Hormone Therapy for Menopause:Hormone Therapy for Menopause:Current DataCurrent Data

Jan Shepherd, MD, FACOGJan Shepherd, MD, FACOG

ObjectivesObjectives

• Discuss data on the risks and benefits of HT generated since the initial publication from the Women’s Health Initiative.

• Discuss current evidence regarding the effect of HT on cardiovascular and breast cancer risk.

• Apply current evidence regarding HT to clinical practice.

CaseCase

• A 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) Hormone Therapy (HT or MHT)

• Combination Therapy (EPT, was HRT) – replacing estrogen and progesterone– Progesterone necessary to protect uterus

• Estrogen Therapy (ET, was ERT) –

replacing estrogen alone– Used in women who have had a hysterectomy

• Until 2002, thought to be almost always beneficial

Symptoms of the ClimactericSymptoms of the Climacteric

• Menstrual Changes• Vaginal Dryness and

Genital Tract Atrophy • Hot Flashes• Sleep Disturbances• Mood Changes• Cognitive Changes• Other

OsteoporosisOsteoporosis

OsteoporosisOsteoporosis

Sequelae of the MenopauseSequelae of the Menopause

• Heart disease• Women relatively

protected until menopause– Adverse lipid changes– Vascular effects

MenopauseMenopause

• Symptoms can interfere with women functioning to their full physical and mental abilities

• Health risks– An important time of life for health interventions

• Can replacing estrogen address both of these issues?

The Women’s Health InitiativeThe Women’s Health Initiative

• Randomized, double-blind, placebo-controlled study of Premarin and Provera (Prempro)

• Enrolled 16,600 postmenopausal women at 40 sites in the US

• Halted after 5.2 years because breast cancer risk reached a predetermined threshold

JAMA 2002;288:321JAMA 2002;288:321

Results of WHIResults of WHI

Prempro Placebo RR (95%CI) % Change

CHD 37 30 1.29 (1.02-1.63) 29%

Strokes 29 21 1.41 (1.07-1.85) 41%

DVT/PE 34 16 2.11 (1.58-2.82) ↑ 111%

Breast Ca 38 30 1.26 (1.00-1.59) 26%

Colon Ca 10 16 0.63 (0.42-0.92) 37%

Hip fracture 10 15 0.66 (0.45-0.98) 34%

Incidents per 10,000 women/year

July 22, 2002

Annual Prescriptions:1995-2003Annual Prescriptions:1995-2003

JAMA 2004; 291:47-53.

Questions Raised about WHIQuestions Raised about WHI

• Average 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;291:1701JAMA 2004;291:1701

WHI Premarin-Only ArmWHI Premarin-Only Arm(10,739 women post hysterectomy)(10,739 women post hysterectomy)

Premarin Placebo RR (95% CI) % Change

CHD 49 54 0.91 (.75-1.12) ↓ 9%

Stroke 44 32 1.39 (1.1-1.77) ↑ 39%

DVT or PE 28 21 1.33 (.99-1.79) ↑ 33%

Breast Ca 26 33 0.77 (.59-1.01) ↓ 23%

Colon Ca 17 16 1.08 (.75-1.55) ↑ 8%

Hip fracture 11 17 0.61 (.41-.91) ↓ 39%

Incidents per 10,000 women/year

What do we think we learned?What do we think we learned?

RISKS• Venous thrombosis• Stroke• CHD

(combined therapy)• ↑ Breast cancer

(combined therapy)

BENEFITS• Symptom relief• Sexual function• Osteoporosis and

fracture prevention• ↓ Colon cancer (combined therapy)

Newer DataNewer DataDiabetesDiabetes

Heart DiseaseHeart Disease

StrokeStroke

Breast CancerBreast Cancer

Reduced Onset Type 2 DiabetesReduced Onset Type 2 Diabetes

RR 95% CI % Change

HERS1 0.65 0.48-0.89 - 35%

WHI/HT2 0.79 0.67-0.93 - 21%

WHI/ET3 0.88 0.77-1.01 - 12%

1. 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

Circulation 2002;106:913Circulation 2002;106:913

Effects of Estrogen on VasculatureEffects of Estrogen on Vasculature

• Direct– Binds to endothelial β2-adrenergic receptors

→ NO release → Vasodilation Platelet aggregation, thromboxane

• Biochemical– ↑ HDL-C, ↓ LDL, ↑ triglycerides (oral)– ↑ C-reactive protein (oral only)

Thrombogenic Effects of EstrogenThrombogenic Effects of Estrogen

• First-pass effects– ↑ Factors VII and X, APC resistance– ↓ Antithrombin, Proteins C and S

• Explains increased DVT/VTE• Some oral estrogens may be more

thrombogenic than others1

• No increase in DVT/VTE shown with transdermal preparations2,3

1. JAMA 2004;292:1581 2. Lancet 2003;362:428 3. Circulation 2007;115:840

Potential Effects of ProgestinPotential Effects of Progestin

• Can reverse estrogen’s positive effect on lipid profile

• May block estrogen’s positive effect on vasculature

J Cinical Endocrin Metab;2001;86:5396J Cinical Endocrin Metab;2001;86:5396

HT and Atherosclerosis in MonkeysHT and Atherosclerosis in Monkeys

0102030405060708090

100

No Rx Early E Early E+P Late E

Further Analysis of WHIFurther Analysis of WHI(Both arms combined)(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)

JAMA 2007;297:1465-1477.JAMA 2007;297:1465-1477.

