Therapeutic choices for menopausal symptoms
Published in MedicineWise News
Date published: About this date
- Discuss a woman’s goals and concerns about menopause and her treatment preferences
- Oestrogen with or without progestogen is the most effective treatment for women with menopausal symptoms
- Consider potential benefits and harms and assess cardiovascular risk
- Tailor the dose and duration of therapy according to individual symptoms and existing risks
- Inform women about the limited efficacy and safety data on complementary and alternative medicines
a description of the Women’s Health Initiative trial and its findings further details of the data on breast cancer risk an insert covering the claims and uncertainties about ‘bioidentical’ hormone therapy a tabular summary of evidence for efficacy and safety of complementary medicines for menopausal symptoms.
Discuss a woman’s treatment goals and concerns about menopause
Enquire about each woman’s particular goals or concerns about menopause and her attitude towards taking HRT and other therapiesOestrogen-based hormone replacement therapy (HRT) has benefits and harms that vary significantly from woman to woman. Providing personalised information can help women to make informed choices. Individualise the decision to use HRT based on:
- symptom severity
- age and background risk (e.g. cardiovascular, venous thromboembolism [VTE] , stroke, breast cancer)
- years since menopause at treatment initiationtype of therapy (oestrogen only or combined oestrogen plus progestogen)
- route of administration
- duration of therapy
- personal choice.
Oestrogen with or without progestogen is the most effective treatment
HRT decreases hot flushes by about 18 episodes per week more than placebo1
The primary indication for systemic HRT is to reduce moderate to severe menopausal symptoms, including hot flushes, night sweats, urogenital symptoms, sexual problems and, with oestrogen plus progestogen, arthralgia.2,3
Consider intravaginal oestrogens for predominantly vaginal symptoms
Women who have moderate to severe, predominantly vaginal symptoms and who do not respond to non-hormonal lubricants and moisturisers may wish to consider local intravaginal oestrogens instead of other forms of HRT.5 Symptoms can take 4–6 weeks to improve, or longer for dyspareunia.2,5 Low dose vaginal oestrogen does not reduce vasomotor symptoms or fracture risk.5 Vaginal oestrogens are considered safer than oral, transdermal or implant HRT because there is little systemic absorption.2,5 Rarely, breast tenderness may indicate systemic absorption and possible overdosing.5
Consider potential benefits and harms and assess cardiovascular risk
Provide written information to assist in decision-making
Written information can help women understand the range of potential benefits and harms, and to decide whether to try HRT.
The NHMRC booklet Hormone replacement therapy: exploring the options for women is intended to help women make decisions about HRT and also includes some information about complementary and alternative medicines. Bear in mind that risks may be calculated and reported in different ways.
The absolute risks of HRT may increase with age.
The major harms of oestrogen with or without progestogen found in the Women’s Health Initiative (WHI) study are summarised in Table 1.
As women age, their background risk of some events will increase and the balance of risks and benefits may change. Many non-smoking women in their 50s taking HRT are likely to experience only small absolute increases in risk, because of their low background risk.6 Unlike other risks that may increase over time, the risk of VTE is greatest in the first 1–2 years of use after which it remains relatively constant.6
Breast cancer risk increases with the duration of combined oestrogen and progestogen therapy
Oestrogen plus progestogen: Breast cancer risk was increased with 5 years of oestrogen plus progestogen HRT.7,8 Breast cancer risk increases with duration of therapy and declines within a few years of stopping.6,7,9
Oestrogen alone: There was no increase in breast cancer risk with up to 7 years of oestrogen-only HRT in women without a uterus.10
Both combined and oestrogen-only HRT increase the proportion of abnormal mammograms.7,10 This can cause concern even when breast cancer is not diagnosed.
Assess cardiovascular risk when initiating therapy in women over 60 years
In women in their 60s or older, coronary heart disease (CHD) risk may be elevated from the first year after starting oestrogen with progestogen therapy.8 Starting oestrogen-based HRT several years after menopause may have a greater vascular risk, while women closer to menopause may benefit.6,11 However, this ‘timing hypothesis’ remains speculative.6 Time since menopause is not thought to affect stroke, VTE or cancer risk.
