)insufficient evidence to make recommendation on use of HRT for primary preventionof stroke and death from cerebrovascular diseaseReference shy CMAJ 2004 Apr 27170(9)1388 fullshytext

Evidence for Overall Risks vs Benefit

Cochrane review

longshyterm hormone replacement therapy increases risk of coronary events venousthromboembolism stroke breast cancer and death due to lung cancer in postmenopausalwomen (level 1 [likely reliable] evidence)

based on Cochrane reviewsystematic review of 23 randomized trials lasting ge 1 year comparing HRT vs placebo in42830 postmenopausal womenall results included data from WHI and WISDOM trials summarized belowcompared to placebo in relatively healthy women combined continuous HRT associatedwith increased risk of

coronary events (myocardial infarction [MI] or cardiac death) after 1 year (absoluterisk [AR] 4 per 1000 95 CI 3shy7)venous thromboembolism after 1 year (AR 7 per 1000 95 CI 4shy11)stroke after 3 years (AR 18 per 1000 95 CI 14shy23)breast cancer after 56 years (AR 23 per 1000 95 CI 19shy29)gallbladder disease requiring surgery after 56 years (AR 27 per 1000 95 CI 21shy34)death from lung cancer (nonshysmall or small cell) after 56 years use plus 24 yearsfollowshyup (AR 9 per 1000 95 CI 6shy13)dementia among women gt 65 years old after 4 years (AR 18 per 1000 95 CI 11shy30)

compared to placebo in relatively healthy women estrogenshyonly therapy associated withincreased risk of

venous thromboembolism after 1shy2 years (AR 5 per 1000 95 CI 2shy10)stroke after 7 years (AR 32 per 1000 95 CI 25shy40)gallbladder disease after 7 years (AR 45 95 CI 36shy57)

in women with cardiovascular disease combined continuous HRT increased risk of venousthromboembolism after 1 year (AR 9 per 1000 95 CI 3shy29)compared to placebo in all women

combined HRT associated with decreased risk of fractures after 56 years (AR 86 per1000 95 CI 79shy84)


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estrogenshyonly therapy associated with decreased risk of fractures after 71 years (AR102 per 1000 95 CI 91shy112)

Reference shy Cochrane Database Syst Rev 2012 Jul 11(7)CD004143 commentary on earlierversion can be found in EvidenceshyBased Medicine 2006 JanshyFeb11(1)22 Cochrane forClinicians summary of earlier version can be found in Am Fam Physician 2006 Nov174(9)1501 fullshytext

Womens Health Initiative (WHI) trial

longshyterm use of HRT associated with more risks than benefits in healthy postmenopausalwomen (level 2 [midshylevel] evidence)

based on randomized trial with early terminationWomens Health Initiative (WHI) is largest randomized trial of HRT stopped early due torisks exceeding benefits16608 postmenopausal women aged 50shy79 years with intact uterus were randomized toHRT (equine estrogens 0625 mgmedroxyprogesterone acetate 25 mg [Prempro]) vsplacebo orally once daily for mean 52 years (range 35shy85 years)few women had cardiovascular disease at baseline (16shy19 had history of myocardialinfarction 28shy29 had history of angina 11shy15 had history of CABG or percutaneouscoronary intervention 07shy1 had history of stroke)discontinuation of study drug occurred in 42 HRT and 38 placebo patients whileaddition of HRT through personal clinician was started in 62 HRT and 107 placebopatients intentionshytoshytreat analysis was performed so results likely underestimate perprotocol resultsno differences in overall mortality or endometrial cancerresults reported as annualized percentages (event rates per year of therapy)

number needed to harm (NNH) or treat for benefit (NNT) reported as number treatedwith HRT for 1 yearcomparing HRT vs placebo (for adverse outcomes more common with HRT)

coronary heart disease events 037 vs 03 (P lt 005 NNH 1428)differences related to nonfatal myocardial infarctionsstroke 029 vs 021 (p lt 005 NNH 1250)invasive breast cancer 038 vs 03 (p lt 005 NNH 1250)venous thromboembolic event 034 vs 016 (p lt 005 NNH 555)pulmonary embolism 016 vs 008 (p lt 005 NNH 1250)absolute excess in risk 17 vs 151 (p lt 005 NNH 526) based on globalindex of death coronary heart disease event stroke pulmonary embolismbreast cancer endometrial cancer colorectal cancer or hip fracture

comparing HRT vs placebo (for adverse outcomes less common with HRT thanplacebo)

colorectal cancer 01 vs 016 (p lt 005 NNT 1667)hip fracture 01 vs 015 (p lt 005 NNT 2000)vertebral fracture 009 vs 015 (p lt 005 NNT 1429)any osteoporotic fracture 147 vs 191 (p lt 005 NNT 228)

Reference shy JAMA 2002 Jul 17288(3)321editorial can be found in JAMA 2002 Jul 17288(3)366 commentary can be found in BMJ2008 May 10336(7652)1033 (commentary can be found in BMJ 2008 May24336(7654)1148)considerable commentary can be found in JAMA 2002 Dec 11288(22)2819 CMAJ 2002Aug 20167(4)377 fullshytext ACP J Club 2002 SepshyOct137(2)41 J Fam Pract 2002


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Oct51(10)821 Evid Based Nurs 2003 Jan6(1)20 Can Fam Physician 2003 Feb49157Curr Rheumatol Rep 2003 Feb5(1)43 JAMA 2003 Dec 24290(24)3193 JAMA 2003 Jun25289(24)3241 JAMA 2004 Aug 11292(6)683 JAMA 2005 Mar 16293(11)1322JAMA 2006 Jul 19296(3)280 S Afr Med J 2003 Aug93(8)554 Evid Based Med 2008Oct13(5)142editorial commentary can be found in BMJ 2002 Jul 20325(7356)113 fullshytext (correctioncan be found in BMJ 2002 Aug 24325(7361)435) BMJ 2002 Nov 2325(7371)1036 fullshytext BMJ 2002 Nov 23325(7374)1243 fullshytextHRT did not have clinically meaningful effect on healthshyrelated quality of life in WHItrial (N Engl J Med 2003 May 8348(19)1839) editorial can be found in N Engl J Med2003 May 8348(19)1835 commentary can be found in ACP J Club 2003 NovshyDec139(3)60 Am Fam Physician 2004 Jan 1569(2)423 N Engl J Med 2004 Feb5350(6)622 HRT associated with modest reduction in frequency of joint pain but increasedswelling at 1 year (level 2 [midshylevel] evidence)

based on post hoc analysis of WHI trialReference shy Menopause 2013 Jun20(6)600

HRT may increase risk of ovarian cancer (level 2 [midshylevel] evidence)based on followshyup study of WHImean followshyup 56 yearsannualized risk of invasive ovarian cancer was 004 with HRT vs 003 withplacebo (not significant)HRT did not increase risk of endometrial cancer (006 vs 007 annualized risk)but due to vaginal bleeding more women required endometrial biopsies (33 vs 6P lt 005 NNH 37)Reference shy JAMA 2003 Oct 1290(13)1739 commentary can be found in JAMA2004 Jan 7291(1)42

3 years after halt of WHI trial HRT associated with higher rates of cancer but notcardiovascular disease (level 2 [midshylevel] evidence)

based on postintervention phase of randomized trial15730 women from WHI trial were followed for mean 24 years after halt of trial

8052 women from HRT group7678 women from placebo group

comparing HRT vs placebo during postintervention phaseallshycause mortality 29 vs 26 (not significant)malignancies (including invasive breast cancer endometrial or colorectalcancer) in 35 vs 28 (p lt 005 NNH 142)invasive breast cancer in 009 vs 008 (not significant)total cardiovascular disease events in 43 vs 42 (not significant)any fracture in 42 vs 45 (not significant)

Reference shy JAMA 2008 Mar 5299(9)1036 commentary can be found in JAMA2008 Jun 18299(23)2744 ACP J Club 2008 Aug 19149(2)11

HRT may not be associated with increased risk for lung cancer but may increase riskof mortality from lung cancer (level 2 [midshylevel] evidence)

based on postintervention phase of WHI randomized trial16608 women from WHI trial were followed for mean 24 years after halt of trialcomparing HRT vs placebo during postintervention phase

lung cancer in 016 vs 013 per year (not significant)nonshysmallshycell lung cancer in 014 vs 011 per year (not significant)smallshycell lung cancer in 002 vs 002 per year (not significant)


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death from lung cancer in 011 vs 006 per year (p = 001)death from nonshysmallshycell lung cancer in 009 vs 005 per year (p = 0004death from smallshycell lung cancer in 002 vs 001 per year (not significant)poorly differentiated nonshysmallshycell cancer in 004 vs 002 (p = 003)nonshysmallshycell lung cancer distant metastases in 006 vs 003 (p = 004)

no significant differences in local or regional nonshysmallshycell lung cancer or in anyother cancer grade of nonshysmallshycell lung cancerReference shy Lancet 2009 Oct 10374(9697)1243 fullshytext editorial can be found inLancet 2009 Oct 10374(9697)1217 commentary can be found in Lancet 2010 Jan9375(9709)117

vasomotor symptoms may worsen after stopping estrogen therapybased on postintervention phase of WHI randomized trial3496 women from WHI trial continued assigned intervention to trial closure andcompleted symptom surveys 7 years after study initiation and after stoppingintervention (306 days after trial closure)after stopping intervention vasomotor symptoms reported by 98 estrogen group vs32 placebo group (p lt 005)among women with no moderate or severe symptoms at baseline hot flashes reportedafter stopping intervention in 72 estrogen group vs 15 placebo groupReference shy Menopause 2010 SepshyOct17(5)946 fullshytext

HRT associated with increased risk of breast cancer at 11 yearsbased on additional follow up of WHI trial12788 women with no prior hysterectomy followed for mean 11 yearscomparing HRT vs placebo

invasive breast cancer incidence 042 per year vs 034 per year (hazard ratio[HR] 125 95 CI 107shy146)breast cancer mortality 003 per year vs 001 per year (HR 19 95 CI 1shy404)allshycause mortality after breast cancer diagnosis 005 per year vs 003 peryear (HR 157 95 CI 101shy248)

HRT associated with increased risk of nodeshypositive breast cancer (HR 178 95 CI123shy258)Reference shy JAMA 2010 Oct 20304(15)1684 editorial can be found in JAMA 2010Oct 20304(15)1719

estrogen alone does not have benefits that outweigh risks overall in postmenopausal womenwith prior hysterectomy (level 2 [midshylevel] evidence)

based on randomized trial with early termination10739 postmenopausal women aged 50shy79 years with prior hysterectomy in WomensHealth Initiative (WHI) trial randomized to conjugated equine estrogen 0625 mg (Premarin)vs placebo orally daily for mean of almost 7 yearstrial stopped early by NIH since there was no benefit in primary outcome of reducingcardiovascular diseasecomparing estrogen vs placebo groups

coronary heart disease death or myocardial infarction in 333 vs 367 (notsignificant)stroke in 298 vs 217 (p lt 005 NNH 123)venous thromboembolism in 19 vs 144 (not significant)invasive breast cancer in 177 vs 228 (hazard ratio 126 95 CI 1shy159)colorectal cancer 115 vs 107 (not significant)hip fracture 072 vs 118 (p lt 005 NNT 217)


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any fracture 7 vs752 (p lt 005 NNT 192)overall mortality 548 vs 532 (not significant)

Reference shy JAMA 2004 Apr 14291(14)1701 editorial can be found in JAMA 2004 Apr14291(14)1769 Nephrol News Issues 2004 Aug18(9)54 61 commentary can be found inJAMA 2004 Aug 11292(6)683 summary can be found in Am Fam Physician 2005 Jan1571(2)371 no significant differences in most outcomes after 10 years

based on 107 year followshyup of 7645 women from Womens Health InitiativeEstrogenshyAlone Trialpostintervention annualized risk for outcome comparing estrogen vs placebo

coronary heart disease 064 vs 067 (not significant)stroke 036 vs 041 (not significant)deep vein thrombosis 017 vs 027 (hazard ratio 063 95 CI 041shy098)invasive breast cancer 026 vs 034 (not significant)hip fracture 036 vs 028 (not significant)

no significant differences in mortality coronary heart disease mortality myocardialinfarction pulmonary embolism or colorectal cancerReference shy JAMA 2011 Apr 6305(13)1305 fullshytext editorial can be found inJAMA 2011 Apr 6305(13)1354 (correction can be found in JAMA 2011 Jun15305(22)2418)

estrogen alone did not have clinically meaningful effect on healthshyrelated quality of life inWHI trial (Arch Intern Med 2005 Sep 26165(17)1976) commentary can be found in BMJ2005 Oct 22331(7522) commentary can be found in Am Fam Physician 2006 Apr1573(8)1453 commentary can be found in EvidenceshyBased Medicine 2006 MayshyJun11(3)76

estrogen with or without progesterone may not have overall benefits at 13 years (level 2[midshylevel] evidence)

based on followshyup of WHI trials above27347 postmenopausal women aged 50shy79 years were evaluated75 participated in extension phases of trialsmedian overall followshyup 13 yearscomparing HRT vs placebo

coronary heart disease in 055 vs 053 (not significant)invasive breast cancer in 043 vs 033 (p = 0007 NNH 1000)endometrial cancer in 008 vs 013 (p = 0007 NNT 2000)

no significant differences in stroke pulmonary embolism colorectal cancer hip fracture orallshycause deathcomparing estrogen alone vs placebo

coronary heart disease in 068 vs 072 (not significant)invasive breast cancer in 027 vs 034 (not significant)

no significant differences in stroke pulmonary embolism colorectal cancer endometrialcancer hip fracture or allshycause deathReference shy JAMA 2013 Oct 2310(13)1353 editorial can be found in JAMA 2013 Oct2310(13)1349

WISDOM trial

HRT increases risk of cardiovascular disease and venous thromboembolism in olderpostmenopausal women (level 1 [likely reliable] evidence)


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based on randomized trial5692 postmenopausal women aged 50shy69 years (mean age 63 years) who had ge 80compliance during 12 week runshyin period were randomized to hormone replacement therapyvs placebo

women with uterus were randomized to combination HRT (Prempro) vs placebo dailywomen without uterus and unwilling to take placebo were randomized to Prempro vsestrogen alone (Premarin) 0625 mg orally dailywomen without uterus and willing to take placebo were randomized to Prempro vsPremarin vs placebo daily

medroxyprogesterone acetate 5 mg (Premique) orally daily given to women with uterus andwithin 3 years of last period women aged 50shy53 years and older women with unacceptablebreakthrough bleedingmedian followshyup 119 months due to early closure of trialmajor cardiovascular disease defined as unstable angina requiring hospitalizationmyocardial infarction (fatal or nonshyfatal) or sudden coronary deathcomparing combination therapy vs placebo in analysis of 4385 women

major cardiovascular disease in 032 vs 0 (p lt 005 NNH 312)rate of major cardiovascular disease 269 vs 0 per 10000 personshyyears (p = 0016NNH 371 personshyyears)venous thromboembolism in 1 vs 014 (NNH 116)rate of venous thromboembolism 851 vs 115 per 10000 personshyyears (p lt 0001NNH 136 personshyyears)osteoporotic fractures 18 vs 26 (p lt 005 NNT 125)rate of osteoporotic fractures 1553 vs 2262 per 10000 personshyyears (p = 007)no significant differences in rates of cerebrovascular disease cancer or death

comparing combination HRT vs estrogen alone in 1641 womenno significant differences in major cardiovascular disease venous thromboembolismcancer osteoporotic fracture or deathsome combination HRT women counted in this analysis and in analysis compared toplacebo

of 11 women who had major cardiovascular events 9 were gt 64 years old and had othercardiovascular risk factorsReference shy WISDOM trial (BMJ 2007 Aug 4335(7613)239 fullshytext) editorial can befound in BMJ 2007 Aug 4335(7613)219 fullshytext commentary can be found in Evid BasedMed 2008 Apr13(2)52

