Main morbidities recorded in the women's international study of long duration oestrogen after menopause (WISDOM): a randomised controlled trial of hormone replacement therapy in postmenopausal women
BMJ 2007; 335 doi: https://doi.org/10.1136/bmj.39266.425069.AD (Published 02 August 2007) Cite this as: BMJ 2007;335:239
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I question this persons information and statement that use of
contraceptive pills and HRT are different - they both contain the same
replication of hormones oestrogen and progesterone. Both carry risks if
taken - read the warnings enclosed with them. Gonadotrophins produce the
hormones required for non-ovulation (FSH) and ovulation (LH) which starts
in anterior pituitary gland. Therefore, it is all in the head. It is a
natural cycle of LIFE that your body stops producing these hormones when
it is ready to stop producing children. When your body is ready to move
into the third phase of LIFE it will do so and nothing can halt it. Many
informed women use HRT in order to prevent the discomfort, embarassment
and fatigue of flushing after trying many alternatives, however, HRT is
not meant to be taken long-term, just as contraception is contraindicated
if over the age of 35, and is neither a cure nor preventative for any
other possible fatal condition, predisposed or otherwise. I suggest she
stop reading so much literature and listens carefully to her mind and
body.
Competing interests:
None declared
Competing interests: No competing interests
The authors of the WISDOM study report an increased risk of
cardiovascular events and thromboembolism using equine estrogens and
medroxyprogesterone acetate (MPA) (1), essentially confirming the previous
results of HERS and WHI (2). The results of the WISDOM trial not
surprising at all, and similar to the HERS and WHI investigators and based
on their findings the WISDOM authors draw conclusions regarding “hormone
replacement” therapy in general. (1,2).
We previously indicated that a mix
of hormones derived from horse urine are not suitable and do not represent
a “replacement” of natural human estrogens such as 17-beta estradiol (2)
because equine hormones also contain androgens and several sex steroids of
yet unknown vascular activity (3). Regulation of estrogen targets, the
classical estrogen receptors alpha and beta (and the novel membrane
estrogen receptor GPR30, which is highly expressed in structurally intact
human arteries (4)), is sensitive to natural estrogens (4). Despite the
fact that high estrogen levels in premenopausal women and in
postmenopausal women receiving hormone therapy are associated with reduced
inflammation and improved stability of atherosclerotic plaques (5,6), the
role of estrogen receptors during atherogenesis is still unclear (6).
Interestingly, in a 7.4 year follow-up analysis of the Women’s Health
Initiative Manson et al. recently reported a reduction in coronary calcium
in young surgically postmenopausal treated with unopposed equine estrogens
(7), indicating that even equine estrogens – in the absence of MPA - can
reduce coronary calcification if treatment is started early after
menopause (7). However, therapeutic success of any hormone treatment in
postmenopausal will be depending on the presence of concomitant risk
factors such as hypertension, obesity, hypercholesterolemia, and aging
(6). Surprisingly, beneficial effects of natural 17-beta estradiol on
vascular reactivity are still present in younger postmenopausal women even
in the presence of angiographically documented coronary atherosclerosis
(8). However, these beneficial effects diminish with age and are
essentially abrogated in women aged 70 years and older (8). This indicates
that changes in the vascular wall related to aging may be much more
important than previously appreciated, and that even natural hormones such
as 17-beta estradiol might lose their ability to improve vascular
homeostasis with advanced aging.
1. Vickers MR, MacLennan AH, Lawton B, Ford D, Martin J, Meredith
SK, DeStavola BL, Rose S, Dowell A, Wilkes HC, Darbyshire JH, Meade TW;
WISDOM group. Main morbidities recorded in the women's international study
of long duration oestrogen after menopause (WISDOM): a randomised
controlled trial of hormone replacement therapy in postmenopausal women.
