ISSUES IN WOMEN'S HEALTH
| RECENT FINDINGS AND RECOMMENDATIONS —Judith M. Walsh, MD, MPH, Associate Professor of Clinical Medicine,
Women’s Health Clinical Research Center, University of California, San Francisco, School of Medicine
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Cardiovascular Disease (CVD) Prevention
| Low-dose aspirin study: randomized controlled trial (RCT) of ≈40,000 healthy women who took aspirin every other day;
followed for 10 yr; average age 54 yr; 87% nonsmokers; 26% with hypertension; 30% with hyperlipidemia; 10-yr risk of
coronary heart disease (CHD) <5%; results—no reduction in major cardiovascular (CV) events; reduction in stroke risk
(ischemic stroke); no reduction in hemorrhagic stroke; no reduction in myocardial infarction (MI); increased risk of gastrointestinal
(GI) bleeding requiring transfusion; subgroup analysis—in women >65 yr of age, significant reduction in
major CV events, ischemic stroke, and MI; greater benefit in former smokers and those who never smoked;
conclusion—in healthy women, aspirin associated with reduction in stroke, but not in major CV events; greater benefit
in women ≥65 yr of age (at higher risk)
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| Meta-analysis with women and men: assessed previous aspirin studies that included women; men—32% reduction in MI
risk; nonsignificant increase in stroke; women—19% reduction in stroke; no reduction in MI; conclusion—aspirin not
associated with reduced MI or CV death in healthy women; aspirin associated with reduction in MI in men (men in study
at higher risk); more benefits in women >65 yr of age
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| Recommendations: United States Preventive Services Task Force (USPSTF)—aspirin for men and women with 10-yr
risk of CHD >6%; American Heart Association—aspirin for men and women with 10-yr risk >10%; more complex in
women (no reduction in MI or CVD death); conclusion—consider overall CHD risk and other risk factors in making decision
about recommending aspirin
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Osteoporosis
| Background: treating women with osteoporosis reduces risk of hip fracture; criteria for screening based on ability to reduce
risk of outcome in question; no study has shown screening reduces risk of hip fracture
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| Current screening recommendations: National Osteoporosis Foundation—all women ≥65 yr of age; women 50 to 64
yr of age with additional risk factors; USPSTF—all women ≥65 yr of age (although evidence indirect); National Institutes
of Health (NIH)—insufficient evidence to recommend screening
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| Osteoporosis screening study: to determine whether population screening associated with fewer fractures than usual care;
not RCT; nonconcurrent cohort study; controlled for some potential confounders, eg, physical activity, history of fracture,
estrogen therapy; for elderly women at high risk for falls, study created “frailty index” to estimate level of risk (unintentional
weight loss; weakness; self-reported exhaustion; slow walking speed; low physical activity); ≈1300 women tested
for bone density; 1600 received usual care; followed for ≈5 yr; results—fewer fractures in screened group (4.8 per 1000
person years vs 8.2); relative hazard of hip fracture significantly lower in screened group; results similar for women and
men; limitations—not RCT; unmeasured confounders; wrist and vertebral fractures not included; conclusions—first
study to show screening linked to reduced hip fracture; may affect guideline development, especially for men
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Hormone Replacement Therapy (HRT)
| Background: Women’s Health Initiative (WHI) found women who took estrogen-progestin combination had increase in
heart disease, stroke, cognitive decline, breast cancer, thrombolic events, as well as decrease in osteoporotic fractures and
colorectal cancer; overall global index consistent with harm (not benefit); continuation of WHI—because evidence of
early harm lacking, estrogen-only arm continued beyond 2002
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| Estrogen-alone study: >10,000 women who had hysterectomy followed for average of 6.8 yr; results—no reduction in
colon cancer (reduced in estrogen-progestin arm); nonsignificant increase in pulmonary embolism (significant increase in
other arm); reduced risk of fracture (present in both arms); trend toward reduction in breast cancer (increased in estrogen-
progestin arm); global index not consistent with harm (unlike other arm); impact for 10,000 person years—12 additional
strokes; 6 fewer fractures; no reduction in CHD (early harm may be less); trend toward reduced breast cancer needs
more study
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| Questions unanswered by WHI: what about other estrogen-progestin combinations? (besides conjugated equine estrogen
0.625 mg/day with progestin 2.5 mg/day); what about younger women? (average age of women in WHI ≈64 yr); what
about symptomatic treatment? (women with menopausal symptoms unlikely to enroll in WHI and risk getting placebo)
