This is a handout I produced for the American Academy of Family Physicians Annual Scientific Assembly that was held in San Diego, CA, September 19 and 20, 2008. My desire in making this information freely available is to help women who are wrestling with menopausal symptoms, and who are considering natural medications, to make wise decisions in conjunction with their personal healthcare professional.
Although this handout is written for healthcare professionals, I believe it will be helpful for others interested in the topic. The full handout, the summary chart, and all citations can be accessed here.
Objectives – after this discussion, participants should be able to:
- Describe the natural medications women are using for menopause,
- Describe the evidence supporting or refuting the use of each, and
- Be able to use an evidence-based clinical grid in advising patients.
Take Home Points
- No therapy for menopausal symptoms is more effective than conventional HT.
- Lifestyle changes can be highly effective for menopausal symptoms.
- The North American Menopause Society (NAMS) consensus recommendation is: “In women who need relief for mild vasomotor symptoms, (we recommend) first considering lifestyle changes, either alone or combined with a nonprescription remedy, such as dietary isoflavones or black cohosh…Prescription systemic estrogen-containing products remain the therapeutic standard for moderate to severe menopause-related hot flashes. Recommended options for women with concerns or contraindications relating to estrogen-containing treatments include prescription progestogens, venlafaxine, paroxetine, fluoxetine, or gabapentin.”
- Yet, with concerns about conventional therapies and the difficulties surrounding compliance to lifestyle changes, many women are turning to natural medicines for menopausal symptoms.
- However, there is little evidence of effectiveness and safety of most natural medicines (herbs, vitamins and supplements) for the treatment of menopausal symptoms. Furthermore, these products are not regulated in the U.S.
- The American College of Obstetricians and Gynecologists (ACOG) states, “Given the general lack of standardization of products, the relatively short duration of therapy and follow-up in the available data, and the difficulty of interpreting the available clinical data, few recommendations can be made with confidence.”
- A 2004 systematic review form NAMS concluded, “When lifestyle changes are not adequate to achieve the desired level of relief from mild hot flashes, adding a nonprescription remedy may be considered. A trial of dietary isoflavones or supplements containing black cohosh or vitamin E may be an option, primarily because these remedies are not associated with serious side effects. However, because of inconclusive efficacy data, this is not a consensus recommendation.”
- The most recent systematic review and meta-analysis on the topic of nonhormonal therapies for menopausal hot flashes, published in JAMA in 2006, found 43 trials that met their inclusion criteria, including 10 trials of antidepressants, 10 trials of clonidine, 6 trials of other prescribed medications, and 17 trials of isoflavone extracts.
- The authors concluded that “The frequency of vasomotor symptoms in menopause was not reduced in meta-analysis of trials of red clover isoflavone extracts and results were mixed for soy isoflavone extracts. Evidence of the efficacy of other therapies is limited due to the small number of trials and their deficiencies. Trials do not compare different therapies head-to-head and relative efficacy cannot be determined.”
- “Soy” the NMCD recommends, “has the most evidence for effectiveness and may be worth trying for some women. Soy foods are preferred over soy supplements which have concentrated isoflavones.” Another review agrees: “Less is known about the safety of soy supplements.”
- Women with a history of breast cancer should avoid any supplement containing a phytoestrogen or suspected of having estrogenic effects.
- “Black cohosh” the NMCD concludes, “has less evidence than soy, but might help some women.”
- There is really not enough safety or efficacy data to recommend unopposed transdermal progesterone, bioidentical hormone therapy, or testosterone.
- The NMCD tells us, “There is really not enough safety or efficacy data to recommend red clover, DHEA, flaxseed, chasteberry, kudzu, alfalfa, hops, licorice, evening primrose, Panax ginseng, wild yam, or vitamin E. They haven’t been studied enough to recommend. Tell patients not to use dong quai due to safety concerns.”
- NAMS recommends, “Given the lack of efficacy data, (we do) not recommend dong quai, evening primrose oil, ginseng, licorice, Chinese herb mixtures, acupuncture, or magnet therapy for hot flash relief.”
- NAMS also reminds us, “Clinicians are advised to enlist women’s participation in decision making when weighing the benefits, harms, and scientific uncertainties of therapeutic options. Regardless of the management strategy adopted, treatment should be periodically reassessed as menopause-related vasomotor symptoms will abate over time without any intervention in most women.”
