Publications : General Interest Articles

NEW YORK, Feb 25 (Reuters Health) - Nearly half of all women over 40 are plagued with fibroids--benign tumors of the uterus. Now researchers have identified a gene defect in some women with a rare form of inherited fibroids, a discovery that could provide clues to the cause of the more common form of the condition.

Uterine fibroids usually lurk without symptoms. But they can grow as large as a cantaloupe, and interfere with childbirth. They can also prompt abnormal bleeding and if symptoms persist, they may need to be removed or treated. Fibroids are the number one cause of hysterectomy, a surgical removal of the uterus.

The cause of fibroids is unknown, though researchers suspect there might be a genetic component. Women in general have a lifetime risk of developing fibroids of almost 10%, but that risk rises to nearly 16% if their mother had fibroids and more than 26% if their sister is diagnosed with the tumors.

With their study, researchers led by Dr. Ian Tomlinson of the Imperial Cancer Research Fund, London, UK, and two other groups of researchers, looked at families with a rare, inherited condition in which they developed benign skin tumors and fibroids.

The investigators discovered that people with the disorder often had a mutation in a gene called fumarate hydratase (FH). According to Tomlinson, FH helps to provide fuel to cells and is one of several "housekeeping" genes that are expressed in every cell in the body. Defects in housekeeping genes are rare because their function is critical, and those born with a FH deficiency may not survive until adulthood.

In the study, the researchers obtained DNA samples from 42 members of families with the inherited skin and fibroid condition. In these families, the tumors begin to form between the ages of 20 and 35.

Tomlinson and colleagues found mutations in the FH gene in 25 of these 42 people, compared with no mutations in over 150 individuals without the disorder. This suggested that FH was, indeed, involved in causing fibroids--at least in these families, according to the report in the advance online publication of the journal Nature Genetics.

The researchers directly measured FH activity in the skin tumors of four of the study participants with the disease. They found that all of the tumors showed almost no FH activity compared with samples of normal skin, further identifying FH as a cause of the disorder.

In addition, three families the team examined had a tendency to develop kidney cancer as well as fibroids, suggesting that the FH gene defect may be linked not only to fibroids, but also to kidney cancer in some way.

"The identification of mutations in FH as a cause of fibroids may provide clues to understanding, treating and preventing the common form of this disease," the researchers conclude.

According to Tomlinson, the defect in FH suggests that metabolism, in which FH plays a key role, may be at the root of fibroids.

"Our hope is that when we or others have worked out the role of this gene and related genes...we can base medical therapies on this work, thus reducing the need for surgical treatment of fibroids," he told Reuters Health.

The next step is to determine what role FH plays in fibroids in women without an inherited condition. Tomlinson said he wants to examine "the relevance and importance of changes in FH to the large numbers of women in the general population who have fibroids."

"We have been anticipating the discovery of this gene and are very excited to learn that it has been identified," said Karen Gross, of the Center for Uterine Fibroids at Brigham and Women's Hospital and Harvard Medical School in Boston, Massachusetts. "Although fibroids are a major public health problem, research into causes and treatments, unfortunately, is limited. So, discovery of a fibroid-related gene has important implications for the field.

"It is important to note, however, that this gene has been shown to be involved in a specific hereditary fibroid-associated syndrome," said Gross, who has done research into fibroid genetics for four years. "It still remains to be determined whether mutations in this gene predisposes women to the development of sporadic uterine fibroid tumors."

SOURCE: Nature Genetics 2002;10.1038/ng849.

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CHICAGO (Reuters Health) Nov 26 - Results of a pilot study of MRI-guided focused ultrasound surgery (FUS) for leiomyoma of the uterus suggest that the investigational procedure is safe and effective, said Dr. Clare Tempany of Harvard Medical School.

Dr. Tempany said FUS "melted away" fibroids in nine patients who underwent the procedure at Brigham and Women's Hospital, Boston. She presented the study here at the 87th Scientific Assembly and Annual Meeting of the Radiological Society of North America.

