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The mission of the FI Branch (formerly the Reproductive Sciences Branch) is to encourage, enable, and support scientific research aimed at alleviating human infertility, uncovering new possible pathways to control fertility, and expanding fundamental knowledge of processes that underlie human reproduction. To this end, the FI Branch provides funds for basic, clinical, and translational studies that will enhance our understanding of normal reproduction and reproductive pathophysiology, as well as enable the development of more effective strategies for the diagnosis, management, and prevention of conditions that compromise fertility, with the ultimate goal of promoting a better quality of life for all individuals.
- U.S. Department of Agriculture/NIH Dual Purpose with Dual Benefit Program
- Advances from the FI Branch-Funded Specialized Cooperative Centers Program in Reproduction and Infertility Research (SCCPIR)
- New Approach for Treating Female Infertility Due to Low or Absent Ovarian Follicle Reserve Results in Live Birth
It is well known that older women and those receiving cancer treatments have insufficient ovarian follicular reserves that impact their ability to become pregnant. In addition, doctors have known for many years that some infertile women can become pregnant after the removal a small piece of their ovaries, but there was no available explanation for such a paradoxical effect. New work by FI Branch-funded Dr. Aaron Hsueh and his colleagues provides a possible mechanism and describes the birth of a baby to a previously infertile woman following the treatment. Dr. Hsueh found that fragmenting the ovaries disrupts the action of a molecule called Hippo. Hippo maintains the optimal size of organs, and its loss prompts the ovary to regrow. When the fragments are stimulated with a molecule called Akt, they grow even better. Using this treatment, Dr. Hsueh was able to stimulate the ovaries of a woman with Primary Ovarian Insufficiency (POI), or menopause before the age of 40, to produce mature eggs. Following in vitro fertilization, the embryo generated from one of those eggs was implanted into the woman's uterus, and a healthy baby was born. This treatment provides hope for fertility in older women who do not have enough remaining eggs to conceive without help, and for women who have lost most of their eggs due to cancer treatment. http://www.ncbi.nlm.nih.gov/pubmed/24082083
- Timing Puberty
- Puberty begins when the brain increases the frequency and overall level of secretion of the master reproductive hormone, gonadotropin-releasing hormone (GnRH). GnRH triggers a release of other hormones that ultimately increase the production of testosterone in males and estrogen in females. Although scientists knew that the timing for the onset of puberty is at least partly regulated by genetic factors, the factors themselves were unknown. Now work by Dr. Ursula Kaiser and her team have uncovered a gene called MKRN3 that contributes to the timing of puberty. This gene is maternally imprinted, meaning that an individual will only express the copy of the gene that was inherited from their father, while the copy they inherited from their mother remains silent. Dr. Kaiser studied families with children who went through puberty too early (called precocious puberty, before the age of 8 to 9 years), to find that in about a third of them, the MKRN3 gene had mutations that disrupted its function. The gene is expressed in the arcuate nucleus of the brain, an area intimately associated with puberty, and its expression slowly dwindles as puberty approaches. The finding suggests that normally, the product of MKRN3 somehow suppresses the release of GnRH until the appropriate time for puberty. Visit http://www.ncbi.nlm.nih.gov/pubmed/23738509 for more information on this study.
- At the other end of the spectrum of puberty timing, Dr. Samuel Quaynor and Dr. Lawrence Layman found a never-before-seen genetic cause for delayed puberty in an 18-year old woman. Their investigations revealed a mutation in the gene that encodes the main receptor for the hormone estrogen. Although the woman's ovaries produce copious amounts of estrogen, the hormone can't exert its usual effects, including breast development and the start of menstrual periods, because it can't bind to this defective receptor. Without receptor binding, the tissues that normally use estrogen had no way of knowing that there was any estrogen being produced; and because the brain couldn't sense the high estrogen levels, it kept telling the ovaries to produce even more. This state, called estrogen resistance, had never been seen in a woman before. Visit http://www.ncbi.nlm.nih.gov/pubmed/23841731 for more information about this study.