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| Ultra-low dose estrogen: thought to be safe alternative by some patients and physicians; study of safety and efficacy in
preventing bone loss—RCT of ultra-low dose transdermal estradiol (0.14 mg/day; ≈25% of usual dose); involved 417
women (mean age 67 yr); results—2.6% increase in bone mineral density (BMD) at 2 yr; nonsignificant incidence of
endometrial hyperplasia; conclusion—ultra-low-dose estrogen increased BMD without increasing endometrial hyperplasia;
fracture data absent (need evidence of reduced risk of fractures); may be useful for preventing osteoporosis in
older women; possibility that rise in circulating estradiol increases risk of breast cancer requires larger, longer studies
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Selective Estrogen Receptor Modulators (SERMS)
| Background: “designer estrogens” intended to maximize positive and minimize negative effects of estrogen; tamoxifen—
reduces risk of recurrence of breast cancer; prevents breast cancer in high-risk women; side effects include thromboembolic
events and uterine cancer; raloxifene—newer drug; Multiple Outcomes of Raloxifene (MORE) study showed raloxifene
reduces fracture risk in women with osteoporosis (no effect on hip fracture); may reduce risk for breast cancer
(study promising but inconclusive)
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| Raloxifene study: Continuing Outcomes Relevant to Evista (CORE) study extended MORE study; women given 60 mg/
day of raloxifene for additional 4 yr; results—reduction in total breast cancer (hazard ratio [HR] 0.34; 66% reduction)
and estrogen receptor (ER)–positive breast cancer (HR 0.24); risk of thromboembolic events persisted over 8 yr (at odds
with suggestion that risk decreases after early rise during HRT and SERM therapy); no increased risk for endometrial
cancer (in contrast to tamoxifen); comments—magnitude of breast cancer reduction persisted during additional 4 yr; not
all trial participants continued (selection bias possible); longest trial of exposure to raloxifene; while some estrogen risk
seems to be diminishing, thromboembolic risk persists
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| USPSTF recommendations: tamoxifen or raloxifene not recommended for breast cancer prevention in women at low risk;
discuss therapy with women at high risk
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Cancer Screening: Public Expectations
| Enthusiasm for cancer screening: survey of 500 men and women with no history of cancer; 87% believe routine screening
almost always good; <33% believe they will ever stop screening; 66% would be tested even if nothing could be done;
75% said they would rather have total body computed tomography (CT) than $1000
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Breast Cancer Screening
| Background: mammography—shown to reduce mortality; reduction not seen in women 40 to 49 yr of age; less sensitive
in dense breast tissue of younger women; women at high risk—disease in women with BRCA1 and BRCA2 mutations
or significant family history often diagnosed at young age; fast growing tumors can develop between screenings; atypical
mammography changes in women with BRCA mutations
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| Magnetic resonance imaging (MRI): evaluated in high-risk women by 2 studies; currently used as diagnostic tool in
women with breast cancer; not affected by breast density; specificity variable; expensive; study in BRCA carriers—
assessed test sensitivity and specificity; 236 women evaluated with MRI, ultrasonography, and mammography annually,
with clinical breast examination every 6 mo; results—22 cancers detected, 6 ductal carcinoma in situ (DCIS); sensitivity
95% for 4 tests combined vs 45% for mammography and clinical breast examination alone; sensitivity—MRI highest,
77%; mammography, 36%; clinical breast examination, 9%; specificity—MRI least specific, 95%; specificity high for
both mammography, 99.8% and clinical breast examination, 99%; second study—in women with lifetime risk of ≥15%
(BRCA and other familial risks); screened annually with MRI and mammography, every 6 mo with breast examination;
sensitivity and specificity similar in both studies; fewer positive axillary nodes and micrometastases in MRI group; impact
on clinical practice—MRI screening may be useful in high-risk women, but effect of screening on mortality unknown;
not currently recommended in average-risk women
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Cervical Cancer Screening
| Current screening recommendations: USPSTF—in all women who are or have ever been sexually active and have cervix;
begin screening at onset of sexual activity; repeat at least every 3 yr; can stop in women >65 yr of age in whom previous
Papanicolaou (Pap) tests consistently normal and not at high risk; American Cancer Society—start within 3 yr of
onset of vaginal intercourse (allows time required for abnormality to develop); can stop in women >70 yr of age with ≥3
normal Pap tests and no abnormal tests in previous 10 yr
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| Unnecessary screening common: survey of >16,000 women with no history of cancer found 55% of women without history
