The onset of vasomotor symptoms occurs in the perimenopausal state. Hot flushes begin as a sudden sensation of heat centered on the face and upper chest which rapidly becomes generalised. The sensation of heat lasts a few minutes, can be associated with profuse perspiration, and can be followed by chills and shivering. Symptoms result from inappropriate peripheral vasodilatation leading to rapid heat loss and a decrease in core body temperature, and shivering then occurs to restore the core temperature to normal.
Approximately two-thirds of postmenopausal women will experience hot flushes, with 10–20% experiencing severe symptoms. For most women, symptoms spontaneously resolve within a few years. However, one third of postmenopausal women will experience symptoms for up to 5 years, and 20% will have symptoms for up to 15 years.
Risk factors for developing hot flushes include higher body mass index, tobacco use, African American or Caucasian ethnicity, and surgically-induced menopause. For women with surgically-induced menopause, 90% experience hot flushes during the first year. Vasomotor symptoms appear to be less common in Asian women, which may be secondary to cultural differences with respect to reporting symptoms. Dietary factors may also contribute to the difference in risk as the Asian diet is higher in soy intake, and soy has been shown to be an effective treatment for hot flushes in some studies.
Hot flushes represent thermoregulatory dysfunction, thought to occur at the level of the hypothalamus in response to estrogen withdrawal. However, the exact mechanism of this dysfunction is unknown. Core body temperature is normal at the beginning of a flush but then falls below normal after, indicating rapid heat loss. Premenopausal women initiate mechanisms to dissipate heat when the core body temperature increases by 0.4°C. However, the thermoneutral zone is narrowed in women with vasomotor symptoms, and postmenopausal women initiate mechanisms to dissipate heat at lower increases in body temperature. Hot flushes may be initiated by endogenous central opioid peptide withdrawal, and estrogen has been shown to increase activity of this peptide. In an animal model in which hot flushes are induced by opiate withdrawal, estrogen administration eliminated such temperature changes.
Pharmacological treatment options
Hormone replacement therapy (HRT) is the most effective treatment of vasomotor symptoms, improving symptoms in 80–90% of women. The Women's Health Initiative (WHI), a randomised, placebo-controlled trial evaluating the effects of hormone therapy in postmenopausal women, demonstrated that the risks of hormone replacement therapy outweigh its benefits. In the WHI, over 16 000 postmenopausal women were randomised to receive either conjugated equine estrogen (CEE) with progesterone or placebo. The study was stopped early after 5.2 years, secondary to a statistically significant higher number of cardiovascular events, pulmonary embolisms, and breast cancers in the treatment arm. As part of the WHI, over 10 000 postmenopausal women who had undergone hysterectomy were randomised to receive either CEE daily or placebo. This trial was also stopped early after 6.8 years secondary to a higher number of cases of stroke in the treatment arm. Given the older age of the WHI participants, the study results may not be valid for younger postmenopausal women. A secondary analysis of the WHI data, published in 2007, suggested that there was not an increased risk of cardiovascular events among menopausal women who were younger or who had recent onset of menopause. Furthermore, Fournier et al. published their study in 2008 which demonstrated that the risk of breast cancer among postmenopausal women receiving combination HRT varied significantly according the type of progestogen used. However, while this study was very large including over 80 000 participants, interpretation of its data is limited as it was a prospective cohort study.
Because of its potential risks, HRT is not first-line in the treatment of most postmenopausal symptoms because other treatments that are equally or more effective are currently available. Nevertheless, HRT remains the most effective treatment of vasomotor symptoms, and vasomotor symptoms remain an indication for HRT use according to the Medicines and Healthcare products Regulatory Agency (MHRA) and the United States Food and Drug Administration (FDA).[15, 16] However, both the MHRA and US FDA advise prescribing the lowest dose for the shortest duration possible. Given the potential adverse events associated with HRT, other treatment options for vasomotor symptoms have emerged over recent years, including behavior modification, pharmacological agents, as well as herbal and complementary medicines.
Behaviour modification, when applicable, should be the first-line treatment for women with vasomotor symptoms. For women with mild symptoms, keeping the room temperature cool and dressing in layered clothing may provide adequate relief. Small studies have demonstrated that paced respiration, a relaxation-based method which consists of slow, rhythmic breathing, has a modest effect on hot flushes. Cigarette smoking has been associated with a higher risk of experiencing vasomotor symptoms, and the risk appears to be directly proportional to the number of cigarettes smoked. Exercise, while beneficial in other respects, has not been consistently shown to improve hot flush symptoms. Given the additional health benefits of regular exercise and tobacco cessation, both behavior changes should be encouraged as they may also improve vasomotor symptoms.
Data from randomised, placebo-controlled trials have consistently demonstrated a significant placebo effect of a 20–50% reduction in hot flush symptoms, highlighting the importance of a placebo arm in trials investigating treatment options for vasomotor symptoms. Conclusions from therapy trials that lack a placebo arm may therefore be limited. Several pharmacological agents have been shown to be effective in treating vasomotor symptoms. The most common agents used are clonidine, gabapentin, selective serotonin reuptake inhibitors, and venlafaxine. These agents have been demonstrated to reduce vasomotor symptoms at twice the rate of placebo in randomised, placebo-controlled trials.
