Back to the Future: Applying New Evidence in Menopause Management Michael Policar, MD, MPH.

Back to the Future: Back to the Future: Applying New Evidence Applying New Evidence in Menopause in Menopause ManagementManagement

Michael Policar, MD, MPHwww.PolicarLectures.comwww.PolicarLectures.com

Topics To Be DiscussedTopics To Be Discussed

New information from the WHINew information from the WHI The expanding range of treatments for The expanding range of treatments for

managing menopausal symptomsmanaging menopausal symptoms– Which treatments are available to your patient?Which treatments are available to your patient?

Practice RecommendationsPractice Recommendations– How can your patient use these treatments safely, How can your patient use these treatments safely,

effectively, and conveniently?effectively, and conveniently?

NAMS DefinitionsNAMS Definitions

Progestogen Progestogen Progesterone or progestin (P) Progesterone or progestin (P) ETET Estrogen (E) therapy Estrogen (E) therapy EPTEPT Combined E+P therapyCombined E+P therapy HT HT Hormone therapy (ET and EPT)Hormone therapy (ET and EPT) CC-EPT CC-EPT Continuous-combined E+P therapyContinuous-combined E+P therapy - E+P given every day- E+P given every day

CS-EPT CS-EPT Continuous-sequential E+P therapyContinuous-sequential E+P therapy - E daily with P added on set - E daily with P added on set

sequence sequenceNAMS position statement. NAMS position statement. MenopauseMenopause 2007. 2007.

Let’s Get This Out Let’s Get This Out of the Way….of the Way….

Act 1Act 1

The WHI Re-analyzedThe WHI Re-analyzed

Background: HBackground: HRRT 1960-1980sT 1960-1980s Menopause seen as endocrine deficiency Menopause seen as endocrine deficiency

requiring hormone requiring hormone replacementreplacement therapy therapy 1960s: successful oral contraceptive introduction1960s: successful oral contraceptive introduction

– ““The Pill” freed women from fear of pregnancyThe Pill” freed women from fear of pregnancy

– HHRRT offered women freedom from fear of agingT offered women freedom from fear of aging 1972: 1972: Forever FeminineForever Feminine by Robert A. Wilson, MD by Robert A. Wilson, MD 1980s: Expanding uses of HRT1980s: Expanding uses of HRT

– Initially used to treat hot flashes, vaginal sxsInitially used to treat hot flashes, vaginal sxs

– Later uses…protection of bone and heartLater uses…protection of bone and heart

Background: Background: Late 1980sLate 1980sBackground: Background: Late 1980sLate 1980s In 40 retrospective observational studies, both EPT and In 40 retrospective observational studies, both EPT and

ET reduced the risk of heart attack by 50%ET reduced the risk of heart attack by 50%

– Most studies included women in their 50sMost studies included women in their 50s

– Women were self-selected for hormone use (or not); Women were self-selected for hormone use (or not); studies were subject to selection biasstudies were subject to selection bias

Conventional wisdomConventional wisdom

– All women should use HT for heart protection, All women should use HT for heart protection, unless there was a reason not to do so unless there was a reason not to do so

– Women with CVD risk factors, Women with CVD risk factors, especiallyespecially previous previous MI, stroke, HTN or diabetes, should use HTMI, stroke, HTN or diabetes, should use HT

Background:Background:1990s1990s

1990: Wyeth requested that FDA add labeling to 1990: Wyeth requested that FDA add labeling to HT products that included cardioprotectionHT products that included cardioprotection

FDA insisted that RCTs be performed to prove FDA insisted that RCTs be performed to prove that HT improved that HT improved CVD outcomes CVD outcomes vs. placebovs. placebo

Two RCTs initiated to evaluate cardioprotectionTwo RCTs initiated to evaluate cardioprotection

– HERS: secondary prevention trialHERS: secondary prevention trial

– WHI: primary prevention trialWHI: primary prevention trial

HERS Study: HERS Study: 19981998

Does EPT reduce MIs in women Does EPT reduce MIs in women withwith CHD? CHD? 2,763 women randomized to CC-EPT or placebo2,763 women randomized to CC-EPT or placebo

– Entry: MI, CABG, balloon angioplasty, + angiogramEntry: MI, CABG, balloon angioplasty, + angiogram– Menopausal, intact uterus, 44-80 years of age Menopausal, intact uterus, 44-80 years of age – Average follow up: 4.1 yearsAverage follow up: 4.1 years

Study findingsStudy findings– EPT had no value in reduction of MIs or CHD deathsEPT had no value in reduction of MIs or CHD deaths

» More deaths in year 1; neutral thru year 8More deaths in year 1; neutral thru year 8» Not seen in prior observational studiesNot seen in prior observational studies

– 3-fold increased risk of VTE events3-fold increased risk of VTE events

Hulley, JAMA 1998:280:605Hulley, JAMA 1998:280:605

Women’s Health Initiative (WHI): Women’s Health Initiative (WHI): 20022002

1993-2005: RCT with 17,000 women1993-2005: RCT with 17,000 women Postmenopausal women 50-79 years oldPostmenopausal women 50-79 years old

