Standard current treatment
Over the past decade, there has been much controversy about the use of HRT after the publication of the Women’s Health Initiative (WHI) and Million Women studies. Recent re-analysis of the WHI data, along with results from other studies, has clarified the benefits and risks of HRT for specific populations.1 It is now known that low-dose HRT has a better safety profile when initiated within 10 years of the menopause and before the age of 60.1,2 Starting HRT around the time of the menopause may even reduce the risk of cardiovascular disease and cognitive decline.1 Starting HRT 10 or more years after the last natural period is associated with increased risks.1
Women notice an improvement in their hot flushes within four weeks of starting HRT, with maximum benefits achieved by three months.3 Oestrogen-only replacement therapy should only be used in women who have had a hysterectomy. For women who still have a uterus, oestrogen is given continuously alongside a progestogen. The progestogen can either be given sequentially (if the woman is still menstruating) or continually (if there has been 12 months or more of amenorrhoea). The addition of progestogen is vital to provide endometrial protection against the development of endometrial hyperplasia or adenocarcinoma with unopposed oestrogen use.
Progestogens can be either given orally, transdermally in a patch (in combination with oestrogen), vaginally or via an IUS. Mirena is a good option if contraception is required, if other formulations have resulted in progestogenic side-effects or if heavy bleeding is experienced with sequential HRT. Prescribing oestrogen replacement therapy with micronised progesterone, dydrogesterone or non-oral therapy is useful for women who suffer from progestogenic side-effects such as fluid retention, mastalgia, headaches and mood swings.
HRT can be administered in various forms. Usually oral treatment is prescribed first line as it is cheaper and more acceptable to women. If oral administration is not tolerated or there are relative contraindications, oestrogen patches or gels can be tried. Non-oral therapy avoids first-pass liver metabolism, thereby avoiding increased synthesis of coagulation factors, triglycerides, CRP and sex hormone binding globulin.1
Contraindications to HRT
There are a number of absolute contraindications to the use of HRT. They include:
- A past medical history of breast cancer or an oestrogen-dependent cancer
- Venous thromboembolism (VTE)
- Current cardiovascular disease
- Uncontrolled hypertension
- Active liver disease
- Endometrial cancer
- Undiagnosed vaginal bleeding
Relative contraindications to the use of oral HRT include:
- Malabsorption problems
- Lactose intolerance
- Liver enzyme-inducing drug usage
- Increased VTE risk
- Liver disease
- Cardiovascular risk factors
A meta-analysis of observational studies has shown that the risk of VTE is highest when oral oestrogen is taken and in the first year of use.4 As non-oral HRT avoids first-pass liver metabolism, transdermal HRT users have the same risk of VTE as the baseline population.5
The WHI study suggested that long-term use of HRT was associated strongly with the development of breast cancer. However, recent re-analysis of this study, along with publication of several others, provides conflicting results. There appears to be little change in the risk of breast cancer in women using oestrogen replacement therapy, and so the addition of progestogen to HRT is key to the potentiation of breast cancer cells. But overall risks remain small.
HRT should always be given at the lowest effective dose to alleviate symptoms, and for the shortest duration of time. In general, the use of HRT should be assessed on an annual basis, with the GP assessing any potential risk and the woman assessing the benefits.3 Any potential breast cancer risks of using HRT start from the age of 50. Use of HRT for less than five years after this age is unlikely to result in serious adverse effects.3 Prolonged use is acceptable, provided that women are fully informed of the potential risks.
There are various non-hormonal medications that can be prescribed for help with hot flushes, although recent NICE guidelines suggest these should not be routinely offered as a first-line treatment for vasomotor symptoms alone.5,6 Clonidine is the only non-hormonal drug with a licence for this. A meta-analysis has shown that it is slightly better than placebo at controlling flushes.2 It can be given at a dose of 50µg to 100µg twice daily, but is associated with nausea, dry mouth, dizziness, sedation and insomnia.3
Low-dose SSRIs and SNRIs may improve hot flushes. A study of postmenopausal women found there was a mean decrease of hot flushes by 37% in the placebo group, 62% in the group taking 12.5mg paroxetine daily, and 65% in the group taking 25mg paroxetine daily.7 Paroxetine should be started at 12.5mg and can be increased to 25mg a day, while fluoxetine should be started at 10mg and increased to 20mg a day, depending on symptom control. SSRIs are associated with nausea and decreased libido.3
The best evidence exists to support the use of venlafaxine, which should initially be started at 37.5mg daily and increased to 75mg a day if needed. Venlafaxine is associated with nausea, drowsiness, blurred vision, dry mouth and decreased libido. It should be noted that higher doses of SSRIs and SNRIs appear to be no more effective than low to moderate doses for symptom control.7
Gabapentin has also been shown to decrease hot flushes by around 50% when compared with a placebo.4 Its dose should be slowly increased by 300mg at weekly intervals to a maximum dose of 900mg a day.2 To avoid associated troublesome side-effects, such as dry mouth, drowsiness and dizziness, the patient could try taking this at night.