Menopausal symptoms can persist for weeks to years and the severity of symptoms can vary from woman to woman. Vasomotor symptoms (hot flashes [in up to 85% of menopausal women] and night sweats [hot flashes with drenching sweats]) and vaginal dryness are the most common menopausal complaints. A 2005 systematic review concluded that vasomotor symptoms and vaginal dryness were most consistently associated with menopause. Sleep disturbance, somatic complaints, urinary complaints, sexual dysfunction, mood, and quality of life were inconsistently associated with menopause. Many women are exploring non-pharmacological therapies fro menopause, especially “natural” health products. In 2000, before results from the WHI and HERS studies were known, women spent $600 million on these products. Since HRT has fallen out of favor, natural approaches have become even more popular. Women who take natural products often consider them safer than other approaches.
Lifestyle modification is the first step in managing menopausal symptoms. Women who increase daily exercise, change to a healthy diet (eating fruits and vegetables, while decreasing saturated fat intake), and stop smoking can see a reduction in menopausal symptoms, an increase in their sense of well-being, and also have a lower the risk for cardiovascular disease, breast cancer, and osteoporosis. Paced breathing and relaxation techniques as behavioral approaches to addressing hot flashes have shown promise in several studies and were found to be safe. The North American Menopause Society (NAMS) recommends, “When therapy is desired, various nonpharmacologic and pharmacologic options are available. The recommended clinical management approach includes lifestyle modification followed by nonprescription and/or prescription therapies, when needed.”
Hormonal Treatments (HT)
Conventional HT with estrogen/progestin will likely maintain a major role in treatment. It is very effective for hot flashes. NAMS recommends, “Prescription progestogen alone can be used to treat hot flashes of varying severity. In clinical trials, DMPA, MPA, and megestrol acetate have demonstrated efficacy. Short-term use of these drugs seems reasonable in women without contraindications who do not wish to try estrogen but who are not opposed to trying another hormone, although progestogens have been linked to breast cancer risk in some studies.” Yet, many women have been researching and using natural products to treat menopausal symptoms. In 2000 the retail sales of products for menopause accounting for approximately $600 million. Less than one in three menopausal women currently chooses conventional HT.
Unopposed Transdermal Progesterone
A 2005 systematic review by Wren agreed that currently available progesterone creams cannot be recommended for treatment of symptoms associated with menopause. He found, “Eight studies of transdermal progesterone have been published in peer-reviewed journals. Their results are not generally supportive of the therapy.” He also reminds us, “The use of saliva to monitor levels of progesterone has been shown to be based on erroneous assumptions and should be abandoned as a means of managing postmenopausal women.” Thus, choosing to prescribe this therapy may “attract medicolegal scrutiny.”
The bottom line according to ACOG’s Task Force Report on Hormone Therapy is, “Review of studies to date has found no evidence that treatment with (unopposed transdermal progesterone) has any significant effect on hot flashes.” NAMS agrees, concluding, “Scientific data are lacking regarding the efficacy and safety of topical progesterone creams for relief of hot flashes … Additionally, safety concerns regarding systemic progestogen preparations may also apply to topical progesterone preparations.”
Commonly prescribed bioidentical estrogen therapies include: (1) Estriol only, (2) Estradiol (20%) and estriol (80%) – Biest, and (3) Estradiol (10%), estriol (80%) and Estrone (10%) – Triest. Proponents of Bioidentical HT claim superiority to conventional HT due to “decreased risk of breast and endometrial cancers;” however, there is no evidence to support this claim. To date, there are no double-blind, placebo-controlled studies available to assess the efficacy and safety of Bioidentical HT in the treatment of hot flashes or other menopausal symptoms.
A 2005 Committee Opinion of ACOG concluded, “Most compounded products, including bioidentical hormones, have not undergone rigorous clinical testing for either safety or efficacy.” They also pointed out, “There is no scientific evidence to support claims of increased efficacy or safety for individualized estrogen or progesterone regimens prepared by compounding pharmacies.” ACOG’s opinion also reminded clinicians that salivary hormone level testing used to “tailor” HT is not meaningful because salivary hormone levels vary within each woman depending on her diet, the time of day, the specific hormone being tested, and other variables.
