hormone therapy for menopause: current data jan shepherd, md, facog
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Hormone Therapy for Menopause:Current Data
Jan Shepherd, MD, FACOG
ObjectivesDiscuss data on the risks and benefits of HT generated since the initial publication from the Womens Health Initiative.Discuss current evidence regarding the effect of HT on cardiovascular and breast cancer risk.Apply current evidence regarding HT to clinical practice.
CaseA 52 year-old Caucasian female g2p2, LMP 6 months ago, presents with significant hot flashes interfering with her daily activities and sleep. She has read that HT can cause breast cancer and heart attacks. What is your initial advice?
Hormone Therapy (HT or MHT) Combination Therapy (EPT, was HRT) replacing estrogen and progesteroneProgesterone necessary to protect uterusEstrogen Therapy (ET, was ERT) replacing estrogen aloneUsed in women who have had a hysterectomyUntil 2002, thought to be almost always beneficial
Symptoms of the ClimactericMenstrual ChangesVaginal Dryness and Genital Tract Atrophy Hot FlashesSleep DisturbancesMood ChangesCognitive ChangesOther
Sequelae of the MenopauseHeart diseaseWomen relatively protected until menopauseAdverse lipid changesVascular effects
MenopauseSymptoms can interfere with women functioning to their full physical and mental abilitiesHealth risksAn important time of life for health interventionsCan replacing estrogen address both of these issues?
The Womens Health InitiativeRandomized, double-blind, placebo-controlled study of Premarin and Provera (Prempro)Enrolled 16,600 postmenopausal women at 40 sites in the USHalted after 5.2 years because breast cancer risk reached a predetermined threshold
JAMA 2002;288:321Results of WHIIncidents per 10,000 women/year
PremproPlacebo RR (95%CI)% ChangeCHD 37 301.29 (1.02-1.63) 29%Strokes 29 211.41 (1.07-1.85) 41%DVT/PE 34 162.11 (1.58-2.82) 111%Breast Ca 38 301.26 (1.00-1.59) 26%Colon Ca 10 160.63 (0.42-0.92) 37%Hip fracture 10 150.66 (0.45-0.98) 34%
July 22, 2002
Annual Prescriptions:1995-2003JAMA 2004; 291:47-53.
Questions Raised about WHIAverage age 63 (only 3.4% were 50-55), asymptomatic patients does this data apply to newly menopausal women? One-size-fits-all approach does this data apply to all forms and doses of HT?Only E+P studied - does progestin play a role in risk?
JAMA 2004;291:1701WHI Premarin-Only Arm(10,739 women post hysterectomy)Incidents per 10,000 women/year
Premarin PlaceboRR (95% CI)% ChangeCHD 49 540.91 (.75-1.12) 9%Stroke 44 321.39 (1.1-1.77) 39%DVT or PE 28 211.33 (.99-1.79) 33%Breast Ca 26 330.77 (.59-1.01) 23%Colon Ca 17 161.08 (.75-1.55) 8%Hip fracture 11 170.61 (.41-.91) 39%
What do we think we learned?RISKSVenous thrombosisStrokeCHD (combined therapy) Breast cancer (combined therapy)
BENEFITSSymptom reliefSexual functionOsteoporosis and fracture prevention Colon cancer (combined therapy)
Newer DataDiabetesHeart DiseaseStrokeBreast Cancer
Reduced Onset Type 2 Diabetes1. Ann Intern Med 2003;138:1-19. 2. Diabetalogia 2004;47:1175-87. 3. Diabetalogia 2006;49:459-68. Etiology uncertain May insulin sensitivity May be secondary to centripetal weight gain
RR95% CI% ChangeHERS10.650.48-0.89- 35%WHI/HT20.790.67-0.93- 21%WHI/ET30.880.77-1.01- 12%
Circulation 2002;106:913Effects of Estrogen on VasculatureDirectBinds to endothelial 2-adrenergic receptors NO release Vasodilation Platelet aggregation, thromboxaneBiochemical HDL-C, LDL, triglycerides (oral) C-reactive protein (oral only)
Thrombogenic Effects of EstrogenFirst-pass effects Factors VII and X, APC resistance Antithrombin, Proteins C and SExplains increased DVT/VTESome oral estrogens may be more thrombogenic than others1No increase in DVT/VTE shown with transdermal preparations2,31. JAMA 2004;292:1581 2. Lancet 2003;362:428 3. Circulation 2007;115:840
Potential Effects of ProgestinCan reverse estrogens positive effect on lipid profileMay block estrogens positive effect on vasculature
J Cinical Endocrin Metab;2001;86:5396HT and Atherosclerosis in Monkeys
J Cinical Endocrin Metab;2001;86:5396
Further Analysis of WHI(Both arms combined)
For women < 10 years since menopause, CHD risk (RR .76, 95% CI 0.50-1.16)For women < age 60, mortality risk (RR .70, 95% CI 0.51-0.96)
