- What are the options for the treatment of hot flushes in women who do not wish to take estrogen?
A variety of treatments are available but they tend to be less effective than estrogen. Apart from clonidine, the drugs are not licensed for this use. The evidence for efficacy of clonidine is conflicting in RCTs. However it may be of limited help in women with tamoxifen-induced hot flushes. Side effects include dry mouth, sedation, dizziness, nausea and nocturnal restlessness. The dose is 50–75 micrograms twice daily. Selective serotonin reuptake inhibitors (SSRIs) and serotonin and noradrenaline reuptake inhibitors (SNRIs) such as fluoxetine, paroxetine, citalapram and venlafaxine have been found to be effective in several studies. However, most are short lasting only a few weeks. Side effects include gastrointestinal symptoms (nausea) and sexual dysfunction ( delayed or absent orgasm). Some early evidence suggests that SSRIs may cause bone loss. There are concerns that paroxetine use during tamoxifen treatment is associated with an increased risk of death from breast cancer. The most convincing data are for the SNRI (venlafaxine) at a dose of 37.5mg bd. A randomized trial of a new SNRI desvenlafaxine, has shown a 64% reduction of hot flushes at 12 weeks.
Gabapentin reduces hot flushes at a dose of 900mg/day by about 50%. Side effects include dry mouth, dizziness and drowsiness which may improve with continued use.
Progestogens such as 5 mg/day norethisterone or 40 mg/day megestrol acetate can be effective. Availability of megestrol acetate 40mg tablets varies world wide. Of concern doses of progestogens that achieve control of vasomotor symptoms, the risk of venous thromboembolism may be increased. Also safety with regard to the breast is uncertain.
The antidepressants veralipride and moclobemide have also been studied. However, they are of limited effectiveness and there are concerns about adverse effects. The evidence regarding beta blockers is also poor and there are concerns about side effects.
Further reading
Kelly CM, Juurlink DN, Gomes T, et al. Selective serotonin reuptake inhibitors and breast cancer mortality in women receiving tamoxifen: a population based cohort study. BMJ. 2010;340:c693. doi: 10.1136/bmj.c693.
Nelson HD, Vesco KK, Haney E, et al. Nonhormonal therapies for menopausal hot flashes: systematic review and meta-analysis. JAMA 2006;295:2057-71.
- What advice should I give regarding herbal therapies?
Evidence from randomized trials that herbal therapies improve menopausal symptoms or have the same benefits as estrogen is poor. There are concerns about herb-drug and herb-herb interactions. Severe adverse reactions, including renal and liver failure and cancer, have been reported. There are also concerns about interactions with chemotherapeutic drugs. Little is known about the active ingredients which may vary between preparations depending on the manufacturing process.
Concern also exists about the quality control of production. Some have been found to be contaminated, contain unlabeled ingredients such as conventional medicines (steroids) or banned substances, or have different amounts of ingredients than are listed on the label. Moreover, some preparations contain high levels of heavy metals, such as arsenic, lead and mercury. The European Union Directive on traditional herbal medicinal products will not cover preparations bought by women outside Europe.
Herbal products used by menopausal women include:
Soy
Red clover
Actaea racemosa (black cohosh)
Piper methysticum (kava kava)
Oenothera bienis (evening primrose)
Angelica sinensis (dong quai)
Ginkgo biloba (gingko)
Panax ginseng (ginseng)
Others, such as wild yam cream, dong quai, St John’s wort, Agnus castus (Chasteberry), liquorice root, hops, milk thistle, Chinese herbal medicines, pollen extracts and Valerian root
Further reading
Chan A, Yap K. Detection and management of oncology drug interactions: Can we do better?
Maturitas. 2010; 65: 181-182.
Herbal treatments for menopausal symptoms. Drug Ther Bull. 2009; 47: 2-6.
European Commission, 2004. Directive 2004/24/EC of the European Parliament and of the Council of 31 March 2004 amending, as regards traditional herbal medicinal products, Directive 2001/83/EC on the Community code relating to medicinal products for human use. Official Journal of the European Union 2004; 136: 85–90. [online]. Available: http://www.mhra.gov.uk/home/groups/es-herbal/documents/websiteresources/con009359.pdf.
- A woman with premature menopause at the age of 35 has been told that she should stop HT at the age of 40: what advice should I give her?
Untreated premature menopause increases the risk of osteoporosis, cardiovascular disease, dementia, cognitive decline and parkinsonism. The standard advice is that HT should be continued until the average age of the natural menopause and then the patient reassessed. There is no evidence that HT in this situation increases the risk of breast cancer.
Further reading
Ewertz M, Mellemkjaer L, Poulsen AH, et al. Hormone use for menopausal symptoms and risk of breast cancer. A Danish cohort study. Br J Cancer 2005; 92: 1293-7.
Shuster LT, Rhodes DJ, Gostout BS et al. Premature menopause or early menopause: long-term health consequences. Maturitas. 2010;65:161-6.
