• Type of HRT
• When to use HRT
• Alternatives to HRT
• Complementary medicines in HRT
• Case study 59:
• Erratum: NPS News 61: Topical issues in dermatology
• Insert: Compounded and ‘bioidentical’ hormone therapy — claims and uncertainties

Oestrogen-based hormone replacement therapy (HRT) effectively treats menopausal symptoms, but fear of long-term harms can limit use. Discussions about treating menopausal symptoms should be informed by the evidence, the woman’s individual circumstances and a realistic appraisal of the alternatives.

HRT is the most effective treatment for menopausal symptoms

Oestrogen, with or without a progestogen, is the most effective proven treatment for menopausal symptoms[1-3] (see Box 1), decreasing hot flushes by 17–20 episodes per week more than placebo.[4] HRT reduces fracture risk and helps maintain bone density.[2]

Large clinical trials initiating HRT in older postmenopausal women have not shown benefits for cardiovascular disease, mortality, cognition or dementia.[3]

Box 1: Benefits of HRT[3,5,6]

HRT reduces
Menopausal symptoms	Other effects
Hot flushes/night sweats Urogenital symptoms Sleep problems[A] Arthralgia (oestrogen plus progestogen HRT) Sexual problems	Osteoporotic fracture risk Colorectal cancer risk (oestrogen plus progestogen HRT only) Diabetes risk[B]

[A] Sleep may be improved because of reduced vasomotor and urogenital symptoms[3]
[B] Self-reported diagnosis of diabetes in a subgroup of participants of the Women’s Health Initiative study, with glucose measured in a small subsample

Consider potential benefits and harms for individuals

Most risk estimates come from the Women’s Health Initiative (WHI) study, but this population was not typical of women considering HRT for menopausal symptoms (see WHI inset, next page). Risks for women using HRT around menopause may be lower than popularly perceived (see Box 2).

The balance of benefits and potential harms for each woman depends on individual factors, including:

• symptom severity
• type of therapy (oestrogen only or combined)
• dose
• age
• duration of therapy
• years since menopause at treatment initiation
• route of administration
• background risk (e.g. cardiovascular, venous thromboembolism [VTE], stroke, breast cancer)
• personal choice.

Type of HRT

Combined HRT (oestrogen plus progestogen) is used for women with an intact uterus, to reduce risk of endometrial cancer, while unopposed oestrogen is used for women without a uterus. With this treatment approach, risks with oestrogen-only HRT were lower than for combined HRT for most outcomes in the WHI trials (except stroke).[7]

Observational data suggest a lower VTE risk with transdermal compared with oral HRT; however, long-term randomised trials have not been conducted.[1,8] Transdermal preparations may be more appropriate for women with hard-to-control hypertension, hypertriglyceridaemia, increased risk of cholelithiasis, significant liver disease, bowel dysfunction and inadequate control on oral therapy.[1,2]

Age

Women in their 50s have a lower age-related risk of most events — such as stroke and coronary heart disease — than older postmenopausal women (> 60 years), so any increased risk with HRT is likely to be small (see Box 2).[7] As women age, their background risk of some events will increase and the balance of risks and benefits may change.

Duration of therapy

The risks of breast cancer (with combined HRT) and endometrial cancer (with unopposed oestrogen in women with a uterus) increase with duration of therapy. The risk of VTE is greatest in the first 1–2 years of use, especially for obese women and those with thrombophilia.[7,9] Determine the appropriate length of therapy individually; general recommendations cannot be made.[7,10] Treatment durations greater than 5 years with combined HRT are thought to increase risk, but a risk-free treatment interval cannot be determined from available evidence, even below 5 years.[7,10]

Breast cancer risk

Oestrogen plus progestogen HRT: Breast cancer risk increases with duration of therapy and declines 2–3 years after stopping.[7,11,14] The size of the increased risk in WHI was an extra 8 cases per 10,000 person years (or 4 per 1000 women taking combined HRT for 5 years).[11,12] Using Australian data on breast cancer incidence, the NHMRC estimated a baseline risk of 11 breast cancers per 1000 non-HRT-users, increasing to 15 breast cancers per 1000 women using combined HRT for 5 years.[15]

Increased risk was mainly in women who had used HRT before the study. Nonetheless, all participants had an increased risk over time of breast cancer.[16]

Oestrogen-only HRT: Oestrogen-only HRT did not increase breast cancer risk after 7 years in the WHI trial in women without a uterus, with unexpectedly fewer cases with oestrogen than placebo (statistically significant after adherence adjustment).[13,17] Some observational studies suggest increased risk with oestrogen only[7], but after much longer treatment durations (e.g. 20 years).[18] Observational studies are prone to bias and confounding and randomised data provide the best evidence.