– 33%: 50-59 yrs old; 45%: 60-69 yo; 22% 70-79 yo33%: 50-59 yrs old; 45%: 60-69 yo; 22% 70-79 yo– Average age: 64 years oldAverage age: 64 years old

End pointsEnd points– Primary prevention of MI and strokePrimary prevention of MI and stroke– Hip fracture, various cancers Hip fracture, various cancers

Treatment armsTreatment arms– If uterus: CC-EPT (CEE+MPA) vs. placebo If uterus: CC-EPT (CEE+MPA) vs. placebo – If no uterus: ET (CEE) vs. placeboIf no uterus: ET (CEE) vs. placebo

WHI: EPT Arm Study ResultsWHI: EPT Arm Study ResultsReleased July 2002: Findings after 5.2 yearsReleased July 2002: Findings after 5.2 years

EventEvent RR RR Risk/10K/yr Benefit/10K/yr Risk/10K/yr Benefit/10K/yr

Heart attackHeart attack 1.291.29 77

StrokeStroke 1.411.41 88

Breast cancerBreast cancer 1.261.26 88

TE eventTE event 2.112.11 18 18

Colorectal CAColorectal CA 0.630.63 66

Hip fracturesHip fractures 0.660.66 55 Discontinued early, as “risks greater than benefits”Discontinued early, as “risks greater than benefits”

WHI : ET-Only Study Arm WHI : ET-Only Study Arm Released Released 20042004: Findings after 7 years: Findings after 7 years

OutcomeOutcome Change vs. PlaceboChange vs. Placebo

Coronary heart diseaseCoronary heart disease No difference in riskNo difference in risk

Breast cancerBreast cancer No difference in riskNo difference in risk

StrokeStroke Increased riskIncreased risk

Hip fracturesHip fractures Decreased riskDecreased risk

Dementia,Dementia, cognitive cognitive Trend toward Trend toward increasedincreased

Change (Change (>> 65 years old) 65 years old) riskrisk

WHI and HERS: WHI and HERS: The The 2004 2004 Take Home MessageTake Home Message

HT does HT does notnot protect women from heart protect women from heart attacks over the long termattacks over the long term

……and actually may and actually may increase increase the risk of the risk of MI in the first year of HT useMI in the first year of HT use

The rest is “specialty-specific” perception The rest is “specialty-specific” perception of of benefitbenefit and and riskrisk

The Women’s Health InitiativeThe Women’s Health Initiative Was not Was not a menopause studya menopause study Was Was a drug study of the effect of hormones a drug study of the effect of hormones

on CVD, cancer, fractures, and memory in on CVD, cancer, fractures, and memory in older women (average 64 year old)older women (average 64 year old)

Was the WHI designed to evaluate the Was the WHI designed to evaluate the safety and efficacy of EPT in treating safety and efficacy of EPT in treating menopausal changes?menopausal changes?

How Different How Different Were Were WHI Findings WHI Findings Compared to Earlier Studies?Compared to Earlier Studies?

Manson JE, Menopause 2006;13:139

WHI: HT and Risk of CV Disease by WHI: HT and Risk of CV Disease by Age and Years Since MenopauseAge and Years Since Menopause

Roussow JE.Roussow JE. JAMA JAMA. 2007: Combined secondary analysis. 2007: Combined secondary analysis

*Statistically significant defined as p<0.01.

Age at HT initiationAge at HT initiation Heart attackHeart attack StrokeStroke Death from Death from any causeany cause

50–59 years50–59 years ↓ ↓ 7%7% ↑ ↑ 13%13% ↓↓ 30%30%

60–69 years60–69 years ↓↓ 2%2% ↑↑ 50%50% ↑↑ 5%5%

70–79 years70–79 years ↑↑ 26%26% ↑↑ 21%21% ↑↑ 14%14%

“Women who initiated HT Women who initiated HT closer to menopausecloser to menopause tended to have tended to have reduced CHD riskreduced CHD risk compared with the increase in CHD risk among women more distant from compared with the increase in CHD risk among women more distant from menopause, but this trend test did not meet our criterion* for statistical menopause, but this trend test did not meet our criterion* for statistical significance.”significance.”

WHI (EPT arm) Re-analyses WHI (EPT arm) Re-analyses Age vs. Years Since MenopauseAge vs. Years Since Menopause

Manson JE, et al. N Engl J Med. 2003;349:523-34

0.5 1.0 1.5 2.0 2.5

Hazard Ratio for CHD

1.27

1.05

1.44

0.89

1.22

1.71

Age (years)Age (years)

50–5950–59

60–6960–69

70–7970–79

Years Since MenopauseYears Since Menopause

<10<10

10–1910–19

2020

% difference in relative risk

Events/ 10,000 WY of CEE therapy

Total mortality -29 (0.46-1.11 -11

Coronary heart disease

-37 (0.36-1.09) -11

Stroke -11 (0.47-1.69 -2

New onset DM -12 (0.77-1.01) -14

Fracture -30 (0.59-0.83) -56

Breast cancer -18 (0.65-1.04) -8

VTE +37 (0.70-2.68) +4

WHI: Estrogen and Major Health OutcomesWHI: Estrogen and Major Health Outcomes in Women in Women Under 60 Years of AgeUnder 60 Years of Age

