About every 2 years since the WHI study was published in 2002 there have been studies published with very different results. Most observers have agreed that the methodology of the WHI study was seriously flawed, most obviously because the women were more than a decade post menopause at recruitment.
A new Danish randomised study published online in BMJ oct 9 2012 showed for women commencing HRT at an average age of 50 and continuing for over 10 years there was a reduction of 52% in cardiovascular (CV) end points ( AMI, heart failure and death), with no increased risk of breast cancer or stroke at 16 years.
This is the first randomised study to recruit women at the time of menopause, and although the study was small with 1006 women, it supports the observational studies and subgroup analyses of WHI which have shown the risk of CV disease to be small in women aged 50-60.
This study was initially to run for 20 years, however the 10 year followup coincided with the WHI study publication, and women were advised to stop treatment (while followed for a further 6 years)
The numbers for breast cancer were 10 in the HRT group of 502 and 17 in the control group of 504.
Note - I wrote this nearly 18 months ago - a relative risk reduction of nearly 60% with HRT, and I still have not seen this in any media alerts as was the case when the WHI reported bad results.
Reporting bias at work yet again.
The authors admit the sample size is too small to assess the risk of DVT ( blood clots)
The hormones used in this study were different from WHI - here 17 beta-oestradiol 2mg was used with norethindrone, rather than the conjugated equine oestrogens (yes, horse oestrogens) with medroxyprogesterone (provera).
While this is reassuring information, it does not change my understanding of conventional HRT - anyone who read the WHI study knew its faults, (which were magnified by incorrect reporting by The Cancer Council)
Neither does it alter my belief in the benefits of bioidentical progesterone over progestagens and non oral hormone preparations over tablets in preventing disease and maintaining health.
Another Paper from Herbal Medicine - this one 5th year and unfinished
Pros and Cons of HRT
Oestrogen has been used as replacement
therapy since the 1940’s.
Unopposed oestrogen given in the 1970’s
was found to increase the risk of endometrial cancer - estimated as
4.6 - 13.5 times the risk. Since then all women with an intact uterus
are prescribed a progestagen in addition - known as combined HRT.
Combined cyclic HRT reduces the risk of endometrial cancer to half
that of women not taking HRT.(Katsung B 1995)
The WHI study of 16,608 women,
published in 2002, changed thinking about HRT.
The findings were widely misinterpreted
and caused panic among doctors and women using HRT.
This study found that for every 10,000
women taking Premarin ( conjugated equine oestrogens or CEE) and
Provera , compared to the control group, 8 more will develop breast
cancer, 7 more will have a heart attack, 8 more will have a stroke
and 18 more will have a blood clot . On the positive side there would
be 6 less cases of bowel cancer and 5 less hip fractures. These
findings proved that HRT would not prevent cardiovascular disease, as
had been suggested by the US Nurse’s Health Study of 1985. (Cabot)
However, the risk of death from osteoporotic fractures is higher than
the risk from heart attacks, breast cancer and strokes combined. (Yap
2002, Goldman 2004)
The WHI study was widely criticised for
the age of women included (average age 64 - too old for a prevention
study - and up to 79!), the use of HRT for up to 10 years prior to
the study, and other cardiovascular risk factors.
Interestingly, the oestrogen - only arm
of the study, in women who had undergone hysterectomy, showed a 25%
REDUCTION in the breast cancer risk, and no increase in
cardiovascular disease.
At 7 years follow up there was a
significant decrease in cardiovascular disease in the younger age
group (50-59 years)
While it has been suggested that the
study was so poorly constructed that no conclusions can be drawn from
either arm, some have suggested that the synthetic progestagen,
Provera, is responsible for the adverse effects on both
cardiovascular disease and breast cancer. (Yap 2002, Goldman 2004)
The PEPI trial, another large study,
looked at the effect of several HRT regimes on cardiovascular risk
factors, but its results were overshadowed by The WHI study. The
placebo group of women showed a small decrease in HDL (“good
cholesterol”); In women using CEE alone there was a large increase
in HDL; those on CEE and provera had a small increase in HDL ( equal
to placebo) and those on CEE and oral micronised progesterone had a
large increase in HDL. The authors concluded that “ for women
with an intact uterus, CEE and micronised progesterone appears to
spare the endometrium and preserve the bulk of oestrogen’s
favourable effects on CV factors including HDL” (PEPI working
party).
Livial (tibolone) was found to reduce
HDL by 34%, probably by an androgenic effect, and triglycerides by
25%. (Modeloska 2002)
The largest epidemiological study of
breast cancer risk is the E3N in France, which is investigating
cancer risk in 98,997 women born between 1925 and 1950.
This study confirmed the increased
breast cancer risk in women using both oral ( relative risk 1.2 at <2
years; 1.6 at 2-4 yrs and 1.9 at > 4yrs) and transdermal/
percutaneous ( relative risk 1.6 at <2 years, 1.4 at 2-4 years and
1.2 at > 4 years) oestrogen with synthetic progestagens compared
to no HRT use. Thus the relative risk with oral oestrogen combined
with synthetic progesterone increases over time, reaching nearly
twice that of non users. However, where micronised progesterone was
use in conjunction with transdermal oestrogen there was a small
decreased risk in the first 4 years - relative risk of 0.9 at <2
years, 0.7 at 2-4 years and 1.2 at > 4yrs. compared with non
users.
Venous thrombosis is a significant risk
with oral oestrogen replacement therapy, resulting from induction of
activated protein C resistance which promotes blood coagulation.
Transdermal oestrogen was not found to cause increased blood
coagulability compared with placebo. (Oger et al 2003)
Sleep disturbance during postmenopause
was significantly improved in women taking combined Premarin and
micronised progesterone (200mg orally) compared with Premarin and
Provera (5mg). ( Montplaisir 2001).In a cross-sectional survey,
micronised progesterone was superior to provera for menopausal
symptoms including vasomotor, somatic and anxiety and depressive
symptoms. (Fitzpatrick LA 2000)
Katsung
B. 6th
Ed. Basic and Clinical Pharmacology. 1995. Appleton & Lange.
Connecticut.
Yap
D, Farrell E. Managing the Menopause.What to do now. Medicine Today.
Vol 3, No 12.Dec 2002.
Goldman
J. The Women’s Health Initiative 2004 - Review and Critique.
Medscape Ob/Gyn & Womens Health 6(3), 2004.
PEPI
Working Party. Effects of Estrogen or Estrogen/Progestin Regimens on
Heart Disease Risk Factors in Postmenopausal Women.
Modeloska
K, Cummings S. Tibolone for Postmenopausal Women: Systematic Review
of Randomised Trials.
The
Journal Of Clinical Endocrinology & Metabolism. Vol 87, No 1
16-23.
Oger
E, Alhenc-Gelas M, Lacut K et al
Differential
Effects of Oral and Transdermal Estrogen/Progesterone Regimens on
Sensitivity to Activated Protein C Among Postmenopausal Women.
Arterioslerosis, Thrombosis and Vascular Biology. 2003; 23: 1671-1684
Montplaisir
J, Lorrain J, Denesle R et al. Sleep in menopause: differential
effects of two forms of hormone replacement therapy. Menopause.
Volume 8 (1) Jan 2001. p 10-16.
Fitzpatrick
LA, Wiita B. Comparison of regimens containing oral micronized
progesterone or medroxyprogesterone acetate on quality of life of
postmenopausal women: a cross-sectional survey. J. Women’s Health
Gend Based Med. 2000 May; 9(4): 381-7.
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