Abnormal mammography

Both combined and oestrogen-only HRT increase breast density and abnormal mammography, which may concern women, even if breast cancer is not diagnosed.[3,11,13]

Coronary heart disease (CHD)

CHD risk may be elevated in the first year of treatment in older postmenopausal women starting combined HRT.[5,12] In the WHI trials, 85% of CHD events were in women over 60 across both treatment regimens.[19] Some data suggest that starting HRT in older women several years after menopause increases vascular risk, while women closer to menopause may benefit because of differences in the vasculature after menopause.[2,7] This ‘timing hypothesis’ is under debate and remains speculative until specific randomised data are available.[7] The hypothesis does not relate to all outcomes (stroke, VTE, cancer).

The Women’s Health Initiative trials (WHI)[20] dramatically altered HRT prescribing worldwide Trial populations: older women (average age 63 years) 13–14 years post menopause — not typical of women likely to start HRT for symptom management. 2 large-scale randomised controlled trials looking for CHD-prevention benefits seen in observational studies. Trial 1: Combined HRT trial: conjugated equine oestrogens 0.625 mg with medroxyprogesterone 2.5 mg daily vs placebo (in women with a uterus) Stopped early — with no cardiovascular benefits after 5 years, the benefit-to-harm ratio for women in the trial was unacceptable. The global harm index (including breast cancer, CHD, stroke, pulmonary embolism, death) exceeded the pre-specified boundary and was not offset by benefits in prespecified outcomes. Trial 2: Oestrogen-only trial: conjugated equine oestrogens 0.625 mg daily vs placebo (in women without a uterus) Stopped after 7 years because there was no CHD benefit and an elevated risk of stroke — but the global index of harms was not exceeded.

Box 2: Potential harms of HRT (based on data from older postmenopausal women in the WHI study)[6]

Event	Increased risk per 10 000 women per year using HRT (instead of placebo)[C]
	Oestrogen-only	Oestrogen and progestogen HRT
Stroke	12 extra strokes	8 extra strokes
VTE	8 extra VTEs[D]	18 extra VTEs
Coronary heart disease	No increase	6 extra CHD events
Breast cancer	No increase	8 extra cases
Endometrial cancer	Increased risk[E]	No increased risk

[C] Annualised incidence based on 6.8 years (for oestrogen-only) + 5.2 years’ data (for oestrogen + progestogen).
[D] Statistically significant only for deep vein thrombosis.
[E] From observational studies. The WHI oestrogen-only group all had prior hysterectomy.

CASE REVIEW: Marjorie’s story Marjorie is 51, active and married. Her periods have been irregular for about 6 months and she feels tired, irritable and has 3 or 4 hot flushes a day. Her uterus is intact. She’s heard that HRT causes breast cancer and wants to discuss her treatment options. Is HRT an option? What information will help her decide? Your discussion with Marjorie could include: Typical experiences of menopause and midlife. Informing Marjorie how HRT will help her symptoms. Advise that short-term use of low-dose HRT (3–5 years) is often appropriate and the risks relatively small in her age group. Consider her risk factors such as age, personal and family medical history and cardiovascular and thrombotic risk. Telling Marjorie about the potential risks of combined HRT (see Box 2). Mention that risk declines after stopping treatment (but only after 2–3 years for breast cancer). Advise that the duration of therapy varies from woman to woman but you will discuss ongoing need and any change in risks and benefits annually.

When can HRT be used?

HRT is recommended for moderate to severe menopausal symptoms, using the lowest effective dose for the shortest necessary duration (up to 5 years).[2,3,21] Some women may need longer treatment.

When using HRT:

• start with a low dose — it may take 2 or 3 visits over the first 6 months to tailor the dose, route and regimen to the individual
• low and ultra-low doses reduce vasomotor symptoms, with fewer short-term adverse effects than standard doses (e.g. breast tenderness and bleeding)[2]; while it is not known if low doses reduce fracture risk, they help maintain BMD[22]
• vasomotor symptoms often need 2–5 years of treatment, and symptoms may recur after stopping (see below)
• review any change in the woman’s risk profile annually and consider if therapy is still needed.[7,21,23]

Observational studies suggest that using HRT in women with premature or surgical menopause, reduces cardiovascular disease and osteoporotic fracture[3] but there are no randomised data. Being younger, their risk of other events is relatively low. Consider early specialist review.

