Feminine Forever

Applying Best Evidence to Menopause Management

Judith Walsh, MD, MPH

Division of General Internal Medicine

Women’s Health Center of Excellence

UCSF

Overview

� Natural history of menopause

� Hormone therapy: Risks and Benefits

� Menopausal symptoms

� Current role of hormone therapy for menopausal symptoms

� Non-hormonal treatment of menopausal symptoms

MENOPAUSE IS NOT A DISEASE

“Feminine Forever”

� Dr. Robert Wilson, 1966

� Replacing estrogen is like diabetics replacing insulin

� Women “will be much more pleasant to live with and will not become dull and unattractive.”

� Wyeth-Ayerst funded all expenses

Menopause Is A Positive Step

� Gallup poll 1997: Most middle aged American women “welcome menopause as a new and fulfilling life stage.”

� Goal: Support women in achieving a successful transition

Natural History of Menopause

� Average age is 51� Predictors of age at menopause

– Genetics– Family history– Ethnicity

» Earlier in Latino and later in Japanese American compared to Caucasians

– Smoking: about two years earlier– Reproductive history

» Never having children and shorter cycle length associated with earlier menopause

Vasomotor Symptoms

� Minnie Pause is a 53 year old woman who had her last menstrual period 18 months ago. She is still having hot flashes and awakens at least twice a night with them. She is considering taking estrogen but wants to know how much longer this will last. What do you tell her?

What do you tell her about when they will go away?

� Average duration is about 2 years and so they should be gone in about 6 months.

� Average duration is about 4 years

� They will never go away

Background

� Treatment for menopausal symptoms is based on their transitory nature

� Many clinical guidelines suggest that symptom duration is approximately 2 years

– Many studies do not follow women more than 2 years

� Risks and benefits of hormone therapy depend on duration of use

– “Use lowest dose for shortest duration”

Duration of Vasomotor Symptoms

� Politi MC et al. Revisiting the duration of vasomotor symptoms of menopause: a meta-analysis. JGIM 2008:23: 1507-13

� Objective: to estimate the natural progression of menopausal symptoms

Vasomotor symptoms

� Rigorous meta-analysis included 10 studies with over 35,000 participants

� Clear definition of vasomotor symptoms

� Assessed prevalence of symptoms and “bothersome symptoms”

Results

� Percent of women with symptoms increased in the two years before the final menstrual period (FMP) , peaked one year after the FMP and did not return to premenopausal levels until 8 years after the FMP

� 50% of women had symptoms during the 4 years after FMP

� 10% of women had symptoms up to 12 years after FMP

Results: Bothersome Symptoms Duration of Hot Flushes

� Most prior studies examined populations of older women

� Newer evidence suggests that these durations might be longer when younger women are included

� Counseling regarding duration of hot flushes may inform clinical decision making

The News

�Duration of menopausal hot flushes and associated risk factors

– Freeman, EW et al. Obstetrics and Gynecology, May 2011

�Aim: To estimate the duration of moderate-to-severe menopausal hot flushes and identify potential risk factors for hot flush duration.

Methods

� Penn Ovarian Aging Study - 436 premenopausal women, ages 35-47 years (not using hormonal therapy of any type); followed for 13 years

– Analytic Subsample: 259 women did not report hot flushes at baseline but did experience mod/severe sx during follow-up

� Measures: validated menopausal symptom list embedded in structured interview, hormones

� Assessments made at 9-month intervals during study years 0-5, then annually until year 10, every other year until study completion

Menopausal stages

� Premenopause: regular menstrual cycles 22-35 days long

� Late premenopause: change of more than 7 days in cycle length

� Early transition: changes in cycle length of 7 days or more in either direction for 2 consecutive menstrual cycles OR 60 days amenorrhea

� Late transition: 90 d to 11 months amenorrhea

� Postmenopause: 12 months or more amenorrhea

Soules, et al. Climacteric 2001

Results

Results – Hazard Ratiofor Likelihood of Hot Flashes Ending

Variable HR (95% CI)