Table 1: Evidence from the Women’s Health Initiative study on harms of oestrogen with or without progestogen12A
||Oestrogen + progestogen
(compared with placebo)
(compared with placebo)
|Hazard ratio (95% confidence interval)||Absolute risk difference per 10 000 patient–yearsB||Hazard ratio (95% confidence interval)||Absolute risk difference per 10 000 patient–years
|Venous thromboembolism (VTE)C
||2.06 (1.57 to 2.70)
||1.32 (0.99 to 1.75)
||1.31 (1.02 to 1.68)
||1.37 (1.09 to 1.73)
|Coronary heart disease
||1.24 (1.00 to 1.54)
||0.95 (0.79 to 1.15)
||1.24 (1.01 to 1.54)
||0.80 (0.62 to 1.04)
||0.81 (0.48 to 1.36)
B. Absolute risk difference estimates indicate the number of extra cases per 10 000 women on treatment for 1 year, compared with women who took a placebo.
C. Observational data suggest a lower VTE risk with transdermal compared to oral HRT, however, long-term randomised trials have not been conducted.6
Tailor the dose and duration of therapy according to individual symptoms and existing risks
Start with a low dose
Breast tenderness and vaginal bleeding are very common with medium-dose oestrogen with progestogen.3 Low and ultra-low doses reduce vasomotor symptoms, with fewer short-term adverse effects.11 Oestrogen without progestogen should only be prescribed to women who have had a hysterectomy.
It may take 2–3 visits over the first 6 months to tailor the dose, route and regimen to suit the individual. Inform women that adverse effects may resolve after 3 months or so of treatment or after adjusting therapy.13
See table of HRT products and regimens here.
A risk-free treatment interval has not been identified
Determine the appropriate length of therapy individually. There are insufficient data to estimate how long oestrogen with progestogen can be taken before risk of breast cancer increases and general recommendations about the appropriate length of therapy cannot be made.6,14
Review any change in the woman’s risk profile annually and consider if therapy is still needed6
Small, unblinded trials suggest little difference in rebound symptoms between gradually and abruptly stopping HRT.15,16 Some guidelines suggest gradually tapering the dose in equal steps over 6 weeks for women whose symptoms were mild initially, and up to 6 months gradual reduction for those with initially severe symptoms.11
Menopausal symptoms may recur in 30% to 50% of women after stopping HRT.14,17 If symptoms return persistently, review the risks and benefits before prescribing a further course. Vasomotor symptoms mostly need 2–3 years of treatment, but some women may need longer.13
Other pharmacological treatment options
Bioidentical hormone therapy has no evidence of efficacy and may be harmful
The safety and efficacy of compounded hormone products — often marketed as ‘bioidentical’, ‘customised’ or ‘natural’ therapy — have not been evaluated in randomised trials. Claims of superior safety are based on animal studies and trials with oestriol using inadequate doses.18 Compounded products are not subject to the same Therapeutic Goods Administration regulation as conventional prescription medicines, and there are medico-legal concerns about prescribing them.