Advise women that symptoms may return after stopping HRT

Symptoms recur after stopping HRT in 30% to 50% of women (including vasomotor symptoms, pain or stiffness and vaginal dryness).[10,24] Small unblinded trials suggest little difference in rebound symptoms between gradually and abruptly stopping HRT.[25,26][F]

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.[2] Women who experience a return of symptoms may wish to extend their duration of therapy beyond 5 years; advise about the specific risks and benefits for the woman and her HRT regimen.[2]

[F] The dose was tapered over 2 weeks (alternate days) in one trial[26] and reduced by 1 day per month over 6 months in another.[25]

Consider intravaginal oestrogens for predominantly vaginal symptoms

Marjorie’s story It becomes apparent that Marjorie is most worried about her vaginal symptoms. Advise using water-based lubricants (Sylk, KY Jelly) and polycarbophil-based vaginal moisturiser (Replens). If these are insufficent, use topical vaginal oestrogens. Inform her that local oestrogen will not reduce non-vaginal symptoms.

Local vaginal oestrogens are useful if non-hormonal lubricants and moisturisers are insufficient, when moderate to severe vaginal symptoms (such as dryness) predominate.[27] A local oestrogen can be added if women continue to experience vaginal symptoms on low-dose systemic HRT. Symptoms can take 4–6 weeks to improve, or longer for dyspareunia.[1,27] Low-dose vaginal oestrogen does not reduce vasomotor symptoms or fracture risk.[27]

The effects of HRT on urinary tract infections are unclear[27,28] but urinary incontinence may be worsened by oral HRT.[29]

Vaginal oestrogens are considered safer than systemic HRT because there is little systemic absorption, although this can still occur.[1,27] Use the lowest effective dose and advise women about correct dosing and application. Rarely, breast tenderness may indicate systemic absorption and possible overdosing.[27]

There is a lack of safety data beyond 1 year of use[27] but some women may need long-term therapy. If vaginal preparations are used long term, a 12-day course of progestin every 6–12 months can be considered to protect the endometrium[2], although some experts consider this unnecessary, citing a lack of evidence.[27,30]

Topical oestrogens available in Australia include creams (Ovestin) and pessaries (Vagifem, Ovestin Ovula). None has been shown to be better than any other — consider patient preference.[31]

Women using hormonal contraception

HRT preparations use much lower hormone doses than oral contraceptives but do not protect against conception in women with evidence of ovulation.[2]

Low-dose oral contraceptives are sometimes suggested for menopausal symptoms in non-smoking women requiring contraception.[32] Although there is little evidence, it can be assumed that combined oral contraceptives have similar risks to oral hormone replacement therapy for this age group.[33] (See NPS News 54: Hormonal contraceptives about appropriate hormonal contraception for women older than 40 years).

What are the alternatives to HRT?

Marjorie’s story Marjorie has talked with friends, family, her doctor, her pharmacist and health shop workers. She’s heard there are alternatives to HRT, some prescribed and some not. Ask which therapies Marjorie is considering, in a non-judgmental manner, and what she expects from treatment Advise about lifestyle changes, as a first step Use the information on pages 4–5 to help you discuss the alternatives to HRT, including complementary medicines.

Non-pharmacological changes

Lifestyle modifications such as regular light exercise, light clothing and reducing stress may help manage symptoms. Sleeping in a cooler room, relaxation therapy and sleep hygiene may help with sleep problems. Advise women to avoid possible triggers such as caffeine, smoking, alcohol and spicy foods.[23] Smoking is a risk factor for many conditions after menopause (e.g. osteoporosis): advise women to quit.

Tibolone

Tibolone has oestrogenic, progestogenic and androgenic activity.[1] It improves vaginal dryness, vasomotor symptoms, and libido[34] and reduces fracture risk.[35] In trials it increased stroke risk in older women but not younger women.[35] Avoid use in older women and those with cardiovascular risk factors.

Tibolone increased the risk of breast cancer recurrence in women receiving adjuvant therapy and it is contraindicated in women with a history of breast cancer.[2,36] Effects on breast cancer risk in women without breast cancer and on the endometrium are uncertain.[34,37] Tibolone may be unsuitable in perimenopausal women because it increases breakthrough bleeding.[2] There is insufficient evidence to determine if tibolone is safer than HRT.

Testosterone: long-term adverse effects are unknown

The use of testosterone (and dehydroepiandrosterone [DHEA]) in postmenopausal women is controversial; no products are TGA approved for this use in Australia. Small trials suggest that testosterone with oestrogen moderately improves sexual function compared with oestrogen alone.[38] Other than for surgical menopause, clinical guidelines recommend caution in using testosterone for the menopause because of limited understanding about its role, the diagnosis and treatment of androgen deficiency, and a lack of long-term safety data (e.g. for cardiovascular health and cancer risk).[1,39] (See insert on compounded and ‘bioidentical’ hormone therapy.)

Selective serotonin reuptake inhibitors (SSRIs) may be an option in breast cancer

Trials of SSRIs and venlafaxine for hot flushes in menopausal women and women with breast cancer have had mixed results, with at best a reduction of 1 hot flush per day.[40] Trials in women with breast cancer using tamoxifen or other selective oestrogen-receptor modulators more often showed a benefit.[34,40]

Venlafaxine or paroxetine may be useful for women with breast cancer and severe flushes[2] or for those who do not wish to use HRT and understand the limited benefit of an antidepressant.[41] For most menopausal women the benefit-to-harm ratio is probably unfavourable; use is off-label in Australia.

