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Consensus of the Belgian Menopause Society regarding Hormone Therapy

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					Consensus of the Belgian Menopause Society regarding Hormone therapy after the menopause
Last update 5.02.07

Methodology
• These experts came together and proposed the following consensus because they felt that the recent publications (WHI estrogen+progestin & estrogen only arm, One Million, E3N-Epic, DAHORS…) modified considerably their HT strategy. They considered meta-analyses, randomised trials and large epidemiological observational studies only. In January 2005 a first consensus was written. This is an update of the first consensus using the same strategy. • The experts hope that this document will also facilitate the clinical practice of physicians in the field. The proposed consensus represent the shared view of these experts. In some cases no consensus was reached and these points will be mentioned also.

• Levels of evidence…. • The current literature defines « standard estrogen dose » as the equivalent of 2mg E2, or O.625 CEE; « low » dose as 1 mg E2 or equivalent and « ultralow dose » as 0.5 mg or lower. • WHO Rare

HT definitions
• By estrogen therapy (ET), we mean all systemic estrogen provided orally or parenterally (transdermal, percutaneous, implant, nasal spray). The Estrogen-progestin therapy (EPT) includes regimens combining estrogens and progestins. Hormone therapy (HT) includes all regimens containing steroids for the treatment of menopausal symptoms with inclusion of ET, EPT and tibolone. Topical administration of estrogens concerns vaginal forms.

Patient information
• Individualised advice is needed. Risks and benefits need to be explained preferably using absolute risk estimation for women considering HT. • Women should be informed about other health strategies. • Therapeutic management should be reviewed regularly.

The use of HT in the following topics have been reviewed
• • • • • • • Climacteric symptoms Quality of life Urogenital atrophy Osteoporosis Breast cancer risk Premature menopause Other cancer risks : Colon cancer risk, Endometrial cancer, Ovarian cancer, Others • Cardiovascular diseases, venous thrombo-embolic diseases • Alzheimer Disease • Miscellaneous

Climacteric symptoms
• Presence of disturbing symptoms:
– Severe symptoms disturb women’s life for variable (short to very long) duration.

• In women suffering from severe symptoms, HT is the most efficacious treatment. In these women, it improves the quality of life. • (Level of evidence I )

Climacteric symptoms
• Some symptoms are attributed to the climacteric but may result from other causes. • In asymptomatic women, HT does not ameliorate objectively the overall quality of life. • (level 1 of evidence)

Urogenital atrophy
• HT reduces the risk of symptoms due to genital atrophy. • Local (topical) treatments should be preferred in the absence of other indications. This regimen may reduce the incidence of recurrent urinary tract (RUT) infections. • (Level 1 of evidence) • Urinary incontinence is not an indication for HT.

Osteoporosis
• Life style counselling should occur in all women. • In women at risk for osteoporosis adequate intake of calcium and vitamin D should be supplied. • HT (ET, EPT and Tibolone) is efficacious in preventing menopause-related bone loss and in preventing vertebral and/or hip fractures. (Level 1 of evidence) • Nevertheless, since these regimens need to be used for long periods of time, potential long term risks should also be weighted against benefits. • In established osteoporosis there is more evidence for using other drugs (biphosphonates, SERMS, Strontium, PTH…).

Breast cancer risk
• Women should be counseled that life style factors influence the BC risk (obesity and alcohol use increase it and exercise decreases it). (level 2 of evidence) • Screening for breast cancer should occur whether or not women are using HT.

Breast cancer risk
• EPT: Randomized data using one regimen (CEE+MPA) of EPT show an increased risk of breast cancer beyond 5 years of use (WHI). (level 1 of evidence) • This means for example using the WHI data, that in a cohort of 1000 postmenopausal women aged 50-79 years, using EPT during a period of 10 years, the absolute risk of BC is 38 in EPT users vs 30 /1000 women in placebo users, which means 8 additional cases. This additional risk is comparable to that of some life style factors. • Some observational data show that this risk may start earlier and may be higher in women with a low BMI (MWS). Others found that lower dose of EPT (DAHORS) are not associated with an increased risk or that this risk may be different according to the progestin used (lower risk with micronised progesterone, dydrogesterone) (E3N). Sequential EPT as well as tibolone may entail lower risk than continuous combined regimens (MWS). (level 2 of evidence)

Breast cancer risk
• ET: Standard ET doses, used during an average period of 6.8 years, did not modify breast cancer incidence in a prospective randomised large study, in contrast to EPT (WHI) (level 1 of evidence). Therefore, the addition of a progestin is not indicated in hysterectomised women. • EPT interferes with mammography screening in about + 20% of the women. This is less the case using ET and using tibolone.

