Megestrol acetate (Megace®)

Megestrol acetate at a dose of 20mg/day (can use up to 40mg/day) reduced hot flushes by 73% compared with 26% in the placebo group in a double-blind randomised clinical trail (3), and is perhaps the most effective drug treatment excluding HRT. Some women can experience a flare of hot flushes in the first few days of use. Low-dose norethisterone 520mg can also be used. The main drawback of progestogens is the possibility of an initial flare of symptoms, when hot flushes may become worse. There is also a significant delay of about 20 days before beneficial effects are obtained. The long-term effects of progestogens include weight gain.

Tibolone (Livial, Organon)

This is a synthetic steroid with a mixed profile of oestrogenic, progestogenic and androgenic activity. It reduces vasomotor symptoms to a similar extent to combined HRT preparations. It is also effective in improving depression and libido, which may be an effect of its androgenic action. A randomised comparison has shown tibolone to be at least as effective as HRT in the management of menopausal symptoms (4). In addition it has beneficial effects on bone density. The side effects include weight gain, fluid retention, irregular vaginal bleeding, headache and increased growth of facial hair.

Preclinical studies have found that tibolone does not stimulate breast tissue and does not increase mammographic density in women (5). However, the Million Women study (6) found that there was a small increase in breast cancer risk in women taking Tibolone (relative risk 1.45). The aim of the study was to investigate the effects of specific types of HRT on the incidence and survival of women who developed breast cancer.

Organon is currently conducting a multinational, double blind; placebo controlled trial involving 2,600 women. The LIBERATE study (Livial intervention following breast cancer: efficacy, recurrence and tolerability endpoints) will assess the effect of tibolone on breast cancer recurrence, menopausal symptoms, bone loss and quality of life (7).

Venlaflaxine

This anti-depressant has been shown to reduce the frequency of vasomotor symptoms (8). In a study to determine the efficacy of venlafaxine in reducing hot flushes, 191 women were randomised into one of four treatments for 28 days. These were 37.5mg extended-release (ER) daily, 75mg ER daily, 150mg daily after titration, or placebo. The results demonstrated a reduction in the score of hot flushes from the baseline by 37% in women taking 37.5mg, 61% taking 75mg and 61% taking 150mg of venlafaxine.

All doses may cause nausea, which is temporary and which declines after about one week of therapy. Other side effects are dry mouth and a decrease in appetite. 75mg/day is the highest recommended dose for control of vasomotor symptoms. At higher doses, e.g. 150 mg, the side effects are greater and intolerable. The authors recommend that the starting dose should be 37.5mg/day and can be gradually increased to 75mg/day.

Clonidine

Studies examining the effects of clonidine in reducing hot flushes have produced conflicting results, but the largest randomised study has looked at the effects of 0.1mg/day in 194 post-menopausal women with breast cancer experiencing tamoxifen-induced hot flushes. It demonstrated that there was a greater decrease in hot flushes after 4 weeks of treatment in the clonidine group (37%) compared with the placebo group (20%) and after 8 weeks of treatment the reduction was 38% compared with 24% respectively. Mean quality of life scores were better in the clonidine group, however responses to both clonidine and placebo varied considerably. Therefore, further large randomised controlled studies are required. In this study the toxicity of clonidine was low, with difficulty sleeping being the only variable that differed significantly (9). Other known side effects of clonidine that can be problematic include postural hypotension, dry mouth, constipation and drowsiness.

Non-pharmacological interventions (detailed below) can be used alone or in addition to drug therapy. For such interventions there is a great sparcity of evidence to support their effectiveness. Therefore not all of the therapies mentioned are evidence based. However, some women report that they are helpful.

Relaxation therapy has been reported to reduce hot flushes in women with breast cancer. Different strategies reported to be helpful including progressive muscle relaxation, which involves slowly tensing and then releasing each muscle group individually (10), paced respiration, which is a technique using slow controlled diaphragmatic breathing (11), relaxation audio-tapes (12) and applied relaxation (13). Applied relaxation aims are to teach the client to recognise the early signs of anxiety and cope with it rather than be overwhelmed.  This method consists of different relaxation techniques to transfer into everyday situations.

Acupuncture may reduce hot flushes and is sometimes available through the NHS as a complementary therapy. Specific acupuncture techniques can be used for patients with troublesome hot flushes and night sweats caused by hormone manipulation in cancer patients.

An uncontrolled study of 22 women with breast cancer who had received unsuccessful conventional treatment for hot flushes was carried out to assess the effects of acupuncture. Analysis of data showed that 82% experienced effective relief from hot flushes and all reported some reduction in symptoms. However, results may have been influenced by lifestyle modifications, such as dietary changes (14). There have also been studies examining the effects of acupuncture in men experiencing hot flushes. A study evaluating a 10-week course of acupuncture in men with prostate cancer demonstrated a decrease in hot flushes in 70% (15).

However, further randomised controlled trials are required to clarify acupuncture points and frequency and duration of treatment. Studies evaluating acupuncture are underway.

Plant Phytoestrogens Phytoestrogens are plant oestrogens that can have a very weak oestrogen-like effect in people. Black cohosh contains phytoestrogens and soy and red clover products contain chemicals called isoflavones, which are one type of phytoestrogen. 