Heart and EstrogenProgestin Replacement Study (HERS) trial

HRT does not reduce overall rate of coronary events in postmenopausal women withestablished coronary disease (level 1 [likely reliable] evidence)

based on randomized trial (Heart and Estrogenprogestin Replacement Study [HERS])2763 postmenopausal women lt 80 (mean age 667) with coronary disease (stable for at least6 months) and intact uterus randomized to conjugated equine estrogens 0625 mg plusmedroxyprogesterone acetate 25 mg in 1 tablet (Prempro) vs placebo orally once dailymultiple exclusion criteria including poor compliance in placebo runshyin periodmean followshyup 41 years82 those assigned to hormone treatment were taking it at 1 year 75 at 3 yearsno significant differences comparing Prempro vs placebo in

primary outcome of nonfatal myocardial infarction or coronary heart disease mortality(125 vs 127) coronary mortality (51 vs 42)


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nonfatal myocardial infarction (84 vs 93)coronary revascularizationunstable anginaheart failureresuscitated cardiac arreststroke or transient ischemic attackperipheral arterial diseaseallshycause mortality

no overall effect despite 11 lower LDL cholesterol and 10 higher HDL cholesterol levelsin hormone groupstatistically significant time trend with more coronary events in hormone group in year 1and fewer in years 4 and 5increased risks comparing Prempro vs placebo

venous thromboembolic events (25 vs 09 NNH [number needed to harm] 60)gallbladder disease (61 vs 45 NNH 625 borderline statistical significance)

no increased risk of fracture cancer or total mortality interpretation

based on pattern of early increase in risk of coronary events starting HRT notrecommend for secondary preventiongiven favorable pattern of coronary events after several years of therapy it could beappropriate for women already receiving HRT to continue

Reference shy JAMA 1998 Aug 19280(7)605 editorial can be found in JAMA 1998 Aug19280(7)650 commentary can be found in ACP J Club 1999 JanshyFeb130(1)8 JAMA1999 Mar 3281(9)794 J Am Geriatr Soc 2000 Dec48(12)1717 JAMA 2001 Nov28286(20)2544 JAMA 2003 Jun 25289(24)3241 HRT only improves quality of life in women with postmenopausal symptomsotherwise worsens quality of life (level 1 [likely reliable] evidence)

based on HERS trialamong women with flushing at baseline hormones associated with improved mentalhealth and fewer depressive symptoms compared to placeboamong women without flushing at baseline hormones associated with declines inphysical function and energyfatigue compared to placeboage and clinical illness had greater affect on quality of life measures than hormone useReference shy JAMA 2002 Feb 6287(5)591 editorial can be found in JAMA 2002 Feb6287(5)641 commentary can be found in JAMA 2002 May 1287(17)2210 EvidBased Nurs 2002 Jul5(3)83 fullshytext ACP J Club 2002 NovshyDec137(3)105 EvidBased Ment Health 2002 Nov5(4)112 fullshytext

Benefits of HRT

Overview of benefits

estrogen proven to alleviate menopausal symptoms see MenopauseHRT may prevent bone loss and osteoporotic fracturesHRT may reduce colorectal cancer riskother potential benefits

possible reduction in total mortality in women lt 60 years oldmay reduce risk of diabetesmay reduce risk of osteoarthritis


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may reduce risk of cataracts

HRT may prevent bone loss and osteoporotic fractures

hormone replacement therapy (HRT) prevents bone loss (increases bone mineral density) (level 3[lacking direct] evidence) and fractures in randomized trials but risks of longshyterm use mayoutweigh benefitslargest randomized trial of estrogenprogestin combination therapy (Womens Health Initiative[WHI] with 16608 patients) showed reduction in hip fractures (NNT 2000 per year) vertebralfractures (NNT 1429 per year) and osteoporotic fractures (NNT 228 per year)estrogen alone may reduce fracture rates but increases risk for stroke and possibly venousthromboembolism (level 2 [midshylevel] evidence)systematic reviews of randomized trials before WHI trial found HRT associated with reduced riskfor

nonvertebral fractures but only significant for women lt 60 years oldvertebral fractures

observational studies find association between longshyterm HRT use and reduced fracturesfracture risk reduction may require use of HRT for at least 5 yearsfracture risk reduction appears to diminish rapidly after cessation of HRT

alendronate (Fosamax) 10 mg orally once daily prevents bone density loss after discontinuation ofHRT

see Hormonal replacement therapy (HRT) and osteoporosis for details

HRT may reduce risk of colorectal cancer

estrogen plus progestin therapy associated with reduced risk of colorectal cancer but notcolorectal cancer mortality (level 2 [midshylevel] evidence)

based on followshyup study of Womens Health Initiative trial16608 postmenopausal women were randomized to conjugated equine estrogens 0625 mgplus medroxyprogesterone acetate 25 mg (hormone replacement therapy [HRT]) vs placeboper daymean treatment duration was 56 years and mean followshyup was 116 yearsfrequency of bowel screening exams during trial and followshyup were similar for each group263 colorectal cancers diagnosedcomparing HRT vs placebo

invasive colorectal cancer incidence 012 per year vs 016 per year (p = 0014NNT 2500 per year)colorectal cancer mortality 004 per year vs 003 per year (not significant)lymph nodeshypositive cancer in 505 vs 286 (p lt 0001) in subgroup of womenwho developed cancer

comparing stage of cancer at diagnosis for HRT vs placebo in subgroup of women whodeveloped cancer

distant or regional stage in 688 vs 514local stage in 312 vs 486HRT associated with trend toward diagnosis of colorectal cancer at more advancedstage (p for trend = 0003)

Reference shy J Clin Oncol 2012 Nov 1030(32)3983 fullshytext report of effect of HRT oncolorectal cancer at 52 years followshyup can be found in N Engl J Med 2004 Mar4350(10)991 fullshytext


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HRT may not alter risk of small adenomasbased on cohort study59002 postmenopausal women from Nurses Health Study were followed up to 14 yearscurrent hormone users less likely than nonusers to develop colorectal cancer and adenomas gt1 cmpast use and duration of hormone replacement not significantly related to colorectal cancerriskReference shy Ann Intern Med 1998 May 1128(9)705 PDF

use of estrogen replacement therapy (ERT) or HRT associated with decreased risk of coloncancer in observational studies (level 2 [midshylevel] evidence)

based on 1 metashyanalysis 1 cohort study and 1 caseshycontrol studymetashyanalysis of 18 epidemiologic studies

20 reduction in risk of colon cancer and 19 reduction in risk of rectal cancer forpostmenopausal women who had ever taken hormone therapy compared with womenwho had never taken hormones most of apparent reduction in colorectal cancerlimited to current hormone usersReference shy Am J Med 1999 May106(5)574 commentary can be found in J AmGeriatr Soc 2002 Apr50(4)768DynaMed commentary shyshy observational studies unable to control for bias ofunrecognized healthier lifestyles

cohort study of 7701 women aged 44shy98 years followed 14 yearsageshyadjusted colorectal cancer incidence rate per 1000 personshyyears

267 for women who had ever used estrogen330 for lifetime nonusersRR 081 95 CI 063shy104

recent users had oneshythird the incidence of lifetime nonusers (RR = 066 95 CI 044shy098)no significant differences in colorectal cancer mortalityReference shy Dis Colon Rectum 1999 Oct42(10)1300DynaMed commentary shyshy assuming current users have incidence of 11 per 1000personshyyears and estrogen is truly protective 455 women need to take postmenopausalestrogen continuously to prevent 1 case of colorectal cancer

risk reduction with transdermal estrogen may be greater than with oral estrogen based oncaseshycontrol study (Br J Cancer 2004 Jan 2690(1)76 fullshytext)

Mortality reduction in younger women

HRT might reduce total mortality in postmenopausal women lt 60 years old (level 2 [midshylevel] evidence)

based on subgroup analysis of WHI trials with inadequate statistical power in individualtrialssecondary analysis of 2 large WHI trials

16608 postmenopausal women without hysterectomy randomized to conjugatedequine estrogens plus medroxyprogesterone acetate (combined HRT) vs placeboincluding 5522 women aged 50shy59 years10739 postmenopausal women with hysterectomy randomized to conjugated equineestrogens (estrogen alone) vs placebo including 3310 women aged 50shy59 years

total mortality comparing HRT vs placebo in subgroups of women aged 50shy59 yearsin combined HRT trial 123 vs 175 (hazard ratio 069 95 CI 044shy107)in estrogen alone trial 208 vs 287 (hazard ratio 071 95 CI 046shy111)


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in combined subgroup analysis 154 vs 218 (hazard ratio 07 95 CI 051shy096NNT 157 95 CI 94shy1147)

Reference shy JAMA 2007 Apr 4297(13)1465 correction can be found in JAMA 2008 Mar26299(12)1426 commentary can be found in JAMA 2007 Aug 8298(6)623 ACP J Club2007 SepshyOct147(2)29


based on metashyanalysis with methodologic limitationssystematic review of 19 randomized trials of hormone replacement therapy vs placebo or notreatment with mean age lt 60 years treatment duration ge 6 months and report of at least 1deathDynaMed commentary shyshy trial selection criteria may bias results by excluding data fromsome trials with younger women and including data from older women and by excludingtrials with no deathstrials in analysis included subgroup analyses from WHI trials (but not subgroup analysesfrom any other trials)DynaMed commentary shyshy specific metashyanalysis results not reported here because

data analyzed counted WHI estrogen alone subgroup twice because of erroneouslyusing combined subgroup data in place of the other WHI trialstatistical method did not clearly analyze data in traditional metashyanalysis

Reference shy Am J Med 2009 Nov122(11)1016these same authors previously reported metashyanalyses supporting HRT for women lt 60years old but these metashyanalyses were flawed by not including WHI subgroup data and byweighing metashyanalysis contribution by deaths (numerator data) instead of sample size(denominator data)

systematic review and metashyanalysis of 30 randomized trials with 26708 womenHRT not associated with significant effect on overall mortalityReference shy J Gen Intern Med 2004 Jul19(7)791 fullshytext editorial can befound in J Gen Intern Med 2004 Jul19(7)810 fullshytext commentary can befound in BMJ 2005 Jan 1330(7481) ACP J Club 2005 JanshyFeb142(1)1 J GenIntern Med 2005 Feb20(2)212 fullshytextDynaMed commentary shyshy conclusion of lower mortality in women aged lt 60years in this review not considered valid because

analysis was based on 4141 women in trials with mean age lt 60 yearsanalysis did not include 5522 women aged 50shy59 years in WHI trial(which had mean age 63 years)analysis with WHI trial would find no difference in mortality

DynaMed commentary shyshy entire metashyanalysis fundamentally flawed byweighting studies based on number of deaths instead of sample size

for example consider the metashyanalysis of trials with mean age lt 60 yearswhich included 17 trials and 4141 women1 trial with high mortality in 130 ovarian cancer patients provided 3 ofthe overall sample size but was calculated as providing 41 of the weightin this metashyanalysis

similar conclusions for outcome of coronary heart disease events (reduced risk inwomen lt 60 years old) reported in metashyanalysis of 23 trials with 39049 womenconducted by same authors (J Gen Intern Med 2006 Apr21(4)363 fullshytext) butsimilar methodologic flaws limit validity of conclusion (DynaMed commentary)

HRT may reduce risk of diabetes


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HRT may reduce risk of diabetes in women with coronary disease (level 2 [midshylevel]evidence)

based on post hoc analysis of HERS trial2763 postmenopausal women with coronary heart disease were randomized to HRT vsplacebo for 4 years2029 did not have diabetes mellitus at baselineincidence diabetes was defined as selfshyreport of diabetes or disease complication fastingglucose level 69 mmolL or greater (gt 125 mgdL) or initiation of therapy with diabetesmedicationdiabetes developed in 62 with HRT vs 95 with placebo (p lt 005 NNT 30)Reference shy Ann Intern Med 2003 Jan 7138(1)1 fullshytext) editorial can be found in AnnIntern Med 2003 Jan 7138(1)69 commentary can be found in ACP J Club 2003 SepshyOct139(2)39 Ann Intern Med 2003 Dec 16139(12)1043 PDF Ann Intern Med 2003 Jan7138(1)69 PDFDynaMed commentary shyshy prevention of diabetes as defined may not be clinically relevant asthere was not an overall reduction in heart disease among patients with diabetes glycemiccontrol is not as important as other factors in preventing heart disease

HRT may reduce risk of osteoarthritis

hormone replacement therapy may not affect risk of hip or knee replacement butunopposed estrogen might be associated with fewer hip replacements (level 2 [midshylevel]evidence)

based on randomized trial with borderline significance26321 communityshydwelling women aged 50shy79 years in WHI were randomized toconjugated equine estrogen 0625 mg (plus medroxyprogesterone 25 mg if intact uterus) vsplacebo once daily

10720 with hysterectomies were randomized to estrogen vs placebo for mean 71years16049 without hysterectomies were randomized to estrogenprogestin vs placebo formean 56 years

comparing estrogen alone vs placeboany arthroplasty in 44 vs 52 (p = 005 NNT 125) or 62 vs 74 cases per 10000personshyyearstotal knee replacement in 33 vs 38 (not significant)total hip replacement in 11 vs 16 (p = 007)

comparing estrogen plus progestin vs placebo27 vs 26 had any arthroplasty or 48 vs 48 cases per 10000 personshyyears (notsignificant)17 vs 18 had total knee replacement or 30 vs 32 cases per 10000 personshyyears(not significant)11 vs 09 had total hip replacement or 19 vs 16 cases per 10000 personshyyears(not significant)

Reference shy Arthritis Rheum 2006 Oct54(10)3194 fullshytextobservational studies suggest decreased risk of radiographic osteoarthritis with hormonereplacement

postmenopausal estrogen replacement therapy associated with reduced rate ofradiographic osteoarthritis of hip (level 3 [lacking direct] evidence) in crossshysectionalstudy of 4366 white women gt 64 years old (Arch Intern Med 1996 Oct 14156(18)2073)continuous HRT gt 1 year associated with decreased risk of radiographic osteoarthritis


