Task Force Takes a Closer Look at the GENDER GAP.

MS, as well as other autoimmune diseases such as rheumatoid arthritis (RA) and systematic lupus erythematosis (usually called lupus), affects many more women than men. There are other noticeable differences in the ways women and men tend to experience MS in terms of symptoms, severity, and disease patterns. But questions about MS and sex difference have not received major research attention in the past. There is a large gender gap in scientific knowledge of MS.

To redress this problem, the National MS Society convened a Task Force on Gender, MS, and Autoimmunity, with Dr. Caroline C. Whitacre, professor of medical microbiology and immunology at Ohio State University, as its chair. The task force reviewed all available data pertaining to sex difference and MS. They then made specific recommendations for research directions. The full report, published in the February 26, 1999 issue of Science, the Journal of the American Association for the Advancement of Science, has been widely circulated in the MS research community.

Five targets for research

The task force identified 5 scientific questions for top research priority:

* Immune response 

Preliminary studies suggest that, in general, women have higher levels of certain antibodies and particular immune system cells, and more vigorous immune responses. The task force proposed that the immune responses of women and men be studied comparatively.

* Sex hormone mechanisms

In women, a certain level of one form of the hormone estrogen seems to make the immune system more responsive, while a higher level of the same hormone apparently inhibits immune responses. Some animal studies have shown that the testosterone hormone can reduce the severity of the animal model of MS. A small human study also suggested that some men with MS might have lower than average levels of this hormone. The task force asked for more information on how all hormones--estrogens, progesterone, testosterone, prolactin, growth hormone, insulin-like growth factor I, and others--interact with the immune system in women and men.

* Menstruation, pregnancy and menopause

A comparison of how women with MS, RA, and lupus experience menstruation, pregnancy, and menopause offers some insight into the way hormones interact with the immune system. In MS and RA, women often report a worsening of symptoms right before menses. A few studies suggested that women who used the older oral contraceptives with high estrogen levels may have been more protected from developing MS or RA. In both diseases, women have a well-documented decrease in disease activity during pregnancy. In contrast, some women with lupus have more disease activity during pregnancy.

All this persuaded the task force to recommend broad clinical studies of the fluctuating levels of sex hormones and their effects on the development and course of autoimmune diseases in women.

* Genetic factors

The gene-mapping studies done so far suggest that several autoimmune diseases share the same "candidate gene", although each particular disease almost certainly has other genes that are responsible for that susceptibility. The task force asked for further research to determine whether gender-related autoimmune responses are inherited.

* Sex differences and disease course

Statistical differences in autoimmune disease between the sexes have been known for a long time. In MS, women tend to develop symptoms at an earlier age. Men tend to have more progressive and severe forms of MS. The task force would like researchers to find out whether there are sex differences in response to specific therapies, and whether any of the sex hormones themselves might offer effective therapies.

New gender research projects underway

As soon as the recommendations were delivered, the Society began actively encouraging research on gender differences in MS. The Society is giving supplementary funds to any current research project that adds in the exploration of sex differences; 12 grantees have received extra funds for doing so. Five research projects that will directly address some of the questions around MS and sex differences have also been approved for funding.

Task force chair Caroline Whitacre, PhD, is directing a large study of sex differences and disease severity and susceptibility in mice and rats with EAE (an animal model of MS). EAE exhibits a sex bias that is similar to the human disease, and hopefully Dr. Whitacre's experiments will provide insights into why.

Three other Society-funded projects are also looking at animal models of MS. Byung Kim, PhD, of Northwestern University in Illinois, and Halina Offner, PhD, of Oregon Health Sciences University, are studying the influence of sex hormones on disease severity and the influence of sex hormones on susceptibility in MS-like diseases in laboratory animals. Cory Teuscher, PhD, of the University of Illinois at Urbana-Champaign, is looking for genes that control sex-based differences in susceptibility to an MS-like disease.

A pilot clinical trial of estriol, a form of estrogen, is being conducted by Rhonda Voskuhl, MD, at UCLA. Estriol is a pre-dominant hormone in pregnancy, and this trial is investigating its potential value and safety as a treatment for MS.

