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Year 2002 and HRT Panic

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					         Year 2002 and HRT Panic

Presented by
Dr. Khairyah Al Salem
MBBCh Egypt
DGO Dublin
                                   1
What was the cause
  of HRT panic
   on year 2002?
                     2
Woman's
  Health
Initiative
   Trial
  (WHI)
             3
A  randomized , double blind,
  Placebo-controlled, primary
  preventive trial.
 Designed to assess the major
  benefits and risks of the most
  common prescribed continuous
  combined HRT among
  postmenopausal women in US,
  (CEE 0.625 mg+ MPA 2.5 mg/day).
                                    4
 Women    recruited were between
 50-79 yrs old with mean age 63 yrs.
 Total 16,608 women with intact
  uterus at baseline were recruited by
  40 US centers from years 1993 –
  1998.
 They were assigned to receive
  continuous combined HRT (No= 8,506
  pt) or placebo Sugar pills (No= 8,102
  pt).
                                     5
 The trial was planned to last 8.5
 years to be completed in year2005.
 After 5.2 years the study was
 halted on May/2002 according to
 recommendation of WHI-Data and
 Safety Monitoring Board (DSMB),
 when reviewed the health status of
 women in the trial.
                                  6
DSMB recommended on May/2002
  was:
 Women in the study of estrogen plus
  progestin (1st arm of the trial) stop their
  study pills, because the risks now exceed
  the benefits.
 Women in the study of estrogen alone
  (2nd arm of the trial included 10,000
  women) continue taking their study pills
  as before, because it remains uncertain
  whether the benefits outweigh the risks.
                                                7
Results:
 Events                CEE, MPA   Placebo
 Heart attacks        37 Cases    30 Cases
 Strokes              29 "        21 "
 Breast Cancer        38 "        30 "
 Blood clots          34 "        16 "
 Colorectal Cancer    10 "        16 "
 Hip fractures        10 "        15 "
 Endometrial cancer   5    "      6 "
 Deaths               52 "        53 "



                                              8
1 - 41% increase in strokes.
2 - 29% increase in heart attacks.
3 - Doubling rates of venous
    thromboembolism.
4 – 22% increase in total cardiovascular
    diseases.
5 – 26% increase in breast cancer.
6 – 37% reduction in colorectal cancer.
7 – One third reduction in hip fracture rates.
8 – 24% reduction in total fractures rates.
9 – No difference in total mortality rates.
                                             9
10
11
12
13
    Recommendations of WHI
 Clinician shouldn't prescribe HRT for long
  term use.
 Focus hormone therapy use for short-term
  vasomotor symptoms relief.
 Define alternative option to treat or
  prevent Common diseases in
  postmenopausal women such as
  osteoporosis, breast cancer and
  cardiovascular events.
                                           14
        Conclusions of WHI
 Hormone    regimen should not be
  instituted or continued for the primary
  prevention of CHD.
 Do not use HRT to prevent chronic
  diseases.
 Focus on well-proven treatment to
  reduce the risk of chronic diseases.

                                       15
 Analysis
of Women's
   Health
 Initiative
     Trial
              16
1. Profile of the study subjects:
 We should notice that the study
  included American women, average
  age was older than 63 years and
  majority were over weight.
 30% already had preexisting
  cardiovascular risk factors.
 40% ex-smokers, 10% were still
  smoking during the study period.
                                     17
2. Drop – out from the study:
 40% drop out rate mostly due to vaginal
  bleeding.
 Another 3% undergone Hysterectomy.
 3. Hormone preparation and regimen:
 The trial tested only one preparation and
  one regimen of continuous combined HRT.
 The results dose not necessarily apply to
  other regimen and formulation of local or
  systemic preparations.
                                              18
4. Relation between oral combined
  contraception use in older women and HRT:
 The WHI finding do not apply to OCs
 as it does not increase breast cancer
 risk, regardless of duration and age of
 the users.
 The OCs increases risk of
 thromboembolism and cardiovascular
 events so over weight , smoking and
 high risk patients shouldn't receive
 OCs.
                                         19
5. Progestin are synthetic drugs:
 “Progestin is the cause of the problems but
  natural progesterone protects the breast”,
  as Dr. John R. Lee M.D said.
 Cowan et al from John Hopkins reported in
  1981 that premenopausal women with
  progesterone deficiency are 5.4 times
  more likely to develop breast cancer than
  women with normal progesterone levels.