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of knee (level 3 [lacking direct] evidence) in study of 606 postmenopausal women (AnnRheum Dis 1997 Jul56(7)432 PDF)

Additional potential benefits of HRT

estrogen alone or in addition to progestogen may reduce sexual dysfunction inperimenopausal and postmenopausal women (level 2 [midshylevel] evidence)

based on Cochrane review of trials with methodologic limitationssystematic review of 27 randomized trials comparing hormone therapy vs placebo or nointervention in 16393 women with menopausal symptoms who had their menstrual periodwithin the past 12 months (symptomatic perimenopausal) or postmenopausal womenall trials had ge 1 limitation including

unclear allocation concealmenthighshydropout rate or high loss to followshyup

primary outcome was composite of arousal and sexual interest orgasm andor painimproved composite score in symptomatic perimenopausal or early postmenopausal womenwith

estrogen (standardized mean difference [SMD] 038 95 CI 023shy054) in analysis of3 trials with 699 womenestrogen plus progestogen (SMD 042 95 CI 019shy064) in 1 trial with 335 women

nonsignificant improvement in composite score with tibolone bazedoxifene (selectiveestrogen receptor modulator) and bazedoxifene plus estrogen in single trialsReference shy Cochrane Database Syst Rev 2013 Jun 5(6)CD009672

combination HRT associated with improvements in most postmenopausal symptoms andsome quality of life measures (level 2 [midshylevel] evidence)

based on randomized trial with low followshyup rate3721 postmenopausal women aged 50shy69 years with a uterus randomized to combined HRT(conjugated equine estrogen 0625 mg plus medroxyprogesterone acetate 255 mg) vsplacebo for 1 yearquality of life data available for 572significant improvements with combined HRT vs placebo (all p le 0001)

vasomotor symptomssexual functioningsleep problemshot flushesnight sweatsaching joints and musclesinsomniavaginal dryness

combined HRT also significantly associated with increased breast tenderness and vaginaldischargeno significant differences in other menopausal symptoms depression or overall quality oflifeReference shy BMJ 2008 Aug 21337a1190 fullshytext

limited evidence regarding effect of hormone therapy on skin appearancelowshydose HRT for 48 weeks may not affect ageshyrelated facial skin changes (level 2 [midshylevel] evidence)

based on randomized trial with uncertain allocation concealment485 postmenopausal women randomized to placebo vs norethindrone acetate 1


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mgethinyl estradiol 5 mcg vs norethindrone acetate 1 mgethinyl estradiol 10 mcg for48 weeksno significant differences in coarse and fine facial wrinkling skin laxitysagging skintexturedryness or wrinkle depth at 24 and 48 weeksReference shy J Am Acad Dermatol 2008 Sep59(3)397

estrogen replacement therapy might decrease probability of dry skin and skinwrinkling in postmenopausal women (level 2 [midshylevel] evidence)

retrospective review of 3875 postmenopausal women gt 39 years old followed at least10 yearsprevalence of skin wrinkling dryness and atrophy lower in AfricanshyAmerican womenpostmenopausal estrogen therapy showed improvements even after correction for agebody mass index and sunlight exposure in white women but not in AfricanshyAmericanwomenReference shy Arch Dermatol 1997 Mar133(3)339 in QuickScan Reviews in Fam Pract1997 Sep22(6)29 commentary can be found in Arch Dermatol 1997Nov133(11)1460

postmenopausal estrogen therapy may be associated with reduced risk for cataractspostmenopausal estrogen therapy associated with reduced risk for lens opacities in study of529 women 66shy93 years old (Arch Intern Med 2001 Jun 11161(11)1448)postmenopausal estrogen may be protective of ocular crystalline lens (Ophthalmology 1997Jun104(6)970

Risks of HRT (including Contraindications and Side Effects)

Overview of risks

increased risk of endometrial cancer (if estrogens used without progestins)increased risk of breast cancer shy see Hormonal replacement therapy (HRT) and breast cancerpossible increased risk for cardiovascular diseaseincreased risk of venous thromboembolismincreased risk of gallstones and gallbladder diseasepossible increased risk in ovarian cancerpossible worsening of urinary incontinence

Contraindications

precautions (not clearly contraindications)personal history or known high risk of thromboembolic diseasebreast canceruncontrolled hypertensionunexplained abnormal vaginal bleedingabnormal liver functionhistory of endometrial or ovarian cancerhighshyrisk gallbladder diseaseReference shy BMJ 2012 Feb 16344e763

Side effects

vaginal bleeding breast tenderness breast swelling mastodynia (BMJ 2012 Feb 16344e763)


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weight gain may be transient but no sustained adverse effect on weightevidence shows no effect of estrogen or estrogenprogestin on weight gain weight gain aftermenopause similar with or without hormone replacement therapy 22 trials reviewed 24trials awaiting assessment systematic review last updated 1999 May 13 (Cochrane DatabaseSyst Rev 2000(2)CD001018)hormone replacement therapy over 15shyyear period not associated with excess weight gain orcentral obesity (JAMA 1996 Jan 327546 in QuickScan Reviews in Fam Pract 1996Jul21(4)18)

older women starting HRT commonly discontinue HRT due to adverse effects485 women gt 65 years old entered 3shymonth openshylabel trial of HRT during runshyin phaseprior to randomized trial comparing HRT to alendronate for osteoporosis prevention112 (23) discontinued HRT within 3 months73 (15) discontinued for reasons considered HRTshyrelated including breast swelling ortenderness bloating bleeding or spottingReference shy J Womens Health Gend Based Med 2001 May10(4)343 in JAMA 2001 Aug2229286(8)902

estrogen but not estrogenprogesterone use may be associated with Raynauds phenomenon497 postmenopausal women interviewed 76 not using hormones 13 used estrogenalone 10 used estrogen and progesterone84 women using hormone replacement therapy reported unusual cold sensitivity and colorchange of fingers significantly more common among women using estrogen aloneReference shy Ann Intern Med 1998 Aug 1129(3)208 fullshytext

HRT and breast cancer

combined estrogen and progestin (hormone replacement therapy [HRT]) associated with increasedrisk for breast cancer but evidence for ongoing risk after stopping treatment is conflicting

hormone replacement therapy associated with increased risk for invasive breast cancer (level2 [midshylevel] evidence)current use of HRT associated with increased risk of breast cancer incidence and mortality(level 2 [midshylevel] evidence)conflicting evidence for ongoing risk of breast cancer after stopping HRT

longshyterm use of estrogen alone may increase risk for breast cancerestrogen alone does not appear to increase risk for invasive breast cancer but may increaserisk for abnormalities on followshyup mammograms (level 2 [midshylevel] evidence)estradiol alone for gt 5 years associated with increased risk for breast cancer (level 2 [midshylevel] evidence)use of unopposed estrogen for gt 20 years might be associated with increased risk of invasivebreast cancer (level 2 [midshylevel] evidence)

HRT may increase risk for recurrent breast cancer in breast cancer survivors but evidence isconflicting

HRT appears to increase risk of recurrent breast cancer (level 2 [midshylevel] evidence) in 2randomized trialsHRT does not appear to increase risk for recurrent breast cancer based on systematic reviewof observational studiesHRT associated with nonsignificant increase in risk of new breast cancer event andcontralateral breast cancer after 10 years (level 2 [midshylevel] evidence)among women with breast cancer prediagnostic use of hormone therapy may be associatedwith decreased breast cancer mortality (level 2 [midshylevel] evidence)


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see Hormonal replacement therapy (HRT) and breast cancer for details

HRT and endometrial cancer

unopposed estrogen replacement associated with increased risk of endometrial cancerunopposed estrogen and tibolone use each associated with increased risk of endometrialcancer in postmenopausal women

based on cohort study716738 postmenopausal women in United Kingdom without previous cancer orhysterectomy followed for mean 34 years1320 women (018) developed endometrial cancercompared with never users of HRT risk of endometrial cancer was

increased with unopposed estrogen (relative risk [RR] 145 p = 004)increased with tibolone (RR 179 p lt 00001)lower with use of continuous combined estrogen plus progestin (RR 071 p =0005)unchanged with cyclic progestin plus estrogen (RR 105 p = 05)

Reference shy Lancet 2005 Apr 30365(9470)1543 editorial can be found in Lancet2005 Apr 30shyMay 6365(9470)1517 commentary can be found in Lancet 2005 Jul16shy22366(9481)200

risk of endometrial cancer with unopposed estrogen appears to increase with durationof use

based on prospective cohort study68419 postmenopausal women with intact uteri and without history of cancer exceptnonmelanoma skin cancer enrolled in NIHshyAARP Diet and Health study in 1996shy1997 completed baseline risk questionnaire to establish use of hormone replacementtherapy and were followed until 2006885 women diagnosed with epithelial endometrial cancer during study of which 85were endometrioiduse of unopposed estrogen associated with increased risk of endometrial cancer(relative risk 174 95 CI 12shy254)greater risk in women using unopposed estrogen for ge 10 years (RR 393 95 CI262shy589)Reference shy Int J Cancer 2013 Jan 15132(2)417 fullshytext

estradiol alone appears to increase risk for uterine bleeding endometrial biopsy andendometrial hyperplasia (level 2 [midshylevel] evidence)

based on randomized trial with allocation concealment not stated218 postmenopausal women with intact uteri were randomized to micronized 17shybetashyestradiol 1 mg vs placebo daily for 2 or 3 years in 1 of 2 randomized trialspatients had transvaginal ultrasound annuallycomparing estradiol vs placebo

at least 1 episode of uterine bleeding in 67 vs 11 (p lt 0001 NNH 2)endometrial biopsy 48 vs 4 (p lt 0001 NNH 2)endometrial hyperplasia in 94 vs 0 (mostly simple hyperplasia without atypia)

Reference shy Obstet Gynecol 2007 Mar109(3)581 sequential estradiolshyprogestin therapy for ge 5 years associated with increased risk ofendometrial cancer

based on cohort study224015 postmenopausal Finnish women gt 50 years old using estradiolshyprogestin therapy forge 6 months from 1994 to 2006 were included in analysis


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06 developed endometrial cancersequential estradiolshyprogestin therapy regimen for ge 5 years associated with increased risk ofendometrial cancer compared to general population

69 risk increase if progestin added monthly276 risk increase if progestin added at 3shymonth intervals

Reference shy Obstet Gynecol 2009 Dec114(6)1197 continuous combined hormone replacement therapy may prevent development ofendometrial hyperplasia associated with unopposed estrogen

no cases of endometrial hyperplasia or cancer found in longshyterm followshyup of 534postmenopausal women taking 17shybetashyestradiol 2 mg and norethisterone acetate 1 mg orallydaily for 1shy6 yearsdata on endometrial specimens available in 526 women after 9 months 465 women after 24shy36 months and 345 women at 5 yearsReference shy BMJ 2002 Aug 3325(7358)239 fullshytext) editorial can be found in BMJ 2002Aug 3325(7358)231 fullshytext

higher progestin doses in oral contraceptives might be associated with lower risk ofendometrial cancer in women with body mass index ge 221 kgm2 (level 2 [midshylevel]evidence)

based on caseshycontrol study with 434 endometrial cancer cases and 2557 controlsReference shy Gynecol Oncol 2006 Nov103(2)535

HRT and cardiovascular disease

routine use of combined estrogen and progestin not recommended for prevention of chronicconditions in postmenopausal women (USPSTF Grade D)hormone replacement therapy (HRT) associated with increased risk for cardiovascular diseasevenous thromboembolism and stroke in systematic reviews and randomized trials

HRT does not reduce risk of cardiovascular disease but does increase risk of stroke andvenous thromboembolic events in postmenopausal women (level 1 [likely reliable] evidence)HRT increases risk of cardiovascular disease and venous thromboembolism in olderpostmenopausal women (level 1 [likely reliable] evidence)hormone therapy associated with increased risk of stroke in postmenopausal women (level 2[midshylevel] evidence)

observational studies have inconsistent evidence

see Hormonal replacement therapy (HRT) and cardiovascular disease for details

HRT and venous thromboembolism

HRT does not reduce risk of cardiovascular disease but does increase risk of stroke (level 1 [likelyreliable] evidence) and may increase risk of venous thromboembolism (level 2 [midshylevel]evidence) in postmenopausal womenoral HRT increases risk of venous thromboembolic disease (level 1 [likely reliable] evidence)estrogen alone may increase risk of thromboembolism (level 2 [midshylevel] evidence)transdermal HRT may not increase risk of venous thromboembolism (level 2 [midshylevel] evidence)

see Hormonal replacement therapy (HRT) and venous thromboembolism for details

HRT and gallstones and gallbladder disease


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HRT increases risk of gall bladder diseaseestrogen (with or without progestin) increases risk of gallbladder disease (level 1 [likelyreliable] evidence)

8376 women (without cholecystectomy) with hysterectomy randomized to conjugatedequine estrogens 0625 mg vs placebo daily for mean 71 years

annualized incidence of any gallbladder event 078 vs 047 (NNH 322 peryear)annualized incidence of cholecystectomy 065 vs 034 (NNH 322 per year)annualized incidence of cholecystitis 063 vs 035 (NNH 357 per year)annualized incidence of cholelithiasis 067 vs 036 (NNH 322 per year)

14203 women (without cholecystectomy) without hysterectomy randomized toconjugated equine estrogens 0625 mg plus medroxyprogesterone acetate 25 mg vsplacebo daily for mean 56 years


Reference shy WHI trial (JAMA 2005 Jan 19293(3)330) commentary can be found inAm Fam Physician 2005 May 171(9)1783

hormone replacement therapy (HRT) may increase risk of hospital admission forgallbladder disease oral HRT may increase risk more than transdermal HRT (level 2[midshylevel] evidence)

based on prospective cohort study1001391 postmenopausal women (mean age 56 years) were followed for mean 61years

32 were current users of HRT (77 oral 18 transdermal 5 other orunknown)18 were past users of HRT

19 women had first hospital admission for gallbladder disease during followshyup17 had cholecystectomyhospital admissions for gallbladder disease in

16 of never user of HRT21 for current users of transdermal HRT (p lt 005 vs never use NNH 200)26 for current users of oral HRT (p lt 005 vs never use NNH 100 p lt 005vs transdermal NNH 200)

cholecystectomy in14 of never users of HRT23 of current users of HRT (p lt 005 vs never use NNH 112)18 of former users of HRT (p lt 005 vs never use NNH 250)

Reference shy BMJ 2008 Jul 10337a386 fullshytextHRT associated with increased risk for gallstones in Heart and EstrogenprogestinReplacement Study (HERS) (level 2 [midshylevel] evidence)

2763 postmenopausal women lt 80 years old with coronary disease and intact uterusrandomized to conjugated equine estrogens 0625 mg plus medroxyprogesteroneacetate 25 mg in 1 tablet (Prempro) vs placebo orally once daily followshyup averaged41 yearshormone use increased risk of gallbladder disease (61 vs 45 NNH 625borderline statistical significance)Reference shy JAMA 1998 Aug 19280(7)605 in J Fam Pract 1998 Nov47(5)333


