1. Non-hormonal therapy M. Gambacciani and P. Albertazzi

2. Potential health benefits of dietary phytoestrogens: a review of the clinical, epidemiological, and mechanistic evidence Phytoestrogens (isoflavones and lignans) are plant compounds that have been shown to have both estrogenic and antiestrogenic properties A wide range of commonly consumed foods contain appreciable amounts of these different phytoestrogens Accumulating evidence from molecular and cellular biology experiments, animal studies, and, to a limited extent, human clinical trials suggests that phytoestrogens may potentially confer health benefits related to cardiovascular diseases, cancer, osteoporosis, and menopausal symptoms Tham DM, et al. J Clin Endocrinol Metab 1998;83:2223–35

3. Potential health benefits of dietary phytoestrogens: a review of the clinical, epidemiological, and mechanistic evidence These potential health benefits are consistent with the epidemiological evidence that rates of heart disease, various cancers, osteoporotic fractures and menopausal symptoms are more favorable among populations that consume plant-based diets, particularly among cultures with diets that are traditionally high in soy products Tham DM, et al. J Clin Endocrinol Metab 1998;83:2223–35

4. Critical review of health effects of soyabean phytoestrogens in postmenopausal women Limited evidence of the effect of phytoestrogen on hot flushes Concerns over long-term safety, particularly at high doses http://phytohealth.org Cassidy A, et al. Proc Nutr Soc 2006;65:76–92

5. Effects superior to placebo Effects of a standardized soy extract on hot flushes: a multicenter, double-blind, randomized, placebo-controlled study 1 Benefits of soy isoflavone therapeutic regimen on menopausal symtoms 2 Vasomotor symptom relief by soy isoflavone extract tablets in postmenopausal women: a multicenter, double-blind, randomized, placebo-controlled study 3 Clinical effects of a standardized soy extract in postmenopausal women: a pilot study 4 The effect of dietary soy supplementation on hot flushes 5 Isoflavones from red clover (Promensil ® ) significantly reduce menopausal hot flush symptoms compared with placebo 6 Soy protein and isoflavone effects on vasomotor symtoms in peri- and postmenopausal women: the Soy Estrogen Alternative Study 7 1 Faure EA, et al. Menopause 2002;9:329–34; 2 Han KK, et al. Obstet Gynecol 2002;99:389–94; 3 Upmalis AH, et al. Menopause 2000;7:236–42; 4 Scambia G, et al. Menopause 2000;7:105–11; 5 Albertazzi P, et al. Obstet Gynecol 1998;91:6–11; 6 Van de Weijer P, et al. Maturitas 2002;42:187–93; 7 Burke GL, et al. Menopause 2003;10:147–53

6. Is there a proven place for phytoestrogens in the menopause? Phytoestrogens are estrogens derived from plants We need: –Differentiation of different agents –standardization of dosages –safety and efficacy labelling Currently, there is no reliable evidence confirming a substantial role for phytoestrogens in the treatment of postmenopausal women Their increasing promotion should not be endorsed by the medical profession by accepting promotional materials in journals or at meetings Ginsburg J, Prelevic G. Climacteric 1999;2:75–8

7. Doses used in different studies Murkies, 199545 mg Baber, 199840 mg Albertazzi, 199876 mg Nestel, 199840–80 mg Washburn, 199934 mg Nachtigall, 199940 mg Howes, 200038 mg Kok, 2005100 mg Kreijkamp-Kaspers, 200599 mg

8. 4 positives 6 effects not superior to placebo Huntley AL. Maturitas 2004;47:1–9 Soy for the treatment of perimenopausal symptoms: a systematic review 10 clinical studies Doses 34–143 mg Time of observation 6–24 weeks

9. Isoflavone treatment for acute menopausal symptoms Double-blind prospective study 51 women finished the 12-week study In women receiving 60 mg isoflavones daily, hot flushes and night sweats were reduced by 57% and 43%, respectively Cheng G, et al. Menopause 2007;14:468–73 Conclusions: This short-term prospective study implies that isoflavones could be used to relieve acute menopausal symptoms