For women in whom oestrogen-containing HRT is contraindicated, oral progestogen can be tried. Medroxyprogesterone acetate 10mg per day may reduce flushes and sweats by 60%, but its use is off label. Norethisterone 5mg per day can also be tried. Recent studies looking at the use of HRT have suggested that the breast cancer risk may be higher in women using combined (oestrogen and progestogen) HRT compared with oestrogen replacement therapy. To date, there are no long-term data on the safety of unopposed progestogen, so it is advised to avoid the use of this in women with a history of breast cancer.
Transdermal progesterone cream has been marketed over the past 10 years or so for skeletal protection and management of menopausal symptoms. There are no data available that confirm the cream has any benefit on hot flushes, bones or the endometrium.3
Non-drug options, including over-the-counter options
Sufferers of vasomotor symptoms often find that their symptoms can be dramatically improved simply by making basic lifestyle changes. Women should wear light, natural-fibre clothing and try to sleep in a cool room. Some women find the Chillow Pillow (a personal cooling pad) and Koolabanda (a cooling scarf) useful. Both can be purchased online.
Undertaking regular exercise may decrease the incidence of hot flushes, and women should be encouraged to spend two and a half hours per week engaging in moderate aerobic activity. Smoking cessation will help with hot flushes, decrease the risk of osteoporosis and improve an individual’s response to the use of HRT. Maintaining a normal body mass index of 25 or less will also help these symptoms, along with avoiding alcohol, spicy foods, hot drinks and caffeine.
Many menopausal women use complementary and alternative therapies, believing that they are safer and ‘more natural’, but there are limited data to suggest they reduce vasomotor symptoms.8 There are no long-term safety studies for herbal remedies and they may interact with other medications, particularly anticoagulants, so caution must always be exercised before use.3,5 In addition, some herbal products contain oestrogenic compounds, which may adversely affect women who have a hormone-dependent cancer.3
Red clover extracts may reduce hot flushes by 1.5 flushes per day, according to some studies.8 Black cohosh may alleviate hot flushes as well as emotional symptoms, but the Medicines and Healthcare Products Regulatory Agency has warned against its use as it is associated with liver damage.
Dietary phytoestrogens (found in soy products, nuts, legumes, oil seeds, red clover and wholegrain cereals) are related structurally to oestradiol.3 These may reduce hot flushes but can cause breast tenderness, weight gain and menstrual changes.5,8
A randomised controlled double-blinded trial that compared a daily dose of 0.625mg of conjugated equine oestrogen with phytoestrogens over a six-month period showed that phytoestrogens decrease hot flushes as effectively as oestrogen.9 There is no safety evidence available regarding the use of phytoestrogens in women with oestrogen-dependent cancers or venous thromboembolism.
What’s newly available?
There are few new products available for the treatment of hot flushes. In the near future, we may see the launch of Duavive, which combines 0.45mg conjugated equine oestrogen with 20mg bazedoxifene, a selective oestrogen receptor modulator (SERM), which protects against endometrial hyperplasia. When available, this will be licensed for the treatment of moderate to severe hot flushes and prevention of postmenopausal osteoporosis, although it may also be a useful option for women with progestogen intolerance.
What has fallen out of fashion?
Following the publication of the WHI and Million Women’s studies in the early 2000s, systemic HRT prescribing fell dramatically by 66% and has remained unchanged. Previously, there was a trend to prescribe HRT in higher doses (conjugated equine oestrogen 1.25mg or 2mg oestradiol) in the belief that this would achieve better symptom control and osteoporosis prevention. It is now known that lower doses will give adequate symptom control and bone mineral density protection.
Merck, Sharp and Dohme recently stopped manufacturing and distributing oestradiol implants because only a small number of women were using this form of HRT and the company felt there were suitable alternatives. A number of women, however, found this form of HRT highly beneficial and it is therefore hoped that another manufacturer will bring a similar product onto the market in the future.
Special cases and their management
Healthcare professionals have concerns about prescribing HRT to migraine suffers with focal aura. This is because combined hormonal contraceptives have been linked with an increased risk of stroke in such women and are contraindicated. However, there are no data showing a similar risk for such women taking systemic HRT. In fact, HRT may help reduce migrainous episodes perimenopausally when hormonal fluctuations can exacerbate these headaches. In a migraine sufferer, it is preferable to use non-oral HRT rather than oral preparations as they maintain a constant level of oestradiol and progestogen.
Dr Diana Mansour is a consultant in community gynaecology and reproductive healthcare and Dr Joanna Speedie is an ST6 trainee in community sexual and reproductive healthcare, both at Newcastle Hospitals NHS Foundation Trust.