of abnormal Pap tests undergo annual screening; 38% of women 75 to 84 yr of age and 20% >85 yr of age continue
annual screening; increased risk of vaginal cancer in women who had ovarian cancer sole reason for screening in absence
of cervix (vaginal cancer rare; <250 deaths per year; no evidence screening effective); in 2002, 69% of women ≥18 yr of
age screened within past 3 yr (same percentage as 1992, before recommendation changed); in response to previous public
health campaigns, women remain committed to annual screening; change in recommendation has not taken hold; belief
that cost is basis of current screening recommendations strongest predictor of reluctance to reduce frequency of screening
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| REVIEW OF CURRENT MANAGEMENT STRATEGIES —Dr. Walsh
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Ovarian Cancer Screening
| Should women be screened? benefit of screening dubious in rare disease with lifetime risk of 1.2%; while survival rate
much higher when limited to ovaries, ability to detect such disease doubtful; risk factors—advancing age; nulliparity;
North American or European descent; history of endometrial, colon, or breast cancer; family history of ovarian cancer;
possibly use of fertility drugs; protective factors—>1 full-term pregnancy; breast-feeding; oral contraceptive use
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| Approach to screening: techniques—serum CA 125 assay; transvaginal ultrasonography; serum CA 125 plus ultrasonography;
clinical trial—involved 22,000 women in United Kingdom; screened annually for 3 yr, with 7-yr follow-up;
screening (CA 125 assay; if elevated, ultrasonography; if abnormal, pelvic surgery); results—slight increase in mean
survival; no difference in mortality (reduced mortality justification for screening); conclusion—many women must be
screened to detect few cases (leads to unnecessary surgery in healthy women); increase in survival small (quality of life
unknown); utility of test in rare disease main issue (high sensitivity and specificity results in many false positives and subsequent
investigations)
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| What to do: NIH statement—no evidence screening reduces mortality; screening might increase morbidity and mortality;
women at high risk—women with ≥2 relatives with ovarian cancer should be referred to gynecologic oncologist for
counseling; greater chance of disease warrants recommendation for annual pelvic examination, CA 125 assay, and transvaginal
ultrasonography; primary prevention—oral contraceptives (may increase risk of breast cancer in women with
positive family history); pregnancy; breast-feeding
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Eating Disorders
| Definitions: anorexia nervosa—refusal to maintain ideal body weight; intense fear of weight gain; disturbance in body
image; absence of ≥3 consecutive menstrual cycles; bulimia nervosa—recurrent episodes of binge eating with lack of
control during episodes; compensatory behavior to prevent weight gain (self-induced vomiting; laxatives; diuretics; over-
the-counter diet pills; fasting; vigorous exercise); behavior occurs ≥2 times weekly for at least 3 mo; persistent overconcern
with body shape and weight
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| Epidemiology: 95% women; seen in all ethnic populations; bulimia more common than anorexia; anorexia—occurs in
≈1% of adolescent girls; risk factors for anorexia—middle to upper class woman; participation in activities valuing
thinness; family history of eating disorder; precipitated by stressful situation; highest mortality of any psychiatric disorder
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| Osteoporosis and anorexia: associated with hypothalamic hypogonadism (low follicle-stimulating hormone [FSH] and
luteinizing hormone [LH]; no circulating estrogen); low BMD (may not return to baseline after recovery); risk of fracture
7 times greater than age-matched women; physical activity has limited protective effects; treatment—oral contraceptives
or hormone therapy until resumption of normal menses; calcium supplements and multiple vitamins
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Contraception
| Oral contraceptives: combined estrogen-progestin effective and well tolerated by most women; generally safe up to time
of menopause (smokers at risk for thromboembolic events); progestin-only formations used in nursing mothers and
smokers (side effects include irregular bleeding and depression)
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| Intrauterine devices: provide option; although once thought unsafe in nulliparous women, recent study demonstrated their
safety; used extensively in other countries
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Educational Objectives
| The goal of this program is to educate the listener about common topics in women’s health. After hearing and assimilating
this program, the clinician will be better able to:
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 | 1. Select women likely to benefit from taking aspirin to prevent cardiovascular disease.
