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Women at menopause

Women at menopause. Dr. Helen Roberts MB, MPH, FAChSHM Research Manager Family Planning Senior Lecturer Women’s Health Department Obstetrics and Gynaecology University of Auckland New Zealand.

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Women at menopause

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  1. Women at menopause Dr. Helen Roberts MB, MPH, FAChSHM Research Manager Family Planning Senior Lecturer Women’s Health Department Obstetrics and Gynaecology University of Auckland New Zealand

  2. HRT remains an appropriate treatment only for women with moderate to severe vasomotor symptoms of menopause. • It has no role in the primary or secondary prevention of • cardiovascular or cerebrovascular disease

  3. Indications for HT use • Indications for HT are hot flushes, night sweats and genito- urinary symptoms • Longitudinal study evidence does not suggest that mood changes or cognitive disturbance related to the menopausal transition http://consensus.nih.gov/

  4. Which women should not use HT? • Previous breast cancer • Previous deep vein thrombosis (DVT) • Previous pulmonary embolus • Previous heart attack • Previous stroke • High risk of cardiovascular disease

  5. How many women have these symptoms and how long do they last? Flushes • 30% of women while still having periods-don’t do hormone levels to decide who to treat • Majority of women they are self limiting and stop within a few years • 80% women they last 5 years-10% even longer

  6. How many women have these symptoms and how long do they last? Genito–urinary symptoms • 50% of women • Symptoms are vaginal dryness, dyspareunia, recurrent urinary tract infections • Symptoms are long term

  7. Decision about stopping hormone therapy • Mrs Grant is a 54 year old woman was referred by her general practitioner to discuss her ongoing use of oral hormone therapy • She started this when she was 46 years old because of night sweats. At this time she was still menstruating and has continued to have regular periods while taking hormone therapy • Her general practitioner has advised her that she can now probably stop using hormones as her flushes are likely to have gone, but she is keen to continue treatment. She asked to be referred for a second opinion. Roberts H. BMJ 2010; 341:c2421

  8. Types and doses of hormones • What regimen of HT is this woman using? ……….sequential • If she had wanted a subsidised Rx what would you give her? • “guidelines are for lowest dose possible for symptom relief” –so what would you Rx?

  9. How can we give these hormones? Estrogen • Oral- only one fully subsided • Patch/gel • Spray • Implant • Vaginal cream Progestogen • Oral • IUS-Mirena

  10. What HT do we usually start with? • Oral—only delivery Rx fully subsidised • E only if hysterectomy • E+P if uterus • E is given continuously every day • P 10-14 days/month if menopause<1 yr ago-sequential • P continuous if menopause>1yr ago

  11. Types and doses of hormones Estrogen -different from E in contraception • CEE (conjugated equine estrogens)-mares • 17 β estradiol. • Estradiol valerate…..fully funded Progestogen- often same as P in contraception • Medroxyprogesterone acetate…fully funded • Levonorgestrel • Norethisterone • Utrogestan-what is this?

  12. Furness S, Roberts H, Lethaby A, Farquhar C Cochrane Database of Syst Rev 2009 CD000402

  13. What low dose products are available? • Kliovance-1 mg E2 + 0.5mg NETA (NZ) • Angelique- 1mg E2 + 2mg drospirinone • Novofem- 1mg E2 + 12days 1mg NETA • Eviana- 0.5mg E2 + 0.1 mg NETA

  14. How well do hormones help symptoms? • Placebo response for flushes up to 50% • HT – 75% improvement (2-3 less per day) - takes a few weeks to help Cochrane Review MacLennan 2002 • Progestogens alone-Depo Provera or oral MPA 10-20mg daily-almost similar response to estrogen • Other treatments SSRI/SNRI -1.13 flushes less/day than placebo Clonidine -1.63 less Gabapentin-2.05 less

  15. Genito –urinary symptoms • Not self limiting-may need long term treatment • Vaginal estrogen better than oral • A level evidence for vaginal atrophy • B level evidence for recurrent UTIs • May help urgency in women with overactive bladder • May make stress incontinence worse

