Life after menopause
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Menopause typically occurs around age 51 and is defined as the cessation of menstrual periods for one year. It marks a major decline in estrogen and progesterone levels. Common symptoms include hot flashes, sleep disturbances, mood changes, and vaginal dryness. Long-term risks of estrogen deficiency include osteoporosis, heart disease, and cognitive decline. Historically, hormone replacement therapy (HRT) was widely used to treat menopausal symptoms but large studies in the early 2000s like the Women's Health Initiative found increased risks of breast cancer and heart disease with HRT use. This led to a reevaluation of HRT recommendations focusing on using the lowest effective dose for the shortest duration possible to manage menopausal symptoms
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Life after menopause
- 2. Defined as cessation of menses for one year Average age – 51 years old Major milestone in majority of women Menopause
- 3. Age-Related Changes of Hormones in Women Premenopause Perimenopause Postmenopause Progesterone Estradiol 50% Progesterone deficit Age 40-50 yrs Estrogen deficit Age 45-53 yrs Androgen deficit Age 55-65 yrs
- 4. Estrogen Deficiency SymptomsEstrogen Deficiency Symptoms and Ageand Age
- 6. I’m still hot, but now it comes in flashes!
- 7. You look so flushed! Did you just finish a zumba class? I love zumba!
- 9. Onset of Symptoms and Disorders in Relation to Age and Menopause Vasomotor Symptoms Sleep Disorders Menstrual Disorders Mood Changes Vaginal Atrophy Dyspareunia Skin Atrophy Osteoporosis Atherosclerosis Coronary Heart Disease Cerebrovascular Disease 40 yrs 50 yrs Menopause 60 yrs
- 10. Age (years) EstrogenSecre 40 45 50 55 60 65 70 ≥75 Development of subclinical disease Urogenital symptoms Cardiovascular disease Short-term Symptoms Long-term Diseases Cognitive decline (Alzheimer’s disease) Hot flushes Mood, sleep, and/or acute cognitive changes Osteoporosis Estrogen Loss and Manifestation ofEstrogen Loss and Manifestation of Health Risks Over TimeHealth Risks Over Time Prof. G. Rosano
- 11. 1. Periods, symptoms and contraception Date of last menstrual period [could she be pregnant?] Frequency, heaviness and duration of periods Hot flushes and night sweats? Vaginal dryness? Other symptoms? Contraception History
- 12. 2. Personal or family medical problems Breast/ ovarian/ bowel cancer in close family members Deep vein thrombosis or pulmonary embolism Risk factors for heart disease and strokes? Risk factors for osteoporosis Other History
- 13. 3. What does the patient want? History
- 14. BMI BP Breast examination and pelvic examination if indicated Examination
- 15. “Every woman alive today has the option of remaining feminine forever,” he wrote. “No longer need she fret about the cruel irony of women aging faster than men. It is simply no longer true that the sexuality of a woman past forty necessarily declines more rapidly than that of her husband.”
- 16. • HERS IHERS I • HERS IIHERS II • WHIWHI • Million Women StudyMillion Women Study • HERS IHERS I • HERS IIHERS II • WHIWHI • Million Women StudyMillion Women Study And the bubble bursts….
