Hormones, Hot Flashes, & Highlights in Womens Health

Hormones, Hot Flashes, & Highlights in Womens HealthLaura Davisson, MDAssistant Professor, Section of General Internal MedicineClinical Care Co-Director, Center of Excellence in Womens Health

History of Womens Health

History of Womens Health1941: Diethylstilbestrol (DES) approved by FDA 1953: Study published showing ineffectiveness at preventing miscarriage Until 1971: Continued to be aggressively marketed and routinely prescribed 1971: Identified as cause of vaginal clear cell adenocarcinoma in DES daughters1971: FDA advised physicians to stop prescribing to pregnant women and national effort begun to find women prescribed DES while pregnant

3History of Womens HealthSuch tragedies in pregnant women led to fear of using women of childbearing age in trials1970s: regulations restricted testing in women of reproductive ageUltimately led to widespread exclusion of women from trialsThroughout most of 20th century: treatments tested solely on men1990: GAO report brought to light under-representation of women in federally funded trials

History of Womens HealthNowSeveral Federal agencies have changed policies to promote inclusion of women in studiesLearning that women affected by some diseases at different rates than men Learning that women can present differently than menThere is emerging body of gender-specific research to guide practice in womens health

Todays GoalsReview literature regarding several important womens health topicsIncrease awareness of emerging discipline of womens health

6OutlineHormonesHot flashesHighlights

7Preferred TerminologyET: estrogen therapyEPT: combined estrogen-progestogen therapyHT: Hormone therapy (encompasses both ET and EPT)Note: hormone therapy (HT) as opposed to hormone replacement therapyProgestogen encompasses both progesterone and progestinNorth American Menopause Society (NAMS), 2007 Position Statement

81990s Recommendations based on observational studiesWomen who have coronary heart disease or who are at increased risk of coronary heart disease are likely to benefit from hormone therapyAmerican College of Physicians, 1992

Probable beneficial effect of estrogen on heart diseaseAmerican College of Obstetricians and Gynecologists, 1992

Estrogen replacement therapy does look promising as a long-term protection against heart attackAmerican Heart Association, 1996

Heart and Estrogen/Progestin Replacement Study (HERS) 1998

10HERSPurpose:To evaluate secondary prevention of CHD with hormone therapy (HT) in postmenopausal women with known coronary disease

11HERSMethods:Randomized, double blinded, placebo-controlled trialOver 2700 women with CHD and intact uteri Mean age 67Average follow-up: 4.1 yearsHormone formulation: conjugated equine estrogen (CEE) 0.625mg + medroxyprogesterone acetate (MPA) 2.5 mg daily

HERSResults:No significant differences in CHD found in treatment vs. placebo groups

HERS II (2002)Subsequent unblinded follow-up of HERS subjects Looked at long-term outcomes for 2.7 more years Confirmed HERS findings that HT did NOT decrease risk of CHDin women with known history of CHD

HERS I and IIInterpretation of HERS trials: HT not effective in secondary prevention of CHD

WHI

Womens Health Initiative16WHIObservational Study Clinical Trials:Hormone TherapyDietary ModificationCalcium/Vitamin D

17Some of the 100+ WHI papers:Estrogen plus progestin and the risk of coronary heart disease. NEJM, 2003Effect of estrogen plus progestin on stroke in postmenopausal women. The womens health initiative: a randomized trial. JAMA, 2003Estrogen plus progestin and colorectal cancer in postmenopausal women. NEJM, 2004Estrogen plus progestin and risk of venous thrombosis. JAMA, 2004Conjugated equine estrogens and coronary heart disease: the womens health initiative. Arch Intern Med, 2006Venous thrombosis and conjugated equine estrogen in women without a uterus. Arch Intern Med, 2006

18WHIMulti-million dollar, 15-year project sponsored by NIH, NHLBI Over 160,000 women aged 50-7940 Clinical Centers across USOne of most definitive, far-reaching clinical trials of post-menopausal women's health ever done