- Should bisphosphonates be given to women under the age of 40?
Bisphosphonates have mainly been studied in women over 60 with osteoprosis or at risk of the disease. There is no evidence in this age group on fracture and there are concerns about the safety of long term use. Also should pregnancy occur, there are no long-term studies on the effect of bisphosphonates on the skeleton in fetal or later life. Thus any consideration of bisphosphonates should be undertaken with an osteoporosis expert.
Further reading
Cohen A. Should bisphosphonates be used in premenopausal women? Maturitas. 2010; 66:3-4.
- What are the safety issues of long term vaginal estrogens?
Local treatment options include low dose natural estrogens such as vaginal estradiol by tablet or ring or estriol by cream or pessary. Systemic absorption with estradiol vaginal tablets or ring is low without systemic effects and hormone levels remain within the postmenopausal range. Thus if the recommended topical estradiol and estriol preparations are used there is no need to add a progestogen for endometrial protection.
Conjugated equine estrogen (CEE) cream is well absorbed from the vagina and can cause endometrial stimulation. Thus if conjugated equine estrogens are used on a long-term basis, a progestogen should be taken for endometrial protection.
6. Is HT contraindicated in a woman who has had a previous venous thromboembolism?
In this case it is essential to find out if the woman really had a previous venous thromboembolism (VTE). When in doubt, if a patient was anticoagulated at the time, it is prudent to consider the event confirmed.
A history of VTE is the biggest risk factor for future VTE and is a relative contraindication to HT. However it might be felt in some cases that the risk is outweighed by the benefits of HT, for example severe vasomotor symptoms that have not responded to hormonal agents or premature menopause. A thrombophilia screen should be considered, as the finding of a severe defect or a combination of defects might alter the perceived risk–benefit assessment. A negative thrombophilia screen must not be used to give false reassurance.
If a decision to use HRT is made, the transdermal route is probably safer than oral therapy. Also there may be differences with regard to progestogens in that norpregnane derivatives may be thrombogenic, whereas micronized progesterone and pregnane derivatives do not increase risk.
Further reading
Canonico M, Oger E, Plu-Bureau G, et al. Estrogen and Thromboembolism Risk (ESTHER) Study Group. Hormone therapy and venous thromboembolism among postmenopausal women: impact of the route of estrogen administration and progestogens: the ESTHER study. Circulation 2007;115:840–5.
Canonico M, Plu-Bureau G, Lowe GD, Scarabin PY. Hormone replacement therapy and risk of venous thromboembolism in postmenopausal women: systematic review and meta-analysis.
BMJ. 2008 31;336:1227-31.
- Can HRT be started before menstruation stops
The simple answer is yes. The options available are monthly or three-monthly sequential regimens. For women with infrequent menstruation and those who are intolerant of progestogens, a three-monthly preparation can be considered. Only one is available: it contains estradiol valerate and medroxyprogesterone acetate. Continuous combined regimens should not be used in perimenopausal women because of the high risk of irregular bleeding. Intrauterine delivery of the progestogen can be considered in women who wish to have ‘no bleed therapy’ in the perimenopause.
- What does intrauterine delivery of progestogen provide?
Levonorgestrel can be delivered directly into the uterus using the levonorgestrel intrauterine system. As well as inducing amenorrhoea it also provides an effective form of contraception. It is also helpful in women with heavy menstrual bleeding.
- How can I give an answer about fracture risk?
The FRAX tool has been developed by the World Health Organization to evaluate fracture risk. It is based on individual patient models that integrate the risks associated with clinical risk factors as well as femoral neck bone mineral density. The clinical risk factors comprise body mass index (BMI), a prior history of fracture, a parental history of hip fracture, use of oral glucocorticoids, rheumatoid arthritis and other secondary causes of osteoporosis, current smoking, and alcohol intake 3 or more units daily.
The FRAX models have been developed from studying population-based cohorts from Europe, North America, Asia and Australia. The FRAX algorithms give the 10-year probability of hip and other major osteoporotic fracture. Advice for management can then be obtained from the National Osteoporosis Guideline Group (NOGG) whose web site is linked to FRAX.
FRAX - WHO Fracture Risk Assessment Tool www.sheffield.ac.uk/FRAX/
National Osteoporosis Guideline Group (NOGG) http://www.shef.ac.uk/NOGG/index.html
- Can a woman with fibroids take HT?
Fibroids (leiomyomas) are estrogen-dependent tumours that tend to shrink after the menopause. These may become enlarged with estrogen treatment and cause heavy or painful bleeding. The evidence of the effect of different types of hormone replacement therapy (HT) on fibroid growth is poor. Ultrasound examinations may be helpful in documenting the fibroids, and, if clinically indicated, regular pelvic examinations may be necessary.
Further reading
Yang CH, Lee JN, Hsu SC, et al. Effect of hormone replacement therapy on uterine fibroids in postmenopausal women – a 3-year study. Maturitas 2002;43:35-9.