Consensus of the Belgian Menopause Society regarding Hormone therapy after the menopause

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Consensus of the Belgian Menopause Society
regarding Hormone therapy after the menopause

• Last update 5.02.07

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Methodology

• These experts came together and proposed the
  following consensus because they felt that the
  recent publications (WHI estrogenprogestin
  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.

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• 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

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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.

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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.

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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

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Climacteric symptoms

• Presence of disturbing symptoms
• Severe symptoms disturb womens 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 )

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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)

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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.
  

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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).

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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.

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Breast cancer risk

• EPT Randomized data using one regimen (CEEMPA)
  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)

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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.

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Breast cancer risk

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

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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).

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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).

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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).

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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 age-related. 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).

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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.

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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.

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Alzheimers disease and cognitive function

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

22
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.

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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.

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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.

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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.

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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