Multiple Sclerosis is a multifactorial inflammatory disease that is characterized by the loss of myelin, the coating of the encephalon and spinal cord neurons, causing a neuronal degeneration process, which involves the loss of the neurons themselves. It is a disease that manifests itself differently in each individual. In fact, it can remain clinically silent and not be diagnosed for many years. There are people who, after diagnosis, do not experience relapses for a long time, and in this case there is no progression towards disability. Whilst others may experience relapses which manifest close together in acute episodes, causing a rapid progression of the disease.
This is a pathology which is much more common in women than men, with a ratio of 2.6:1, according to data reported in 2009 by a group of Dutch scientists. This means that multiple sclerosis affects more than twice as many women as men, in fact. Additionally, the age of onset often coincides with the childbearing age for women and is usually between 20 and 40 years.

At the root of this disease is primarily an autoimmune reaction, that is, an abnormal immune system response against the nervous system. In people with Multiple Sclerosis, the immune system attacks the body rather than against infectious agents, as it should do normally. In particular, certain cells of the immune system, T cells, in patients with multiple sclerosis recognize myelin as a pathogen and give rise to inflammation, which causes the formation of “plaques of demyelination”. In addition to the loss of the myelin sheath, some parts of the neuron are also lost, and it is precisely for this reason that the disease can lead to permanent disability.

Why are women more affected than men?

Compared to male subjects, women, as well as those with multiple sclerosis, are generally more often affected by autoimmune diseases. For a long time many scientists have researched, and still wonder, about the reasons that underlie the different characteristics of the immune system in the 2 sexes.

An innocent mistake, made by Abigail Russi, a graduate student in the Department of Microbiology and Immunology at Northwestern University of Chicago led scientists to a discovery that offers new insights on  precisely why women are more likely than men to develop autoimmune diseases, like multiple sclerosis. Abigail accidentally used male mice instead of females during an experiment and uncovered startlingly different results.

The discovery, published in The Journal of Immunology in May 2015, focuses on the innate lymphoid cells, which show different immune system activity in males compared to females (see full article). The innate lymphoid cells (ILCs, Innate lymphoid cells) are immune cells that regulate the initial immune responses against viruses, bacteria and parasites through the release of soluble factors.

Multiple sclerosis is a disease that affects the brain and spinal cord and is the result of a dysregulated immune response. Using a mouse model of MS (i.e. using genetically modified mice in the laboratory), the study showed that the innate lymphoid cells are active and protect males from the disease, while in females, these cells are inactive and do not protect them.

“Women are three to four times more likely than men to develop MS, and much of the current research focuses on the question, ‘Why do females get worse disease?”

said Melissa Brown, lead author of the research and Professor of Microbiology and Immunology at Northwestern University Feinberg School of Medicine.

“Now, thanks to a serendipitous moment in the laboratory, we are approaching this research from the opposite way, asking, ‘Why are males protected from disease?’” Brown said. “Understanding the mechanisms that limit disease in men can provide information that could be used in future therapy to block disease progression in women.”

As in most laboratories studying the mouse model of this disease, female rats were used in almost all of the experiments of Brown.

“When we induce the disease in this strain of female mice, virtually 100 percent of them get very sick,” Brown said. “Male mice either get no disease or very little, so MS researchers typically use females in their studies.”

Some years ago, a Brown graduate lab student was asked to perform an experiment using two groups of female mice. One group was normal, while the other had a genetic mutation in a receptor of the growth factor c-kit that prevented the development of a subset of immune cells. However, instead of using female mice, the student has used male mice in error.

“It was an honest mistake, but the results were striking; the male mice with the mutation got very, very sick,” Brown said. “Because this strain of male mice never get very sick, I thought there was some sort of mistake, so I asked the student to repeat the experiment.”

The results were the same, and Brown and his colleagues realized that the mutation behaved differently in males and females. Brown has therefore asked the doctoral student Abigail Russi, who worked in her laboratory, to investigate further.

Russi thus found that the mice with the c-kit mutation did not display the innate lymphoid cells of type 2. These cells are normally present in bone marrow, lymph nodes and the thymus of males and females. Researchers think that in males these cells produce a protein that can help to protect against the disease by interfering with the harmful immune response.

“In the paper we show that when these cells are missing in the males with the mutation, that changes the whole immune response of the male animals and causes this lack of protection,” Russi said. “We are now looking at what activates these cells preferentially in males and not in females. The next question is can we activate the innate lymphoid cells in females to decrease disease susceptibility?”

Suffice to say that this is not the first study that is based on sexual difference in the field of MS research. In 1990, in fact, some scientists discovered that testosterone is a protective hormone for women with MS, but the long-term treatment of women with MS is not a viable option because of the many side effects (see next paragraph).