Hodis HN, Mack WJ. Menopause Management 2008

The Unified The Unified HypothesisHypothesis

20052005

Phillips LS, Langer RD, Phillips LS, Langer RD, Postmenopausal hormone Postmenopausal hormone therapy: critical reappraisal therapy: critical reappraisal and a unified hypothesis. and a unified hypothesis. Fertility and Sterility 2005;Fertility and Sterility 2005;83:558-6683:558-66

WHIWHI

Clinical Implications: Unified HypothesisClinical Implications: Unified Hypothesis

Mild cardioprotectionMild cardioprotection– Women in their early-mid 50s, whoWomen in their early-mid 50s, who– Initiate HT soon after menopause, with Initiate HT soon after menopause, with – Few or no heart disease or stroke risk factorsFew or no heart disease or stroke risk factors– And who use estrogen-only regimensAnd who use estrogen-only regimens

Increased heart disease riskIncreased heart disease risk– Women in their mid-60s or later, whoWomen in their mid-60s or later, who– Initiate HT long after menopause, who haveInitiate HT long after menopause, who have– Heart disease or stroke risk factorsHeart disease or stroke risk factors– And who use estrogen And who use estrogen andand progestin regimens progestin regimens

Benchmark HT Cardioprotection StudiesBenchmark HT Cardioprotection Studies

Primary Prevention Primary Prevention

““Healthy women”Healthy women”

Secondary PreventionSecondary Prevention

Women with known Women with known heart diseaseheart disease

ObservationalStudies

•Nurses Health Study

Various small studies

Randomized Clinical Trials

•WHI•KEEPS

•HERS

Key Points: Key Points: NAMS March 2007NAMS March 2007Position Statement Position Statement on Hormone Therapyon Hormone Therapy

The North American Menopause Society. The North American Menopause Society. Estrogen and progestogen use in peri- and Estrogen and progestogen use in peri- and postmenopausal women: March 2007 position postmenopausal women: March 2007 position statement of The North American Menopause statement of The North American Menopause Society. Society. Menopause Menopause 2007 2007

Copyright 2007Copyright 2007

HT and Coronary Heart Disease HT and Coronary Heart Disease

ET/EPT not recommended as single or ET/EPT not recommended as single or primary indication for coronary primary indication for coronary protection in women of any ageprotection in women of any age

Data do not currently support EPT Data do not currently support EPT in secondary prevention of CHDin secondary prevention of CHD

NAMS position statement. NAMS position statement. MenopauseMenopause 2007. 2007.

HT and Stroke HT and Stroke

Both ET and EPT appear to increase the risk Both ET and EPT appear to increase the risk of ischemic stroke in postmenopausal womenof ischemic stroke in postmenopausal women

No HT regimen should be used for the No HT regimen should be used for the primary or secondary prevention of strokeprimary or secondary prevention of stroke

HT should be avoided for women who have HT should be avoided for women who have elevated baseline risk of strokeelevated baseline risk of stroke


HT and Venous ThromboembolismHT and Venous Thromboembolism

Significant increase in VTE risk in Significant increase in VTE risk in postmenopausal women using systemic HTpostmenopausal women using systemic HT

Risk increased with both EPT and ET Risk increased with both EPT and ET VTE risk appears during first 1-2 years after VTE risk appears during first 1-2 years after

therapy initiation and decreases over timetherapy initiation and decreases over time Transdermal 17ß-estradiol and oral therapies may Transdermal 17ß-estradiol and oral therapies may

have different riskhave different risk Lower doses of oral estrogens may be safer than Lower doses of oral estrogens may be safer than

higher doses higher doses


EPT and Breast Cancer RiskEPT and Breast Cancer Risk

Breast cancer risk increases with EPT use Breast cancer risk increases with EPT use beyond 5 yearsbeyond 5 years

Increased absolute risk in WHI is viewed as Increased absolute risk in WHI is viewed as rare (4-6 additional invasive cancers/10,000 rare (4-6 additional invasive cancers/10,000 women/year when use EPT used for ≥ 5 yrs)women/year when use EPT used for ≥ 5 yrs)

Not clear whether risk differs between CC-EPT Not clear whether risk differs between CC-EPT and CS-EPT and CS-EPT


ET and Breast Cancer RiskET and Breast Cancer Risk (cont’d)(cont’d)

Women in WHI’s ET arm had 8 Women in WHI’s ET arm had 8 fewer fewer cases of cases of invasive breast cancer/10,000 women/yr of ET useinvasive breast cancer/10,000 women/yr of ET use

Available evidence suggests ET for < 5 years has Available evidence suggests ET for < 5 years has little breast cancer risk impact little breast cancer risk impact

Limited observational data suggest ET given Limited observational data suggest ET given longer than 15 years longer than 15 years may increase riskmay increase risk


Therapeutic InterventionsTherapeutic InterventionsNon-HormonalNon-Hormonal

Act 2Act 2

General Health RecommendationsGeneral Health Recommendations ExerciseExercise: aerobic + strength training: aerobic + strength training

– Reduction in hot flashes in some womenReduction in hot flashes in some women– Healthier heart; stronger bonesHealthier heart; stronger bones

National Osteoporosis FoundationNational Osteoporosis Foundation (NOF) (NOF) Feb 2008Feb 2008– Adults Adults underunder age 50 need, per day age 50 need, per day