- 17. A Long History of Hormone Replacement Therapy 900-1500 1890 1928 1935 - 41 1943 60’s 70’s 80’s 90’s 2002 - 04 China: urine extract to treat “sexual debility” and keep women young Europe: ovarian extracts used for “hysterical” women Germany: estrogens found in “pregnancy urine” EU/US: efficacy in hot flushes, bone loss Conjugated estrogen pill developed Menopause – a preventable disease Estrogens cause endometrial cancer Endometrium protected by progestogens 20-30% of women take HRT in US and EU HERS, WHI, MW lead to a HRT reassessment and a move to LOW DOSE
- 18. Just over a decade ago: Knowledge of a small increase in breast cancer but overall, positive risk – benefit relation because of • efficacy in menopausal symptoms • prevention of osteoporosis and heart attacks • probably prevention of stroke and Alzheimer‘s disease • breast cancer on HRT was believed to have a better prognosis History of HRT
- 19. What Happened? After several decades of effective treatment with HRT the results of a few but major studies are shaking the world. • HERS stopped after 5 years - no improvement in prognosis of CVD • WHI stopped early, in July 2002 – increased risk of CVD • Wisdom stopped early, end of 2002 - … because of WHI • WHIMS data of the WHI memory study in May 2003 – no benefit in cognitive function, potential worsening of dementia • WHI data on breast cancer stage while on HRT, May 2003 • Million Women Study data on breast cancer
- 20. WHI and MW Studies Extra breast cancer cases per 1000 HRT users -7.0-5.00E only 51.50E only 1960E + P 10 years5 yearsNever usersMWS 1860E + P 7 years5 yearsNever usersWHI Million Women Study Collaborators, Lancet 2003 Aug; 362: 419-27 WHI Investigators, JAMA. 2002 Jul 17;288(3):321-33 WHI Investigators, JAMA. 2004 Apr 14;291(14):1701-12
- 21. The PerceptionThe Perception An increased risk of breast cancer was perceived by the patients as the most worrisome. Cardiovascular events were worrisome for authorities and prescribers. Breast Cancer • 2nd leading cause of cancer deaths in U.S. women • Over 46,000 women die of breast cancer annually Cardiovascular Disease, the No. 1 Killer.
- 22. 1. Do Not Ignore It How Do We Deal With theHow Do We Deal With the Risk?Risk?
- 23. Randomised, placebo controlled trial Placebo vs E alone vs E + P E + P 16,608 women, mean age 63 years E + P arm stopped at 5 years because of increased breast cancer risk E alone 10,739 women, mean age 64 years E alone arm stopped at 7 years Women’s Health InitiativeWomen’s Health Initiative -- Level 1 evidenceLevel 1 evidence WHI Investigators, JAMA. 2002 Jul 17;288(3):321-33 WHI Investigators, JAMA. 2004 Apr 14;291(14):1701-12
- 24. Million Women Study Collaborators, Lancet 2003 Aug; 362: 419-27 • Observational study ( hear say only, mentioned the word “estimate” 50 times) • 1,084,110 women • Completed questionnaire before routine mammography • Flagged on NHS Central Registers • Cancer registrations notified • Deaths notified Million Women StudyMillion Women Study -- Level 2-III evidenceLevel 2-III evidence
- 25. On 31 May 02, the Data and safety monitoring board recommended stopping the E+P vs Placebo trial after a mean of 5.2 years of follow-up: 1. Invasive breast cancer test statistic exceeded the stopping boundary for this adverse effect 2. Global index statistic supported risks exceeding benefits All data on the major clinical outcomes up to 30 April 02 WHI - ResultsWHI - Results WHI Investigators, JAMA. 2002 Jul 17;288(3):321-33
- 26. Risks – as Reported from the WHIRisks – as Reported from the WHI Placebo (n = 8102), Prempro® (n = 8506) at 5.2 years Prempro® vs Placebo Placebo Prempro® Event Hazard Ratio Absolute Risk per (95% CI) 10,000 Person-yrs Breast cancer (known) 1.26 (1.00-1.59) 30 38 Δ + 8 Heart attack (NEW) 1.29 (1.02-1.63) 30 37 Δ + 7 Stroke (NEW) 1.41 (1.07-1.85) 21 29 Δ + 8 DVT (known) 2.07 (1.49-2.87) 13 26 Δ + 13 Hip fracture (NEW) 0.66 (0.45-0.98) 15 10 Δ - 5 Colorectal cancer (known) 0.63 (0.43-0.92) 16 10 Δ - 6 Level 1 evidence WHI Investigators, JAMA. 2002 Jul 17;288(3):321-33
- 27. The chance for a woman of not getting breast cancer in a year of HRT use: BrCa(+) BrCa(-) No HRT use – 99.70% per year 30/10,000 9,970/10,000 HRT use – 99.62% per year 38/10,0009,962/10,000 so, her actual risk increases 0.08% From WHI: To your patients
- 28. The chance for a physician to be confronted with a woman of breast cancer attributable to HRT is 1 /1250 treated If you treat per year, for a whole year: 100 women (2 per week), 1 in every 12.5 years 200 women (4 per week), 1 in every 6+ years 400 women (8 per week), 1 in every 3+ years From WHI: To your patients