10. Phytoestrogen therapy for menopausal symptoms? There's no good evidence that it's any better than placebo Women experiencing mild menopausal symptoms may gain relief by dietary modification and lifestyle changes, such as reducing smoking and consumption of caffeine and alcohol, stress management, and increased exercise However, there is no evidence to support the belief that even a very high intake of soy products will alleviate hot flushes, night sweats, and other symptoms such as vaginal dryness, mood changes, and musculoskeletal symptoms No absolute conclusions can be drawn from the few studies of the effects of phytoestrogens on bone. As with other interventions of unproved efficacy, long-term randomized trials will be required to determine the place (if any) of phytoestrogens in the management of postmenopausal women Davis SR. Br Med J 2001;323:354–5

11. Phytoestrogen and climacteric symptoms 25 randomized controlled trials (Medline and the Cochrane Library, 1996–2004) 2348 postmenopausal women (mean age 53.1 years, mean time since menopause 4.3 years, 7.1 hot flushes/day) No significant effects vs. placebo The available evidence suggests that phytoestrogens available as soy foods, soy extracts, and red clover extracts do not improve hot flushes or other menopausal symptoms Krebs EE, et al. Obstet Gynecol 2004;104:824–36

12. Menopausal complementary and alternative therapies unsupported by systematic review Medline and the Cochrane Library database: 70 relevant trials were identified 48 of the studies looked at soy-derived phytoestrogens, vitamins, proteins, diets, osteopathic manipulation, mind- body therapies, meditation, Chinese and ayurvedic medicine, energy-based treatments such as reflexology and magnet therapy or other biologically based treatments There was not enough good-quality data to recommend any of the treatments Many of the studies had a large placebo effect that might contribute to the expanding market of dietary menopausal supplements Nedrow A, et al. Arch Intern Med 2006;166:1453–65

13. HRT versus placebo for hot flushes In a Cochrane review of 24 trials involving 3329 participants, there was an overall reduction in hot flushes –75% (95% CI 64–82%) with oral estrogen –57% (95% CI 45–67%) with placebo MacLennan AH, et al. Cochrane Database of Systematic Reviews 2004, Issue 4. Art. No CD002978. DOI: 10.1002/14651858.CD002978.pub2

14. Not all placebos are equally pleasing Given the 57% reduction in hot flushes seen in the placebo groups of randomized controlled trials of oral HRT, there is understandable scepticism about claims for the efficacy of products, usually complementary medicine, which find a reduction in vasomotor symptoms equal to or less than the normal 57% placebo effect A statistically significant effect may be claimed in such studies because the placebo effect was unusually small Sturdee DW, MacLennan AH. Climacteric 2006;9:401–3

15. The effect of isoflavone extracts on menopausal symptoms Double-blind, placebo-controlled prospective trial of 37 postmenopausal women randomized to receive placebo, or 40 mg or 160 mg of an isoflavone extract Knight DC, et al. Climacteric 1999;2:79–84

16. Effect of isoflavones on hot flush frequency Placebo in HRT studies Murkies, 1995 (53 mg/day) Albertazzi, 1998 (76 mg/day) Scambia, 2000 (50 mg/day) Albert, 2001 (35 mg/day) Faure, 2002 (70 mg/day) Penotti, 2003 (72 mg/day) Knight, 2001 (77 mg/day) Burke, 2003 (58 mg/day)

17. † Effect of soy isoflavones on vasomotor symptoms *33.3 mg taken 3 times/day for 4 months † p < 0.01 for change from baseline, and for placebo vs. isoflavones at 4 months Han KK, et al. Obstet Gynecol 2002;99:389–94 10 11.3 9.9 8.2 12 10 8 6 4 2 0 BaselinePost-treatment Rating on Kupperman Index (mean ± SE) Placebo (n = 40) Isoflavones* (n = 40)

18. Alternative therapies Safety

19. The four harms of harmless therapies There may be recognized or unrecognized side-effects or drug interactions The high cost of using ineffective treatments and the waste of health dollars The possibility that effective evidence-based treatment may be delayed or denied Increasing disappointment, disillusionment and also depression, when the placebo effect wears off and the promises of each unproven therapy are unfulfilled MacLennan AH. Climacteric 1999;2:73–4