» 1,000 mg of calcium1,000 mg of calcium**» 400-800 IU of vitamin D400-800 IU of vitamin D33

– Adults Adults 50 and over 50 and over need, per day need, per day » 1,200 mg of calcium1,200 mg of calcium**» 800-1,000 IU of vitamin D800-1,000 IU of vitamin D3 3

* In divided doses, preferably with meals* In divided doses, preferably with meals

Hot Flashes: Lifestyle ChangesHot Flashes: Lifestyle Changes

Exercise routinely, at least 3-4 days/weekExercise routinely, at least 3-4 days/week Cool room temperature, especially at nightCool room temperature, especially at night Dress in layers (remove outer layers if warm)Dress in layers (remove outer layers if warm) Avoid hot and spicy foodsAvoid hot and spicy foods Relaxing activitiesRelaxing activities Avoid cigarettesAvoid cigarettes Minimize alcoholMinimize alcohol

North American Menopause Society. Menopause. 2004;11:11-33; Kronenberg F, Fugh-Berman A. Ann Intern Med. 2002;137:805-13; Huntley AL, Ernst E. Menopause. 2003;10:465-76.

Botanicals and PhytoSERMsBotanicals and PhytoSERMs

ProbablyProbably better than placebo better than placebo Black cohoshBlack cohoshNo evidence of efficacyNo evidence of efficacy Soy isoflavonesSoy isoflavones Not better than pboNot better than pbo Red clover isoflavonesRed clover isoflavones Not better than pboNot better than pbo Evening primrose oilEvening primrose oil Not better than pboNot better than pbo Dong quaiDong quai Not better (as monotx)Not better (as monotx) GinsengGinseng Not better than pboNot better than pbo Vitamin EVitamin E Not better than pboNot better than pbo Chasteberry (Vitex)Chasteberry (Vitex) No studiesNo studies

Botanicals: Black CohoshBotanicals: Black Cohosh

Total of 14 trials reported, including 4 randomized Total of 14 trials reported, including 4 randomized trials using placebo and/or estrogen treatment armtrials using placebo and/or estrogen treatment arm– 3 of 4 RCTs found black cohosh to be beneficial3 of 4 RCTs found black cohosh to be beneficial– 12 of 14 trials reported 12 of 14 trials reported somesome benefit benefit– Currently, longest trial is 6 monthsCurrently, longest trial is 6 months

NIH-funded, large, randomized, prospective, NIH-funded, large, randomized, prospective, 2-year trial ongoing2-year trial ongoing– Preliminary data fail to show binding to E receptorsPreliminary data fail to show binding to E receptors– Binding to serotonin receptor notedBinding to serotonin receptor noted

Botanicals: Black CohoshBotanicals: Black Cohosh Available as Remifemin, Available as Remifemin,

Estroven, or other single or Estroven, or other single or combination productscombination products

Dosage: 40-80 mg dailyDosage: 40-80 mg daily Adverse effects: headaches, Adverse effects: headaches,

stomach discomfort, stomach discomfort, heaviness in legs heaviness in legs

Hot Flashes

Hot Flashes

Non-hormonal Hot Flash TherapiesNon-hormonal Hot Flash Therapies

DrugDrug Hot Flash ReductionHot Flash Reduction

Antidepressants Antidepressants

•ParoxetineParoxetine 62-65%62-65%

•VenlafaxineVenlafaxine 38-60%38-60%

•FluoxetineFluoxetine 20% 20%

AnticonvulsantsAnticonvulsants

•GabapentinGabapentin 45%45%

AntihypertensivesAntihypertensives

•MethyldopaMethyldopa 65%65%

•ClonidineClonidine 38%38%

Menopause 2004; Menopause 2004; 11(1): 11-3311(1): 11-33

ACOG Task Force on HT ACOG Task Force on HT Obstet Gynecol 2004; Obstet Gynecol 2004; 104:106s-17s.104:106s-17s.

Therapeutic Interventions:Therapeutic Interventions:Hormonal MedicationsHormonal Medications

Act 2Act 2

Prescription HT Options: ET and EPTPrescription HT Options: ET and EPT

OralOral TransdermalTransdermal IntravaginalIntravaginal

ET • Micronized estradiol • Conjugated equine

estrogens (CEE)• Synthetic conjugated

estrogens• Esterified estrogens• Estropipate• Estradiol acetate

• Patches• Gels• Emulsion• Spray

• Creams• Intravaginal

tablet• Rings

EPT • CC-EPT• CS-EPT

• E+P (combination) patches

Med Lett Drugs Ther 2004; 46:98.

