Special Bonus for Subscribers to the John R. Lee, M.D. Medical Letter October 1998
A Commentary On The New Buzzword of Conventional Medicine:
by John R. Lee, M.D.
Evidence-based medicine is the new buzzword in medical
literature. It refers to the desirability of basing one's medical decisions on
adequate, good quality research. This, of course, is a position against which
no one would argue. However, it is being used in some circles to denigrate
observational research and, particularly, to stem the present flow of patients
from conventional to alternative physicians and to steer people away from
over-the-counter nutritional therapy back to prescription drugs. The
presumption is that conventional physicians use drugs that are backed by good
research whereas health food store items lack proper research. Is this
presumption correct? Let us look at some recent evidence.
I. The Tamoxifen Question
Conventional medicine supports the notion that tamoxifen
prevents breast cancer, presumably by binding to estrogen receptors in breast
tissue to reduce the cancer risk of one's endogenous estrogen. Historically,
tamoxifen's role has been confined to use in women who have had mastectomy for
breast cancer. It is now being proposed that all women at risk of breast cancer
should be put on prophylactic tamoxifen. Is this proposal based on good
evidence? The 11 July 1998 issue of Lancet contains reports of two studies that
cast grave doubt on this proposal. While the US study (BCPT) was of 24 month's
duration, the duration of studies reported in Lancet were 46 months and 79
months. Both studies found no difference in breast cancer frequency relative to
controls. They did find significant increases in the incidence of endometrial
cancer, vascular (venous thromboses) events, and hypertriglyceridemia.
1. Veronesi U, Maisonneuve P, Costa A, et al., Prevention of
breast cancer with tamoxifen: preliminary findings from the Italian randomised
trial among hysterectomised women. Lancet 1998; 352: 93-97.
2. Powles T, Eeles R, Ashley S, et al., Interim analysis of
the incidence of breast cancer in the Royal Marsden Hospital tamoxifen
randomized chemoprevention trial. Ibid, pgs 98-101.
3. Commentary by Pritchard K, "Is tamoxifen effective in
prevention of breast cancer? Ibid, pg 80.
II. HRT and Prevention of Coronary Heart Disease (CHD)
It is widely advertised that conventional HRT should be
given to all postmenopausal women to prevent coronary heart disease. But is
there good evidence for this claim? The reference most widely used to claim a
heart benefit from HRT is the Nurses Questionnaire Study, which was neither
randomized, nor placebo controlled. A critique of this study appears in chapter
13 of my book, What Your Doctor May Not Tell You About Menopause. Recently JAMA
published a randomized blinded study of 2,763 postmenopausal women followed for
five years. One half of the women received Premarin 0.625 mg and Provera 2.5 mg
daily; and the other half received placebo. After five years of follow-up,
there was no evidence of a cardiac benefit from hormone therapy. There was,
however, a three-fold increase in the incidence of thromboembolic events [blood
clots in the legs and lungs] and a significant increase in gallbladder disease
in the treatment group compared to controls.
Similarly, the long-running Framingham study has compared
the incidence of coronary heart disease with postmenopausal hormone replacement
therapy and found no correlation.
If evidence-based medicine is your guide, the claim that HRT
prevents CHD must be discarded.
1. Hulley S, Grady D, Bust T, et al., Randomized trial of
estrogen plus progestin for secondary prevention of coronary heart disease in
postmenopausal women. JAMA 1998; 280: 606-613.