In an interview with Reuters Health, Dr. Tempany said that all women in the pilot study went on to hysterectomy, "so we have pathological results to demonstrate that FUS caused necrosis in the fibroids." Early next year she will begin enrolling "20 to 30 women with symptomatic fibroids in a study of FUS as definitive treatment," she said.

Centers in Britain and Israel are also studying FUS for uterine fibroids, so a total of 28 women have undergone FUS treatment, Dr. Tempany explained. She said the treatment is very well tolerated. "One or two women have experienced some uterine cramping, two had skin blisters and one reported some bleeding." But most women come to the hospital "in the morning, lie on a table for 4 hours of treatment, and after that they get up and go home to resume normal lives."

She said FUS technology has been available since 1962 but "we needed MR guidance to make it practical. This is a perfect fit of two technologies." The FUS system is placed "inside the magnet," which acts like a magnifying glass to focus the ultrasound rays on the fibroid. Those rays "heat up the tissue, which cuts off the blood supply and causes the fibroid to necrose."

On pathologic examination the area of necrosis "exceeds the treatment area, which suggests that cutting off the blood supply in one area extends the therapeutic benefit," Dr. Tempany said.

She said FUS treatment is probably impractical for women with "15 to 20 fibroids, because the time to treat would be prohibitive." In her study women had one to five fibroids and treatment time averaged 4 hours. But Dr. Tempany added that eliminating symptoms "only requires treating the [specific] fibroid that causes bleeding or pain." As the technology develops, she predicted, it will be possible to pinpoint the symptomatic fibroid.

Her protocol requires that a radiologist be present "throughout the treatment," which makes it labor-intensive, but she estimated that it costs "only a couple of thousand dollars, which is less than surgery."

Dr. Tempany said her group is also studying FUS in breast cancer and next year plans a study of FUS for treatment of neurofibromatosis.

Insightec-TxSonics in Dallas, Texas, the maker of the FUS device, funded the study.

At a time when sheep cloning is making headlines around the world, gene mapping is routine and proceeding apace. Since 1983, while a postdoctoral fellow in the laboratory of Harvard Medical School Chairman of Genetics Philip Leder, MD, Morton has mapped hundreds of human genes. Today she is a participant in the Human Genome Project, an international effort to identify and locate all 100,000-plus genes by the year 2000. Much of Morton's energy is focused on genes that underlie a major health problem in American women: benign tumors of the uterus known as fibroids.

Present in as many as 77 percent of American women, fibroids are the leading cause of hysterectomy, or surgical removal of the womb, the most common surgical procedure after cesarean section. "These non-cancerous tumors account for more than 200,000 hysterectomies every year," Morton notes. An expert on tumor-causing genes, Morton happened upon the fibroid problem while setting up a clinical laboratory to examine solid tumors. "In talking with gynecologists," she says, "I found out that fibroids are the most common, least studied tumors in the world."

Many women never even know they have fibroids. But the tumors can cause excessive bleeding, severe pelvic pain, constipation and incontinence. Invaders of the womb, fibroids can also cause premature labor, spontaneous abortion and infertility. "Women don't like to complain about fibroids," observes Morton, explaining their status as an unspoken problem. "They don't make for good cocktail party conversation."Morton remembers the moment her team found the first fibroid gene, dubbed HMGIC, after months of sleuthing. "It felt like winning the lottery," she says. "The next step is to figure out what role the gene plays in fibroids' development. And the next step, down the road, is to see whether we can use that knowledge to come up with effective new medical treatments."

AS AN EIGHTH GRADER, Cynthia Morton got hooked on human genetics through a term paper on twinning. The project set her on the path to graduate school and advanced training at Children's Hospital and Harvard Medical School. In 1987, she came to Brigham and Women's Hospital to direct a clinical laboratory dedicated to analyzing human chromosomes. Serving not one but three medical centers-BWH, its Partners HealthCare System affiliate, the Massachusetts General Hospital, and Children's Hospital-the Cytogenetics Laboratory bridges the gap between the laboratory bench and the bedside. Here, technicians apply geneticists' rapidly accumulating knowledge to the diagnosis of chromosomal abnormalities.

