Supplements for Hot Flashes – The Power of Placebo

Red Clover: From flickr member freebird4

As a follow-up to a previous post on bioidentical hormone replacement, I thought it would be helpful to quickly review the major herbal and alternative medicine products available to treat menopausal symptoms. The market is large, and the treatments are ubiquitous in pharmacies, so they’re worth of some science-based scrutiny.

What is menopause?

Menopause is formally defined as a full year without menstruation. Typically, this occurs around age 50, although the onset can vary between ages 40 and 58. [1] A few generations ago, when life expectancy was about 50 years, menopause wasn’t a big concern. Now that women are living into their eighties and beyond, they may experience up to thirty or more menopausal years.

The transition to menopause, called perimenopause, can last up to 6 years. [2] For some women, this can be a smooth process, with erratic periods as the noticeable signal. However, many women report vasomotor symptoms (hot flashes and night sweats), and non-vasomotor symptoms (e.g., insomnia, headache, irritability, vaginal dryness, mood swings) during this time. These symptoms are typically more common, and severe, in women with early or induced (e.g., hysterectomy) menopause. [2] Perimenopause is a normal process, but the transition can be debilitating.

Once menopause is established, hot flashes generally end within a few years. For some women, however, they can continue for 15 years or more. [2] As each hot flash can be accompanied by sweating, palpitations and other unpleasant effects, many women seek medical advice and treatment.

What evidence-based recommendations exist for the treatment of hot flashes and night sweats?

Menopause is not a disease, and requires no specific treatment, unless symptoms interfere with day-to-day life. For years, hormone replacement (estrogen and progestins) were the standard treatment used for menopausal symptoms, but data now shows that there are risks that accompany the benefits of this therapy. (For more information on hormone replacement, see my previous post on bioidentical hormones.) Hormone replacement is now used less frequently, and for shorter periods.

The Society of Obstericians and Gynaecologists of Canada (SOGC), in their 2009 guidelines [PDF], offer the following treatment advice for symptoms like hot flashes: [2]

• Lifestyle modifications, including reducing core body temperature, regular exercise, weight management, smoking cessation, and avoidance of triggers (e.g., hot drinks, alcohol) may be recommended.
• Hormone replacement is the most effective therapy for the medical management of menopausal symptoms.
• Non-hormonal prescription therapies can be considered when hormone therapy is not appropriate or desired.

The SOGC then points out that:

“There is limited evidence of benefit for most complementary and alternative approaches to the management of hot flashes. Without good evidence for effectiveness, and in the face of minimal data on safety, these approaches should be advised with caution. Women should be advised that, until January 2004, most natural health products were introduced into Canada as “food products” and did not fall under the regulatory requirements for pharmaceutical products. As such, most have not been rigorously tested for the treatment of moderate to severe hot flashes, and many lack evidence of efficacy and safety.”

The remainder of this review will elaborate on this final point, and examine the efficacy and safety of herbal and alternative treatments for hot flashes.

Lower Standards for Herbal and Alternative Products

Previous Science-Based Pharmacy articles have illustrated that in Canada, the USA, and around the world, regulated pharmaceutical products are held to much higher effectiveness standards than supplements and alternative medicines. This is also the case with the treatment of hot flashes. The standard for prescription products is that they must be effective in women experiencing approximately 7 hot flashes per day (50 per week). Most studies of alternative products have been tested in women with as few as 1 or 2 hot flashes per day. [2]

Better quality research studies compare a treatment to a placebo, and “blind” both the patient and the researcher to the actual treatment. Remarkably, trials involving alternative treatments for hot flashes have documented that up to 50% of women may report that the placebo treatment is effective. [3] This suggests that for every 100 women that take any form of supplement for their hot flashes, 50 of them could be expected to report that it’s effective – even if the therapy has no medicinal effect. This placebo response may help explain why women report that alternative products are effective, when clinical trials cannot demonstrate that they have any effect. In light of this placebo effect, our focus will be on whether any product is more effective than a placebo treatment.