The innate lymphoid cells of type 2 are held liable to promote allergic inflammation. But this is only the first study to show that these cells show sex differences in their behaviour and are actually able to protect against autoimmune diseases.


The role of hormones in Multiple Sclerosis

The onset of the disease and its clinical course differ greatly in both sexes. The onset with motor disturbance is more frequent in men, as well as problems with the intellectual sphere, while the sensory symptoms, such as pain, are more prevalent in women.
The course of the disease in women is generally better than in men, who tend to develop more aggressive forms of multiple sclerosis, reaching severe disability before women at the same stage of the disease.

In women, the changes in the levels of estrogen and progesterone (sex hormones) that occur during the menstrual cycle can explain some clinical aspects. The premenstrual period, in fact, has been proven to be related to the worsening of the symptoms of multiple sclerosis, such as fatigue, muscle aches, increasing muscle stiffness, depression, weakness, coordination disorders, and visual sensitivity, which can in part be explained by the rise in body temperature that occurs at this time of the menstrual cycle. Unfortunately at the moment there is little scientific data available.

In one of the studies made in this regard participants were made to fill out a questionnaire given to 149 women; of these, 70% testified that their symptoms seemed to worsen at a particular time of the menstrual cycle (Giesser, B.S. et al., 1991).
The majority of those who reported a change in the symptoms, have indicated that the latter usually involves a worsening that occurs from seven days before and up to three days after menstruation (the final phase of the menstrual cycle).
Weakness, imbalance, fatigue and depression were the most frequently reported symptoms. Among the patients who did not complain about these disorders in the premenstrual period, a high percentage used oral contraceptives.

These results were also obtained from other small uncontrolled studies, and it is for this reason necessary that much more research is done to characterize the relationship between MS and the menstrual cycle.
With the help of the MS under 50 Italian facebook group, which gathers a large number of MS patients of both sexes and under 50 years of age, I could make a small survey purely for information purposes. I asked a sample of 60 women with MS between 18 and 50 years if, during the menstrual period they DETECTED exacerbation of disease symptoms. The result of this survey, I reiterate that has no scientific value other than to simply offer an additional insight, confirmed the study of Giesser: 80% in fact claimed to experience a worsening of symptoms. Participants indicated in particular; the increase of fatigue, exhaustion, headaches, irritability and anxiety, difficulties in vision, tingling and heaviness especially in the lower limbs. In the 20% who said there is no change in symptoms, some used oral contraceptives.

The worsening of symptoms during a woman’s menstrual cycle seems also tied to some specific factors, such as heat. It is well known, in fact, that just before menstruation, and during the second half of the female menstrual cycle, body temperature increases by about one degree centigrade. This increase in temperature can lead to a worsening of MS symptoms, the same way in which hot environments or episodes of fever can lead to a relapse in MS patients.

Some drugs used to treat the symptoms of MS can also cause irregular menstrual periods. Among them, a group of antidepressants called “selective serotonin reuptake inhibitors” (SSRIs).
Mitoxantrone, sometimes a drug used to treat the progressive form, has been attributed to the cause of some menstrual irregularities.
In relapse-remitting form interferon beta can cause several problems, such as small menstrual episodes during the complete cycle. It has been established, moreover, that the Natalizumab (Tysabri) causes more severe menstrual irregularities, while it is known that the glatiramer acetate (Copaxone) has no apparent effect on menstruation.

More recently, studies have been made which have also made use of nuclear magnetic resonance to study the relationship between the concentration of sex hormones (estrogen and progesterone hormones produced by the ovaries in women and testosterone produced by the testes in men) and characteristics of tissue damage through conventional magnetic resonance imaging used on individuals of both sexes with relapsing-remitting MS (RRMS). The MRI data indicated that women more frequently showed inflammatory demyelinating lesions than men, who are more susceptible to neuronal degeneration. Recognizable MRIs of neuronal loss areas are known by the technical term – blacks holes (Tomassini et al., 2009).

Hormonal treatments as a cure?

In laboratory experiments, testosterone, estrogen and progesterone have been shown to be able to protect neurons of the spinal cord from the toxic damage induced by a substance called glutamate. The hormones have even been shown to stimulate the growth of some parts of the neuron itself. The estrogens, however, are also able to reduce the real death of neurons, known by the technical term of apoptosis, and they can increase the formation of certain parts of the neuron. Progesterone then favors the coating process on the part of the brain myelin, the so-called myelination, increasing the proliferation of oligodendrocyte precursor cells. It is also able to modulate the immune response.

