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. Oscillations in the development of a new drug. Great idea. The new wonder drug. It\'s poison!. Rational prescribing. Promising reports. Damaging studies. Adapted from Laurence Clinical Pharmacology 1973Inspiration from Scott\'s Parabola, BMJ 2001;323:1477. The changing place of HRT. HERS 1998WHI
Controversies in HRT

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1. Controversies in HRT Mr Tim Hillard DM FFRSH FRCOG Consultant Obstetrician & Gynaecologist Poole Hospital, Poole, Dorset

3. The changing place of HRT HERS 1998 WHI 2002-7 MWS 2003, 2005,2007 WHI [unopposed oestrogen arm] 2004, 2006 CSM statements 2003, 2004 Media reporting

4. Change in Attitudes towards HRT Sweden: Hoffman et al Maturitas Sept 2005 HRT use fallen from 40.5% to 25.3% Use of complementary therapies rose 9.6% to 18% Worldwide: Many doctors now state that HRT is too dangerous 50% fall in HRT prescriptions in UK since 2002 Many women have stopped HRT Many women are regretting having stopped Huge growth in use of unregulated products worth over $27 billion dollars/annum in US

5. Change in Attitudes towards HRT Recent controversies have polarised views on HRT between epidemiologists and clinicians and have stifled rational debate Many women and health professionals remain confused about HRT Our role as experts is to provide upto date information, advice and guidance

6. What are the Controversies? Why does anyone need HRT? Is HRT safe? Who should I give it to and for how long? What alternatives can be used? What new preparations are there?

7. HRT Benefits Risks Vasomotor symptoms Breast Cancer Urogenital Symptoms & VTE Sexual function Stroke Osteoporosis Endometrial cancer Colon Cancer Uncertainties Cardiovascular disease and stroke Alzheimer?s Ovarian cancer Quality of life

8. The Impact of the Menopause Short-term

9. The Impact of the Menopause Medium-term Uro-Genital menopause: Genito-urinary atrophy Dyspaerunia Recurrent UTI?s Pmb Readily improved with oestrogen Peak incidence of urinary incontinence and prolapse

10. Why does anyone need HRT? Is HRT safe? Who should I give it to and for how long? What alternatives can be used? What new preparations are there?

11. HRT Benefits Risks Vasomotor symptoms Breast Cancer Urogenital Symptoms & VTE Sexual function Stroke Osteoporosis Endometrial cancer Colon Cancer Uncertainties Cardiovascular disease and stroke Alzheimer?s Ovarian cancer Quality of life

12. Breast Cancer ? WHI JAMA 2002;288:321-33 JAMA 2004;291:1701-12 E+P arm stopped at 5.2 years Overall RR 1.24 (1.02-1.50) After 5 years RR 1.35 (1.2-1.49) i.e. 4 extra cancers/1000 women after 5 years These risks are small and consistent with previously stated risks E only stopped @ 7 years, no increased risk RR 0.77 = 8 fewer cases/5 years

13. Breast Cancer ? Million Women?s Study Lancet 2003;362:419-27 RR Breast Cancer Never users 1.00 (0.96-1.04) Past Users 1.01 (0.95-1.08) Current Users Oestrogen only 1.30 (1.22-1.38) Oestrogen/progestin 2.00 (1.91-2.09) Tibolone 1.45 (1.25-1.67)

14. IMS Global Statement: Breast Cancer Perception All types of HRT cause an increased risk of breast cancer within a short duration of use.

15. Risk for post-menopausal women (mean age 63) developing breast cancer over a five year period (15 out of 1000)

16. Risk factors for breast cancer First pregnancy >30yr BMI > 35 before menopause BMI > 30 after menopause Alcohol use 3 units/day High intake saturated fats Delayed menopause (5yrs) Current use oral contraception Eating ? grapefruit/day Current use HRT (E+P) HRT (E only) use Relative Risk 1.48 0.70 1.48 1.38 2.00 1.14 1.24 1.20 1.26 (>5 yrs) 0.77 (>5yrs)

17. Risks associated with HRT (based on WHI women aged 50-59) Extra Events/1000 women on 5 years HRT Condition Placebo E only E+P Breast Cancer 16 0 +4 (+/-4) Stroke 8 +2 (+/-2) +1 (+/-1) VTE 6 +1 (+/-1) +4 (+/-3)