Breast cancer risk
• The effect of HT on the breast cancer riskrelated prognosis and mortality is still controversial (level 1,2 and 3 of evidence).

Other cancers risks
• Randomized trials report a reduced risk of colon cancer in EPT users (but not in the ET users) (level 1 of evidence). Currently, colon cancer prevention is not a recognized indication for HT. • Endometrial cancer : ET use is associated with substantially increased risk. Observational data are conflicting as to whether sequential EPT reverses this risk to the baseline risk (level 2 of evidence). However, continuous combined EPT is not associated with increased risk (level 1 of evidence). • Although some concern has been raised concerning Tibolone (MWS) (level 2 of evidence), a 2 year randomised trial has not shown an increased risk of endometrial pathology (THEBES)(level 1 of evidence).

Other cancer risks
• There is a need for more data on the effect of HT on other cancers (such as the ovary and the lung).

Venous Thromboembolic diseases (VTE)
• Randomized and observational studies reported that HT increases the risk of VTE (2 to 3 fold) (level 1, 2 of evidence). This means that in a cohort of 1000 women using HT, an additional 2 cases occur per year of use on a typical baseline risk of 1 per 1000 woman-years. • Standard ET doses were associated with a rare, but significant increase in VTE (WHI) (0.8 excess/ 1000 women-year). Major identified risk factors are age, overweight, sedentarity and thrombophilia. The risk is highest during the first year of use. • This risk may be lower using low oral doses of HT or using HT regimens with transdermal or percutaneous estrogens (level 2 of evidence).

Cardiovascular diseases : CHD
• Experimental and observational studies reported in the past reduced risk of atherosclerosis and CHD in HT users (level 2, 3 of evidence). • Recent randomized trials with EPT reported increased CHD risk. This risk may be age-and menopausal agerelated. It is essentially in women above the age of 70 that this risk was obvious (WHI) (level 1 of evidence). Observational data (NHS) suggest a reduced risk in early menopause (level 2 of evidence). • Standard ET doses, used during an average period of 6.8 years, did not change CHD incidence nor mortality in a prospective randomised large study (WHI). However, there was a trend to a lower incidence of CHD in women less than 10 years after menopause (WHI) (level 1 of evidence).

Cardiovascular diseases : Stroke
• HT (EPT, ET and Tibolone) increase the risk of stroke (level 1 of evidence). • Standard ET doses increased the incidence of stroke resulting in an excess of 12 cases /10 000 women- year on a baseline incidence of 32/ 10 000 women -year. • Observational studies suggest that low doses HT confer a lower risk of stroke (level 2 of evidence). • HT is contraindicated in women with a past history of stroke.

Cardiovascular diseases (CVD)
• Nor primary neither secondary CVD prevention as such, are currently indications for HT. It is not clear whether these results can be extrapolated to women with precocious menopause.

Alzheimer’s disease and cognitive function
• There is insufficient evidence whether HT affects cognitive function or prevents/delays Alzheimer’s dementia. Therefore HT should currently not be used for this indication.

Early menopause
• Data gathered from studies in postmenopausal women aged 50 or more can not necessarily be extrapolated to younger postmenopausal women. • Because these women present often more pronounced symptoms, HT will be more often indicated.

Good clinical practice
• Life style counselling is essential for preventing and treating cardiovascular diseases, breast cancer and osteoporosis. • While HT is efficient in preventing bone loss and fractures, it is not currently its primary indication treatment. • The main indication of HT is climacteric symptoms. In this case, the necessity to alleviate symptoms and the lowest effective dose regimen should be re-evaluated regularly on an individual base. In case of recurrence of symptoms, restarting may be considered, keeping in mind that the absolute risk of HT related to BC and CVD increase steadily with age.

Good clinical practice
• HT remains a priori, contraindicated in women with a history of stroke and /or BC. • Some experts consider in situ BC and atypical hyperplasia as an absolute contra indication, others as a relative one. • Similarly, some consider that transdermal or percutaneous ET may be used in women with a history of VTE/ or known thombophilia, but others do not.

Additional remarks
• In case of Hysterectomy, only ET should be used. • More studies are needed evaluating other regimens, different routes of administration and the use of (micronised) estradiol, progesterone and other progestins, and tibolone which are currently more often used in Europe.

Conflict of interest declaration
• The Belgian Menopause Society wishes to thank the following companies who support us with unrestricted educational grants allowing us to fulfill our missions but exercise no control over the content of the consensus: AVENTIS, BESINS, ELI-LILLY, DAIICHI-SANKYO, MERCK, MITHRA, MSD - MERCK SHARP & DOHME, ORGANON, SCHERING, SERVIER, SOLVAY PHARMA, ROCHE, WYETH


				
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