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editorial can be found in JAMA 1998 Aug 19280(7)650 commentary can be foundin JAMA 1999 Mar 3281(9)794 JAMA 2001 Nov 28286(20)2544 JAMA 2003Jun 25289(24)3241increased risks for venous thromboembolism and biliary tract surgery reportedwith longer followshyup of HERS trial

after 41 years of randomized treatment openshylabel HRT was prescribed atphysicians discretion and 2321 (93 of surviving cohort) continued followshyupfor 27 yearsproportions with 80 adherence to hormones decreased from 81 to 45 inHRT group and increased from 0 to 8 in placebo groupsignificant risks over 68 years with HRT were found for venousthromboembolism (NNH 50shy65) and for biliary tract surgery (NNH 31shy35)Reference shy JAMA 2002 Jul 3288(1)58 editorial can be found in JAMA 2002Jul 3288(1)99 summary can be found in Am Fam Physician 2002 Dec166(11)2147 commentary can be found in ACP J Club 2003 JanshyFeb138(1)7

HRT and ovarian cancer

majority of evidence suggests an association between hormone replacement therapy (HRT) andovarian cancer

HRT use for 5 years associated with excess incidence of ovarian cancer of about 1 casein 1000 in postmenopausal women (level 2 [midshylevel] evidence)

based on pooled analysis of individual patient data from observational studies85334 postmenopausal women (mean age 64 years) from 52 studies with data onhormone therapy use parity oophorectomy hysterectomy and ovarian cancer wereanalyzed

17 studies with 12110 women with ovarian cancer and 40717 controls includedprospective data on hormone therapy use35 studies with 9378 women with ovarian cancer and 23129 controls includedretrospective data on hormone therapy use

compared to never users of hormone therapy increased risk of ovarian cancerassociated with

ever use (relative risk [RR] 114 95 CI 11shy119)current use for lt 5 years duration (RR 127 95 CI 118shy137)current use for ge 5 years duration (RR 134 95 CI 128shy141)past use for ge 5 years duration with last use lt 5 years prior (RR 125 95 CI113shy139)past use for ge 5 years duration with last use ge 5 years prior (RR 111 95 CI103shy12)

consistent results in analyses limited to prospective studiescompared to never users of hormone therapy current or recent use associated withsignificantly higher risk of serous tumors and endometrioid tumors but significantlylower risk of clearshycell tumorsestimated 5shyyear excess incidence of ovarian cancer

1 in 1000 women with 5 years of hormone therapy1 in 600 women with 10 years hormone therapy

Reference shy Lancet 2015 May 9385(9980)1835 fullshytext editorial can be found inLancet 2015 May 9385(9980)1804

HRT associated with increased risk of ovarian cancer (level 2 [midshylevel] evidence)based on 3 cohort studies


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cohort of 909946 Danish women aged 50shy79 years without hormoneshysensitive canceror bilateral oophorectomy were followed for mean 8 years

3068 ovarian cancers occurred (of which 2681 were epithelial cancers)incidence rate ratios with current use of HRT vs HRT never users

138 (95 CI 126shy151) for all ovarian cancer144 (95 CI 13shy158) for epithelial ovarian cancer

incidence rates (per 1000 years) were 052 with current vs 04 with never useof HRT (absolute risk increase 012 per 1000 years approximates 1 extraovarian cancer for roughly 8300 women taking HRT yearly)no significant difference in risk of ovarian cancer with current HRT use withdifferent hormone therapies or duration of userisk declined with years since last use

122 (95 CI 102shy146) with 0shy2 years098 (95 CI 075shy128) with gt 2shy4 years072 (95 CI 05shy105) with gt 4shy6 years063 (95 CI 041shy096) with gt 6 years

Reference shy JAMA 2009 Jul 15302(3)298 commentary can be found in JAMA2009 Nov 25302(20)2203

cohort of 948576 postmenopausal women in United Kingdom Million Women Studywho did not have previous cancer or bilateral oophorectomy were followed mean 53years for ovarian cancer and 69 years for death

2273 (024) developed ovarian cancer and 1591 (017) died from ovariancancercurrent users of HRT had increased risk of ovarian cancer (relative risk 12 95CI 109shy132) and death from ovarian cancer (relative risk 123 95 CI 109shy138) compared to never userspast users of HRT not at increased riskReference shy Lancet 2007 May 19369(9574)1703 editorial can be found inLancet 2007 May 19369(9574)1667 commentary can be found in Lancet 2007Sep 15370(9591)932

cohort of 909946 women aged 50shy79 years without prior hormoneshysensitive cancer orbilateral oophorectomy were followed for mean 8 years and stratified by use ofhormone therapy

women who used estrogen with or without progestin were compared to nonusersof hormone therapy03 developed epithelial ovarian cancercompared to no hormone therapy

oral estrogens without progestins associated withincreased risk for serous tumors (incidence rate ratio [IRR] 1795 CI 14shy22)increased risk for endometrioid tumors (IRR 15 95 CI 1shy24)decreased risk for mucinous tumors (IRR 03 95 CI 01shy08)

estrogen plus progestin therapy associated with increased risk for serousand endometrioid tumors

Reference shy Am J Epidemiol 2012 Jun 15175(12)1234 fullshytextestrogen use gt 10 years associated with ovarian cancer (level 2 [midshylevel] evidence)

based on 3 cohort studiespostmenopausal estrogen use gt 10 years associated with increased risk of ovariancancer mortality in prospective study

211581 postmenopausal women followed for 14 years


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944 ovarian cancer deaths occurredwomen using estrogen at baseline had increased risk of death due to ovariancancer (relative risk 151 95 CI 116shy196)annual ageshyadjusted ovarian cancer mortality rates per 100000 women were383shy644 for estrogen use gt 10 years and 264 for never usersReference shy JAMA 2001 Mar 21285(11)1460 commentary can be found inJAMA 2001 Jun 27285(24)3089DynaMed commentary shyshy if estrogen is causal NNH was 746 for any use ofestrogen replacement therapy

unopposed estrogen use gt 10 years and combined estrogenprogestin use gt 5years each associated with ovarian cancer

based on cohort study with 97638 women aged 50shy71 years followed for up to42 years214 ovarian cancers occurreduse of unopposed estrogen ge 10 years associated with increased risk of ovariancancer among all women compared to no hormone therapy (relative risk 18995 CI 122shy295)in women with intact uteri compared to no hormone therapy

sequential progestin (lt 15 days per cycle) associated with increased riskof ovarian cancer (relative risk 309 95 CI 168shy586)continuous progestin (ge 15 days per cycle) associated with increased riskof ovarian cancer (relative risk 182 95 CI 103shy323)

Reference shy J Natl Cancer Inst 2006 Oct 498(19)1397 fullshytextunopposed estrogen use gt 10 years associated with ovarian cancer in cohort study

44241 postmenopausal women followed for 21 years329 developed ovarian cancerin analyses adjusted for age menopause type and oral contraceptive useovarian cancer was significantly associated with ever use of

estrogen only (rate ratio [RR] 16 95 CI 12shy2)estrogen only use for 10shy19 years (RR 18 95 CI 11shy3)estrogen use for gt 20 years (RR 32 95 CI 17shy57)

no statistically significant risks with estrogenshyprogestin useReference shy JAMA 2002 Jul 17288(3)334 commentary can be found in JAMA2002 Nov 27288(20)2538 correction can be found in JAMA 2002 Nov27288(20)2544 summary can be found in Am Fam Physician 2002 Dec1566(12)2298

increasing estrogen dose with HRT associated with increasing risk of ovarian cancer(level 2 [midshylevel] evidence)

based on caseshycontrol study with 376 cases and 1111 controlsincreasing doses of estrogen associated with increased risk of ovarian cancer (oddsratio 131 95 CI 101shy17 per 5 g of estrogen)Reference shy Arch Intern Med 2004 Nov 8164(20)2253

HRT may not increase risk of ovarian cancer (level 2 [midshylevel] evidence)based on randomized trial with nonsignificant findings16608 postmenopausal women in United States (WHI trial) randomized to HRT(conjugated equine estrogens 0625 mg plus medroxyprogesterone acetate 25 mg) vsplacebo once dailymean followshyup 56 yearsannualized risk of invasive ovarian cancer was 004 with HRT vs 003 withplacebo (not statistically significant hazard ratio 158 95 CI 077shy324)


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HRT did not increase risk of endometrial cancer (006 vs 007 annualized risk)but due to vaginal bleeding more women required endometrial biopsies (33 vs 6NNH 4)Reference shy JAMA 2003 Oct 1290(13)1739 commentary can be found in JAMA2004 Jan 7291(1)42

HRT and urinary incontinence

HRT may be associated with increased risk of developing or worsening urinary incontinenceestrogen (with or without progestin) associated with developing or worsening urinaryincontinence in WHI trial

based on randomized trial27347 postmenopausal women aged 50shy79 years randomized to conjugated equineestrogen 0625 mgday (plus medroxyprogesterone acetate 25 mgday if nohysterectomy) vs placebo 23296 women (85) had urinary incontinence symptomsrecorded at baseline and at 1 yearamong 5183 women without urinary incontinence at baseline randomized to estrogenplus progestin vs placebo

stress incontinence at 1 year developed in 16 vs 87 (p lt 0001 NNH 13)urge incontinence at 1 year developed in 114 vs 108 (p = 006 NNH 166)mixed incontinence at 1 year developed in 37 vs 28 (p = 001 NNH 111)

among 3073 women without urinary incontinence at baseline randomized to estrogenvs placebo (posthysterectomy)


among women with urinary incontinence at baseline estrogen (with or withoutprogestin) associated with worsening amount worsening frequency and worseninglimitations of daily activities related to urinary incontinence at 1 year but results onlypresented as relative risks so NNH cannot be determinedReference shy Womens Health Initiative (WHI) trial (JAMA 2005 Feb 23293(8)935)editorial can be found in JAMA 2005 Feb 23293(8)998 commentary can be found inCMAJ 2005 Apr 12172(8)1003 fullshytext commentary can be found in BMJ 2005 Jun11330(7504) commentary can be found in EvidenceshyBased Medicine 2005 JulshyAug10(4)121 commentary can be found in JAMA 2005 Dec 7294(21)2696

hormone replacement therapy associated with development of incontinencebased on randomized trial2763 postmenopausal women lt 80 years old were randomized to conjugatedestrogens 0625 mgmedroxyprogesterone acetate 25 mg vs placebo orally once dailyfor mean 42 yearsin analysis of 1208 women who reported no loss of urine in previous 7 days atbaseline 64 HRT users vs 49 placebo group reported weekly incontinence (p lt0001 NNH 6)highest risk of incontinence within first 4 monthsReference shy Obstet Gynecol 2005 Nov106(5)940 fullshytext

hormone replacement therapy associated with worsening of incontinencebased on randomized trial2763 postmenopausal women lt 80 years old were randomized to conjugatedestrogens 0625 mgmedroxyprogesterone acetate 25 mg vs placebo orally once dailyfor mean 4 years


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analysis of 1525 women who had incontinence at least once weekly at baselinecomparing hormone replacement therapy vs placebo

worsening of incontinence in 39 vs 27 (p = 0001 NNH 8)improvement in incontinence in 21 vs 26

difference observed for both urge and stress incontinenceReference shy Obstet Gynecol 2001 Jan97(1)116

postmenopausal hormone therapy associated with increased risk of developing urinaryincontinence in longitudinal cohort study of 39436 postmenopausal women followed for 4years in Nurses Health Study relative risks ranged from 134 for oral estrogen and progestinto 168 for transdermal estrogens (Obstet Gynecol 2004 Feb103(2)254

ultrashylowshydose unopposed estrogen (transdermal estradiol 0014 mgday) may not beassociated with development improvement or worsening of urinary incontinence in 2shyyearrandomized placeboshycontrolled trial of 417 postmenopausal women 60shy80 years old (ObstetGynecol 2005 Nov106(5)946 fullshytext)estrogen may improve symptoms of overactive bladder (frequency urgency incontinence firstsensation to void bladder capacity) based on systematic review of 11 randomized placeboshycontrolled trials with 466 women (Acta Obstet Gynecol Scand 2004 Oct83(10)892 in ACP J Club2005 MarshyApr142(2)48)

HRT and other conditions

systemic lupus erythematosus (SLE) hormone replacement therapy associated with increased risk of systemic lupuserythematosus (SLE) in women (level 2 [midshylevel] evidence)

based on prospective cohort study238308 women from Nurses Health Study (NHS) and NHSII cohorts were evaluated262 incident cases of SLE diagnosed between 1976 and 2003 and confirmed bymedical record reviewsignificant menopauseshyrelated risk factors for SLE in older women aged 30shy55 years atstart of NHS

surgical menopause (RR 23 95 CI 12shy45)use of postmenopausal hormones (RR 19 95 CI 12shy31)duration of postmenopausal hormone use

lt 5 years (RR 18 95 CI 1shy3)ge 5 years (RR 2 95 CI 11shy36)

time since last postmenopausal hormone usege 5 years (RR 23 95 CI 11shy5)lt 5 years (RR 28 95 CI 15shy54)current use (RR 17 95 CI 1shy29)

Reference shy Arthritis Rheum 2007 Apr56(4)1251 fullshytext editorial can be found inArthritis Rheum 2007 Apr56(4)1048 fullshytext

hormone replacement therapy (HRT) may increase risk of disease flares in women withSLE (level 2 [midshylevel] evidence)

based on randomized trial with high rates of nonadherence to intervention351 menopausal patients (mean age 50 years) with inactive (815) or stableshyactive(185) SLE were randomized to HRT (conjugated estrogen 0625 mgday plusmedroxyprogesterone 5 mg for 12 days per month) vs placebo for 12 monthstrial discontinued early after Womens Health Initiative report of increased risk ofbreast cancer stroke and cardiovascular disease in women taking HRTcomparing HRT vs placebo


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proportion of patients followed for 12 months 82 vs 87 (not significant)12shymonth nonadherence rate (study termination for any reason other than severeflare) 35 vs 27 (p = 008)SLE disease flare occurred in 64 vs 51 (p = 001 NNH 7)severe SLE flare occurred in 75 vs 45 (not significant)rate of mild to moderate flares per personshyyear 114 vs 086 (p = 001)rate of severe flares per personshyyear 0081 vs 0049 (not significant)

adverse events with HRT included death (1 patient) stroke (1 patient) and thrombosis(3 patients) compared to thrombosis in 1 patient taking placeboReference shy Ann Intern Med 2005 Jun 21142(12)953 PDF editorial can be found inAnn Intern Med 2005 Jun 21142(12)1014 PDF