Any oestrogenic compound with similar benefits to oestrogen-based HRT is likely to have the same risks. In addition, these formulations may contain too little progestogen to offer adequate endometrial protection; there have been 3 reported cases of endometrial cancer in women taking bioidentical hormones for several years.19,20 Furthermore, testosterone and DHEA ‘bioidenticals’ may result in undesirably high levels of testosterone.21
Low-dose oral contraceptives are sometimes suggested for menopausal symptoms in non-smoking women requiring contraception. Although there is little evidence, combined oral contraceptives are likely to have at least similar risks to oral hormone replacement therapy.22 Tibolone may be as effective as oestrogen with progestogen for vasomotor symptoms23 Tibolone also improves vaginal dryness and libido, and reduces fracture risk.23,24
Avoid tibolone in older women and those at increased risk of stroke.25 In one placebo-controlled trial with older women, tibolone increased stroke risk, but not in another trial with younger women.24,26 There is insufficient evidence to determine if tibolone is safer than oestrogen-based HRT.Tibolone may be unsuitable in perimenopausal women because it increases breakthrough bleeding.11
Selective serotonin reuptake inhibitors (SSRIs) are an option in breast cancer–related hot flushes11
Trials of SSRIs and venlafaxine for hot flushes in menopausal women and women with breast cancer have had mixed results.27 Trials in women who had breast cancer treated with selective oestrogen receptor modulators were more likely to show a benefit.23,27
Inform patients about the limited efficacy and safety data on complementary and alternative medicines
Complementary medicines are widely used, but evidence is lacking
Most complementary medicines have little evidence of efficacy and poor quality safety data. Anecdotal evidence is particularly unreliable, as hot flushes improve by up to 60% with placebo, partly due to natural fluctuation in symptoms.1
The data for red clover, soy isoflavones and black cohosh do not support a significant treatment effect. The benefits found in some trials were mostly not clinically significant.28–30
Adverse events have occurred with some complementary medicines
The sheer size of the WHI study (over 26 000 women) allowed very small risks to be identified. There are no equivalent data for HRT alternatives and therefore their relative safety is uncertain.
Hepatotoxicity has been reported for black cohosh, with cases needing liver transplantation.31 One 5-year study of a high dose soy isoflavone extract in older women found a 3% increase in endometrial hyperplasia.32 However, other short-term studies of soy isoflavones, black cohosh or red clover have not found adverse effects on the endometrium or breast density when these were assessed.30,33 There are few safety data for dong quai, chasteberry or wild yam.34 Natural ‘progesterone’ creams lack proven efficacy and may not protect the endometrium sufficiently when used in combination with oestrogenic therapies.
Professor Alastair H. MacLennan, Head of Discipline of Obstetrics & Gynaecology, School of Paediatrics & Reproductive Health, The Women's and Children's Hospital, University of Adelaide.
Clinical Professor Bronwyn Stuckey, Keogh Institute for Medical Research, Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, School of Medicine and Pharmacology, University of Western Australia.
- MacLennan AH, Broadbent JL, Lester S, et al. Oral oestrogen and combined oestrogen/progestogen therapy versus placebo for hot flushes. Cochrane Database Syst Rev 2004:CD002978.
- Cobin RH, Futterweit W, Ginzburg SB, et al. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the diagnosis and treatment of menopause. Endocr Pract 2006;12:315–37.
- Welton AJ, Vickers MR, Kim J, et al. Health related quality of life after combined hormone replacement therapy: randomised controlled trial. BMJ 2008;337:a1190.
- Osteoporosis Australia. Prevent the next fracture: GP guide. 2008. (accessed 21 July 2009).
- The role of local vaginal estrogen for treatment of vaginal atrophy in postmenopausal women: 2007 position statement of The North American Menopause Society. Menopause 2007;14:355-69.
- Medicines and Healthcare products Regulatory Agency. UK Public Assessment Report. Hormone replacement therapy: safety update. 2007. (accessed 23 June 2009).
- Chlebowski RT, Hendrix SL, Langer RD, et al. Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: the Women's Health Initiative Randomized Trial. JAMA 2003;289:3243–53.
- Farquhar CM, Marjoribanks J, Lethaby A, et al. Long term hormone therapy for perimenopausal and postmenopausal women. Cochrane Database Syst Rev 2009:CD004143.
- Chlebowski RT, Kuller LH, Prentice RL, et al. Breast cancer after use of estrogen plus progestin in postmenopausal women. N Engl J Med 2009;360:573–87.
- Stefanick ML, Anderson GL, Margolis KL, et al. Effects of conjugated equine estrogens on breast cancer and mammography screening in postmenopausal women with hysterectomy. JAMA 2006;295:1647–57.
