Sex hormones may contribute to the development of brain tissue damage typical of multiple sclerosis (MS), according to an Italian study published in the February Journal of Neurology, Neurosurgery, and Psychiatry. Investigators from “La Sapienza” University in Rome analyzed the sex hormone levels of healthy people and compared them with those of men and women with relapsing-remitting MS. “Evidence has suggested that gender affects the clinical course of MS,” said Carlo Pozzilli, MD, PhD, and colleagues. “Using MRI in a large cohort of patients, we have previously shown that there is a pathologic counterpart for the different clinical course, with women having more inflammatory but less destructive lesions than men.” The results of the present study partially substantiated those findings, he added.

HORMONE IMAGING

The study cohort consisted of 60 patients with MS (35 women) and 36 healthy controls (18 women). The average age of the participants was 32, and those with MS had had their disease for an average of six years, Prof. Pozzilli elaborated. The hormones tested included follicle-stimulating hormone, luteinizing hormone, estradiol, testosterone, dehydroepiandrosterone sulfate, and progesterone. In women, all hormone levels save those of progesterone were tested during both the follicular and luteal phases of their menstrual cycle to account for variations, he noted. Progesterone was tested only during the luteal phase. None of the women had used oral contraceptives, and all had normal menstrual cycles.

The patients with MS also underwent brain MRI to identify areas of tissue damage and inflammation caused by the disease. The number of enhancing lesions as well as the volume of T2-hyperintense and T1-hypointense lesions (“black holes”) was determined, Prof. Pozzilli said.

GENDER BIAS IN MS?

Compared with healthy women, those with MS had lower levels of testosterone in both phases of their menstrual cycle. Among women with MS, those who had lower testosterone levels also had a higher number of gadolinium-enhancing lesions on MRI as compared with women with normal testosterone levels; however, women with MS and higher levels of testosterone had greater levels of brain damage and a trend toward increased disability, as measured by the Expanded Disability Status Scale, the investigators reported.

Among men, there were no differences in sex hormone levels between those with MS and the control group. However, the researchers did find that men with MS and elevated levels of estrogen had the greatest degree of brain tissue damage on MRI.

For both sexes, none of the other hormones registered any significant impact on the findings, Prof. Pozzilli reported. Regarding the MRI findings, the degree of overall brain damage was similar in men and women, but women tended to have more signs of inflammation than men, he added. This finding partially supported previous research but failed to demonstrate any difference in the proportion of lesions evolving into “black holes” on MRI, “probably because of the small sample size,” the group said.

QUESTIONS OF CAUSALITY

The investigators concluded that estrogen and testosterone play a role in modulating the development of brain tissue damage in relapsing-remitting MS and asserted that the observed differential effect of sex hormones on brain damage in MS could be at least partially explained by experimental data. In rat studies of traumatic brain injury, “Emerson et al have suggested that estrogen treatment has both receptor mediated and receptor independent effects on cellular energy metabolism. The deleterious effects noted in women but not in men probably reflect the fact that the female brain has a much greater receptor binding capacity (up to 100%) than the male brain, and consequently is at greater risk of receptor mediated excitotoxicity and cell death,” they related.

Because the investigation did not address causality, “determining whether increases in serum hormone levels reflected the brain’s compensatory repair mechanisms during injury or if these molecules actually contribute to the development of tissue damage was not possible,” they noted. Nevertheless, “the respective contribution of [estrogen and testosterone] and their types of actions and interactions deserve further analysis.”

NR

—C. Justin Romano

Suggested Reading
Emerson CS, Headrick JP, Vink R. Estrogen improves biochemical and neurologic outcome following traumatic brain injury in male rats, but not in females. Brain Res. 1993;608:95-100.
Pozzilli C, Falaschi P, Mainero C, et al. MRI in multiple sclerosis during the menstrual cycle: relationship with sex hormone patterns. Neurology. 1999;53:622-624.
Pozzilli C, Tomassini V, Marinelli F, et al. “Gender gap” in multiple sclerosis: magnetic resonance imaging evidence. Eur J Neurol. 2003;10:95-97.
Tomassini V, Onesti E, Mainero C, et al. Sex hormones modulate brain damage in multiple sclerosis: MRI evidence. J Neurol Neurosurg Psychiatry. 2005;76: 272-275.

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