  16. Vaginal estrogens • Ovestin cream/pessary-estriol 0.5 mg • Funded- so cost $15 for 3/12 • Vagifem-estradiol 25 mcg vaginal tabs • Not funded- cost $75 for 30 tabs but Mercy pharmacy $47.80 + courier (09-6235703) • Each night PV for first 2 weeks the twice weekly • Takes 4-6 weeks to work • Estring: vaginal ring:90 days-Pfizer under Section 29. Cost $75 + pharmacy charge (0800736363)

  17. Long term Rx with vaginal E • Systemic absorption smallest with estriol • Vagifem:E2 levels in normal postmenopausal range NAMS position statement • Progestogen not generally indicated • Insufficient data to recommend annual endometrial surveillance in asymptomatic women • Continue Rx for women as long as symptoms remain NAMS Menopause 2007;3:357-69 Notelovitz Obstet Gynecol 2002;99:556-62

  18. Her GP had talked to Mrs Grant about the results from WHI • What would have been discussed?

  19. HRT v placebo With uterus 0.625 mg Premarin +2.5mg Provera 16,608 women Stopped at 5.2 years ERT v placebo No uterus 0.625mg Premarin 10,739 women Stopped at 7 years Women’s Health Initiative StudyRandomised placebo controlled study Postmenopausal women 50-79 yrs

  20. How are results of the WHI presented? • Presented as Hazard Ratio (HR) • If HR is 1.0- then no change in risk • If HR is more than 1.0 eg 1.4 then that is an increased risk • HR of 1.4 means 40% increase in risk • If HR is 2-then double the risk • If HR is less than 1.0 eg 0.6 then that is a decreased risk • HR of 0.6 is 40% decrease in risk

  21. Hazard ratio (HR) results for WHI * * No increase in mortality with these publications

  22. Hazard ratio (HR) results for WHI

  23. WHI-Absolute risks 10,000 women/yraged 50-79 JAMA 2004;291:1701-1712 JAMA 2002;288:321-333

  24. New HT pamphlet for women • Google “Family Planning” • Resources • View our free resources • Scroll down to women • Hormone therapy • http://www.familyplanning.org.nz/LinkClick.aspx?fileticket=jowmpHhWWOo%3d&tabid=922&mid=815

  25. E+P and breast cancer • Increased incidence of breast cancer HR=1.25(1.07-1.46) • Diagnosed at more advanced stage • Increased abnormal mammograms • Higher risk if previously on HT before study • Higher risk if started HT within 5 years of menopause Chlebowski. JAMA 2003;289:3243-53

  26. E+P -Breast cancer: the issue of the time frame !

  27. Time frame for increase in breast cancer • Effects of HT on mammograms and breast Ca stage suggested that E+P hinders breast cancer diagnosis, thus making the assessment of HT safety of short term use problematic • Use for a short period may appear safe, when in fact breast cancers are being stimulated and masked from diagnosis during therapy.” Geller and Chlebowski Sexuality , Reproduction and Menopause 2003;1:5-9

  28. How can I individualise the CVD risk for Mrs Grant? • Predict computer programme • Coloured pictures by Rod Jackson in MIMS

  29. How can I individualise the CVD risk for Mrs Grant? • Trial evidence can be translated to individual decisions by transforming RR into absolute risks. • HT increase risk of stroke by 40%-RR 1.4 • Mrs Grant with 5% baseline risk has 5X1.4=7% risk if uses HT...2% increase • If she has 25% baseline risk has (25x1.4) 35% risk if uses HT………….10% increase Col N American Journal Medicine 2005;118:155S-162S

  30. Risk after stopping HT • If she stopped the HT now when would her risk of cardiovascular disease and breast cancer return to normal?

  31. Stopping combined HT-follow up WHI • Most women stopped Rx pills when instructed 2002 and 1 year later only 4% using HT not related to study • Breast risk with combined HT-declined “likely due to the regression of preclinical cancers following withdrawal of hormones • Cardiovascular risks –stroke ,VTE had disappeared at 2.4 years of follow up • Hip fracture benefit-also disappeared at 2.4 years NEJM 2009;360:573-87

  32. Increase in Mortality : WHI Post intervention follow up • WHI halted 2002 and women asked to stop study Rx • After 2.4 years of post intervention follow up-now increase in mortality • HR 1.87 (1.22-2.88) deaths from non-small-cell- lung cancer (unrelated to smoking) • Thought to be due to stimulation of growth on already established cancers • No increase with E alone Lancet 2009;374:1243-51

