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Easing vasomotor symptoms: Besides HRT, what works?

Now that many menopausal women prefer to avoid taking hormone replacement therapy, what are the best alternative treatments when hot flashes are a problem?

Sarah E. McBane, PharmD, CDE, BCPS, CPP

Sarah McBane practices in the Department of Community and Family Medicine, Duke University Medical Center, Durham, North Carolina, and is on the faculty at the Campbell University School of Pharmacy, Buies Creek, North Carolina. She has indicated no relationships to disclose relating to the content of this article.

Menopause is defined as the permanent cessation of menstruation and is generally agreed to have occurred after amenorrhea has persisted for 12 months. Laboratory tests can corroborate the diagnosis but usually are not necessary (see Table 1). Menopause occurs with the loss of ovarian function, whatever the cause. In the United States, the mean age of natural menopause is 51 years, and it occurs in the majority of women between the ages of 45 and 55 years.¹

A variety of symptoms can trouble menopausal women, ranging from hot flashes to mental confusion. Vasomotor symptoms (hot flashes and night sweats) may be the most commonly reported complaint (see Figure 1). These symptoms have generally been attributed to the relative estrogen deficiency that occurs as a woman approaches menopause, but the precise cause is uncertain. Other factors that may play a role include dysregulation of the alpha-adrenergic thermoregulation system and the opioidergic system.² For many women, vasomotor symptoms disappear or improve dramatically within 5 years of menopause.³

The effects of vasomotor symptoms on quality of life are variable.² Clinicians should assess how much these symptoms interfere with day-to-day function; the frequency and severity of hot flashes should be assessed, and significant consideration should be given to the patient’s treatment goals and expectations. Other likely causes of hot flashes, notably hyperthyroidism, should be ruled out.

HORMONE REPLACEMENT THERAPY

As its name implies, hormone replacement therapy (HRT) serves to replenish declining levels of endogenous hormones, and it remains the most effective therapy for treating vasomotor symptoms. Most symptoms are alleviated with estrogen, with progestin having a lesser role. Progestin therapy is necessary for women with an intact uterus to prevent endometrial proliferation.²

Many different formulations of HRT are available and can be used in equipotent doses to alleviate menopausal symptoms (see Table 2). Premarin (conjugated estrogens) has been available since 1942 and was the second most commonly prescribed drug in the United States in 2000.⁴ HRT is contraindicated in women with estrogen-sensitive cancers, active liver disease, or active or past thromboembolic disease. Hormones should be prescribed only with caution in women with many other conditions, including depression and diabetes.⁵ Clinicians who treat menopausal patients should familiarize themselves with established guidelines, such as those published by the North American Menopause Society and the American Association of Clinical Endocrinologists.^2,3

The Women’s Health Initiative Many older small or retrospective studies had suggested that HRT can protect against cardiovascular disease and dementia, and the Women’s Health Initiative (WHI) was the first large-scale study to prospectively examine these earlier findings. Funded by the National Institutes of Health and the National Heart, Lung, and Blood Institute, the WHI enrolled more than 160,000 women aged 50 to 70 years in one of several randomized controlled trials or in an observational study and followed them for 15 years. Approximately 27,000 women were randomized to receive either 0.625 mg of conjugated estrogen daily (with or without 2.5 mg of medroxyprogesterone acetate [MPA]) or a placebo.^6,7

The combination HRT trial showed an increased risk of MI, stroke, venous thromboembolism, and breast cancer in women who took hormones; the risks of colorectal cancer and fractures were reduced in this group.⁸ The estrogen-alone trial found a similar reduction in fractures and increase in strokes, but other outcomes were not statistically distinguishable.⁹ Many summaries of the WHI data are available to allow patients and clinicians to assess the effects of HRT on various outcomes (see Figure 2 and Figure 3).