2. Editorial by Petitti D in the same journal.
III. Estrogen Supplementation of Postmenopausal Women for
It is widely taught that osteoporosis is due to estrogen
deficiency, and that estrogen essentially falls to zero at menopause. These two
hypotheses lead, of course, to the conclusion that postmenopausal women should
receive estrogen supplementation to prevent and treat osteoporosis. A recent
study reported in the New England Journal of Medicine casts great doubt on both
hypotheses. This study compared the risk of hip and vertebral fractures in
older women (age 65 and older) to serum concentrations of estradiol, sex
hormone binding globulin (SHBG), and 1,2-dihydroxy-vitamin D. None of the women
used supplemental estrogen (ERT or HRT). It was found that women with
undetectable serum estradiol concentrations (<5 picograms per milliliter
[pg/ml]) had a relative risk of 2.5 for hip and vertebral fracture compared to
women with detectable serum estradiol concentrations. However, the relative
risk did not decrease further with progressive increases of endogenous
estradiol concentrations (from 5 to >10 pg/ml). Only 33% of the women had
serum estradiol concentrations less than 5 pg/ml. Thus, the majority of women
over age 65 continue to make estradiol in sufficient amount to create optimal
estrogen-related bone benefit (it restrains osteoclast-mediated bone
The great majority of women continue to make estrone after
menopause by aromatization of andro-stenedione in body fat. Estrone is
inter-converted to estradiol in the liver and the gut. Thus, it is ignorant
nonsense to assume that estrogen levels fall to zero at menopause.
Osteoporosis is a multi-factorial disease. Despite adequate
estradiol, osteoporosis occurs. This proves that factors other than estradiol
deficiency cause osteoporosis. One of the major factors is progesterone
deficiency, as I describe in What Your Doctor May Not Tell You About Menopause.
This, however, was not considered in this study in NEJM.
The study also showed that SHBG reduces the bioavailability
of estradiol. Those women with more SHBG showed an increased risk of fracture
despite having adequate serum estradiol.
Both the authors of the study and the editorial that
accompanied the article lamented the fact that there was no simple test to
measure bioavailable estradiol. It is rather strange and a sad commentary on
the knowledge of presumed experts that they did not know that saliva hormone
assay is readily available and measures only the non-protein bound steroid
hormones, i.e., the bioavailable hormone.
Conclusion: The evidence clearly indicates that the two
assumptions on which estrogen supplementation for prevention and treatment of
osteoporosis are untrue in the majority of postmenopausal women. Evidence-based
medical decisions should recognize that the majority of women 65 years or older
have sufficient endogenous estrogen for bones. Further, conventional ERT and
HRT dosages that raise serum estradiol levels to >40 pg/ml clearly are
excessive and unwarranted.
Cummings SR, Browner WS, Bauer D, et al., Endogenous
hormones and the risk of hip and vertebral fractures among older women. NEJM
1998; 339; 733-738.
The Problem With "Scientific" Experiments such as
Randomized, Double Blind, Placebo-Controlled Testing
"Scientific" testing is based on the belief that the
treatment group differs from the control group only in
the factor being tested. While this works well in testing
of inanimate objects as in the physical sciences, it is
far from clear that such testing works all that well for
health matters. Living organisms are simply too complex
and illness is often so multifactorial that parity of
the treatment group and the control group can not be presumed.
In the case of hormones and osteoporosis, operative factors
include sex hormone binding protein (SHBG) and cortisol
binding protein (CBG), genetic traits, exercise, sun exposure,
digestive differences, stress, program compliance, adiposity,
diet, nutrients such as magnesium, calcium, silicon, and
boron, or vitamins such as C, A, E, D, and K, as well
as the influence of other hormones such as androgens,
growth hormone, and thyroid. Also involved are numerous
drugs and medications used by the test subjects. While
some of these factors (such as height, weight, adiposity,
and medications) are easily "controlled" (i.e., accounted
for), many of them are not.
Obviously, the more confounding factors there are, the
more difficult it is assure parity between the treatment
and the control groups. Medical history is studded with
examples of spurious conclusions resulting from uncontrolled
or unrecognized confounding factors.
For example, the current vogue of calcium supplementation
at 1500-2000 mg/day resulted from studies of a generation
ago when women subjects were given a diet containing excessive
protein. At that time it was not recognized that excess
dietary protein induced urinary calcium loss and a negative
calcium balance. Instead of the 4-5 ounces of protein
(equivalent to 16-20 ounces of steak) consumed each day
by the subjects of these earlier tests, we now know that
1.5 ounces of protein daily is a more suitable intake
for the average healthy adult. Under those conditions,
total daily calcium intake is optimal at 600-800 mg/day.
It is argued that, with sufficient number of subjects,
randomization will correct for unrecognized confounding
factors. When the number of confounding factors are great,
the number of subjects required becomes unmanageable.
