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Clinical Reviews

HRT: 4 experts chart a new course

To clarify the issues raised by the Women’s Health Initiative, OBG Management asked 4 experts the inevitable: Now what? Here, the physicians discuss the findings and detail how this will affect the way they—and you—treat menopausal women.

September 2002 · Vol. 14, No. 9
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Our expert commentators

Lorraine Fitzpatrick, MD, is professor of endocrinology and medicine and director of the Women’s Health Fellowship, Mayo Hospital and Mayo Foundation, Rochester, Minn.

Andrew M. Kaunitz, MD, is professor and assistant chair in the department of OBG at the University of Florida Health Science Center in Jacksonville. He also serves as coprincipal investigator at the University of Florida’s Jacksonville site of the Women’s Health Initiative.

Anthony Luciano, MD, is director of the Center for Fertility and Women’s Health, New Britain General Hospital, New Britain, Conn.

John F. Randolph, Jr., MD, is associate professor and director, division of reproductive endocrinology and infertility, department of OBG, University of Michigan Health System, Ann Arbor, Mich.


  • Bisphosphonates and calcitonin, in conjunction with calcium and vitamin D, are as effective as HRT in reducing fragility fractures. Raloxifene also reduces fracture risk.
  • Clonidine hydrochloride, a centrally acting antihypertensive agent, has been used successfully as a viable alternative to HRT in the management of vasomotor symptoms.
  • Women using HRT for vasomotor symptom relief will benefit from periodic assessment—with guidance from their Ob/Gyn—of the pros and cons of continuing the therapy.

Choosing whether or not to begin hormone replacement therapy (HRT) is among the most important health decisions menopausal women face. For years, though, physicians have had to guide their patients through the uncertain waters of HRT with only the help of sometimes conflicting, often inconclusive data. But now a new report offers hard-and-fast evidence to aid in this decision-making process.

In July, the estrogen-progestin arm of the Women’s Health Initiative (WHI)—a large-scale, randomized, controlled clinical trial involving 16,608 women—was halted after researchers concluded that the therapy’s risks outweighed its benefits. For this portion of the study, the subjects (all aged 50 to 79 and all with an intact uterus) received either placebo or a combination of 0.625 mg conjugated equine estrogens (CEE) and 2.5 mg medroxy-progesterone acetate (MPA) daily.1

Researchers found that women assigned to the combined HRT regimen were at greater risk for stroke, heart attack, blood clots, and invasive breast cancer than those in the placebo group. Specifically, for every 10,000 women taking HRT for 1 year, there were 7 more coronary heart disease (CHD) events than among women taking placebo. There also were 8 additional strokes, 8 more cases of breast cancer, and 18 more incidents of pulmonary embolism (PE).

The study also confirmed some beneficial effects: For every 10,000 woman-years of HRT use, there were 5 fewer hip fractures and 6 fewer cases of colorectal cancer.1

Clearly, the increased risk of breast cancer and cardiovascular disease in the estrogen-progestin arm of the WHI study is small. Still, more than 6 million US women currently take this therapy, and they undoubtedly will be seeking answers, alternatives, and assurances. As a result, Ob/Gyns now must reassess the standard HRT regimens and tailor their recommendations to each woman’s medical history (see “Managing menopause: a patient history”) and personal preferences.

Here, 4 experts offer their advice on interpreting the WHI findings and individualizing treatment protocols to offer preventive and therapeutic alternatives.

HRT: Still an option?

OBG Management: In light of the WHI findings, are there patients who would still benefit from taking HRT?

Kaunitz: It is still the most effective therapy for vasomotor symptoms and related sleep, mood, and memory disorders. I continue to recommend HRT or estrogen replacement therapy (ERT) for these symptoms. The WHI findings of an increased risk of myocardial infarction (MI), stroke, and thromboembolic disease in HRT users do not apply to hysterectomized women using or contemplating ERT. Nor do they apply to young surgically castrated women, who will continue to benefit from ERT as well as, in some cases, estrogen-androgen therapy.

