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Update on Hormone Therapy: Evidence-Based Approaches

HT’s risks and benefits vary, based on timing, menopausal symptom severity, and underlying risks for CVD and breast cancer.

Concepts about the risks and benefits of hormone therapy have changed dramatically during the past decade. Results from the Women’s Health Initiative (WHI), a trial that involved more than 27,000 postmenopausal women (age range, 50–79) who were followed for an average of 5 to 7 years, revealed an overall unfavorable risk-benefit ratio in the estrogen-progestin arm and an excess risk for stroke that was not offset by a lower risk for coronary heart disease (CHD) in the estrogen-only arm (JW Womens Health Aug 7 2002 and JW Womens Health May 2 2006).1,2 Based on these results, HT is indicated for treatment of moderate-to-severe menopausal symptoms, and its use for prevention of chronic disease is no longer recommended. However, many questions remain about use of HT among women who are near menopause.

Individual experiences of menopause, as well as the type and severity of symptoms that occur, vary widely. For women with mild symptoms, no pharmacologic therapy is warranted. However, some women have bothersome and disruptive vasomotor symptoms (often interrupting sleep), vulvovaginal symptoms, and other symptoms affecting quality of life. Each woman’s risk-benefit ratio, as well as her personal preference regarding treatment, should be considered. Relevant factors include the patient’s age, time since onset of menopause, type of menopause (i.e., surgical, natural, or other causes), severity of menopausal symptoms, and underlying risk for diseases such as cardiovascular disease (CVD), cancer, and osteoporosis. Potential side effects, particularly vaginal bleeding associated with use of combined estrogen-progestin formulations, should be discussed when considering HT. Contraindications to HT include liver disease and history of deep venous thrombosis, pulmonary embolism, uterine or breast cancer, stroke, and heart disease.

TREATMENT OF MENOPAUSAL SYMPTOMS

Vasomotor symptoms are the most common menopausal complaint; however, symptom intensity, duration, frequency, and effects on quality of life are highly variable. Estrogens effectively reduce the frequency and severity of vasomotor flushing (hot flashes) by 75% to 80%.3 A recent systematic review revealed no substantial differences in efficacy between routes of administration or formulations of estrogen.4 For women who prefer to avoid hormone exposure or who have other contraindications to HT, less-effective alternatives include certain antidepressants (venlafaxine, fluoxetine, and paroxetine), gabapentin, and clonidine. Soy-based products and phytoestrogens also might have some effect for mild-to-moderate symptoms.

For isolated vulvovaginal symptoms such as vaginal dryness, itching, and dyspareunia, intravaginal creams, pills, or devices that deliver estrogen locally are often very effective and entail low systemic exposure to estrogens.

HT DOSE

The publication of the WHI results has elicited a shift toward lower daily doses of HT: 0.3-mg oral conjugated estrogens, 0.25- to 0.5-mg oral micronized 17β-estradiol, or 0.025-mg transdermal estradiol patch. Compared with prior "standard-dose" therapy, these provide nearly equivalent relief of vasomotor and vulvovaginal symptoms.5 Lower-dose preparations are anticipated to have more favorable risk-benefit ratios, although this has not yet been proven in trials.

TIMING OF INITIATION

Because the WHI trials were designed to assess HT’s risk-benefit profile for primary prevention of chronic disease, participants had a mean age of 63 and were more than a decade past menopause. Therefore, relatively few women had experienced menopause fewer than 5 years before randomization; however, these younger postmenopausal women are the most likely to initiate HT for treatment of symptoms and have the lowest absolute rates of adverse clinical events. The WHI results showed no increased risk for CHD6,7 or total mortality (JW Womens Health May 3 2007)8 associated with HT in women who were ≤10 years past menopause. Also, results of a recent study of younger WHI participants (age range, 50–59) showed that coronary-artery calcified plaque burden, a marker of CHD risk, was lower in women who received active estrogen than in those who received placebo (JW Womens Health Jun 21 2007).9

DURATION OF USE

In determining HT’s risk-benefit ratio, duration of use is critical. Short-term use (<5 years) for relief of symptoms near the time of menopause — when absolute CVD risk is relatively low — likely is associated with low risk. For women with higher absolute risk for CVD (based on Framingham risk score and overall number of risk factors) or breast cancer, more caution in prescribing HT should be exercised.