Randomization and placebo control do not adequately control
for each subject's individuality. When individuality is
ignored, test results are confounded by unknown variables.
And statistical calculations can lead to false conclusions.
For example, if a given populations experiences 50% mortality
by age 1, and the rest all live to age 80, the average
(mean) life span in this population is 40. Yet, no one
dies at 40. In another population, children do not die
but most of the population does die at 40. The average
life span for this population is also 40. Yet the ages
of death are totally different between the two groups.
Similarly, a river of average depth of 2 feet will have
channels deep enough for people to drown.
Given the above, a more logical experiment would be to
test BMD change serially in women in whom the only difference
to their treatment is the addition of progesterone. If
those women whose decline of BMD is well recorded and
the addition of physiologic doses of progesterone results
in BMD improvement over the next few years, it is good
evidence that progesterone does indeed enhance bone building.
That is the sort of experiment I conducted with patients
of average age 65. If more physicians would do as I did,
the more they would realize the importance of progesterone
not only in treating osteoporosis but also for all the
other progesterone benefits their patients will demonstrate.
John R. Lee, MD
Editor, The John Lee Medical Letter
Junk Science: Garbage In, Garbage Out
The Exalted Peer Review
An Essay from John R. Lee, M.D.
The advance of medicine, looked at historically, has
occurred most commonly by intelligent observation and
serendipity. The insightful observation coming at a propitious
time in medicine leads to new directions that eventually
find fulfillment in a change of medical practice. Older
erroneous conceptions are, however, surprisingly difficult
to overthrow. Change in medicine is sometimes glacial
despite overwhelming evidence for it.
Bleeding therapy, for example, was the standard of care
for many years, having been strongly advocated (but never
justified) by the eminent Benjamin Rush, MD, in the late
1700's. George Washington's demise was undoubtedly hastened
by multiple bleedings. Publication in established medical
journals is one way new concepts become known. The implication
is that, if some alternative concept is worth reading,
it will be accepted for publication. Conversely, if the
alternative concept is not accepted for publication, the
implication is that the paper is probably not worth reading.
Since most established medical journals receive far too
many papers for publication than can be accommodated,
the question becomes - who decides what is published?
The principal mechanism for this these days is peer review.
The idea of peer review, on the surface, is a good one.
Let reviewers with experience and education comparable
to the author's read and judge the credibility of the
paper being presented for publication. But if the paper's
concept is innovative and challenging, who is the author's
peer? If the review panel represents established orthodoxy,
might there not be a bias against the unorthodox viewpoint?
Peer review in grant applications raises the same concerns.
This was recently examined by Simon Wessely of the Department
of Psychological Medicine, King's College School of Medicine,
in The Lancet, 25 July 1998, 352: 301-305. The answer
is that good answers are hard to come by. Those that "win" think
the process is fine; those that are denied find the process
unfair. Case in point: A well-done study showing prostate
cancer cell growth driven by estrogen and blocked by progesterone
is turned down by a major cancer journal. The peer reviewers
had no criticism of the study but denied publication with
the excuse that it would have been accepted if the scientist
authors had used a progestin instead of a progesterone
in their research.
It is of some interest that The Lancet published the
Wessely report at this particular time since it has been
taking some flak for a major article it published in its
March 14, 1998, issue. That article, "Dietary sodium intake
and mortality: the National Health and Nutrition Examination
Survey (NHANES I)" by Michael H. Alderman, Hillel Cohen,
and Shantha Madhavan, was reviewed and given poor marks
by the Nutrition Action Health Letter, June 1998. The
study is based on baseline dietary information acquired
during 1971- 75 in a sample of 20,729 adults (aged 25-75).
Eventually, 11,346 participants underwent medical examination
and nutrition examination, and their "vital status" was
obtained by June 1992. Of this group, 3,923 of the participants
had died. The authors then compared the sodium and calorie
intakes of those who had died with that of the survivors.