BMJ. 2007; 335: 239-
2. Pines A, Sturdee DW, Maclennan AH, Schneider HP, Burger H, Fenton
A. The heart of the WHI study: time for hormone therapy policies to be
revised. Climacteric. 2007;10:267-269.
3. Barton M, Dubey RK. Postmenopausal hormone-replacement therapy. N
Engl J Med. 2002;346:63-65.
4. Haas E, Meyer MR, Schurr U, et al. Differential effects of 17beta
-estradiol on function and expression of estrogen receptor alpha, estrogen
receptor beta, and GPR30 in arteries and veins of patients with
atherosclerosis. Hypertension. 2007;49:1358-1363.
5. Burke AP, Farb A, Malcom G, Virmani R. Effect of menopause on
plaque morphologic characteristics in coronary atherosclerosis. Am Heart
J. 2001;141:S58-S62.
6. Barton M, Meyer MR, Haas E. Hormone replacement therapy and
atherosclerosis in postmenopausal women: does aging limit therapeutic
benefits? Arterioscler Thromb Vasc Biol. 2007;27: 1669-1672
7. Manson JE, Allison MA, Rossouw JE, et al. Estrogen therapy and
coronary-artery calcification. N Engl J Med 2007;356: 2591-2602
8. Sherwood A, Bower JK, McFetridge-Durdle J, Blumenthal JA, Newby
LK, Hinderliter AL.Age moderates the short-term effects of transdermal 17-
beta-estradiol on endothelium-dependent vascular function in
postmenopausal women. Arterioscler Thromb Vasc Biol. 2007; 27: 1782-1787
Competing interests:
None declared
Competing interests: No competing interests
There are ethical considerations for use of estrogen alone in the
trial especially in women in the age group (50-69 years) who are already
high-risk group for adverse effect of estrogen e.g. cancers,
thomboembolism, etc1,2. We do not like to prescribe oral contraceptives in
women more than 35 years of age.
To judge the effect on breast cancer or any other cancer a minimum
follow-up period of five years is required. After a median 11.9-month
follow-up instead of the planned 10 years of treatment, the WISDOM study
was ended3.
I also want to draw attention to the following lines in the article3:
Cardiovascular events- The 11 cardiovascular events recorded were all in
women randomised to hormone replacement therapy (nine to combined therapy
and two to oestrogen therapy). All but two of these women were over 64
years of age at trial entry and had one or more cardiovascular risk
factors (three had a history of myocardial infarction or angina, two had
diabetes, four smoked, and eight had a body mass index 25)3. These are
not excluded in the study4. Such high risk women should not have been
enrolled, it is unethical. According to a study published in New England
Journal of Medicine, neither estrogen alone nor estrogen plus
medroxyprogesterone acetate affected the progression of coronary
atherosclerosis in women with established disease and the results
suggested that such women should not use estrogen replacement with an
expectation of cardiovascular benefits5.
Very low dose hormones in pulsatile manner with diurnal rhythm
mimicking the natural hormonal cycle may be ideal, who knows.....??!!
References:
1. Ejeby K, Högland A, Eggens I, Engfeldt P. [Are hormones
dangerous? Physicians as well as patients need more information about
postmenopausal hormone therapy]
[Article in Swedish] Lakartidningen. 1997 ; 94(12):1080-3.
2. Ito K. Hormone replacement therapy and cancers: the biological
roles of estrogen and progestin in tumorigenesis are different between the
endometrium and breast. Tohoku J Exp Med. 2007; 212(1):1-12.
3. Vickers MR, MacLennan AH, Lawton B, et al. Main morbidities
recorded in the women's international study of long duration oestrogen
after menopause (WISDOM): a randomised controlled trial of hormone
replacement therapy in postmenopausal women BMJ 2007; 335: 239;
doi:10.1136/bmj.39266.425069.AD.