- Endocrinology Expert Group. Therapeutic Guidelines: Endocrinology. Version 4. Melbourne: Therapeutic Guidelines Ltd, 2009.
- Prentice RL, Anderson GL. The women's health initiative: lessons learned. Annu Rev Public Health 2008;29:131–50.
- CKS. Menopause - Management.Clinical Knowledge Summaries. NHS Clinical Knowledge Summaries. NHS Institute for Innovation and Improvement 2009. (accessed 17 March 2009).
- Utian WH, Archer DF, Bachmann GA, et al. Estrogen and progestogen use in postmenopausal women: July 2008 position statement of The North American Menopause Society. Menopause 2008;15:584–602.
- Aslan E, Bagis T, Kilicdag EB, et al. How best is to discontinue postmenopausal hormone therapy: immediate or tapered? Maturitas 2007;56:78–83.
- Haimov-Kochman R, Barak-Glantz E, Arbel R, et al. Gradual discontinuation of hormone therapy does not prevent the reappearance of climacteric symptoms: a randomized prospective study. Menopause 2006;13:370–6.
- Ockene JK, Barad DH, Cochrane BB, et al. Symptom experience after discontinuing use of estrogen plus progestin. JAMA 2005;294:183–93.
- Cirigliano M. Bioidentical hormone therapy: a review of the evidence. J Womens Health (Larchmt) 2007;16:600–31.
- Eden JA, Hacker NF, Fortune M. Three cases of endometrial cancer associated with "bioidentical" hormone replacement therapy. Med J Aust 2007;187:244–5.
- MacLennan AH, Sturdee DW. The 'bioidentical/bioequivalent' hormone scam. Climacteric 2006;9:1–3.
- Jean Hailes Foundation for Women's Health. Testosterone therapy for women. Melbourne: Jean Hailes Foundation, May 2008. (accessed 24 July 2009).
- ACOG Committee on Practice Bulletins–Gynecology. ACOG practice bulletin. No. 73: Use of hormonal contraception in women with coexisting medical conditions. Obstetrics & Gynecology 2006;107:1453–72.
- Menopausal Symptoms. Clinical Evidence 2007. (accessed 17 March 2009).
- Cummings SR, Ettinger B, Delmas PD, et al. The effects of tibolone in older postmenopausal women. NEJM 2008;359:697–708.
- Australian Medicines Handbook. Adelaide: Australian Medicines Handbook Pty Ltd, 2009.
- Kenemans P, Bundred NJ, Foidart JM, et al. Safety and efficacy of tibolone in breast-cancer patients with vasomotor symptoms: a double-blind, randomised, non-inferiority trial. Lancet Oncol 2009;10:135–46.
- Nelson HD, Vesco KK, Haney E, et al. Nonhormonal therapies for menopausal hot flashes: systematic review and meta-analysis. JAMA 2006;295:2057–71.
- Howes LG, Howes JB, Knight DC. Isoflavone therapy for menopausal flushes: a systematic review and meta-analysis. Maturitas 2006;55:203–11.
- Lethaby AE, Brown J, Marjoribanks J, et al. Phytoestrogens for vasomotor menopausal symptoms. Cochrane Database Syst Rev 2007:CD001395.
- Nedrow A, Miller J, Walker M, et al. Complementary and alternative therapies for the management of menopause-related symptoms: a systematic evidence review. Arch Intern Med 2006;166:1453–65.
- Medicines and Healthcare products Regulatory Agency. Black Cohosh. UK Public Assessment Report. (accessed 17 March 2009).
- Unfer V, Casini ML, Costabile L, et al. Endometrial effects of long-term treatment with phytoestrogens: a randomized, double-blind, placebo-controlled study. Fertil Steril 2004;82:145–8.
- Alternatives to HRT for management of symptoms of the menopause. Scientific Advisory Committee Opinion paper 6. Canberra: Royal College of Obstetricians and Gynaecologists, 2006.(accessed 17 March 2009).
- Herbal medicines for menopausal symptoms. Drug Ther Bull 2009;47:2–6.