Phytoestrogens

Phytoestrogen is a term used to describe a plant-based product which has estrogen-like activity. This effect was first observed back in the 1940’s, when Australian farmers noticed that sheep grazing on clover were becoming infertile. [4] While phytoestrogens do not chemically resemble estrogen, they’re believed to bind with estrogen receptors. Depending on the natural estrogen levels in the body, they may have an anti-estrogen effect, by blocking the action of the more-potent estrogen molecule.  There are three major types of phytoestrogens: isoflavones (e.g., soy and other beans, red clover) lignans (e.g., flaxseed) and coumestans (also in red clover). [1]

Soy is among the best-studied products for menopausal symptoms, and there are many soy-based products on the market. Diets with high amounts of soy appear to have very modest effects on hot flashes. [1] However, this effect has not been shown in all studies.

One study compared black cohosh, a mixed cocktail of botanicals, botanicals plus dietary soy, regular hormone therapy, and a placebo, in a well designed, well-conducted clinical trial. Participants in the soy group were encouraged to consume 12 to 20 grams of dietary soy per day, and on average, women increased their consumption by 1.1 servings per day. Over twelve months, botanicals with or without soy, had no impact on hot flashes. [5]

A well-done systematic review examined nine trials that studied soy extracts, and concluded that soy foods, beverages, powders, and extracts have no impact on menopausal symptoms.[6]

Nutrafem is a popular product in Canada and other countries and worthy of a bit more scrutiny, as the website is loaded with sciencey-looking graphs and charts, with claims that it’s “clinically proven” and “safe-no side effects, no effects on the endometrium, and no liver toxicity”. A combination of Vigna radiata (mung beans) and an extract from the bark of the tree Eucommia ulmoide, the distributors tout that the product offer a 90% reduction in hot flashes, a 77% reduction in menopause symptoms, and an 79% reduction in “psychological symptoms”, while promising that it is free of cancer risk and side effects. It sounds too good to be true. Unfortunately there is no published evidence to substantiate these claims. While a double-blind, randomized controlled trial is referred to, it has not been published. In fact, there are zero published studies with this product, so there is no way to verify any of these claims. No data exists to support or refute the safety claims with this product. Nutrafem has no science to substantiate it, and until it does, it is not recommended.

Red clover is widely available and in a number of pharmacy products (e.g., Promensil). It’s a source of four different isoflavones. It has a number of traditional uses and has been studied for its ability to reduce hot flashes. Studies have been small and the results are not impressive: The better quality studies suggest it is as effective as a placebo. [1] [3] A Cochrane review, the gold standard of studies, also concluded that there is no evidence that phytoestrogens like Promensil are effective. [7] There is also a lack of long-term safety data. [1]

The Center for Science in the Public Interest has singled out Promensil as being deceptively marketed. Consequently the manufacturer agreed to remove claims that Promensil is “clinically proven.” Without scientific evidence to support claims of efficacy, red clover-containing products are not recommended.

Flax is a source of lignan phytoestrogens, and also provides omega-3 fatty acids, alfa-linolenic acid, and fibre. It’s available in the pharmacy as the oil, and also as capsules. Occasionally the whole seeds are sold as well.

With respect to menopausal symptoms, data is conflicting and there is not enough persuasive evidence to demonstrate that flax is effective. [1] Flax’s other potential benefits are outside the scope of this review, but in general it’s considered to be a healthy alternative to other fats. It’s important to note that lignans are only released when the seeds are ground or milled before being consumed  – whole seeds pass through the body intact. Flax oil contains few lignans unless noted on the bottle. Flax may interact with warfarin (Coumadin) – consult a pharmacist or physician for more information. [1]

Black cohosh appears in a wide variety of products (e.g., Remifemin, Nufem, and many “menopause kits”).  While black cohosh does appear to demonstrate estrogen-like effect [1] its efficacy has not been demonstrated clearly.[8] Studies that have been done are of general poor quality [3] and the more well-done trials more consistently and persuasively show that it is no better than a placebo therapy, and significantly less effective than hormone replacement for treating hot flashes and night sweats. [1] [5]

The safety data on black cohosh is concerning. While studies of up to six months show that it is well tolerated, with few side effects, concerns have been raised about its long-term safety. [1] There have been cases of severe liver damage, some leading to liver transplantation, associated with black cohosh. [1] A warning about this risk was issued by Health Canada in 2006. While we cannot conclude that black cohosh caused this damage, a cautious approach suggests liver function tests are important if taken for more than six months. (The Terra Sigillata blog has more discussion on the liver toxicity issue). Overall, there is little evidence to suggest that black cohosh will offer any benefit to women or that the questionable benefit is worth the possible risk.