MenopausalPremenopausal or Late PremenopausalEarly TransitionLate Transition or Postmenopausal

Ref. 3.26 (1.78-5.97)5.14 (2.70-9.77)

Age39 or younger40-4445-4950 or older

0.33 (0.14-0.78)0.52 (0.30-0.91)Ref.1.00 (0.54-1.87)

White Race (Ref: African American) 1.73 (1.11-2.68)

BMI 30 or more (Ref: BMI under 30) 1.94 (1.25-3.02)

Estradiol (mean) 0.82 (0.64-1.05)

Take Home Message

� In this population-based cohort, median duration of moderate-to-severe hot flushes was…10.2 years!

– Adding mild hot flushes…duration was 11.6 years

� Younger, thinner, African-American women are likely to have longer hot flush duration

� Effect of hormone therapy on hot flush duration was not evaluated

� Clinicians counseling patients about hot flash duration should be mindful that the earlier the hot flashes start, the longer they are likely to last!

Hormone Therapy

� What have we learned from the Women’s Health Initiative?

� What questions still remain unanswered?

� What is the current role of HT ?

Hormone therapy is recommended for prevention of which of the following

conditions?

� Osteoporosis

� CHD

� Colorectal Cancer

� 1 and 3

� None of the above

Women’s Health initiative

� Aim was to determine the health risks and benefits of estrogen/progestin in healthy women

� 16,608 women aged 50-79 with a uterus– Randomized to estrogen/progestin or placebo

� Primary outcomes– CHD (CHD death or non-fatal MI)

– Invasive breast cancer• Writing Group for WHI JAMA 2002

� E/P arm stopped at 5.2 years

WHI OUTCOMES

OTHER WHI PUBLICATIONS

� Effects on the brain

� Effects on CHD

� Effects on breast cancer

� Effects on colorectal cancer

� Effects on osteoporosis

� Effects on venous thrombosis

� Effects on gallbladder disease

� Effects on incontinence

� Effects of estrogen alone

HT and the Brain

� WHI Memory Study– Subgroup of WHI

– Slight increase in dementia in hormone therapy group

» Absolute number of cases was small

– Greater decrease in modified mini mental status exam in hormone therapy group

• Rapp, JAMA 2003; Shumaker, JAMA 2003

� Increase in stroke in HT group– 1.8% vs 1.3%

– Hazard ratio 1.31 (1.02, 1.68) • Wassertheil-Stoller, 2003

HT AND CHD: WHI

� Final results of the effects of estrogen and progestin on CHD outcomes

� HT users had a hazard ratio for CHD higher than non-users

– HR 1.24 (95% C.I. 1.00, 1.54)

� Risk was highest in the first year– HR 1.81 (95% C.I. 1.09, 3.01)

• Manson, NEJM 2003

BREAST CANCER OUTCOMES: WHI

� Since the WHI, use of hormone therapy (HT) in the U.S. has decreased

� Breast cancer incidence has also decreased in the U.S.

� What is the long term impact of HT on breast cancer?

Adherent Participants in WHI: Invasive Breast Cancers by Group

Chlebowski RT et al:JAMA 2003; 289: 3243-3253

Figure 2. Incidence of Invasive Breast Cancer in the WHI Clinical Trial

Chlebowski, R. T. et al. JAMA 2010;304:1684-1692

Copyright restrictions may apply.

Breast Cancer Outcomes: WHI

� Combined E+P therapy increases the cumulative risk of invasive breast cancer, and diagnosed cancers are more likely to be node-positive

� This risk becomes evident within about 4.7 years of randomization and is persistent through a total of 11 years of follow-up

� There were more breast cancer deaths in the combined E+P group

• Chlebowski JAMA 2010

OSTEOPOSIS RESULTS: WHI

� 11.1% of placebo treated women compared with 8.6% of estrogen treated women had a fracture

– Hazard ratio 0.76 (95% C.I. 0.69, 0.83)

� Effects did not differ by age, BMI, smoking status, history of falls, family history of osteoporosis, past use of hormone therapy or BMD

