Figuring out fibroids: studies examine a common, yet mysterious, tumor.

There was a lot that Cynthia Morton didn't know about uterine fibroids when she began studying them in 1989. She didn't know, for instance, that she already had or would soon develop one. That revelation came during her pregnancy in 1991, when a fibroid showed up on an ultrasound test she had received to monitor the pregnancy. For Morton, a geneticist at Brigham and Women's Hospital in Boston, the mass of fibrous, abnormal tissue in her uterus has not caused any noticeable problems. But some women who develop fibroids have trouble getting pregnant, and others experience heavy menstrual bleeding and intense pain that can be alleviated only by surgical removal of the uterus. In the United States, fibroids are the leading cause for that operation, a hysterectomy.

Like a cancer, a fibroid arises from a single abnormal cell that multiplies and forms a tumor. In contrast to malignant tumors, however, fibroids rarely spread to other parts of the body but rather remain in the uterus. There, one fibroid or several independent fibroids can crop up at any point during a woman's reproductive years and can grow many centimeters across.

Some escape detection or get discovered incidentally, as Morton's did. Others cause the uterus to expand to a size that isn't normally reached until a woman is 4 to 5 months into a pregnancy.

The uterus' pressure can cause back pain, constipation, and frequent urination, says Elizabeth A. Stewart, also of Brigham and Women's Hospital. Furthermore, she says, "many women have such heavy bleeding that it really interferes with their ability to work and care for their children and go about the tasks of daily living."

"A lot of health care dollars are spent dealing with fibroids," Morton adds. For example, hysterectomies to remove fibroids cost more than $1 billion per year nationally, she says.

In recent years, Morton, Stewart, and other researchers have made progress toward understanding who gets fibroids, which fibroids are most likely to cause problems, and how certain genetic factors may allow fibroids to develop. The scientists' data suggest that an overwhelming majority of women develop at least one fibroid during their lives. For reasons that remain poorly understood, factors such as race and reproductive history appear to influence a woman's risk of developing fibroids. Furthermore, relatively small fibroids appear more likely than larger ones to cause health problems, and fibroids may reduce fertility even when they aren't symptomatic. Finally, scientists have identified the first genetic factor to be linked to fibroids.

BLACK AND WHITE? Black women are about twice as likely as white women to have a hysterectomy because of fibroids, surgical records show. Epidemiologist Donna Day Baird of the National Institute of Environmental Health Sciences in Research Triangle Park, N.C., and her colleagues began in 1996 to explore this phenomenon and other mysteries surrounding fibroids.

Baird's team contacted 1,364 black and white women ages 35 to 49 who were members of a health insurance plan in Washington, D.C. Through interviews, medical records, and ultrasound scans, the researchers determined which of the women had at least one fibroid and how large the tumors were. Ultrasound can identify fibroids even if they don't cause symptoms and might escape a physician's notice during a routine exam.

Among the oldest women in the study, more than 80 percent of blacks and nearly 70 percent of whites had developed at least one fibroid during their lives. While the likelihood of having fibroids rises with age for all women, blacks tended to develop the tumors earlier in life than whites did, the researchers reported in the January 2003 American Journal of Obstetrics and Gynecology.

Unfortunately, there is no known measure that women can take to prevent fibroids. "We don't know enough about [controllable] risk factors," Baird says. Nevertheless, age, race, and other demographic traits associated with fibroids offer clues as to their causes. For example, some data have suggested that female sex hormones spur the growth of fibroids. A woman's exposure to the hormones depends in part on her reproductive history, which influences how many times she menstruates in a lifetime. Being pregnant and breastfeeding reduce the number of menstrual cycles.

Each menstrual cycle exposes uterine tissues to fluctuating concentrations of several sex hormones, and such hormonal swings can lead cells to change in harmful ways, says Baird. A woman's chances of developing breast and ovarian cancers, for example, are related to the number of menstrual cycles she has experienced. But no clear relationship between sex hormones and fibroid development has emerged.

To further investigate fibroids and reproductive history, epidemiologist Lauren A. Wise of Boston University and her colleagues contacted tens of thousands of women, mainly subscribers to Essence, a magazine aimed at black women. The effort yielded nearly 23,000 study participants who were black, had never had a hysterectomy, hadn't yet experienced menopause, and had never been diagnosed with a fibroid.

The researchers gathered data on each woman, including her age, weight, height, and educational background; whether she smoked; when and how frequently she had given birth; and what methods of birth control she had used, if any. They also looked at some volunteers' medical records. The researchers followed the women from 1995 to 2001 to see which of them would develop fibroids.

Among these women, risk was elevated in individuals who began menstruating at an early age, Wise's team reported in the February American Journal of Epidemiology. Mothers were less likely to develop fibroids than were women who never had children, but how many children a woman had didn't seem important.

Among mothers, those who had their first child before age 20 were almost twice as likely to develop fibroids as were those who delayed having kids until age 30 or later. Also, the length of time that had passed since a woman last gave birth was proportional to her risk of fibroids, Wise's team found.

