Institute Activities and Advances
Through its intramural and extramural organizational units, the NICHD supports and conducts a broad range of research on uterine fibroids. Short descriptions of this research are included below.
Genetic Cause of Infertility Associated with Uterine Fibroids
Uterine fibroids are tumors that arise within the wall of the uterus. Although they can make it difficult for a woman to get pregnant or maintain a pregnancy, scientists do not fully understand exactly how fibroids affect fertility.
A set of genes known as the tuberous sclerosis complex (TSC) can cause noncancerous tumors (like fibroids) to grow. To determine whether TSC genes were involved in infertility related to fibroids, scientists supported by the Gynecologic Health and Disease Branch (GHDB) used a mouse model of TSC. They compared normal mice with mice lacking TSC and looked for differences throughout the reproductive system.
The scientists found that TSC was involved in several parts of different reproductive processes. For example, in mice without the TSC genes, many egg cells did not mature properly. Egg cells that did mature correctly were able to be fertilized, but they could not exit the fallopian tube to enter the uterus for implantation. The results from this study indicate that any disruption to the function of TSC could likely lead to infertility. (PMID: 22128018)
Impact of Uterine Fibroids
To assess the impact of fibroids on women's health and quality of life, GHDB-supported researchers surveyed nearly 1,000 women in the United States who reported having uterine fibroids. On average, the women reported having had fibroids for between 6 to 8 years. Many women did not seek treatment right away; only 25% of women sought treatment within the 1st year of experiencing symptoms. Most women reported that they tried to manage their symptoms themselves before seeking treatment. However, the majority of women with fibroids reported symptoms including backache or leg pains, fatigue, and pelvic pain. Some women also reported that having fibroids interfered with their daily and social activities and affected their relationships with their family. Almost 1/3 of women with fibroids who were employed reported missing work due to symptoms of fibroids. Women expressed a strong desire for treatments that did not require hysterectomy, whether or not they intended to have more children. (PMID: 23891629)
Potential Drug Treatment for Uterine Fibroids Shows Promise in Early Clinical Tests
Uterine fibroids are the most common noncancerous tumors in women of childbearing age. The fibroids are made of muscle cells and other tissues that grow within and around the wall of the uterus. Fibroids can cause pain, bleeding, and reproductive problems, including infertility.
Surgery remains the main treatment option. However, NICHD researchers have been testing a new potential drug treatment that can treat fibroids without surgery. In a small-scale randomized clinical trial, scientists supported by the Fertility and Infertility (FI) Branch administered the drug to 42 women suffering from fibroids. They found that women who received the drug treatment showed reduced fibroid size, decreased bleeding, and improved quality of life. The medication was well tolerated.1,2
This medication represents a new approach to treat fibroids, especially in women who wish to preserve their fertility. It has already been approved for use in Europe, and an application for approval in the United States is being prepared. (PMID: 21330545)
Race and Postpartum Birth Control Method Are Associated with Natural Shrinking of Uterine Fibroids
While some women with fibroids may have no symptoms, others may experience infertility, bleeding, and/or pain. In many women, fibroids may be eliminated or decrease in size during pregnancy or in the postpartum period. Understanding why fibroids naturally shrink during pregnancy may help scientists develop new treatments for women with fibroids who are not pregnant.
To analyze the factors that might help fibroids shrink in pregnancy, researchers supported by the Pregnancy and Perinatology Branch studied more than 200 women with fibroids who became pregnant. The scientists used ultrasound to measure the fibroids during early pregnancy, and then again between three and six months after delivery. Researchers gathered information on the participants' antibiotic use, breastfeeding, and postpartum contraception use, in addition to demographic information and the gestational age of their newborn.
The study found that in 72% of the women, fibroids shrank in size between the early pregnancy and postpartum periods. Black, non-Hispanic women were less likely to have fibroid regression. Participants using progestin-only birth control methods postpartum had significantly less fibroid regression than those using a combined estrogen-progestin contraceptive or a non-hormonal contraceptive method. Neither the method of delivery (cesarean or vaginal birth) nor the gestational age of the infant was associated with fibroid regression. Similarly, none of the other factors in the study was associated with changes in fibroid size—including the woman's age, body mass index, characteristics of the fibroids, breastfeeding, smoking, or antibiotics. (PMID: 21492823)
Vitamin D Shrinks Fibroid Tumors in Rats
Researchers supported through the Fertility and Infertility (FI) Branch found that treatment with vitamin D reduced the size of uterine fibroids in laboratory rats predisposed to developing the benign tumors. Additional research is needed to confirm vitamin D as a potential treatment for women with uterine fibroids.
The researchers tested the vitamin D treatment on a strain of rats genetically predisposed to developing fibroid tumors. After examining the animals and confirming the presence of fibroids in 12 of them, the researchers divided the rats into two groups of six each: those that would receive vitamin D and those that would not.
