ABSTRACT: Many nonhormonal options are touted for their ability to relieve menopausal symptoms, but evidence supporting their efficacy is limited at best.

CME OBJECTIVE: The reader will be aware of options for treating menopausal symptoms and important factors that require an individual approach for each patient.
Cynthia K. Sites, MD, Revival Soy supplied soy and placebo for NIH-sponsored studies

Although some studies of alternative therapies for menopausal symptoms provide evidence of symptomatic relief, estrogen taken as the US Food and Drug Administration (FDA) recommends — the lowest dose for the shortest amount of time — remains the most effective treatment, says obstetrician and gynecologist Cynthia K. Sites, MD, director of UAB’s Division of Reproductive Endocrinology and Infertility.

With many outstanding questions surrounding hormone therapy’s (HT) safety, the 25 million women who will experience menopause in the next decade must choose either estrogen or an alternative therapy to alleviate their symptoms. An array of alternatives makes the decision difficult, and a paucity of data augments confusion. Only a few — soy with isoflavones, the herb black cohosh, and some prescription medications developed for other indications — may reduce menopausal symptoms, but none work as well as HT.

In the wake of the 2002 Women’s Health Initiative (WHI) findings that plunged estrogen plus progestin therapy into uncertainty, researchers continue to pinpoint hazards and benefits of estrogen-based regimens. Studies link long-term use of HT to serious health risks such as breast cancer, heart attacks, stroke, and dementia.

Short-term estrogen use — 3 to 5 years — seems safe, but many women experience menopausal symptoms for as long as 10 years. The most common symptom is vasomotor instability — hot flashes and night sweats. Half of menopausal women need treatment for hot flashes that interfere with daily activities or sleep. Other problems include insomnia, urogenital atrophic symptoms, irritability, dyspareunia, and decrease in libido.

For some women, a high risk for serious medical outcomes with estrogen use is a contraindication for HT. Those who should not take estrogen include women with a history of breast or uterine cancer or an elevated risk for breast or other estrogen-sensitive cancers based on genetic factors, family history, or both; and those who have had previous venous or arterial thrombotic events or are at high risk for cardiovascular disease or blood clots in the legs. Women with endometriosis or uterine fibroids also may be motivated to seek nonhormonal therapies to treat menopausal symptoms.

SSRIs, SNRIs
A few short-term, well-designed trials of antidepressants indicate moderate relief of menopausal symptoms. Highly symptomatic women who cannot take estrogen may find selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) useful for relieving hot flashes. “They cannot expect 100% relief, but a 50% or 60% reduction in symptoms is better than the 20% decrease associated with placebo,” says Sites. A 2006 systematic review and meta-analysis published in the Journal of the American Medical Association reported some efficacy with SSRIs and SNRIs in reducing menopausal symptoms (JAMA. 2006;295[17]2057-2071). Specifically, several randomized, placebo-controlled trials showed venlafaxine and paroxetine reduced hot flash frequency (JAMA. 2003;289:2827-2834; J Clin Oncol. 2005;23:6919-6930). However, other clinical trials of SSRIs and SNRIs have produced mixed results and, despite some evidence of efficacy, adverse effects and costs make them unsuitable for many women.

Other Medications
Although not FDA-approved for menopausal symptoms, gabapentin and clonidine have demonstrated relief of hot flashes, insomnia, and mood symptoms. The JAMA meta-analysis reported supportive evidence for efficacy of both drugs. Compared with placebo, gabapentin, an antiseizure drug, demonstrated reduced hot flashes (up to 50% fewer) and produced better sleep in 2 large randomized, double-blind trials (Obstet Gynecol. 2003;101:337-345; Proc Am Soc Clin Oncol. 2004;23:8015).

The meta-analysis found the older antihypertensive drug clonidine showed a limited reduction of hot flashes (about 1 less per day) in 3 fair-quality clinical trials. “The clonidine patch is somewhat beneficial,” says Sites, “and is a good option for breast cancer patients who are suffering severe menopausal symptoms.”

Soy Isoflavones
Investigators, motivated by epidemiologic data showing milder menopausal symptoms in women who consume large amounts of soy, have conducted a substantial number of studies of soy isoflavones.

Scientific literature offers both positive and negative results. The JAMA meta-analysis reviewed 6 trials of soy isoflavones, finding contradictory outcomes. The authors concluded there was no statistically significant benefit to soy isoflavones compared with placebo, as did two systematic reviews predating the JAMA report.

Sites is recruiting participants aged 45 to 60 years for a study of soy isoflavones’ effect on body fat distribution and insulin sensitivity in obese postmenopausal women. The study includes analysis of isoflavones’ effects on hot flashes. The problem with many soy studies is they use only isoflavones — the plant estrogen — without a soy protein. The combination of isoflavones with a soy protein produces a better result. Administration is important too, she says. Soy remains active 6 to 8 hours and must be taken twice a day.

Soy supports bone and heart health and is a safe and effective dietary supplement for the majority of the population. Investigators have voiced concerns, however, about soy isoflavones, which produce weak estrogenic effects and may increase chances of developing breast cancer in women already at high risk. One Italian study reported increased occurrence of endometrial hyperplasia in women who consumed soy tablets (Fertil Steril. 2004;82[1]:145-148), but preliminary results from National Institutes of Health-funded research refuted that finding as part of an ongoing 2-year study of women consuming 58 mg of soy isoflavones a day.

Black Cohosh
Black cohosh is the most studied botanical product for menopausal symptoms, but results for it, too, are mixed, and studies often contain methodological errors. A 2005 review found most studies show extract of black cohosh improves symptoms (Am J Med. 2005;118[Suppl 12B]:98-108). Another review contradicted: “There is little evidence to support its [black cohosh] treatment for hot flashes” (Arch Intern Med. 2006;166:1453-1465). Two studies of women taking tamoxifen for breast cancer showed black cohosh reduced hot flashes as well as improved sleep, fatigue, and sweating (Cancer Invest. 2004;22:515-521; Maturitas.2003;44[ Suppl 1]:S59-S65). The recently completed National Institutes of Health-sponsored Herbal Alternatives for Menopause study found no difference in the number of hot flashes and night sweats for any of the herbal supplements studies, including black cohosh (Ann Intern Med. 2006;145:869-879).

Other Alternatives
A raft of claims surround other complementary and alternative remedies, including the botanicals kava, dong quai root, ginseng root, and acupuncture, reflexology, and other techniques to relieve symptoms, but few reliable trials have been published, and most have methodological deficiencies that prevent generalization.

Mind/body and behavioral therapies, such as aerobic exercise, yoga, and stress management are worth considering, says Sites, who often recommends them. “Such modalities address the overall decrease in well-being many postmenopausal women experience. Patients generally feel better, their mood improves, and they sleep more soundly.”

More than 40% of all menopausal women seek medical attention for symptom relief. “Short-term estrogen/progesterone remains an appropriate and effective option for healthy women,” says Sites. “Some alternatives are appropriate for highly symptomatic women who are either hesitant to take estrogen/progesterone or who have medical reasons not to take hormone therapy,” she says. Because of the recently reported 7% drop in breast cancer cases since the WHI findings, there is a renewed need for research on alternatives to HT.

“Health care providers must tailor treatment for each individual, balancing benefits against potential risks for each patient. Primary care physicians should understand both the various formulations of hormones available as well as alternative options and how all options pertain to each patient,” she says.

For more information
Dr. Cynthia Sites
1.800.UAB.MIST
mist@uabmc.edu