Although the absolute risks of HRT are relatively small, the adverse outcomes from the WHI prompted the early termination of the hormone treatment studies. Many women stopped using hormones, and many clinicians stopped prescribing them. Between July 2002 (when results from the WHI were released) and 2003, prescriptions for HRT declined by about one-third.¹⁰ In the mid-1990s, attitude surveys had indicated that most women had positive perceptions of HRT, but these perceptions declined dramatically after the announcement of the WHI results.^10,11 After the WHI results were released, all HRT formulations also received a black box warning regarding their potential for increasing cardiovascular risk.⁵

A closer, more careful look More recent analyses of WHI data suggest that the risks of cardiovascular disease in women taking HRT may differ according to age and years since menopause. Younger women (aged 50-59 years) had the same risk of coronary heart disease (CHD) whether they took HRT or placebo.¹² Women randomized to take HRT fewer than 10 years after menopause actually had fewer cases of CHD than the placebo group, although the difference was not significant.¹² Conversely, older women (aged 70-79 years) or those taking HRT more than 20 years after menopause had an increased risk of CHD.¹²

Many questions regarding the risks of using HRT remain unanswered. The risks may be relatively low when HRT is used for a short period of time around menopause in relatively young women. In addition, the WHI studied specific doses of estrogen and medroxyprogesterone, so the results may or may not apply to other doses and forms of HRT. One European study suggested, for example, that transdermal HRT may confer a lower risk of venous thromboembolism than oral HRT.¹³

COMPLEMENTARY AND ALTERNATIVE THERAPIES

Women troubled by menopausal symptoms have sought relief from a variety of supplements. Those used most commonly include soy isoflavones, black cohosh, dong quai, evening primrose oil, red clover, ginseng, wild yam, vitamin E, and other herbal or supplementary therapies (see Table 3).

Soy isoflavones likely are the supplement taken most commonly for menopausal symptoms. Use of soy isoflavones is based on epidemiologic studies of Asian populations in which women were noted to have a significantly lower incidence of breast cancer, cardiovascular disease, and osteoporosis than did Western women. One study compared hot flashes in Western women and Chinese women, noting that approximately 80% of Western women report experiencing hot flashes and only 20% of Chinese women report similar symptoms.¹⁴ This difference was postulated to be a result of dietary soy intake.^14,15

Soy isoflavones are estrogenic compounds, although they are considerably less potent than estradiol. Some in vivo studies have found them to be estrogenic at some receptors and antiestrogenic at other receptors. Soy isoflavones may be found in both foods and supplements. The usual dose of soy isoflavones is 50 mg daily or 50 g of dietary soy protein. Soy protein has been a staple of Asian diets for centuries and is considered safe; it is very low in cholesterol and lactose free. The safety of soy-containing foods may not extend to soy isoflavone supplements, however. Anyone with a soy allergy should avoid soy isoflavones. Soy may cause some GI upset.^15,16 In vitro, soy isoflavones have bound to thyroid peroxidase, an enzyme catalyzing thyroid hormone synthesis. No clinical interaction with thyroid hormone has been documented, although practitioners should be aware of this potential.¹⁷

In 2002, a meta-analysis reviewed 11 trials of the effects of soy on vasomotor symptoms.¹⁶ The populations studied were women aged 29 to 70 years complaining of hot flashes. The trials were randomized and placebo-controlled and lasted 4 to 28 weeks. Interventions included soy extracts, foods, and supplements. Three of eight trials lasting longer than 6 weeks demonstrated a statistically significant improvement in vasomotor symptoms experienced by women in the treatment arms.¹⁶ The longest trial (28 weeks) showed no difference in menopausal symptoms.¹⁶

Black cohosh, or Actaea racemosa, is also frequently used for vasomotor symptoms. The brand-name product Remifemin contains 20 mg of black cohosh extract and is the most commonly studied preparation. Several small studies of Remifemin revealed a trend towards reducing vasomotor symptoms. A larger study randomized 304 women to Remifemin, 40 mg twice daily, or placebo, for 12 weeks and demonstrated a statistically significant reduction in hot flashes.¹⁸ None of these studies evaluated adverse events associated with black cohosh; however, GI upset, headache, and dizziness have all been previously reported.^15,16,19

Black cohosh’s mechanism of action is unclear. Data are conflicting on its estrogenicity, and its safety in breast cancer patients remains unclear. In vivo studies of black cohosh have also demonstrated CYP3A4 inhibition, so a potential exists for drug interactions.²⁰