- 30. Incidence rates per 100,000 (age-standardized) Worldwide 35.7 United States 96.7 Northern Europe 73.2 Western Europe 78.2 Southern Europe 56.2 Eastern Europe 49.4 Western Asia 27.9 Southeast Asia 25.6 Eastern Asia 18.1 Breast Cancer Incidence RatesBreast Cancer Incidence Rates Krieger N. Am. J. Public Health 2002; 92:611
- 31. Breast Cancer Risk FactorsBreast Cancer Risk Factors USA 2000 data, for all races, 19.5 cases of invasive breast cancer per 1000 women aged 50 -64 years 9 0 5 10 15 WHI, E for 6.8 years on average 8 WHI, E+P for 5.2 years on average 7 Age >30 years at 1st delivery 6 Obesity (BMI >28.8) 5 Alcohol (30 to <60 g/day = 2-5 drinks) 4 Passive smoking 3 Heavy Smoking (>20 cigs/day) for 40 years 1 11.7 16.2 9.8 - 4.5 5.1 6.9 8.0 7.6 Additional invasive breast cancer cases per 1000 women aged 50 to 64 Breast cancer in mother 2
- 32. No good evidence of extra risk of breast cancer with estrogen alone Breast Cancer & ERT WHI Investigators, JAMA. 2004 Apr 14;291(14):1701-12
- 33. Chronological Development of Breast Cancer Growth 1cm 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Years 2,5 cm1mm Premammographic Mammographic Window Clinically detected Breast Tumor Speroff L et al., Clin Gyn end and inf 1999; 16: 631
- 34. Indications for HRTIndications for HRT Estrogen deficiency symptoms in postmenopausal women (using the lowest effective dose for the shortest duration) Prevention of osteoporosis in postmenopausal women at high risk of future fractures who are intolerant of, or contraindicated for, other medicinal products approved for this Solvay SmPC, issued 29 March 2004
- 35. Who could, and should use HRT?Who could, and should use HRT?
- 36. Women with Hot Flushes and Night Sweats “Short term” Treatment Women with vaginal atrophy HRT improves quality of life The Health of women on HRT is regularly checked.
- 37. But as Women Differ ByBut as Women Differ By • Genetics • Age and stage of menopausal (peri- or post-menopausal) • Symptoms and needs (vasomotor symptoms, urogenital atrophy, prevention of osteoporosis) • Risk factors (e.g. for breast cancer, thromboembolism) • Preferences (form of administration, withdrawal bleeds) • Habits (life style, dietary factors) • Fears Individualize Therapy
- 38. Bottom line: hormone replacement therapy is not all good or all bad!
- 39. The key is to use the LOWEST possible dose to achieve symptoms relief for the SHORTEST duration possible!
- 45. Thank You! Dr. Christine Lee MBBS, MRCOG Department of Obstetrics and Gynaecology Sarawak General Hospital
Editor's Notes
- As women go into the menopause, the female hormones start to decline. Progesterone production is the first hormone which decreases and this can often lead to luteal insufficiency with irregular or short cycles. Thereafter, the estradiol starts to decrease. This leads to the vasomotor symptoms often experienced by women in the menopause.
- This diagram shows that estrogen deficiency can lead to several symptoms and also diseases.
- This diagram shows more clearly the time frame when certain climacteric symptoms and age/hormone related diseases would likely appear.
- This diagram also shows the time frame when certain climacteric symptoms and age/hormone related diseases would likely appear.
- 2. Personal or family medical problems a] Breast/ ovarian/ bowel cancer in close family members in parents, sisters or brothers or the patient? at what age did they develop it? b] Deep vein thrombosis or pulmonary embolism in parents, brothers or sisters or the patient when and why: was it after a hip or knee replacement? was the person on the “Pill” or pregnant? did they have any test to confirm the clot? were they treated with warfarin? c] Risk factors for heart disease and strokes? has the patient had a heart attack or stroke already ? have her parents, brothers or sisters had a heart attack or stroke and if so at what age? smoking and if so how many? hypertension or diabetes? high cholesterol level? d] Risk factors for osteoporosis was the menopause before the age of 45? systemic corticosteroids for 6 months&apos; or more? anorexia or significant weight loss? family history (especially mother or sister) ? low calcium or Vitamin D intake or deficiency, or malabsorption disorders has the patient had a fracture already, and if so how did it happen and where was it? e] Other migraines, not just headaches what medicines are being taken including herbal remedies and vitamin supplements risk of pregnancy?