Bioidentical hormone therapy has no evidence of efficacy and may be harmful — see insert.

Complementary medicines are used, but evidence is still lacking

Marjorie’s story Marjorie mentions that friends have recommended black cohosh or red clover, which are natural and don’t have side effects. She is keen to try them. Advise Marjorie that these alternative medicines don’t have convincing evidence for helping hot flushes. Discuss possible severe liver toxicity with black cohosh and lack of efficacy data for red clover. Encourage Marjorie to let her health professionals know about any OTC medicines she may choose to take.

Despite more research, the evidence for complementary medicines is still inconclusive. Most have little efficacy and poor quality safety data. ‘Natural’ alternatives can provide a sense of wellbeing[42], but they have financial costs and may not improve symptoms.[41]

Bear in mind that:

• hot flushes improve by up to 60% with placebo, partly due to natural fluctuation in symptoms[43]; anecdotal and uncontrolled reports of effectiveness are unreliable
• 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.

Efficacy: The evidence for red clover, soy isoflavones and black cohosh do not show a significant treatment effect. Some poor-quality trials indicate benefits, but these are usually clinically insignificant (e.g. 1 less hot flush per day), and are no greater than the placebo effect in HRT trials.[44–46] (See insert for details on efficacy and safety of commonly used complementary medicines.)

Safety: Hepatotoxicity requiring liver transplant has been reported for black cohosh.[47] Short-term studies of soy isoflavones, black cohosh and red clover do not show adverse effects on the endometrium, breast density or lipids[41,44], although one 5-year study of a daily high-dose soy isoflavone extract in older women found a 3% increase in endometrial hyperplasia.[48] Dietary soy is probably safe.[1,41] There are few safety data for dong quai, chasteberry or wild yam.[49] Natural ‘progesterone’ creams may not protect the endometrium.[40]

Expert reviewers

Professor Alastair H MacLennan, Head of Discipline of Obstetrics and Gynaecology School of Paediatrics and 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.