� No global benefit even in high risk women» Cauley, JAMA 2003

COLORECTAL CANCER: WHI

� Reduced rate of colorectal cancer in hormone therapy users

– Hazard ratio 0.56; 95% C.I. 0.38, 0.81)

� Invasive cancers in the hormone group had a greater number of positive lymph nodes and were more advanced

» Chlebowski NEJM 2004

VTE Outcomes: WHI

� Risk increased overall in HT users– HR 2.06 (95% C.I. 1.57, 2.70)

� Risk higher in older women– HR 4.28 (95% C.I. 2.38, 7.72) for women aged 60-69

– HR 7.46 (95% C.I. 4.32, 14.38) for women aged 70-79

� Risk higher in obese women– HR 3.8 (95% C.I. 2.08, 6.94) for overweight

– HR 5.61 (95% C.I. 3.12, 10.11) for obese

� Factor V Leiden increased HT associated risk• Cushman, JAMA 2004

Gallbladder Disease: WHI

� Increased risk of any gallbladder disease or surgery in hormone therapy users

– HR 1.67 (95% C.I.. 1.35, 2.06) in estrogen users

– HR 1.59 (95% C.I. 1.28, 1.97) in estrogen/progestin users

� Increased risk of cholecystitis, cholelithiasis, and cholecystectomy in both groups

� NNH– 323 for CEE

– 500 for E plus P• Cirillo JAMA 2005

Urinary Incontinence: WHI

� HT has long been thought to relieve the symptoms of urinary incontinence

� HT increased the incidence of all types of urinary incontinence at 1 year among women who were continent at baseline

� Among women with UI at baseline, frequency worsened in hormone users

� Did not assess vaginal estrogens» Hendrix JAMA 2005

HT and Quality of Life

� In the WHI there were small improvements in quality of life among women who had vasomotor symptoms

� Hormone therapy is associated with improvement in some quality of life measures in women with vasomotor symptoms and may improve sexual function and vitality

• Hess, 2008; Welton, 2008

WHI: Estrogen Alone

� 10,739 postmenopausal women aged 50-79 with prior hysterectomy

� Intervention phase ended early after reviewing data through November, 2003

� Average follow-up 6.8 years

WHI: Estrogen Alone

� Non-significant reduction in breast cancer– RH 0.77 (95% C.I. 0.59, 1.01)

� No reduction in colon cancer– RH 1.08 (95% C.I. 0.75, 1.55)

� Non-significant increase in pulmonary embolism– RH 1.34 (95% C.I. 0.87, 2.06)

� Lower risk of fractures – RH 0.70 (95% C.I. 0.63, 0.79)

� Increased risk of stroke

� Global index not consistent with harm– RH 1.01 (95% C.I. 0.91, 1.12)

WHI: Outcomes after Stopping CEE

� Follow-up after treatment with CEE– CEE use median 5.9 years

– Mean follow-up 10.7 years

� No increase or decrease in CHD, DVT, stroke, hip fracture, CRC or total mortality

� Decreased risk of breast cancer continued» LaCroix, JAMA 2011

Adherent Participants In WHI: Invasive Breast Cancers In E Alone Study

LaCroix, JAMA, 2011

23% reduction in BCover 11 years with 6 years of CEE in womenwithout a uterus.

WHI OUTCOMES (E +P)

� Recently updated from all WHI studies

� Treat 10,000 women for a year– 9 strokes

– 9 P.E.s

– 12 DVTs

– 8 invasive breast cancers

– 5 more lung cancer deaths

– 6 fewer hip fractures

– 46 fewer fractures

– 22 cases of dementia

– 20 cases of gall bladder disease

– 872 cases or urinary incontinence– Nelson et al. Ann Intern Med 2012:157:104-113

WHI Outcomes (E alone)

� Recently updated from all WHI studies

� Treat 10,000 women for a year– 56 fewer fractures

– 8 fewer invasive breast cancers

– 2 fewer deaths

– 11 more strokes

– 7 more DVTs

– 33 more cases of gallbaldder disease

– 1,271 more cases of urinary incontinence

– Nelson et al. Ann Inern Med 2012: 157:104-113.