- does she want to take HRT or not? if yes, what preparation would she prefer if not what are her most important treatment endpoints
- physical examination should include BMI and BP. In March 2001, The Committee on Safety of Medicines (CSM) advised that clinical examination of the breasts and pelvic examination is not routinely necessary in all women taking HRT, but should be performed if clinically indicated. These recommendations are in line for women taking the oral contraceptive pill. Women should also be encouraged to participate in the national cervical screening programme (cervical smear testing), which invites women aged 25-64 in England and age 20-60 in Scotland. The national mammography screening programme and breast awareness must be discussed. In the UK all women aged 50-70 years are invited to have a mammogram every 3 years. This screening is also offered to older women but currently there is no automatic invitation. In the UK, the National Institute for Clinical Excellence has produced clinical guidance for the classification and care of women at risk of familial breast cancer in primary, secondary and tertiary care. The words &quot;clinically indicated&quot; for pelvic examination should relate to past or current disease, symptoms or family history. It is important not to miss a pelvic mass, or a pregnancy. It is a woman&apos;s evidence based patient choice to take or not to take HRT, and her decision must be recorded in the notes.
- There has been a long history of hormone replacement.
- Only seven years ago, it was known that there is a small increase in breast cancer with HRT uses but overall, there was a positive risk – benefit relation because of: efficacy in menopausal symptoms prevention of osteoporosis and heart attacks probably prevention of stroke and Alzheimer‘s disease breast cancer on HRT was believed to have a better prognosis
- Several studies took place.
- This table compares the results from the WHI and the MWS. The results are similar for E+P but different for E alone.
- The results of the WHI were perceived differently by different groups. The patients felt that an increased risk of breast cancer was the most worry some. The authorities and prescribers found the cardiovascular events to be more worry some.
- Only seven years ago, it was known that there is a small increase in breast cancer with HRT uses but overall, there was a positive risk – benefit relation because of: efficacy in menopausal symptoms prevention of osteoporosis and heart attacks probably prevention of stroke and Alzheimer‘s disease breast cancer on HRT was believed to have a better prognosis
- Only seven years ago, it was known that there is a small increase in breast cancer with HRT uses but overall, there was a positive risk – benefit relation because of: efficacy in menopausal symptoms prevention of osteoporosis and heart attacks probably prevention of stroke and Alzheimer‘s disease breast cancer on HRT was believed to have a better prognosis
- Writing Group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women – principal results from the Women’s Health Initiative randomized controlled trial. JAMA. 2002 Jul 17;288(3):321-33 Design: Estrogen plus progestin component of the Women&apos;s Health Initiative, a randomized controlled primary prevention trial (planned duration, 8.5 years) in which 16608 postmenopausal women aged 50-79 years with an intact uterus at baseline were recruited by 40 US clinical centers in 1993-1998. Interventions Participants received conjugated equine estrogens, 0.625 mg/d, plus medroxyprogesterone acetate, 2.5 mg/d, in 1 tablet (n = 8506) or placebo (n = 8102). Conclusions: Overall health risks exceeded benefits from use of combined estrogen plus progestin for an average 5.2-year follow-up among healthy postmenopausal US women. All-cause mortality was not affected during the trial. The risk-benefit profile found in this trial is not consistent with the requirements for a viable intervention for primary prevention of chronic diseases, and the results indicate that this regimen should not be initiated or continued for primary prevention of CHD. Women’s Health Initiative Investigators.Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women&apos;s Health Initiative randomized controlled trial. JAMA. 2004 Apr 14;291(14):1701-12. OBJECTIVE: To assess the effects on major disease incidence rates of the most commonly used postmenopausal hormone therapy in the United States. DESIGN, SETTING, AND PARTICIPANTS: A randomized, double-blind, placebo-controlled disease prevention trial (the estrogen-alone component of the Women&apos;s Health Initiative [WHI]) conducted in 40 US clinical centers beginning in 1993. Enrolled were 10 739 postmenopausal women, aged 50-79 years, with prior hysterectomy, including 23% of minority race/ethnicity. INTERVENTION: Women were randomly assigned to receive either 0.625 mg/d of conjugated equine estrogen (CEE) or placebo. CONCLUSIONS: The use of CEE increases the risk of stroke, decreases the risk of hip fracture, and does not affect CHD incidence in postmenopausal women with prior hysterectomy over an average of 6.8 years. A possible reduction in breast cancer risk requires further investigation. The burden of incident disease events was equivalent in the CEE and placebo groups, indicating no overall benefit. Thus, CEE should not be recommended for chronic disease prevention in postmenopausal women.