                                           20
 InJanuary /2000 issue of JAMA
 published a study (Menopausal
 Estrogen + Progestin Replacement
 Therapy and Breast Cancer)
 comparing menopausal women in
 ERT with women in combined HRT
 and breast cancer risks .

                                21
 Results:
 Women on combined HRT are at
  higher risks than women in ERT.
 Women on conventional HRT for
 5 years have a 40% higher risk of
  breast cancer than women not
  using HRT.
                                 22
Progesterone and progestin
 what's are the difference?
                              23
1. Why do fertility physicians use
  progesterone and not progestin?
2.Why does progestin cause birth
  defects, while progesterone is
  essential for a viable and healthy
  pregnancy ?
3.Why doesn’t synthetic progestin
  show up in blood and saliva tests of
  progesterone levels in the body?
                                         24
4. In pregnancy progesterone
 increases up to 300 mg daily in
 the last trimester, with no side
 effect on the women breast?
5. Why doesn't natural
 progesterone cause the side
 effect of synthetic progestin?
                               25
WISDOM


         26
(Women's International Study of
  long Duration Oestrogen after
  Menopause)
 The study aims to answer
  important questions about the
  long- term risks and benefits of
  taking HRT.

                                     27
 The   study aims to include 16,000
  postmenopausal women from UK, plus
  6000 from Australia and New Zealand.
 It had recruited 5,700 women since
  1999.
 It is investigating the long term effects
  of HRT on cardiovascular diseases,
  breast cancer, dementia, and
  osteoporosis.
                                         28
 Itinvolves more than 400 GP
  through out UK, and it’s due on
  year 2012.
 The trial over seen by two
  independent committees, The
  Data Monitoring & Ethics
  Committee (DMEC), and Trial
  Steering Committee (TSC).
                                    29
Thelast statement from the
 committees:
They ended the study to
 for patient safety, as
 there result came like
 WHI study result .
                              30
Combined HRT
and
 Cardio-
 vascular
 Diseases
   Risks
               31
HERS I


         32
Heart Estrogen/Progestin Study.
 A randomized ,double blinded,
  placebo-controlled, secondary
  preventive trial.
 Included 2,763
 postmenopausal women from
 20 US centers.
                              33
For an average follow up time
 of 4.1 years.
Women were randomized to
 receive either a combined
 HRT (CEE 0.625 mg + MPA
 2.5 mg ) or placebo once
 daily.
                             34
Objective
Primary Out come:
  non fatal MI or CHD death.
Secondary out come:
  Coronary revascularization,
  unstable angina, CHF and
  Cardiac arrest.
                                35
Results/Conclusion :
1. 176 women in the placebo group (n
  = 1,383) and 172 in the control group
  (n = 1,380) had an MI or CHD death.
2. A significant increase in CHD events
  in hormone therapy group was noted
  as compared to the placebo group in
  the first year, but the risk decreased
  in subsequent 3 to 5 years.
                                      36
3  folds increase of thromboemolic
  events.
 Increased risk of gall bladder
  disease by 40%.
Authors concluded: that daily use
  of HRT is not recommended for
  secondary prevention of CHD.