In a clinical study conducted by Soldan et al. (2004) female patients with MS relapsing-remitting and secondary progressive were given estriol (one of various conjugated estrogens that are used against symptoms of menopause). It was found that patients displayed an increase in production of 2 anti-inflammatory substances, called interleukin 5 and interleukin 10, and a reduction in the production of pro-inflammatory called tumor necrosis factor alpha substance, reflecting the role of estrogen in the displacement of the immune response mediated by pro-inflammatory Th1 lymphocytes into the inflammatory mediated by lymphocytes Th2.

In support of this data, in a scientific work of 2005, conducted on 124 male and female patients suffering from MS, Dutch scientists came to the conclusion that, compared with men, women with MS had higher levels of substances pro- in the inflammatory phase of the disease progression.

A further study published online by Lancet Neurology in November 2015, has been completed by Rhonda Voskuhl, Professor at the UCLA Department of Neurology and Director of UCLA’s Multiple Sclerosis Program. For the purposes of this interesting scientific inquiry, it was taken into account the well-known fact that during the second half of pregnancy, women with RRMS experience reduced episodes of relapse. And during this period the placenta produces the aforementioned estriol, increasing the hormone levels in the blood throughout the woman’s body. This protection during pregnancy occurs not only against multiple sclerosis, but also against other autoimmune diseases such as psoriasis and rheumatoid arthritis.
Voskuhl has speculated that the rise of ‘estriol in the blood could play a role in suppressing the immune system of a woman so that the fetus is not rejected as “foreign”, because it posseses half of it’s proteins from the father. The team led by Voskuhl, found that treatment with estriol, therefore, served a protective function.

In the laboratory, Voskuhl and her team have found that estriol has a dual effect against the disease; reducing the ability of immune cells to attack the brain and at the same time making brain cells more resistant to damage. In particular, researchers have shown that treatment with estriol improves cognition and prevents the atrophy of cognitive brain regions. It seems that during pregnancy, estriol is able to suppress the immune system and protect the brain, which is not only  additionally important to prevent rejection of the fetus, but it is also essential to protect the fetal brain during development. And while these two effects are naturally designed to protect the fetus, they can be exactly reproduced in women with MS.

“The beauty of estriol is that it is not a shot and can be taken in pill form, and also that it’s not a new drug. It has decades of safety behind it,” said Voskuhl. “Also, current MS treatments are very complex to manufacture. These findings hopefully will pave the way for oral, safe treatments that are more widely accessible, since estriol is simple and naturally occurring.”

Although several studies have provided rather strong evidence for the use of hormonal treatment in the course of the disease, there remains a need to conduct further studies to better understand the molecular mechanisms underlying the beneficial effects of treatment with hormones. In particular, we must establish the safety of hormonal treatment, especially in light of the well-known relationship between estrogen and breast and uterine cancer, and between testosterone and prostate cancer.

So we will just have to wait for future research. I, as always, will keep you updated.

Sources:
Coyle, P., 2000. Women’s Issues in Multiple Sclerosis: Diagnosis, Medical Management and Rehabilitation, J.S. Burks, K.P. Johnson (eds). Demos Medical Publishing, New York.

Darlington, C., 2002. Overview – Multiple Sclerosis and gender. Current Opinion in Investigational Drugs, 3 (6), 911-914.

Eikelenboom MJ, Killestein J, Uitdehaag BM, CH Polman. Sex differences in proinflammatory cytokine profiles of patients in progressive multiple sclerosis. Mult Scler. 2005; 11 (5): 520-3.

Giesser, B.S. et al., 1991. Multiple Sclerosis symptoms fluctuate During menstrual cycle. MS Exchange, 3 (5).

Gold SM, Voskuhl RR. Estrogen and testosterone therapies in multiple sclerosis. Prog Brain Res. 2009; 175: 239-51.

Tomassini V, Pozzilli C. Sex hormones, brain damage and clinical course of multiple sclerosis. J Neurol Sci. 2009; 286: 35-9.

Sandyk, R., 1995. Premenstrual exacerbation of Symptoms in Multiple Sclerosis is Attenuated by Treatment with Weak Electromagnetic Fields, International Journal of Neuroscience Volume 83, Issue 3-4.

Soldan SS, Alvarez Retuerto AI, Sicotte NL, Voskul RR. Immune modulation in multiple sclerosis patients treated with the pregnancy hormone estriol. J Neuroimmunol. 2004; 146: 209-15.

Zorgdrager, A. & De Keyser, D., 1996. Menstrually related worsening of symptoms of multiple sclerosis. The Journal of the Neurological Sciences, 149, 95-97.

https://mssociety.ca/en/pdf/MS_Womens_Health_En.pdf
http://www.northwestern.edu/newscenter/stories/2015/05/protecting-women-from-multiple-sclerosis.html
http://www.eurekalert.org/pub_releases/2015-11/uoc–sfo113015.php

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