- Beral V; Million Women Study Collaborators. Breast cancer and hormone-replacement therapy in the Million Women Study.Lancet. 2003 Aug 9;362(9382):419-27. BACKGROUND: Current use of hormone-replacement therapy (HRT) increases the incidence of breast cancer. The Million Women Study was set up to investigate the effects of specific types of HRT on incident and fatal breast cancer. METHODS: 1084110 UK women aged 50-64 years were recruited into the Million Women Study between 1996 and 2001, provided information about their use of HRT and other personal details, and were followed up for cancer incidence and death. FINDINGS: Half the women had used HRT; 9364 incident invasive breast cancers and 637 breast cancer deaths were registered after an average of 2.6 and 4.1 years of follow-up, respectively. Current users of HRT at recruitment were more likely than never users to develop breast cancer (adjusted relative risk 1.66 [95% CI 1.58-1.75], p&lt;0.0001) and die from it (1.22 [1.00-1.48], p=0.05). Past users of HRT were, however, not at an increased risk of incident or fatal disease (1.01 [0.94-1.09] and 1.05 [0.82-1.34], respectively). Incidence was significantly increased for current users of preparations containing oestrogen only (1.30 [1.21-1.40], p&lt;0.0001), oestrogen-progestagen (2.00 [1.88-2.12], p&lt;0.0001), and tibolone (1.45 [1.25-1.68], p&lt;0.0001), but the magnitude of the associated risk was substantially greater for oestrogen-progestagen than for other types of HRT (p&lt;0.0001). Results varied little between specific oestrogens and progestagens or their doses; or between continuous and sequential regimens. The relative risks were significantly increased separately for oral, transdermal, and implanted oestrogen-only formulations (1.32 [1.21-1.45]; 1.24 [1.11-1.39]; and 1.65 [1.26-2.16], respectively; all p&lt;0.0001). In current users of each type of HRT the risk of breast cancer increased with increasing total duration of use. 10 years&apos; use of HRT is estimated to result in five (95% CI 3-7) additional breast cancers per 1000 users of oestrogen-only preparations and 19 (15-23) additional cancers per 1000 users of oestrogen-progestagen combinations. Use of HRT by women aged 50-64 years in the UK over the past decade has resulted in an estimated 20000 extra breast cancers, 15000 associated with oestrogen-progestagen; the extra deaths cannot yet be reliably estimated. INTERPRETATION: Current use of HRT is associated with an increased risk of incident and fatal breast cancer; the effect is substantially greater for oestrogen-progestagen combinations than for other types of HRT.
- From JAMA, 2002; 288:321-333
- Data adapted from JAMA, 2002; 288:321-333 For those outcomes included in the “global index”, absolute excess risks per 10,000 person-years in the group treated with PREMPRO were 7 more CHD events, 8 more strokes, 8 more PEs, and 8 more invasive breast cancers, while absolute risk reductions per 10,000 person-years were 6 fewer colorectal cancers and 5 fewer hip fractures. The absolute excess risk of events included in the “global index” was 19 per 10,000 person-years. There was no difference between the groups in terms of all-cause mortality. Includes metastatic and non-metastatic breast cancer with the exception of in situ breast cancer A subset of the events was combined in a “global index”, defined as the earliest occurrence of CHD events, invasive breast cancer, stroke, pulmonary embolism, endometrial cancer, colorectal cancer, hip fracture, or death due to other causes. DVT not included in Global Index. In general, the increases in stroke and VTE/PE were more pronounced in the first year of treatment and are broadly in line with results anticipated from previous observational studies. It is well known that the incidence of both increase with age whether on HRT or not. Despite over 25% of the women reporting previous use of HRT, there was little evidence of an increase in breast cancer in the HRT users under about 4-5 years of use, although breast cancer incidence was commoner in past users. However, there was no evidence of an associated increased risk with HRT use in women potentially at higher risk, e.g. a family history of breast cancer or other known “lifestyle” risks. The increase in CHD was unexpected, but there may be an explanation for these results. Despite the increased incidence of some conditions, there was no increase in total deaths, either from cancer or other causes. The reductions in fractures and colo-rectal cancers were shown to increase with duration of use. There was no evidence of an increased risk of endometrial cancer with an average 5.2 years on this ccHRT. The actual RR = 0.83, which might suggest a small but non-significant reduction.