HT RegimensHT RegimensMonth 1Month 1 Month 2Month 2

EstrogenEstrogenProgestin 14dProgestin 14d Off for 14 dOff for 14 d Off for 14 dOff for 14 d

Continuous-sequential (CS) EPTContinuous-sequential (CS) EPT

EstrogenEstrogenProgestinProgestin

Continuous combined (CC) EPTContinuous combined (CC) EPT

EstrogenEstrogenEstrogen Therapy (ET)Estrogen Therapy (ET)

3d3d

Continuous-pulsed (CP) EPTContinuous-pulsed (CP) EPT

Choice of HT RegimenChoice of HT Regimen

If no uterus: If no uterus: estrogen onlyestrogen only If uterus presentIf uterus present

– Goal is to avoid vaginal bleeding entirely, or, at Goal is to avoid vaginal bleeding entirely, or, at least, to make it predictableleast, to make it predictable

Endometrial activity predicts bleeding patternEndometrial activity predicts bleeding pattern

– Recent spontaneous or induced bleedingRecent spontaneous or induced bleeding

»Continuous sequential Continuous sequential

– No bleeding for >2-3 cyclesNo bleeding for >2-3 cycles

»Continuous combined Continuous combined

ET Oral TabletsET Oral Tablets

ProductProduct BrandBrandStandard Standard

dosedoseLow doseLow dose

EstropipateEstropipate

OgenOgen

Ortho-estOrtho-est

GenericGeneric

0.625 m0.625 m nonenone

Micronized EMicronized E22 EstraceEstrace

GenericGeneric1.0 mg1.0 mg 0.5 mg0.5 mg

Estradiol acetateEstradiol acetate FemtraceFemtrace 0.9 mg0.9 mg 0.45 mg0.45 mg

ET Transdermal: Patch*ET Transdermal: Patch*

Brand nameBrand name Mg/24 hrMg/24 hr Use/ wkUse/ wk

AloraAlora 0.025, 0.05, 0.075, 0.10.025, 0.05, 0.075, 0.1 22

EsclimEsclim 0.025, 0.0375, 0.05, 0.075, 0.10.025, 0.0375, 0.05, 0.075, 0.1 22

EstradermEstraderm 0.05, 0.10.05, 0.1 22

VivelleVivelle 0.05, 0.10.05, 0.1 22

Vivelle-DotVivelle-Dot 0.025, 0.0375, 0.05, 0.075, 0.10.025, 0.0375, 0.05, 0.075, 0.1 22

ClimaraClimara 0.025, 0.0375,0.05, 0.06, 0.075, 0.10.025, 0.0375,0.05, 0.06, 0.075, 0.1 11

MenostarMenostar 0.014 ☼0.014 ☼ 11

* All contain 17B- estradiol only☼ Indicated only for prevention of osteoporosis

ET Transdermal: ET Transdermal: Gels, Emulsions, Sprays*Gels, Emulsions, Sprays*

Brand Brand name name

TypeType mg/24 hrmg/24 hr UseUse

DivigelDivigel GelGel0.25, 0.5, 1 mg/ 0.25, 0.5, 1 mg/ packetpacket

1 packet daily1 packet daily

ElestrinElestrin GelGel 0.87 gm pump0.87 gm pump 1 pump daily1 pump daily

EstroGelEstroGel GelGel 1.25 gm pump1.25 gm pump 1 pump daily1 pump daily

EstrasorbEstrasorb EmulsionEmulsion 1.74 gm/ pouch1.74 gm/ pouch 2 pouches daily2 pouches daily

EvamistEvamist SpraySpray 1.53 mg/ spray1.53 mg/ spray 1 spray daily1 spray daily

* * All contain 17B- estradiol onlyAll contain 17B- estradiol only

Choice of EstrogensChoice of Estrogens

Start Start low doselow dose transdermal or oral estrogen transdermal or oral estrogen If suboptimal response, modify by:If suboptimal response, modify by:

– Change the estrogen dose (upward)Change the estrogen dose (upward)– Change the estrogen preparationChange the estrogen preparation– Change delivery systems (oral transdermal)Change delivery systems (oral transdermal)– Consider an estrogen-androgen combinationConsider an estrogen-androgen combination

Injectable estrogen not recommendedInjectable estrogen not recommended– Dosage equivalencies are not known Dosage equivalencies are not known – Estrogen cannot be discontinued easilyEstrogen cannot be discontinued easily

Route of Administration Route of Administration Non-oral routes of ET/EPT administration may Non-oral routes of ET/EPT administration may

offer advantages and disadvantages vs oral routes, offer advantages and disadvantages vs oral routes, but the long-term risk-benefit ratio has not been but the long-term risk-benefit ratio has not been demonstrated demonstrated

Possible lower risk of deep venous thrombosis Possible lower risk of deep venous thrombosis (DVT) with non-oral route(DVT) with non-oral route

Similar increased breast cancer risks with oral and Similar increased breast cancer risks with oral and transdermal estrogens, per large observational studytransdermal estrogens, per large observational study


Oral vs. TD-E: The Risk of VTEOral vs. TD-E: The Risk of VTEThe ESTHER StudyThe ESTHER Study

Scarabin P-Y, et al. Lancet. 2003;362:428-432

Ad

just

ed O

dd

s R

atio

(95

% C

I) OR = 4.0 (1.9-8.3)

1.0

3.5(1.8-6.8)

0.9(0.5-1.6)

0

1

2

3

4

5

Nonusers Oral estrogenusers

Transdermalestrogen users

““First Line” Use of First Line” Use of Transdermal EstrogenTransdermal Estrogen

Underlying medical conditionsUnderlying medical conditions– History of DVT or PTEHistory of DVT or PTE– High triglyceride levelsHigh triglyceride levels– Gall bladder diseaseGall bladder disease