18. Is HRT Good for the Heart or Not?

19. Is HRT Good for the Heart or Not? RCTs WHI reported ?no beneficial effect for HRT and may increase risk?. But mean age 63, many had risk factors for CHD and over 20% > 70 years ?WHI not designed nor powered to investigate consequences of HRT in women under 60? Reanalysis in women under 60 has shown clearly that HRT does not cause early harm and reduces cardiovascular mortality and morbidity

21. Cardiovascular disease Perception HRT increases the risk of coronary heart disease (CHD) Because of limitation of time, I will be able to present only highlights from the document. Each perception is followed by citation of the scientific evidence and its scientific level. Grade A level comes from randomized, double-blind, placebo-controlled studies, whereas Grade B is derived from good quality observational or case-control studies. Let?s start with the cardiovascular system:Because of limitation of time, I will be able to present only highlights from the document. Each perception is followed by citation of the scientific evidence and its scientific level. Grade A level comes from randomized, double-blind, placebo-controlled studies, whereas Grade B is derived from good quality observational or case-control studies. Let?s start with the cardiovascular system:

22. Is HRT Safe? The risk of breast cancer is small and even less with oestrogen alone HRT started around menopause is unlikely to have any harmful effects on cardiovascular risk and may be positive In symptomatic healthy women under the age of 60 the risk/benefit balance is in favour of HRT

23. Does anyone need HRT? Is HRT safe? Who should I give it to and for how long? What alternatives can be used? What new preparations are there?

24. The Impact of the Menopause Premature Menopause Symptoms Fertility Sexual dysfunction Long-term health risks

25. HRT ? Who should have it? Premature Ovarian failure ? at least until 50 Symptomatic menopausal women It will prevent osteoporosis in women taking it Potential role in women under 60 at increased risk of osteoporosis who are asymptomatic Review indications and risk/benefit balance on a regular and individual basis

26. Bone Perception HRT should not be used for bone protection because of its unfavourable safety profile. Official recommendations (MHRA, EMEA, FDA) limit HRT to a second-line alternative.

27. Meta-Analysis of Osteoporosis Therapies: Total Hip BMD Systematic reviews of randomized trials of a number of osteoporosis therapies were recently conducted by ORAG.1-7 The weighted mean difference (% change in BMD from controls) and 95% CIs for total hip BMD with each therapy are shown in this slide. These differences were calculated using a random-effects model. The largest treatment effects were seen with alendronate (10?40 mg) and HT. Significant treatment effects were seen with all therapies except calcium and calcitonin. The number of studies included for each of the treatments were: HT (n = 9); alendronate, 5 mg (n = 8); alendronate, 10?40 mg (n = 5); risedronate (n = 7); raloxifene (n = 4); calcitonin (n = 9); and calcium (n = 8).Systematic reviews of randomized trials of a number of osteoporosis therapies were recently conducted by ORAG.1-7 The weighted mean difference (% change in BMD from controls) and 95% CIs for total hip BMD with each therapy are shown in this slide. These differences were calculated using a random-effects model. The largest treatment effects were seen with alendronate (10?40 mg) and HT. Significant treatment effects were seen with all therapies except calcium and calcitonin. The number of studies included for each of the treatments were: HT (n = 9); alendronate, 5 mg (n = 8); alendronate, 10?40 mg (n = 5); risedronate (n = 7); raloxifene (n = 4); calcitonin (n = 9); and calcium (n = 8).

28. How Long? For most women 3-5 years is sufficient (At least until 50 for women with POF) No specific time limit, but reappraise risk/benefit regularly Stopping HRT Dose can be lowered gradually Add in vaginal oestrogens if indicated Add in bisphosphonates if high risk of Osteoporosis

29. Why does anyone need HRT? Is HRT safe? Who should I give it to and for how long? What alternatives can be used? What new preparations are there?