                                  37
HERS II


          38
 Follow up trial to HERS I .
 2,321 postmenopausal women
 consented from the original 2,763 for
 period of 2.7 years.
Objective: - Primary outcome: non
              fatal MI or CHD death
            - Secondary out come :
 coronary revascularization, sudden
 death and strokes.
                                     39
Results/Conclusion:
 There were no significant decrease
  in rates of primary or secondary
  cardiovascular events in women on
  hormonal therapy.
 132 CHD deaths in control group and
  122 in placebo group.
 The study concluded: that
  postmenopausal hormone therapy
  should not be used to reduce risk of
  CHD events in women with CHD.
                                     40
PEPI

       41
Postmenopausal Estrogen/Progestin
  Interventions Trial.
Objective:
To assess pair wise differences
  between placebo, unopposed
  estrogen and each of three
  estrogen/progestin regimens on
  selected heart disease risk
  factors in healthy
  postmenopausal women.
                                    42
Design : A 3 year, multi-
  centre, randomized, double-
  blind, placebo- controlled trial.
Participants:
 A total of 875 healthy
  postmenopausal women.
 Aged 45 - 64 years .
 Had no known contraindications
  to hormone therapy.
                                      43
Intervention: Participants were
     randomly assigned in equal numbers to
     the following groups:-
1.   Placebo.
2.   Permarin (CEE 0.625 mg / day).
3.   CEE taken with cyclic MPA 10 mg /day for
     12 day a month.
4.   CEE plus consecutive MPA 2.5 mg /day.
5.   CEE plus cyclic micronzed progesterone
     200 mg /day for 12 days a month.
                                            44
Primary end points :
Four end points were chosen to represent
  four biological systems related to the risk of
  cardiovascular diseases:
1. High – density Lipoprotein cholesterol
  (HDL-C).
2. Systolic blood pressure.
3. Serum insulin.
4. Fibrinogen (a protein in the blood-clotting
  process).
                                              45
Analysis:
 Analysis presented are by
 intention to treat P values for
 primary endpoints are adjust for
 multiple comparisons.
 95% confidence intervals around
 estimated effects were calculated
 without this adjustment.
                                 46
Results:
 Mean changes in HDL-C segregated
   treatment:
  1. Placebo decrease of 0.03 mmol I/L.
  2. MPA regimens increase of 0.03-0.04
     mmol/L.
  3. CEE with cyclic MPA increase of 0.11
     mmol/L.
  4. CEE alone increase of 0.14 mmol /L.
  5. Active treatment decreased mean
     low- density lipoprotein.
                                       47
 Systolicblood pressure increased.
 Post – challenge insulin levels
  decreased during the trial.
 Compared with other active
  treatments, unopposed estrogen was
  associated with a significantly
  increased risk of a typical endometrial
  hyperplasia (34% vs 1%) and
  Hysterectomy (6% vs 1%).
                                        48
Conclusions of PEPI trail:
Estrogen alone or in
 combination with progestin
 improves Lipoproteins and
 lowers fibrinogen levels,
 without detectable effects on
 insulin or blood pressure.
                                 49
 Unopposed   estrogen is the optional
  regimen for elevation of HDL-C, but
  the high rate of endometrial
  hyperplasia restricts its use to women
  without a uterus.
 Women with a uterus, CEE with cyclic
  MPA has the most favorable effect on
  HDL – C ,and no excess risk of
  endometrial hyperplasia.
                                       50
 Combined
 HRT and
 Increased
   Breast
Cancer risks
               51
 InJanuary/2000 issue of the
 Journal of American Medical
 Association ( JAMA ), the results of
 a Cohort study of follow up data
 from 1980 – 1995 of Breast
 Cancer Detection Demonstration
 Project, a nation wide breast
 cancer screening program were
 revealed .
                                   52
 Over  46,000 women with an
  average age 58 years were
  included.
 The women were screened at 29
  centers through out US ,during
  follow up breast cancer was
  identified in 2,082 of the women.
 Results: The risk of breast
  cancer increases with each year’s
  use of HRT.
                                  53
 Increased   breast cancer risk
  associated with estrogen or
  estrogen/progestin combination was
  restricted to women who had used
  this hormone in the last four years.
 The relative risk in women who used
  combined estrogen/progestin therapy
  was 1.4 to 1.2 for women in estrogen
  alone.
                                     54
Nurses Health
    Study

                55
   The study was Published on The American
    Journal of Obs/Gyn on 1995.
Results:
 Long-term and Short-term use of Premarin
  had a 40% increased risk of breast cancer.
 Synthetic estrogen /progestin had a 50%
  increased risk of breast cancer.
 Older women (60-65years) had a 70%
  higher risk for breast cancer.

