Starting and StoppingStarting and StoppingHormone TherapyHormone Therapy

Marcelle I. Cedars, MDMarcelle I. Cedars, MDDirector,Director, Division of Reproductive EndocrinologyDivision of Reproductive Endocrinology

University of California, San FranciscoUniversity of California, San FranciscoWomen’s Health—Mount ZionWomen’s Health—Mount Zion

San Francisco, CaliforniaSan Francisco, California

““Yes”Yes”

Most effective Most effective treatment strategy treatment strategy available foravailable forvasomotor vasomotor symptomssymptoms

Known risksKnown risks

““No”No”

Risks outweigh Risks outweigh benefitsbenefits

No risk is No risk is acceptableacceptable

Should Symptomatic Women Be Should Symptomatic Women Be Offered Hormone Therapy?Offered Hormone Therapy?

ApproachApproach Risk/Benefit Risk/Benefit FocusFocus WHI ConclusionWHI Conclusion

Population-based Population-based strategiesstrategies

Documentable Documentable “hard” disease, “hard” disease, such as CVD, stroke, such as CVD, stroke, osteoporosisosteoporosis

Global index of net Global index of net harmharm11

Patient-based Patient-based carecare

Individual risks (eg, Individual risks (eg, family history, family history, lifestyle) and patient lifestyle) and patient symptoms and symptoms and desiresdesires

Absolute, Absolute, attributable risk is attributable risk is smallsmall11

CVD = cardiovascular disease; WHI = Women’s Health Initiative.

Population Management vs Population Management vs Individual Care ConcernsIndividual Care Concerns

1. [No Author]. JAMA. 2002;288:321.

Vasomotor SymptomsVasomotor Symptoms

Common complaintCommon complaint

– Negatively impact quality of lifeNegatively impact quality of life

– Typically abate within 2–3 yearsTypically abate within 2–3 years

– Most clearly linked to hormonal changesMost clearly linked to hormonal changes

Most common indication for initiation of Most common indication for initiation of hormone therapyhormone therapy

Additional Problems Associated with Additional Problems Associated with MenopauseMenopause

Vulvar and vaginal atrophyVulvar and vaginal atrophy

Postmenopausal osteoporosisPostmenopausal osteoporosis

Sleeping difficultiesSleeping difficulties

Alterations in mood (?)Alterations in mood (?)

Alterations in cognition (?)Alterations in cognition (?)

Gold EB, et al. Am J Epidemiol. 2000;152:463.

Vasomotor SymptomsVasomotor SymptomsEpidemiologyEpidemiology

Study of Women’s Health Across Study of Women’s Health Across the Nation (SWAN) (2000)the Nation (SWAN) (2000)

– 16,000+ women aged 40–55 years16,000+ women aged 40–55 years

– >50% of late perimenopausal study >50% of late perimenopausal study patients experienced symptoms patients experienced symptoms Impact of socioeconomic status, Impact of socioeconomic status,

race/ethnicity, body mass index, smoking race/ethnicity, body mass index, smoking status, and physical activitystatus, and physical activity

Woods MF, et al. Am J Med. 2005;118:14.

Vasomotor SymptomsVasomotor SymptomsEpidemiologyEpidemiology

Review of published longitudinal studies Review of published longitudinal studies (2005)(2005)

– Prevalence throughout the transitionPrevalence throughout the transition Late reproductive stage, 6%–13%Late reproductive stage, 6%–13%

Early to late menopausal stages, 4%–46%Early to late menopausal stages, 4%–46%

Late menopausal transition, 33%–63%Late menopausal transition, 33%–63%

Postmenopause, 79%Postmenopause, 79%

Vasomotor SymptomsVasomotor SymptomsWhen Is It Appropriate To Prescribe?When Is It Appropriate To Prescribe?