19WHI Hormone Therapy TrialLong-term study to evaluate HTs effects on CHD, osteoporotic fractures, and breast cancer in postmenopausal womenTwo arms:Estrogen plus Progestin (E+P)Estrogen Alone (E Alone)

20WHI Hormone Therapy Trial: E+P arm

WHI: E+P armMethods:Over 16,000 women with intact uteriRandomly assigned to E+P vs. placebo for 5 years (planned duration 8.5 years)Hormone formulation: CEE 0.625mg plus MPA 2.5mg daily

WHI: E+P armResults:Trial halted early--July 2002 Overall harm found in treatment group

WHI: E+P armDecreased risk of:Colorectal cancer (34%)Hip fractures (34%)Outweighed by increased risk of:Breast cancer (26%)Pulmonary embolism (113%)Coronary heart disease (29%)Strokes (41%)

WHI: E+P armAbsolute excess risks:Excess CHD events: 7/10,000 woman-yearsExcess stroke events : 8/10,000 woman-yearsExcess pulmonary emboli: 8/10,000 woman-years Excess invasive breast cancer: 8/10,000 woman-years

25WHI: E+P armAbsolute Benefits: Fewer colorectal cancers: 6/10,000 woman-years Fewer hip fractures: 5/10,000 woman-years

WHI: E+P armSummary of additional adverse events: 19 per 10,000 woman-yearsNumber needed to harm for 5 years E+P use: 101

27WHI Hormone Therapy Trial: E Alone arm

WHI: E Alone arm

Methods:Over 10,000 women aged 50-79 with prior hysterectomyRandomly assigned to 0.625mg CEE vs. placebo Followed for average 6.8 years

WHI: E Alone armResults:Trial halted one year early--February 2004 Increased risk of stroke among women in hormone group

WHI: E Alone armResults:Reduced risk of hip fracture (39%)Increased risk of stroke (39%)No effect on heart disease, breast cancer, pulmonary embolus, colorectal cancer, total mortality, or global indexNo overall benefit

WHI: E Alone armMajor Clinical Outcomes RRHip fracture0.61*Breast cancer0.77CHD0.91Total Mortality1.04Colorectal cancer1.08CVA1.39*

32Adapted from N Engl J Med 2006;355:2338-2347WHI Hormone Therapy TrialRelative Risks and Absolute Risk Differences among Women 50-54

OutcomeE+P RR (95% CI)Absolute Risk DifferenceE Alone RR (95% CI)Absolute Risk DifferenceCHD1.29 (1.02-1.63)0.260.91 (0.75-1.12)---CVA1.41 (1.07-1.85)0.201.39 (1.10-1.77)0.20Pulmonary embolism2.13 (1.39-3.25)0.451.34 (0.87-2.06)---Breast cancer1.26 (1.00-1.59)0.930.77 (0.59-1.01)---Colon Cancer0.63 (0.43-0.92)-0.181.08 (0.75-1.55)---Hip fracture0.66 (0.45-0.98)-0.100.61 (0.41-0.91)-0.12Net outcomes per 1000 women years1.560.0833WHI Hormone Therapy Trial: Divergent resultsHeart diseaseIncreased: E+PNeutral: E AlonePulmonary embolismIncreased: E+PNeutral: E AloneBreast cancerIncreased: E+P Neutral: E AloneColorectal cancerDecreased: E+PNeutral: E AloneGlobal indexIncreased: E+PNeutral: E Alone

34WHI Hormone Therapy Trial: Concordant resultsIncreased:StrokesDementia (>65)GallstonesUrinary incontinenceDecreased:FracturesVasomotor symptomsDiabetes

Neutral:HRQOL

35WHI Hormone Therapy TrialLimitations:Only tested CEE and MPA hormone regimensEarly termination of trials can lead to bias Average age mid-60s, not typical 50 year-old women seeking relief from menopausal symptomsPossible that recently menopausal women with low baseline risk of heart disease may have more favorable balance of benefits and risks