In 2001, the U.S. Food and Drug Administration (FDA) analyzed a variety of 29 product samples from 12 compounding pharmacies and found that 34% of them failed one or more standard quality tests. Additionally, 9 of the 10 failing products failed assay or potency tests, with all containing less of the active ingredient than expected. ACOG recommends that all bioidentical hormones should be considered to have the same safety issues as those hormone products that are approved by the FDA. Furthermore, bioidentical hormones may have additional risks unique to the compounding process.
The Endocrine Society released a position statement in 2006 on “Bioidentical Hormones” in October 2006,:
No medical or scientific evidence exists to support the idea that the adverse and/or beneficial effects found in the WHI resulted from the molecular structure of the synthesized hormones, nor is there any sound scientific evidence to show that a different or “customized” dose of hormones would have changed the outcome. If dosage and purity were equal, then all estrogen-containing hormone therapies, “bioidentical” or “traditional,” would be expected to carry essentially the same risks and benefits.
The controversies surrounding the safety and efficacy of “bioidentical hormones” illustrate the need for further scientific and medical scrutiny of these substances. Until such studies are completed, physicians should exercise caution when prescribing “bioidentical hormones” and counsel their patients about the controversy over the use of these preparations.
The Endocrine Society is concerned that patients are receiving potentially misleading or false information about the benefits and risks of “bioidentical hormones.” Therefore, the Society supports FDA regulation and oversight of all hormones—“bioidentical” and traditional—regardless of chemical structure or method of manufacture.
A Cochrane meta-analysis on testosterone in menopause concluded, “There is evidence that adding testosterone to HT has a beneficial effect on sexual function in postmenopausal women.”
In a 2005 Position Statement on testosterone therapy in postmenopausal women, NAMS concluded:
Postmenopausal women with decreased sexual desire associated with personal distress and with no other identifiable cause may be candidates for testosterone therapy. Testosterone treatment without concomitant estrogen therapy cannot be recommended because of a lack of evidence. Laboratory testing of testosterone levels should be used only to monitor for supraphysiologic levels before and during therapy, not to diagnose testosterone insufficiency.
Transdermal patches and topical gels or creams are preferred over oral products because of first-pass hepatic effects documented with oral formulations. Custom-compounded products should be used with caution because the dosing may be more inconsistent than it is with government-approved products.
Testosterone products formulated specifically for men have a risk of excessive dosing, although some clinicians use lower doses of these products in women. Testosterone therapy is contraindicated in women with breast or uterine cancer or in those with cardiovascular or liver disease. It should be administered at the lowest dose for the shortest time that meets treatment goals. Counseling regarding the potential risks and benefits should be provided before initiating therapy.
Risks? You bet! Researchers from Boston’s Brigham and Women’s Hospital and Harvard Medical School analyzed data on more than 120,000 women in the Nurses’ Health Study and found the more than 800 women who had taken estrogen with testosterone – which was targeted at boosting depressed mood and sex drive and lessen bone deterioration – faced a higher risk of breast cancer. The combination of estrogen and testosterone raised the risk of developing breast cancer by 77 percent compared to women not taking hormones. Estrogen therapy alone carried a 15 percent higher risk and estrogen combined with progesterone – taken to cut the attendant risk of ovarian cancer – carried a 58 percent higher risk.
Unresolved safety issues led to the FDA to reject the testosterone patch in December 2004, citing substantial concerns over cardiovascular safety and breast cancer risk. One review concluded, “Don’t recommend testosterone products to women with menopausal symptoms.”
The most commonly used group of natural products for vasomotor symptoms are phytoestrogens or “plant estrogens.” The three mains kinds are isoflavones, lignans, and coumestans. Isoflavones are the most potent and the most common in supplements. Phytoestrogens are also found in many common food sources. Foods containing phytoestrogens are probably safe, but advise patients with breast cancer concerns to avoid excessive consumption of these foods or concentrated phytoestrogen supplements.
Soy (Glycine max) and soy isoflavones are the most commonly used phytoestrogens…and the best studied. The NMCD review concludes, “Consuming soy protein, 20 to 60 grams per day, containing 34 to 76 mg of isoflavones, seems to modestly decrease the frequency and severity of hot flashes in menopausal women.” Soy extracts in tablet form, providing 35-150 mg of isoflavones daily, also seems to have beneficial effects. Soy supplements appear to be helpful in about 30% of postmenopausal women. One review concluded that isoflavone preparations seemed to be less effective than soy foods.