- Sperm Regeneration Using Stem Cell Transplantation: A New Approach For Young Cancer Survivors
After puberty, men make sperm continuously; spermatogonial stem cells divide to make more stem cells that ultimately go on to become fully mature sperm capable of fertilizing an egg. Exposure to environmental toxins, including drugs used in chemotherapy, can kill sperm and their precursor stem cells, leaving the cancer survivor infertile. While adult men can bank sperm prior to chemotherapy to preserve their fertility options, boys who have not yet reached puberty do not have that option. In this proof-of-principle experiment using macaque monkeys, investigators tried a different approach: harvesting spermatogonial stem cells of immature animals and transplanting them back to the donor after a regimen of chemotherapy made the animals infertile. The re-introduced spermatogonial stem cells, which carried a molecular identification tag, divided and produced functional sperm that could fertilize eggs and produce embryos. This work suggests that harvesting and re-introducing spermatogonial stem cells might be a way to preserve the fertility of young boys who survive cancer. To read about this study, visit http://www.ncbi.nlm.nih.gov/pubmed/23122294.
- Branch-Supported Advances
- Stem Cell Fate: A Mechanism That Links Male Infertility with Tumor Formation
Men produce sperm continuously thanks to a pool of cells called spermatogonial stem cells (SSCs). Spermatogonial stem cells can either divide to make more of themselves, or start the process that will ultimately transform them into sperm. The balance between those two fates is critical, and disruption of the balance will lead to infertility. In addition, testicular germ cell tumors can form if the transition process goes awry. Now Dr. John Oatley and his colleagues have found that Retinoblastoma 1 (RB1), a protein known for its role as a tumor suppressor, is also involved in the balance of fate between renewal of stem cells and sperm production. Mice lacking RB1 cannot make more spermatogonial stem cells, so that eventually all the sperm are used up and the mice become infertile. In addition, some of the cells started to take on tumor-like properties. This work highlights the links between stem cell fate and fertility, and stem cell fate and normal cell growth. http://www.ncbi.nlm.nih.gov/pubmed/24089198
- Higher Vitamin A Levels May Contribute to Higher In Vitro Fertilization (IVF) Success Rates
Some infertile couples can use IVF to try to conceive children. The IVF procedure involves retrieving an egg from the woman, fertilizing it in the laboratory, and then reintroducing the resulting embryo into the uterus of the woman. Several factors influence the quality of egg, sperm, and the embryo and dramatically affect the efficiency of IVF. Branch-funded Dr. Neil Sidell and his colleagues at Emory University speculated that the level of retinoids, a class of compounds closely related to vitamin A, might be an important factor in the success of IVF. They measured retinoids in the fluid surrounding a women's egg, and correlated that with the quality of embryos derived from those eggs. They observed that retinoids play an important role in egg development and quality. They also found reduced levels of retinoids in the fluid around the egg in women with endometriosis, a condition in which uterine tissue improperly grows outside of the uterus, which might help to explain why some women with endometriosis are infertile. This approach could be developed into a standard method for predicting the egg and embryo quality in the IVF procedure. http://www.ncbi.nlm.nih.gov/pubmed/23427183
- Fertility After Cancer Is Not Correlated with Hormone Levels or Number Of Egg
Many cancer patients survive due to chemotherapy, but then go on to face infertility because of its damaging effects on their reproductive systems. While recent advances in technology give survivors hope of bearing a biological child after cancer treatment, physicians still can't accurately predict which survivors are at the highest risk of long-term infertility. In this study, Dr. Clarisa Gracia and her colleagues compared reproductive hormonal profiles, the number of remaining eggs, and pregnancy rates in young cancer survivors with women of similar age without cancer, over an average of 25 months. Compared to women without cancer, survivors had lower reproductive hormone levels and fewer eggs. However, survivors were still able to achieve pregnancies at a rate similar to women who never had cancer. Although more research is needed to better understand the infertility risk in cancer survivors, Dr. Gracia and colleagues demonstrate that some patients have the ability to have biological children after receiving cancer treatment despite lingering side-effects to their reproductive systems. http://www.ncbi.nlm.nih.gov/pubmed/24038829
- Molecule Found To Be Critical in Providing Energy for Embryo Implantation
Many early miscarriages occur not because the very early embryo, or blastocyst, is unhealthy, but because it fails to implant into the uterus where it can continue to grow. The cells of the lining of the uterus have to increase themselves and specialize to provide a healthy environment for a blastocyst to implant. Dr. Bert O'Malley and his colleagues found that a molecule called steroid receptor coactivator-2 (SRC-2) is essential for preparing the uterus for implantation. Their research showed that SRC-2 increases the cellular energy available to uterine cells that begin to proliferate and differentiate into decidual cells, the specialized cells necessary for implantation. Without this energy burst, the uterus could not adequately prepare itself even in response to adequate levels of the pregnancy hormone progesterone. Altering the energy levels available to cells, through regulating levels of SRC-2, could provide new hope for women at risk for early miscarriage. http://www.ncbi.nlm.nih.gov/pubmed/24204309
- Where Do Testis Cells Come From?