Morton and colleagues use a wide variety of methods to screen patients for genetic abnormalities. Many patients are would-be parents; others are still in the womb. From the chromosomes of cells grown from blood or amniotic fluid, the staff can determine whether they are at risk for certain hereditary disorders.

Using computer imaging equipment introduced a few years ago, technicians can examine a patient's full complement of chromosomes on the screen. They look for numerical and gross structural changes-for example, three copies of chromosome 21, which indicates Down syndrome; or rearrangements of pieces of chromosomes, as in certain forms of leukemia. Such scramblings can yield clues about a patient's prognosis and guide physicians in selecting a course of therapy.

Through the identification and molecular analysis of chromosomal aberrations found in fibroids, Morton hopes to shed light on these tumors' varied behavior and troubles they cause (see sidebar on page 19). A long-run goal is to find a drug that counteracts the gene defects and shrinks or eradicates the tumors, providing an effective alternative to surgery.In early studies, Morton and colleagues discovered that in some fibroids, a piece of chromosome 12 had traded places with part of chromosome 14. "We began looking for our fibroid gene right around the breakpoint," explains Morton, beginning with chromosome 12, since that chromosome is known to be damaged in many kinds of tumors.

Morton believes that HMGIC regulates the activities of other genes. When damaged, HMGIC causes a string of genes to go awry, perhaps sparking excess production of substances known as growth factors. The resulting cell growth and division may be unruly indeed; the largest fibroid ever recorded weighed 140 pounds.

Interestingly, Morton notes, these tumors stop short of spreading in the way that cancerous tumors do. Uncovering the steps by which fibroids form and grow could shed light on the crucial difference between benign tumors, which aren't necessarily life-threatening, and cancerous tumors, which spread throughout the body.

In the short term, Morton predicts, researchers will focus on finding a way to counteract the effects of the HMGIC gene in fibroids, to limit growth-factor production and stop tumors from growing. In the long run, gene therapy holds out hope for introducing repaired genes into the body. To date, scientists have logged few successes with this approach, but the field is in its infancy-just as human genetics was in the 1980s.

At BWH, using knowledge gained in the laboratory to improve patient care is known as "translational" research. In an effort to enhance the diagnosis, prevention and treatment of disease and birth defects, Morton is working to bring BWH geneticists and clinicians closer together.

The potential rewards of such a collaboration are clear. "I didn't set out specifically to tackle a major women's health issue," says Morton. "But as a woman, I'm glad to be doing just that."

Alternatives to hysterectomy?

Scientists and clinicians search for new medical treatments

Elizabeth A. Stewart, M.D. outlines nonsurgical fibroid treatment options, including the drug pirfenidone, to a patient.

For years, hysterectomy has been routinely recommended for gynecological maladies ranging from pain to hemorrhaging to an abnormal pap smear. Although the reasons for symptoms weren't always clear, the response was uniform: Take it out.

"Doctors used to think that once childbearing was over, it made no sense to keep the uterus, and they saw no harm in removing it," says Brian Walsh, MD, Chief of Surgical Gynecology at Brigham and Women's. But times have changed. "While hysterectomy offers immediate relief from painful fibroids and is the only effective option for many women," he says, "it is major surgery, requiring six weeks' recuperation and the loss of work and family time."

And that's not all, notes Madelon Ali, MS, RN, CS, a gynecologic nurse who counsels women considering hysterectomy. "The uterus is integral to a woman's body image," she says. Like the breasts, "it is so much a part of womanhood that many women are psychologically unprepared to part with it."

New research suggests that the uterus may in fact have roles beyond reproduction. Preliminary evidence suggests that it is an important part of the hormone system-a source of natural pain killers, for example, as well as substances that reduce blood clotting. Currently, alternatives to hysterectomy are limited. Myomectomy, or surgical removal of fibroids themselves, is an option for some women that can frequently be performed through the vagina. Some women benefit from medications that shrink fibroids by blocking hormone production.