However, a 2005 systematic review of soy was less positive: “The available evidence suggests that phytoestrogens available as soy foods (and) soy extracts… do not improve hot flushes or other menopausal symptoms…Of the 8 soy food trials reporting hot flush frequency outcomes, 7 were negative. Of the 5 soy extract trials reporting hot flush frequency, 3 (including the 2 largest trials) were negative.” According to the NMCD, “The reason for these conflicting findings is not clear. But it may be due to high placebo response rates in some trials. Patient expectations of treatments can significantly impact perceived benefits.”
Nevertheless, NAMS recommends “for women with frequent hot flashes, clinicians may consider recommending soy foods or soy isoflavone supplements. Most hot flash studies used isoflavone amounts of 40 to 80 mg/day…Effects, if any, may take several weeks. Isoflavones exhibit a low incidence of side effects, although caution is advised when estrogenicity is a concern.” ACOG concludes, “Soy and isoflavones may be helpful in the short-term (<2 years) treatment of vasomotor symptoms.” NAMS adds, “Soy and isoflavone intake over prolonged periods may improve lipoprotein profiles and protect against osteoporosis. Soy in foodstuffs may differ in biological activity from soy and isoflavones in supplements.”
When ConsumerLab.com (an independent quality testing lab that requires a subscription to access their full test results ) tested soy isoflavones in 2005, two of twelve supplements failed testing because they contained, respectively, 50% and 59% of their listed total isoflavones and were low in specific isoflavones (daidzin/daidzein and glycitin/glycitein). A soy/red clover isoflavone product also failed because it would not break apart properly, suggesting that some of its ingredients might pass through the body unused. The other products passed the testing — they contained their key ingredients, had no contaminants, and broke apart properly for absorption.
Some women might ask about ipriflavone. It’s a synthetic soy derivative. Some research suggests that it reduces bone loss. But, unfortunately, it does not have any effect on hot flashes.
Some research suggests that constituents in soy, genistein and daidzein, may stimulate existing breast tumor growth and antagonize the effects of tamoxifen. The NMCD says, “Tell women with breast cancer who take tamoxifen not to use soy.”
Breast cancer survivors often have significant problems with hot flashes. Although soy seems to be helpful for some with hot flashes, it doesn’t seem to be effective for women who have hot flashes related to breast cancer treatment. Caution patients on warfarin to be cautious about adding soy to their diet. Soy can reduce the international normalized ratio (INR) and decrease warfarin effectiveness.
Red clover (Trifolium pratense) is widely promoted and used for hot flashes. It contains isoflavones similar to soy, but red clover it not nearly as well studied as soy. The extract most researched (Promensil [Novogen, Australia], a standardized product containing 40 mg isoflavones) was independently tested by ConsumerLab.com and did pass quality testing. A 2005 systematic review concluded, “The available evidence suggests that phytoestrogens available as…red clover extracts do not improve hot flushes or other menopausal symptoms. Red clover trials showed no improvement in hot flush frequency.” The NMCD says, “Taking red clover extract does not significantly reduce hot flashes compared to placebo. Don’t recommend it.”
Flaxseed (Linum usitatissimum) is a rich source of lignan phytoestrogens, as well as omega-3 fatty acids, alpha-linolenic acid, and fiber. Some research suggests that dietary flaxseed used in place of other dietary fats might be as effective as estrogen for mild menopausal symptoms. The NMCD says, “This is promising, but preliminary. There isn’t enough convincing evidence to recommend this approach for all women. But flaxseed is a healthy alternative to other fats and very safe. Some women may be interested in giving it try.” However, flaxseed oil has little or no lignan because lignans are bound to the fiber, which is lost when the oil is pressed from the seeds.
Chasteberry (Vitex agnus-castus) seems to bind to estrogen receptors and to stimulate progesterone expression. Also, chasteberry also appears to stimulate the growth of experimental breast cancer cells. The NMCD recommends, “Like other phytoestrogens, tell women with a history of breast cancer that chasteberry might not be safe.” The NMCD review concludes, “There is some evidence that chasteberry might help for symptoms of premenstrual syndrome. But there’s no reliable evidence that it helps for menopausal symptoms.”