References

1. 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.
2. Endocrinology Expert Group. Therapeutic Guidelines: Endocrinology. Version 4. Melbourne: Therapeutic Guidelines Ltd, 2009.
3. Australian Government National Health and Medical Research Council. Hormone replacement therapy: A summary of the evidence. Canberra: NHMRC, 2005. (accessed 23 June 2009).
4. Nelson HD. Commonly used types of postmenopausal estrogen for treatment of hot flashes: scientific review. JAMA 2004;291:1610–20.
5. Vickers MR, MacLennan AH, Lawton B, et al. Main morbidities recorded in the women's international study of long duration oestrogen after menopause (WISDOM): a randomised controlled trial of hormone replacement therapy in postmenopausal women.[see comment]. BMJ 2007;335:239.
6. Prentice RL, Anderson GL. The women's health initiative: lessons learned. Annu Rev Public Health 2008;29:131–50.
7. Medicines and Healthcare products Regulatory Agency. UK Public Assessment Report. Hormone replacement therapy: safety update. 2007. (accessed 23 June 2009).
8. Canonico M, Plu-Bureau G, Lowe GD, et al. Hormone replacement therapy and risk of venous thromboembolism in postmenopausal women: systematic review and meta-analysis. BMJ 2008;336:1227–31.
9. Curb JD, Prentice RL, Bray PF, et al. Venous thrombosis and conjugated equine estrogen in women without a uterus. Arch Intern Med 2006;166:772–80.
10. 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.
11. 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.
12. Farquhar CM, Marjoribanks J, Lethaby A, et al. Long term hormone therapy for perimenopausal and postmenopausal women. Cochrane Database Syst Rev 2005:CD004143.
13. 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.
14. 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.
15. Australian Government National Health and Medical Research Council. Making Decisions: Should I use hormone replacement therapy? (HRT). Canberra: NHMRC, 2005. (accessed 23 June 2009).
16. Anderson GL, Chlebowski RT, Rossouw JE, et al. Prior hormone therapy and breast cancer risk in the Women's Health Initiative randomized trial of estrogen plus progestin. Maturitas 2006;55:103–15.
17. Anderson GL, Limacher M, Assaf AR, et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial.[see comment]. JAMA 2004;291:1701–12.
18. Chen WY, Manson JE, Hankinson SE, et al. Unopposed estrogen therapy and the risk of invasive breast cancer. Arch Intern Med 2006;166:1027–32.
19. Rossouw JE, Prentice RL, Manson JE, et al. Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause. JAMA 2007;297:1465–77.
20. Anderson GL, Kooperberg C, Geller N, et al. Monitoring and reporting of the Women's Health Initiative randomized hormone therapy trials. Clin Trials 2007;4:207–17.
21. Royal Australian and New Zealand College of Obstetricians and Gynaecologists. Hormone Therapy Advice. Melbourne: 2007. (accessed 17 March 2009).
22. Management of osteoporosis in postmenopausal women: 2006 position statement of The North American Menopause Society. Menopause 2006;13:340–67.
23. CKS. Menopause - Management. NHS Clinical Knowledge Summaries. NHS Institute for Innovation and Improvement 2009. (accessed 17 March 2009).
24. Ockene JK, Barad DH, Cochrane BB, et al. Symptom experience after discontinuing use of estrogen plus progestin. JAMA 2005;294:183–93.
25. 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.
26. Aslan E, Bagis T, Kilicdag EB, et al. How best is to discontinue postmenopausal hormone therapy: immediate or tapered? Maturitas 2007;56:78–83.
27. 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; quiz 70–1.
28. Moehrer B, Hextall A, Jackson S. Oestrogens for urinary incontinence in women. Cochrane Database Syst Rev 2003:CD001405.
29. Hendrix SL, Cochrane BB, Nygaard IE, et al. Effects of estrogen with and without progestin on urinary incontinence. JAMA 2005;293:935–48.
30. MacLennan AH, Sturdee DW. Is endometrial monitoring required with the use of long-term unopposed vaginal estrogen? Climacteric 2006;9:321–2.
31. Suckling J, Lethaby A, Kennedy R. Local oestrogen for vaginal atrophy in postmenopausal women. Cochrane Database Syst Rev 2006:CD001500.
32. Birkhauser MH, Panay N, Archer DF, et al. Updated practical recommendations for hormone replacement therapy in the peri- and postmenopause. Climacteric 2008;11:108–23.
33. ACOG Committee on Practice Bulletins-Gynecology. ACOG practice bulletin. No. 73: Use of hormonal contraception in women with coexisting medical conditions. Obstetrics Gynecol 2006;107:1453–72.
34. Menopausal Symptoms. Clinical Evidence 2007. (accessed 17 March 2009).
35. Cummings SR, Ettinger B, Delmas PD, et al. The effects of tibolone in older postmenopausal women. N Engl J Med 2008;359:697–708.
36. 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.
37. Australian Medicines Handbook. Adelaide: Australian Medicines Handbook Pty Ltd, 2008.
38. Somboonporn W, Bell R, Davis S. Testosterone for peri- and postmenopausal women. Cochrane Database Syst Rev 2005:CD004509.
39. Wierman ME, Basson R, Davis SR, et al. Androgen therapy in women: an Endocrine Society Clinical Practice guideline. J Clin Endocrinol Metab 2006;91:3697–710.
40. Nelson HD, Vesco KK, Haney E, et al. Nonhormonal therapies for menopausal hot flashes: systematic review and meta-analysis. JAMA 2006;295:2057–71.
41. 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).
42. Williamson M, Tudball J, Toms M, et al. Information use and needs of complementary medicines users. Sydney: National Prescribing Service, 2008. (accessed 17 March 2009).
43. 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.
44. 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.
45. Lethaby AE, Brown J, Marjoribanks J, et al. Phytoestrogens for vasomotor menopausal symptoms. Cochrane Database Syst Rev 2007:CD001395.
46. Howes LG, Howes JB, Knight DC. Isoflavone therapy for menopausal flushes: a systematic review and meta-analysis. Maturitas 2006;55:203–11.
47. Adverse Drug Reactions Advisory Committee. Hepatotoxicity with black cohosh. Australian Adverse Drug Reactions Bulletin 2006;25(2).
48. 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, quiz 265.
49. Herbal medicines for menopausal symptoms. Drug Ther Bull 2009;47:2–6.
    

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Erratum: NPS News 61: Topical issues in dermatology

Table 1: Topical therapies for solar keratoses from the December 2008 issue of NPS News has been amended to clarify the limited evidence for the efficacy of 5-fluorouracil and to help provide a more reliable estimate of efficacy.

Topical treatment options for solar keratoses include photodynamic therapy, 5-fluorouracil, diclofenac and imiquimod (see Table 1). The table below presents a summary of their reported efficacy and possible side effects. Studies have not assessed whether topical therapies for solar keratoses prevent invasive skin cancer.

Differences between trials, such as in patient populations and outcome assessment, mean that it is not possible to reliably compare results presented for different therapies. Studies directly comparing the efficacy of topical therapies are few in number and often of poor quality.