4. Vickers MR, Martin J, Meade TW and the WISDOM Study Team. The
women's international study of long duration oestrogen after menopause
(WISDOM): a randomised controlled trial. BMC Women's Health 2007;7:2.
www.biomedcentral.com/1472-6874/7/2[CrossRef][Medline]
5. Herrington DM, Reboussin DM, Brosnihan KB, Sharp PC, Shumaker SA,
Snyder TE, Furberg CD, Kowalchuk GJ, Stuckey TD, Rogers WJ, Givens DH,
Waters D. Effects of estrogen replacement on the progression of coronary-
artery atherosclerosis. N Engl J Med. 2000;343(8):522-9.
.
Competing interests:
None declared
Competing interests: No competing interests
Sir,
further results on benefits and risks of hormone replacement therapy (HRT)
are welcome in order to diffuse evidence based messages to menopausal
women. In fact, previous publications on HRT have generated - in Italy as
well as in other countries - a fan of often conflicting positions,
interpretations and recommendations produced from institutions or
scientific societies. Also associations of citizens/patients promoting
woman health have produced information material, whose messages are often
at variance with available evidence. Therefore, women today still receives
contrasting information on HRT benefits and risks from the medical
community, media and consumer associations. This puzzled information lead
to uncertainty and confusion making difficult to achieve informed
decision.
In this context a full understanding of the information needs is
crucial. To helps in this directions PartecipaSalute (1) and the Istituto
Superiore di Sanità, the technical and scientific body of the Italian
National Health Service, planned a national Consensus Conference entitled
“Which information for the woman in menopause on the HRT”, it will be held
on 16-17 May 2008 in Torino. The Consensus Conference will be the results
a preparatory work involving two working groups that, with an explicit
methodology, will address: a) the scientific controversy, b) the
information conveyed by journalists and by consumers’ associations. It is
also expected that the conclusion of the Consensus Conference will be
implemented and a before-after study will monitor how the information on
HRT risk and benefit balance will be improved as consequence of the
Consensus Conference. This project is supported by Compagnia San Paolo-
Torino, a charity foundation, and no found from pharmaceutical companies
will be accepted.
(1) Mosconi P, et al. PartecipaSalute, an Italian project to involve
lay people, patients’ associations and scientific-medical representatives
on the health debate. Health Expectations 2007, 10: 194-204
Competing interests:
None declared
Competing interests: No competing interests
After a median 11.9-month follow-up instead of the planned 10 years
of treatment, the WISDOM study was ended, concluding that hormone
replacement therapy (HRT) increases cardiovascular and thromboembolic risk
in women aged 50-69 years at randomization (1). Three studies were
conducted at the Pennington Center of the University of Louisiana in Baton
Rouge that used 24-hour ambulatory blood pressure monitoring. Study
participants included Caucasian and African American women, some of whom
were on HRT. Their age ranged from 40 to 59 years (mean ± SD: 48.2 ± 6.3
years). Women on HRT were invariably found to have decreased heart rate
variability (HRV), gauged by the 24-hour standard deviation of heart rate,
measured automatically by ABPM around the clock (P<_0.01 from="from" binomial="binomial" test="test" corrected="corrected" for="for" a="a" decreasing="decreasing" trend="trend" in="in" hrv="hrv" as="as" function="function" of="of" age.="age." p="p"/>Decreased HRV is a predictor of vascular disease risk not only in patients
suffering from coronary artery disease, valvular disease or congestive
heart failure (2, 3), but also in apparently healthy people (4). Should
the decreased HRV underlie the observed increased cardiovascular disease
risk associated with HRT, an easily assessable marker would be available
to identify women who may be at risk from HRT and women who may benefit
from it without undue increased cardiovascular disease risk.
1. Vickers MR, MacLennan AH, Lawton B, Ford D, Martin J, Meredith SK,
DeStavola BL, Rose S, Dowell A, Wilkes HC, Darbyshire JH, Meade TW. Main
morbidities recorded in the women’s international study of long duration
oestrogen after menopause (WISDOM): a randomized controlled trial of
hormone replacement therapy in postmenopausal women. BMJ 11 Jul 2007. doi:
10.1136/bmj.39266.425069.AD .