A new generation of fibroid treatments will be based on understanding how fibroids grow and develop-the sort of knowledge Cynthia Morton, PhD, and colleagues are amassing in the laboratory. Obstetrician-gynecologist Elizabeth A. Stewart, MD, plans to conduct tests of a new drug, pirfenidone, which blocks a chemical that helps fibroids grow. Morton will analyze chromosomes from patients' tumors following their treatment to explore pirfenidone's effects. "The more you understand fibroids' biological behavior, the better you're equipped to find a treatment that works," Stewart says.

New Techniques Expand Treatment Options to Help Women Avoid Major Surgery

By Gail McBride
Special to The Washington Post
Tuesday, April 6, 1999; Page Z09

They may affect up to half of women of childbearing age and can cause bleeding, pain and perhaps infertility. Yet until recently, medical research paid scant attention to those benign growths in the uterus called fibroids.

Now a range of new procedures--from a technique that blocks blood vessels in the uterus to experimental drugs--may allow many women more options besides major surgery to treat uterine fibroids. For years, the principal treatment has been hysterectomy, in which the whole uterus is removed, or another operation called myomectomy in which the individual fibroids are cut out. But increasingly it looks like fibroids may be forced into submission in other ways.

The newest treatment shrinks fibroids by cutting off their blood supply. Called uterine artery embolization (UAE), it was first performed in Paris in 1991 by gynecologist Jacques-Henri Ravina. Today it is done in many countries, including the United States.

In this procedure, a catheter is inserted into an artery in the groin. With X-ray guidance, a specially trained "interventional radiologist" directs the catheter into the two arteries that supply the uterus and the fibroids with blood. Small plastic or gel particles are injected through the catheter into the arteries, causing the blood to clot. The result is closure of the arteries, marked shrinkage of the fibroids and cessation of bleeding.

The procedure takes 60 to 90 minutes, according to interventional radiologist Scott Goodwin, who with gynecologist Bruce McLucas has performed more than 200 of them at UCLA Medical Center. Patients are sedated but do not have to undergo general anesthesia. Afterward, there is considerable cramp-like pelvic pain, and pain medication is necessary. Infections occasionally occur. Patients are encouraged to take a week off from work or other daily routines.

For some women, this treatment is a welcome alternative to a hysterectomy. "My uterus was full of fibroids, and I had been to four or five gynecologists," said Susan DeBoismilon of Orinda, Calif. "They all urged me to have a hysterectomy." Then she heard about McLucas' work. "The procedure made sense to me, and I had it done a month later. It's definitely the best course."

Goodwin said that about 80 percent of the 2,000 women worldwide who underwent UAE have had relief of symptoms, shrinkage of fibroids and no need for a hysterectomy.

Six patients of Goodwin and McLucas have become pregnant and had normal or C-section deliveries after UAE, but no one really has kept close track of patients' attempts to get pregnant until very recently. There is some concern, Goodwin said, that the blood supply to the ovaries may be damaged by UAE in 1 percent to 2 percent of cases, and he warns women about this if they want to maintain fertility.

Until the uncertainties about long-term results and pregnancy are resolved, the procedure "probably will be best for women at the end of their reproductive lives," said Bryan Cowan, professor of obstetrics and gynecology and director of the division of reproductive endocrinology at the University of Mississippi in Jackson.

"On the other hand, someone needs to be out there doing new procedures."

Another relatively new procedure destroys fibroids by zapping them with electricity or a laser. Called myolysis, it was introduced in the United States in 1990 by gynecologist Herbert Goldfarb of Montclair, N.J., and Manhattan.

In this approach, a woman first takes drugs such as Lupron to suppress the production of estrogen, known to enlarge fibroids, for about three months. Then after surgery to remove the uterus's inner layer, the patient undergoes a laparoscopic procedure, in which the surgeon makes small incisions in the abdomen and uses tiny instruments employing magnification to guide the operation.