When deciding on the most appropriate treatment approach, consider the site, number and thickness of lesions as well as individual patient factors (i.e. age, comorbidity, preference and treatment cost).[1] Refer to NPS News 61 Topical issues in dermatology for more information about considerations in selecting topical therapies for solar keratoses.

Table 1: Topical therapies for solar keratoses

Topical therapy	Reported efficacy	Possible side effects
5-fluorouracil 5%(Efudix)	Systematic review suggests an average complete clearance in about 50%[G] of patients (range 0%-96%).[2] This result should be interpreted with caution because of the poor quality of studies, many of which were unblinded, had unclear allocation concealment and did not account for dropouts.	Pain, burning, redness, itching, hyperpigmentation, blistering and cracking of the skin in the treated area.[3]
Imiquimod 5% (Aldara)	45% to 84%[G] complete clearance of lesions (2–8 weeks after the end of treatment).[4-7]	Local skin reactions (itching, burning, pain, erythema, flaking, scaling, dryness, scabbing, crusting, erosion and ulceration) are common and can be severe.[5,8] In 1 trial, 4% of imiquimod treated patients withdrew because of local skin reactions, 41% of patients required at least one rest period but most resumed treatment thereafter.[5] Systemic flu-like symptoms may occur (e.g. malaise, fever, nausea, myalgia).[8]
Photodynamic therapy using methyl aminolevulinate (Metvix)	69% to 91%[H] complete response in short-term comparative trials (3–6 months of follow-up).[9-12] Cryotherapy may be more suitable for thicker lesions[9,12] and those in less cosmetically sensitive areas.[10,11,13]	Temporary pain, burning, erythema, itching, oedema and crusting.[14] Pain is sometimes severe and may require analgesia and/or local anaesthesia, or rarely, treatment cessation.[15]
Diclofenac (Solaraze 3% gel)	50%[G] complete clearance vs 20% with placebo (30 days follow-up after the end of treatment).[16]	Contact dermatitis, erythema, rash, inflammation, irritation, pain, itching, tingling or blistering in the treated area.[17]

      
[G] Percentage of patients with complete clearance of all treated lesions    
[H] Percentage of treated lesions cleared completely

References

1. Therapeutic Guidelines Limited. Therapeutic Guidelines: Dermatology; Version 3. 2009
2. Askew DA, et al. Int J Dermatol 2009;48:453-63.
3. Valeant Pharmaceuticals Australasia Pty Ltd. 1 June 2008.
4. Lebwohl M, et al. J Am Acad Dermatol 2004;50:714-21.
5. Korman N, et al. Arch Dermatol 2005;141:467-73.
6. Szeimies RM, et al. J Am Acad Dermatol 2004;51:547-55.
7. Stockfleth E, et al. Arch Dermatol 2002;138:1498-502.
8. iNova Pharmaceuticals (Australia) Pty Limited. 2 April 2009.
9. Szeimies RM, et al. J Am Acad Dermatol 2002;47.
10. Kaufmann R, et al. Br J Dermatol 2008;158:994-9.
11. Morton C, et al. Br J Dermatol 2006;155:1029-36.
12. Freeman M, et al. J Dermatolog Treat 2003;14:99-106.
13. de Berker D, et al. Br J Dermatol 2007;156:222-30.
14. Galderma Australia Pty Ltd. 1 August 2008.
15. Australian Medicines Handbook, 2009.
16. Wolf JE Jr, et al. Int J Dermatol 2001;40:709-13.
17. CSL Limited. 12 December 2008.

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Insert: Compounded and ‘bioidentical’ hormone therapy — claims and uncertainties[1–7] 

(Compounded and ‘bioidentical’ hormone therapy — claims and uncertainties - pdf)

What is claimed	What is known
Bioidentical’ hormones are promoted as being identical to those produced by a woman’s body (e.g. oestriol), rather than ‘synthetic’.	Bioidentical hormones may contain oestradiol, oestriol, oestrone, progesterone, testosterone and dehydroepiandrosterone (DHEA), formulated in various combinations in buccal trouches, lozenges and topical creams. The formulations ‘triest’ and ‘biest’ are commonly used, in which oestriol is the principal component. In reality ‘bioidentical hormones’ may be from plant, animal or synthetic sources.
Compounded bioidentical hormone therapy can be ‘tailored’ or ‘customised’ to the woman’s hormone needs, sometimes using salivary measures of hormone levels.	There are no peer-reviewed data of appropriate salivary levels required for a clinical response, and salivary measures are unreliable hormone assays.[4]
Promoted as being safer, gentler and more natural than pharmaceutical HRT.	Some substances used in bioidentical hormone therapy are available in conventional HRT; for example, many conventional HRT products contain oestradiol, an oestrogen that naturally occurs in the body. Any oestrogenic compound with similar benefits to those of conventional HRT may also have the same risks. There is a further risk of inadequate endometrial protection, with 3 reported cases of endometrial cancer in women taking bioidentical hormones (including progesterone, dose unknown) for several years.[5] Testosterone and DHEA ‘bioidenticals’ may cause high testosterone levels, with unknown safety.[6]
Claim to be supported by evidence	Compounded products have not been shown to be effective in randomised trials. Safety claims are based on animal studies and trials with oestriol using inadequate doses.[7] There are medicolegal concerns about the prescription of unproven, non-TGA-approved bioidentical hormones.