                                               56
Breast Cancer risk
    subsides after
        HRT

                     57
A   study done by Linda. K. Weiss
  PhD, an epidemiologist and chief
  of the National Cancer Institutes .
 It was published on
  December/2002 by The American
  Journal of Obs/Gyn.
 The study confirms the finding of
  WHI trial.
                                    58
Results:
 Combined   estrogen /progestin
  increases a women's risk of breast
  cancer.
 The study added to WHI, that on
  discontinuing HRT use, the risk
  dissipates six months after
  stopping.
                                   59
 The  study evaluated risks from
  various forms of hormone
  replacement therapy.
 They also questioned women who
  had been diagnosed with breast
  cancer about their hormone use
  and other potential risk factors for
  breast cancer.
                                     60
 They  enrolled 3,823 post-menopausal
  women .
 1,870 had a history of breast cancer,
  while 1,953 had no history.
 Women who had taken combined HRT
  continuous therapy for 5 years or
  more were 1.54 times more likely to
  develop breast cancer than women
  who took other preparations.
                                     61
 Sequential hormone therapy did not
  increase breast cancer risk. (taking
  progestin for 5 to 14 days of a
  month).
 No increased risk of breast cancer in
  women who took estrogen alone,
  however it increases risk of uterine
  cancer .
Advice: Combined HRT should be
  taken in minimum dosage for less
  than 5 years.
                                          62
     HRT Does not
Elevate Breast Cancer
           Risks

                        63
    A new study done by Vanderbilt
    University Medical Centre,
    Nashville US, published on March
    1999 by The Journal Cancer, puts
    another piece in the puzzle of
    risks associated with hormone
    replacement therapy for
    menopause.
                                   64
 The study was done by William
 Dupoint PhD professor of preventive
 Medicine.
The study concluded: that Estrogen
 replacement therapy (ERT) does not
 significantly elevate the risk of breast
 cancer in women with histories of
 benign breast disease.
                                        65
 The patients studied by Dupoint
  were part of Mashville Breast
  Cohort trial.
 These women originally under
  went breast biopsies revealing
  benign breast disease between
  1952 – 1978 at Baptist, St.
  Thomas and Vanderbilt University
  Hospitals.
                                 66
 The  study included 10,000
  women and had spent 20 years
  studying breast cancer risk factors
  for these women.
 Results: shown no significant
  increase in benign breast cancer
  group which were on ERT than
  women in placebo .
                                   67
Prescribing HRT
         for
a Diabetic woman?

                    68
 HRT reduce the incidence of
 diabetes by 35% in
 postmenopausal women with
 heart disease.
 According to the results of a
 randomized, double-blind,
 placebo-controlled trial.
 Published in Jan/2003 issue of
 Internal Medicine Journal .
                                   69
 In HERS 1 trial 734 subjects were
  diabetic, 218 with impaired
  glucose, 1,811 normoglycemic.
 FBS increased significantly in the
  placebo group than the group on
  HRT.
 Initiation of glucose-lowering
  agents was 6.2% in the HRT
  group and 9.5% in the placebo
  group.                           70
The study concluded: that HRT
 should be limited to diabetic
 women with bothersome
 vasomotor and menopause
 related symptoms, with no other
 risk factors such as heart
 disease, smoking, hypertension,
 obesity, lipid disorder,
 nephropathy and retinopathy.
                                   71
Should
men get
HRT ?
          72
A round the world men are 3 times
 more likely to have heart disease
 than women before menopause .
 A review of research finds that
 twice as many men with heart
 disease have low testosterone
 levels compared with men without
 heart disease .
                                73
 Men   with high testosterone levels
  have high LDL, low HDL, high
  triglycerides, diabetic and have
  high blood pressure.
 The very issue of giving men
  hormone replacement therapy is
  very complicated and a lot more
  work is need to be done in this
  area.
                                        74
 What are
     the
Alternative
       to
   HRT?
              75
1. Selective Estrogen
   Modulators .
2.Natural Alternatives.

