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.
Institute Activities and Advances
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.1
Press release: http://www.nichd.nih.gov/news/releases/Pages/030112-vitaminD-fibroids.aspx
NIH Podcast: http://www.nih.gov/news/radio/podcast/2012/e0155.htm
A Novel Animal Model for Human Uterine Fibroids
The underlying causes of uterine fibroids are poorly understood partly because of the absence of a good model system in which to study these tumors. The only available authentic animal model is the Eker rat, in which scientists can study both uterine fibroids and uterine cancer. Uterine fibroids develop in female Eker rats with a frequency of 60% to 70%. The genetic mutation in this rat model leads to the development of tumors in several different organs, including the spleen, kidneys, lungs, and uterus. Although the Eker rat has been valuable as an animal model for uterine fibroids, its usefulness is limited because the rats are expensive and difficult to breed.
In this work, Fertility and Infertility (FI) Branch-supported researchers created, for the first time, an authentic mouse model that can successfully grow engrafted human fibroid tissues. Human fibroid tissues collected at the time of hysterectomy were cut into small pieces, treated with a special marker gene, and inserted under the skin on the flank of mice with severe combined immunodeficiency. The treated fibroid tissues continued to grow for 30 days after being implanted. The number of proliferating and apoptotic cells and the expression level of smooth muscle, estrogen receptors, and progesterone receptors were similar between the grafts retrieved from the treated group and the original hysterectomy tissue sample.
This model provides a useful tool for testing novel anti-fibroid therapeutics, including various nutritional supplements and hormone modulators. It can also be used to identify and characterize novel biomarkers for uterine fibroids, which could make early diagnosis and treatment easier.2
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 rates 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.3
Study Links Dairy Intake & 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.4
Uterine Fibroids, the Extracellular Matrix (ECM), & Cell Signaling
NICHD researchers within the Unit on Reproductive Endocrinology & 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 extracellular matrix (ECM), which is a complex structural framework that surrounds and supports the body's cells.5,6,7,8
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.9,10
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.
(Source: This manuscript is currently under review.)
Fibroids within a Broader Context
The Biostatistics & Bioinformatics Branch, within the Division of Epidemiology, Statistics, and Prevention Research, 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.
Other Activities & 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.
International Congress on Uterine Fibroids
The NICHD is one of several NIH Institutes and HHS agencies to support the International Congress 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.
Endometrium Database Resource (EDR)
The 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.
- Halder, S. K., Sharan, C., & Al-Hendy, A. (2012). 1,25-dihydroxyvitamin d3 treatment shrinks uterine leiomyoma tumors in the eker rat model. Biology of Reproduction, 86, 116. Retrieved December 8, 2011 from http://www.biolreprod.org/content/86/4/116.long [top]
- Hassan, M. H., Eyzaguirre, E., Arafa, H. M., Hamada, F. M., Salama, S. A., & Al-Hendy, A. (2008). Memy I: A novel murine model for uterine leiomyoma using adenovirus-enhanced human fibroid explants in severe combined immune deficiency mice. American Journal of Obstetrics and Gynecology, 199, 156.e1–8. Retrieved December 8, 2011 from http://www.sciencedirect.com/science/article/pii/S0002937808001464 [top]
- Hassan, M. H., Salama, S. A., Zhang, D., Arafa, H. M., Hamada, F. M., Fouad, H., et al. (2010). Gene therapy targeting leiomyoma: Adenovirus-mediated delivery of dominant-negative estrogen receptor gene shrinks uterine tumors in Eker rat model. Fertility and Sterility, 93, 239–250. Retrieved December 8, 2011 from http://www.sciencedirect.com/science/article/pii/S0015028208041277 [top]
- Wise, L. A., Radin, R. G., Palmer, J. R., Kumanyika, S. K., & Rosenberg, L. (2010). A prospective study of dairy intake and risk of uterine leiomyomata. American Journal of Epidemiology, 171, 221–232. Retrieved December 8, 2011 from http://aje.oxfordjournals.org/content/171/2/221.long [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]