Evidence for efficacy and safety of complementary medicines available for menopausal symptoms

Efficacy for hot flushes and menopausal symptoms	Safety
Black cohosh — equivocal, inconsistent evidence of benefit
3 of 6 trials reported improvements on a menopausal symptom severity score.[8,9] The best quality 1-year publicly funded study found no benefit.[10,11] The extract in this study was a non-proprietary product, similar to marketed products. Women were aged 45–55, with an average of 6.5 hot flushes per day.[10,11]	Hepatotoxicity has occurred.[12] Advise people to report liver symptoms. No short-term adverse effects identified in small studies up to 1 year. Gastrointestinal upset may occur rarely. Effects on breast have not been studied[13] No endometrial thickening seen after 3 months[13] No long-term data
Quality of evidence[I] Evidence reviewed: systematic reviews of 6 trials, in 1170 peri- or postmenopausal women. 217 women with breast cancer risk or history.[8] Quality: fair–poor, with only one good-quality study.[8] Average duration: 3 months, one 12-month study.
Phytoestrogens/isoflavones
Red clover extract — treatment effects range from small to none in systematic reviews[14–16]
At best, 1 fewer hot flush per day in women experiencing 5–9 flushes per day.[16] A good-quality 12-week study in mostly postmenopausal women found no benefit.[17] In this study, symptoms were reduced by 35% to 40% in both placebo and 2 red clover study groups (Promensil and Rimostil). Despite this, women in all three groups were still experiencing more than 5 hot flushes per day after 12 weeks.[17]	No serious short-term adverse effects were identified. No effects on breast density, lipids, endometrial thickness or bone were found in a 3-year study in women with a family history of breast cancer. 320 of the 401 women were premenopausal; may not generalise to postmenopausal women.[18] 2 trials reported no effect on endometrial thickness, 2 reported a decrease in endometrial thickness.[14] Red clover extracts may contain coumarins and can affect INR.
Quality of evidence Evidence reviewed: systematic reviews of 6 placebo-controlled trials, all of the brand Promensil; including about 300 women.[13] Average duration: 12-16 weeks. Quality: fair–poor, with 1 good-quality study.[8,14]
Soy isoflavones
Dietary soy (flour, powder or beverages) — no evidence of an effect on hot flush frequency or severity[14,15]
7 of 9 studies found no differences in hot flushes.[14] 1 good-quality trial found no difference from placebo after 12 weeks 90 mg/day.[8]	Short-term effects include unpleasant taste and gastrointestinal effects (bloating, weight gain). No data to assess longer term adverse effects.
Quality of evidence Evidence reviewed: systematic reviews of 10–11 trials.[8,14] Average duration: 12–24 weeks, 1 trial of 96 weeks.[8] Quality: most poor to fair. 1 good-quality trial.[8]
Soy isoflavone extracts (usually tablets) — mixed results, with no consistent evidence of benefit, in mostly poor-quality trials
5 of 9 trials reported significant differences in frequency or severity of hot flushes[14] At best, 1 less hot flush per day.[15]	5 trials evaluated endometrial thickness and found no difference during course of trial (longest trial 1 year).[15] Short term effects include bloating, nausea, weight gain, concerns about bowel function.[14] Studies measuring effects on vaginal ph and vaginal maturation indices had mixed results.[14] One poor quality trial found increased endometrial hyperplasia in older postmenopausal women taking a soy extract for 5 years compared with placebo.[19]
Quality of evidence Evidence reviewed: 3 systematic reviews of 9–11 trials[14,15,16], including around 1200 women. 1 systematic review included around 600 women with breast cancer.[15] Average duration: 12–24 weeks, one 2-year study. Quality: Fair–poor.[14,15]
Other interventions
Dong quai — no effect on number of hot flushes or the Kupperman Index[20][J]	May have oestrogenic effects and has shown in-vitro proliferation of breast-cancer cells — do not use in breast cancer and other oestrogen-sensitive conditions.[21] One small trial found no effect on endometrial thickness, or vaginal maturation indices. Contains coumarins and can increase INR.[21] Has antiplatelet and anticoagulant effects.
Quality of evidence: 1 poor-quality trial of 71 postmenopausal women.[20]
Wild yam, progesterone topical creams — no effect on hot flushes[8]	Wild yam is incorrectly believed to be a natural progesterone, but it cannot be converted to progesterone in the body and does not oppose oestrogen.[22] Do not use as the progestogen component of HRT.[22]
Quality of evidence: 2 poor-quality trials in 80 women using wild yam for 12 weeks.[8]
Ginseng — no effect on menopausal symptoms including mood, psychological wellbeing and cognition	May interact with warfarin to reduce INR.[23]
Quality of evidence: 2 trials (6–16 weeks); 1 trial used a standardised ginseng extract, the other panax ginseng with gingko.[23]
Vitamin E — no differences in hot flushes or severity with 800 units daily[8]	Doses of vitamin E > 400 units per day have been associated with increased mortality in observational data.[13]
Quality of evidence: 1 fair-quality trial in 125 women with previous breast cancer[8]