HRT use associated with increased risk for dry eye syndrome (JAMA 2001 Nov7286(17)2114) commentary can be found in JAMA 2002 Feb 6287(5)585 estrogen or HRT use associated with increased risk of new diagnosis of asthma (level 2 [midshylevel] evidence)

based on prospective cohort studyNurses Health Study evaluated new diagnosis of asthma or chronic obstructive pulmonarydisease by questionnaire during 546259 personshyyears of followshyupcompared to no hormone use

current use of estrogen alone associated with increased risk asthma (multivariate rateratio 229 95 CI 159shy329current users of estrogen plus progestin had similarly increased rate of newlydiagnosed asthma

Reference shy Arch Intern Med 2004 Feb 23164(4)379 commentary can be found in ArchIntern Med 2004 Dec 13shy27164(22)2501

hormonal replacement therapy (HRT) may not affect frequency of urinary tract infectionsbased on randomized placeboshycontrolled trial of 2763 postmenopausal women followed for mean4 years (Obstet Gynecol 2001 Dec98(6)1045 HRT may be associated with decline in kidney function (level 3 [lacking direct] evidence)

based on prospective cohort study without clinical outcomes5845 women gt 66 years old with 2 serum creatinine measurements over 2 years (1459 usedHRT (estrogenshyonly progestinshyonly or both) and 4386 did not use HRT)HRT use associated with significant loss of mean estimated GFR (eGFR) (p = 0004)estrogenshyonly use associated with additional decline in mean eGFRReference shy Kidney Int 2008 Aug74(3)370

postmenopausal HRT associated with increased risk for gastroesophageal reflux disease(GERD) (level 2 [midshylevel] evidence)

based on 2 cohort studiesprospective cohort with 51637 postmenopausal women

12018 women (23) had GERD symptomsodds ratios for GERD symptoms compared to nevershyusers of postmenopausalhormones

for past users 146 (95 CI 136shy156)for current estrogen users 166 (95 CI 154shy179)for current estrogenprogesterone users 141 (95 CI 129shy154)

risk of GERD symptoms increased with higher dose and longer duration of hormonesReference shy Arch Intern Med 2008 Sep 8168(16)1798 fullshytext

crossshysectional study with 21686 twins in Swedish Twin Registry4365 (20) had refluxany use of postmenopausal estrogen associated with reflux (odds ratio 132 95 CI


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118shy147)no association with oral contraceptivesReference shy Gastroenterology 2008 Apr134(4)921 fullshytext

postmenopausal estradiol but not combination estradiol plus progestin may be associatedwith increased risk for meningioma (level 2 [midshylevel] evidence)

based on retrospective cohort studynational cohort of all women ge 50 years old who used hormonal replacement therapy for ge 6months in 1994shy2009 in Finland

131480 women used estradiol only131248 women used estradiol plus progestin

mean followshyup 9 yearscompared to general population risk of meningioma

increased with any estradiolshyonly therapy (standardized incidence ratio [SIR] 12995 CI 115shy144)increased with use of estradiolshyonly for ge 3 years (SIR 14 95 CI 118shy164)not significantly affected by use of estradiol plus progestin (SIR 093 95 CI 08shy106)

Reference shy Am J Epidemiol 2012 Feb 15175(4)309 fullshytext

HRT and Cognitive Function

Effect on cognitive function

HRT does not appear to improve or prevent cognitive decline in postmenopausal women HRT may be associated with increased risk of probable dementia

based on randomized trial4532 postmenopausal women gt 65 years old in WHI trial who were free of probabledementia were randomized to HRT (conjugated equine estrogen 0625 mg plusmedroxyprogesterone 25 mg) vs placebo orally once daily and followed for mean 4yearsprobable dementia developed in 40 patients (18) with HRT vs 21 patients (09)with placebo (p = 001 NNH 111) rate 45 vs 22 per 10000 personshyyears (NNH 435for 1 year)no differences in mild cognitive impairmentReference shy JAMA 2003 May 28289(20)2651 editorial can be found in JAMA 2003May 28289(20)2717 commentary can be found in CMAJ 2003 Jul22169(2)133 fullshytext JAMA 2003 Oct 1290(13)1706 Evid Based Ment Health2003 Nov6(4)111 fullshytext ACP J Club 2003 NovshyDec139(3)62 Can FamPhysician 2004 Feb50235 PDFHRT did not improve cognitive function compared to placebo in this trial basedon 4381 participants who provided at least 1 valid cognitive function score (JAMA2003 May 28289(20)2663) similar trend in estrogen alone arm in WHI trial

2947 women aged 65shy79 years were randomized to conjugated equine estrogens0625 mg vs placebo daily for mean 52 years within WHI trialincidence of probable dementia 37 vs 25 per 10000 personshyyears (p = 018)incidence of probable dementia or mild cognitive impairment 126 vs 91 per10000 personshyyears (p = 004)Reference shy JAMA 2004 Jun 23shy30291(24)2947


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another analysis found estrogen alone group had Modified MinishyMental StateExam scores 026 lower than placebo group on average (JAMA 2004 Jun 23shy30291(24)2959) editorial can be found in JAMA 2004 Jun 23shy30291(24)3005 commentary can be found in BMJ 2004 Sep 4329(7465)

conjugated equine estrogens (CEE) does not appear to improve cognitivefunction or affect in postmenopausal women with prior hysterectomy (level 2[midshylevel] evidence)

based on subgroup analysis of randomized trial866 postmenopausal women (mean age 74 years) with prior hysterectomywithout dementia and enrolled in Womens Health Initiative (WHI) and WHIMemory Study (WHIMS) Conjugated Equine Estrogens (CEE)shyAlone trialrandomized to 0625 mg CEE daily vs placebono significant difference between groups in

verbal knowledgefluencymemoryattention and working memoryfine motor speedaffect

Reference shy J Clin Endocrinol Metab 2009 Nov94(11)4152 fullshytextHRT does not appear to benefit overall cognitive function in postmenopausal women(level 2 [midshylevel] evidence)

based on Cochrane review of trials with methodologic limitationssystematic review of 24 randomized trials evaluating effect of estrogen replacementtherapy or hormone replacement therapy on cognitive function in postmenopausalwomenonly 16 trials with 10114 women had analyzable dataestrogen replacement therapy for 5 years and hormone replacement therapy for 4 yearsnot associated with prevention of cognitive impairment compared to controlReference shy Cochrane Database Syst Rev 2008 Jan 23(1)CD003122

estrogen (with progestin if intact uterus) may not have effects on cognitive measures inpostmenopausal women with recent stroke or transient ischemic attack (level 2 [midshylevel] evidence)

based on randomized trial without intentionshytoshytreat analysis664 postmenopausal women with recent stroke or transient ischemic attackrandomized to estradiol 17beta vs placeboamong 461 women estrogen therapy did not have a significant effect overall oncognitive measures at mean followshyup of 3 yearspossible benefit reported in subgroup with normal minishymental status exam (MMSE)at baseline (Am J Obstet Gynecol 2005 Feb192(2)387 in Am Fam Physician 2005Nov 172(9)1881)

ultrashylowshydose transdermal estradiol not associated with differences in cognition orquality of life in 2shyyear randomized placeboshycontrolled trial in 417 postmenopausal women(only 16 of whom had hot flashes at baseline) (Arch Neurol 2006 Jul63(7)945)HRT not associated with cognitive benefits (and possibly associated with cognitivedecline) in 2shyyear followshyup of 13807 women aged 70shy81 years in Nurses Health Study(Neurology 2004 Jul 1363(1)101)estrogen therapy does not appear to affect cognitive function in postmenopausalwomen (level 2 [midshylevel] evidence)

based on small randomized trial57 healthy postmenopausal women were randomized to micronized 17shybetashyestradiol


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025 mg vs placebo daily for 3 yearsall women who had not had hysterectomy also given micronized progesterone 100mgday orally for 2 weeks every 6 monthsno differences between groups on any neurocognitive measures or depressioninstrumentsReference shy J Am Geriatr Soc 2007 Mar55(3)426

longshyterm use of estrogen with or without progestin may not reduce incidence ofdementia in women (level 2 [midshylevel] evidence)

based on prospective cohort study2906 women aged ge 75 years old (52 hormone users) without dementia at baselineadjusted hazard ratio for dementia 134 (95 CI 095shy19) for estrogen users and 123(95 CI 094shy16) for estrogenprogestin usersReference shy Am J Epidemiol 2008 Mar 15167(6)692 fullshytext

HRT in women with menopausal symptoms appears to improve cognitive decline (level 2[midshylevel] evidence)

based on systematic review of small trials without metashyanalysissystematic review of 29 studies (9 small randomized trials and 20 observational studies)evaluating hormone replacement therapy for cognitive decline and dementia in healthypostmenopausal womenno randomized trials with outcome of dementiatrials not combined in metashyanalysis due to heterogeneitybenefit found for measures of cognitive decline only in trials of patients with menopausalsymptoms no benefit in asymptomatic patientsmetashyanalysis of 2 cohort studies and 10 caseshycontrol studies suggest that HRT associatedwith decreased risk for dementiaReference shy JAMA 2001 Mar 21285(11)1489 commentary can be found in J Fam Pract2001 Jun50(6)547 commentary can be found in JAMA 2001 Jun 20285(23)2974

HRT may not be associated with differences in cognitive function in younger women (level 2[midshylevel] evidence)

based on secondary analysis of 2 randomized trials1326 postmenopausal women aged 50shy55 years randomized to conjugated equine estrogens0625 mgday if prior hysterectomy and 0625 mgday plus medroxyprogesterone acetate 25mgday if intact uterus vs matched placebo (mean trial duration 7 years) and telephoneshyadministered cognitive battery given at mean 72 years after trials ended and repeated 1 yearlaterno significant differences in global cognitive function scores or for any individual cognitivedomainReference shy WHIMSY trial (JAMA Intern Med 2013 Aug 12173(15)1429 editorial can befound in JAMA Intern Med 2013 Aug 12173(15)1437)

HRT and Alzheimer disease

postmenopausal hormone use not associated with change in risk of Alzheimer disease (level 2[midshylevel] evidence)

based on systematic review without reporting assessment of study qualitysystematic review of 15 studies (1 randomized trial 9 prospective cohort studies and 5nested caseshycontrol studies) evaluating postmenopausal hormone therapy use and risk ofAlzheimer disease or dementiastudy followshyup period ranged from 1 to 16 yearscompared to never using a hormone any hormone use not associated with a significant


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difference in risk of Alzheimer disease (relative risk 088 95 CI 066shy116) in analysis of 9studies with 14368 women with moderate statistical heterogeneityReference shy Epidemiol Rev 201436(1)83

HRT reported to decrease risk of Alzheimer disease in elderly women ONLY if initiatedwithin 5 years of menopause and continued for ge 10 years (level 2 [midshylevel] evidence)

based on prospective cohort study without adjustments for analysis of multiple outcomes1768 elderly women (mean age 75 years) with known age at menopause were followed formean 7 years625 had history of hormone replacement therapy (HRT) use10 developed Alzheimer diseasecompared to no HRT use use of any type of HRT initiated within 5 years of menopause andtaken for ge 10 years was associated with decreased risk of Alzheimer disease (hazard ratio063 95 CI 041shy098)no significant differences in risk of Alzheimer disease comparing

no HRT use vs HRT initiated within 5 years of menopause and taken for lt 10 yearsno HRT use vs HRT initiated gt 5 years after menopause

use of opposed HRT starting within 3 years of study baseline associated with trend towardincreased risk of Alzheimer disease (hazard ratio 193 95 CI 094shy396)Reference shy Neurology 2012 Oct 3079(18)1846 fullshytext earlier report at 3 years followshyupcan be found in JAMA 2002 Nov 6288(17)2123

Alternatives to HRT

Overview of HRT alternatives

depending on reasons for HRT alternatives to HRT may includephytoestrogensblack cohoshtiboloneraloxifeneselective serotonin reuptake inhibitors (SSRIs)DHEA supplements cannot yet be recommended

bioidentical hormones (plantshyderived hormones prepared by pharmacist)American College of Obstetricians and Gynecologists (ACOG) committee opinion oncompounded bioidentical menopausal hormone therapy

conventional hormone therapy preferred over compounded hormone therapy based onavailable datainsufficient evidence to support superiority claims of compounded bioidenticalhormones over conventional menopausal hormone therapycustomized compounded hormones pose additional risk due to

variable purity and potencylack of efficacy and safety datapossibility of underdosage or overdosage (variable bioavailability andbioactivity)

insufficient evidence to support claims of increased efficacy or safety forindividualized hormone therapy regimens based on salivary serum or urinary testingReference shy ACOG Committee Opinion 532 on compounded bioidentical menopausalhormone therapy (Obstet Gynecol 2012 Aug120(2 Pt 1)411 fullshytext) reaffirmed2014 Jul


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FDA warns claims of bioidentical hormone replacement therapy safety and effectivenessare unsupported by medical evidence and are considered false and misleading (FDA PressRelease 2008 Jan 9) bioidentical hormone replacement therapy associated with endometrial cancer in 3case reports

authors speculate cases may be due to insufficient progestin component produced bycompounding pharmacistsReference shy Med J Aust 2007 Aug 20187(4)244

review of bioidentical hormone therapy can be found in J Am Board Fam Med 2011 MarshyApr24(2)202 fullshytext

tibolone and conventional hormone treatment appear to have similar climacteric effect andmay improve different aspects of female sexual function (level 2 [midshylevel] evidence)

based on randomized trial with allocation concealment not stated140 postmenopausal women randomized to 1 of 3 groups and followed for 6 months

tibolone 25 mg plus one Cal+D tablet (calcium 500 mg and vitamin D 200 units)dailyconjugated equine estrogen 0625 mg plus medroxyprogesterone 25 mg (CEEMPA)plus one Cal+D tablet dailyone Cal+D tablet daily (control)

no significant difference between tibolone and CEEMPA invasomotor symptoms (both groups significantly improved vs control)total sexual function scores and sexual satisfaction subscores

tibolone improved female sexual function scores in domains of desire arousal and orgasm (plt 0001 vs CEEMPA for each domain)CEEMPA improved female sexual function scores in domains of lubrication anddyspareunia (p lt 0001 vs tibolone for each domain)Reference shy Climacteric 2010 Apr13(2)147

review of alternatives to HRT for menopausal symptoms can be found in Lancet 2005 Jul30366(9483)409

Phytoestrogens

soy protein supplementation (phytoestrogens) may relieve vasomotor symptoms based on limitedevidence from randomized trials see discussion in menopause postmenopausal supplementation with soy protein may not improve cognitive function bonemineral density or plasma lipid levels (level 2 [midshylevel] evidence)

based on randomized trial without intentionshytoshytreat analysis200 healthy women aged 60shy75 years randomized to 256 g of soy protein (isoflavones 99mg) daily vs placebo for 12 monthsamong 175 women completing ge 1 postintervention assessment no significant differences incognitive function bone mineral density or plasma lipidsReference shy JAMA 2004 Jul 7292(1)65 commentary can be found in Am Fam Physician2004 Nov 1580(10)1978

continual soy use for 5 years associated with risk of endometrial hyperplasia (level 3 [lackingdirect] evidence)

based on nonclinical outcome in randomized trial376 postmenopausal women with intact uterus were randomized to soy tablets 150 mgdayvs placebo for 5 yearsamong 298 women completing trial