Dong quai is a traditional Chinese medicine, used as a treatment mainly for hot flashes.  It is an ingredient in hundreds of supplements, alone or in “menopause relief” combination products. Dong quai may have estrogen-like effects and may stimulate breast cancer cells, similar to estrogen. [1] Dong quai has not been demonstrated to be effective and may contain chemicals that are carcinogens. [1] [9] It also interacts with several prescription drugs. Dong quai, alone or in any menopause treatment, should be avoided.

Evening primrose oil is an established pharmacy product purported to help with hot flashes. There is no data to demonstrate it is more effective than a placebo. Its use is not recommended. [1] [8]

Wild yams are the precursors to some bioidentical hormones. The key ingredient, diosgenin, must be converted in a laboratory to something the body recognizes as a hormone. The body cannot do this. Consequently, any products containing wild yams will be completely ineffective for the treatment of hot flashes and night sweats. [1]They should be avoided.

So what’s the bottom line for women?

Until evidence appears to demonstrate otherwise, the science currently shows that no alternative or complementary treatment for hot flashes or night sweats is any better than a placebo treatment. These products are significantly less effective than prescription drugs for the treatment of these menopausal symptoms. And the risks of some treatments are far from clear.

In Canada, despite the appearance of Natural Health Product regulations in 2004, there is little evidence that any substantive enhancements have been made to the dismal safety and efficacy standards of complementary and alternative products.  In what appears to remain a largely unregulated market, there exists an entire industry intent on taking advantage of women who seek non-prescription treatments for their symptoms. It is truly a buyer beware market.

Overall, for the treatment of hot flashes and night sweats, the products with the most promising risk/benefit ratio seem to be soy products and flax products, which if not helpful, at least do not appear to be harmful. Both products may have other health benefits, as well. As more than 50% of women may experience relief from hot flashes simply due to a placebo effect, many may find these therapies provide relief.

Claims about non-prescription menopause relief products should be viewed sceptically. Promoters, including non-science-based pharmacists, may tout these products as safe, “clinically proven” and effective alternatives to prescription hormones. The science just doesn’t back up these claims.

For More Information

Informed Health Online, from the German-based Institute for Quality and Efficiency in Health Care, has a nice overview of menopause and management strategies, and discusses hormones and non-prescription alternatives.

References:

[1] Natural Medicines Comprehensive Database [database on the Internet]. Stockton (CA): Therapeutic Research Faculty; 1995-2009 [cited 23 April 2009] Available from: http://www.naturaldatabase.com. Subscription required to view.

[2] Vasomotor Symptoms. In: Menopause and osteoporosis update 2009. Journal of Obstetrics and Gynaecology Canada 2009. 31 (1). Supplement 1.

[3] Nedrow, A., Miller J., Walker M., Nygren P., Hoyt Huffman L., & Nelson H.D. (2006). Complementary and Alternative Therapies for the Management of Menopause-Related Symptoms: A Systematic Evidence Review Archives of Internal Medicine, 166 (14), 1453-1465 DOI: 10.1001/archinte.166.14.1453

[4] de Lemos, ML. Phytoestrogens: A natural alternative? Pharmacy Practice 2007: 35-38.

[5] Newton KM, Reed SD, LaCroix AZ, et al. Treatment of vasomotor symptoms of menopause with black cohosh, multibotanicals, soy, hormone therapy, or placebo. Ann Intern Med 2006; 145(12): 869-79.

[6] Krebs EE, Ensrud KE, MacDonald R, Wilt TJ. Phytoestrogens for treatment of menopausal symptoms: a systematic review. Obstetrics and Gynecology 2004; 104(4): 824-836

[7]Lethaby AE, Brown J, Marjoribanks J, Kronenberg F, Roberts H, Eden J. Phytoestrogens for vasomotor menopausal symptoms. Cochrane Database of Systematic Reviews 2007, Issue 4. Art. No.: CD001395. DOI: 10.1002/14651858.CD001395.pub3.

[8]Author not specified (2009). Herbal medicines for menopausal symptoms Drug and Therapeutics Bulletin, 47 (1), 2-6 DOI: 10.1136/dtb.2008.12.0031

[9] Dong Quai. In CAMline [database on the Internet]. Toronto, ON [cited 25 April 2009] Available from: http://www.camline.ca