With the patient under general anesthesia, each fibroid is treated individually by repeated application of an electric current (which Goldfarb uses) or a high-intensity laser beam that destroys cells on contact. There is some pain and discomfort with the one-day procedure, Goldfarb said, although less than with UAE. Goldfarb reports a success rate of nearly 90 percent in the 400 patients he has treated.

The problem with myolysis is that scar tissue may form after the surgery and entangle internal structures, including fallopian tubes. This can interfere with pregnancy. Some gynecologists advise women who want to become pregnant to do so as soon as possible after myolysis.

Charles March, professor of obstetrics and gynecology at the University of Southern California, is cautious about both myolysis and UAE. "They are probably best suited to carefully selected patients who are not concerned about fertility or who don't want to undergo major abdominal surgery," he said. "Certainly, only doctors with a lot of experience should be doing them."

Meanwhile, researchers are also looking into gene therapy and experimental drugs. At Brigham and Women's Hospital's Center for Uterine Fibroids in Boston, cell biologist Romana Nowak is studying two substances called growth factors that stimulate the formation of collagen or new blood vessels and accelerate the growth of tumors. Several agents that inhibit both growth factors are being considered for fibroid treatment, Nowak said.

Just what causes fibroids is not known. Cynthia Morton, a molecular geneticist at Harvard Medical School and Brigham and Women's Hospital is looking for genetic clues. She and her colleagues are investigating two of the chromosomal abnormalities that occur in 40 percent of fibroids. In addition, they and others at the Center for Uterine Fibroids are recruiting sisters or other close family members who have fibroids in an effort to identify a common genetic factor.

Doctors point out that many women with fibroids have no symptoms. As March noted, "it's only necessary to remove fibroids when they are causing symptoms." Many women with symptomatic fibroids try to hang on until menopause, hoping the fibroids will shrink as their hormone levels decrease. Fibroids are sensitive to both estrogen and progesterone, said cell biologist Janet Andersen of the State University of New York at Stony Brook. After menopause, when levels of these hormones decline, many women experience relief.

For women whose symptoms require treatment, hysterectomy remains the only true cure: no uterus, no fibroids. However, hysterectomy carries the risks of all major surgical procedures. Also, recovery requires a lot of "down time," and some patients contend there are lasting adverse effects on health and sexual function.

Moreover, many women just don't want to lose their uteri. The only surgical alternative is myomectomy, but this operation is not always successful. Blood transfusions may be needed during surgery, and fibroids recur in 30 percent of cases. In addition, the operation can lead to problems from scar tissue.

For women who still want children, myomectomy has been the only route, although Caesarean section is required for delivery because the uterus is too weak. Now there are alternatives.

Are they better than myomectomy? "Let's put it this way," said McLucas. "If myomectomy were a better procedure, I wouldn't be advocating UAE--or even myolysis. New procedures may come along in a few years, but right now, if I were a woman who wanted to become pregnant, I'd consider UAE as my first alternative."

Resources

There are at least three fibroid web sites in the Internet:

* www.fibroids.net is maintained by the Center for Uterine Fibroids, Brigham and Women's Hospital, Boston.

* www.fibroidcorner.com is maintained by gynecologist Francis L. Hutchins Jr. and interventional radiologist Robert L. Worthington-Kirsch, both of the Philadelphia area.

* www.fibroids.org is maintained by the UCLA Medical Group Uterine Artery Embolization team.

Fibroid Tumors at a Glance

Uterine fibroids are benign tumors. They occur in more than 20 percent of women of childbearing age, although symptoms do not generally develop until the patient is in her late thirties or forties.

Fibroids are the most common cause of hysterectomies. They are named for their position in the uterus. Submucosal or intramural fibroids are often associated with abnormal bleeding, while pelvic and back pain are frequently caused by intramural and subserosal fibroids.

Source: Georgetown University Medical Center

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