Multiple regression analyses were done to assess the relations
with mortality. The authors claim they found that the
death rate was slightly higher among people who reported
eating the least sodium, and this finding was statistically
significant. This is contrary to the general wisdom. The
authors, however, must have felt a little uneasy with
this finding since, in their conclusion, they state that "This
observation does not justify any particular dietary recommendation"; "nor
[does it] justify advice to increase salt intake or to
decrease its concentration in the diet." Despite spending
God knows how much money from the National Center for
Health Statistics of the Center for Disease Control and
Prevention, the National Institute on Aging, the National
Cancer Institute, and other institutes of the National
Institutes of Health, and all their multiple regression
analyses, they are uncertain whether their years of work
mean anything at all.
Let us take a closer look at the study. ( Their nutritional
examination, by which they determined each participant's
twenty years of nutritional intake, consisted of a single
24 hr recall. Even if accurate, why would anyone believe
that one day's food intake is representative of 20 years
of food intake? As far as that goes, I'm not sure I can
accurately remember everything I ate yesterday. ( Those
who reported lower sodium intake were more likely to have
high blood pressure which would have raised their risk
of dying. Whether they actually ate less salt or whether
merely reported eating less salt (to indicate they followed
doctor's orders) is not important; by being patients with
high blood pressure their risk of dying was higher than
participants without high blood pressure. (Those who reported
low sodium intake also reported implausibly low calorie
intake. But they weighed no less than the average participant.
Thus it is clear that their food intake reports were inaccurate,
or possibly falsified. Thus their low sodium intake is
equally likely to be inaccurate or falsified. The phrase
for this is - garbage in, garbage out.
When looking at the ratio of sodium per 1,000 calories,
those with a higher concentration of sodium in the diet
had a higher risk of dying. The authors' conclusion of
an inverse association of sodium to risk of dying is false
by their own data. (The fact that lead author Michael
Alderman had been consultant to the industry's Salt Institute
should probably be overlooked.) The Nutrition Action Health
Letter is not alone in condemning the study. Dr. Lawrence
Appel of Johns Hopkins University states, "No good researcher
would even [want to] publish the unadjusted data. I don't
know how this study got published. It's outrageous." My
concern is not about salt in the diet; it is about the
belief that peer review establishes good science. This
example points out that good medical journals with a strong
tradition of peer review can publish papers that lack
merit. The reality is that publishing in a good orthodox
journal is not a guarantee of good science; nor is it
true that publishing in an alternative journal means less
good science. Wherever the paper is published it must
stand on its own merits. If a study clearly reports its
methods and findings, it is up to the individual reader
to judge its contents and merit. The fact of peer review
does not remove this obligation.
John R. Lee, M.D.
Rhubarb of the Month*
Keeping an eye on the medical literature is almost an
exercise in futility. First of all, the literature is
now so vast that, like the tower of Babel, it is beyond
comprehension. Second, no matter what the topic, you can
be sure that various references on the same subject will
report contradictory results. And third, summaries are
simply too treacherous for judging the validity of the
reference's claims: you have to read the entire study.
Serendipity is another factor: sometimes the accidental
timely coincidence of contradictory articles will produce
insights that otherwise would have never occurred.
This month's example involves two articles on postmenopausal
osteoporosis, one from JAMA (Dec 2, 1998) and the other
a 1990 study from the J. Bone Mineral Research sent to
me by a keen-eyed friend, both of them by coincidence
emanating from Chicago. The 1990 study involved oophorectomy-induced
bone loss in mature rats. The bone loss was evident 20
weeks after oophorectomy, at which point some rats were
put on estradiol and a second group was put on progesterone
in physiologic doses. Twenty weeks later, the bone mineral
density (BMD) of the E2-treated rats showed stabilization
of bone loss, whereas the progesterone-treated rats showed
a statistically significant improvement of BMD. Not only
had the BMD increased to pre-oophorectomy levels, but
so also did the calcium content and the femur strength,
indicating a reversal of the oophorectomy-induced bone
loss. This report was printed not only in the J. Bone
Mineral Research but also in something called Cell and
Materials Supplement 1, 1991, (pg 108) in Scanning Microscopy
International, Chicago, IL 606663. Thus, there exists
a well-done animal study confirming that progesterone,
even in the absence of estrogen, does indeed promote new
bone formation and reversal of osteoporosis. This is strong
evidence for including progesterone in the management
and treatment of postmenopausal osteoporosis.