Evidence Suggests: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 CHD– May ↑ risk when started postmenopausally – May ↓ risk when begun at menopause

New Data on Stroke RiskNew Data on Stroke Risk

• Population-based case control study from UK Database (15,710 cases of stroke matched to 59,958 controls)

Cases Controls RR (95% CI)

Transdermal 103 441 0.95 (0.75-1.20)

< 50 μg estradiol 76 384 0.81 (0.62-1.05)

> 50 μg estradiol 27 57 1.89 (1.15-3.11)

Oral 618 2025 1.28 (1.15-1.42)

<.625mg CE, 2mg E 515 1753 1.25 (1.12-1.40)

>.625mg CE, 2mg E 103 272 1.48 (1.16-1.90)

BMJ 2010;340:c2519.BMJ 2010;340:c2519.

Effects of E and P on the BreastEffects of E and P on the Breast

• Persistent high endogenous estrogen is known to be associated with breast cancer

• Mitotic activity in the breast peaks during the luteal phase (progesterone-dominant)

HT and Risk of Breast CancerHT and Risk of Breast Cancer

• Observational studies– Average RR 1.35– ↑ Risk with ↑ duration of therapy– Little or no risk with estrogen alone

• WHI– RR 1.24 (CI 1.00 – 1.59)– No risk with estrogen alone

N Engl J Med 2007; 356:1670-1674.N Engl J Med 2007; 356:1670-1674.

SEER DataSEER Data

Newer Data from WHINewer Data from WHI

New Engl J Med 2009;360:573-587.New Engl J Med 2009;360:573-587.

Evidence Suggests:Evidence Suggests:

• There is a small increased risk of breast cancer with combination HT, which likely increases with increased duration of use

• E alone may have less impact• HT may potentiate tumors that are already

present• Withdrawal of HT may lead to regression of

preclinical cancers

Relative Risk of Breast CancerRelative Risk of Breast Cancer

Relative Relative risk of risk of breast breast cancercancer

Family Family historyhistory

BRCA1-2 BRCA1-2 mutationmutation

Early Early menarchemenarche

Late age Late age at birth at birth of 1st of 1st childchild

Benign Benign breast breast

diseasedisease

Hormone Hormone replacement replacement

therapytherapy

Alcohol Alcohol useuse

Hormone Therapy and MortalityHormone Therapy and MortalityMeta-Analysis for Women < Age 60Meta-Analysis for Women < Age 60

Am J Med 2009;122:1016-22.Am J Med 2009;122:1016-22.

What do we think we know about HT?What do we think we know about HT?

RISKS• Venous thrombosis (oral)• Stroke• CAD (combined therapy,

older women)• Breast cancer

(esp. combined therapy, prolonged use)

BENEFITS• Symptom relief• Sexual function• Osteoporosis prevention• ↓ Diabetes

May ↓ CAD (younger women)

May mortality (if begun before age 60)

Menopause 2010;17(2):242-255.Menopause 2010;17(2):242-255.

2010 NAMS Statement2010 NAMS Statement

• Treatment of moderate to severe vasomotor symptoms remains the primary indication for HT

• When vulvovaginal atrophy is the sole indication, first-line therapy should be topical

• Oral HT increases the risk of VTE, particularly in the first 1-2 years and in women over age 60

• Data show a reduction in CHD with HT initiated within 10 years of menopause and an increase after 10 years

• ET/HT in early menopause for primary prevention of CHD needs further evaluation; HT should not be used for secondary prevention of CHD

2010 NAMS Statement2010 NAMS Statement• Initiating HT after age 65 for prevention of dementia is

not recommended; data for early menopause insufficient• Both ET and HT may increase risk of stroke• Both 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 nonusers– Estrogen 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 Statement2010 NAMS Statement

• Use the lowest effective dose consistent with treatment goals, benefits, and risks

• Extended use is acceptable if informed patient believes benefits outweigh risks

• Specific regimens and forms of administration may have different outcomes, but evidence is insufficient

• There is inadequate evidence on endometrial safety to recommend alternatives to standard EPT regimens

• Compounded “bioidentical” hormones should be used with caution

http://www.menopause.org

How well do women understand How well do women understand the research on HT?the research on HT?

• Women aged 45-65 - UF Women’s Clinics

• Dramatically overestimated the risks of HT– 1/3 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?What can we tell our patients?

• Clarify misconceptions resulting from media coverage

• Help each woman understand the risks and benefits for her individual situation

NAMS