Where are we now with hormone replacement therapy?
BMJ 2004; 328 doi: https://doi.org/10.1136/bmj.328.7436.357 (Published 12 February 2004) Cite this as: BMJ 2004;328:357All rapid responses
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It is true that most mammals do not have a menopause. Most mammals
also do not have language or computers, an adolescent growth spurt, or
(except for primates) menstruation. Humans are both similar to and
different from other mammals. Life history theory (e.g., Bogin, 1999) has
suggested that the human life course is unique in the lengthening of life
stages found in other mammals and in adding new life stages. Menopause in
humans is unusual in being universal and under genetic control. Pavelka
and Fedigan (1991) suggest that menopause is unique even when humans are
compared with other primates, who sometimes do have a period during old
age during which they do not reproduce: These primates are typically very
old (rather than, as humans are, still relatively healthy and nowhere near
the end of the known life span); the phenomenon is not universal as it is
in humans; and the primates do not deplete ovarian follicles. The data on
life expectancy in human prehistory based on skeletal remains is
methodologically controversial.
Bogin, B. (1999). Patterns of Human Growth. Cambridge:Cambridge
University Press.
Pavelka, M., & Fedigan, L. (1991). Menopause: A comparative life
history perspective. Yearbook of Physical Anthropology, 34, 13-38.
Competing interests:
None declared
Competing interests: No competing interests
The great tragedy of the WHI study on HRT is that it is now highly
unlikely that any further proper study will now be conducted. The WHI
study missed the whole point of HRT which is to pharmacologically delay
the menopause, and (in terms of cardiac risk) prevent the development of
atherosclerotic disease. This is very different from taking women who are
10-20 years post-menopause, and then treating them. The majority of the
women in the WHI study were overweight and a large percentage obese, hence
suffering the metabolic syndrome and predisposed to heart disease.
We have known for many years that oestrogens promote thrombosis. With
pre-existing arterial disease this effect comes to the fore. If the study
had been properly designed and followed women from the Menopause, I
suspect the results would have been very different. It was good after all
to see that HRT improved lipid profiles.
It is heartening to me to at last see an article that states that
heart disease was only increased in the first year of treatment (The
Kaplan Meyer Graphs clearly showed this, and support the concept that
those with pre-existing heart disease were the only ones with increased
risk).
It is also good to see it stated that HRT may only be promoting the
growth of Breast cancer in women who were going to get it anyway, rather
than be "causing" breast cancer. It seems to me that present studies
cannot differentiate between cause and promotion of breast cancer. This is
not just semantics - the medico-legal implications are huge for those of
us at the coal face of practice.
Competing interests:
None declared
Competing interests: No competing interests
THis is a bit off the trail here but as a male on testosterone
injections, I often come up for review by the hormone specialists. This
past year - there were three endocrinologists involved debating stopping
to see if my body would self-correct. Two said try while the other said
NO. In the end the natural levels dropped causing the need for even more
via injection. In my case we are battling
-4.2 steroid induced osteoporosis, caused by over zealous doctors trying
to solve my severe spinal pain concerns.
Competing interests:
None declared
Competing interests: No competing interests
Klim McPherson's editorial is a timely summary of a sensible position
on HRT. It does, however, perpetuate the myth that the Women's Health
Initiative study published in JAMA (2002:288:321-33) shows that combined
HRT increases the risk of breast cancer. That study shows no such thing,
although it may have if it was able to continue.
Competing interests:
None declared
Competing interests: No competing interests
I would only take issue with one, early, point and that is is the
menopause a natural event in humans? As far as I can ascertain the only
other mammal that goes through a menopause is the elephant whose natural
life expectancy is 60, they have no natural predators and they only die
when their teeth wear out and they effectively starve to death. From
skeletal examinations our pre-civilisation anscestors (defined as before
framing about 10 000 years ago) had a life expectancy of 30 for women and
35 for men so most of us are well past those ages and are alive largely
because we don't have to hunt and don't have to run away from larger
faster animals with big teeth and claws.