  33. Increase in Mortality : WHI Post intervention follow up • Although breast cancer incidence declined after women stopped HT • After total mean follow up of 11 years • Still increased incidence if assigned combined HT v placebo • HR 1.25 (1.07-1.46) and cancers more likely to be node positive • Also now increase in breast cancer deaths if assigned combined HT v placebo • HR 1.96 (1.00-4.04) Lancet 2009;374:1243-51

  34. Would Mrs Grant have had a different risk if on E alone? • 5 years of E only use: HR= 0.80(0.62-1.04) • Fewer breast cancers with localised disease but not fewer more advanced cancers • The decreased effect was concentrated in women who had not used E prior to study entry Stefanick ML et al JAMA 2006;2951647-57

  35. Would Mrs Grant have had a different risk if on E alone? • 1/11 women had short interval avoidable mammogram • 1/50 women had breast biopsies-false positive • Unlike E+P no delay in breast cancer diagnosis • Smaller increase in breast density at 2 years • 3% with E compared to 7% with E+P Chlebowski RT J Clin Oncol 2010;28:2690-7

  36. Stopping E only-follow up WHI • 10.7 years since baseline • E use median 5.9 yrs but median adherent time for 80% women was 3.5 years • No overall increased or decreased risk of CHD, deep vein thrombosis, stroke, hip fracture, colorectal cancer, or total mortality. • A decreased risk of breast cancer persisted JAMA. 2011;305(13):1305-1314

  37. Breast cancer risk after stopping E only Editorial comment: The lack of an adverse effect of unopposed estrogen when used for a short period in the WHI does not counter the larger body of evidence of an elevated risk of breast cancer with increasing duration of use ...... JAMA 2011;305:1354-5

  38. Other outcomes after stopping E only JAMA 2011;305:1354-5

  39. Editorial • These data are derived from .......subgroup analyses of randomized clinical trials and are not sufficient to alter professional guidelines. Eiran Z. Gorodeski, MD, MPHHeart and Vascular InstituteCleveland Clinic Menopause: The Journal of The North American Menopause Society 2011 ;18:935-6

  40. RCT for younger women • Will the National Institutes of Health or industry invest in a second edition of the Women’s Health Initiative? • Sample size required to show 30% treatment effect for age 50-54 would be 17,251

  41. Different viewpoints on low CHD risk 50-59 years • Timing hypothesis or • Window of opportunity ”If only HT was started early enough before vasculature is compromised then it may be cardioprotective”

  42. Surrogate outcome studies Coronary Artery Calcium Study –subset WHI (WHI-CACS) • Women < 60 years at study entry • Randomised to Estrogen only • Decreased coronary artery calcium on E v placebo • No data re combined HT. • So suggestion of potential cardioprotective effect in younger women NEJM 2007;356:2591-2602

  43. Are surrogate outcomes useful? • HT and individual biomarkers • Complex interplay of multiple pathways relating to factors such as clotting, atherosclerosis, and inflammation • So difficult translate into the overall effect of HT on CVD • Clinical endpoints eg MI are needed Am J Epidemiol 2009;170:24-8

  44. ESHRE-European Society of Human Reproduction and Embryology • In the E only WHI study a subgroup analysis among women • aged 50-59 found 14 less CHD events for women taking E • The number needed to treat to prevent • one CHD in a year would be 1000. • Human Reproduction Update 2006;12:483-497

  45. Back to Mrs. Grant • On further discussion, she had other reasons for wishing to continue using hormone replacement. • She had recently asked her general practitioner to send her for a bone mineral density scan, and she brought the result with her. • The report said that she had osteoporosis (t score −2.5 at the femoral neck), which she felt was another good reason to continue with the treatment.

  46. Fig 1 Bone density in the spine is 2.3 standard deviations below the mean in young women without osteoporosis

  47. Fig 2 Bone density in the proximal femur is 2.5 standard deviations below the mean in young women without osteoporosis

  48. BMD scan report • This patient is a 54 year old woman on hormone replacement therapy, which is planned to stop soon. • Scans of the lumbar spine and left proximal femur were performed using a lunar dual energy x ray absorptiometry device. Anatomy is unremarkable at both sites. • Bone density in the spine is 2.3 standard deviations below the mean value in the young normal population. In the proximal femur it is 2.5 standard deviations below the young normal mean.

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