Dong quai, a traditional Chinese herb also known as Angelica sinensis, is also used to alleviate menopausal symptoms. Some studies suggest that dong quai is estrogenic, but others have not verified estrogenic activity. Little has been published about dong quai monotherapy. A small study of women randomized to 4.5 g daily of dong quai root or placebo disclosed no difference in menopausal symptoms.¹⁵ In traditional Chinese medicine, dong quai makes up part of an herbal combination administered in conjunction with lifestyle modifications. Dong quai contains coumarins and can potentiate the activity of warfarin. Photosensitivity has been recorded with dong quai. Although the estrogenic properties of dong quai are not clear, women with estrogen-sensitive cancers should probably avoid it.¹⁶

Evening primrose oil, or Oenothera biennis, was originally used in Native American medicine. It contains the omega 6 fatty acids linolenic acid and linoleic acid and can improve lipid parameters. Adverse effects seem to be rare, consisting of mild headache and GI upset, although a few cases of altered seizure threshold have been reported.¹⁵ Few data are available regarding the use of evening primrose oil in menopausal women. A single study randomizing 56 women to 2 g of evening primrose oil or placebo daily reported no difference in menopausal symptoms.¹⁶ Women taking antiepileptic medications, antidepressants, or other medications that affect the seizure threshold should consider other options for hot flash relief.

Red clover, or Trifolium pretense, contains phytoestrogens, which are plant-based compounds that act like estrogen in the body. The four phytoestrogens in red clover are formononetin, biochanin A, daidzein, and genistein. Many different red clover-containing products exist, but the brand name product Promensil is commonly recommended to menopausal women. Data on red clover are conflicting. Two studies published in the same issue of Climacteric evaluating varying doses of Promensil revealed no change in menopausal symptoms.¹⁶ A more recent study assessed the efficacy of Estrofactors, a supplement containing red clover in addition to vitamin E, B vitamins, and vitamin K.²⁰ This study of 31 women showed a reduction in hot flashes but did not report the statistical significance of results.²⁰

Ginseng has been tried for many different complaints, including menopausal symptoms. Ginsenosides are considered to be the active components of ginseng, and they have been suggested to have estrogenic effects. Evidence that they can ease menopausal symptoms is limited, however. A single Swedish study evaluating the effects of ginseng or placebo in nearly 400 women revealed no difference in menopausal symptoms, but ginseng did produce an overall improvement in mood symptoms and quality of life.¹⁴

Wild yam, or Dioscorea villosa, differs from previously mentioned herbal compounds because it contains diosgenin, an active ingredient more structurally like progesterone. This substance can be converted in vitro to progesterone, although the human body lacks the appropriate enzyme to make this conversion. Wild yam is generally marketed as a topical product. As might be expected, a 3-month study of wild yam cream revealed no improvement in menopausal symptoms.¹⁴

Vitamin E was evaluated in several poorly controlled studies conducted in the 1940s and 1950s. These studies suggested that vitamin E could reduce menopausal symptoms. A more recent study evaluated vitamin E in more than 100 breast cancer survivors and noted a reduction of 1 hot flash per day.¹⁶ The clinical significance of these results is questionable, especially when consideration is given to a possibility of increased all-cause mortality with high doses of vitamin E.²¹

The complete safety and efficacy profiles of many herbal therapies are uncertain. In 1994, the FDA passed the Dietary Supplement Health and Education Act, which states that manufacturers of these products are responsible for safety but does not require prior approval by or registration with the FDA. The FDA only monitors postmarketing concerns received by voluntary adverse event reporting. Consumers have no guarantee of product integrity or consistency, both of which will affect the intended therapeutic results of herbal supplements.

BIOIDENTICAL HRT

Commonly referred to as natural HRT, bioidentical HRT consists of individually compounded hormones that are chemically identical to those secreted by the female body. Many different formulations can be compounded as well, including creams, gels, lotions, tablets, capsules, and injectables.

