menopausal hormone replacement professor gordana prelevic, md, dsc, frcp consultant endocrinologist...

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