**5. Future perspectives**

which could be attributed to additional neuroprotective effects of female sex hormones [127]. Another study has registered hormonal disturbances in 56% of women with MS and abnormal

Little data are available about the impact of hormonal decline during menopause on the course of MS. Smith and Studd [129] have found increased disability in 54% of menopausal women with MS and Holmquist et al. [130] have reported worsening of MS symptoms related to

Onset of MS in men (age 30–40) usually occurs later in life than in women, coinciding with the age at which serum testosterone levels normally begin to decline [53]. Examination of serum testosterone concentrations has shown divergent results. Abnormally low levels have been found by Wei and Lightman [131] in 24% of male MS patients with primary or secondary progressive MS. Foster et al. [94] have observed the same disturbance in all four men (three with relapsing‐remitting and one with secondary progressive MS) with sexual dysfunctions. On the contrary, male patients with relapsing‐remitting MS, studied by de Andrés et al. [132] have presented elevated testosterone blood concentrations compared to the healthy controls and a tendency toward reduction during the relapse phase. The small sample size may account for these contradictory results, suggesting that larger studies are needed for more detailed examination of hormonal status and its relation to disease activity in MS. A recent longitudinal study, comprising 96 male patients with MS or clinically isolated syndrome, has found hypogonadal status (testosterone levels below the lower limit of normal) in 39% of the subjects. A negative age‐adjusted correlation between total testosterone and EDSS has been revealed and higher baseline testosterone levels have been associated with less cognitive decline,

Gender differences are observed not only in susceptibility and clinical manifestations but also in brain damage characteristics. A study in a large cohort of MS patients has shown that men are prone to develop less inflammatory, but more destructive brain lesions than women [134]. Intracortical lesions are more frequent in men [135]. The relationship between sex hormone levels and tissue damage has been explored in MS. A MRI study of disease activity during different phases of the menstrual cycle has shown significant correlation between progester‐ one/17β‐estradiol (PEL) ratio in the luteal phase and the number of gadolinium‐enhanced CNS lesions [136, 137]. Another study has found a significantly higher number of Gd‐enhanced lesions in women with abnormally low testosterone levels. In men, estradiol concentration has correlated with the volume of T1 lesions and the contrast‐enhanced T2 lesions [138]. These data provide evidence that sex hormones modulate the development of brain tissue damages and repair in MS. Luchetti et al. [139] have extended the research in gender differences of steroid synthesis and signaling in the brains of MS patients. They have studied gene expression of these pathways and of inflammatory cytokines in MS lesions and normal‐appearing white matter of male and female patients and controls. In MS lesions in males, local upregulation of aromatase (an enzyme involved in estrogen biosynthesis), ERβ, and TNFmRNA has been found; whereas in females, local upregulation of 3β‐hydroxysteroid‐dehydrogenase (a progesterone synthetic enzyme), and of progesterone receptor has been detected. Aromatase and ERαmRNA levels have positively correlated with that of TNF in primary cultures of

hormonal pattern correlated with the intensity of MRI pathology [128].

measured by SDMT during longitudinal follow‐up [133].

menopause in 40% of the patients.

266 Trending Topics in Multiple Sclerosis

Promising results of testosterone, estrogens and progesterone in EAE have initiated pilot studies in humans, in which sex hormones are used separately or in combination with each other or with another immunomodulatory drug.

The first clinical study using sex hormones in women with MS has been performed with oral estriol 8 mg/day, given for 6 months to 10 patients (six with a relapsing‐remitting course and four with a secondary progressive course). In the relapsing‐remitting patients, the trial has been extended after a 6‐month posttreatment period with a 4‐month retreatment period, during which estriol has been given in combination with progesterone. Estriol treatment has decreased gadolinium enhancing lesion numbers and volumes on MRI, significantly increased production of IL‐5 and IL‐10 and decreased secretion of TNF‐α. When estriol administration was stopped, MRI‐lesions increased to pretreatment levels, but after treatment reinstitution, they significantly decreased again [140, 141].

Female sex hormones, given in addition to interferon‐β therapy, have reduced the number of relapses and delayed progression of disability [142].

Larger, placebo controlled, clinical trials of estrogens in MS are ongoing. These include a multicenter placebo controlled trial of estriol in combination with glatiramer acetate (Clini‐ calTrials.gov: NCT00451204) and a trial, examining the potential of estradiol and progestin to prevent postpartum relapses—POPART'MUS trail (NCT00127075) [112, 143].

Ten male patients with relapsing‐remitting MS have been treated with testosterone 100 mg/day via transdermal application for 12 months. Improvement of cognitive performance and slowing of brain atrophy, as measured by MRI, have been observed under testosterone treatment. Immunological changes consisted of decreased production of IL‐2 and increased production of TGFβ1, BDNF, and PDGF‐BB from PBMCs [144, 145].

The main expected adverse event about these high‐dose hormonal treatments is the increased risk of malignancies. Data in the literature demonstrate that breast and uterine endometrial cancer are both mediated through ERα. Treatment with an ERβ ligand has shown neuropro‐ tective effect in EAE and can be explored as a potential therapeutic strategy in multiple sclerosis [64]. On the other side, 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 [80].

The variations in the susceptibility and in the clinical course of MS reflect the differences in immune responses between the genders. Now it is widely accepted that these differences are partially due to the impact of sex hormones. Estrogens, progesterone and androgens change the cytokine secretion and interactions between immune cells and through this suppress the disease activity. Their direct neuroprotective properties enhance the amelioration of EAE and MS. Several pilot clinical trials using sex steroids as treatment agents in MS patients established positive results and need to be confirmed and expanded in larger cohorts.

In conclusion, a large amount of evidence about the influence of sex hormones on the patho‐ logical processes in MS has been accumulated. Although they are not a primary pathogenic factor, immunomodulatory and neuroprotective effects of sex steroids provide opportunities for development of new disease‐modifying strategies.