30. Managing the Menopause Holistic approach Lifestyle opportunities Reducing health risk Complimentary and Alternative therapies HRT Other prescription drugs

31. Alternatives to HRT Non-prescription Lifestyle Changes e.g. dietary, exercise Complementary Therapies e.g. acupuncture Herbal remedies e.g. black cohosh ?bio-identical? hormones e.g. Natural Progesterone gel, DHEA Phytoestrogens e.g. red clover Prescription Clonodine, propanolol Anti-depressants/SSRIs/SNRIs Gabapentin

32. Alternative therapies for menopause Ma et al Menopause 2006;13:506-16 Ness et al Maturitas 2006;53:356-61 Use of Herbal and Soy products now approaching use of HRT Most women do not tell their doctor Most preparations unregulated Very limited data on efficacy and safety Potential hazards e.g. hepatitis with black cohosh

33. Phytoestrogens Isoflavones are similar to estrogen molecule and can bind to estrogen receptors with weak estrogenic and anti-estrogenic activity High content in soy beans, legumes and red clover Red Clover Isoflavones Mixed results with very mixed products 5/6 RCT showed no improvement in hot flushes (Nelson et al 2006) Gastrointestinal side effects common May induce endometrial hyperplasia (Unfer et al 2004)

34. Why does anyone need HRT? Is HRT safe? Who should I give it to and for how long? What alternatives can be used? What new preparations are there?

35. New Developments Low Dose Oestrogens Vaginal Oestrogens Progestogens Testosterone Patch Non-hormonal treatments e.g SERMs/SPRMS/STRMS

36. OESTROGEN DOSE HIGH DOSE 1950s - STANDARD DOSE 1980s - LOW DOSE 1990s ? ULTRA LOW DOSE 2000 -

37. Lower and lower doses HRT ? why? Control of Menopausal symptoms possible Fewer side-effects Lower doses may still prevent osteoporosis. Safer (?) Fewer major adverse effects at lower doses, i.e. VTE & Stroke Lowest dose not always most appropriate Premature ovarian failure Failure to respond to lower doses Low bone density

38. Progestogens Progestogen addition required for endometrial protection C19 - Levonorgestrel (IUS) - Norethisterone acetate (patch) C21 - Dydrogesterone - Medroxy-progesterone acetate (MPA) C17 - Drosperinone anti-mineralocorticoid activity Pharmacological profile resembles natural progesterone Opposes salt and water retention; Natural progesterone ? micronised (tablet/pessary/gel)

39. Breast Cancer Risk v type of HRT: EN3 EPIC cohort (European Prospective Investigation into Cancer and Nutrition) ? 5.8y FU Fournier et al Int J Cancer 2005

40. A 60-month non-comparative study on bleeding profiles with LNG IUS in transition from reproductive age contraception to menopausal age endometrial protection during ERT Tim Hillard DM, FRCOG, Poole Hospital, England Professor Herman Depypere, U.Z.Gent, Belgium Professor Risto Erkkola, Turku, Finland Eeva Lukkari-Lax, MD, PhD, Bayer Schering, Oy, Finland Michael Kunz, PhD, Bayer Schering, Berlin, Germany Pia Rautiainen, M.Sc, Bayer Schering Oy, Finland Johannes Schram, MD Albert Schweitzer Ziekenhuis, Netherlands

41. Subject Disposition by Phase

42. TESTOSTERONE Suitable for women with ovaries removed Used for loss of libido and fatigue Available as implant and now also a transdermal patch Patch (300mcg/day) is only licensed for use in women taking concomitant estrogen

43. Tissue Selective Estrogen Complex (TSEC) The TSEC Concept Will the appropriate grouping of a SERM with one or more estrogens provide a clinical profile representative of what has been the goal of a SERM and ET, individually? Pero que pasaria si yo pudiese?.. Es diferente al del e2 al de los serms y al sinergismo estrogenico o antiestrogenico. Tiene un efecto unico particular de los tsec.Pero que pasaria si yo pudiese?.. Es diferente al del e2 al de los serms y al sinergismo estrogenico o antiestrogenico. Tiene un efecto unico particular de los tsec.

44. Summary HRT remains the most effective treatment for menopausal symptoms but is only one option For most women under 60 the Risk/benefit ratio for HRT is beneficial Vulnerable groups such as POF need particular attention Our role as experts is to provide upto date information, advice and guidance

45. MENOPAUSE & HRT INFORMATION For Doctors and Nurses: British Menopause Society: www.thebms.org Stratford 25th-26th June 2010 For patients Menopause Matters: www.menopausematters.co.uk Women?s Health Concern: www.womens-health-concern.org Locally Poole Menopause Centre 01202 442651


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