[I] Indicators of quality were adequacy of randomisation, allocation concealment, blinding, power, intention-to-treat analysis (the least-biased, most conservative method; results are analysed according to randomisation regardless of dropouts).[8,14]
[J] A scale rating severity of symptoms, including hot flushes, numbness/tingling, insomnia, arthralgia, nervousness, weakness, depression, vertigo, headache, palpitations and formication.[23]

References

1. US Food and Drug Administration. Bio-Identicals: Sorting Myths from Facts. 2008. (accessed 13 Aug 2009).
2. Australasian Menopause Society. Bioidentical hormones for menopausal symptoms. Buderim: Australasian Menopause Society, 2007. (accessed 23 June 2009).
3. Monash University. "Bioidentical" hormones. 2009. (accessed 23 June 2009).
4. MacLennan AH, Sturdee DW. The 'bioidentical/bioequivalent' hormone scam. Climacteric 2006;9:1–3.
   
5. Eden JA, Hacker NF, Fortune M. Three cases of endometrial cancer associated with "bioidentical" hormone replacement therapy. Med J Aust 2007;187:244–5.
   
6. Jean Hailes Foundation for Women's Health. Testosterone therapy for women. Melbourne: Jean Hailes Foundation, May 2008. (accessed 17 March 2009).
7. Cirigliano M. Bioidentical hormone therapy: a review of the evidence. J Womens Health (Larchmt) 2007;16:600–31.
   
8. 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.
9. Borrelli F, Ernst E. Black cohosh (Cimicifuga racemosa) for menopausal symptoms: A systematic review of its efficacy. Pharmacol Res 2008;58:8–14.
   
10. Reed SD, Newton KM, LaCroix AZ, et al. Vaginal, endometrial, and reproductive hormone findings: randomized, placebo-controlled trial of black cohosh, multibotanical herbs, and dietary soy for vasomotor symptoms: the Herbal Alternatives for Menopause (HALT) Study. Menopause 2008;15:51–8.
11. Newton KM, Reed SD, LaCroix AZ, et al. Treatment of vasomotor symptoms of menopause with black cohosh, multibotanicals, soy, hormone therapy, or placebo: a randomized trial. Ann Intern Med 2006;145:869–79.
12. Adverse Drug Reactions Advisory Committee. Hepatotoxicity with black cohosh. Australian Adverse Drug Reactions Bulletin 2006;25(2).
    
13. 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).
14. Lethaby AE, Brown J, Marjoribanks J, et al. Phytoestrogens for vasomotor menopausal symptoms. Cochrane Database Syst Rev 2007:CD001395.
    
15. Nelson HD, Vesco KK, Haney E, et al. Nonhormonal therapies for menopausal hot flashes: systematic review and meta-analysis. JAMA 2006;295:2057–71.
    
16. Howes LG, Howes JB, Knight DC. Isoflavone therapy for menopausal flushes: a systematic review and meta-analysis. Maturitas 2006;55:203–11.
    
17. Tice JA, Ettinger B, Ensrud K, et al. Phytoestrogen supplements for the treatment of hot flashes: the Isoflavone Clover Extract (ICE) Study: a randomized controlled trial. JAMA 2003;290:207–14.
    
18. Powles TJ, Howell A, Evans DG, et al. Red clover isoflavones are safe and well tolerated in women with a family history of breast cancer. Menopause Int 2008;14:6–12.
    
19. 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, quiz 265.
    
20. Hirata JD, Swiersz LM, Zell B, et al. Does dong quai have estrogenic effects in postmenopausal women? A double-blind, placebo-controlled trial. Fertil Steril 1997;68:981–6.
    
21. Dong Quai. Stockton, California: Natural Medicines Comprehensive Database [online], 2009. (accessed 20 Feb 2009).
22. Australian Medicines Handbook. Adelaide: Australian Medicines Handbook Pty Ltd, 2008.
23. Herbal medicines for menopausal symptoms. Drug Ther Bull 2009;47:2–6.