In the first group, small pumps implanted under the skin delivered a continuous dose of vitamin D for three weeks. The researchers then examined the animals in both groups. The fibroids increased in size in the untreated rats, whereas in the rats receiving vitamin D, the tumors had shrunk dramatically. On average, the uterine fibroids in the group receiving vitamin D were 75% smaller than those in the untreated group.
The amount of vitamin D the rats received each day was equivalent to a human dose of roughly 1,400 international units. The recommended amount of vitamin D for teens and adults age 70 and under is 600 units daily, although up to 4,000 units is considered safe for children over age 9, adults, and women who are pregnant or breastfeeding.
These study results provide a promising new lead in the search for a non-surgical treatment for fibroids that doesn't affect fertility. (PMID: 22302692) Learn more about this NICHD-supported research in the Institute news release or NIH podcast.
A Rat Model of Gene Therapy for Uterine Fibroids
Researchers supported through the Fertility and Infertility (FI) Branch are investigating new treatments for fibroids with the hope of finding an option that will provide long-term relief without compromising fertility. One possibility is a form of gene therapy that affects estrogen receptors. A recent NICHD-supported study examined the safety and efficacy of this gene therapy in rats with uterine fibroids. Researchers randomly assigned the rats to fibroid gene therapy, an alternate gene therapy unrelated to fibroids, or no treatment at all. Results revealed that the fibroid gene therapy shrunk fibroids by 45% at day 8 after the treatment and 80% at day 15. Treatment effects remained significant at day 30, with a 77% decrease in fibroid size compared to pretreatment size. In contrast, the fibroids in rats in the two control groups doubled in size over the course of 30 days.
The gene therapy treatment was not only effective but safe. Tests revealed no damage to uterine tissue surrounding the fibroids or changes in liver function that might suggest toxicity. In most cases, the gene therapy did not seem to spread beyond the uterus, although some of the treated rats did show faint traces in the liver. This study provides preclinical data to support the development of gene therapy as an alternative to surgical and hormonal treatments of uterine fibroids. (PMID: 19144333)
Study Links Dairy Intake and Uterine Leiomyomata
Researchers funded by the Fertility and Infertility (FI) Branch are studying the role that diet may play in the high incidence of fibroids in African American women. Earlier studies showed that established risk factors for fibroids do not fully explain why African American women are more likely to develop fibroids at younger ages and with more severe symptoms and larger fibroids than women of other population groups. Using data from the Black Women's Health Study, a large prospective study of 59,000 African American women in the United States, researchers compared dairy intake to the risk of fibroids. After 10 years of follow-up, during which 5,871 new cases of fibroids were reported, high dairy intakes were associated with a lower risk of fibroids. The risk of fibroids among women who consumed four or more dairy servings a day was 30% lower than the risk among women who had less than one serving a day.
This is the first study to show a positive association between high dairy intake and a lower risk of acquiring uterine fibroids. The results could explain why fibroids are more common in African American women, who consume fewer dairy products than do white women, and suggest that changing diet to include more dairy could help decrease the risk for uterine fibroids.(PMID: 19955473)
Uterine Fibroids, the Extracellular Matrix (ECM), and Cell Signaling
NICHD researchers within the Unit on Reproductive Endocrinology and Infertility, in the Division of Intramural Research Program in Reproductive & Adult Endocrinology, found that one prominent feature of uterine fibroids is that the cells within the tumors produce a disordered and excessive ECM, which is a complex structural framework that surrounds and supports the body's cells.3,4,5,6
Previous Unit research examined the characteristics of the fibroids cells that might lead to excessive and fibrotic ECM production. The work found that mechanical signaling—a method of cell communication and activation—was altered in the cells within the fibroid.7,8
For information about the Unit's more recent research, visit http://2012annualreport.nichd.nih.gov/urei.html.
Non-surgical Treatments for Fibroids
More recently, the researchers in the Unit on Reproductive Endocrinology & Infertility examined the relationship of mechanical signaling to fibroid cells in greater detail and completed a collaborative clinical trial of MRI-guided high-frequency ultrasound (HIFU) for the non-surgical treatment of uterine fibroids. The results of this pilot study confirmed that the HIFU platform is a highly accurate method for targeting uterine fibroids. (PMID: 22626269)
PRAE researchers also studied the effects of the drug liarozole on genes known to create the fibrosis that is the main cause of fibroid symptoms. Liarozole is effective in treating the skin diseases ichthyosis and psoriasis by blocking a particular metabolic pathway known to affect cell growth and differentiation. Prior studies demonstrated that fibroids could be particularly susceptible to treatments like liarozole. Scientists found that treatment of fibroid cells with liarozole decreased the function of important fibrosis genes. When administered at pharmacologic concentrations, liarozole decreased the ability of fibroid cells to multiply, and decreased genes involved in creating the fibrosis involved in symptoms. These results provide evidence that liarozole or similar compounds may be effective therapies for women suffering from fibroids. (PMID: 22925684)
Fibroids within a Broader Context
The Biostatistics and Bioinformatics Branch, within the Division of intramural Population Health Research (DIPHR), is examining fibroids within the broader context of menstrual cycle function through the Modeling of Menstrual Cycle Function Project.