2. La Rovere MT, Bigger JT Jr, Marcus FI, Mortara A, Schwartz PJ, ATRAMI
Investigators. Baroreflex sensitivity and heart rate variability in
prediction of total cardiac mortality after myocardial infarction. Lancet
1998; 351: 478-84.
3. Task Force of the European Society of ardiology, the North American
Society of Pacing Electrophysiology. Heart rate variability. Standards of
measurement, physiological interpretation, and clinical use. Circulation
1996; 93: 1043-65.
4. Tsuji H, Venditti FJ Jr, Manders ES, Evans JC, Larson MG, Feldman CL,
Levy D. Reduced heart rate variability and mortality risk in an elderly
cohort. The Framingham Heart Study. Circulation 1994; 90: 878-83.
Germaine Cornélissen1, Frank L Greenway2, Franz Halberg1
1 Chronobiology Center, University of Minnesota, Minneapolis, MN
2 Pennington Biomedical Research Center, Louisiana State University
System, Baton Rouge, LA
Competing interests:
None declared
Competing interests: No competing interests
I appreciate the author for writing a very intersting article. It is
very beneficial especially to the postmenopausal women who are eager to
undergo HRT and are concerned about its long term effects. However, the
sample population of post hysterectomy women needs only oestrogen therapy
as cited by a study saying that therapy after hysterectomy is undertaken
in the majority of cases with oestrogen alone, with no need for
progestogen addition (Rees 2005).T his is further supported by an article
which stated after hysterectomy and bilateral salpingo-oophorectomy, women
need oestrogens, sometimes in the higher dose than for more mild symptoms
(J.STUDD ).
I would like also to suggest a further and deeper study of the risk of
breast cancer which alarms most women. In a recent study on Womens Health
(Fairlie) women aged 50 who take oestrogen only HRT for five years, about
33.5 in every 1000 will get breast cancer and those taking combined HRT the
number of cases that would be diagnosed by after 15 years would be 38
cases in a 1000 after 5 years.
The article, however is very informative.
Competing interests:
None declared
Competing interests: No competing interests
Biological scientists must know that the actions of hormones do not
vary with the reasons for which they are given. It may be fashionable to
believe that contraceptive pills are different from HRT pills but, in
reality, the overall effects are the same including the increased risks of
vascular diseases.1
All combined contraceptive and menopausal pills are designed to act
predominantly like progesterone which is necessary to prevent endometrial
hyperplasia and endometrial cancer due to oestrogen dominance.2 The
biological power of combined pills is not obvious from the doses used as
the potency of different progestogens can vary more than 12 times.3 This
means that pill combinations with lower doses can be more powerful than
pills containing higher doses. Similar or identical doses of
norethisterone, norgestrel, levonorgestrel and medroxyprogesterone acetate
have been used for both contraception and HRT. Synthetic ethinyl
estradiol in contraceptive pills is more powerful than natural estradiol
or mares’conjugated urinary oestrogens in HRT. Therefore microgram doses
of synthetic oestrogen are used for contraception and milligram doses of
“natural” oestrogens are used for HRT pills but both will have, more or
less, the same effect.
In 3 studies the relative risk of thrombosis for oral contraceptive
users was 4.0, 4.1, and 6.0 respectively.4-6 In another 3 studies, the
relative risk of thrombosis for current HRT users was 2.1, 3.5, and 3.6.
The risks were double at 6.7- 6.9 for the first 1-12 months of use.7-9
The increased risk of myocardial infarction with oral contraceptives
for current versus past or never users was 4.65 in a World Health
Organisation study in 1997. The odds risk ratio for acute myocardial
infarction was 31 for hormone users over age 35 who did not smoke. The
risk increased massively to 400 for oral contraceptive users older than
age 35 who also smoked.10
Although the risk of thrombosis is higher for new users in their
first year, the risk also increases with longer term use. Therefore, it is
important to know the results for trial volunteers from the first time
they started to take hormones. It is unsatisfactory for randomised HRT
trials to give results from the date women were first randomised as many
would be continuing and many would be stopping long-term hormone use but
still have some residual effects. Relatively few women would be starting
first ever use. Such confusions underestimate the harmful effects of
taking hormones and have even led to spurious claims of benefit, including
prevention of heart attacks.
