A large body of evidence supports the therapeutic potential of testosterone and estrogens in animal models of multiple sclerosis. Mechanisms of action include both immunomodulatory and neuroprotective pathways thus suggesting that sex hormones represent novel treatment options that could beneficially affect the inflammatory as well as the neurodegenerative component of the disease. We now also have first clinical evidence for the effectiveness of testosterone and estriol in MS from two completed pilot studies. As a result, a phase II trial is underway for oral estriol treatment in female patients with RRMS. Both testosterone and estriol have a favorable safety profile in men and women, respectively. Both hormones also have an advantageous route of administration compared to available treatments in MS since testosterone can be applied transdermally and estriol may be taken orally. Thus, these treatments, tailored to each gender, represent an attractive alternative to currently approved therapeutic agents such as interferon-β and glatiramer acetate, which are each taken by injection only.
More research is needed to understand the pathways and mechanisms underlying the beneficial effects of sex hormones on MS pathology. For estrogens, there is accumulating evidence that anti-inflammatory and neuroprotective effects are selectively mediated via ERα and ERβ pathways. One must consider the risk/benefit ratio of any estrogen treatment when considering its use in MS. The goal is to optimize efficacy and minimize toxicity. Hence, determining which estrogen receptor mediates the neuroprotective effect of estrogen treatment is of central importance. The reviewed data demonstrating that treatment with an ERβ ligand is neuroprotective are of clinical relevance, because breast and uterine endometrial cancer are both mediated through ERα, not ERβ. Thus, treatment could be tailored to minimize the risk/benefit ratio for individual patients. If certain conditions such as a known risk for breast or uterine cancer prohibit the use of estriol, the patient may benefit from a standard anti-inflammatory treatment in combination with ERβ ligand treatment. This way, the neuroprotective properties of estrogen treatment could be maintained while avoiding the increased risk of cancer in the breast and uterus.
Comparatively little is known about the anti-inflammatory and neuroprotective mechanisms of testosterone. Testosterone is converted to estrogen in the brain by aromatase, and the neuroprotective properties of testosterone treatment in vivo may be due at least in part to this conversion. However, some studies using the non-convertible dehydrotestosterone (DHT) have also shown testosterone can be directly beneficial.
Testosterone therapy has potentially harmful side effects as it may worsen pre-existing prostate cancer in some men. Testing of prostate specific antigen levels is recommended before and during testosterone therapy. However, testosterone replacement is widely used in aging and hypogonadal men and there is no clear evidence that higher levels of circulating testosterone, within the physiological range, are linked to an increased risk of prostate cancer.
In this review, we have focused on hormonal influences on MS. The gender gap in MS however may be due to effects of sex hormones, genetic differences or a combination of the two. A nonmutally exclusive alternative hypothesis includes a direct genetic effect on the immune system and/or the CNS. That is, specific gene products, which are not induced by gonadal hormones, yet are expressed in a sexually dimorphic manner could induce gender differences in MS pathogenesis and progression. In human studies, these factors cannot be dissected since men and women differ with regard to both sex chromosomes as well as sex hormones. However, there are now sophisticated transgenic mouse models available that allow the examination of effects of sex hormones versus sex chromosomes independently. Recently, our laboratory has employed this model to examine the contribution of gonadal gene complement on immune responses (Palaszynski et al., 2005
) as well as susceptibility to autoimmune disease (Smith-Bouvier et al., 2008
). Findings suggest that the XX sex chromosome complement, as compared to XY complement, can indeed promote autoimmunity. Taken together, one must consider the contribution of both sex hormones and sex chromosomes in complex autoimmune diseases such as MS.