Nonpharmacological treatment options
Approximately 50–75% of postmenopausal women will use nonpharmacological agents including vitamins and herbal medicines to treat their hot flushes. A randomised controlled trial of 120 women receiving 800 international units of Vitamin E daily demonstrated a modest benefit over placebo, with an average reduction of one hot flush per day.
Many herbal medicines have been studied in the treatment of vasomotor symptoms, and the degree of regulation of these products varies from country to country. In countries in which there is little or no regulation, the amount of active ingredient in a product may vary from sample to sample and may also include other additional herbal agents. The results of studies investigating the effect of a variety of botanicals on vasomotor symptoms are limited and conflicting. In addition, the use of products that are not chemically identical in different studies make comparisons among studies difficult. There are no consistent data to support the use of dong quai, evening primrose oil, ginseng, gingko biloba, chasteberry, kava kava, or wild yam in the treatment of vasomotor symptoms, and there have been several positive, as well as neutral, studies published on soy, red clover, and black cohosh.[6, 21, 22] Of the complementary therapies, soy, red clover, and black cohosh have been the most heavily investigated.
Soy is the most common plant containing phytoestrogens; plant-based estrogens that bind to estrogen receptors. Newton et al. reviewed 16 randomised controlled trials investigating the effect of soy on hot flush symptoms. Eight trials demonstrated that soy was superior to placebo, and eight demonstrated that soy was comparable to placebo in the treatment of hot flushes. From the positive studies, the average reduction in symptoms with soy ranged from 25–55%, compared to an average reduction of 20–30% with placebo. Interestingly, most of the trials on soy (average length of 12 weeks, with a range of 4–52 weeks) were longer in duration than trials on pharmacological therapies (average length of 4–6 weeks, with a range of 4–36 weeks). Given the natural history of vasomotor symptoms, longer trials are more likely to demonstrate less of a treatment effect, therefore possibly underestimating the effects of soy.
There have been no adverse effects associated with soy. There are data to support the claim that phytoestrogens act like selective estrogen receptor modulators, binding to estrogen receptors and exerting estrogenic and antiestrogenic effects. However, the estrogenic and antiestrogenic effects may depend on the specific tissue and concentration of circulating endogenous estrogen. Therefore, phytoestrogens may cause potential harm in women with estrogen-dependent tumors and may also antagonise the antitumor effect of tamoxifen. Because of this potential harm, phytoestrogens are typically avoided in women who have a personal history of breast cancer, who are at high risk for breast cancer, or who are undergoing treatment with tamoxifen.
Red clover (Trifolium pretense) is a legume that also contains high amounts of phytoestrogens. Two meta-analyses have demonstrated that there is no statistically significant difference between red clover and placebo in treatment of vasomotor symptoms.[6, 23] There have been concerns about red clover altering platelet aggregation; however, a recent randomised controlled trial demonstrated that there were no significant adverse events with red clover taken daily for 1 year.
Black cohosh originates from the plant, Cimicifuga racemosa, which is native to the eastern United States and Canada. It has been used in Europe, particularly in Germany, to treat hot flushes for over 50 years. It is the active ingredient in standardised products which have been used in most clinical studies. Preparations of black cohosh may contain phytoestrogens and therefore should also be avoided in the same patient populations who should avoid soy and red clover. Several small randomised, controlled trials comparing black cohosh to placebo in the treatment of hot flushes have demonstrated conflicting results, but a large randomised, placebo-controlled trial of 1-year duration was published in 2006. A total of 350 women between 45 and 55 years old were randomised to one of five arms: 1) Black cohosh 160 mg daily, 2) a multibotanical containing 200 mg black cohosh daily, 3) the multibotanical plus dietary soy counselling, 4) CEE 0.625 with or without 2.5 mg progesterone daily, or 5) placebo. Fifty-two per cent of the women were perimenopausal. After 1 year of treatment, all three black cohosh treatment arms were comparable to placebo. Women in the hormone therapy arm had a statistically significant reduction in symptoms compared to the other treatment arms and placebo (59.7% vs. 0% reduction in symptoms beyond placebo, respectively). The authors concluded that black cohosh was not superior to placebo in the treatment of hot flushes.
Despite these results, it may still be reasonable to recommend the use of soy, red clover, and black cohosh given that:
- there are no significant adverse side effects associated with these agents as long as they are used in women who do not have a personal history of breast cancer, who do not have high risk of breast cancer, and who are not taking tamoxifen;
- there is a significant placebo effect found in all randomised, placebo-controlled therapy trials for vasomotor symptoms. Women would likely experience a placebo effect of a 20–30% reduction in symptoms with the use of black cohosh or red clover and possibly achieve an even greater reduction in symptoms with the use of soy.
There are limited data on the effect of other complementary therapies such as acupuncture, reflexology and magnetic therapy on vasomotor symptoms. Current, small studies demonstrate that their benefits are no greater than placebo in the treatment of vasomotor symptoms.[27, 28] Additional, larger studies in the future will help determine the efficacy of these complementary therapies in the treatment of hot flushes.