It may well be therefore that the human menopause is not a natural
event and is a result of our surviving well beyond our natural life span.
It does not however make the menopause any more tolerable and the real
issue is can we find an HRT which is effect neutral or even beneficial to
our ladies
Jonathan
Competing interests:
None declared
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Finally, a BMJ editorial that addresses the thorny HRT issue with an
balance - far better than the damage-controlling effort published by Ryman
after WHI first broke.
To Cobie Brinkman - I'm sure you've seen the results of the WHIMS
study (a subgroup analysis from WHI, I'm afraid, but a prespecified and
biologically relevant one) (1).
An extra 23 cases of dementia per 10,000 women treated with HRT
doesn't sound neuroprotective. Do you have any other data from large scale
prospective RCTs (or other high quality sources) to indicate
neuroprotective benefit?
(1) JAMA 2003; 298; 2651-2662
Competing interests:
None declared
Competing interests: No competing interests
Dear Editor,
If the hormones are that important for the welfare of women why does
Nature, unless we presume nature to be foolish, stop hormone supply after
menopause? Our presumption that we are wiser than Nature, using our
reductionist science, has been proven wrong time and again. Even in this
instance another vital information comes to fore. Hormones have improved
the fat profile of women but have worsened their cardiovascular risk!
We are still groping in the dark in the realm of risk factors. In the
holistic concept of illness and wellness there are, probably, as many
asset factors as there are risk factors. It is the balance that keeps man
well or ill purely by CHANCE, the very thing that our statistical methods
are trying to avoid! The greatest discovery of the twenty-first century is
the discovery of man's ignorance. Science rarely could answer the question
"why" although it could explain "how". Science only makes models, mostly
mathematical constructs. Any complicated question, when looked at from a
new angle, only becomes more complicated. That is where we are with HRT
today.
With all our advances we can not predict as to why a young man at
thirty dies suddenly after a myocardial infarct while an elderly
octogenarian goes on with his stable angina, many a time with all three
vessels badly obstructed, for decades? The fat theory is based on very
shaky foundation, but is a good commercial proposition, anyway.
Reductionism might not be able to unravel the life course in biology. The
infradian rhythm of the menstrual cycle has the influence even from the
gravitational pull of the Moon!
Time evolution, in a dynamic system, depends on the total initial
state of the organism and might not change for the better by altering one
or two initial parameters. In that context Tucker’s estimate, quoted in
the article, might not be reliable either.
Long term drug therapy of many chronic illnesses is beset with
similar problems, if one were to critically analyze drug therapy of raised
sugar, cholesterol and, even, blood pressure, while all of them could be
helpful to allay symptoms. One always argues that hypertension is a silent
killer and needs long term therapy in apparently healthy individuals. In
my long experience of four decades of managing hypertensives (experience
is not measurable scientifically) I am yet to encounter an absolutely
asymptomatic significant hypertensive, unless he/she is an alcoholic or a
heavy smoker. In the latter event the minor symptoms get masked and the
physician has to be over cautious. I also felt that there is never a
situation where the blood pressure gets elevated without any reason. Most,
if not all, “so called” idiopathic hypertensives have enough and more
emotional and psychological problems if one goes deep into their make up.
The relevance of this to menopausal symptoms, which are made out to
be disabling, is significant. While menopause is a problem for the
literate working women and the knowledgeable class, it is rarely felt by
the illiterate village women that we get to see in our setting in
government hospitals. The incidence in five-star, hi-tech, private
hospitals in India could be comparable to the west, though. Menopausal
symptoms have a lot to do with the woman's background, her psyche, her
knowledge of health matters, her access to unfiltered information in the
internet and, her awareness of the advertisement blitz about the HRT's
potential to prevent almost all killer diseases. For the ignorant it is
bliss and not an event in life at all as there are more important things
to worry about, most of all not knowing where the next meal comes from!
This article beautifully sums up the truth about the unpredictability
of hitherto unknown risks of long term drug therapy in modern medicine. We
have been predicting the unpredictable. Whereas drugs, by and large, are
good for symptom relief, consequently a boon to the ill, they could pose
serious risks in the long run unbeknownst to medical science. There are
many imponderables in the game of wellness and illness management.