CLINICAL QUESTIONS

� What about other estrogen/progestin combinations?

� What about younger women?– Does it matter when you start HT?

� What about symptomatic treatment?

Transdermal Estrogen

� Transdermal estrogen avoids hepatic first pass metabolism

� Transdermal estrogen may be associated with a lower risk of VTE

• Canonico, 2007

� Transdermal estrogen associated with a lower risk of stroke

• Renoux BMJ 2010

Age at Initiation: Background

� RCTs and observational studies have found differing results of the effect of HT on CHD

� Observational studies have generally shown benefit

– Women in observational studies are generally younger and started HT closer to the time of menopause

� Mean age of women in the WHI was 63

Hormone Therapy inYounger Women

� Secondary analysis of WHI data

� Combined the women who received E plus P with the women who received E alone

� Risk for CHD with HT increased with increasing time since menopause

– < 10 years: 0.76 (0.50, 1.16)

– 10-19 years: 1.10 (0.84, 1.45)

– 20 or more years 1.28 (1.03, 1.58)

» P for trend=0.02 • Roussow JAMA 2007

Hormone Therapy in Younger Women

� Hormone therapy increased risk of stroke regardless of age or years since menopause

» HR 1.32 (1.12, 1.56)

� Non-significant trend for the effects of hormone therapy on total mortality to be more favorable in younger women

Estrogen Alone: Results by Age at Enrollment

Statistically significant age interactions (greater safety and benefit for younger women, potential harm among older women) were shown for: CHD, total MI, colorectal CA,

total mortality and the global index.La Croix et al. JAMA 2011

Take home message

� Statistically significant age interactions for CEE group– greater safety and benefit for women in 50s

– potential harm among older women

� Timing of HT initiation relative to age or menopause onset may influence CHD risk– Less underlying atherosclerosis in younger women?

� Clinicians should counsel women differently based on age and hysterectomy status

– Unlikely to change current recommendations for HT use

Danish Osteoporosis Study: CV Outcomes

� 1006 healthy recently menopausal women aged 45-58

� Open-label randomization to triphasicestradiol/norethisterone or placebo (hysterectomy: treatment with estradiol alone) for 10 years

� Outcomes: • Composite outcome of death or admission

for myocardial infarction or heart failure

• Individual components of primary endpoint, admission for stroke

Schierbeck et al. BMJ 2012; 345:e6409.

Results

WHI: mean age 63

WHI: 13% with increased lipids

WHI: 4% with DM

WHI: 36% with HTN

Primary endpoint and mortality for hormone replacement therapy

Schierbeck L L et al. BMJ 2012;345:bmj.e6409

Take Home Messages

� The findings from this study substantiate the “timing theory” but…

– Different type and dose of estrogen used

– Underpowered to determine effect of Estrogen monotherapy

– Unclear if primary composite outcome was prespecified

� Minimal risk associated with therapy but…– Likely underpowered to detect differences in DVT/PE, CVA, and possibly

breast CA

� Overall: reassured about using HT in symptomatic healthy menopausal women, but would not prescribe for primary prevention

Menopausal Symptoms

Menopausal Symptoms: Prevalence

� Hot flushes (50% or more)» Often with perspiration

� Night sweats (50% or more)

� Sleep disturbance (40-60%)

OTHER SYMPTOMS

� Other symptoms happen at the time of menopause but are less clearly related to menopause

– Mood changes

– Cognition

– Changes in sexual function

– Urinary complaints

Treatment of Menopausal Symptoms

What do you most commonly recommend for the treatment of severe

vasomotor symptoms?

