Menopause


Figure 1: Increasing Effect of Different Treatment Strategies for Reducing Hot Flushes


Placebo


Soy/vitamin E Black cohosh Clonidine


Antidepressants (e.g. venlafaxine) Gabapentin/preglabaline Progestins


Probably the best investigated group of agents is the selective serotonin re-uptake inhibitors (SSRIs) venlafaxine, paroxetine, sertraline and fluoxetine. A recent meta-analyses of placebo-controlled trials reported a consistently superior effect for all SSRIs over placebo.8


effective from 37.5 to 150mg. The recommended dose is 75mg/day with 37.5mg/day in the first week to overcome initial nausea. Venlafaxine is more effective than clonidine in reducing hot flushes in breast cancer patients.9


Complementary Medicine


The ability of complementary therapies that contain isoflavones (naturally occurring compounds that have oestrogenic effects) to reduce or prevent hot flushes has been investigated. Such therapies include black cohosh, dong quai, red clover and soy proteins. The potential benefits of vitamin E have also been investigated. However, placebo-controlled clinical trials have failed to demonstrate a significant benefit of any of these agents in either healthy post-menopausal women or women with a history of breast cancer.19–22


Venlafaxine is


Acupuncture has long been investigated for its possible effect on menopausal symptoms. It has demonstrated superiority to controls, as confirmed in a new trial.23


Despite this, acupuncture failed to


Paroxetine also demonstrated a significant effect in reducing the frequency and composite score for hot flushes. A dose-dependent effect was not demonstrated in either of the trials, but there were fewer adverse events with the lower dosages (10 or 12.5mg).10,11


Concerns have been raised regarding the interference of SSRIs with tamoxifen metabolism. Tamoxifen is metabolised via CYP 3A and CYP 2D6 to endoxifen, the active metabolite. Studies have demonstrated that paroxetine is a very potent CYP 2D6 inhibitor resulting in a reduced endoxifen concentration comparable to that in homozygous genotype variants, whereas venlafaxine is the least potent inhibitor.12 least for tamoxifen users, other agents might be preferred.


In a recent randomised trial, 12 weeks of acupuncture was compared with 12 weeks of venlafaxine treatment. The results indicated an identical effect in reducing hot flushes at the end of therapy.25


demonstrate an overall superior effect compared with sham puncture in another trial.24


After treatment cessation, the venlafaxine patient reported a quicker increase in hot flushes. After three months there was no difference in the treatment arms. Side effects (e.g. nausea, dry mouth, dizziness and anxiety) were reported only in the venlafaxine group. Acupuncture had the additional benefit of increased sex drive in some women and most reported an improvement in their energy, clarity of thought and sense of wellbeing.25


Therefore, at


The second non-hormonal agent is gabapentin, a gamma-aminobutyric acid (GABA) analogue that has been used in a variety of neurological and psychiatric disorders. This agent has also been demonstrated to be effective in controlling hot flushes. The exact mechanism is unclear, but it may reduce noradrenergic hyperactivity.


Gabapentin was first reported to be a promising new therapy for the relief of hot flushes in a case series report.13 two pilot trials, again reporting promising results.14,15


This was followed by A subsequent


placebo-controlled trial in 59 post-menopausal women reported that gabapentin 900mg/day given over 12 weeks decreased the hot flush frequency rate by 45 and 54%, respectively.16


This was


significantly better than the placebo, which had decreases of 29 and 31%, respectively. The adverse effects of gabapentin included somnolence and dizziness. A meta-analysis of all placebo-controlled trials confirmed the single trial results and showed that 900mg/day of gabapentin seems to be the optimal dose.


After six weeks of treatment with pregabalin, another GABA agent, there was a significant reduction in hot flush score of 65% with 75mg twice daily and 71% with 150mg twice daily compared with 50% with placebo (p=0.009 and p=0.007, respectively). Its effects appear to be roughly comparable to those reported with gabapentin and SSRIs.17


A hot flush reduction of 60% is good, but not good enough. The combination of gabepentin and a SSRI antidepressant was therefore compared with gabapentin alone.18


The data from


the trial failed to give any suggestion that the combination is more efficacious than gabapentin alone. Despite this, it was demonstrated that the combination resulted in an increased self-reported rate of nervousness.


40


Urogenital Symptoms Vaginal Dryness


Vaginal dryness occurs as a result of oestrogen deprivation. It is commonly reported by women who are going through the menopause


EUROPEAN OBSTETRICS & GYNAECOLOGY


Hypnosis as a treatment appears to have some effect. It led to a reduction in hot flushes compared with an untreated control group. By the end of the treatment period hypnosis resulted in a significant decrease in hot flush score of 68% (p=0.001). There were also additional improvements in self-reported anxiety, depression and sleep.26


In a pilot study, a stellate ganglion block was investigated to reduce hot flushes. Preliminary data look promising, with a probable long-term reduction in the severity and/or frequency of hot flushes and improvement in quality of sleep.27


Hormones


The most effective agents in reducing hot flushes are steroidal hormones. Given the concerns raised by the HABITS trial, HRT should not generally be recommended. Exceptions might be patients with a hormone-receptor-negative carcinoma. Oestrogens might be preferred to combination therapies, at least in women who have undergone a hysterectomy. Otherwise a progestin has to be given at least every three to four months to prevent endometrial hyperplasia and induction of endometrial cancer. HRT should only be applied after a careful risk–benefit assessment and exhaustion of non-hormonal alternatives, and in close collaboration with the gynaecologist.


In a subsequent trial, a single injection of 400mg MPA was significantly more effective in reducing hot flushes than venlafaxine.29


Progestins as sole treatment are able to reduce hot flushes almost completely. MPA intramuscularly 500mg three times every two weeks seems to be more effective in maintenance of response after treatment cessation than megestrole acetate (40mg orally four times daily for six weeks).28


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