Project researchers are developing statistical models to appropriately account for the intricacies of the menstrual cycle biology. Using these models, they are able to study associations between hormone levels, cycle characteristics, and various reproductive outcomes, such as fertility, miscarriage, uterine fibroids, and cardiovascular disease.
Investigators in the Unit on Reproductive Endocrinology and Infertility are collaborating to create a Uterine Fibroid Tissue Bank.
Other Activities and Advances
To achieve its goals for uterine fibroid research, the NICHD supports a variety of other activities. Some of these activities are managed through the components listed above; others are part of NIH-wide or collaborative efforts in which the NICHD participates. Some of these activities are listed below.
- The NICHD is one of several NIH Institutes and HHS agencies to support the International Congress on Uterine Fibroids meetings. The conference brings together researchers working in the fields of medicine, epidemiology, basic research, and therapeutics to exchange scientific information about fibroids. Topics include treatment options, epidemiology, mechanisms of fibroid development and growth, environmental influences, hormonal therapies, and genetic characteristics. Select a link below to review information about and from each meeting.
- The NICHD also held a conference on classification for uterine fibroids in 2007. A summary of that conference is available at http://www.sciencedirect.com/science/article/pii/S0015028210024635 .
- The Endometrium Database Resource (EDR), supported through the Fertility and Infertility (FI) Branch, aims to be an evolving bioinformatics resource for genes associated with the uterus. More information about the EDR is available at http://endometrium.bcm.tmc.edu/edr/ui_home.seam .
- Nieman, L. N., Blocker, W., Nansel, T., Mahoney, S., Reynolds, J., Blithe, D., et al. (2011). Efficacy and tolerability of CDB-2914 treatment for symptomatic uterine fibroids: A randomized, double-blind, placebo-controlled, Phase IIb study. Fertility and Sterility, 95(2), 767–772. Retrieved June 20, 2013, from http://www.fertstert.org/article/S0015-0282(10)02671-3/abstract [top]
- Levens, E. D., Potlog-Nahari, C., Armstrong, A. Y., Wesley, R., Premkumar, A., Blithe, D. L., et al. (2008). CDB-2914 for uterine leiomyomata treatment: A randomized controlled trial. Obstetrics and Gynecology, 111(5), 1129–1136. Retrieved June 20, 2013, from http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2742990/ [top]
- Catherino, W. H., Leppert, P. C., Stenmark, M. H., Payson, M., Potlog-Nahari, C., Nieman, L. K., et al. (2004). Reduced dermatopontin expression is a molecular link between uterine leiomyomas and keloids. Genes, Chromosomes & Cancer, 40, 204–217. Retrieved December 8, 2011, from http://onlinelibrary.wiley.com/doi/10.1002/gcc.20035/abstract;jsessionid=3BB1D23398422CF08AA1E966E3ACB25E.d01t04 [top]
- Leppert, P. C., Baginski, T., Prupas, C., Catherino, W. H., Pletcher, S., & Segars, J. H. (2004). Comparative ultrastructure of collagen fibrils in uterine leiomyomas and normal myometrium. Fertility and Sterility, 82, 1182–1187. Retrieved December 8, 2011, from http://www.fertstert.org/article/S0015-0282(04)01135-5/abstract [top]
- Leppert, P. C., Catherino, W. H., & Segars, J. H. (2006). A new hypothesis about the origin of uterine fibroids based on gene expression profiling with microarrays. American Journal of Obstetrics and Gynecology, 195, 415–420. Retrieved December 8, 2011, from http://www.sciencedirect.com/science/article/pii/S0002937806000068 [top]
- Norian, J. M., Malik, M., Parker, C. Y., Joseph, D., Leppert, P. C., Segars, J. H., et al. (2009). Transforming growth factor beta3 regulates the versican variants in the extracellular matrix-rich uterine leiomyomas. Reproductive Sciences, 16, 1153–1164. Retrieved December 8, 2011, from http://rsx.sagepub.com/content/16/12/1153.long [top]
- Rogers, R., Norian, J., Malik, M., Christman, G., Abu-Asab, M., Chen, F., et al. (2008). Mechanical homeostasis is altered in uterine leiomyoma. American Journal of Obstetrics and Gynecology, 198, 474.e1–11. Retrieved December 8, 2011, from http://www.sciencedirect.com/science/article/pii/S0002937807022399 [top]
- Norian, J. M., Owen, C. M., Taboas, J., Korecki, C., Tuan, R., Malik, M., et al. (2012). Characterization of tissue biomechanics and mechanical signaling in uterine leiomyoma. Matrix Biology, 31, 57–65. Retrieved December 8, 2011, from http://www.sciencedirect.com/science/article/pii/S0945053X11000898 [top]