                          76
Selective estrogen receptor
 modulators ( SERMs): may
 offer postmenopausal women an
 alternative to HRT that avoids
 increased breast cancer risk as
 shown in an article published in
 Jan/ 2002 issue of The Journal
 Cancer.
                                    77
The article was written by
Greek physicians, it focuses
on the potential of SERMs ,
which bind to the estrogen
receptor and modulate its
effect on gene transcription.
                                78
 The Greek researchers pointed out
 that although SERMs such as:
 Tamoxifen ( Nolvadex), Raloxifene
 (Evista) ,Phytoestrogens ,clomaphine
 citrate (clomid), Tibilone ( Livial) and
 Aromatase Inhibitors are in clinical
 use, the potential of this class of
 drugs have begun to be unraveled.

                                        79
    Tamoxifen
 Used for treatment of breast cancer.
 Reduce bone loss.
 Lower total cholesterol and LDL but had
    no effect on HDL.
 Increase risk of blood clots.
 Dose not treat vasomotor flushes .
 Associated with abnormal growth of uterine
  lining and small increased risk of
  endometrial cancer and polyp.
                                          80
Raloxifene (Evista)

Prevent  bone loss.
Had no effect on breast tissue.
There are studies that proves
 it can lower risk of breast
 cancer in high risk women.
                               81
Decrease  total cholesterol and
 LDL but no effect on HDL.
 Increase risk of deep venous
 thrombosis.
Dose not relive vasomotor
 flushes and vaginal dryness .
 Its common side effect is hot
 flushes.
                               82
    Phytoestrogen
 Are plant-derived compounds with
 estrogen –like activity, found in soy beans,
 tofu, miso, soy milk.
 Have no effect on bone.
 No evidence of it effect on breast tissue.
 May reduce LDL.
 Effect on blood clots unknown.
 Dose not relive vaginal dryness, it may
 reduce vasomotor flushes.
                                           83
Tibilone ( livial)

A synthetic steroid, designed to
 combine the favorable effects
 of estrogen, progesterone and
 androgens into a single
 substance as HRT.
 Have anti-ovulatory,anti-cancer
 properties.
                               84
 Agonist and promote estrogen
  production in some estrogen
  receptor ( bone , lipid).
 Antagonists in other estrogen
  receptors preventing estrogen
  production ( breast , uterus).
 The is being used widely in UK.


                                    85
A  study is undergoing in the
  University Medical Researches in
  US.
 The study planned to recruited
  80-100 women for 3 years trial.
 They will be randomized to
  receive Tibilone , combined
  estrogen/progestin and placebo.
                                     86
 The  women will be periodically test
  for BMD and cardiovascular
  conditions.
 “It provides the benefits that
  current treatment gives to
  postmenopausal women without
  the risk of causing cancer,” as Dr.
  Stephen Glasser professor of
  epidemiology said.
                                    87
    Aromatase inhibitors

 Anti-estrogen therapy to lower the amount
  of estrogen being produced by the body.
 Limiting the amount of estrogen produced,
  will limit cancer cells growth.
 In post-menopausal women, estrogen is
  no longer produced by the ovaries, but
  produced from converting androgen
  hormone.
                                          88
 Aromatase   inhibitors block the action
  of the aromatase enzymes and
  prevents conversion of androgen into
  estrogen.
 Aromatase inhibitors current use, is
  primarily for post-menopausal women
  with metastatic breast cancer.
 Arimidex, Femara, Aromasin

                                        89
 Preliminary Research Finds Arimidex
  more effective than Tamoxifen in
  postmenopausal women with early-
  stage breast cancer.
 These preliminary results were
  announced at the San Antonio Breast
  Cancer Conference on December/
  2001.