The JAMA report4 is entitled "Primary Prevention of Postmenopausal
Osteoporosis" with the subheading, "Updates Linking Evidence
and Experience." It is a remarkably short article, considering
the complexities of bone physiology, only 2 pages, buttressed
with (I kid you not) only 17 references. The report promotes
the uses of calcium and vitamin D (all in one paragraph),
hormone replacement therapy (HRT) (without defining it),
and bisphosphonates. The bisphosphonate portion describes
their rather minimal benefit of 0.7% increase in BMD overall
and 3.5% increase in lumbar BMD after two years of treatment,
comparing that to HRT which showed a 1%-2% greater response
than 5 mg of alendronate. The authors never mentioned
the bone effect of diet, nutrition, exercise, progesterone
or testosterone. They never mentioned the fact that the
estrogen effect was dependent on the sex hormone binding
globulin (SHBG), the protein to which estrogen is bound
and which blocks estrogen bioavailability. They did not
reference the recent NEJM study5 that showed SHBG concentrations
were more important (in a negative way) than estradiol
concentrations, per se. Nor did they mention that estradiol
levels sufficient for optimal bone protection are present
in two-thirds of women aged 65-80 without any estrogen
supplementation. Nor that the estradiol supplement dosage
necessary to restore estradiol concentrations to optimal
bone-sparing levels in estradiol-deficient women is only
one-tenth of that used in conventional HRT.
It should be obvious to knowledgeable physicians that
this JAMA article is a totally inadequate and unconvincing
piece of work, feebly supported by a highly selective
and minimal list of 17 references (out of perhaps 1700
appropriate references). This has no place in a journal
such as the JAMA that purports to advance the education
of its readers. One wonders how it came about. The clue
for its publication, I believe, lies in its subtitle concerning
the new buzz-word, "evidence." Conventional medical journals
are touting the claim that conventional medicine is evidence-based,
and alternative medicine is not. If this is their proof
of "evidence", the alternative physicians have nothing
by John R. Lee, M.D.
*1. Am. Heritage Dictionary: rhubarb (3); heated discussion,
quarrel, or fight
2. Barengolts EI, Gajardo HF, Rosol TJ, et al. Effects
of progesterone on postovariectomy bone loss in aged rats.
J. Bone Miner. Res. 1990; 5(11): 1143-7/
3. Barengolts EI, et al. Comparison of the effects of
progesterone and estrogen on established bone loss in
ovariectomized rats. Cell and Materials Supplement 1,
1991, pg 108, in Scanning Microscopy International, Chicago
4. Levinson W, Altkorn D. Primary prevention of postmenopausal
osteoporosis. JAMA 1998; 280: 1821-2.
5. Cummings SR, Browner WS, Bauer D, et al. Endogenous
hormones and the risk of hip and veterbal fractures among
older women. NEJM 1998; 339: 733-8.
By John R. Lee, M.D.
Solving a mystery is often fun. Recently, an article
I came across in reading Chemical Abstracts, Vol. 128,
No. 8, 1998, resolved a mystery that had been bugging
me for some time. It started out in November, 1997,
when I received a letter from a Prof. David Purdie of
Hull Royal Infirmary, Hull, UK, challenging me to debate
him on the subject of using transdermal progesterone
for the prevention and treatment of osteoporosis. Given
the topic, it was difficult to turn down such a challenge.
The debate was held on April 27, 1998, at the Royal
College of Physicians, in Regents Park, London. The
terms of the debate required me to lead off with a 20-minute
argument in favor of using transdermal progesterone
for osteoporosis, after which Prof. Purdie would have
20 minutes to argue that transdermal progesterone has
no place in osteoporosis prevention or treatment. Prior
to the debate, I wondered why Prof. Purdie, an OB/GYN
academician, would feel it necessary to challenge me
about using progesterone for osteoporosis. To my knowledge,
he had not published any research concerning progesterone
The mystery deepened the day before the debate when
I discovered that Drs. Cooper and Whitehead had written
a letter to be published that weekend in Lancet, claiming
that they had proved that progesterone is not absorbed
well enough through the skin to have any therapeutic
effect. Further, they had managed to have a press release
released to the British media announcing this "fact" prior
to the actual publishing date, a practice not usually
allowed by Lancet. Drs. Cooper and Whitehead are not
only leading hormone researchers in England but are
friends and associates of Prof. Purdie. The timing of
their letter and the press release on the same day as
the debate was certainly a curious coincidence.
