The extensive literature and the work from our laboratory illustrate the large number of complex processes affected by estrogen that might contribute to the striking ability of 17beta-estradiol (E2) and its derivatives to inhibit clinical and histological signs of experimental autoimmune encephalomyelitis (EAE) in mice. These effects require sustained exposure to relatively low doses of exogenous hormone and offer better protection when initiated prior to induction of EAE. However, oral ethinyl estradiol (EE) and fluasterone, which lacks estrogenic side effects, could partially reverse clinical EAE when given after the onset of disease. The three main areas discussed in this review include E2-mediated inhibition of encephalitogenic T cells, inhibition of cell migration into central nervous system tissue, and neuroprotective effects that promote axon and myelin survival. E2 effects on EAE were mediated through Esr1 (alpha receptor for E2) but not Esr2 (beta receptor for E2), as were its antiinflammatory and neuroprotective effects. A novel finding is that E2 up-regulated the expression of Foxp3 and CTLA-4 that contribute to the activity of CD4(+)CD25(+) Treg cells. The protective effects of E2 in EAE suggest its use as therapy for MS, although the risk of cardiovascular disease may complicate treatment in postmenopausal women. This risk could be minimized by using subpregnancy levels of exogenous E2 that produced synergistic effects when used in combination another immunoregulatory therapy. Alternatively, one might envision using EE or fluasterone metabolites alone or in combination therapies in both male and female MS patients.
Because of the increased susceptibility of females to autoimmune diseases, some have assumed that female sex hormones, including estrogen, actively facilitate the disease process. In contrast to this view, our studies clearly demonstrate an important regulatory role of estrogen in EAE. Both estrogen and testosterone had inhibitory effects on immunity, and it may be that the enhanced susceptibility to autoimmune disease in females vs. males is due simply to less potent natural inhibition by estrogen than by testosterone.
DHEA is one of the three principal adrenal steroids, a precurosor of both androgens and estrogens, including 17b-estradiol, which is the focus of this review. Along with its active metabolites, DHEA has been described as a natural “antiglucocorticoid”, “immune stimulatory”, and “anti-inflammatory agent, attenuating many of the undesirable effects of glucocorticoid (GC) hormones…….
DHEA and its synthetic analogue fluasterone are steroidal compounds that attenuate disease in several mouse models of EAE with an efficiency similar to that reported for IFN-b. However, benefit in the rodent is observed only at high doses of fluasterone, which may not be readily achievable in man. Other metabolites might be more potent in limiting EAE than the parent compound and would therefore require lower doses to provide therapeutic benefit, a distinct advantage for possible MS trials. This would drive the development of more practical therapeutic strategies, (i.e., tansmucosal (buccal), transdermal, or s.c. administration ) to ameliorate MS in man. Because the steroid-like compounds are nontoxic, are inexpensive to produce, and are as good as or better than IFN-b in limiting EAE, similar or greater efficacy in man, at more readily achievable doses, would provide real clinical as well as economic benefit to patients with MS.
There is growing evidence suggesting that hormones, including sex hormones, can affect and be affected by the immune system. For example, both estrogen and progesterone, two important female sex hormones, may suppress some immune activity. Testosterone, the primary male hormone, may also act as an immune response suppressor. During pregnancy, estrogen and progesterone levels are very high, which may help explain why pregnant women with MS usually have less disease activity. The higher levels of testosterone in men may partially account for the fact that women with MS outnumber men with MS by 2-3 to 1.
Sexual dysfunction is quite common in MS and is generally attributed to autonomic dysfunction resulting from spinal cord damage……..The results of this study are the first to demonstrate that serum testosterone levels are reduced in male mice with passive EAE and in some men with MS. The significance of this finding is twofold. First, the reduction in serum testosterone levels may play a role in the high frequency of sexual dysfunction that occurs in MS. Second, because testosterone is known to suppress inflammatory immune responses, a reduction in serum testosterone levels may act to increase the severity or prolong the duration of disease attacks.
The decrease in circulating testosterone levels in men with MS may have significant implications for disease progression. Inflammatory mediators secreted during a demyelinating episode may disrupt the hypothalamic-pituitary-gonadal axis resulting in low serum testosterone levels. Because testosterone is immunomodulatory, reduction in testosterone levels during an MS exacerbation might increase the severity and/or duration of the attack. The increased sensitivity of the male HPG axis to inflammatory cytokines may provide a partial explanation for the increased incidence of progressive MS in men. Further study of the importance of testosterone and the HPG axis in disease severity in males with MS is warranted.
“Studies are now showing that the sex steroid hormones, mainly testosterone, but also DHEA, androstenedione and even estradiol, have an impact on a man’s bone, heart, and sexual health thoughout his lifetime……Men….lose approximately 1% of their testosterone and 2.5% of their DHEA per year beginning at age 30.”
Scientists have identified the first direct link between stress and aging, a finding that could explain why intense, long-term emotional strain can make people get sick…
Chronic stress appears to hasten the shriveling of the tips of the bundles of genes inside cells, which shortens their life span and speeds the body’s deterioration….
If the findings are confirmed, they could provide the first explanation on a cellular level for the well-documented association between psychological stress and increased risk of physical disease….
The researchers examined structures inside cells called telomeres. Telomeres are the caps at the ends of chromosomes—the molecules that carry genes. Every time a cell divides, telomeres get shorter. In the natural aging process, the telomeres eventually get so short that cells can no longer divide, and they then die....
The researchers found that chronic stress appears to accelerate this process....
The researchers studied telomeres and telomerase in white blood cells taken from blood samples. Prematurely aged white blood cells alone could make people more prone to illness because white blood cells are a key part of the immune system. But the findings probably hold true for other types of cells as well……
It is unclear exactly how stress might affect telomeres and telomerase levels, but it could be that chronically elevated levels of stress hormones such as cortisol damage the telomeres and other genes in the body and lower telomerase levels, inhibiting the cells’ ability to respond.
Chronic stress appears to have the potential to shorten the life of cells, at least immune cells.
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