Clinical decision-making = best available Clinical decision-making = best available evidence + clinical judgment + patient evidence + clinical judgment + patient educationeducation– Balance between population statistics and Balance between population statistics and

individual patient fears and symptomsindividual patient fears and symptoms

– >97% of women in WHI had no negative impact >97% of women in WHI had no negative impact from hormone therapyfrom hormone therapy11

Most appropriate use with least controversyMost appropriate use with least controversy– Generally healthy women for short-term relief of Generally healthy women for short-term relief of

intolerable menopausal symptomsintolerable menopausal symptoms

– Lowest dose for shortest durationLowest dose for shortest duration

1. NIH. WHI HT Update–2002. Available at: http://www.nhlbi.nih.gov/health/women/upd2002.htm.

Starting and Stopping Starting and Stopping Hormone TherapyHormone Therapy

The needThe need

– Symptomatic patients with few effective Symptomatic patients with few effective alternativesalternatives

The problemThe problem

– Lack of high-quality dataLack of high-quality data

What to do?What to do?

– The importance of individualizationThe importance of individualization

Starting and Stopping Hormone TherapyStarting and Stopping Hormone TherapyPremature Ovarian FailurePremature Ovarian Failure

Early menopauseEarly menopauseaa should not be should not be accorded the same concerns asaccorded the same concerns asage-appropriate hormonal changesage-appropriate hormonal changes

Limitation to 5 years (or any presetLimitation to 5 years (or any presettime frame) is artificialtime frame) is artificial

Benefits largely outweigh the risksBenefits largely outweigh the risks

aPrior to 40 years of age.

Starting Hormone TherapyStarting Hormone TherapyLate Reproductive Years/Early TransitionLate Reproductive Years/Early Transition

Potential problems (still cycling) Potential problems (still cycling)

– Abnormal bleeding (heavy, irregular)Abnormal bleeding (heavy, irregular)

– Vasomotor symptomsVasomotor symptoms

– Vaginal drynessVaginal dryness

– Increasing “PMS”Increasing “PMS”

PMS = premenstrual syndrome.

Route of administrationRoute of administration– ? impact on specific symptoms? impact on specific symptoms

– Mood and headache may benefit from transdermal (continuous Mood and headache may benefit from transdermal (continuous dosing)dosing)

DosingDosing– Additional goal of suppressing endogenous cycles and mimic Additional goal of suppressing endogenous cycles and mimic

of circulating levelsof circulating levels

– Transverse menstrual cycle mean: approximatelyTransverse menstrual cycle mean: approximately100 pg/mL100 pg/mL

Cyclic vs continuousCyclic vs continuous– Side-effect profile in cycling women with combined continuous Side-effect profile in cycling women with combined continuous

dosingdosing

Starting Hormone TherapyStarting Hormone TherapyLate Reproductive Years/Early TransitionLate Reproductive Years/Early Transition

Starting Hormone TherapyStarting Hormone TherapyMid-to-Late Transition Through PostmenopauseMid-to-Late Transition Through Postmenopause

Problems (largely not cycling)Problems (largely not cycling)

– Vasomotor symptomsVasomotor symptoms

– Vaginal drynessVaginal dryness

– Urinary symptomsUrinary symptoms

Route of administrationRoute of administration– Patient preferencePatient preference

– Mood and headache may benefit from transdermal Mood and headache may benefit from transdermal (continuous dosing)(continuous dosing)

– Vulvo-vaginal symptoms – importance of local Vulvo-vaginal symptoms – importance of local

DosingDosing– Lowest effective doseLowest effective dose

Cyclic vs continuousCyclic vs continuous– Patient preference for cyclesPatient preference for cycles

– Information regarding higher breast cancer risk with Information regarding higher breast cancer risk with continuous progestincontinuous progestin11

– Alternative progestin dosing/route of administrationAlternative progestin dosing/route of administration

Starting Hormone TherapyStarting Hormone TherapyMid-to-Late Transition Through PostmenopauseMid-to-Late Transition Through Postmenopause

1. Heiss G, et al. JAMA. 2008;299:1036.

Stopping Hormone TherapyStopping Hormone Therapy

Stopping (by choice) afterStopping (by choice) after12 months of starting12 months of starting

– 62% older women (≥65 years)62% older women (≥65 years)

– 48% younger women (50–55 years)48% younger women (50–55 years)

– Reason: vaginal bleedingReason: vaginal bleeding

Ettinger B, et al. Menopause. 1999;6:282.

Grady D, et al. Obstet Gynecol. 2003;102:1233.