337 with soy vs 0 with placebo had endometrial hyperplasia


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no cases of malignancy detected by biopsy70 with soy vs 81 with placebo had endometrium classified as atrophic ornonassessable

Reference shy Fertil Steril 2004 Jul82(1)145 in BMJ 2004 Sep 11329(7466)632)commentary can be found in Lancet 2004 Dec 11shy17364(9451)2081

some plant products especially soy have weak estrogenic effect and some antiestrogeniceffects

dose and purity of commercial phytoestrogens unknown possible adverse effects unknown3 trials with 300 women suggest that soy protein supplementation or increased dietary intakeof soybean foods reduce symptoms of menopause but not all results statistically significantand results reported in such a way as to make clinical significance unclearReference shy The Medical Letter 2000 Feb 2142(1072)17

The North American Menopause Society consensus opinion on role of isoflavones in menopausalhealth can be found in Menopause 2000 JulshyAug7(4)215review of phytoestrogens can be found in Arch Intern Med 2001 May 13161(9)1161high dietary phytoestrogen intake (isoflavones) associated with higher lumbar bone mineral densityamong postmenopausal but not premenopausal women in study of 650 Chinese women (J ClinEndocrinol Metab 2001 Nov86(11)5217 fullshytext

Black cohosh

active ingredient unknownblack cohosh not a phytoestrogen in classic sense as its constituents do not bind to estrogenreceptors may have selective estrogenic actionmost studied product is isopropanolic extract of black cohosh known as Remifeminwidely advocated for treatment of menopausal symptoms

usual dose of black cohosh 20 mg (1 tablet) twice daily using Remifemin70shy80 response rates reported but insufficient evidence to determine efficacy relative toplacebo (level 2 [midshylevel] evidence)dose of 130 mgday appears no more effective than 40 mgday (level 2 [midshylevel] evidence)

concern of hepatotoxicity based on small number of case reports with clinical hepatotoxicityblack cohosh should not be confused with the hepatotoxic herb blue cohoshsee Black cohosh for menopausal symptoms for details

Raloxifene (Evista)

Prescribing information

raloxifene (Evista) is a selective estrogen receptor modulator (SERM) with estrogen agonistactivity on bone and estrogen antagonist activity on breast and uterine tissuedose 60 mg orally once dailyraloxifene used in postmenopausal women for

prevention and treatment of osteoporosisreduction in incidence of invasive breast cancer

see Raloxifene for details

Efficacy in postmenopausal women with or at risk for coronary artery disease

raloxifene reduces risk of breast cancer and clinical vertebral fracture but increases risk of


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fatal stroke and venous thromboembolism (level 1 [likely reliable] evidence)based on randomized trial10101 postmenopausal women gt 55 years old with coronary heart disease or multiple riskfactors for coronary heart disease were randomized to raloxifene (Evista) 60 mg vs placeboonce daily for median 56 years913 (9) discontinued the study and 1149 (11) died during the studyno significant differences comparing raloxifene vs placebo for many outcomes

primary coronary events (533 vs 553 or 206 vs 216 per year)total stroke (249 events vs 224 events or 095 vs 086 per year)total death (554 deaths vs 595 deaths or 207 vs 225 per year)cardiovascular death (362 deaths vs 355 deaths or 135 vs 134 per year)clinical nonvertebral fractures (428 vs 438 or 167 vs 173 per year)

raloxifene reduced risk for some outcomesinvasive breast cancer in 40 cases vs 70 cases or 015 vs 027 per year (NNT 833per year)clinical vertebral fractures in 64 vs 97 or 024 vs 037 per year (NNT 769 peryear)

raloxifene increased risk for some outcomesfatal strokes in 59 vs 39 (NNH 1428 per year)venous thromboembolism events in 103 vs 71 (NNH 833 per year)hot flashes in 8 vs 48 (NNH 31)leg cramps in 97 vs 67 (NNH 33)peripheral edema in 144 vs 121 (NNH 43)gallbladder disease in 56 vs 45 (NNH 91)

Reference shy RUTH trial (N Engl J Med 2006 Jul 13355(2)125 fullshytext) editorial can befound in N Engl J Med 2006 Jul 13355(2)190 fullshytext commentary can be found in CMAJ2006 Jul 18175(2)147 fullshytext Am Fam Physician 2006 Nov 174(9)1598 ACP J Club2006 NovshyDec145(3)73results of RUTH trial did not differ across subgroups except risk of stroke differed bysmoking status (Stroke 2009 Jan40(1)147 fullshytext)

Efficacy in postmenopausal women with osteoporosis

raloxifene may reduce risk of vertebral fracture (level 3 [lacking direct] evidence) but notnonvertebral fractures (level 2 [midshylevel] evidence) in postmenopausal women withosteoporosis

based on randomized trial with allocation concealment not stated7705 women aged 31shy80 years in 25 countries who had been postmenopausal for ge 2 yearsand met World Health Organization criteria for osteoporosis were randomized to raloxifene60 mgday vs 120 mgday vs placebo and followed for up to 36shy40 monthsall women given supplemental calcium 500 mgday and cholecalciferol 400shy600 unitsday6828 women (886) had evaluable radiographs at 36 months

Rates of New Vertebral Fracture on Xshyray

Raloxifene 60mgday

Raloxifene 120mgday Placebo

Overall cohort 66 (NNT 29) 54 (NNT 21) 101Subgroup of 2304women with previousvertebral fractures

147 (NNT 15) 107 (NNT 10) 212


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Subgroup of 4524women withosteoporosis but noprior vertebralfracture

23 (NNT 45) 28 (NNT 59) 45

Abbreviation NNT number needed to treat for 3 years to prevent 1 new vertebral fracturecompared to using placebono significant differences in rates of nonvertebral fracture by interviewscompared with placebo raloxifene increased bone mineral density in femoral neck by21shy24 and in spine by 26shy27 (p lt 0001)women receiving raloxifene had 31 times increased risk of venous thromboembolism (1with raloxifene 60 mg vs 1 with raloxifene 120 mg vs 03 with placebo NNH 143)adverse events significantly more common with raloxifene included influenza syndrome hotflashes leg cramps peripheral edema and endometrial cavity fluid adverse eventssignificantly more common with placebo included hypertension hypercholesterolemiahematuriaraloxifene did not cause vaginal bleeding or breast pain and was associated with lowerincidence of breast cancer (statistically significant but absolute numbers not given)Reference shy MORE trial (JAMA 1999 Aug 18282(7)637 fullshytext) correction can be foundin JAMA 1999 Dec 8282(22)2124 editorial can be found in JAMA 1999 Aug18282(7)687 commentary can be found in J Fam Pract 1999 Nov48(11)911 JAMA 2000May 3283(17)2236 ACP J Club 2000 MarshyApr132(2)58raloxifene reduced incidence of clinical vertebral fracture in this trial with clinical vertebralfracture defined as new vertebral fracture associated with signs and symptoms such as backpain

among 6828 women (886) with baseline and followshyup xshyrays over 3 years newclinical vertebral fractures were reported in

35 placebo group21 with raloxifene 60 mgday (NNT 72)17 with raloxifene 120 mgday (NNT 56)

Reference shy Arch Intern Med 2002 May 27162(10)1140 fullshytextreduction in new vertebral fractures with raloxifene still significant at 4 years no significantdifference in nonvertebral fractures (J Clin Endocrinol Metab 2002 Aug87(8)3609 fullshytext)raloxifene reduced vertebral fractures and breast cancer in both women with and withoutprior hormone therapy in MORE trial (J Fam Pract 2004 Oct53(10)789)vitamin D deficiency did not affect response to raloxifene in this trial (J Clin EndocrinolMetab 2005 Aug90(8)4566 fullshytext)

raloxifene associated with decreased risk of breast cancer in postmenopausal women withosteoporosis (level 2 [midshylevel] evidence)

based on randomized trial (MORE trial) with allocation concealment not statedin MORE trial 7705 postmenopausal women aged 31shy80 years with osteoporosis wererandomized to raloxifene 60 mgday vs 120 mgday vs placebo and followed for up to 36shy40 months in CORE trial 5133 participants continued randomized assignment (with 60mgday used for both raloxifene groups) for 8 yearsin MORE trial 78 raloxifene patients vs 75 placebo patients completed trial

13 cases of breast cancer confirmed among 5129 women (025) assigned toraloxifene vs 27 among 2576 women (105) assigned to placebo (p lt 0001 NNT126)raloxifene increased risk of venous thromboembolic disease based on chart review


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(NNH 143 for thromboembolic disease and NNH 500 for pulmonary embolism)raloxifene did not increase risk of endometrial cancer in subgroup of 1781 womenwho underwent transvaginal ultrasonographyraloxifene associated with more hot flashes (NNH 25) and leg cramps (NNH 33) nosignificant differences in vaginal bleeding or breast painno significant differences in mortalityReference shy JAMA 1999 Jun 16281(23)2189 in J Fam Pract 1999 Sep48(9)659correction can be found in JAMA 1999 Dec 8282(22)2124 editorial can be found inJAMA 1999 Jun 16281(23)2243 commentary can be found in JAMA 2000 Jan19283(3)338 JAMA 2001 Apr 25285(16)2079

raloxifene reduced vertebral fractures and breast cancer in both women with and withoutprior hormone therapy in MORE trial (J Fam Pract 2004 Oct53(10)789in CORE trial (an extension of the MORE trial)

5213 MORE participants continued raloxifene 60 mgday (if previously assigned 60mg or 120 mg) vs placebo (if previously assigned placebo) for another 4 yearscomparing raloxifene vs placebo

incidence of invasive breast cancer during trial extension was 2 vs 5 per 1000womanshyyears (NNT 334 womanshyyears)8shyyear risk of pulmonary embolism was 062 vs 016 (NNH 217)no significant difference in mortality

Reference shy CORE trial (J Natl Cancer Inst 2004 Dec 196(23)1751 fullshytext)commentary can be found in Am Fam Physician 2005 Apr 171(7)1390 fullshytext

raloxifene appears to increase risk for venous thromboembolic events in women withosteoporosis (level 2 [midshylevel] evidence)

based on MORE trial with allocation concealment not statedanother report of MORE trial includes different numbers than 1999 report partiallyexplained by adding retinal vein thrombosis to total numberscomparing combined raloxifene groups vs placebo group

deep vein thrombosis in 084 vs 027 (p = 001 NNH 175)pulmonary embolism in 035 vs 008 (not significant)retinal vein thrombosis in 008 vs 019 (not significant)any venous thrombosis in 115 vs 054 (p = 001 NNH 164)

Reference shy Obstet Gynecol 2004 Oct104(4)837 raloxifene not associated with reduction in cardiovascular events in women withosteoporosis (level 2 [midshylevel] evidence)

based on MORE trial (with allocation concealment not stated) and CORE trial (extension ofMORE trial)no overall differences in combined outcome of cardiovascular events (myocardial infarctionunstable angina coronary ischemia stroke or transient ischemic attack) in MORE trial

in subgroup of 1035 women with increased cardiovascular risk at baseline raloxifeneuse was associated with significantly lower risk of cardiovascular eventsReference shy JAMA 2002 Feb 20287(7)847 commentary can be found in J Fam Pract2002 May51(5)481 JAMA 2002 Jul 3288(1)42

in CORE trial (4shyyear follow up of MORE trial)4011 postmenopausal women with osteoporosis randomized to raloxifene 60 mg vsplacebo orally once daily for 4 years as part of MORE trial then 4 more years as partof CORE trial (range 26shy591 months between end of MORE trial and beginning ofCORE trial)effect of raloxifene on incidence of cardiovascular events not predefined objective ofCORE trial but adjudication and analysis for cardiovascular events specified before


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trial endno significant differences comparing raloxifene vs placebo in incidence of

cardiovascular events (55 vs 47)cardiac events (31 vs 26)cerebrovascular events (27 vs 23)

Reference shy Am J Cardiol 2006 Feb 1597(4)520 fullshytext alendronate plus raloxifene combination may increase bone mineral density (BMD) morethan either monotherapy in women with osteoporosis (level 3 [lacking direct] evidence)

based on randomized trial without clinical outcomes135 postmenopausal women with osteoporosis randomized to alendronate 70 mgweek vsraloxifene 60 mgday vs combination for 12 monthsalendronate and raloxifene alone and in combination significantly increased BMD in lumbarspine femoral neck and total hipcombination had greater increase in BMD compared to either monotherapy (p lt 00001)Reference shy Climacteric 2011 Jun14(3)369

teriparatide zoledronate alendronate and risedronate each reported to be more effectivethan raloxifene or calcium plus vitamin D for preventing nonvertebral fractures in patientswith osteoporosis (level 3 [lacking direct] evidence)

based on systematic review with mostly indirect comparisonssystematic review of 116 randomized trials evaluating efficacy of pharmacological agentsfor prevention of hip vertebral and nonvertebral fractures in 139647 patients with or at riskfor osteoporosismost trials were in postmenopausal womendrug therapy included teriparatide denosumab raloxifene zoledronate risedronateibandronate alendronate vitamin D calcium and vitamin D plus calciumsmall number of direct comparison trials reduces precision and confidence in results ofnetwork metashyanalysesin network metashyanalyses of placeboshycontrolled data (combining direct and indirectcomparisons) significant reduction in

new hip fractures with alendronate risedronate zoledronate denosumab and vitaminD plus calciumnew vertebral fractures with teriparatide denosumab zoledronate risedronatealendronate raloxifene and ibandronatenew nonvertebral fractures with teriparatide risedronate zoledronate denosumab andalendronate

comparative efficacy in network metashyanalyses (combining direct and indirect comparisons)for prevention of hip fractures

zoledronate risedronate and alendronate were more effective than raloxifenezoledronate risedronate and alendronate were more effective than calciumandor vitamin Ddenosumab was more effective than calcium alone or vitamin D alone

for prevention of nonvertebral fracturesteriparatide zoledronate and risedronate were more effective than raloxifeneand calcium andor vitamin Dteriparatide was more effective than alendronateibandronate and alendronate were more effective than calcium plus vitamin D

Reference shy J Clin Endocrinol Metab 2012 Jun97(6)1871 fullshytextDynaMed commentary shyshy study funded in part by The Endocrine Society in preparation forevidenceshybased guideline development


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Additional efficacy data in postmenopausal women

raloxifene associated with decrease in allshycause mortality in older postmenopausal women(level 2 [midshylevel] evidence)

based on metashyanalysis without systematic searchmetashyanalysis evaluating mortality from 2 clinical trials of 15234 postmenopausal womentaking raloxifene 60 mgday vs placeboraloxifene associated with

lower allshycause mortality (hazard ratio [HR] 09 95 CI 08shy1) in analysis of 2 trialsfewer noncardiovascular deaths (HR 078 95 CI 065shy093)fewer noncardiovascular noncancerous deaths (HR 072 95 CI 056shy093)

