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Menopausal Hormone Replacement
Professor Gordana Prelevic, MD, DSc, FRCP
Consultant Endocrinologist
Royal Free Hampstead NHS Trust
Whittington Health
Vasomotor symptoms
• Hot flushes• Sweats
Occur in 74% of women
Last 5 or more years in 25%
94 % menopausal symptoms
64 % severe symptoms
3rd European Menopause Survey 2005
Types of menopausal therapy
Conventional HRT• Oestrogen
oral, transdermal, implant
• Oestrogen/progestogen
sequential or continuous combined
Steroid with tissue specific activity• Tibolone
HRT - doses
• Oestrogen– dose
• symptoms
• bone protection (+/- Ca++)
• Progestogen– dose (sequential/continuous combined)
– duration
HRT - follow up
• Symptoms• Bone mineral density• Pelvic US• mammography
Women’s Health Initiative - WHI
Randomized controlled primary prevention trial of 16608 postmenopausal women aged 50-79 with uterus in situ
CEO 0.625 mg + MPA 2.5 mg
Results: RR CI• CHD 1.29 0.85 - 1.97
• Stroke 1.41 0.86 - 2.31
• Breast cancer 1.26 0.83 - 1.92
• PE 2.13 1.26 - 3.55
• Colorectal cancer 0.63 0.32 - 1.24
• Hip fracture 0.66 0.33 - 1.33
JAMA 2002;288:321-333
WHI - estrogen alone
Randomized controlled primary prevention trial of 10739 postmenopausal women aged 50-79years with prior hysterectomy
CEO 0.625 mg
Results: RR CI• CHD 0.91 (0.75 - 1.12)
• Stroke 1.39 (1.10 - 1.77)
• Breast cancer 0.77 (0.59 - 1.01)
• PE 1.34 (0.87 - 2.06)
• Colorectal cancer 1.08 (0.75 - 1.55)
• Hip fracture 0.61 (0.41 - 0.91)
JAMA 2004;291:1707-1712
Menopausal symptoms and quality of life
• Estrogen therapy is gold standard treatment for hot flushes (effectiveness 90%)
• 42% of women restarted HRT because of the return of symptoms (3rd European Menopause Survey 2005)
• Effective doses (0.3 mg CEE, 0.5 mg E2 25mcg transdermal E2)
• Only women with flushes have improvement in emotional measures of quality of life (JAMA 2002;287:591-597)
Breast cancer risk & HRT
Population based case control study 975 women with invasive Breast Ca 65-79 yrs & 1007 population controls
ERT alone - no increased risk
CHRT - 1.7-fold increased risk2.7-fold increased risk of invasive lobular Ca
Relation of HRT to risk of invasive Breast Ca by receptor status
ER+/PR+ ER+/PR- ER-/PR-
E alone 1.0 (0.8-1.4) 0.7(0.4-1.3) 1.0(0.5-1.9)
CHRT 2.3(1.6-3.2) 1.4(0.8-2.4) 1.1(0.5-2.2)
Li et al JAMA 2003;289:3254-3263
Clinical profile of tibolone
• Relief of climacteric symptomsrestores vaginal atrophybeneficial effects on libido and mood
• No endometrial stimulation
• Prevention of osteoporosis & fractures
• Risk of stroke similar to HRT
• Non-estrogenic effect on breast tissue
Less breast tenderness than with conventional HRTNo increase in mammographic breast density
Mammograms beforeand after treatment with tibolone
Woman receivingtransdermal E2/NETA
Same woman 1 year afterSame woman 1 year afterchanging therapy to Livialchanging therapy to Livial
Valdivia and Ortega 1997
Risk of VTE with HRT
• Risk in current users is 3-4 x higher than in non-users
– one case in 5000 users per year
• The baseline risk of VTE between the ages of 50 and 70 is higher
• Increased risk appears to be concentrated in new users
• VTE risk is not increased with transdermal E (oral 3.5 vs TRD 0.9)ESTHER study - Lancet
2003;362:428-432
HRT & stroke
• Risk increased for 39% (CEE alone) - 41% (CEE/MPA)
• 29% increased risk in a meta-analysis (BMJ 2005;330:342-345)
• ischaemic stroke
• risk is cumulative
• important factor increasing age
Low dose TRDE2 no significant risk of stroke
HRT - Cognitive function & Alzheimer’s Disease prevention
• E may improve cognitive performance in recently menopausal women with menopausal symptoms (JAMA 2001;285:1489-1499)
• WHIMS - women taking either CEE alone or CEE/MPA had higher risk of dementia (JAMA 2003;289:2651)
• Negative impact on cognitive abilities when starting HRT after 65years and with existing cognitive problems (JAMA; 2004;291:2959-2968)
• E in the treatment of AD - no benefit (Neurology 2000;54:295)
HRT in women - who should get what?
• Who ?
Women with menopausal symptoms
• When ?
At the time of menopause / perimenopause
• What ?Minimal dose which controls symptoms (0.5mg oral, 25mcg TRD)
Transdermal estradiol (obesity, DM, Hypertension, Liver disease)
Estrogen alone (Mirena IUS) Vaginal estriol
Tibolone
Type of progestogen ?
• How long ?3 - 5 years post-menopausal
Key points (1)
• Primary use of any form of HRT is to control menopausal symptoms
• HRT should only be prescribed for the short-term relief of menopausal symptoms and prevention of osteoporosis
• HRT should not be prescribed in the hope or expectation of any protection against arterial CVD or Alzheimer’s disease
• Oral and non-oral oestrogen have different metabolic profiles that may impact on side-effects and therapeutic risks (VTE risk)
Key points (2)
• Combined E/PRG preparations have different profiles compared to E alone (lipids, CHD)
• An increase in breast cancer risk is related to the duration of use and also concurrent use of progestogens. The role of E and/or PRG dose is unclear
• Tibolone has significantly smaller risk of Breast Cancer compared to E/PRG preparations
Data on HRT associated risks should not be extrapolated to women with premature menopause
Appropriate & effective doses and regimens need to be individualized
HRT should be part of overall strategy
– life style
– increase exercise
– decrease alcohol intake
– decrease smoking
– fight obesity