1. Put into practice lessons from the Women’s Health Initiative concerning hormone replacement therapy (HRT).

2. Focus on symptom relief in using HRT in postmenopausal women.

3. Consider the potential for cardioprotection when deciding whether to prescribe HRT.

4. Implement cervical cancer screening based on recent findings about the effectiveness of liquid-based cytology and the benefits of the human papillomavirus test.

5. Counsel women about the risks and benefits of oral contraceptives.

Hormone Replacement Therapy (HRT): Who Do You Dare Give it To?
Cynthia A. Stuenkel, MD, Clinical Professor of Medicine, University of California, San Diego, School of Medicine

Women’s Health Initiative (WHI): 2002 results indicated risks of HRT outweighed benefit; paradigm change— prevention out (for now); symptom relief in (if necessary)

Potential cardiac protection: some still think HRT protects heart; WHI estrogen-alone arm—found no increase or decrease in cardiac events overall

Subsequent analysis: considered woman’s age and time since menopause; evidence that younger women had better response; women 50 to 59 yr of age at baseline —evaluation of all cardiac end points found 30% to 40% reduction in cardiac events in young women on unopposed estrogen; coronary artery calcium scores—unopposed estrogen appeared to reduce amount of coronary calcium in 50- to 59-yr age group; investigators failed to look at women >60 yr of age for potential benefits

Combined therapy: adding progestin increased incidence of heart disease; increased risk seen in women >70 yr of age; younger women (<10 yr from menopause) had neither benefit nor increased risk

Major study: evaluated >25,000 women from unopposed-estrogen and combined-therapy arms; significant increase in heart disease limited to women >70 yr of age; increased risk for stroke appeared in women 60 to 70 yr of age; possible difference in total mortality between younger and older women

Advising patients: HRT (unopposed estrogen or combined) relatively safe; not ready to recommend HRT for prevention of heart disease

Other benefits: HRT still recommended by Food and Drug Administration (FDA) for women without uterus; primary indication for treating vasomotor symptoms (“lowest dose; shortest duration”); some women reported less joint pain and stiffness

Lower doses: most therapies available in ≈50% of dose used in WHI; “challenging the edge of the envelope with ‘how low can you go?’” under investigation—14-µg patch (25% WHI dose) effective in reducing symptoms (took longer to have effect); gels with estradiol levels of 8 to 10 pg/mL found effective; clinical application—start low or, if patient already on therapy, dial down dose

HRT contraindications: pregnancy; failure to use contraception; unexplained vaginal bleeding; history of stroke or myocardial infarction (MI) in past year, according to FDA (or any history, according to speaker); history of blood clots; active liver disease

Alternatives to HRT: none as effective as estrogen; selective serotonin reuptake inhibitors (SSRIs); selective serotonin-norepinephrine reuptake inhibitors (SSNRIs); gabapentin

Vaginal symptoms: second main FDA indication; use vaginal hormones; various options; do not confuse estradiol vaginal ring (Estring; very low levels of estrogen) with estradiol acetate vaginal ring (Femring; used vaginally for systemic therapy for vasomotor symptoms); larger doses may be required initially, but can be dialed down

Decreased bone mineral density (BMD): third FDA indication for HRT in women meeting requirements for osteoporosis therapy but unable to take bisphosphonates; small study found ultralow-dose estrogen patch (0.014 mg) increased BMD in women 60 to 80 yr of age

Bioidentical hormones: widely promoted as alternative to standard HRT; produced by compounding pharmacies; ingredients unknown; women not told of potential risks; American Medical Association (AMA) said term “bioidentical” should be restricted to FDA-approved products; inform patients that many FDA-approved HRT agents contain bioidentical hormones

How long to continue therapy: standard recommendation ≈5 yr; risk for breast cancer underlies concerns; risk depends on type of HRT (unopposed estrogen or combined) and length of therapy; unopposed estrogen study found no increased risk for breast cancer after 7 yr (women adherent to therapy had reduction in ductal cancer); Harvard Nurses Study (observational, not clinical trial) found increased risk after 15 to 20 yr; unopposed estrogen seems to confer longer window of safety than combined therapy

