There's No Good Evidence
That It's Any Better Than Placebo
By Susan
R Davis, FRACP, PhD
Popular media would have us believe that
plant constituents with a phenolic structure similar to estrogen,
known as phyto (plant) estrogens, provide a natural alternative
to the use of postmenopausal hormone replacement therapy.
Are the popular media right?
Phytoestrogens, found in a wide variety
of edible plants, may display both estrogenic
and antiestrogenic effects.
Epidemiological studies, primarily comparing
Asian and Western populations, have been interpreted to indicate
that consumption of a diet rich in phytoestrogens ameliorates
estrogen deficiency symptoms in postmenopausal women and may
protect against breast cancer, bone loss, and cardiovascular
disease.
Consequently there is a global movement
towards increased consumption of foods rich in phytoestrogens,
and tablet formulations of concentrated isoflavone extracts
are being heavily promoted.
However, more recent intervention studies
question the validity of
the proposed benefits of phytoestrogen supplementation,
with little data
in postmenopausal women to support a role for phytoestrogens
as an alternative to conventional hormone replacement therapy.
The biological actions of these compounds
are extremely complex. Their ultimate cellular actions are
determined by many factors, including the relative levels
of estrogen receptors and , the diverse mix of coactivators
and corepressors present in any given cell type, and the nature
of the response elements with which the receptors interact
on the estrogen regulated genes.1
Effects vary according to the phytoestrogen
studied, cell line, tissue, species, and the response being
evaluated. Hence results from in vitro and in vivo studies
are inconsistent.
Japanese women are said to experience
a lower frequency of hot flushes at the menopause than Western
women, and this has been partly attributed to their high phytoestrogen
consumption.2
However, the apparently low frequency
of hot flushes in Japanese women may
be due to underreporting of symptoms rather than
a genuinely lower prevalence.
The first study to show that certain dietary
phytoestrogens can exert mild estrogenic effects in postmenopausal
women was published in 1990 and showed an increase in the
vaginal cell maturation index (an indicator of estrogenic
activity).3
Subsequent reports of their effects on
vasomotor symptoms have not been consistent. Considerable
differences exist between studies, with no clear
correlation between estrogenic changes in vaginal cytology
and effects on vasomotor symptoms.
In a placebo controlled study Murkies
et al showed no
benefit of soy over wheat flour supplementation
for hot flushes and vaginal cytology after 12 weeks.4 Similarly,
in a study of soy versus linseed versus wheat supplemented
diets the reduction in the rate of hot flushes after 12 weeks
was greatest in the wheat diet phase, when the women had very
low urine isoflavone excretion.5
In contrast, a small reduction in hot
flushes was reported in postmenopausal women treated with
isolated soy protein versus casein. However about 25% of the
participants dropped out of this study and the effects were
not clinically significant.6
Two studies of an over the counter tablet
preparation of isoflavones extracted from red clover (40 mg/tablet)
versus placebo in postmenopausal women showed that doses of
both 40 mg/day and 160 mg/day had no greater benefit than
placebo for vasomotor or other menopausal symptoms. 7 8
There are acknowledged difficulties in
objectively assessing vasomotor symptoms in studies because
of the natural resolution of these symptoms over time and
the high placebo response rate.
Nevertheless, conventional
estrogen therapy has been shown to reduce hot flushes
effectively in comparison to placebo, and for phytoestrogens
to be a viable alternative to hormone replacement therapy
the same standard should apply. Phytoestrogens have not been
shown to improve other symptoms that characterize the menopausal
transition, such as anxiety, mood changes, arthralgia, myalgia,
and headaches.
Some data indicate a cardioprotective
effect of soy, 9 10 primarily due to favorable lipoprotein
lipid effects, but whether the observed effects are due to
the isoflavone component of soy or to other moieties is still
unclear.
There is little data to support the claim
that phytoestrogens protect against bone loss, with published
studies not having controlled for confounding factors such
as exercise and the interventions having been relatively short
term. That phytoestrogens prevent breast cancer also cannot
be substantiated.