36WHI Hormone Therapy TrialConclusions:HT should not be recommended for chronic disease prevention in postmenopausal womenRate of adverse events was higher with E+P than E AlonePossible that progestins exacerbate risksPossible that other formulations, routes of administration, or lower doses might be associated with fewer adverse events (little supportive evidence)

37Divergence of clinical trials from observational studiesHighlights importance of randomized controlled clinical trialsConfounding may explain lower heart disease rates in hormone users in observational studies because they were:LeanerLess likely to smokeMore physically activeMore likely to see doctors regularlyMore highly educatedAnother possible explanation for discrepancy: timing of initiation of HT

38Timing of initiation of HTEmerging data suggests disparities may be related to timing of initiation of HT in relation to proximity of menopauseOn average, women in WHI and HERS initiated HT more than a decade after menopauseInsufficient numbers of younger, symptomatic, newly postmenopausal women to determine whether similar patterns apply to themTrial results should be extrapolated to recently postmenopausal women only with caution

Meta-analysis:Mortality by treatment assignment and age groupAdapted from J Gen Intern Med 2004;19:791-804

GroupOdds Ratio (95% CI) for MortalityAll ages0.98 (0.87-1.18)60 years1.03 (0.90-1.18)40Rossouw, JE, et al. JAMA. Apr 4, 2007;297:1465-1477

Timing of initiation of HTPurpose:To explore whether the effects of HT on risk of cardiovascular disease vary by age or years since menopause beganJAMA. Apr, 2007;297:1465-1477

Timing of initiation of HTMethods:Secondary analysis of WHI HT trial resultsCombined data from the two trial arms to improve statistical power to be able to examine trends across categories of age and years since menopauseMain outcome: CHDOther outcomes: mortality and a global indexJAMA. Apr, 2007;297:1465-1477

Timing of initiation of HTResults:Trend for reduced CHD risk in women closer to menopause but no subgroup met statistical significanceNonsignificant tendency for total mortality to be reduced among younger women (50-59) Risk of stroke did not vary by age or time since menopauseJAMA. Apr, 2007;297:1465-1477

Timing of initiation of HTConclusions:Offers reassurance that HT a reasonable option for short-term treatment of menopausal symptomsRaises the question of whether there may be a protective effect against CHD in younger, recently postmenopausal women

JAMA. Apr, 2007;297:1465-1477

45Decrease in HT and Breast CancerCoincidence?After WHI (in 2002), HT use decreased by about 30%Breast cancer incidence dropped 7% from 2002-2003It is suspected that the decreased use of HT may have led to decreased breast cancer incidence but causality cannot be determined from this dataCould also be from decreased mammography rates leading to decreased detection (mammography rates decreased 1% between 2000 and 2003)Ravdin PM, Cronin KA, Howlander N, Chlebowski RT, Berry DA.29th Annual San Antonio Breast Cancer Symposium, Dec. 2006.

46Hormone Therapy (HT): Current Guidelines

HT: current guidelinesIndications by current labeling:Treatment of moderate-severe vasomotor symptoms Treatment of moderate-severe urogenital symptomsPrevention of osteoporosis (not treatment) in women at significant risk

48HT: current guidelinesPer NAMS position statements:Limit use to short term menopausal symptom reliefLowest dose, shortest duration possibleAvoid in women with history of breast cancer, uterine cancer, or thromboembolic diseaseMust add progestin if patient has uterusDo not initiate or continue to prevent CHD2007 revision: benefits of short-term HT for treatment of perimenopausal symptoms likely outweigh risks for younger women

49OutlineHormonesHot flashesHighlights

50Definition of natural menopauseRetrospectively defined: no menstrual period for 12 monthsAverage age: 51-52 years

PerimenopauseAround ages 42-52 yearsIrregular cycles: shorter or longer;heavier or lighter; missed completely Vasomotor symptoms: hot flashes, night sweats Urogenital symptoms: dryness, itching, dyspareunia, incontinence, increased bladder infections FSH rises (often normal range during perimenopause)