• Black cohosh is a member of the buttercup family and is a perennial plant that is native to North America. Anecdotally, it has been reported to improve hot flushes. Side effects include nausea and vomiting, headaches, dizziness, mastalgia and weight gain.
  Few studies have examined this alternative treatment and have generally been of a poor quality (16). One randomised controlled trial examining the effects of black cohosh on hot flushes in 85 women over a period of 60 days, failed to show any statistical differences between the treatment and the placebo arms, although there were reports of fewer sweating problems (17). The current recommended dose is 40-80 mg per day and at least 4 weeks of treatment may be required to experience any therapeutic benefits.
  The American College of Obstetricians and Gynaecologists has stated that black cohosh may be helpful for women with vasomotor symptoms, when used for six months or less (18).  As the current information is controversial, more quality studies are required to fully assess the potential benefits and adverse effects.
  There have been concerns about the potential toxicity and carcinogenicity of this therapy in long-term use. Recent research did not demonstrate oestrogenic activity in a study of assay systems (19).
  The Medicines and Healthcare products Regulatory Agency (MHRA) are keeping the safety of black cohosh under review (20)
• Soy has been evaluated for the treatment for hot flushes. Results of studies have been mixed with 7 randomised trials showing no effect and 4 showing a reduction in hot flushes (21). In the largest of these studies 177 women were randomised to soy tablets or placebo for 4 weeks and then rotated to the opposite arm for 4 weeks. The results showed that there was a 50% reduction in hot flushes in 38% of the women taking the placebo and 35% in the soy arm (22). The authors conclude that the soy product did not alleviate hot flushes in women who had had breast cancer.
  Some studies suggest that high isoflavone levels might increase the risk of breast cancer. Whereas, other studies show that soy may help prevent breast cancer (23). It is thought that dietary soy taken in moderation probably does not help or harm women with a history of breast cancer (24). Currently research data on soy is inconclusive. However, anecdotally some women have soy beneficial in managing hot flushes.
• Red Clover has been studied in few randomised controlled trials. A cross over study of 51 postmenopausal women that were randomised to either placebo or red clover (one Promensil tablet daily) found no significant differences between the two groups (25). Another study by Knight et al, involving 37 women, again showed no statistical differences between the placebo and red clover groups (26). Although the authors of this study note that the participants may have increased their dietary isoflavones, which may have masked the effects of the red clover (27).
  However, in a study of 30 women, a significant reduction in hot flushes was noted in the red clover group compared with those taking the placebo. At the end of a 16-week study period there women in the treatment group had a 48% decrease in the frequency and 47% reduction in severity of hot flushes. (28). In this study the participants were non-vegetarian and had a greater frequency of hot flushes than the women in the other two trials, which suggests that red clover may be beneficial for women with more severe hot flushes (27).

Cognitive behavioural interventions are treatment approaches using both cognitive (e.g., working with thoughts, attitudes and beliefs) and behavioural methods to change visible and hidden behaviours. Therapy may include discussion to clarify and challenge assumptions and to gain understanding about the situation; journal keeping, to assess own symptoms and triggers; relaxation exercises and problem solving. Clinical psychologists or cognitive behaviour therapists may facilitate the therapy.

Few studies have evaluated the effects of therapy on post-menopausal women experiencing hot flushes. Hunter and Liao compared cognitive behavioural therapy (CBT), HRT and no treatment in which both treatment groups demonstrated a 50% reduction in hot flushes. Those receiving CBT had reduced anxiety and depression scores compared to the HRT group (29). However, it is not clear whether relaxation alone would be as effective as CBT and more studies are need to evaluate the different elements of the intervention (30).

Vitamin E has been reported anecdotally to help reduce hot flushes.  One study evaluating the efficacy of Vitamin E showed no substantial differences between the placebo and Vitamin E group (31).  Whereas, a placebo controlled cross over study of 120 women taking 800IU of vitamin E daily had a 25% reduction in hot flushes compared to a 22% reduction in those taking the placebo (32). It is recommended that women should consult their doctor if they have heart disease, diabetes or hypertension before taking Vitamin E.

Where menopausal symptoms arise as a result of tamoxifen therapy Although there is no scientific evidence to support the theory, some patients report anecdotally that dividing the dosage and taking tamoxifen twice a day or taking the dose at night may be of benefit. Some women have reported that changing the brand of tamoxifen is beneficial.

Evening primrose oil Any evidence for the benefit of evening primrose oil is anecdotal only and randomised trials have shown little benefit. In a study comparing placebo to 2g of evening primrose oil over a 24-week period, 56 menopausal women were randomised. In the evening primrose oil group there was a statistically significant improvement in the number of night-time flushes. However, no other benefits were found (33).

Hypnosis has been used to treat a variety of disorders such as pain and anticipatory nausea. In this treatment, the hypnotherapist leads the client into a deeply relaxed state, during which the client is still conscious of the surroundings. The hypnotherapist can then use suggestion to benefit the client in different ways, such as feeling better or gaining some control over symptoms.

However, only one trial has examined the effects of hypnosis on hot flushes. A Canadian study recruited 14 women who had menopausal symptoms, 4 of which had had treatment for breast cancer. Following an introduction to hypnosis the women were treated in small groups for 1-hour sessions, once a week for 4 weeks. Gentle relaxation leading to light-trance hypnosis was carried out for the first 2 sessions and specific instructions were given in the final two sessions to reduce and block hot flushes.

The results demonstrated a statistically significant improvement in the duration and severity of hot flushes. Interestingly, the improvement in symptoms began around Day 14, attributing the benefits to the instructions given in the final 2 sessions of hypnosis. Although this study is the first of its kind, has a small sample size and recruited both healthy women and women with breast cancer, its results are promising and highlights the need for further research (34).  Further studies examining the benefits of hypnotherapy are currently underway.

Unfortunately, hypnotherapy is a profession that is unregulated and is not readily available on the National Health Service. To find a trained hypnotherapist, patients can contact the British Hypnotherapy Association.

Other methods
Some studies have demonstrated that exposure to cold can stop hot flushes. Suggestions include avoiding alcohol and spicy foods, good air circulation, wearing light cotton clothing, sipping cold drinks and lowering room temperature may lower core body temperature and offer some relief from symptoms (35).