Tony Parsons Warwick Medical School August 2008

2 STRAW reproductive aging system Length decreases -2 days

3 Menopause that occurs in women < 40 years old. Utian. Climacteric (About 1% of population or less) CA MS

4 Cessation of menstruation that follows bilateral oophorectomy (surgical menopause), Iatrogenic ablation of ovarian function by chemotherapy or pelvic radiation therapy. (No perimenopause transition for these women) Utian. Climacteric CA MS

5 Early loss of fertility More severe symptoms Greater risk of osteoporosis and CVD Sequelae of underlying disease and its treatment Little research regarding benefits/risks of treatment

6 1.2 million follicles at birth, only about 1,000 by menopause Most follicular loss due to atresia, not ovulation Atresia accelerates at around age 35 to 38 years Age-related uterine changes also contribute to decreased fertility

Main drop after Million Women Study, not WHI Now stable Increasing use of low dose, but in switchers rather than starters Approx 25 % of discontinuers thought to have restarted Fewer new prescriptions

Early menopause Local oestrogens Alternatives to oestrogen Systemic HT

Premature natural menopause (<40) Iatrogenic Bilateral oophorectomy Chemotherapy / radiotherapy No change in practice Estrogen replacement the norm unless contraindicated

15% premenopausal women 10 – 40% postmenopausal 10 – 25% women taking systemic HRT 2/3 by age 75

Atrophy increased significantly with increase in menopausal age (P <.001). Adapted from Versi E, et al. Int Urogynecol J. 2001;12: © 2001, Springer-Verlag. Perimenopause (n = 133) 0–1 Year (n = 52) 2–3 Years (n = 39) 4 Years (n = 67)

Reduced lubrication Dryness Discomfort during intercourse Decreased frequency of intercourse Vaginal and vulval irritation Discharge Bleeding Relationship problems

20 – 25% with symptoms sought help Despite 78% feeling active sex life important, only 17% discussed symptoms with health professional, 59% hide symptoms from partner Bladder symptoms – only 21% discussed with health professional

25% of those with genito-urinary atrophy symptoms who seek help, receive treatment 71% with vaginal symptoms - no treatment 89% with bladder symptoms - no treatment

Ask about symptoms and offer treatment Topical oestrogen may be needed even with systemic HRT No real contraindications A long-term treatment for a long- term problem

Systematic review 70 randomised trials Most studies poor quality or too small Data insufficient to support the effectiveness of any complementary or alternative therapy Nedrow,A et al. Arch Intern Med 2006;166:

43 prospective randomised studies Effective (= one or two fewer flushes per day) SSRIs / Venlafaxine Clonidine Gabapentin Methyldopa Bellergal Ineffective Soy Red clover Nelson, HD et al. JAMA 2006;295:

National Center for Health Statistics. 1999: Coronary Artery Disease Stroke Lung Cancer Breast Cancer Colon Cancer Endometrial Cancer Age (years) Mortality Rate per 100, –7970–7465–6960–6455–5950–5445–4980–8485+

1993 Womens Health Initiative Studies Designed 1996 PEPI 1998 HERS 2002 WHI (EPT) 2003 MWS 2004 WHI (ET)

Stroke Threshold level Early STOP = clear harm Threshold level Early STOP = clear benefit Coronary artery disease Breast cancer Risk Benefit Plan to study until 2005 Additional benefits: Osteoporosis treatment Colon cancer Overall mortality Additional risks: VTE Writing Group for WHI. JAMA 2002.

26% increase Breast cancer VTE Fracture reduction Colon cancer Early STOP=clear harm Threshold level 29% increase Coronary artery disease 41% increase Stroke RiskBenefit Writing Group for WHI. JAMA 2002.

CHD Breast cancer Stroke VTE DVT PE Colorectal cancer Hip fractures Total fractures Overall Hazard Ratio Attributable Risk per 10,000 Women/Year Health Event Benefit per 10,000 Women/Year Overall Relative and Attributable Risk for Women 50 to 80 Years of Age Nominal 95% 1.02– – – – – – – – –0.85 Adjusted 95% 0.85– – – – – – – – –0.92 Confidence Interval DVT = deep vein thrombosis; PE = pulmonary embolism. Writing Group for the Women's Health Initiative Investigators. JAMA. 2002;288:

Even with WHI figures HRT for women with moderate menopausal symptoms will be cost effective

Data on 828,923 postmenopausal women Mean age 55.9 years Mean age 55.9 years Mean time from baseline to cancer diagnosis Mean time from baseline to cancer diagnosis 1.2 yrs 1.2 yrs