Reference shy Am J Med 2010 May123(5)469e1 raloxifene does not affect cognitive function in postmenopausal women

based on randomized trial7478 postmenopausal women with osteoporosis were randomized to raloxifene (60 mg or120 mg) vs placebo daily for 3 yearsmean cognitive scores in all three groups improved slightly with no significant differencesReference shy MORE trial (N Engl J Med 2001 Apr 19344(16)1207) editorial can be foundin N Engl J Med 2001 Apr 19344(16)1242

nonclinical outcomes in postmenopausal womenraloxifene improves bone density compared to placebo but less than conjugated equineestrogen and may reduce LDL cholesterol levels (level 3 [lacking direct] evidence)

based on randomized trial without clinical outcomes619 postmenopausal women (mean age 53 years) with prior hysterectomy wererandomized to raloxifene (60 mgday or 150 mgday) vs conjugated equine estrogen0625 mgday vs placebo for 3 yearsbone density in lumbar spine declined by 2 in the placebo group was stable in bothraloxifene groups and increased by 46 in estrogen group consistent results in bonedensity in total hipraloxifene and estrogen each reduced lowshydensity lipoprotein (LDL) cholesterollevels but only estrogen increased highshydensity lipoprotein (HDL) cholesterol levelsestrogen but not raloxifene was associated with urinary incontinenceReference shy Arch Intern Med 2004 Apr 26164(8)871 fullshytext

raloxifene maintains bone mineral density at 3 years (level 3 [lacking direct] evidence)based on 2 randomized trials of identical design without clinical outcomes1145 healthy postmenopausal women aged 45shy60 years were randomized toraloxifene 30 mgday vs 60 mgday vs 150 mgday vs placebo for 3 yearsall women given elemental calcium 400shy600 mglumbar spine BMD changed from baseline to 36 months by 071 in raloxifene 30 mggroup vs 128 in raloxifene 60 mg group vs 12 in raloxifene 150 mg group vsshy132 in placebo groupcomparable BMD changes in hipchange in serum lowshydensity lipoprotein cholesterol at 36 months

shy121 with raloxifene 150 mg (p lt 0001 vs placebo)shy76 with raloxifene 60 mg (p lt 0001 vs placebo)shy69 with raloxifene 30 mg (p lt 001 vs placebo)shy2 with placebo

no significant differences in study withdrawals due to any reason (37) orwithdrawals due to adverse events (14) only significant adverse effect was hotflashes (25 in 60 mg group vs 18 in placebo group NNH 14)


3643

Reference shy Arch Intern Med 2000 Dec 11shy25160(22)3444 fullshytextraloxifene may decrease insulin sensitivity in postmenopausal women (level 3 [lackingdirect] evidence)

based on small randomized trial without clinical outcomes44 healthy postmenopausal women without diabetes on glucose tolerance testing wererandomized to raloxifene vs estrogen vs placebo for 8 weeksraloxifene decreased insulin sensitivity estrogen and placebo did notReference shy J Am Geriatr Soc 2003 May51(5)683

raloxifene may reduce LDL cholesterol levels (level 3 [lacking direct] evidence)

ultrashylowshydose transdermal estrogen may be similar to raloxifene for effect on bone mineraldensity in postmenopausal women (level 3 [lacking direct] evidence)

based on randomized trial without clinical outcomes500 postmenopausal women with osteopenia randomized to microdose 17shybetashyestradiol(0014 mgday) transdermally vs raloxifene 60 mgday orally for 2 years66shy70 completed trialno significant differences comparing estrogen vs raloxifene

lumbar spine bone mineral density increased by 24 vs 3no bone loss in lumbar spine in 773 vs 805no histological evidence of endometrial stimulation in 99 vs 100mean dense area in breast mammograms 198 vs 19

Reference shy Menopause 2009 MayshyJun16(3)559

DHEA supplements

DHEA refers to dehydroepiandrosterone DHEA may not improve quality of life or menopausal symptoms in menopausal women(level 2 [midshylevel] evidence)

based on Cochrane review of trials with methodologic limitationssystematic review of 28 randomized trials evaluating dehydroepiandrosterone (DHEA) for ge1 week in 1273 women in peri or postmenopausal phasemost trials had ge 1 limitation including

unclear allocation concealmentsmall sample sizeunclear or no blinding

comparing DHEA to placebo or no treatmentno significant difference in quality of life in analysis of 9 trials results limited bysignificant heterogeneityfor effect on menopausal symptoms

no significant difference in mean symptom scores in 2 trials with 83 womenDHEA significantly reduced risk of night sweats loss of libido and tiredness in1 trial with 50 women

DHEA associated with nonsignificant improvement in sexual function in analysis of 6trials but improvement not clinically relevantfor adverse events

9 trials reported no adverse effects overalltotal androgenic adverse effects (acne greasy skin hirsutism) in 234 withDHEA vs 44 with placebo (p = 0019 NNH 5) in 1 trial with 52 womenno significant differences in acne in analysis of 4 trials with 158 women

comparing DHEA to estrogen therapy (alone or with progesterone)


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for effect on menopausal symptomsDHEA significantly improved mean symptom scores in 1 trial with 24 womenno significant differences in risk of night sweats hot flushes and palpitationsand tiredness in 1 trial with 50 women

DHEA associated with nonsignificant improvement in mean sexual function scores inanalysis of 2 trials with 41 women

comparing DHEA to tiboloneDHEA significantly improved mean sexual function and menopausal symptom scoresin 1 trial with 24 womenno significant differences in risk of tiredness hot flushes and palpitations and nightsweats in 1 trial with 50 women

Reference shy Cochrane Database Syst Rev 2015 Jan 22(1)CD011066 DHEA appears similar to HRT for increased sexual function and improved climactericsymptoms in postmenopausal women (level 2 [midshylevel] evidence)

based on small trial with inadequate randomization48 healthy postmenopausal women aged 50shy60 years randomized to 3 groups and thoserefusing HRT had vitamin D 400 units plus calcium carbonate 1250 mgday (to preventosteoporosis) for 12 months

DHEA 10 mg orallydayestradiol 1 mg plus dihydrogesterone 5 mg orallydaytibolone 25 mg orallyday

climacteric symptoms improved in all treatment groups (DHEA estradioldihydrogesteroneand tibolone) compared to baseline at 12 months (no change in vitamin Dcalcium group)increased total sexual function scores with (compared to baseline at 12 months)

DHEA (p lt 0001 vs vitamin Dcalcium not significant vsestradioldihydrogesterone)estradioldihydrogesterone (p lt 0001 vs vitamin Dcalcium not significant vsDHEA)tibolone (not significant)

increased sexual intercourse frequency (in last 4 weeks) with (compared to baseline at 12months)

DHEA (p lt 001)estradioldihydrogesterone (p lt 005)tibolone (p lt 001)no significant differences among groups

no change in sexual intercourse frequency in vitamin Dcalcium group and reducedfrequency compared to hormone treatments (p lt 005)Reference shy Climacteric 2011 Dec14(6)661

DHEA supplementation for 1 year not associated with adverse endometrial effects orchanges in blood lipids or insulin sensitivity (level 3 [lacking direct] evidence)

based on randomized trial without clinical outcomes93 postmenopausal women randomized to DHEA 50 mgday vs placebo for 52 weeksno significant differences in

blood lipidsinsulin resistancebreakthrough bleeding patternadverse endometrial effects

Reference shy Maturitas 2009 Jul 2063(3)240 DHEA appears to have no effect on lipid levels or body fat in older frail women (level 3[lacking direct] evidence)


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based on small randomized trial without clinical outcomes99 women (mean age 76 years) with low DHEAshyS level and frailty randomized to 1 of 4treatments and followed for 6 months

DHEA 50 mgday plus yogaDHEA 50 mgday plus aerobicsplacebo plus yogaplacebo plus aerobics

all women received calcium 1000shy1200 mgday through diet and supplementation andcholecalciferol 1000 unitsdayDHEA associated with increased DHEAshyS oestradiol oestrone and testosterone levels andreduced sex hormoneshybinding globulin levelsno significant differences between treatments or within treatment groups from baseline to 6months in total cholesterol HDL cholesterol LDL cholesterol triglycerides body orabdominal fat fasting glucose or blood pressureReference shy Age Ageing 2010 Jul39(4)451 fullshytext dehydroepiandrosterone (DHEA) appears to have no effect on bone mineral density(BMD) lower extremity strength or function in older frail women

based on secondary analysis of randomized trial aboveReference shy J Am Geriatr Soc 2010 Sep58(9)1707

Discontinuation of HRT

Effects of discontinuing HRT

discontinuation of HRT after myocardial infarction (MI) does not appear to increase ordecrease risk of reinfarction or mortality at 1 year (level 2 [midshylevel] evidence)

based on retrospective cohort study3322 women ge 40 years old with MI surviving ge 30 days after hospital discharge werefollowed for 1 yearall patients prescribed HRT at time of MI66 cardiovascularshyrelated morality 107 allshycause mortality and 85 reinfarctionduring followshyupno significant differences at 1 year comparing discontinuation of HRT after MI vscontinuation of HRT in overall analysis

reinfarction (hazard ratio [HR] 09 95 CI 068shy119)cardiovascularshyrelated mortality (HR 121 95 CI 09shy162)allshycause mortality (HR 122 95 CI 097shy153)

discontinuation of vaginal estrogen after MI associated with reduced risk of reinfarction at 1year compared to continuation (HR 054 95 CI 034shy086)Reference shy BMJ 2012 Mar 27344e1802 fullshytext

discontinuation of estrogen and progestin (HRT) associated with recurrence or onset ofmenopausal symptoms (level 2 [midshylevel] evidence)

based on observational data from randomized trial16608 women with intact uterus in WHI trial randomized to HRT vs placebo and wereinstructed to stop taking study pills by July 8 2002 at which time 9351 (56) were stilltaking study pills and eligible for survey 8405 eligible women (90) completed survey 8shy12 months after cessation of study pillscomparing women discontinuing HRT vs discontinuing placebo hot flashes and nightsweats in


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212 vs 48 overall (p lt 005 NNH 6)555 vs 213 for women with vasomotor symptoms at baseline (p lt 005 NNH 3)216 vs 37 for women with symptoms prior to baseline only (p lt 005 NNH 5)64 vs 12 for women with no prior vasomotor symptoms (p lt 005 NNH 19)

pain or stiffness in 368 women discontinuing HRT vs 222 women discontinuingplacebo (p lt 005 NNH 7Reference shy JAMA 2005 Jul 13294(2)183 editorial can be found in JAMA 2005 Jul13294(2)245

change in quality of life following HRT discontinuation may vary with age (level 2 [midshylevel] evidence)

based on longitudinal study2357 women using HRT in 2002 who completed surveys in 2002 and 2003 43discontinued HRT during the study includedamong women aged 65shy74 years HRT discontinuers had decreased healthshyrelated quality oflife by 4 different measuresamong women aged 85 years and older HRT discontinuers had better healthshyrelated qualityof life than HRT continuers in 3 different measuresReference shy BMC Womens Health 2005 May 1657 fullshytext

Timing of discontinuation

most women may be able to stop HRT abruptly without ill effect (level 2 [midshylevel]evidence)

based on cohort study of 670 women aged 50shy69 years surveyed 6 months after publicationof WHI trial377 (56) tried to stop HRT main reasons for continuing HRT (44) were hot flashes(26) and osteoporosis prevention (19)74 of 377 women attempting to stop HRT successfully stopped HRT (71 abruptly 29tapered)most women who resumed HRT due to symptoms had symptoms within 1 weekReference shy Obstet Gynecol 2003 Dec102(6)1233 commentary can be found in Am FamPhysician 2004 Aug 1570(4)769

gradual and abrupt discontinuation of HRT associated with similar frequency and severityof hot flashes and similar risk of resumption of therapy

based on randomized trial81 postmenopausal women treated with HRT for hot flashes were randomized to gradualtapering vs abrupt discontinuation of HRT and followed up to 12 monthsabout 50 resumed HRT within 1 yearno significant differences in

number or severity of hot flasheshealthshyrelated quality of lifefrequency of resumption of HRT

Reference shy Menopause 2010 JanshyFeb17(1)72 editorial can be found in Menopause 2010JanshyFeb17(1)10

gradual discontinuation of HRT may postpone but not reduce reappearance of menopausalsymptoms

based on randomized trial of abrupt vs gradual HRT discontinuation in 91 postmenopausalwomen using HRT for gt 3 years


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about 40 women resumed HRT within 9 monthsReference shy Menopause 2006 MayshyJun13(3)370

Guidelines and Resources

Guidelines

United States guidelines

Institute for Clinical Systems Improvement (ICSI) guideline on menopause and hormone therapy(HT) collaborative decisionshymaking and management can be found at ICSI PDF 2008 OctAmerican College of Obstetricians and GynecologistsAmerican Society for ReproductiveMedicine (ACOGASRM) Committee Opinion 532 on compounded bioidentical menopausalhormone therapy can be found in Obstet Gynecol 2012 Aug120(2 Pt 1)411 fullshytext reaffirmed2014 Jul or at ACOGASRM 2012 Aug PDF

American College of Obstetricians and Gynecologists (ACOG) Committee Opinion 556 onpostmenopausal estrogen therapy route of administration and risk of venous thromboembolismcan be found at ACOG 2013 Apr PDF

North American Menopause Society (NAMS) position statements onhormone therapy can be found in Menopause 2012 Mar19(3)257 PDF commentary can befound in Menopause 2013 May20(5)587 additional statement can be found at NAMS 2015PDFestrogen and progestogen use in postmenopausal women can be found in Menopause 2010Mar17(2)242

prior NAMS position statement for estrogen and progestogen use in perishy andpostmenopausal women can be found in Menopause 2007 MarshyApr14(2)168summary can be found in Am Fam Physician 2007 Jul 1576(2)295 commentary canbe found in BMJ 2007 Apr 28334(7599)860 fullshytext

role of progestogen in postmenopausal hormone replacement therapy can be found inMenopause 2003 MarshyApr10(2)113

consensus statement on menopausal hormone therapy can be found in Climacteric 2013Apr16(2)203 PDF endorsed by The American Society for Reproductive Medicine Asia PacificMenopause Federation The Endocrine Society European Menopause and Andropause SocietyThe International Menopause Society The International Osteoporosis Foundation and The NorthAmerican Menopause Society

United States Preventive Services Task Force (USPSTF) recommendation on menopausal hormonetherapy for primary prevention of chronic conditions can be found at USPSTF 2012 Oct 23 fullshytext or in Ann Intern Med 2013 Jan 1158(1)47 fullshytext editorial can be found in Ann Intern Med2013 Jan 1158(1)69 or at National Guideline Clearinghouse 2013 Jan 2138537