Longitudinal observational studies are as good, if not better than, the
cross sectional controlled studies. The latter have their inherent defect
in that two human beings can never be identical to compare. We can not
know their genotype and their consciousness, which together with the
phenotype, make the whole man! As of now most of our theories of future
events could only be guesstimates, if there is a word like that. Wrote
Hippocrates: "Cure rarely, comfort mostly, but console always." Very
prophetic indeed!Thanking you,
yours ever,
bmhegde
Competing interests:
None declared
Competing interests: No competing interests
Klim McPherson (February 14, p 357)1 believes that current biological
theory does not predict the effects of hormones on cancer and vascular
disease well. Undoubtedly “we never know as much as we think we do” if we
stubbornly refuse to accept long established biochemical facts.
We have known since 1960s that progestogen/oestrogen oral
contraceptives lowered plasma zinc and raised copper levels.2 In 1979
Marie Curie Research Foundation workers joined me in reporting that
migraine patients with high serum copper/zinc ratios had impaired liver
clearance rates 3 and increased adverse reactions to common foods and
chemicals.4 The commonest cause of frequent severe headaches and migraine
was hormone use.
Evidence has been accumulating for more then 50 years of the
importance of trace minerals in the regulation of immunity.5 Deficiencies
of zinc, copper and magnesium impair the function of B vitamins and block
essential fatty acid pathways. These are all excellent biochemical reasons
for hormone use causing vascular and mental disease and cancers.
Deficiencies of enzyme cofactors are usual in patients with symptoms
at times of hormonal change. Primary dysmenorrhoea, pregnancy sickness,
postpartum depression, premenstrual tension, menopausal symptoms and
osteoporosis are warning signals of biochemical dysfunction, often caused
by previous use of hormones. Although some women’s warning symptoms are
temporarily suppressed, further exposures will increase underlying
biochemical upsets and many women have severe withdrawal symptoms when
they stop HRT.
I completely disagree that HRT is justified for women with symptoms.
Randomised studies still underestimate the real risks, and even
produce spurious apparently decreased risks, such as for fractures and
colon and endometrial cancers, because of the residual effects of previous
almost universal use of contraceptive hormones or HRT before
randomisation. The recorded average use in breast cancer studies is 2-3
years for HRT and contraceptive hormones. Any use of HRT is too long. As
many herbal treatments are oestrogenic, they may also be potentially
carcinogenic.
Essential nutrient analysis is not generally available. No one can
choose the best and safest symptomatic treatment if the most relevant
facts are missing. No wonder the last half century has been disastrous for
women’s health.
1 McPherson K. Where are we now with hormone replacement therapy? BMJ
2004;328: 357.
2 Halsted HJ, Hackly BM, Smith JC. Plasma zinc and copper in
pregnancy and after oral contraception. Lancet 1968;2: 278-283.
3 Capel ID, Grant ECG, Dorrell HM, et al. Disturbed lever function
in migraine patients. Headache 1979;19:270-272.
4 Grant ECG. The pill, hormone replacement therapy, vascular and
mood over-reactivity, and mineral imbalance. J Nutr Environ Med 1998;8:105
-116.
5 Sherman AR. Immune dysfunction in iron, copper, and zinc
deficiencies. In: Bodgen JD, Klevay LM, eds. Clinical Nutrition of the
Essential Trace Elements and Minerals: The Guide for Health
Professionals. Totawa, NJ: Humana Press Inc.,2000: 309-331.