Evidence Suggests:Estrogen may have a negative effect on damaged endothelium A positive effect of estrogen, if it occurs, requires a healthy endothelium
HT and risk of CHDMay risk when started postmenopausally May risk when begun at menopause
New Data on Stroke RiskPopulation-based case control study from UK Database (15,710 cases of stroke matched to 59,958 controls)
CasesControlsRR (95% CI)Transdermal1034410.95 (0.75-1.20) < 50 g estradiol763840.81 (0.62-1.05) > 50 g estradiol27571.89 (1.15-3.11)Oral61820251.28 (1.15-1.42) .625mg CE, 2mg E1032721.48 (1.16-1.90)
Effects of E and P on the BreastPersistent high endogenous estrogen is known to be associated with breast cancerMitotic activity in the breast peaks during the luteal phase (progesterone-dominant)
HT and Risk of Breast CancerObservational studiesAverage RR 1.35 Risk with duration of therapyLittle or no risk with estrogen aloneWHIRR 1.24 (CI 1.00 1.59)No risk with estrogen alone
N Engl J Med 2007; 356:1670-1674.SEER Data
N Engl J Med 2007; 356:1670-1674.
Newer Data from WHINew Engl J Med 2009;360:573-587.
New Engl J Med 2009;360:573-587.
Evidence Suggests:There is a small increased risk of breast cancer with combination HT, which likely increases with increased duration of useE alone may have less impactHT may potentiate tumors that are already presentWithdrawal of HT may lead to regression of preclinical cancers
Relative Risk of Breast CancerRelative risk of breast cancerFamily historyBRCA1-2 mutationEarly menarcheLate age at birth of 1st childBenign breast diseaseHormone replacement therapyAlcohol use
Hormone Therapy and MortalityMeta-Analysis for Women < Age 60Am J Med 2009;122:1016-22.
Am J Med 2009;122:1016-22.
What do we think we know about HT?RISKSVenous thrombosis (oral)StrokeCAD (combined therapy, older women)Breast cancer (esp. combined therapy, prolonged use)
BENEFITSSymptom reliefSexual functionOsteoporosis prevention Diabetes
May CAD (younger women)
May mortality (if begun before age 60)
Menopause 2010;17(2):242-255.2010 NAMS StatementTreatment of moderate to severe vasomotor symptoms remains the primary indication for HTWhen vulvovaginal atrophy is the sole indication, first-line therapy should be topicalOral HT increases the risk of VTE, particularly in the first 1-2 years and in women over age 60Data show a reduction in CHD with HT initiated within 10 years of menopause and an increase after 10 yearsET/HT in early menopause for primary prevention of CHD needs further evaluation; HT should not be used for secondary prevention of CHD
2010 NAMS StatementInitiating HT after age 65 for prevention of dementia is not recommended; data for early menopause insufficientBoth ET and HT may increase risk of strokeBoth ET and HT appear to reduce diabetes risk Breast cancer risk is slightly increased with HT use beyond 5 years (4-6/10,000 women) There is no difference in mortality from breast cancer between HT users and nonusersEstrogen alone may have less impact There is definitive evidence that HT and ET reduce osteoporosis risk, and both may still be considered for women at high fracture risk
2010 NAMS StatementUse the lowest effective dose consistent with treatment goals, benefits, and risksExtended use is acceptable if informed patient believes benefits outweigh risksSpecific regimens and forms of administration may have different outcomes, but evidence is insufficientThere is inadequate evidence on endometrial safety to recommend alternatives to standard EPT regimens Compounded bioidentical hormones should be used with cautionhttp://www.menopause.org
How well do women understand the research on HT?Women aged 45-65 - UF Womens ClinicsDramatically overestimated the risks of HT1/3 believed HT increases risk of CHD 10-30%1/2 believed HT increases risk of breast cancer 10-30% Actual increases were .07% & .08%, respectively
Am J Obstet Gynecol 2004;191:641-7.
What can we tell our patients?Clarify misconceptions resulting from media coverageHelp each woman understand the risks and benefits for her individual situation
**************This was followed by cover stories in magazines such as TIME and Newsweek a few weeks later. *1995 = 58.3 million2001 = 91.0 million2003 = 56.9 million***************************