52PerimenopauseMany vasomotor symptoms will improve within several monthsMost will resolve within 4-5 yearsSubstantial minority (10-15%) continue to have troublesome symptoms for years

Treatment of vasomotor symptomsData to guide therapy is lackingStudies complicated by high rate of placebo effect (around 25%)Trials have been small and brief, providing little information about long-term efficacy and risks

Treatment of vasomotor symptoms: Estrogen

55Treatment of vasomotor symptoms: estrogenMultiple randomized trials have demonstrated its efficacyAll types and routes of administration markedly improve frequency and severity of hot flashesDose-related improvement

Adapted from N Engl J Med 2006;355:2338-2347Efficacy of Treatment of Hot Flushes with Various Doses of Estrogen, as Compared with Placebo

Type/dose of estrogen% Reduction in hot flash frequency Oral conjugated equine estrogen 0.625mg94Oral conjugated equine estrogen 0.45mg78Oral conjugated equine estrogen 0.3mg78Oral 17 Beta-Estradiol 2 mg96Oral 17 Beta-Estradiol 1 mg89Oral 17 Beta-Estradiol 0.5 mg79Oral 17 Beta-Estradiol 0.25 mg59Transdermal 17 Beta-Estradiol 0.1mg96Transdermal 17 Beta-Estradiol 0.05 mg96Transdermal 17 Beta-Estradiol 0.025 mg8657Nelson, HD, Vesco KK, Haney E, et al. Nonhormonal therapies for menopausal hot flashes: Systematic review and meta-analysis. JAMA. 2006;295:2057-2071

58Methods10 trials of antidepressants (SSRIs or SNRIs)10 trials of clonidine6 trials of other prescribed medications17 trials of isoflavone extractsJAMA. 2006;295:2057-2071

59Results and ConclusionsIsoflavone extracts: no definite evidence of benefitSSRIs, SNRIs, clonidine, gabapentin: some evidence of efficacy but less than estrogenFew trials of non-hormonal therapies have been publishedMost have methodological deficienciesGeneralizability limited

JAMA. 2006;295:2057-2071

Evidence of Efficacy of Non-hormonal Prescription Drugs for Treatment of Hot Flashes from Randomized, Controlled Clinical TrialsAdapted from N Engl J Med 2006;355:2338-2347

TreatmentEvidence of BenefitMPAYesMegestrolYesGabapentinYesClonidineMixedMethyldopaNoCitalopramNoFluoxetineMixedParoxetineYesSertralineNoVenlafaxineMixed

Nedrow A, Miller J, Walker M, Nygren P, Huffman LH, Nelson HD. Complementary and alternative therapies for the management of menopause-related symptoms: A systematic evidence review. Arch Intern Med. 2006;166:1453-1465

62Complementary and Alternative TherapiesSystematic review included randomized controlled trials and meta-analysesPhytoestrogens: mixed resultsBlack cohosh: mixed resultsMind-body, energy, manipulative, body-based therapies and whole medical systems: little benefitData insufficient to support effectiveness of any therapy in this review

Arch Intern Med. 2006;166:1453-1465

63Treatment of vasomotor symptoms: black cohosh2006: longest and largest placebo-controlled, double-blind trial to date of black cohosh Showed no improvement in vasomotor symptomsIn combination with other studies provides strong evidence that black cohosh ineffectiveAnn Intern Med. 2006;145:869-879.

64Treatment of vasomotor symptomsNo convincing evidence of efficacy for treatment of vasomotor symptoms for: Evening primrose oilGinsengWild yam creamYogaChinese herbsDong quaiKavaRed clover extractVitamin EANY complementary and alternative therapy

Bioidentical hormone replacement

Bioidentical hormone replacementTerm bioidentical not defined, has no scientific meaningThese products made by compounding pharmaciesIndividualized dosage determined by salivary hormone levelsPromoted by patient testimonials, often celebrities, as safer and more effective than conventional therapyNot produced according to federal Good Manufacturing Practice, not approved by FDANo evidence of effectiveness or safetyCannot be recommended