Friends of mine further discovered that the claim of
progesterone's poor topical or transdermal absorption
was based on serum or plasma tests. With this information
I was able to include in my 20-minute talk the information
that serum or plasma tests measure non-bioavailable
protein-bound progesterone and that it is not a good
test for active hormone in the blood. I explained the
progesterone is absorbed without becoming protein-bound
and thereby the bioavailable portion of the hormone,
being fat-soluble and hydrophobic, would not be adequately
measured by serum or plasma tests. Further, I explained
the superiority of saliva hormone assay in this regard.
My point was that, if Prof. Purdie based his argument
on a serum or plasma test, he was merely misinformed.
And I was still able to present my experience showing
that progesterone did indeed have a benefit in maintaining
and improving bone mineral density, and preventing fracture.
This put Prof. Purdie in an uncomfortable position
since he had based his argument on the presumption of
progesterone's poor absorption, an argument I had just
demolished. He was left with the argument that progesterone's
role in osteoporosis had not, as yet, been studied by
the double blind, placebo controlled, randomized tests
that Prof. Purdie preferred.
In the Q A session that followed, Prof. Purdie was
forced to admit that many advances in medicine come
about from clinical experience and not from tests academicians
such as Prof. Purdie might prefer. Further he admitted
he had never used topical progesterone for any medical
condition, let alone osteoporosis, nor had he ever used
saliva assay for measuring bioavailable hormone concentrations,
nor was he aware of any study that disproved progesterone's
role in bone or in the prevention or treatment of osteoporosis.
A further benefit of the debate was the publication
in Lancet 1998; Vol 352, of my letter explaining the
error of Drs. Cooper and Whitehead in presuming that
plasma or serum accurately reflects the true bioavailable
concentrations of progesterone circulating in blood.
The letter included the 1997 comparison by Dollbaum
CM and Duwe GF of serum and saliva concentrations one
finds when testing the absorption of progesterone after
But a mystery remained. What had motivated Drs. Cooper
and Whitehead, and their stalking horse, Prof. Purdie,
to purposely try to damage the credibility of readily
available transdermal progesterone? The answer has now
become clear. These doctors are involved in research
and promotion of a newly-patented bioadhesive vaginal
gel containing, guess what?, natural progesterone. The
stated purpose of this vaginal natural progesterone
product is to prevent estrogen-induced endometrial hyperplasia
in estrogen-treated postmenopausal women. In their paper
[Am J Obstet Gynecol 1997; 177(4): 937-941], they report
that vaginal doses of progesterone in doses of both
45 mg every 2 days or 90 mg every 2 days prevents endometrial
Why are we not surprised to find this result? The same
effect is obtained by using any transdermal progesterone
applied in doses of 20-30 mg daily. It is no secret
that unopposed estrogen is the cause of endometrial
Clearly, the April 1998 debate was a charade. Prof.
Purdie was not interested in debating the merits of
progesterone for osteoporosis, his purpose was to publicly
discredit existing topical progesterone products in
order to secure a market for their patented bioadhesive
gel product. Their claim that topical progesterone is
poorly absorbed is false and they know it. They used
their considerable reputations to trick Lancet into
publishing their irresponsible letter. The fact that
they failed to reveal their involvement with the promotion
of the vaginal cream at the time of the debate is further
evidence of their connivance in this matter. In their
research involving the vaginal progesterone, they could
have added a test group using transdermal progesterone,
but they did not. When we asked the manufacturer if
they plan to compare their endometrial results with
transdermal progesterone, the answer was "No." The only
purpose of the bioadhesive gel, which is esthetically
unpleasant to users, is that the gel can be patented.
This is blatant commercialism at its worst.
This whole affair is an example showing that even very
good medical researchers can be seduced into shady commercial
exploitation. The interests of good medical practice
are violated for the purpose of non-defensible profit.