- Only seven years ago, it was known that there is a small increase in breast cancer with HRT uses but overall, there was a positive risk – benefit relation because of: efficacy in menopausal symptoms prevention of osteoporosis and heart attacks probably prevention of stroke and Alzheimer‘s disease breast cancer on HRT was believed to have a better prognosis
- Only seven years ago, it was known that there is a small increase in breast cancer with HRT uses but overall, there was a positive risk – benefit relation because of: efficacy in menopausal symptoms prevention of osteoporosis and heart attacks probably prevention of stroke and Alzheimer‘s disease breast cancer on HRT was believed to have a better prognosis
- Only seven years ago, it was known that there is a small increase in breast cancer with HRT uses but overall, there was a positive risk – benefit relation because of: efficacy in menopausal symptoms prevention of osteoporosis and heart attacks probably prevention of stroke and Alzheimer‘s disease breast cancer on HRT was believed to have a better prognosis
- Only seven years ago, it was known that there is a small increase in breast cancer with HRT uses but overall, there was a positive risk – benefit relation because of: efficacy in menopausal symptoms prevention of osteoporosis and heart attacks probably prevention of stroke and Alzheimer‘s disease breast cancer on HRT was believed to have a better prognosis
- Only seven years ago, it was known that there is a small increase in breast cancer with HRT uses but overall, there was a positive risk – benefit relation because of: efficacy in menopausal symptoms prevention of osteoporosis and heart attacks probably prevention of stroke and Alzheimer‘s disease breast cancer on HRT was believed to have a better prognosis
- Only seven years ago, it was known that there is a small increase in breast cancer with HRT uses but overall, there was a positive risk – benefit relation because of: efficacy in menopausal symptoms prevention of osteoporosis and heart attacks probably prevention of stroke and Alzheimer‘s disease breast cancer on HRT was believed to have a better prognosis
- The breast cancer incidence varies throughout the world. Krieger N. Is breast cancer a disease of affluence, poverty, or both? The case of African American women. Am J Public Health. 2002 Apr;92(4):611-3.
- There are several risk factors for developing breast cancer. 1.Terry PD, Miller AB, Rohan TE. Cigarette smoking and breast cancer risk: a long latency period? Int J Cancer 2002;100:723-728. 2.Easton DF. Familial risks of breast cancer. Breast Cancer Res 2002;4:179-181. Epub 2002 Aug 2. 3.Johnson KC, Wells AJ. Active and passive smoking in breast cancer. Epidemiology 2002;13:745-746. 4.Smith-Warner SA, Spiegelman D, Yaun SS, van den Brandt PA, Folsom AR, Goldbohm RA, Graham S, Holmberg L, Howe GR, Marshall JR, Miller AB, Potter JD, Speizer FE, Willett WC, Wolk A, Hunter DJ. Alcohol and breast cancer in women: a pooled analysis of cohort studies. JAMA 1998;279:535-540. 5.Favero A, Parpinel M, Franceschi S. Diet and risk of breast cancer: major findings from an Italian case-control study. Biomed Pharmacother 1998;52:109-115. 6.Clavel-Chapelon F; E3N-EPIC Group. Differential effects of reproductive factors on the risk of pre- and postmenopausal breast cancer. Results from a large cohort of French women. Br J Cancer 2002;86:723-727. 7.Writing Group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women – principal results from the Women’s Health Initiative randomized controlled trial. JAMA 2002;288:321-333. 8.Women’s Health Initiative Investigators. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women&apos;s Health Initiative randomized controlled trial. JAMA 2004;291:1701-1712. 9.SEER Cancer Statistics Review 1975-2000, National Cancer Institute.