In vitro, concentrations of phytoestrogens
equivalent to levels in humans with a moderate phytoestrogen
intake stimulate cell growth in estrogen positive, but not
estrogen negative, cells. In contrast, very high concentrations
(probably greater than circulating levels achievable by diet)
inhibit cell growth in both estrogen positive and negative
cell lines.11
There is no evidence that phytoestrogen
supplementation in tablet form protects against breast cancer,
or is even safe. Furthermore, concurrent use of high dose
phytoestrogen supplements and tamoxifen in women with breast
cancer should also be discouraged, until further information
is available, because of the potential for isoflavones to
antagonize the desired antiestrogenic effects of tamoxifen.12
Women experiencing
mild menopausal symptoms may gain relief by dietary modification
and lifestyle changes, such
as reducing smoking and consumption of caffeine and alcohol,
stress management, and increased exercise.
However, there
is no evidence to support the belief that even a very high
intake of soy products will alleviate hot flushes,
night sweats, and other symptoms such as vaginal dryness,
mood changes, and musculoskeletal symptoms.
No absolute conclusions can be drawn from
the few studies of the effects of phytoestrogens on bone.
As with other interventions of unproved efficacy, long term
randomized trials will be required to determine the place
(if any) of phytoestrogens in the management of postmenopausal
women.
References
1. Montano MM, Katzenellenbogen
BS. The quinone reductase gene: a unique estrogen receptor-regulated
gene that is activated by antiestrogens. Proc Natl Acad Sci
USA 1997; 94: 2581-2586.
2. Lock M. Ambiguities of
aging: Japanese experience and perceptions of menopause. Culture
Med Psychiatry 1986; 10: 23-46.
3. Wilcox G, Wahlqvist ML,
Burger H, Medley G. Estrogenic effects of plant foods of post
menopausal women. BMJ 1990; 301: 905-906.
4. Murkies AL, Lombard C,
Strauss BJG. Dietary flour supplementation decreases postmenopausal
hot flushes: effect of soy and wheat. Maturitas 1995; 21:
189-195.
5. Dalais FS, Rice GE, Wahlqvist
ML, Grehan M, Murkies AL, Medley G, et al. Effects of dietary
phytestrogens in postmenopausal women. Climacteric 1998; 1:
124-129.
6. Albertazzi P, Pansini F,
Bonaccorsi G, Zanotti L, Forini E, De Aloysio D. The effects
of dietary soy supplementation on hot flushes. Obstet Gynecol
1998; 91: 6-11.
7. Baber RJ, Templeman C, Morton
T, Kelly GE, West L. Randomized placebo-controlled trial of
an isoflavone supplement and menopausal symtoms in women.
Climacteric 1999; 2: 85-92.
8. Knight D, Howes JB, Eden
JA. The effect of Promensil, an isoflavone extract, on menopausal
symptoms. Climacteric 1999; 2: 79-84.
9. Clarkson TB, Anthony MS,
Morgan FJ. Inhibition of postmenopausal atherosclerosis progression:
a comparison of the effects of conjugated equine estrogens
and soy phytestrogens. J Clin Endocrinol Metab 2001; 86: 41-47.
10. Anderson JW, Johnstone
BM, Cook-Newell ME. Meta-analysis of the effects of soy protein
intake on serum lipids. N Engl J Med 1995; 333: 276-282.
11. Davis SR, Dalais FS, Simpson
ER, Murkies AL. Phytestrogens in health and disease. Recent
Progress in Hormone Research 1999; 54: 185-212.
12. Schwartz JA, Liu G, Brooks
SC. Genistein-mediated attenuation of tamoxifen-induced antagonism
from estrogen receptor-regulated genes. Biochem Biophys Res
Commun 1998; 253: 38-43.
Jean
Hailes Foundation, 173 Carinish Rd, Clayton, Victoria,
Australia 3168
| 