Although the exact aetiology has yet to be elucidated, its pathophysiology resembles that of an autoimmune disease. MS affects females more often than males, with the ratio being approximately 3:1 in North America.1
There are various patterns of disease progression, with relapsing-remitting MS (RRMS) being the most common, and which as the name implies follows a course of relapse and remission. The second most common type of MS is secondary progressive (SPMS), which is often the sequelae of longstanding RRMS and is characterized not by relapses and remissions, but by a steady progression and worsening of symptoms. The symptoms of MS typically subside, and enter into a state of remission during pregnancy, especially during the third trimester. Further, relapse rates return to normal, sometimes after a temporary increase beyond pre-pregnancy rates, within the first three months post-partum.2
There are numerous physiological changes that occur during Abstract Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system with pathophysiology resembling that of an autoimmune disease.
The use of estriol for MS stems from the observation that women with this disease typically enter into a state of remission when they become pregnant. Promising results from human trials using estriol in non-pregnant women have been reported. Estriol induces an immunological shift from a TH1 to a TH2 dominant state, which can bring about a state of remission. Preliminary evidence from human trials evaluating testosterone treatment for male patients with MS has been positive.
This review discusses how the interplay of sex hormones and the immune system improves the symptoms of MS, and highlights areas of future research. a pregnancy that might explain this phenomenon, but of particular interest is estriol due to its dramatic increase in serum levels (i.e., relative to the other estrogens – estrone and estradiol) during the third trimester, and its sharp fall post-partum; events that coincide with the aforementioned changes in relapse rates.
These observations have sparked great interest in determining whether estriol could successfully be used as a novel treatment for this debilitating disease. Immunologically, MS is classified as being a TH1 dominant condition and is associated with inflammatory cytokines, such as IL-2, IL-12, IFN-γ and TNF-α. During pregnancy, the immune system shifts to a state of TH2 dominance and is associated with anti-inflammatory cytokines, such as IL-4, IL-5, IL-6 and IL-10. This shift to a TH2 dominant state is advantageous as it plays a role in the mother not rejecting the developing foetus.
Effective treatment strategies in MS, therefore, should be aimed at inducing the shift from a TH1 to a TH2 dominant immunological state. In addition to the inflammatory nature of the disease, 2 Journal of Orthomolecular Medicine Vol 27, No 2, 2012 MS is characterized by neurodegeneration of the grey matter.3
Most pharmaceutical treatments for MS are aimed at inhibiting inflammation, but they do not prevent the progression of the disease, as seen in SPMS. Neuroprotective mechanisms would involve substances that cross the blood-brain barrier and directly promote the health of neurons and oligodendrocytes.4
Many studies have been conducted to date using mouse models of experimental autoimmune encephalitis (EAE), and these studies have shown estrogens, both estradiol and estriol, to have a beneficial effect on cytokine profiles. However, in humans, researchers have had to carefully consider whether the use of estradiol has a safe risk-benefit profile. Estradiol preferentially binds estrogen receptor alpha (ERα), and this receptor is found predominantly in the bones, testes, epididymis, prostate, uterus, ovary, liver, mammary gland, heart, vascular system and brain.5 Stimulation of ERα by estradiol for the purposes of hormone replacement therapy can significantly increase the risk of developing endometrial cancer if unopposed by oral progesterone or progestin. However, estriol preferentially binds estrogen receptor beta (ERß), which is found predominantly in the bladder, prostate, ovary, colon, immune system, heart, lung and brain.
Estriol, therefore, is most likely the safest form of estrogen to supplement as it has not been associated with endometrial or ovarian cancer.5 Testosterone, a predominantly male hormone, might be an important intervention for males with MS. It possesses anti-inflammatory and neuroprotective properties, and several mechanisms are posited, including its ability to increase the production of IL-5 and IL-10, as well as decrease the production of IFN-γ and TNF-α. 6 Testosterone may also increase brain-derived neurotrophic factor (BDNF), a protein that supports the survival and growth of nerve cells.7