� Estrogen

� SSRI

� Venlafaxine

� Clonidine

� Gabapentin

� Lifestyle changes and/or complementary therapy

HT for Symptomatic Relief

� Any form of estrogen is highly effective

� Generally can be taken for a few years and gradually stopped

� A progestin should be added for women with a uterus

� Therapy can be tailored to a woman’s preference

� Decision should be made SEPARATELY from decision for disease prevention

Effective Dose Equivalents

� Dose that stops hot flashes in 80% of women

– 1 mg micronized 17 beta estradiol

– 50mcg/day transdermal 17 beta-estradiol

– 0.625 mg conjugated equine estrogens

– 1.25 mg piperazine estrone sulfate

Lower dose hormone therapy

� Lower doses have been effective in some trials

� Estimates of efficacy after 12 weeks– 38% placebo– 63% low dose estrogen– 83% standard dose estrogen

� Lower doses may take longer for maximal symptom relief

– 12 weeks vs 4-8 weeks

� Less bleeding and breast tenderness and may require less progestin

» Ettinger, Am J Med 2005

QUESTION

� Estee Jenn is a 60 year old woman who has been on HT for 10 years. You have been trying to encourage her to stop it for a while but she has not wanted to do it. Her best friend has recently developed breast cancer; she has now decided to stop, and wants your advice on the best way to do it. What do you recommend?

QUESTION

� Taper by decreasing the daily dose over 6-12 months

� Taper by decreasing the number of days a week HT is used over 6-12 months

� Just stop

Discontinuing hormone therapy

� Symptoms will recur in up to 25% of women with stopping therapy

� Unclear if it is best to stop “cold turkey” or to taper

� Taper can be by daily dose or number of days per week

� Taper until mild symptoms– Maintain that dose until symptoms resolve

Progestins

� Concern about VTE and breast cancer risk

� High doses

� Oral megestrol (20-80 mg) has shown efficacy– Some weight gain

• Goodwin J Clin Oncology 2008

� High dose depo-MPA (400 mg) is also effective

– Compared with venlafaxine• Loprinzi J Clin Oncol 2006

QUESTION

� Estee has a resumption of her hot flashes after she stops her estrogen. What pharmacologic alternative do you suggest?

– Paroxitene

– Escitalopram

– Venlafaxine

– Clonidine

– Gabapentin

OTHER DRUG TREATMENTS

� SSRIs

� Venlafaxine

� Desvenlafaxine

� Clonidine

� 50-67% reduction in hot flash frequency with these regimens

� Placebo effects generally large– Generally less than estrogen

Paroxitene

� Paroxitene CR led to a significant decrease in hot flash score

– 62% in 12.5 mg group

– 65% in 25 mg group

– 38% in placebo group

� Avoid in women receiving tamoxifen– Decreases active metabolite of tamoxifen

– Cytochrome P450 CYP2D6

Escitalopram

� Recent study of the efficacy of escitalopram

� Reduction in hot flash frequency– 55% in escitalopram group

– 36% in placebo group

� Effective in African American and Caucasian women

� Effective regardless of coexisting anxiety or depression

» Freeman, JAMA 2011

Venlafaxine

� Significant reduction in hot flashes– 61% vs 27% in placebo (p<0.01)

� 150 mg no more effective than 75 mg• Lopinzi, Lancet 2000

Desvenlafaxine

� Industry sponsored trial of metabolite of venlafaxine

� 700 women with severe hot flashes

� 64% reduction in hot flashes at 12 weeks– Vs 51% with placebo

� Hot flashes less severe in desvenlafaxinegroup

� Not currently FDA approved for this indication

• Speroff, 2008

Clonidine and Gabapentin

� Clonidine– Start with 0.1 mg/day transdermal patch

– 40% reduction in hot flashes

– Side effects can be limiting

� Gabapentin– 45% reduction in hot flashes vs placebo (29%)

– 900 mg a day more effective than placebo

– 300-600 mg at bedtime may help with hot flashes that awaken patients from sleep

Alternatives for treatment of hot flushes

Treatment Dosage (mg/day)

Efficacy (vsplacebo)

Estrogen 0.625 CEE 80% vs 20-30%

Paroxitene 12.5 or 25 62% vs 38%

Escitalopram 10 to 20 55% vs 36%

Venlafaxine 37.5 37% vs 27%

Venlafaxine 75 or 150 61% vs 27%

Desvenlafaxine 100 64% vs 51%

Clonidine 0.1 38% vs 20%

Question

� Estee is tired of medications and would like to try an herbal therapy for treatment of her hot flashes. What treatment do you recommend?