Thousands of genes are up or down regulated by both exogenous and
endogenous progesterone and oestrogen including many affecting blood
vessel development, vasoactive amine levels and clotting mechanisms. For
decades there has been considerable scientific and epidemiological
evidence of increases in thrombosis and heart attacks in young hormone
users long before the age of the menopause.
1 Grant ECG. Hormones, thrombosis and heart attacks. J Nutr Environ
Med 1998;8:159-167.
2 Grant ECG. Hormone balance of oral contraceptives. J Obstet
Gynaecol Br Commonwealth. 1967; 2 :75-9.
3 Dickey R P. Managing contraceptive pill patients. 1995 Essential
Medical Information Systems Inc, Durant, OK, 74702-1607, USA. pp 130-131.
4 World Health Organization Collaborative Study of Cardiovascular
Disease and Steroid Hormone Contraception (1995). Effect of different
progestagens in low oestrogen oral contraceptives on venous thromboembolic
disease. Lancet 1995; 346: 582-8.
5 Bloemenkamp KWM, Rosendaal FR, Helerhorst FM, et al. Enhancement by
factor V Leiden mutation of risk of deep-vein thrombosis associated with
oral contraceptives containing third-generation progestagen. Lancet 1995;
346: 1593±6.
6 Spitzer WO, Spitzer WO, Lewis MA, Heinemann LAJ, et al. On behalf
of the Transnational Research Group on Oral Contraceptives and the Health
of Young Women. Third generation of oral contraceptives and risk of venous
thromboembolic disorders: an international case-control study. BMJ 1996;
312: 83±8.
7 Daly E, Vessey MP, Hawkins MM, et al. Risk of venous
thromboembolism in users of hormone replacement therapy. Lancet 1996; 348:
977±80.
8 Jick H, Derby LE, Myers MW, et al. Risk of hospital admission for
idiopathic thromboembolism among users of postmenopausal oestrogens.
Lancet 1966; 348: 981±3.
9 Grodstein F, Stampfer MJ, Goldhaber SZ, et al. Prospective study of
exogenous hormones and risk of pulmonary embolism in women. Lancet 1966;
348: 983±7.
10 WHO Collaborative Study of Cardiovascular Disease and Steroid
Hormone Contraception. Acute myocardial infarction and combined oral
contraceptives: results of an international case control study. Lancet
1997; 349: 1202±9.
Competing interests:
None declared
Competing interests: No competing interests
I read this paper with interest, I have read many other medical
papers regarding HRT over the last 4 ½ years prompted by the release of
the WHI. I agree with the statement within this paper “implications of
results” – “the medical profession and the media must interpret and
disseminate the results of WISDOM with caution and responsibility”
The “critical window hypothesis” without established atherosclerosis,
I believe, is plausible. Future findings from the American KEEPS study
will provide valuable information that will support or dispute this
theory.
Dr Ellen Grant’s responses to HRT papers I have read before, the
dosage and purpose of hormone use within the contraceptive pill and HRT
are obviously quite different. The endogenous hormones Estrogen and
Progesterone - there are others - are the hormones of life itself. It is
logical for mankind to attempt to replicate these hormones, but their use
has to be executed with care and intelligence
Competing interests:
None declared
Competing interests: No competing interests
WISDOM authors claim to enlighten about the increased risk of
cardiovascular events and thromboembolism when hormone replacement therapy
was started at a mean age of 63.1 However, of women randomized to take
part, 55% had already used HRT for a median 5.3 years. Median use for
current users was even longer at 9 years. Also 31% were younger than age
60. All this probably means that most women started HRT in their 50s.
Furthermore, many women would have previously used progestogens and
oestrogens for contraception. Women who had developed serious conditions
or died due to past hormone use would not be willing or available for
randomization to take more HRT. Only 2% of a possible 284,175 women
screened or checked took the risk of more hormone exposures. WISDOM was
stopped after only 11.9 months because of increases in major
cardiovascular events and thromboembolism but the result does not
represent the effect of the first year of exposure to HRT hormones for
the majority of the women.
