Use of Combination Hormone Replacement Therapy

Introduction

Medscape Women's Health Editorial Board member Dr. Andrew M. Kaunitz, Professor and Assistant Chair at the University of Florida Health Science Center/Jacksonville and Co-Principal Investigator at the University of Florida's Jacksonville site of the WHI, discusses the implications of the WHI findings for physicians and their patients.

Women's healthcare providers should be prepared to field a barrage of questions from their patients with the July 9, 2002 announcement of findings concerning participants in the Women's Health Initiative (WHI) using combination (estrogen plus progestin) hormone replacement therapy (HRT).^[1]

In this large-scale, randomized, controlled clinical trial, 16,608 menopausal women who were 50-79 years of age and who had an intact uterus at the time of enrollment were randomized to receive either HRT in the form of 0.625 mg conjugated equine estrogens and 2.5 mg medroxyprogesterone acetate (Prempro) or placebo. Use of study medication (active or placebo) in this component of the trial was halted after 5.2 years, because researchers found that the therapy's risks outweighed its benefits. Compared with the placebo users, those assigned to the combination HRT group experienced more strokes, heart attacks, blood clots, and an increased risk of invasive breast cancer. Although the HRT users also experienced a reduced risk of colorectal cancer and fractures (including hip fractures), overall, the observed risks outweighed these benefits. It should be noted that the arm of the trial that is evaluating the risks and benefits of unopposed 0.625 conjugated equine estrogens (Premarin) in hysterectomized women is ongoing, with results expected in 2005.

The WHI findings provide definitive evidence that that use of the Prempro formulation of combination HRT increases breast cancer as well as cardiovascular disease events. Although the absolute risk of an adverse outcome for an individual woman is very small, the ramifications of the findings are significant. Most importantly, they are a call for clinicians and their menopausal and postmenopausal patients to reevaluate, on an individualized basis, why combination HRT has been prescribed and whether it makes sense for the particular patient, based on symptoms and risk factors, to continue therapy or consider alternatives.

Physicians should anticipate several clinical implications of these findings:

Unequivocal recognition that combination HRT is not indicated for treating or preventing cardiovascular disease. For those for whom HRT is appropriate -- menopausal women who experience moderate to severe vasomotor symptoms -- the duration of use will optimally be less than 5 years (recognizing that symptoms persist longer than 5 years in some women). However, no other therapy is as effective for vasomotor symptoms as HRT. Certain antidepressants (Effexor and Paxil) provide relief in some symptomatic women. Placebo-controlled trials of soy and black cohosh have not consistently found these agents to be useful.
There may be an increased emphasis on prescribing combination estrogen/progestin regimens that are formulated with progestins other than medroxyprogesterone acetate. Progestins used in such alternate oral combination HRT formulations include norethindrone acetate (Activella or femHrt) and norgestimate (Prefest). A transdermal combination HRT regimen formulated with norethindrone acetate (Combipatch) also is available.
Clinicians may also more frequently prescribe combination HRT regimens using lower doses of estrogens and progestins, such as conjugated equine estrogen (Premarin) or esterified estrogen (Menest), 0.3 mg; 17beta estradiol (Estrace), 0.5 mg; transdermal estradiol (Climara, Esclim, Vivelle), 0.025 mg or 0.0375 mg, with norethindrone (Micronor), 0.35 mg, or medroxyprogesterone acetate (Provera), 2.5 mg.
Combination regimens employing nontraditional approaches to progestin endometrial protection can also be considered. Continuous estrogen administration combined with cyclic progestin (eg, 2 weeks each every 2-3 months) provides almost as much endometrial protection as continuous administration. In addition, estrogen can be combined with use of the levonorgestrel IUD (Mirena), which prevents endometrial proliferation with minimal systemic progestin levels.
There will be a shift to prescribing nonhormonal therapies such as oral bisphosphonates (alendronate, Fosamax; risedronate, Actonel) and selective estrogen receptor modulators (raloxifene, Evista) for prevention of osteoporosis.
Finally, with recognition that combination HRT should not be prescribed to prevent or treat cardiovascular disease, use of traditional lipid-lowering therapy such as statins will likely increase.

Appropriate clinical responses to this new information include the following:

Affirmation of traditional measures to prevent cardiovascular disease (smoking cessation, regular exercise, treatment of hypertension, maintenance of appropriate weight, treatment of dyslipidemia)
Affirmation of traditional measures to prevent osteoporosis (adequate calcium and vitamin D intake, smoking cessation, regular weight-bearing exercise), assessing bone mineral density of the spine and femur
Increased focus on bisphosphonates and raloxifene and decreased use of HRT for treatment of low bone density in menopausal women with a uterus
Increased focus on use of lubricants for intercourse and use of vaginal estrogen such as tablets (Vagifem), ring (Estring), or creams (Estrace, Premarin, Ortho Dienestrol) and decreased use of systemic HRT for treatment of symptomatic genital atrophy
Appropriate breast surveillance for women aged 50 years and older, including annual mammography

It must be emphasized that the WHI findings do not apply to surgically menopausal women (for instance, a 42-year-old woman who has undergone bilateral oophorectomy) or to perimenopausal women (eg, a 47-year-old woman whose menses have become irregular and who is experiencing vasomotor symptoms). Estrogen replacement therapy, either estrogen alone or in combination with androgen (Estratest, Estratest HS), will continue to represent mainstay therapy for young surgically castrated women. For symptomatic perimenopausal women, hormonal management, including combination oral contraceptives (OCs) in healthy nonsmoking patients, will continue to be appropriate.

In addition, the WHI findings do not apply to OCs. Recent high-quality observational data (Women's Care Study) clarify that use of OCs does not increase breast cancer risk.^[2] This reassuring observation was noted regardless of duration and dosage of OC use, timing of use, age at use, or risk status of users (low risk or high risk on the basis of family history). Because combination OC use increases the risk of thromboembolism, OCs should not be prescribed to women at elevated risk for thrombosis, including those with a prior history of clot. In smokers, and presumably in others at increased risk for arterial vascular events (including diabetics or hypertensives with vascular disease or those with systemic lupus erythematosus), use of OCs increases the risk of myocardial infarction and stroke. Therefore, combination OCs are not appropriate for perimenopausal women who smoke or who are, for other reasons, at elevated risk for arterial vascular events.

It will be important in these next few weeks and months for physicians to consider the following:

Become familiar with the preventative and therapeutic strategies mentioned above.
Be prepared for a more intensive time-consuming dialogue with patients. Often this is better handled during a scheduled face-to-face office visit than during a rushed phone conversation.
Become comfortable guiding women as they go off HRT for several months to evaluate whether vasomotor and other symptoms such as insomnia and/or reduced memory return. It is not clear whether abruptly stopping HRT vs tapering off therapy (eg, reducing to every-other-day dosing for 2-4 weeks before discontinuing HRT) makes any clinical difference in this setting. Although the WHI findings apply only to women with an intact uterus using combination HRT, reevaluation of the pros and cons of hormone use will be appropriate for many hysterectomized women on estrogen replacement.

In closing, I see this new information from WHI as an opportunity for us to sit down with our patients to reevaluate their health issues related to menopause and come up with an individualized management plan. If the menopausal women in our practices view us as patient advocates, and not hormone advocates, they will place that much more trust in us as we help them make sound health decisions.

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