Competing interests:
None declared
Competing interests: No competing interests
Is the editor a woman? I have found comment on the risk of HRT to
vary with the sex of the commentator. As a professional woman using HRT it
is worth three months not to have to worry about getting a major hot flush
in the middle of an important meeting, I can assure the editor. As a
neuroscientist, I am disappointed that an editor who is a member of such
an important working party concentrates on what, for indivdiual women,
amount to very small changes in risks of developing, or not, some forms of
disease, and omits all together the strong suggestion from a considerable
number of animal studies that at least estrogen has a neuroprotective
function, and that this aspect of HRT has as yet not been properly been
evaluated in human studies. While many people are skeptical, I find it
hard to believe that in this respect, humans would turn out to be unique
animals. What price to society not to investigate a potential reduction in
CNS damage? I for one will continue to take at least estrogen. I'd rather
run a small risk of having to lose a breast than lose myself.
Competing interests:
None declared
Competing interests: No competing interests
HRT/osteoporosis clinical trials- ethical concerns
The results of the WHI has led to serious rethinking on HRT, and must
I say, a lot of chaos and confusion. Post-WHI, very objective and specific
guidelines are needed; especially those that patients can follow and make
an informed choice. Like radiation, there seems to be no such thing as a
safe dose or a safe duration for HRT(and probably SERMS). In this context,
can the regulatory agencies justify continuing with the estrogen only arm
of the study. My feeling is that the results may be the same as the
discontinued arm. Could someone tell us how many women have chosen to drop
out. Who would take responsibiliy for the harm that may be done if the
outcome were the same. Same with the RUTH trial. Will it go the WHI way?
Can its continuation be justified in view of the surprising results of the
WHI? The status of tibolone hangs in the balance and it would be fair to
women to stop using it as well; considering the findings of the Million
Women Study.
I have always been concerned about the risk of venous
thromboembolism(VTE) in HRT users as well as in SERMS which should be
considered HRT equivalent until proven otherwise. I have always suspected
that methodologies in trials may grossly under-report the true incidence
of VTE and what are reported are the more obvious serious cases. VTE are
indeed the most serious direct complication of HRT/SERMS.All women need to
know this and then decide on using a SERM. Its good to know that the
regulatory agencies in the UK had the conviction to block the use of
raloxifene for breast/endometrial cancer prophylaxis, for lack of robust
data. The drug companies, it seems, will not learn from the WHI! SERMS
can't be prescribed for osteoporosis since there's no robust data on hip
fractures which one's more importantly bothered about.Why should a woman
be risked an episode of VTE also. That leaves just the bisphosphonates
where good data is available for vertebral and hip fractures.The very
future of SERMS seems doubtful. No conscientious doctor would ever
prescribe them for women's health.
One last comment: the regulatory agencies seriously need to
reconsider the very continuation of any placebo-controlled SERM trials in
osteoporosis/woman's health/CHD prevention. Not only are they risky to
women in terms of VTE; the placebo arms seriously harm the health of women
at risk of fracturing. A significant number have vertebral
fractures/radiological evidence of fractures and leaving them "untreated"
constitutes a wilful neglect of a patients' health. Calcium and vitamin
D(which are nutritional supplements) for the placebo arms aren't enough(I
repeat, not enough) considering the availability of superior
therapies(bisphosphonates). "Not treating" women at risk of fracturing/or
those with fractures in a placebo arm is a serious form of medical
negligence by investigators. Such trials can never be justified at this
stage of our scientific knowledge. I have heard the usual story that you'd
need several tens of 1000's of women to do a head on comparison/ "these
women would not have been even taking calcium-vitamin D if they weren't in
the trial";but my argument is that should unsuspecting/poor women be made
to pay a heavy price for such a pathetic(commercial) justification.
Serious ethical concerns on the placebo group, were raised in an editorial
at the time of publication of the raloxifene trial results.
I write this in public interest and wish that you publish this in its
entirety. I hope that regulatory agencies may closely scrutinize all
ongoing trials in the best inerest of women.The comment that companies
hide data is extremely serious. All those who have suffered should go to
the courts. The WHI is a serious wakeup call for all gynaecologists
,endocrinologists and enforcement/regulatory agencies; if not the drug
companies who I must say, can buy just about anyone and get them to write
those :Dear Doctor letters - don't worry the trial drug is safe.....
Competing interests:
Worked earlier till September 2003 in a SERM osteoporosis trial.
Competing interests: No competing interests