Other herbs are used to treat menopause…kudzu (Pueraria lobata), alfalfa (Medicago sativa), hops (Humulus lupulus), and licorice (Glycyrrhiza glabra). The NMCD concludes, “Tell patients there’s no reliable evidence these are effective for menopausal symptoms.”
Chinese ginseng (Panax ginseng, Panax schinseng), also called “Asian,” “Japanese,” or “Korean ginseng,” doesn’t seem to help for hot flashes. The NMCD warns, “Tell women to think of ginseng as possibly having estrogenic effects and tell women with a history of breast cancer to avoid ginseng.” Even though ginseng might have some estrogenic effects, it doesn’t seem to help for hot flashes. But there is preliminary research that suggests it might help menopausal symptoms such as fatigue, insomnia, and depression. According to the NMCD, “Until more is known, don’t recommend it.” Furthermore, ConsumerLab.com has found problems in many ginseng supplements over the years. In a 2006 review, six of thirteen products failed to pass testing due to lead contamination, lack of ingredient, or inadequate labeling.
Dehydroepiandrosterone (DHEA) is an endogenous weak androgen and a precursor to other sex steroids. One University systematic review of DHEA for menopause concluded, “Although circumstantial evidence might suggest potential benefits of DHEA therapy, until large randomized controlled trials using validated scales and hard safety endpoints have been conducted, the prescription of DHEA therapy for treatment of any specific symptoms cannot be recommended.” In addition, since DHEA can be converted to androgens such as testosterone, it can sometimes cause unwanted cosmetic side effects such as an increase in facial hair, acne, and deepening of the voice.
In a 2002 Product Review, ConsumerLab.com found that 3 of the 17 DHEA supplements it tested contained less than their claimed amounts of this hormone. DHEA hype far exceeds DHEA research. For menopausal symptoms, DHEA probably won’t help much, if at all. The NMCD says, “Tell women that it is too soon to recommend DHEA for menopausal symptoms.”
Women use many centrally acting natural products…mostly for non-vasomotor menopausal symptoms. The NMCD recommends that Valerian (Valeriana officinalis) is “possibly effective” for insomnia and that Ginkgo (Ginkgo biloba) may be effective for memory or cognition problems. The NCMD reports that St. John’s wort (Hypericum perforatum) is “possibly effective” for mild to moderate depression. ACOG agrees, concluding, “St. John’s wort may be helpful in the short-term (<2 years) treatment of mild to moderate depression in women.” Nevertheless, NCMD points out that “Although valerian can be effective for insomnia and St. John’s wort can be effective for mild to moderate depression, there’s no reliable evidence that they help for these conditions when they are associated with menopause.”
Black cohosh (Actaea racemosa, formerly Cimicifuga racemosa) is among the top-selling herbs in the U.S. Do not confuse black cohosh with two unrelated plants, blue cohosh (Caulophyllum thalictroides) and white cohosh (Actaea alba) as these have toxic effects. It’s not clear how black cohosh might work for menopausal symptoms. It has been suggested black cohosh might act as an agonist at serotonin receptors and it appears to increase markers of bone formation. In addition, there is speculation that black cohosh has SERM-like activity. Virtually all clinical trials on black cohosh have been conducted with a proprietary formula of black cohosh root extract developed in Germany (Remifemin; GlaxoSmithKline) and standardized to contain 20 mg of the root extract, including 1 mg triterpene glycoside 27-deoxyactein (now known as 26-deoxyactein), per tablet.
According to the NMCD, “Studies using other non-commercial black cohosh extracts have been mostly negative. In fact, one of the most recent, and highest quality studies found that a non-commercial black cohosh extract 160 mg daily standardized to 2.5% triterpene glycosides did not significantly reduce hot flash frequency or other vasomotor symptoms after 3, 6, or 12 months of treatment. The problem is, this product is different than all of the others, which makes it difficult to make an apples-to-apples comparison of the findings.” NAMS recommends, “With its low incidence of side effects, a black cohosh supplement (two 20-mg tablets daily of a 27-deoxyactein standardized preparation) taken for less than 6 months is likely to do no harm and may provide relief of mild hot flashes.”