American College of Preventive Medicine (ACPM) guideline on perimenopausal andpostmenopausal hormone replacement therapy can be found in Am J Prev Med 1999 Oct17(3)250American Society for Reproductive Medicine (ASRM) guideline on estrogen and progestogentherapy in postmenopausal women can be found in Fertil Steril 2004 Jan81(1)231

Canadian guidelines


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Canadian Task Force on Preventive Health Care (CTFPHC) recommendation statements onhormone replacement therapy for primary prevention of chronic diseases can be found inCMAJ 2004 May 11170(10)1535 fullshytextpostmenopausal hormone replacement therapy for primary prevention of cardiovascular andcerebrovascular disease can be found in CMAJ 2004 Apr 27170(9)1388 fullshytext

European guidelines

Italian Consensus Conference Working Group statement on informing women about hormonereplacement therapy can be found in BMC Womens Health 2009 May 29914 fullshytext

expert recommendations on collection and analysis of endometrial biopsies for hormone therapiescan be found in Climacteric 2012 Feb15(1)52 fullshytext

Association of the Scientific Medical Societies in Germany (AWMF) interdisciplinary guideline onhormone therapy in perimenopause and postmenopause can be found in Arch Gynecol Obstet 2011Aug284(2)343 fullshytextZurich Discussion Group (Zurcher Gesprachskreises) consensus statement on complications ofhormonal contraception in climacteric and postmenopausal women can be found in GynakolGeburtshilfliche Rundsch 200949(1)45 [German]

Asian guidelines

Asia Pacific Tibolone Consensus Group updated clinical recommendations on use of tibolone inAsian women can be found in Climacteric 2010 Aug13(4)317 fullshytext

Australian and New Zealand guidelines

Royal Australian and New Zealand College of Obstetricians and Gynaecologists (RANZCOG)evidenceshybased consensus statement on use of postmenopausal hormone therapy can be found atNational Health and Medical Research Council 2004 Aug 12

Review articles

review can be found in BMJ 2012 Feb 16344e763ACOGs Hormone Therapy report in Obstet Gynecol 2004 Oct supplement containscomprehensive information (Obstet Gynecol 2004 Oct104(4 Suppl)1S)review can be found in Obstet Gynecol 2010 Apr115(4)839review can be found in J Fam Pract 2005 May54(5)428review can be found in Arch Intern Med 2004 Nov 22164(21)2308review can be found in Med J Aust 2003 Jun 16178(12)630 fullshytextreview can be found in Adv Stud Med 2003 Apr3(4)205 PDFreview can be found in BMJ 2003 Feb 8326(7384)322 fullshytext commentary can be found inBMJ 2003 Jun 21326(7403)1398 fullshytext BMJ 2003 Jun 21326(7403)1398 fullshytext and replyreview can be found in N Engl J Med 2001 Jul 5345(1)34 commentary can be found in N Engl JMed 2002 Jan 3346(1)63review can be found in West J Med 1999 Jul17127 (Am Fam Physician 2000 Jan 161(1)203)evidenceshybased review can be found in CMAJ 2003 Apr 15168(8)1001 fullshytextbrief review can be found in J Fam Pract 2003 Feb52(2)149


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systematic review of postmenopausal HRT can be found in JAMA 2002 Aug 21288(7)872discussion of clinical applications can be found in JAMA 2002 Aug 21288(7)882 commentarycan be found in JAMA 2003 Jan 1289(1)44 commentary can be found in ACP J Club 2003 MarshyApr138(2)41review of risks and benefits can be found in Med J Aust 2007 Jun 18186(12)643review of lowshydose hormone therapy in management of menopausal symptoms can be found in JAm Board Fam Med 2009 SepshyOct22(5)563 fullshytextreview of longshyterm effects of HRT can be found in Lancet 2002 Sep 21360(9337)942commentary can be found in Lancet 2003 Jan 18361(9353)253review of hormonal replacement therapy can be found in BMJ 1998 Aug 15317(7156)457review of oral contraceptive use and changing to postmenopausal hormone replacement therapy inperimenopausal women can be found in Am Fam Physician 1998 Oct 1558(6)1373review of perimenopause can be found in Ann Intern Med 2015 Feb 3162(3)ITC1

Patient Information

FDA website on hormone therapy includes information in English and Spanish (Am FamPhysician 2003 Dec 168(11)2280)

References

Recommendation grading systems used

United States Preventive Services Task Force (USPSTF) grades of recommendation (after July2012)

Grade A shy USPSTF recommends the service with high certainty of substantial net benefitGrade B shy USPSTF recommends the service with high certainty of moderate net benefit ormoderate certainty of moderateshytoshysubstantial net benefitGrade C shy USPSTF recommends selectively offering or providing the service (based onprofessional judgment and patient preference) with at least moderate certainty of small netbenefitGrade D shy USPSTF recommends against providing the service with moderateshytoshyhighcertainty of no net benefit or harms outweighing benefitsGrade I shy insufficient evidence to assess balance of benefits and harmsReference shy USPSTF Grade Definitions

United States Preventive Services Task Force (USPSTF) grades of recommendation (June 2007shyJune 2012)

Grade A shy USPSTF recommends the service with high certainty of substantial net benefitGrade B shy USPSTF recommends the service with high certainty of moderate net benefit ormoderate certainty of moderateshytoshysubstantial net benefitGrade C shy clinicians may provide the service to select patients depending on individualcircumstances however only small benefit is likely for most individuals without signs orsymptomsGrade D shy USPSTF recommends against providing the service with moderateshytoshyhighcertainty of no net benefit or harms outweighing benefitsGrade I shy insufficient evidence to assess balance of benefits and harmsReference shy USPSTF Grade Definitions


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Canadian Task Force on Preventive Health Care (CTFPHC) grades of recommendationGrade A shy good evidence to recommend clinical preventive actionGrade B shy fair evidence to recommend clinical preventive actionGrade C

conflicting evidence does not allow recommendation for or against use of clinicalpreventive actionother factors may influence decision making

Grade D shy fair evidence to recommend against clinical preventive actionGrade F shy good evidence to recommend against clinical preventive actionGrade I

insufficient evidence (in quantity or quality) to make recommendationother factors may influence decision making

ReferencesCTFPHC new grades for recommendations (CMAJ 2003 Aug 5169(3)207 fullshytext)CTFPHC recommendation statement on hormone replacement therapy for primaryprevention of chronic diseases (CMAJ 2004 May 11170(10)1535 fullshytext)CTFPHC recommendation statement on postmenopausal hormone replacementtherapy for primary prevention of cardiovascular and cerebrovascular disease (CMAJ2004 Apr 27170(9)1388 fullshytext)

DynaMed editorial process

DynaMed topics are created and maintained by the DynaMed Editorial TeamOver 500 journals and evidenceshybased sources (DynaMed Content Sources) are monitored directlyor indirectly using a 7shyStep evidenceshybased method for systematic literature surveillanceDynaMed topics are updated daily as newly discovered best available evidence is identifiedThe participating members of the DynaMed Editorial Team have declared that they have nofinancial or other competing interests related to this topicThe participating reviewers have declared that they have no financial or other competing interestsrelated to this topic unless otherwise indicatedMcMaster University is a partner that provides support in identifying PracticeshyChanging DynaMedUpdates Over 1000 practicing physicians from 61 disciplines in 77 countries rate these articles tohelp you find the most useful new evidence affecting your practiceF1000 is a partner that provides support in identifying PracticeshyChanging DynaMed Updates Over2000 practicing clinicians from 20 disciplines in 60 countries rate these articles to help you findthe most useful new evidence affecting your practice

How to cite

National Library of Medicine or Vancouver style (International Committee of Medical JournalEditors)

DynaMed Plus [Internet] Ipswich (MA) EBSCO Information Services 1995 shy Record No113927 Hormonal replacement therapy (HRT) [updated 2015 Mar 15 cited place citeddate here] [about 29 screens] Available from httpwwwdynamedcomloginaspxdirect=trueampsite=DynaMedampid=113927 Registration and login required


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2012 Jul 17157(2)104 fullshytext

Canadian Task Force on Preventive Health Care (CTFPHC) recommendationsHRT for primary prevention of chronic diseases

use of combined estrogenshyprogestin therapy and estrogenshyonly therapy notrecommended for primary prevention of chronic diseases in menopausal women(CTFPHC Grade D)discuss risks and benefits of HRT for alleviating menopausal symptoms withindividual patientsReference shy CMAJ 2004 May 11170(10)1535 fullshytext

postmenopausal HRT for primary prevention of cardiovascular and cerebrovascular diseaseuse of HRT not recommended for primary prevention of myocardial infarction andcardiovascular death in perimenopausal women without coronary artery disease(CTFPHC Grade D)insufficient evidence to make recommendation on use of HRT for primary preventionof stroke and death from cerebrovascular diseaseReference shy CMAJ 2004 Apr 27170(9)1388 fullshytext

Evidence for Overall Risks vs Benefit

Cochrane review

longshyterm hormone replacement therapy increases risk of coronary events venousthromboembolism stroke breast cancer and death due to lung cancer in postmenopausalwomen (level 1 [likely reliable] evidence)

based on Cochrane reviewsystematic review of 23 randomized trials lasting ge 1 year comparing HRT vs placebo in42830 postmenopausal womenall results included data from WHI and WISDOM trials summarized belowcompared to placebo in relatively healthy women combined continuous HRT associatedwith increased risk of

coronary events (myocardial infarction [MI] or cardiac death) after 1 year (absoluterisk [AR] 4 per 1000 95 CI 3shy7)venous thromboembolism after 1 year (AR 7 per 1000 95 CI 4shy11)stroke after 3 years (AR 18 per 1000 95 CI 14shy23)breast cancer after 56 years (AR 23 per 1000 95 CI 19shy29)gallbladder disease requiring surgery after 56 years (AR 27 per 1000 95 CI 21shy34)death from lung cancer (nonshysmall or small cell) after 56 years use plus 24 yearsfollowshyup (AR 9 per 1000 95 CI 6shy13)dementia among women gt 65 years old after 4 years (AR 18 per 1000 95 CI 11shy30)

compared to placebo in relatively healthy women estrogenshyonly therapy associated withincreased risk of

venous thromboembolism after 1shy2 years (AR 5 per 1000 95 CI 2shy10)stroke after 7 years (AR 32 per 1000 95 CI 25shy40)gallbladder disease after 7 years (AR 45 95 CI 36shy57)

in women with cardiovascular disease combined continuous HRT increased risk of venousthromboembolism after 1 year (AR 9 per 1000 95 CI 3shy29)compared to placebo in all women

combined HRT associated with decreased risk of fractures after 56 years (AR 86 per1000 95 CI 79shy84)


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Overview of risks


Contraindications


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Phytoestrogens







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Black cohosh




Raloxifene (Evista)








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Raloxifene 60mgday



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Black cohosh




Raloxifene (Evista)








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Raloxifene 60mgday



147 (NNT 15) 107 (NNT 10) 212


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Alternatives to HRT








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Phytoestrogens







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Black cohosh




Raloxifene (Evista)








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Raloxifene 60mgday



147 (NNT 15) 107 (NNT 10) 212


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Alternatives to HRT








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Phytoestrogens







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Black cohosh




Raloxifene (Evista)








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Raloxifene 60mgday



147 (NNT 15) 107 (NNT 10) 212


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Alternatives to HRT








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Black cohosh




Raloxifene (Evista)








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Raloxifene 60mgday



147 (NNT 15) 107 (NNT 10) 212


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Alternatives to HRT








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Phytoestrogens







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Black cohosh




Raloxifene (Evista)








3143










Raloxifene 60mgday



147 (NNT 15) 107 (NNT 10) 212


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Alternatives to HRT








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Phytoestrogens







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Black cohosh




Raloxifene (Evista)








3143










Raloxifene 60mgday



147 (NNT 15) 107 (NNT 10) 212


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Raloxifene 60mgday



147 (NNT 15) 107 (NNT 10) 212


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Phytoestrogens







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Black cohosh




Raloxifene (Evista)








3143










Raloxifene 60mgday



147 (NNT 15) 107 (NNT 10) 212


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Alternatives to HRT








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Phytoestrogens







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Black cohosh




Raloxifene (Evista)








3143










Raloxifene 60mgday



147 (NNT 15) 107 (NNT 10) 212


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Alternatives to HRT








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Phytoestrogens







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Black cohosh




Raloxifene (Evista)








3143










Raloxifene 60mgday



147 (NNT 15) 107 (NNT 10) 212


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23 (NNT 45) 28 (NNT 59) 45









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Asian guidelines




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Patient Information


References







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Alternatives to HRT








2943










Phytoestrogens







3043






Black cohosh




Raloxifene (Evista)








3143










Raloxifene 60mgday



147 (NNT 15) 107 (NNT 10) 212


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23 (NNT 45) 28 (NNT 59) 45









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Asian guidelines




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Patient Information


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Alternatives to HRT








2943










Phytoestrogens







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Black cohosh




Raloxifene (Evista)








3143










Raloxifene 60mgday



147 (NNT 15) 107 (NNT 10) 212


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23 (NNT 45) 28 (NNT 59) 45









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DHEA supplements










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Asian guidelines




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4243


Patient Information


References







4343








How to cite




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2843






Alternatives to HRT








2943










Phytoestrogens







3043






Black cohosh




Raloxifene (Evista)








3143










Raloxifene 60mgday



147 (NNT 15) 107 (NNT 10) 212


3243


23 (NNT 45) 28 (NNT 59) 45









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DHEA supplements










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Guidelines










Canadian guidelines


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European guidelines




Asian guidelines




Review articles



4243


Patient Information


References







4343








How to cite




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Alternatives to HRT








2943










Phytoestrogens







3043






Black cohosh




Raloxifene (Evista)








3143










Raloxifene 60mgday



147 (NNT 15) 107 (NNT 10) 212


3243


23 (NNT 45) 28 (NNT 59) 45









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DHEA supplements










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Canadian guidelines


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European guidelines




Asian guidelines




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4243


Patient Information


References







4343








How to cite




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Phytoestrogens







3043






Black cohosh




Raloxifene (Evista)








3143










Raloxifene 60mgday



147 (NNT 15) 107 (NNT 10) 212


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23 (NNT 45) 28 (NNT 59) 45









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Asian guidelines




Review articles



4243


Patient Information


References







4343








How to cite




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Black cohosh




Raloxifene (Evista)








3143










Raloxifene 60mgday



147 (NNT 15) 107 (NNT 10) 212


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DHEA supplements










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Canadian guidelines


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Asian guidelines




Review articles



4243


Patient Information


References







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How to cite




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Raloxifene 60mgday



147 (NNT 15) 107 (NNT 10) 212


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DHEA supplements










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DHEA supplements










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Asian guidelines




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Canadian guidelines


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Asian guidelines




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Patient Information


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Canadian guidelines


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Asian guidelines




Review articles



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Patient Information


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European guidelines




Asian guidelines




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dynamed plus_ hormonal replacement therapy (hrt)

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