Randolph: It is important to inform patients that HRT is a complex medication that acts on many parts of the body and has incompletely understood long-term effects. The primary indications for HRT have not changed: relief of vasomotor symptoms, sleep disturbances, and urogenital atrophy. Women seeking a strategy to reduce osteoporosis or colon cancer risks may also be candidates for HRT.

Luciano: For the majority of peri- and post-menopausal women with significant vasomotor symptoms and vaginal dryness, HRT will continue to be the most important—if not the only—therapeutic option.

Weighing the alternatives

OBG Management: Are there safe alternatives to HRT? If so, what are they? (TABLE 1)

Kaunitz: The bisphosphonates (alendronate and risedronate), available in weekly formulations, offer menopausal women an effective, safe, and convenient nonhormonal approach to preventing and treating osteoporosis. Also, raloxifene, a selective estrogen receptor modulator (SERM), effectively prevents and treats osteoporosis. However, some women will develop vasomotor symptoms or leg cramps with this medication. Still, raloxifene holds promise for its apparent ability to reduce the risk of breast cancer without causing endometrial proliferation.

For genital atrophy, vaginal estrogen tablets and the 3-month estrogen-releasing ring offer women effective treatment of atrophic symptoms with less systemic estrogen absorption than creams. Many of my patients also find the tablets and ring less messy than creams.

Randolph: Safe is a relative term. Any pharmacologic intervention has its own set of side effects. Even “natural” alternatives may have unknown consequences. Vasomotor symptoms may be improved by selective serotonin reuptake inhibitors (SSRIs), especially venlafaxine, or clonidine hydrochloride, an antihypertensive. High-dose progestins also have been effective, but the WHI data raise the possibility that MPA may contribute to a long-term increased health risk. Diet, exercise, and statin therapy all are proven to decrease the risk of CHD. Bisphosphonates and calcitonin, in conjunction with adequate calcium and vitamin D, are at least as effective as HRT in reducing fragility fractures. Raloxifene also reduces the fracture risk and appears to lower the risk of breast cancer through the first 4 years of use.2 However, it has unknown cardiac effects.

Luciano: For the prevention of osteoporosis we have several alternatives, as Dr. Randolph mentioned. Parathyroid hormone also may be available in the near future. Clonidine, a centrally acting antihypertensive agent, has been used successfully as a viable alternative to HRT in the management of vasomotor symptoms, based on the premise that these symptoms are precipitated by a discharge of catecholamine from thermoregulatory centers at the base of the hypothalamus.3 Clonidine may be prescribed as an oral tablet or transdermal patch at a daily dose of 0.1 mg. Adverse reactions are uncommon and include orthostatic hypotension, bradycardia, Raynaud’s phenomenon, and angioedema.

Fitzpatrick: Unfortunately, the efficacy and safety of these alternatives to HRT are not always well proven. Exceptions include the use of oral bisphosphonates or SERMs for the prevention and treatment of osteoporosis. Salmon calcitonin is another option. There is a large body of evidence indicating that these medications will increase BMD. A reduction in hip and vertebral spinal fractures has been well established with the bisphosphonates. As was pointed out earlier, each of these medications has its own side-effect profile that must be considered when counseling patients. For women who are unable to take any of these therapies, intravenous (IV) bisphosphonates are an additional safe alternative.

When it comes to finding alternative therapies for hot flushes, the issue becomes much more complicated. To date, other compounds used to treat hot flushes lack the efficacy of estrogen. Here again, side-effect profiles vary greatly. The most commonly used alternatives to HRT are the SSRIs, including venlafaxine and fluoxetine, and clonidine. Megestrol acetate is thought to be potent in its ability to reduce hot flushes, but side effects may limit its use. It also falls into the progestogen class of compounds.

As for phytoestrogens and other herbal remedies, many questions remain unanswered. Soy protein, which contains isoflavones, has been shown to have no benefit in the reduction of hot flushes in several randomized controlled trials.4,5 Similarly, red clover and dong quai are associated with a number of problems. Little benefit has been shown for these compounds in the attenuation of hot flushes. In Europe, black cohosh is probably the most widely used herbal remedy, and there is some evidence of its efficacy.

