July 22, 2002
Scientists at the National Institute of Child Health and Human Development (NICHD) and the University of South Florida, Tampa, have come one step closer to identifying the cause of uterine fibroids - a condition that affects up to 70 percent of all reproductive age women and can lead to heavy menstrual bleeding, pain, and in some cases, infertility.
Specifically, the researchers identified 145 genes that are involved in the development and growth of uterine fibroids. Most of these genes were not previously known to have a function in the human uterus. The study, which also provides evidence that susceptibility to uterine fibroids is passed from father to daughter, appears in the July issue of Fertility and Sterility.
"Although uterine fibroids are extremely common, little is known about why and how they develop," said Duane Alexander, M.D., Director of the NICHD. "This study helps us better understand how fibroids grow and may lead to the development of a variety of new therapies to treat women who have them."
Uterine fibroids are non-cancerous tumors in the uterus that are made up of smooth muscle cells and connective tissue. While some fibroids are very small, others can cause the uterus to stretch to the size of a five or six month pregnancy. Although scientists know that the female hormones estrogen and progesterone play a role in the growth of fibroids, they have been unable to determine what causes uterine fibroids to develop.
In the current study, the researchers used a new technology, called microarray analysis, to identify genes involved in the development and growth of uterine fibroids. Microarray analysis is unique because it allows researchers to screen a large number of genes at the same time. By examining many genes at once, scientists can identify important genes more quickly than with traditional methods of screening single genes at a time.
Describing the importance of this new technology, John Tsibris, Ph.D., Professor of Obstetrics and Gynecology at the University of South Florida College of Medicine and co-author of the study, said, "In the quest to identify the cause of uterine fibroids, microarray analysis presents us with the first satellite photos of the battlefield where, before now, binoculars were all we had for enemy reconnaissance."
Like an instruction manual, a gene contains information that tells the body how to make one or more specific proteins. A protein, in turn, performs a specific activity or group of activities within the body's cells. The process by which a protein or group of proteins is made from a gene's instructions is called gene expression. To identify genes that were abnormally expressed in fibroid tissue, the researchers obtained uterine tissue samples from nine women with uterine fibroids who had undergone hysterectomy (removal of the uterus). The researchers examined 12,000 genes in both fibroid tissue and healthy myometrium (uterine muscle) from each patient and looked for genes in the uterine fibroid tissue that had more than a two-fold increase or decrease in gene expression as compared to healthy myometrium. The researchers identified 67 genes that were upregulated (produced more messenger RNA) in fibroid tissue as compared to normal uterine muscle tissue and 78 genes that were downregulated (produced less messenger RNA). Messenger RNA serves as a template for the manufacture of proteins in the body.
Many of the upregulated genes identified in the study are involved in tissue differentiation (specialization of function) and growth. "This result suggests that cells that would normally give rise to uterine muscle may differentiate abnormally and cause fibroids," said James Segars, M.D., a member of NICHD's Pediatric and Reproductive Endocrinology Branch and a co-author of the study.
Many of the downregulated genes identified in the study are involved in uterine contractions that occur normally in women. The researchers hypothesize that the underexpression of these genes in uterine fibroids might explain why fibroid tissue does not contract, but instead, grows abnormally.
The researchers also discovered three "paternally expressed" imprinted genes that are upregulated in fibroids as compared to normal myometrium. In paternally expressed imprinted genes, the gene copy received from the father is expressed, while the gene copy received from the mother is not expressed. If these three genes are found to be essential for fibroid growth and development, this implies that a woman's susceptibility to fibroids is determined by her father.
"The results of this study are important because they fill some gaps in our knowledge of gynecologic diseases by uncovering numerous promising, but non traditional, regulators of fibroid development and growth. While before, we thought that the hormones estrogen and progesterone were the main factors involved in fibroid development, this study shows us that they are only part of the story," said Dr. Tsibris.
Next, the researchers plan to study the genes they identified to see if one of them appears to be a "master regulator" of tumor growth. Once they determine how the identified genes and their protein products "feed" uterine fibroids, they hope to develop drugs to counteract them, shrinking the fibroids without surgery and with few side effects.
The researchers noted that up to 70 percent of all reproductive age women and an even greater percentage of African-American women may have uterine fibroids. In fact, just under a quarter of African-American women will have a hysterectomy in their lifetimes as a result of complications from uterine fibroids. Although many women who have fibroids have few or no symptoms, it is estimated that a quarter of all women in their thirties and forties seek medical care for the heavy menstrual bleeding, pain, or infertility, that fibroids can cause.
The NICHD is part of the National Institutes of Health, the biomedical research arm of the federal government. The Institute sponsors research on development, before and after birth; maternal, child, and family health; reproductive biology and population issues; and medical rehabilitation. NICHD publications, as well as information about the Institute, are available from the NICHD Web site, http://www.nichd.nih.gov, or from the NICHD Information Resource Center, 1-800-370-2943; e-mail NICHDIRC@mail.nih.gov.