20. The four harms of harmless therapies “The word natural is often extensively used and abused in the advertising of these products, with the subliminal message being that anything from a natural source cannot be dangerous and must be what our bodies ‘naturally’ need” MacLennan AH. Climacteric 1999;2:73–4

21. Endometrial effects of long-term treatment with phytoestrogens Randomized, double-blind, placebo-controlled trial 298 women completed the 5-year treatment The occurrence of endometrial hyperplasia was significantly higher in women receiving soy tablets vs. placebo (3.37% vs. 0%) Long-term treatment (up to 5 years) with soy phytoestrogens was associated with an increased occurrence of endometrial hyperplasia These findings call into question the long-term safety of phytoestrogens with regard to the endometrium Unfer V, et al. Fertil Steril 2004;82:145–8

22. Phytoestrogens in breast cancer survivors Most phytoestrogens act like estrogen on the estrogen receptor Clinical and experimental data are questionable regarding the antiestrogenic activity or SERM-like action of phytoestrogens Whether these herbal remedies can be used to treat hot flushes effectively and safely in women who have had breast cancer is still unknown

23. Genistein stimulates growth of human breast cancer cells in a novel, postmenopausal animal model Ju YH, et al. Carcinogenesis 2006;27:1292–9

24. Black cohosh may increase breast cancer spread 200 female mice Black cohosh given was comparable to the amount that women take to relieve menopausal symptoms (45 mg for every 1800 calories in the diet) Davis VL, et al. American Association for Cancer Research Annual Meeting, July 11–14, 2003, Washington, DC, abstract #R910

25. MHRA warning: black cohosh is causally linked to liver disorders The UK Medicines and Healthcare Regulatory Agency (MHRA) has increased warnings about the use of black cohosh, after a series of reports of adverse liver reactions Since 2004, when several reports linked the herb to liver disease, the MHRA has issued an alert to health-care professionals about the treatment All black cohosh products should contain a warning saying that they can cause liver damage Women with a history of liver complaints should not use such products without consulting their doctor Posted: 20 July 2006

26. Effect of St. John's Wort on drug metabolism by induction of cytochrome P450 3A4 enzyme St. John's Wort is of questionnable value in treating depression St. John's Wort alters the activity of cytochrome P-450 enzymes, which play a key role in drug metabolism and pharmacokinetics Administration of St John's Wort may result in diminished clinical effectiveness or increased dosage requirements for at least 50% of all marketed medications (including simvastatin, alprazolam, immunosuppressant drugs, amitriptyline and digoxin) Markowitz JS. JAMA 2003;290:1500–4

27. Alternative therapies Neuroactive drugs

28. Biglia N, et al. Maturitas 2003;45:29–38 Menopausal symptoms after chemotherapy in women treated for breast cancer (%)

29. Antidepressant drugs Selective serotonine reuptake inhibitors (SSRIs) Selective serotonine reuptake inhibitors (SSRIs) –Fluoxetine –Paroxetine –Sertraline –Citalopram Serotonin noradrenergic reuptake inhibitors (SNaRIs) Serotonin noradrenergic reuptake inhibitors (SNaRIs) –Venlafaxine –Nefazodone Noradrenergic and specific serotoninergic antidepressant (NaSSA) Noradrenergic and specific serotoninergic antidepressant (NaSSA) –Mirtazapine Noradrenaline reuptake inhibitor (NaRI) Noradrenaline reuptake inhibitor (NaRI) –Reboxetine

30. Citalopram and fluoxetine in the treatment of postmenopausal symptoms Compared with placebo, citalopram and fluoxetine have little effect on hot flushes and cannot therefore be recommended for the long-term treatment of menopausal symptoms, if vasomotor symptoms are the main complaint Whether the improvement of insomnia by means of citalopram affects the quality of sleep needs further investigation Suvanto-Luukkonen E, et al. Menopause 2005;12:18–26

31. Paroxetine controlled release in the treatment of menopausal hot flushes: a randomized controlled trial Hot flush median reductions after 4 weeks of treatment: –62.2% in 12.5-mg/day paroxetine CR –64.6% in 25.0-mg/day paroxetine CR –37.8% in the placebo group Conclusion: Paroxetine CR may be an effective and acceptable alternative to hormone replacement and other therapies in treating menopausal hot flush symptoms Stearns V, et al. JAMA 2003;289:2827–34