The NMCD agrees, “Black cohosh seems to be safe and well tolerated. Tell women that black cohosh might be worth a try.” ACOG also concludes, “Black cohosh may be helpful in the short-term (<6 months) treatment of women with vasomotor symptoms. When ConsumerLab.com tested nine black cohosh supplements in 2005, all passed testing
Dong quai (Angelica sinensis) is used in traditional Chinese medicine, usually in combination with other herbs. In the U.S. dong quai is often used as a single-ingredient remedy for hot flashes and when used alone, does not seem to be effective for relieving hot flashes. One reviewer has pointed out that “practitioners of Traditional Chinese Medicine (TCM) counter that (they) do not use the herb alone…Typically, dong quai is used in conjunction with at least four other herbs…and traditional formulas containing dong quai are highly successful in clinical practice, suggesting there is a synergistic effect among the herbs that was not detected in this single herb study.” However, there’s also a concern that some of dong quai’s constituents might be carcinogenic. So, the NMCD recommends, “Tell women not to use it.”
Evening primrose oil (Oenothera biennis) is sometimes promoted to relieve hot flashes. It doesn’t seem to be effective for relieving hot flashes. Even though a 2005 Product Review by ConsumerLab.com found that all four evening primrose oil products passed quality testing, until there’s better evidence supporting its use for menopausal symptoms, the NMCD concludes, “Don’t recommend it.”
Wild yam (Dioscorea villosa) is often promoted as a source of “natural hormones.” It is often used as a topically applied cream for menopausal symptoms. Promoters falsely claim that a component of wild yam, diosgenin, is converted by the body to progesterone and/or dehydroepiandrosterone (DHEA). Diosgenin can be converted to hormones in the laboratory, but not in the body. Wild yam is not effective for hot flashes. The NMCD bluntly concludes, “Tell women not to waste their money on wild yam creams.”
Vitamin E, 800 IU/day, is an option to try for hot flash relief, although clinical evidence is mixed. One RCT found, “There’s no reliable evidence that vitamin E helps menopausal women. And, the NMCD concludes, “There’s no reliable evidence that vitamin E helps menopausal women.” Nevertheless, NAMS concludes, “Because vitamin E seems to be nontoxic at low doses, inexpensive, and available without a prescription, it is a reasonable option for a trial. Effects, if any, may take weeks.” Like all natural medicines (herbs, supplements and vitamins – which are unregulated in the U.S.), there can be manufacturing issues. In 2004, ConsumerLab.com found that five of fifteen vitamin E products failed to pass their quality testing.
ACOG’s Recommendations for Counseling Patients about Complementary and Alternative Medicine
- All patients should be asked about their use of herbal therapies and dietary supplements. Use of these products should be documented in the patient’s chart.
- “Natural” is not an assurance of safety or efficacy and potentially dangerous drug-herb interactions occur.
- Lack of standardization of botanicals may result in variability of content and efficacy from batch to batch, from a single manufacturer, or between manufacturers.
- Lack of quality control and regulation may result in contamination, adulteration, or potential misidentification of plant products. Further, errors in compounding may result in toxic or lethal outcomes in custom-blended herbal preparations.
- Several botanicals have known adverse effects and toxicities.
- Botanicals should not be taken in larger than recommended doses or for longer than recommended duration.
- Because the expected placebo response for menopausal treatment ranges from 10% to 30%, a small positive response to any treatment, conventional or alternative, may not necessarily represent a pharmacologic effect.
- Anecdotal experience is not a substitute for well-constructed clinical trial.
- Nonetheless, the effect of support, counseling, and empathetic care should not be discounted or dismissed.
ACOG’s advice to our patients seems wise:
- If you decide to use alternative therapies, be sure to tell your physician.
- Some treatments have the potential to cause drug interactions with other medications you are using. Your doctor may recommend that you be monitored more closely for safety’s sake while using alternative or complementary therapies.
- Remember, too, that dietary supplements, including herbal products, are not as strictly regulated by the federal government as are prescription and over-the-counter drugs. As a result, potency may vary from product to product, or even from batch to batch of the same product.
- Bear in mind that just because alternative therapies are referred to as ‘natural’ remedies doesn’t mean they’re without risks or side effects. For this reason, you should take the same care when using alternative supplements or products as you would when using any over-the-counter or prescription medication.
- Be sure to inform your physician that you are using these therapies, as well as any prescription medications, during medical visits.