The safest alternatives are recommendations we should make for all of our patients: exercise, wearing layered clothing, and keeping the environment cool. The avoidance of spicy foods and alcohol also is thought to reduce symptoms. In addition, 1 small randomized controlled trial shows benefits from deep breathing.

Case studies from our panel

A 50-year-old perimenopausal woman at the peak of vasomotor symptoms asks for help in making the transition to menopause. I inform her that she is the ideal candidate for “short-term” cyclic hormone replacement therapy (HRT) with a 20-μg ethinyl estradiol (EE2) oral contraceptive (OC), continuous conjugated equine estrogen (CEE), or 17 estradiol and cyclic progestin. Annual discontinuation would allow her to assess her symptoms and decide whether she wants to resume therapy for further symptomatic relief. Most women will use this approach for 1 or 2 years and then consider alternatives.

A 42-year-old surgically menopausal woman asks about the Women’s Health Initiative (WHI) findings, as she has been taking HRT for a number of years. I explain that she is the type of patient most likely to have significant symptoms of sex-steroid withdrawal for an extended period of time. Continuous estrogen replacement at the lowest dose sufficient to control symptoms remains quite appropriate, since the long-term risk-benefit profile of unopposed estrogen is unclear and is likely to remain so until that arm of the WHI is reported. It is probably prudent to periodically discontinue—perhaps annually—HRT to assess for symptoms and reassess the treatment strategy.

A 65-year-old woman who initiated HRT for vasomotor symptoms and has continued the therapy for long-term health benefits comes in for an examination. I carefully inform her of the actual risks identified in the estrogen-progestin arm of the WHI, then offer her the option of discontinuing HRT to assess her symptoms and reevaluate her goals and alternatives. I also advise her—as I do all my patients—to get regular exercise, eat a balanced diet low in fat and calories, refrain from smoking, examine her breasts regularly and get an annual mammogram, and take daily calcium and vitamin D supplements.—JOHN RANDOLPH, JR., MD


Therapeutic alternatives to HRT





Aspirin: Daily use effective in lowering the risk of stroke and heart attack

Bisphosphonates: Effective in preventing and treating osteoporosis; may cause digestive disorders

Estrogen pills and patches: Highly effective and may pose less risk to breast tissue and cardiovascular health than oral HRT

Estrogen pills and patches: Highly effective and may pose less risk to breast tissue and cardiovascular health than oral HRT

Statins: Effective in women with high and low cholesterol

Raloxifene: Effective in preventing and treating osteoporosis; may cause hot flushes

SSRI antidepressants: Effective in up to 60% of women

Topical estrogen inserted vaginally: Effective in treating dryness

Beta blockers, ACE inhibitors: Reduce risk of heart attack in hypertensive patients

Calcium and vitamin D: Daily intake keeps bones strong and lessens fracture rate

Soy/black cohosh: Conflicting data on its effectiveness

Nonprescription gels and creams: Offer temporary relief of dryness, as well as pain and itching

ACE = angiotensin-converting enzyme; HRT = hormone replacement therapy; SSRI = selective serotonin reuptake inhibitor

Duration of therapy

OBG Management: Since there was no difference in breast cancer rates during the first 4 years of the WHI study between women taking estrogen plus progestin and those taking placebo, do you recommend that some women take HRT for less than or up to 5 years?

Kaunitz: For many women, fewer than 5 years of HRT will be sufficient for relief of symptoms. Clinicians are well aware, however, that some menopausal women remain symptomatic (without treatment) for far more than 5 years.

In this latter group, is it safe to continue HRT longer than 5 years? Ob/Gyns and their patients should recognize that the increased risk of breast cancer noted in estrogen-progestin users in the WHI study is small (RR 1.26) and only marginally achieved statistical significance (95% confidence interval [CI], 1.00-1.59). To appropriately guide clinical decisions, this relative risk needs to be translated into an attributable/absolute risk. For example, as was pointed out earlier, for every 10,000 women taking HRT for 1 year, we would anticipate 8 additional cases of breast cancer. Another way of stating this is that among 100 women using HRT for 10 years, 1 woman would be diagnosed with breast cancer.

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