Need for “steady state” drug releaseNeed for “steady state” drug release– Daily mood swings (especially while on oral HT)Daily mood swings (especially while on oral HT)– Migraine headaches Migraine headaches

Inability to use oral tabletsInability to use oral tablets– Stomach upset due to oral estrogen intake Stomach upset due to oral estrogen intake – Problems with taking a daily pillProblems with taking a daily pill

Lower HT Doses Lower HT Doses

Provide nearly equivalent vasomotor and genital Provide nearly equivalent vasomotor and genital skin symptom relief and preservation of BMD skin symptom relief and preservation of BMD compared to standard dosescompared to standard doses

Additional local ET may be required for Additional local ET may be required for persistent vaginal symptomspersistent vaginal symptoms

Lower HT doses better tolerated and may have a Lower HT doses better tolerated and may have a better risk-benefit ratio than standard dosesbetter risk-benefit ratio than standard doses

(cont’d)(cont’d)


Lower HT Doses Lower HT Doses (cont’d)(cont’d)

Lower-than-standard ET/EPT doses should be Lower-than-standard ET/EPT doses should be considered, such as daily doses ofconsidered, such as daily doses of– 0.3 mg oral conjugated estrogens0.3 mg oral conjugated estrogens– 0.25-0.5 mg oral micronized 17β-estradiol0.25-0.5 mg oral micronized 17β-estradiol– 0.025 mg transdermal 17β-estradiol patch0.025 mg transdermal 17β-estradiol patch– or the equivalentor the equivalent


Progestogen IndicationProgestogen Indication

Primary menopause-related indication is Primary menopause-related indication is endometrial protection from unopposed ETendometrial protection from unopposed ET

Adequate progestogen (as CC-EPT or CS-EPT) Adequate progestogen (as CC-EPT or CS-EPT) recommended with intact uterusrecommended with intact uterus

Progestogen not generally indicated with ET Progestogen not generally indicated with ET post-hysterectomy post-hysterectomy


Progesterone/ Progestin ProductsProgesterone/ Progestin Products

Oral ProgestinOral Progestin Equiv doseEquiv dose Available dosesAvailable doses

MPAMPA 5-10 mg5-10 mg 1.2, 2.5, 5, 10 mg1.2, 2.5, 5, 10 mg

Micronized Micronized progesteroneprogesterone

200-300 mg200-300 mg 100, 200 mg100, 200 mg

DrospirenoneDrospirenone 0.5 mg/d0.5 mg/d 0.5 mg/d0.5 mg/d

Norethindrone Norethindrone acetateacetate

1.0 mg/d1.0 mg/d 0.5, 1.0 mg/d0.5, 1.0 mg/d

NorethindroneNorethindrone 0.7-1.0 mg/d0.7-1.0 mg/d 0.35 mg0.35 mg

NorgestimateNorgestimate 0.09 mg0.09 mg 0.09 mg0.09 mg

NorgestrelNorgestrel 150 mcg/d150 mcg/d 150 mcg/d150 mcg/d

EPT Oral TabletsEPT Oral TabletsEstrogen Progestin Dosing

Activella 17-E2 1 mg NETA 0.5 mg Once daily oral

Angeliq 17-E2 1 mg Drosperinone 0.5 mg Once daily oral

FemHRTEE 5 gEE 2.5 g

NETA 1 mgNETA 0.5 mg Once daily oral

Prefest17- E2 1 mg Micronized

NGM 0.09 mg

E (alone) 3 days

E+P 3 days

Premphase14 active14 placebo

CEE 0.625 mg MPA 5 mg Once daily oral

(CS-EPT)

Prempro 28 active

CEE0.625 mg 0.45 mg0.3 mg

MPA5.0 mg; 2.5 mg2.5 mg1.5 mg

Once daily oral

(CC-EPT)

EPT Transdermal PatchesEPT Transdermal Patches

EstrogenEstrogen ProgestinProgestin DosingDosing

CombiPatchCombiPatch1717-E2 -E2 0.05 mg0.05 mg0.05 mg0.05 mg

NETANETA0.14 0.14 0.25 mg0.25 mg

Twice Twice weekly weekly

Climara ProClimara Pro 1717-E2 -E2 0.045 mg0.045 mg

LNGLNG0.015 mg0.015 mg

Once weeklyOnce weekly

Off-Label EPT Uses Off-Label EPT Uses

Insufficient endometrial safety evidence to Insufficient endometrial safety evidence to recommend off-label use ofrecommend off-label use of– Long-cycle progestogen (ie, P every 3-6 months Long-cycle progestogen (ie, P every 3-6 months

for 12-14 days)for 12-14 days)– Vaginal administration of progesteroneVaginal administration of progesterone– Levonorgestrel intrauterine system (Mirena)Levonorgestrel intrauterine system (Mirena)– Low-dose estrogen without progestogen Low-dose estrogen without progestogen

Close endometrial surveillance recommended with Close endometrial surveillance recommended with these approachesthese approaches


Compounded Bioidentical Compounded Bioidentical HormonesHormones

““Then, suddenly, the Seven Then, suddenly, the Seven Dwarfs of Menopause arrived at Dwarfs of Menopause arrived at my door without warning: Bitchy, my door without warning: Bitchy, Sweaty, Sleepy, Bloated, Sweaty, Sleepy, Bloated, Forgetful, and All-Dried-Forgetful, and All-Dried-Up….What was it that sent those Up….What was it that sent those wretched dwarfs packing? wretched dwarfs packing? Natural bioidentical hormones.”Natural bioidentical hormones.”