Telephone interviews of Kaiser populationTelephone interviews of Kaiser population

– Women aged 50–69 years who took hormone Women aged 50–69 years who took hormone therapy ≥1 year (N = 377)therapy ≥1 year (N = 377)

74% successfully stopped74% successfully stopped

26% resumed treatment26% resumed treatment

– Troublesome withdrawal symptomsTroublesome withdrawal symptoms

– HysterectomyHysterectomy

– Hormone therapy from a nongynecologistHormone therapy from a nongynecologist

– Perceived higher risk for fracturePerceived higher risk for fracture

Stopping Hormone TherapyStopping Hormone TherapyPredictors of Difficulty StoppingPredictors of Difficulty Stopping

Symptoms after stopping hormone therapySymptoms after stopping hormone therapy

in Kaiser-population study in Kaiser-population study

– 70% reported no/minimal symptoms70% reported no/minimal symptoms

– 30% reported troublesome symptoms30% reported troublesome symptoms

62% of women unable to stop treatment62% of women unable to stop treatment

19% of those who successfully quit19% of those who successfully quit

Stopping Hormone TherapyStopping Hormone TherapyWithdrawal SymptomsWithdrawal Symptoms

Grady D, et al. Obstet Gynecol. 2003;102:1233.

Telephone interview of community sampleTelephone interview of community sample– 533 women aged 45–54 years (N = 533)533 women aged 45–54 years (N = 533)

Factors related to discontinuationFactors related to discontinuationof hormone therapyof hormone therapy– Increased understanding of risks/benefitsIncreased understanding of risks/benefits

– ConfidenceConfidence

– Mental health symptoms Mental health symptoms

– History of gynecologic surgeryHistory of gynecologic surgery

– Perception that menopause is naturalPerception that menopause is natural

Stopping Hormone TherapyStopping Hormone TherapyLikelihood of DiscontinuationLikelihood of Discontinuation

Bosworth HB, et al. J Behav Med. 2005;28:105.

Haimov-Kochman R, et al. Menopause. 2006;13:370.

Stopping Hormone TherapyStopping Hormone TherapyTaper vs Abrupt CessationTaper vs Abrupt Cessation

Randomized controlled trial (N = 91)Randomized controlled trial (N = 91) Reappearance of vasomotor symptomsReappearance of vasomotor symptoms

– <3 months after discontinuing therapy<3 months after discontinuing therapy Less-severe symptoms with taper cessationLess-severe symptoms with taper cessation

– At 6 months At 6 months Less-severe symptoms with abrupt cessationLess-severe symptoms with abrupt cessation

– At 9–12 monthsAt 9–12 months No difference in symptoms between taper or abrupt cessationNo difference in symptoms between taper or abrupt cessation

Similar percentage in each groupSimilar percentage in each groupresumed treatmentresumed treatment

Taper vs abrupt cessation may not affect Taper vs abrupt cessation may not affect recurrence of symptomsrecurrence of symptoms11

Taper may allow titration to lowest effective Taper may allow titration to lowest effective dosingdosing22

Taper may allow individualized slow, long taper Taper may allow individualized slow, long taper (hold at dose where symptoms recur then (hold at dose where symptoms recur then attempt taper again after stabilized)attempt taper again after stabilized)33

Stopping Hormone TherapyStopping Hormone TherapyTaper vs Abrupt CessationTaper vs Abrupt Cessation

1. Aslan E, et al. Maturitas. 2007;56:78. 2. Haimov-Kochman R, et al. Menopause. 2006;13:370.3. Grady D. Menopause. 2006;13:323.

ConclusionsConclusions

Individualization is importantIndividualization is important

Quality of life issues are important but should be Quality of life issues are important but should be weighed against an individual patient’s health riskweighed against an individual patient’s health risk11

– Risks are small, but when an event occurs, impact on Risks are small, but when an event occurs, impact on personal QALE is significantpersonal QALE is significant

– Severity of symptoms weighed against CVD riskSeverity of symptoms weighed against CVD risk

Continued treatment should be reviewed annuallyContinued treatment should be reviewed annually

1. Col NF, et al. Arch Intern Med. 1004;164:1634.QALE = quality-adjusted life expectancy; CVD = cardiovascular disease.

BriefBrief

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