Discontinuation of HRT: WHI results indicated stopping HRT decreases risk for estrogen-positive cancer

WHI 3-yr follow-up of combined therapy arm after stopping HRT

Fracture risk: women who took hormones had same fracture risk as women who never used hormones; recommendation—after stopping HRT, either follow BMD or start another antiresorptive agent

Cardiovascular risk: no increased risk for stroke, MI, or blood clots found

Cancer risk: incidence of all cancers—significantly increased (≈24%); however, absolute risk 1.56% in combined therapy group vs 1.26% in placebo group; ≈30 cases per 10,000 women per year; breast cancer— increase nonsignificant; colon cancer—benefit lost; lung cancer—18 cases; increase unexplained; surveillance—required after stopping therapy; annual mammography; no evidence for chest x-rays

When to discontinue therapy: begin discussion after 5 yr of therapy; some experts advise annual discussions; more difficult to stop HRT if started after hysterectomy or for symptom relief (as opposed to disease prevention) and in women on HRT >10 yr; symptoms peak 8 to 12 wk after discontinuation; to allow women to discover intensity of symptoms, wait ≈2 mo before introducing new therapy that may produce symptoms; after discontinuation, WHI found ≈50% of women had vasomotor symptoms (including those without symptoms before starting therapy); for women wanting more control—small sections of patches can be trimmed weekly; may prolong withdrawal for ≤ 1 yr

Questions and answers: androgen therapy—transdermal system not approved by FDA; useful in women who had ovaries removed at young age; in studies, benefits in postmenopausal women unimpressive; HRT for prevention of dementia—may be useful in younger women; WHI found dementia worsened by HRT in women ≥65 yr of age (perhaps due to increased stroke risk); migraine—when accompanied by neurologic manifestations (eg, aura), migraine increases baseline risk for stroke; WHI showed increased risk for stroke with HRT; if HRT used in patient with migraines, speaker suggests very low-dose transdermal system and careful follow-up for change in migraines; definition of bioidentical hormone—hormone documented to have same structure as endogenous hormones and FDA-approved; avoiding systemic progestins—small trials found benefit in using at 3-mo and 6-mo intervals (not FDA-approved); if choosing similar approach, inform patient of problems, and at some point examine endometrium for hyperplasia; stopping HRT in woman with surgical menopause at young age—reasonable to continue estrogen until age of menopause

Recent Developments in Women’s Health
Judith M.E. Walsh, MD, MPH, Professor of Clinical Medicine, Women’s Health Clinical Research Center, University of California, San Francisco, School of Medicine

Human papillomavirus (HPV) causative agent

HSIL significant precancerous lesion

LSIL much more benign: ≈66% of LSIL regresses spontaneously; regression rates lower in older women

Many HPV infections regress spontaneously; regression rates higher in younger women

Speaker’s question: in response to natural history; “how hard should we look for these things, many of which are going to get better on their own?”

HPV test characteristics: more sensitive than conventional cytology but less specific; higher false-positive rate leads to unnecessary tests and procedures

Potential harms of HPV testing: more false positives and increased testing; increased anxiety; potential stigma and labeling; partner discord; potential undermining of cytologic screening (proven effective); extra cost

Potential benefits: decreased frequency of screening, ie, women with negative Pap tests and negative HPV tests can be screened less often; however, screening frequency already reduced in women with several normal Pap tests

Recommendations on HPV testing: American Cancer Society—consider in women ≥30 yr of age, combined with conventional or liquid-based cytology (not more often than every 3 yr); women negative for HPV screened less often; suggestion—in women who have normal Pap test but who carry high-risk HPV type, repeat screening tests in 1 yr and perform colposcopy if either test abnormal; United States Preventive Services Task Force—evidence insufficient to recommend for or against routine use of HPV test for primary screening