The Leydig cells of the testis make testosterone, the hormone that promotes male sex characteristics, libido, and fertility. Leydig cells in a male fetus do not become adult Leydig cells, but instead disappear and are replaced by adult Leydig cells that arise from a different source. These adult Leydig cells can't divide to make more of themselves, but must constantly be replenished from a pool of unidentified progenitor cells. Dr. Capel's work suggests that a cell population associated with the blood vessels feeding the testis might be the mysterious source of the adult Leydig cells. This work also shows that a signaling pathway regulated by a molecule called Notch controls to what extent those cells differentiate into Leydig cells, versus making more of themselves; and that the whole process is sensitive to levels of its ultimate product, testosterone. Problems with this precursor cell population or the regulation of their differentiation into steroid-producing cells could compromise reproductive development or a man's fertility. Visit http://www.ncbi.nlm.nih.gov/pubmed/23467742 for more information.
- An Early Origin of Premature Birth
Premature births are far too common and can pose a danger to both the mother and the long-term well-being of the baby. Although doctors understand some factors behind prematurity, not all cases can be explained, and it's important to know when during pregnancy the problems begin. This study set out to find the early origins of prematurity by studying mice genetically engineered to lack a gene called Trp53. Female mice that lack Trp53 gave birth too early, and the scientists found that many other genes faltered as well. Many of those genes protect the deciduae--the early maternal contribution to the placenta--from oxidative stress. This suggests that very early in pregnancy, possibly at the time of implantation, unhealthy conditions in the mother's uterus can increase the risk for premature birth. To read more on these findings, visit http://press.endocrine.org/doi/pdf/10.1210/en.2012-1335 (PDF - 1.28 MB).
- Healthy Eggs Need Vitamin A: A Link to Infertility in Endometriosis
Vitamin A, or retinol, is critical to normal fertility in women. In ovarian cells, retinol is converted to ATRA, a product that has been shown to influence the quality of a woman's eggs. In this study, scientists compared the levels of retinol and its product, ATRA, in healthy women and women with endometriosis. Both groups of women used in vitro fertilization to try to become pregnant. The study found that eggs from women with significantly higher levels of ATRA in the follicular fluid surrounding those eggs produced high-quality embryos, while those with lower levels of ATRA produced embryos less likely to implant and survive. The study also found that women with endometriosis had 50% lower levels of ATRA in their blood and follicular fluid. This study suggests that low levels of ATRA might contribute to infertility in women with endometriosis and offers a possible approach (e.g., increasing vitamin A levels) to improving fertility in these women. To read more on these findings, visit http://rsx.sagepub.com/content/early/2013/02/18/1933719113477487.full.pdf+html .
- Scientific Article from FI Branch Staff:
- Lamar, C., Taymans, S., Rebar, R., LaBarbera, A., Albertini, D. F., & Gracia, C. (2013). Ovarian Reserve: Regulation and Implications for Women's Health. Proceedings of the 2012 NICHD-ASRM Conference. Journal of Assisted Reproduction and Genetics, 30(3), 285-292. Available at: http://link.springer.com/article/10.1007%2Fs10815-013-9968-2 . You can also learn more about the Branch-supported conference, held October 25, 2012, at Ovarian Reserve: Regulation and Implications for Women's Health .
- Funding Opportunity Announcements:
- PAR-13-204: Dual Purpose with Dual Benefit: Research in Biomedicine and Agriculture Using Agriculturally Important Domestic Animal Species (R01)
Expiration date: September 25, 2015
- PAR-13-385: Developmental Origins of Health and Disease (DOHaD): Epigenetic Modification in Gametogenesis and Transgenerational Inheritance (R01) Expiration date: January 31, 2015