Selection bias Breast cancer incidence greater than in general population HRT use more common Time to diagnosis implausibly short Apparent loss of HRT effect within 1 year of stopping Misclassification of time, type and duration of HRT Multiple errors – poorly written, poorly reviewed

Breast Endometrial Adapted from Lancet 2003;362: Endometrial Cancer Breast Cancer

Revisiting the animal work Early versus late use of HRT – is there really a window of opportunity ? E versus E + P

1 Clarkson TB, et al. J Clin Endocrinol Metab. 1998;83:721-6; 2 Adams MR, et al. Arterioscler Thromb Vasc Biol. 1997;17:217-21; 3 Clarkson TB, et al. J Clin Endocrinol Metab. 2001;86:41-47; 4 Williams JK, et al. Arterioscler Thromb Vas Biol. 1995;15: Premenopausal YearsPostmenopausal Years Ovariectomy Plaque Area (% of placebo) Time Healthy dietCEE + atherogenic diet 1. 70% 1,2 Atherogenic dietCEE + atherogenic diet 2. 50% 3 Healthy diet Atherogenic diet Healthy diet + CEE 3. 0% 4 ~ 6 Year Human Equivalent

New LesionsEstablished Lesions Rosenfeld ME, et al. Atherosclerosis. 2002;164:251-9.

Meta-analysis of 30 trials 27,000 participants Odds ratio for mortality differed with age at enrolment Under Over [Nurses Health Study HRT within 2 years of LMP ] Salpeter et al J Gen Int Med 2004;19:

The dotted vertical line indicates the overall CHD odds ratio (1.24). P-values for interaction were not significant. Manson JE, et al. N Engl J Med. 2003;349: Hazard Ratio for CHD Age (years) 50–59 60–69 70–79 Years Since Menopause <10 10–19 20

Zandi PP, et al. JAMA. 2002;288: Discrete Annual Hazard Age (years) Women HT Nonusers HT Use 10 Years Men

Past users of HRT ( > 10 years) 83 % reduction in risk of AD Current users who started after 60 (using for 3 – 10 years) 112 % increase in risk Zandi et al JAMA 2002

1500 women who had one or both ovaries removed before controls 27 years mean follow-up Only 20% who had bilateral oophorectomy received oestrogen until 50 Incidence of dementia with HT equal to controls Incidence without HT doubled Rocca et al, Neurology 2007

Cumulative Proportion Time (years) Unweighted HR = 1.24 (95% CI, 1.01–1.54) Chlebowski RT, et al. JAMA. 2003;289: E+P Placebo

CEE Placebo Womens Health Initiative Steering Committee. JAMA. 2004;291: Kaplan-Meier Estimate HR = % nCI = 0.59– % aCI = 0.57–1.06

Prospective case-control Women with possible DVT recruited prior to confirmation or exclusion of diagnosis Idiopathic DVT, no risk factors Unopposed oestrogen OR 1.22 [0.57 – 2.61] Combined EPT OR 2.70 [1.44 – 5.07]

Hospital based case-control study Current users oral EPT OR 3.5 [1.8 – 6.8] Current users transdermal OR 0.9 [0.5 – 1.6] Scarabin et al. Lancet,2003;362:428-32

Low doses may confer protection while higher doses may increase risk Risks may be lower with transdermal Thrombogenic effects C-reactive Protein Birge ss Menopause 2006;13(5):

Hazard YearRatio P <.05, significant for decreasing risk over time. Year HR = % nCI = 1.58– % aCI = 1.26–3.55 Writing Group for the Women's Health Initiative Investigators. JAMA. 2002;288:

Change in Plasma CRP (%) 6 Months12 Months CRP = C-reactive protein. Decensi A, et al. Circulation. 2002;106:

Use of HT at the menopause will have different effects from HT started 10 to 15 years later No data to suggest change of indications for HT at the menopause Increasing evidence that progestogen adds to risks esp. breast cancer, DVT Duration of use will usually be influenced by increase in breast cancer risk – is there any with unopposed oestrogen ?

Early menopause or Symptoms affecting quality of life Prevention of osteoporosis/ fracture Prevention of heart disease likely but not a primary indication Protection against other conditions currently unproven (but increasing evidence for dementia, various cancers and osteoarthritis)

Thrombosis Breast cancer

Only breast cancer risk is cumulative Consider Age at menarche Age at first child Breast feeding Smoking Alcohol Premenopausal BMI Family history E or E + P ?

A DATE FOR YOUR DIARY… BMS Conference 3 & 4 July 2008, The Midland Hotel, Manchester