Three different estrogens may be used in bioidentical HRT: estrone, estradiol, and estriol. Estrone is the most prevalent estrogen circulating in postmenopausal women, whereas estradiol is found in higher concentrations in premenopausal women. Estradiol is considered to be the most potent estrogen and estriol the least potent. Some sources endorse estriol as a safer estrogen for HRT because in vitro studies have demonstrated that it opposes the actions of estradiol in breast tissue.²²

Bioidentical HRT uses the progesterone naturally found in the body instead of the synthetic progestin MPA found in many commercially prepared HRT formulations. Many prescribers of bioidentical HRT replace progesterone even in women without an intact uterus, arguing that progesterone receptors are found throughout the female body.

Advocates of bioidentical HRT frequently recommend salivary testing to quantify circulating hormones and guide the formulation of bioidentical HRT. Salivary hormone testing is noninvasive and measures the amounts of free circulating hormones. Unfortunately, the results are not always reproducible, and they may be affected by diet and time of testing. In addition, there are no guidelines for how to interpret results, and no formulas exist to direct prescribers on how to replace hormones based on salivary test deficiencies.^22,23

The lay press offers extensive support for bioidentical HRT, including Web sites and books published by lay professionals and health professionals alike. All these publications champion bioidentical HRT as safer and more effective than traditional, commercially manufactured HRT preparations. They argue that bioidentical HRT relieves more symptoms with fewer adverse effects because the hormones replaced are analogous to what is naturally found in a woman’s body.

Unfortunately, the medical literature provides little evidence to support these claims. Although doses can be individualized, the American College of Obstetricians and Gynecologists states, “There is no scientific evidence to support claims of increased efficacy or safety for individualized regimens of estrogen or progesterone regimens.”²² The compounds have not been approved by the FDA, nor have they been tested for purity, potency, efficacy, or safety. Finally, women and clinicians should remember that bioidentical HRT may confer the same risks as conventional HRT.

OTHER NONHORMONAL TREATMENTS

A variety of neuroendocrine agents have been evaluated for relief of vasomotor symptoms. Clonidine and methyldopa reduced hot flash frequency by more than 50% in some studies,² but they are not FDA-approved for menopausal symptom treatment and may have adverse effects.² Gabapentin, 2,400 mg, has been compared to conjugated estrogens, 0.625 mg, and found to be similar in a small 12-week study;²⁴ however, many women may not tolerate the CNS effects of gabapentin.²⁴ Current data on the use of neuroendocrine agents for vasomotor symptoms is primarily in breast cancer survivors and may not be applicable to all menopausal women.

Antidepressants have been prescribed for vasomotor complaints. Venlafaxine, 75 to 300 mg daily, and controlled-release paroxetine, 12.5 to 25 mg daily, can decrease hot flashes by approximately 60%.² Many women complain of nausea and vomiting with venlafaxine, whereas others experience an increase in BP. Paroxetine can cause somnolence and weight gain and has been associated with anticholinergic side effects. Fluoxetine, 20 mg daily, can reduce hot flashes by about 20%.² Data on the use of antidepressants for vasomotor symptoms are limited and derived almost exclusively from breast cancer survivors.²

Lifestyle modifications can relieve vasomotor symptoms. Simple measures such as wearing easily-removed clothing layers and eating ice chips can be helpful. Deep, controlled breathing can significantly reduce hot flashes up to 50%.¹ Increased weight has been correlated with a 20% increased risk of hot flashes, so maintaining normal weight should be encouraged.² One small trial indicated that yoga may be effective at reducing hot flash frequency and intensity.²⁵

SUMMARY

Prescription HRT is the most effective therapy for vasomotor symptoms, but some patients may find the risks unacceptable. Treatment with lower doses or alternative dosage forms for short periods may reduce risk. Soy isoflavones and black cohosh have a proven ability to reduce hot flashes, but they should not be used when estrogen is contraindicated. Bioidentical HRT may offer no benefits over conventional HRT. Neuroendocrine agents may reduce hot flashes effectively and can be used when estrogen is contraindicated, but these agents may cause significant CNS side effects. Lifestyle modifications are the foundation of vasomotor symptom therapy and are safe to recommend for all women. Clinicians and patients should carefully discuss the expectations for therapy, and the clinician should be prepared to customize the treatment regimen. JAAPA

DRUGS MENTIONED

REFERENCES

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