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| 2. Identify effective measures to lower the risk of fractures in women with osteoporosis.
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| 3. Counsel women considering hormone replacement therapy on implications of the latest findings.
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| 4. Employ recommended screening strategies for breast, cervical, and ovarian cancer.
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| 5. Recognize and manage eating disorders.
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Discussed on This Program
Aspirin (acetylsalicylic acid; ASA) [several trade names]
Raloxifene [Evista]
Tamoxifen citrate [Nolvadex]
Suggested Reading
Ettinger B et al: Effects of ultralow-dose transdermal estradiol on bone mineral density: a randomized clinical trial. Obstet
Gynecol 104:443, 2004; Gourlay ML et al: Clinical considerations in premenopausal osteoporosis. Arch Intern Med
164:603, 2004; Hewitt M et al: Cervical cancer screening among U.S. women: analyses of the 2000 National Health Interview
Survey. Prev Med 39:270, 2004; Jacobs IJ et al: Progress and challenges in screening for early detection of ovarian
cancer. Mol Cell Proteomics 3:355, 2004; Kern LM et al: Association between screening for osteoporosis and the incidence
of hip fracture. Ann Intern Med 142:173, 2005; Kriege M et al: Efficacy of MRI and mammography for breast-cancer
screening in women with a familial or genetic predisposition. N Engl J Med 351:427, 2004; Martino S et al:
Continuing outcomes relevant to Evista: breast cancer incidence in postmenopausal osteoporotic women in a randomized
trial of raloxifene. J Natl Cancer Inst 96:1751, 2004; NIH consensus conference: Ovarian cancer. Screening, treatment,
and follow-up. NIH Consensus Development Panel on Ovarian Cancer, 273:491, JAMA; Ridker PM et al: A randomized
trial of low-dose aspirin in the primary prevention of cardiovascular disease in women. N Engl J Med 352:1293, 2005;
Schwartz LM et al: Enthusiasm for cancer screening in the United States. JAMA 291:71, 2004; Sirovich BE et al: Cervical
cancer screening among women without a cervix. JAMA 291:2990, 2004; Walsh JM et al: Colorectal cancer screening:
clinical applications. JAMA 289:1297, 2003; Walsh JM et al: Drug treatment of hyperlipidemia in women. JAMA
291:2243, 2004; Walsh JM et al: Raloxifene and colorectal cancer. J Womens Health (Larchmt) 14:299, 2005; Warner E
et al: Surveillance of BRCA1 and BRCA2 mutation carriers with magnetic resonance imaging, ultrasound, mammography,
and clinical breast examination. JAMA 292:1317, 2004; Wilson GT et al: Eating disorders guidelines from NICE. Lancet
365:79, 2005.
Faculty Disclosure
In adherence to ACCME guidelines, the Audio-Digest Foundation requests all lecturers to disclose any significant financial
relationship with the manufacturer or provider of any commercial product or service discussed. For this issue, the faculty
member reported nothing to disclose.
Dr. Walsh was recorded at the 33rd Annual Advances in Internal Medicine, May 25-28, 2005, and the Internal Medicine
Board Certification Review, July 11-15, 2004, sponsored by the University of California, San Francisco, School of Medicine,
and held in San Francisco. The Audio-Digest Foundation thanks Dr. Walsh and the University of California, San Francisco,
School of Medicine for their cooperation in the production of this program.
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