Somers S. The Sexy Years: Discover the Hormone Connection: The Secret to Fabulous Sex, Great Health, and Vitality for Women and Men. Front Matter. 2004 Random House, Crown Publishing, NY.

Compounded Hormone TherapyCompounded Hormone Therapy

The The marketing marketing of compounded hormonal therapyof compounded hormonal therapy– Only bioidentical hormones are usedOnly bioidentical hormones are used– Combination of 2 or 3 estrogens is more “natural”Combination of 2 or 3 estrogens is more “natural”– Dosage is tailored to the individualDosage is tailored to the individual– More “pure” than commercial productsMore “pure” than commercial products– Safer delivery systems (no dyes, etc)Safer delivery systems (no dyes, etc)

The realityThe reality– The The samesame hormones are used in commercial and hormones are used in commercial and

compounded 17b-Ecompounded 17b-E22 and progesterone and progesterone

Sources of Exogenous HormonesSources of Exogenous Hormones

Compounded Hormone TherapyCompounded Hormone Therapy

Compounded hormones will probably work, but…Compounded hormones will probably work, but… Salivary hormone levels are not usefulSalivary hormone levels are not useful The value of adding EThe value of adding E11 + E + E33 has not been evaluated has not been evaluated Progesterone skin cream is not absorbedProgesterone skin cream is not absorbed Compounded hormone doses are not standardizedCompounded hormone doses are not standardized FDA-approved HT products will offerFDA-approved HT products will offer

– Bioidentical hormonesBioidentical hormones– Choice of delivery systemsChoice of delivery systems– Formulary coverage/ lower out-of-pocket costsFormulary coverage/ lower out-of-pocket costs

http://www.fda.gov/consumer/updates/bioidenticals010908.pdfhttp://www.fda.gov/consumer/updates/bioidenticals010908.pdf

Practice GuidelinesPractice GuidelinesHow can your patient use these How can your patient use these treatments safely, effectively, and treatments safely, effectively, and conveniently?conveniently?

Act 3Act 3

Treatment of Hot FlashesTreatment of Hot Flashes

If mild sxs, try exercise, black cohosh If mild sxs, try exercise, black cohosh ++ phytoSERM phytoSERM Initiate low dose HT ifInitiate low dose HT if

– Moderate or severe symptomsModerate or severe symptoms– Non-hormonal treatments have failedNon-hormonal treatments have failed– No interest in non-hormonal therapyNo interest in non-hormonal therapy

Titrate estrogen dosage upward Titrate estrogen dosage upward ifif needed needed When estrogen can’t be used, offerWhen estrogen can’t be used, offer

– SSRI or SNRISSRI or SNRI– Gabapentin, clonidine, a-methyldopa, Gabapentin, clonidine, a-methyldopa, – MPA or Megesterol (Megace)MPA or Megesterol (Megace)

Attempt discontinuation after 1-2 yearsAttempt discontinuation after 1-2 years

Treatment of Sleep/ Irritability SxsTreatment of Sleep/ Irritability Sxs

If mild symptomsIf mild symptoms– Lifestyle change, black cohosh, phytoSERMs Lifestyle change, black cohosh, phytoSERMs

If severe symptoms or no response to aboveIf severe symptoms or no response to above– Low dose HT, then titrate upwardLow dose HT, then titrate upward– If mood swings, transdermal E preferredIf mood swings, transdermal E preferred

Depression component, or no response to HTDepression component, or no response to HT– SNRI or SSRI SNRI or SSRI

HT and Vaginal AtrophyHT and Vaginal Atrophy

When HT is considered solely for this When HT is considered solely for this indication, local (not systemic) vaginal ET is indication, local (not systemic) vaginal ET is generally recommended generally recommended

Progestogen generally Progestogen generally not indicated not indicated with low-with low-dose, local vaginal ETdose, local vaginal ET

Vaginal lubricants often improve vaginal Vaginal lubricants often improve vaginal dryness and painful intercoursedryness and painful intercourse


Vaginal Estrogen TherapiesVaginal Estrogen Therapies ProductProduct BrandBrand DosageDosage DoseDose

Conjugated Conjugated estrogen creamestrogen cream

Premarin Premarin creamcream 0.625 mg/ gram0.625 mg/ gram Daily, then 1-3 Daily, then 1-3

time/wktime/wk

Estradiol creamEstradiol cream EstraceEstrace0.01% 0.01% (0.1 mg/ gm)(0.1 mg/ gm)

Daily, then 1-3 Daily, then 1-3 time/wktime/wk

Estradiol vaginal Estradiol vaginal tablettablet VagifemVagifem 25 micrograms25 micrograms Daily for 2 wks, Daily for 2 wks,

BIW BIW

Estradiol ringEstradiol ring EstringEstring 7.5 mcg/ 24 hrs7.5 mcg/ 24 hrs Every 90 daysEvery 90 days