32. Median decrease (%) from baseline to week 4 (95% CI) 37.5 mg 75 mg 150 mg (n = 50) (n = 49) (n = 43) (n = 49) Frequency19 (14 – 28)30 (22 – 53)46 (36 – 63)58 (42 – 67) Score27 (11 – 34)37 (26 – 54)61 (50 – 68)61 (48 – 75) Loprinzi CL. Lancet 2000 Venlafaxine in breast cancer survivors: hot flush frequencies and scores from baseline to treatment week 4 Venlafaxine Placebo

33. Guttuso T Jr, et al. Obstet Gynecol 2003;101:337–45 Gabapentin's effects on hot flushes in postmenopausal women Randomized controlled trial, 59 postmenopausal women with ≥ 7 hot flushes/day, examining effects of gabapentin 900 mg/day on hot flush frequency after 12 weeks of treatment Randomized controlled trial, 59 postmenopausal women with ≥ 7 hot flushes/day, examining effects of gabapentin 900 mg/day on hot flush frequency after 12 weeks of treatment Reduction in hot flush score Reduction in hot flush score –54% in gabapentin 900 mg/day group –31% in placebo group (p = 0.01) 4 patients (13%) in the gabapentin group and 1 (3%) in the placebo group withdrew from the double-blind study because of adverse events. 15 patients (50.0%) in the gabapentin group reported at least one adverse event, compared with 8 patients (27.6%) in the placebo group 4 patients (13%) in the gabapentin group and 1 (3%) in the placebo group withdrew from the double-blind study because of adverse events. 15 patients (50.0%) in the gabapentin group reported at least one adverse event, compared with 8 patients (27.6%) in the placebo group

34. Gabapentin for hot flushes in women with breast cancer Percentage decreases in hot flush severity score between baseline and week 8 p = 0.007 Pandya KJ. Lancet 2005;366:818–24

35. Gabapentin, estrogen and placebo for treating hot flushes Randomized controlled trial (n = 20 in each group) 12th week reduction in hot flush score p = 0.016 p = 0.004 Reddy SY, et al. Obstet Gynecol 2006;108:41–8

36. Non-hormonal therapies for menopausal hot flushes Systematic review, meta-analysis of data sources: –Medline (1966–Oct 2005), PsycINFO (1974–Oct 2005), and the Cochrane Controlled Clinical Trials Register Database (1966–Oct 2005) were searched for relevant published randomized controlled trials Study selection: –All English-language, published, randomized, double-blind, placebo-controlled trials of oral non- hormonal therapies for treating hot flushes in menopausal women measuring and reporting hot flush frequency or severity outcomes Nelson HD, et al. JAMA 2006;295:2057–71

37. Non-hormonal therapies for menopausal hot flushes Data synthesis: –43 trials met inclusion criteria 10 trials of antidepressants 10 trials of clonidine 6 trials of other prescribed medications 17 trials of isoflavone extracts Nelson HD, et al. JAMA 2006;295:2057–71

38. Non-hormonal therapies for menopausal hot flushes Mean difference in number of daily hot flushes with placebo in meta-analyses of: Nelson HD, et al. JAMA 2006;295:2057–71

39. Non-hormonal therapies for menopausal hot flushes Few high-quality trials have been published; most of them have methodological deficiencies; hence, generalizability is limited No effects of red clover isoflavone extracts and results were mixed for soy isoflavone extracts The effects are less than for estrogen The SSRIs or SNRIs, clonidine, and gabapentin trials provide some evidence for efficacy These therapies may be useful for highly symptomatic women who cannot take estrogen Possible adverse effects and the high cost in different countries may restrict use for many women

40. Alternative treatments The efficacy and safety of complementary alternative medicines have not been demonstrated and further studies are required SSRIs, SNRIs and gabapentin are effective in reducing vasomotor symptoms in short-term studies. Their long-term safety needs further evaluation IMS Position Statement. Climacteric 2007;10:181–94