                                        90
Natural alternatives


                       91
1 – Phytoestrogens:- Tofu, Miso, Soy
 milk, roasted soy beans, green
 soy treat menopausal symptoms.
2 – Cohosh:- Black Snakeroot and
 bugbane – preventional
 syndrome and menopausal symptoms.
3 – Angelica:- Used for gas problems,
 water retention and regulations of
 menstruation.
                                   92
4 – Dong quai:-Traditional
 Chinese medicine treat irregular
 cycle, Cramps and menopausal
 symptoms.
5-Evening primrose:- Gamma–
 Linolenic acid treat menopausal
 symptoms.

                                    93
                  Food Steps
   Step 1: Eat more Tofu and Soy
   Step 2: Eat more fruits and vegetables
                Phytoestrogens

     Fruits                        Vegetables
Plums, Prunes, Apple,      Beets, Bell peppers,
Strawberries, Grapes       Tomato’s, Broccoli,
                           Cabbage, Cauliflower,
                           Carrots, Cucumbers


                                                   94
 Step 3: Eat Beans more often its good sources
  of many vitamins and minerals, calcium and low
  fat, protein.
 Step 4: Eat more of the right fats.
              - Switch olive oil and canoed oil.
              - Eat more fish.
              - Eat less animal fat.
              - Limits foods that contain
                 hydrogenated oils.
              - Avoid stick margarine.
 Step 5: Change life style (stop smoking, do
  exercise, loss extra weight, take Calcium and
  Vitamin D) .
                                              95
How to Solve The
 HRT puzzle?       96
Conclusions


              97
1.Health providers should
  recognize:
That what the media highlighted
  about WHI study are a relative
  risks and absolute risks although,
  significant in percentage terms,
  it is actually small in number
  terms.
                                  98
2. Women currently on HRT are
 advised not to panic :
 They  should be counseled by their
  physician to weigh the benefits
  and the risks for each patient, to
  continue or stop treatment.
 Proper follow up of Women on
  HRT.
                                   99
3. Proper counseling of the
 patient before starting HRT:
 Menopause   with no serious side
  effect.
 Several years after menopause.
 High risk of heart diseases or
  breast cancer.
 No HRT are needed.
                                     100
4.Use other HRT combination and
    regimens: which are safer and have
    lower risks .
   Lower doses of Estrogen and Progestin:
    as Conjugated equine estrogen o.625
    mg – Esterified estrogen 0.3 mg – 17
    Beta estradiol 0.5mg- Transdermal
    estradiol 0.025mg- MPA 2.5 mg.
   Natural progesterone : such as
    Norethindrone acetate 0.35mg –
    Norgestimate.
                                         101
 Use other regimens:
 Continuos estrogen and Cyclic
  progestin (2 wks each every 2-3
  months)
 Estrogen with IUCD ( Mirena)
  levonorgestrel which prevents
  endometrial proliferation with
  minimal systemic progestin levels.
                                   102
5.Short term treatment:
Duration  should not exceed 5
 years of use.
 As complications start mostly
 after 5 years.

                                  103
6.Do not use HRT for primary
 or secondary prevention: of
 Cardiovascular Diseases, chronic
 diseases and breast cancer.
 Use traditional measures such as
 stop smoking, regular exercise,
 treat hypertension, lose extra
 weight, treat dyslipidemia by
 using statins.
                                 104
7. HRT for treating menopausal
 symptoms:
There are other alternative to relief
 the patient from postmenopausal
 symptoms like natural alternatives
 such as black cohosh, evening
 primrose and phytoestrogens .

                                    105
8. HRT for treating
 osteoporosis:
Use other alternatives like
 regular exercise ,adequate
 calcium + Vit D intake, stop
 smoking, exposure to sun
 lights and finally osteoporosis
 treatment.
                                   106
  Did we
   solve
   the
HRT puzzle?

              107
THANK YOU
            108

				
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