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