� Evening primrose

� Ginseng

� Dietary soy

� Wild yam

� None of the above

Background

� Soy products have been proposed to provide comparable benefits to estrogen for treating menopausal symptoms, without the risks

� Epidemiologic studies on Asian women suggest that soy-containing foods are of benefit to the skeleton

– Limited by short duration, low dose of soy isoflavones, few participants

� Rapid bone loss occurs during the first 2 years of menopause

SPARE Study: Soy isoflavones

� SPARE study (Soy Phytoestrogens As Replacement Estrogen) – parallel group, placebo controlled, double blind trial

� 248 women (early menopause) were randomly assigned to receive 200mg soy isoflavones or placebo

� Measures:– BMD change– Menopausal symptoms – Vaginal Maturation– Lipids and thyrotropin– Assessed at baseline, 12 mo, & 24 mo

Results

� No significant differences between soy and placebo group:

– Spinal BMD

– Total hip BMD

– Femoral neck BMD

– NTx (N-telopeptide type I bone collagen)

� Subgroup analyses by: race, BMI, estradiol, 25-OH Vit D– Women with low 25-OH vit D at baseline – soy group had lower decrease

in spinal BMD than placebo

� Rate of hot flashes actually increased in soy isoflavone group

– (48% vs 32%: p=0.02)

Summary Of Herbal Evidence

� Evidence: no benefit– Red Clover

– Dong quai

– Ginseng

– Evening primrose

– Wild yam

– Vitamin E

– Acupuncture

� Evidence mixed

– Soy

– Black cohosh

� No data

– Chasteberry

– Licorice

Lifestyle and Complementary Modalities

� Cooling body temperature

� Exercise

� Avoiding hot and spicy foods

� Relaxing therapies– Yoga, massage, mediation, slow breathing, baths

� Mind-body therapies– Relaxation, biofeedback, paced respiration, hypnosis

• NAMS

� Some evidence that weight loss is beneficial

Hot Flash: Self Help - Be Cool!

� Keep house cool

� Avoid caffeine, alcohol, spicy foods, hot drinks

� Dress in layers, cotton

� Light bed linens

� Use fan, cool drinks

� Exercise

Relaxation

� Relaxation therapy– 73% reduction HF

� Diaphragmatic breathing– Simple deep breathing when sense HF

– > 50% reduction HF

Wijma, 1997Freedman 1995

Guidelines for Hormone Therapy Use

Recommendations

� USPSTF: Harmful effects are likely to exceed the chronic disease prevention benefits in most women

� ACOG, AHA, and Canadian Task Force recommend against use of HT for prevention of chronic disease

� NAMS 2012: When alternative therapies not appropriate, extended use of HT appropriate for women at high risk of fracture

NAMS 2012 Recommendations

� Focuses on emerging differences between ET and EPT as varying ages and time intervals since menopause

� Individualization in decision to use HT :consider individual health, personal risk factors and quality of life priorities

� ET has a more favorable risk benefit profile which allows for more flexibility in duration of use

� EPT associated with an increased risk of breast cancer incidence and mortality after 3-5 years

� Premature menopause: HT until median age of natural menopause and then reassess

– Menopause 2012:257-71

Summary

� Average duration of menopausal symptoms is approximately 4 years but seems to be longer in younger women

� Estrogen either alone or with a progestin is not recommended for chronic disease prevention in postmenopausal women

� Risks and benefits may differ in older and younger women

Summary

� Estrogen works best for menopausal symptoms

– Use lowest dose for shortest duration

� Best method for discontinuation is not known

� Start with lifestyle modifications and nonprescription remedies

� Other drug alternatives include venlafaxine, desvenlafaxine, paroxitene, escitalopram, gabapentin, and clonidine

Questions?

Feminine Forever

Documents

Transcript of Feminine Forever