With long-term use (≥5 years) of combined estrogen-progestin therapy, risk for breast cancer increases. Unless a woman has continued, severe menopausal symptoms or other conditions, such as osteoporosis, that might be ameliorated by HT, risks generally will outweigh benefits of long-term combined HT. Moreover, benefits to bone health dissipate rapidly after HT discontinuation (JW Womens Health Mar 4 2008).10

OTHER AREAS OF UNCERTAINTY

Transdermal estrogen preparations have less effect on coagulation factors, raising the attractive possibility that such preparations might not be associated with excess risk for venous thromboembolism; however, large-scale clinical trials have not yielded outcomes data. Transdermal estrogen also might not significantly affect levels of triglycerides, inflammation markers, and sex–hormone-binding globulin.

Whether some progestin preparations have advantages over others is unknown. The optimal pattern of progestin use also is uncertain, but cyclic progestin might result in lower total exposure than does daily dosing. Additionally, very little data exist on preparations that include androgens such as testosterone. "Bioidentical" hormones that are individually compounded according to a clinician’s prescription have risen in popularity; however, no evidence shows that they are safer or more effective than traditional hormones, and batch-to-batch variation can be substantial.

Different estrogens and progestins have distinct biological properties, so care should be taken before extrapolating results from one preparation or dose to another. Overall, a cautious approach dictates that adverse effects that are observed for one agent in a class should be assumed for others unless proven otherwise.

CLINICAL RECOMMENDATIONS

In the face of such uncertainty about HT use, what should clinicians do?

  • Evaluate menopausal symptom severity.
  • Evaluate underlying risks for CVD and breast cancer.
  • Discuss risks and benefits of HT (as well as alternatives) with the patient, and assess the patient’s personal preferences.
  • Minimize estrogen dose.
  • Prescribe HT for the shortest duration necessary to achieve treatment goals, preferably <5 years.

In conclusion, short-term HT can benefit women who have moderate-to-severe menopausal symptoms but should not be used for chronic disease prevention.

— Kathryn M. Rexrode, MD, MPH, and JoAnn Manson, MD, DrPH

Dr. Rexrode is Assistant Professor of Medicine, Division of Preventive Medicine, Harvard Medical School; Associate Physician, Brigham and Women’s Hospital; and a WHI investigator. Dr. Manson is Professor of Medicine and Chief, Division of Preventive Medicine, Harvard Medical School, Brigham and Women’s Hospital; and a WHI principal investigator.

Published in Journal Watch Women's Health July 31, 2008

Citation(s):

1. Rossouw JE et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: Principal results from the Women’s Health Initiative randomized controlled trial. JAMA 2002 Jul 17; 288:321.

2. Anderson GL et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: The Women’s Health Initiative randomized controlled trial. JAMA 2004 Apr 14; 291:1701.

3. MacLennan AH et al. Oral oestrogen and combined oestrogen/progestogen therapy versus placebo for hot flushes. Cochrane Database Syst Rev 2004 Oct 18. (http://dx.doi.org/10.1002/14651858.CD002978.pub2)

4. Nelson HD. Commonly used types of postmenopausal estrogen for treatment of hot flashes: Scientific review. JAMA 2004 Apr 7; 291:1610.

5. North American Menopause Society. Estrogen and progestogen use in peri- and postmenopausal women: March 2007 position statement of The North American Menopause Society. Menopause 2007 Mar/Apr; 14:168.

6. Manson JE et al. Estrogen plus progestin and the risk of coronary heart disease. N Engl J Med 2003 Aug 7; 349:523.

7. Hsia J et al. Conjugated equine estrogens and coronary heart disease: The Women’s Health Initiative. Arch Intern Med 2006 Feb 13; 166:357. [Erratum in: Arch Intern Med 2006 Apr 10; 166:759.]

8. Rossouw JE et al. Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause. JAMA 2007 Apr 4; 297:1465. [Erratum in: JAMA 2008 Mar 26; 299:1426.]

9. Manson JE et al. Estrogen therapy and coronary-artery calcification. N Engl J Med 2007 Jun 21; 356:2591.

10. Heiss G et al. Health risks and benefits 3 years after stopping randomized treatment with estrogen and progestin. JAMA 2008 Mar 5; 299:1036.

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