Neither how long a mother breast-feeds her babies nor the use of oral contraceptives has apparent influence on fibroid risk, the researchers reported.

These observations indicate that reproductive history affects fibroids risk, but they don't reveal a consistent relationship between risk and exposure to sex hormones, Wise says.

Traditionally, doctors have considered pregnancy the time when women tend to develop fibroids. That notion gave rise to the hypothesis that the hormones present during gestation "jump-start" fibroids, says Katherine E. Hartmann of the University of North Carolina at Chapel Hill.

But Wise's study and other recent data suggest that pregnancy causes no increase in risk. Instead, Hartmann says, fibroids may simply get noticed most often during pregnancy because obstetricians examine expectant mothers carefully and the swelling womb can reveal the growths.

A LITTLE PROBLEM What makes fibroids form or grow to cause trouble remains a "real mystery," says Baird, but she's optimistic that answers will come. "Eventually," she predicts, "we'll understand enough that we may well be able to prevent fibroids from forming."

In the short term, she says, doctors may develop ways to stop new fibroids from causing problems. With ultrasound tests, it's already possible to spot fibroids when they're small, but doctors still can't do much to neutralize them, short of invasive treatments.

To avoid fertility problems, finding small fibroids may be more imperative than finding larger ones. Baird, Hartmann, and their colleagues recently used ultrasound to detect fibroids among some 1,600 women who had recently become pregnant. The researchers pinpointed the location and determined the size of each fibroid they found and then followed the women to see which ones had successful pregnancies.

Fibroids that jut into the uterine cavity increase the risk of spontaneous abortion, the researchers found. By altering the inner contours of the uterus, those tumors may interfere with the growth of the fetus, the team speculates.

However, many fibroids grow embedded in the uterine muscle and don't project into the uterine space. In the muscle, fibroids with diameters smaller than 3 cm increase miscarriage risk, Hartmann and her colleagues reported in Houston last March at the annual meeting of the Society of Gynecologic Investigation. In contrast, Hartmann says, larger fibroids don't.

"Counter to our clinical instinct, those are not the fibroids that are associated with problems," Hartmann says. "Women can likely relax about bigger fibroids that aren't in contact with the lining of the uterus."

Researchers are now focusing on the characteristics that might vary among fibroids. "Clearly, the smaller ones behave differently than the larger ones," says Hartmann. "The larger ones are old and dormant. The smaller ones are more active." So far, however, researchers haven't discovered secretions coming from fibroids or other indicators of a fibroid's activity, other than growth.

Hartman asks, "Is it really the fibroid that's causing the problem?" Maybe some characteristics of a uterus both permit fibroids to form and undermine pregnancy.

BACK TO THE BASICS To understand how fibroids can develop, some researchers are exploring the tumors' genetics and biochemistry. Two years ago, researchers discovered a genetic defect that causes a rare syndrome characterized by kidney cancer, skin tumors, and, in women, numerous fibroids (SN: 3/9/02, p. 149). The gene behind the syndrome is called FH because it produces fumarate hydratase, an enzyme that's important for breaking down glucose to produce energy.

To see whether the FH gene influences susceptibility to fibroids in the general population, Morton, Stewart, and their colleagues examined genetic markers from several people in each of 123 families that included women with fibroids.

In an upcoming Genes, Chromosomes, and Cancer, the researchers report that inheriting unusual forms of FH appears to increase a woman's risk of being diagnosed with fibroids by the age of 40. The scientists also note that the majority of fibroids found in women having those FH varieties contain cells that lack one of the two copies of FH that normal cells have.

"Fumarate hydratase is the first [identified biochemical] risk factor in the general population," Morton says. Investigating why fibroids often result from genetic errors that distort this enzyme could help scientists understand why fibroids develop.

But the implicated FH mutations are too rare to explain most cases of fibroids, Morton says. Moreover, they can't account for racial differences in the prevalence of fibroids.

"This is not the major gene that we're hoping to find that puts black women at risk," Morton says. Her team is currently recruiting pairs of sisters with and without fibroids to identify other genes involved in the tumors' formation.

While some scientists are pursuing the causes of fibroids, others are working to improve treatments. Although hysterectomy is the only permanent cure, there are other options for many women, says Stewart. These include myomectomy, or surgical removal of only the portion of a uterus containing a fibroid, and uterine-artery embolization, in which a physician injects the uterus with chemicals that block the fibroid's blood supply. These techniques preserve at least part of the uterus, but new fibroids may arise later.

In June, an advisory group recommended that the Food and Drug Administration approve a noninvasive treatment already being used in some other countries, in which focused waves of ultrasound heat and kill fibroid cells.

In the future, Stewart says, fibroids might be treated with drugs that alter the body's response to sex hormones.

But for now, the standard treatment for an asymptomatic fibroid remains none at all. "We're ages from being able to tell a patient and her doctor whether they should do something about that fibroid," Hartmann says.

That could change as the medical understanding of fibroids improves. "Ultrasound is very good at identifying small [fibroids]," Baird notes. "If we had a way to treat small tumors before they cause health problems, there would never be hysterectomies for fibroids," she says.