Estriol, the dominant estrogen in pregnancy shown to decrease MS symptoms. When Estriol was stopped, MS lesions relapsed. Estriol binds to ERbeta at a rate of 5:1 compared to ER alpha.
Nice article that discusses the interaction between hormones, the immune system and MS in both women and men. Men with the highest aromatase activity shown to have the highest incidence of neurodamage.
Pregnancy has a positive effect on MS patients, especially during the 3rd trimester. Rebound of MS increases in the postpartum period. Estriol is the dominant pregnancy estrogen. Progesterone is also produced at high levels. The withdrawal of these hormones in the postpartum period are likely to lead to this rebound in MS.
A beneficial effect of pregnancy on clinical
symptoms has been observed in MS and other Th1-mediated autoimmune diseases, including rheumatoid arthritis (RA), psoriasis,
uveitis, and thyroiditis
In general, Th1 lymphocytes secrete proinflammatory cytokines (e.g., IL-2, IL-12, IFN-γ, and TNF-α) that promote cellular
immunity, while Th2 lymphocytes produce anti-inflammatory cytokines (e.g., IL-4, IL-5, IL-6, and IL-10) that promote humoral
immunity
Th2 cytokines are associated with the down-regulation of Th1 cytokines and may confer protection from Th1-mediated
autoimmune diseases
MS is in part a Th1 autoimmune disease. Estriol therapy induces a shift to Th2 through increase in Th10. Estriol also decreases TNF-alpha cytokine production.
It is now well recognized
that the disease manifestation is reduced in pregnant women with
relapsing-remitting MS
This occurs particularly during the
third trimester when levels of estrogens (estradiol and estriol) and
progesterone (see Table 2) are elevated
up to about 20 times
This seems
well correlated with a decrease in active white matter lesions detected by MRI
This clinical improvement is
however followed by temporary rebound exacerbations at post-partum, when the
hormone levels decline
a shift from Th1 to Th2 immune response, expansion of
suppressive regulatory T lymphocytes and decrease in the number of circulating
CD16+ natural killer (NK)-cells
Th2 cytokines are
associated with down-regulation of Th1 cytokines and this Th2 shift is believed
to provide protection from allograft rejection during pregnancy as well as from
Th1-mediated autoimmune disease
it is
worth noting that the levels of other hormones with anti-inflammatory activity
(1,25-dihydroxy-vitamin D3, norepinephrine, cortisol) also increase
by 2 to 4 times during late pregnancy
1,25-dihydroxy vitamin D3
induces regulatory T-cell function important for development of self-tolerance
breast-feeding does not alter the
relapse rate in women with MS
Leptin is a pleiotropic
hormone produced primarily by adipocytes but also by T lymphocytes and neurons
Several lines of evidence indicate that leptin
contributes to EAE/MS pathogenesis, influencing its onset and clinical severity,
by acting as a proinflammatory cytokine which promotes regulatory T cell (Treg)
anergy and hyporesponsiveness, resulting in increased Th1 (TNFalpha, INFgamma)
and reduced Th2 (IL-4) cytokine production
circulating leptin levels are increased in relapsing-remitting MS
patients (men and women analyzed together) while the
CD4+CD25+Treg population decreases
As the leptin plasma concentrations are
proportional to the amount of fat tissue, obese/overweight individuals produce
higher levels of leptin
Nielsen et al found that estradiol and progesterone exert
neuroprotection against glutamate neurotoxicity, while MPA antagonizes the
neuroprotective effect of estradiol and exacerbated neuron death induced by
glutamate excitotoxicity
good read on an alternate hypothesis of the pathophysiology of MS. THe author proposes that MS is an inflammatory induced dysfunction of lipid metabolism. This is in contrast to the current held dogma that MS is an autoimmune disease.
Inflammation is the most predominant feature during the early (relaping) phases of the disease and declines with aging of the patients and disease duration
in the process of oligodendrocyte destruction and demyelination in MS lesions iron is liberated from its intracellular ferritin bound stores into the extracellular space, where it is taken up by microglia and macrophages and again stored together with ferritin. When this happens in MS lesions in an environment, where free radicals are produced by oxidative burst, iron can be liberated from ferritin and transformed into reactive Fe++[114], which reacts with hydrogen peroxide to generate highly reactive hydroxyl radicals [36] and thus amplifies oxidative damage and associated cellular injury
anti-inflammatory or immunomodulatory treatments are effective in the relapsing stage, but the benefit is lost when the patients have entered the progressive phase
Inflammation will remain a key target, since the data suggest that microglia activation and oxidative burst is driven by inflammation throughout all stages of the disease.
This article proposes that increased antioxidant enzymatic activity is an adaption to the increased ROS found in MS. This increased ROS disrupts the blood-brain barrier.
Interesting study on glutathione. The study looked at glutathione levels in the brain using MR. The authors found lower glutathione levels in the Grey matter versus normal controls and lower glutathione levels in white matter lesions.