Estradiol ring*Estradiol ring* FemringFemring0.05 mg/d0.05 mg/d0.1 mg/d0.1 mg/d

Every 3 monthsEvery 3 months

*Intended to be used as *Intended to be used as systemic systemic HTHT

There are insufficient data to recommend annual There are insufficient data to recommend annual endometrial surveillance in asymptomatic women endometrial surveillance in asymptomatic women using low-dose, local vaginal ETusing low-dose, local vaginal ET

Closer surveillance may be required if a Closer surveillance may be required if a woman iswoman is

– At high risk for endometrial cancerAt high risk for endometrial cancer

– Using a greater dose of vaginal ETUsing a greater dose of vaginal ET

– Having symptoms such as spotting, Having symptoms such as spotting, breakthrough bleedingbreakthrough bleeding

NAMS position statement. Menopause 2007.

Vaginal ET: Endometrial Surveillance?Vaginal ET: Endometrial Surveillance?

HT and CognitionHT and Cognition Initiating EPT after age 65 not recommended for Initiating EPT after age 65 not recommended for

primary prevention of dementia or cognitive primary prevention of dementia or cognitive decline decline

Insufficient evidence to support ET/EPT for Insufficient evidence to support ET/EPT for primary prevention of dementia when therapy is primary prevention of dementia when therapy is initiated during perimenopause or early initiated during perimenopause or early postmenopausepostmenopause

ET does not appear to convey direct benefit or ET does not appear to convey direct benefit or harm for treatment of Alzheimer’s disease harm for treatment of Alzheimer’s disease


HT and CognitionHT and CognitionHT and CognitionHT and Cognition

Many women experience worsening of short term Many women experience worsening of short term memory with onset of menopausememory with onset of menopause

9 RCTs and 8 cohort studies9 RCTs and 8 cohort studies– HT does not improve cognitive performance in HT does not improve cognitive performance in

women without symptomswomen without symptoms– If symptomsIf symptoms, HT improved verbal memory, , HT improved verbal memory,

reasoning, and motor speed testsreasoning, and motor speed tests Reasonable to provide HT to lessen cognitive Reasonable to provide HT to lessen cognitive

changes in symptomatic menopausal womenchanges in symptomatic menopausal women

Hormone Therapy and Hormone Therapy and Fracture PreventionFracture Prevention

ProsPros Good data on fracture prevention (mainly 2Good data on fracture prevention (mainly 2oo prevention) prevention) Relatively lower cost than boisphosphonatesRelatively lower cost than boisphosphonates Less concern of adverse effects with ET alone (vs EPT)Less concern of adverse effects with ET alone (vs EPT)ConsCons Requires long term use and surveillanceRequires long term use and surveillance Post-menopausal bleeding can be troublesomePost-menopausal bleeding can be troublesome Increased risk of breast cancer after 5 years of useIncreased risk of breast cancer after 5 years of useUtilityUtility Fracture prophylaxis Fracture prophylaxis if using HT for another indicationif using HT for another indication Otherwise, consider bisphosphonates as first line Otherwise, consider bisphosphonates as first line

HT and “Quality of Life”HT and “Quality of Life”

RCTs and retrospective studies show that HT has no RCTs and retrospective studies show that HT has no effect on “quality of life” measureseffect on “quality of life” measures

Many woman who wean from HT state that they “feel Many woman who wean from HT state that they “feel worse”…even after 20 years after menopause!worse”…even after 20 years after menopause!

Conventional wisdomConventional wisdom

– In women who “feel better on/ worse off” of HT, In women who “feel better on/ worse off” of HT, continue low dose HT if few or no risk factorscontinue low dose HT if few or no risk factors

– When (& how often) to re-attempt wean uncertainWhen (& how often) to re-attempt wean uncertain

– Don’t start HT for solely for improving QOLDon’t start HT for solely for improving QOL

The The FinaleFinale

Act 4Act 4

Discontinuation of HTDiscontinuation of HT After 2 years, recommend a trial of HT discontinuationAfter 2 years, recommend a trial of HT discontinuation Is tapering from hormone therapy necessary? Is tapering from hormone therapy necessary?

– Grady D, Obstet Gynecol 2003;102:1233Grady D, Obstet Gynecol 2003;102:1233– n= 377 who attempted discontinuation of HTn= 377 who attempted discontinuation of HT– 74% successfully stopped; 26% resumed74% successfully stopped; 26% resumed– 71% stopped abruptly; 29% tapered: equal success71% stopped abruptly; 29% tapered: equal success

““Rebound” hot flashes occur in some women and can Rebound” hot flashes occur in some women and can last up to 3 months…many experts recommend a taperlast up to 3 months…many experts recommend a taper

Taper hormone therapy over 8-12 weeks Taper hormone therapy over 8-12 weeks – Reduce dose or extend intervals (every 2, then 3 days)Reduce dose or extend intervals (every 2, then 3 days)– Cut patches in halfCut patches in half

If what I just said If what I just said sounded unusually sounded unusually clear, then you clear, then you must have must have misunderstood memisunderstood me

Alan GreenspanAlan Greenspan

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Back to the Future: Applying New Evidence in Menopause Management Michael Policar, MD, MPH.

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