- According to the WHI investigators and the estrogen alone arm, there is no good evidence of extra risk of breast cancer with estrogen alone
- This diagram was taken from Clinical Gynecology Endocrinology and Infertility. “ The doubling time of breast cancer is very variable, but in general, a tumor doubles in size every 100days. Thus, it takes a single malignant cell approximately 10 years to grow to a clinically detectable 1 cm mass, but by this time a tumor of 1cm has already progressed through 30 of the 40 doublings in size which is estimated to be associated with fatal disease. Furthermore, the average size at which a tumor is detected (70-75% of tumors are found by patients themselves) has been (prior to mammography) 2.5cm, a size which has a 505 chincidenceof lymph node involvement.”
- There are 2 indications for HRT. Estrogen deficiency symptoms in postmenopausal women (Note: the lowest effective dose for the shortest duration should be used) Prevention of osteoporosis in postmenopausal women at high risk of future fractures who are intolerant of, or contraindicated for, other medicinal products approved for this
- Women&apos;s Health Initiative Investigators.Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women&apos;s Health Initiative randomized controlled trial.JAMA. 2002 Jul 17;288(3):321-33. DESIGN: Estrogen plus progestin component of the Women&apos;s Health Initiative, a randomized controlled primary prevention trial (planned duration, 8.5 years) in which 16608 postmenopausal women aged 50-79 years with an intact uterus at baseline were recruited by 40 US clinical centers in 1993-1998. INTERVENTIONS: Participants received conjugated equine estrogens, 0.625 mg/d, plus medroxyprogesterone acetate, 2.5 mg/d, in 1 tablet (n = 8506) or placebo (n = 8102). MAIN OUTCOMES MEASURES: The primary outcome was coronary heart disease (CHD) (nonfatal myocardial infarction and CHD death), with invasive breast cancer as the primary adverse outcome. A global index summarizing the balance of risks and benefits included the 2 primary outcomes plus stroke, pulmonary embolism (PE), endometrial cancer, colorectal cancer, hip fracture, and death due to other causes. RESULTS: On May 31, 2002, after a mean of 5.2 years of follow-up, the data and safety monitoring board recommended stopping the trial of estrogen plus progestin vs placebo because the test statistic for invasive breast cancer exceeded the stopping boundary for this adverse effect and the global index statistic supported risks exceeding benefits. This report includes data on the major clinical outcomes through April 30, 2002. Estimated hazard ratios (HRs) (nominal 95% confidence intervals [CIs]) were as follows: CHD, 1.29 (1.02-1.63) with 286 cases; breast cancer, 1.26 (1.00-1.59) with 290 cases; stroke, 1.41 (1.07-1.85) with 212 cases; PE, 2.13 (1.39-3.25) with 101 cases; colorectal cancer, 0.63 (0.43-0.92) with 112 cases; endometrial cancer, 0.83 (0.47-1.47) with 47 cases; hip fracture, 0.66 (0.45-0.98) with 106 cases; and death due to other causes, 0.92 (0.74-1.14) with 331 cases. Corresponding HRs (nominal 95% CIs) for composite outcomes were 1.22 (1.09-1.36) for total cardiovascular disease (arterial and venous disease), 1.03 (0.90-1.17) for total cancer, 0.76 (0.69-0.85) for combined fractures, 0.98 (0.82-1.18) for total mortality, and 1.15 (1.03-1.28) for the global index. Absolute excess risks per 10 000 person-years attributable to estrogen plus progestin were 7 more CHD events, 8 more strokes, 8 more PEs, and 8 more invasive breast cancers, while absolute risk reductions per 10 000 person-years were 6 fewer colorectal cancers and 5 fewer hip fractures. The absolute excess risk of events included in the global index was 19 per 10 000 person-years. CONCLUSIONS: Overall health risks exceeded benefits from use of combined estrogen plus progestin for an average 5.2-year follow-up among healthy postmenopausal US women. All-cause mortality was not affected during the trial. The risk-benefit profile found in this trial is not consistent with the requirements for a viable intervention for primary prevention of chronic diseases, and the results indicate that this regimen should not be initiated or continued for primary prevention of CHD.
- Therapy needs to be individualized as women differ by: Genetics Age and stage of menopausal (peri- or post-menopausal) Symptoms and needs (vasomotor symptoms, urogenital atrophy, prevention of osteoporosis) Risk factors (e.g. for breast cancer, thromboembolism) Preferences (form of administration, withdrawal bleeds) Habits (life style, dietary factors) Fears