RELATED ARTICLE: A possible bridge over the Gender Gap

Following the recommendations of the Task Force on Gender, MS, and Autoimmunity, many scientists are turning their attention to the complex interactions of sex hormones and MS. Dr. Rhonda Voskuhl's microscope was already focused on the issue. She is currently conducting a small clinical trial of the hormone estriol with funding from the Society to determine whether it might be a safe and effective treatment for women with MS.

Dr. Voskuhl, of the department of Neurology, School of Medicine at UCLA, will be the keynote research speaker at the National MS Society's National Leadership Conference in Anaheim, California, this November. For the first time ever, this presentation will be web-cast live, allowing those who aren't at the conference to hear the talk. Afterwards, a panel of experts will answer questions from the attending audience and via e-mail. The experts will include Dr. Voskuhl, Dr. Leslie Weiner, MS researcher at the University of Southern California, and Dr. Stephen Reingold, vice president of Research Programs at the National MS Society. The session will then be archived on the site.

Dr. Voskuhl will discuss the research on sex hormones to date, including the estriol trial. Research on pregnancy and MS has shown that women have fewer symptoms and fewer attacks in the third trimester. Dr. Voskuhl worked with mice with EAE, the animal model of MS, to isolate the hormone that may be responsible for this decrease in disease activity: estriol, a form of estrogen that is only present during pregnancy and which seems to have anti-inflammatory properties. If results from her small clinical trial, which involves 12 nonpregnant women who have relapsing-remitting or secondary-progressive MS, look promising, larger clinical trials will follow.

Access Dr. Rhonda Voskuhl's webcast live from the National Leadership Conference on Friday, November 12, 1999, from 4 to 7 pm ET (1 to 4 pm PT) at the Society's web site (www.nmss.org).

RELATED ARTICLE: Fact sheet on hormones

Gender Task Force member Dr. Barbara Giesser, a neurologist who specializes in MS, answers some of the most common questions about MS and hormones in the Society's new 4-page hand-out, "Hormones in Multiple Sclerosis". The gender gap in MS knowledge means that conclusive answers to many questions are in short supply--at least for now.

Dr. Giesser's overview tells what's currently known, what preliminary studies seem to suggest, and what isn't yet known to help people answer their practical, real-life questions. Dr. Giesser's overview offers mostly reassuring advice about issues such as breast-feeding (it seems to be OK), the second half of the monthly cycle (yes, many women report increased MS symptoms then), and fertility (having MS doesn't affect it).

The fact sheet is available from National MS Society chapters by calling 1-800-FIGHT MS, option #1, or it can be downloaded from the Society's web site at www.nmss.org (click on "MS Info", then "Publications", then "Booklets and Brochures").

RELATED ARTICLE: Rauh family gift to fill the gender gap

The Rauh family of Cincinnati has pledged a 5-year leadership gift of $1 million to jump-start research on key questions about the differences in MS between men and women. Answers should help clarify the basic causes of MS. Other scientists will be spurred by the Task Force recommendations to design relevant studies. Other donors will join the Rauh family to keep a pool of research funds available.(*)

Margie and Louis Rauh were introduced to MS when their daughter Beth, then age 30, was told she had probable MS. That was 4 years ago.

"We have 4 granddaughters," said Margie Rauh. "It's critical to see if we can find out why MS happens so many more times to young women. In a way, our interest is purely selfish, but answers would benefit a lot of people."

MS pushed Beth Rauh into a very early retirement, but she's unlikely to sit on the sidelines. She, her partner Lisa Campbell, and her 8-year-old daughter Kate all volunteer for Operation Smile, a nonprofit group that sends surgeons to Third World countries to fix childhood facial defects like cleft palate. And Beth Rauh plans to be involved in seeing that her family's gift encourages other potential donors.

"Solving the MS puzzle through this type of research is very important to me. I'm also concerned about building programs for other people with MS. I have a great partner. Lisa has been in this with me all the way. I have a wonderful daughter, great parents, good friends. I even have good disability insurance. But so many others don't have my freedom from worry." Indeed, the Rauh family has already acted on this with important gifts to the Southwest Ohio/Northern Kentucky Chapter.

(*) To discuss partnering with the Rauh family in funding this research, call John Kivimaki, vice president for Major Gifts. He can be reached at 303-813-6628

Lorna Smedman is managing editor of this magazine.