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Estrogen effect in multiple sclerosis more nuanced than described.

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Estrogen Effect in Multiple Sclerosis More
Nuanced Than Described
Jerome Tanzer, MD
In their discussion of noninfectious risk factors for multiple
sclerosis (MS), Ascherio and Munger1 state that “estrogens in
high levels” favor a noninflammatory immune response, and
they relate this effect as a potential cause in the diminished
clinical MS activity observed during pregnancy. I propose
that using the blanket term estrogen in describing the estrogenic effects in MS is neither helpful nor accurate.
Three significant forms of estrogen exist in the female
body: estradiol, estrone, and estriol. Estrone is a relatively
weak estrogen. Estradiol is the major form in the nonpregnant woman. Estriol predominates through most of pregnancy, whereas estradiol levels increase rapidly in the third
The reduced incidence of clinical flares of MS during
pregnancy has been postulated to be estriol induced, and administration of oral estriol to nonpregnant women has been
shown to have a protective effect.2 The significant increase in
estradiol level in the third trimester could explain the tendency to postpartum flaring.
Why are such distinctions important? Estradiol rather
than estriol appears to be the link in the female estrogen/MS
relationship. Increased estrogen levels in the form of estradiol, rather than being protective as the authors appear to
suggest, is more likely to activate clinical disease, as suggested
by its increased prevalence in women and its onset predominately at or after the initiation of menarche.
In addition, the various estrogens have the potential to be
degraded via dietary intervention into less active forms,3 and
their effect can also be modulated at receptor sites utilizing
dietary phytoestrogens. Perhaps more important, a significant
amount of estradiol is produced in adipose tissue via aromatase activity. Adiposity, via leptin mediation reflecting sufficient fat stores, is a trigger for menarche. The dramatic increase in adiposity, which has occurred over the past few
generations, has resulted in a generally earlier menarche and
a more pronounced hyperestrogenic (estradiol) state, possibly
explaining an observed earlier onset of clinical disease4 and
offering an alternative pathway to modulating the overall estrogen effect.
In conclusion, I would suggest that in the nonpregnant
female individual it is low estrogen (estradiol) and not “high
estrogen levels” that would provide the most protection from
clinical disease, and that in the pregnant female individual it
is not high “estrogen,” but rather a high estriol level, that is
Department of Medicine, Mount Auburn Hospital,
Cambridge, MA
1. Ascherio A, Munger KL. Environmental risk factors for multiple
sclerosis. Part II: noninfectious factors. Ann Neurol 2007;61:
504 –513.
2. Sicotte NL, Liva SM, Klutch R, et al. Treatment of multiple
sclerosis with the pregnancy hormone estriol. Ann Neurol 2002;
52:421– 428.
3. Fowke JH, Longcope C, Hebert JR. Brassica vegetable consumption shifts estrogen metabolism in healthy postmenopausal
women. Cancer Epidemiol Biomark Prev 2000;9:773–779.
4. Cocco E, Sardu C, Lai M, et al. Anticipation of age at onset in
multiple sclerosis. Neurology 2004;62:1794 –1798.
DOI: 10.1002/ana.21273
Alberto Ascherio, MD, DrPH,1–3
Kassandra L. Munger, MSc1
The hypothesis that estriol and estradiol have opposite effects
on risk for multiple sclerosis, proposed by Dr Tanzer, is interesting, but to our knowledge, an adverse effect of estradiol
is not supported by experimental data. In experimental allergic encephalomyelitis, castration of female mice led to earlier
disease onset, an effect that was reversed by long-term treatment with high levels of estradiol.1 Significant differences between estrogens may, however, exist in potency, as a longer
delay in disease onset in the same experiment was observed
with estriol than with estradiol.1 The protective effect of estradiol appears to be mediated by estrogen receptor signaling,
because it was reversed by estrogen receptor antagonists.2 A
possible association between adiposity and multiple sclerosis
incidence and age at onset is certainly worth exploring, but
such association would not directly imply increasing levels of
estradiol because there are several alternative explanations, including an adverse effect of low levels of circulating vitamin
D,3 which are more common in obese individuals.4
Departments of 1Nutrition and 2Epidemiology, Harvard
School of Public Health, and 3Channing Laboratory,
Department of Medicine, Brigham and Women’s Hospital,
and Harvard Medical School, Boston, MA
1. Jansson L, Olsson T, Holmdahl R. Estrogen induces a potent
suppression of experimental autoimmune encephalomyelitis and
collagen-induced arthritis in mice. J Neuroimmunol 1994;53:
2. Elloso MM, Phiel K, Henderson RA, et al. Suppression of experimental autoimmune encephalomyelitis using estrogen
receptor-selective ligands. J Endocrinol 2005;185:243–252.
3. Munger KL, Levin LI, Hollis BW, et al. Serum 25hydroxyvitamin D levels and risk of multiple sclerosis. JAMA
4. Wortsman J, Matsuoka LY, Chen TC, et al. Decreased bioavailability of vitamin D in obesity. Am J Clin Nutr 2000;72:
690 – 693.
DOI: 10.1002/ana.21307
© 2008 American Neurological Association
Published by Wiley-Liss, Inc., through Wiley Subscription Services
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estrogen, effect, nuanced, described, sclerosis, multiple
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