Practical/behavioral measures Paced respirations Dress in layersLower ambient temperatureAvoid turtlenecks, down comforters, alcohol, spicy foods, bright lights

68Summary of Treatment Options for Vasomotor SymptomsPractical/behavioral measuresfirst line for mild symptomsHT for moderate to severe symptomsmost effectiveTopical treatment if urogenital symptoms onlyNon-hormonal drugs can be tried if want to avoid estrogens (off-label):Antidepressants including venlafaxine, fluoxetine, paroxetine GabapentinClonidine

Treatment of vasomotor symptomsif HT used:Follow NAMS guidelines (avoid use in patients with contraindications, use low doses/short durations)Reasonable to try discontinuing every 6-12 months since vasomotor symptoms are usually temporaryPossible that women will have recurrence of symptoms after stoppingIf symptoms recur, try gradually tapering dose or number of days per week used (no guidelines)

70OutlineHormonesHot flashesHighlights

71Low-Fat Dietary Pattern and Risk of Colorectal Cancer

Low-Fat Dietary Pattern and Risk of Invasive Breast Cancer

The Womens Health Initiative Randomized Controlled Dietary Modification Trial

JAMA, February 8, 2006;295

72WHI Dietary Modification TrialBackground:Observational data suggests association of dietary fat intake with breast cancer, cardiovascular disease, and colorectal cancer Purpose: to evaluate effectiveness of low-fat diet

WHI Dietary Modification TrialMethods:Over 48,000 women, aged 50-79Subjects randomized to low-fat/high fruit, vegetable, grain diet vs. usual eating pattern Followed for mean of 8.1 years

WHI Dietary Modification TrialResults--no significant reduced risk of any outcome:Breast cancerColorectal cancerStrokeCHD

WHI Dietary Modification TrialLimitations:Did not specify types fats--potential for benefit of diet lower in saturated and trans fat Few met target of 20% calories from fat--may have been underpowered to detect differencePositive trend toward decreased coronary heart disease, breast cancer, and colon polyps as trial progresseddid not reach statistical significanceHealth implications of diet may take years to be fully realized--benefits may show up in future follow-up

Womens Intervention Nutrition Study (WINS)Randomized, prospective, multicenter clinical trialTested dietary intervention for reducing recurrence of breast cancerIntervention: decrease fat intake to 15% of calories (30% at baseline)Over 2000 women with resected, early-stage breast cancer receiving conventional cancer managementAnalysis performed after median follow-up of 60 monthsJ Natl Cancer Inst. 2006 Dec 20;98(24):1767-76

Womens Intervention Nutrition Study (WINS)Results:Intervention group achieved fat intake of 20% of calories (29% in control group)Intervention group weighed 6 pounds less than control group (same at baseline)24% risk reduction for relapse in intervention groupNumber needed to treat: 38Subgroup analysis suggested most benefit in hormone receptor negative cancers (not statistically significant)J Natl Cancer Inst. 2006 Dec 20;98(24):1767-76

Womens Intervention Nutrition Study (WINS)Limitations:Effect could have been from weight loss rather than the dietary fat on its ownGeneralizability of benefit of low fat diet is limited: only studied recurrence of breast cancer in women with previous breast cancer history J Natl Cancer Inst. 2006 Dec 20;98(24):1767-76

Interpretation of these trials: Should women bother eating a low-fat diet?Studies need to be interpreted with caution because conducting clinical trials of lifestyle changes is difficult WINS study suggests that reduced dietary fat intake with influence on weight may benefit breast cancer patients WHI Dietary Modification trial did not show benefit, but experts are not recommending change in current recommendations Longer follow-up of these trials will answer more questions about its benefitLow-fat diet still recommended for overall health

ConclusionsHormonesHT trialsLimited role for HTHot flashesMenopause/perimenopauseLimited options for vasomotor symptomsHighlightsLow-fat diet trialsSeveral recent trials have changed treatment of women

81