While obviously more women die of vascular diseases and cancers as
they become older, the increased risks caused by contraceptive or HRT
hormones are due to the activation of thousands of genes. This affects
women of all ages and is not related to the age of the menopause.
1. Vickers MR, MacLennan AH, Lawton B, et al.
Main morbidities recorded in the women's international study of long
duration oestrogen after menopause (WISDOM): a randomised controlled trial
of hormone replacement therapy in postmenopausal women
BMJ 2007; 0: bmj.39266.425069.ADv1
Competing interests:
None declared
Competing interests: No competing interests
Long-term risk of pharmaceuticals: have we been looking at the all the right end-points?
I have questioned, in eLetters, whether we might have been
overlooking important end-points in assessing the long-term administration
of pharmaceuticals, notably the effect of statins upon outcomes from acute
illnesses.
A large [8506 HR vs 8102 placebo]study of the long-term effects of
HR, the results of which were published in The Lancet this week (1),
makes this question more pressing for what it shows is that neither the
risk of developing small cell nor non-small lung cancer was increased by a
once-daily tablet of 0·625 mg conjugated equine oestrogen plus 2·5 mg
medroxyprogesterone acetate but the risk of dying from lung cancer was
greatly increased. It was suggested in an accompanying editorial that HR
might have exerted its adverse effects upon cancer growth by promoting
angiogenesis.
"More women died from lung cancer in the combined hormone therapy
group than in the placebo group (73 vs 40 deaths; 0·11% vs 0·06%; HR 1·71,
1·16—2·52, p=0·01), mainly as a result of a higher number of deaths from
non-small-cell lung cancer in the combined therapy group (62 vs 31 deaths;
0·09% vs 0·05%; HR 1·87, 1·22—2·88, p=0·004). Incidence and mortality
rates of small-cell lung cancer were similar between groups".
That HR should have had such a large effect upon the risk of dying
from lung cancer is of profound significance because risk is usually
assessed by measuring the incidence of new cancers not outcome from
cancers should they develop. As angiogenesis would appear to be implicated
in the growth of all cancers and their metastases in how many other
cancers might this effect be apparent? The thought is alarming for it
makes one wonder just how many surprises might be lurking behind the
anticipated reports of long-term outcomes from other pharmacueticals or
combinations thereof. The thought is even more alarming for these studies
might not even have considered all the relevant outcomes and it will be so
easy to falsely ascribe unrelated causes to them.
1. Prof Rowan T Chlebowski MD, Prof Ann G Schwartz PhD, Heather
Wakelee MD, Garnet L Anderson PhD, Prof Marcia L Stefanick PhD, Prof JoAnn
E Manson MD, Rebecca J Rodabough MS, Jason W Chien MD, Prof Jean Wactawski
-Wende PhD, Margery Gass MD, Prof Jane Morley Kotchen MD, Prof Karen C
Johnson MD, Prof Mary Jo O'Sullivan MD, Prof Judith K Ockene PhD, Prof Chu
Chen PhD, Prof F Allan Hubbell MD, for the Women's Health Initiative
Investigators. Oestrogen plus progestin and lung cancer in postmenopausal
women (Women's Health Initiative trial): a post-hoc analysis of a
randomised controlled trial. The Lancet, Volume 374, Issue 9697, Pages
1243 - 1251, 10 October 2009
Competing interests:
None declared
Competing interests: No competing interests