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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)
- Making Good Eggs Depends on Good Neighbors
Germ cells can only develop properly when they are surrounded by specialized somatic cells. Yet the molecular basis for these somatic/germ-cell interactions is still poorly understood. In the final phase of oocyte maturation, signals from the somatic cell prompt the oocyte to resume meiosis. At this point the oocyte has stopped transcribing its DNA instructions into messenger RNA (mRNA), and it presumably has all the information it needs stored in its cytoplasm. However, an oocyte still relies on somatic cells for optimal development, and it was not clear why. SCCPIR-supported scientists have identified the molecular basis for the interaction between the cell types. They found that when compared to mouse oocytes cultured by themselves, there was increased translation of a subset of the stored mRNAs into cellular proteins in oocytes cultured with somatic cells. They also found that epidermal growth factors, made by somatic cells, were responsible for that increase, and that the factors acted through a molecular signaling network called the PI(3)K-AKT-mTOR pathway. These findings provide a mechanistic explanation for the observation that the quality of an oocyte is dependent on its association with somatic cells. It also opens new avenues for assessing oocyte quality. Visit http://www.ncbi.nlm.nih.gov/pubmed/24270888 for details.
- 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
- Mutation in Meiosis Gene Results in Ovarian Failure
Premature ovarian failure (POF), also known as POI, occurs when women lose their fertility before the age of 40. Branch-supported researchers studied a large family with several women with POF and found that they all suffered from the loss of a single DNA base in both of their copies of a gene called STAG3, which encodes a protein that helps hold chromosomal copies together during an early stage of meiosis. The alteration changed the code to insert a “stop” signal, producing a greatly shortened protein that can’t function normally in meiosis. The women with two copies of this mutation had POF, while those with at least one normal copy of STAG3 had normal ovarian function. The team also found that mice genetically engineered to carry the STAG3 mutation lost all of their oocytes as early as a week after birth because of the defect in meiosis. While STAG3 mutation is probably not a common cause of POF, this work shows that POF can occur due to very early defects in meiosis. For more information, visit http://www.ncbi.nlm.nih.gov/pubmed/24597867.
- The Importance of Race in Estimating Reproductive Age
A woman’s fertility begins to decline dramatically about 10 years before menopause, even as she continues to have normal menstrual periods. The decline is partly due to a decrease in the number of ovarian follicles, referred to as the ovarian reserve. Branch-supported scientists recently found that measurement of anti-müllerian hormone (AMH) can estimate a woman’s ovarian reserve, an index of her remaining fertility. The researchers studied AMH levels in women to see what variables other than age affect AMH levels and found a significant effect of race. At younger ages, Latina and African American women had significantly lower levels of AMH compared to white women at the same ages. While that difference persisted with age in the Latina women, AMH levels were less affected by aging in the African American women, so that at middle and older ages there was no difference in AMH level between African American and white women. These data tell us that race as well as age must be considered when using AMH levels to estimate ovarian reserve and remaining fertility. Visit www.ncbi.nlm.nih.gov/pubmed/24182412 for more information.
- Which Y genes for male fertility?
Males and females have identical genomes, except that females have matching XX sex chromosomes, while males have an XY pair. The Y chromosome holds SRY, the gene that triggers the development of the testes, and many other genes that are important for making abundant, high-quality sperm. Infertile men often have deletions of Y-chromosome genes that cause them to produce very few or low-quality sperm. Branch-supported scientists found that, among genetically engineered mice, only two Y chromosome genes were strictly necessary for male fertility under laboratory conditions. Mice with only SRY and another Y gene called Eif2s3y make gametes that can fertilize eggs if injected directly into them, and those fertilized eggs can sometimes develop into live mouse pups. Although these data aren’t directly applicable to infertile men because of differences in the human Y chromosome, it does suggest that much of the Y chromosome is devoted to genes that improve the efficiency of making sperm, and improve the quality of those sperm so that they can fertilize an egg naturally. Visit http://www.ncbi.nlm.nih.gov/pubmed/24263135 for details.
- 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
- 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
- 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.
- 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