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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.
FI Branch High Program Priority Topic Areas
The FI Branch has identified ten high program priority topic areas using input from the NICHD Vision process, various advisory panels, meeting proceedings, and Branch staff. These areas (in alphabetical order) for the Branch for calendar years 2015 and 2016 are:
- Developmental Studies Specifically Addressing the Maternal-Zygotic Transition
- Early Pregnancy Loss (EPL) with special focus on oocyte aneuploidy, sperm quality, pre-placental processes including decidualization, implantation, vasculogenesis, embryo-uterine cross-talk, and development of biomarkers, screening tests, etc., to predict those at risk for EPL
- Epigenetic Bases of Reproductive Diseases and Disorders
- Genetics of Idiopathic Male and Female Infertility
- Improvement of Fertility Preservation Outcomes by Improving Existing and Developing Novel Technologies
- Ovarian Aging and Reproductive Decline with special focus on developmental dynamics of primordial follicle pool establishment and regulation and development of new technologies and algorithms to assess and predict ovarian reserve
- Relationship of Male Fertility Status to Overall Health and Health of Offspring
- Role of Non-Coding RNAs in Reproductive Health and Disease
- Role of the Tissue/Cellular Microbiomes in Reproductive Health and Disease
- Systems Approaches to Assess the Interplay of Clock Genes, Metabolism, and Reproduction Throughout the Lifespan
Applications submitted to the NIH addressing these priority areas that fall below the institute payline will receive special consideration for discretionary funding opportunities. It should be noted, however, that due to current budgetary constraints, the number of applications supported via these funding opportunities will be very limited.
- 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)
- Urine Levels of Gene Causing High Androgens Could Identify Polycystic Ovary Syndrome (PCOS) Women
PCOS is a common condition that causes infertility in women because their ovaries produce too much of the androgen hormone, testosterone. Studies had shown that PCOS can be inherited, and by comparing the genomes of thousands of women, researchers compiled a list of "candidate" genes that could be the cause. New work by Dr. Jan McAllister and her colleagues now shows that an unusual product of one of these candidate genes, called DENND1A.V2, alters the synthesis of androgens by the ovaries. Reducing the level of DENND1A.V2 in the steroid producing cells of the ovaries, the thecal cells, in women with PCOS reduced the production of androgens, while forcing overexpression of DENND1A.V2 in normal thecal cells caused them to make too much androgen, just like PCOS cells. In addition, levels of DENND1A.V2 are high in the urine of women in PCOS, providing hope that a simple urine test could diagnose PCOS in the future. (PMID: 24706793 or see the press release at http://www.nichd.nih.gov/news/releases/Pages/041514-PCOS-androgens.aspx )
- Androgens and Obesity Synergize To Cause PCOS
In addition to high testosterone levels, 90% of women with PCOS are overweight or obese. A study by Dr. Judy Cameron and colleagues found that while both high levels of testosterone and obesity alone can cause signs of PCOS, the combination of the two increased the severity of the symptoms. Monkeys that were given testosterone implants before puberty, and then fed a high-fat, Western-style diet starting post-puberty, were less sensitive to insulin, had more small follicles in their ovaries at mid-cycle, and had lower levels of progesterone during the luteal phase of the menstrual cycle—all signs of metabolic disruption and ovary malfunction that are common in women with PCOS. (PMID: 24735887)
- Of Mice and (Infertile) Men
Infertility affects 10-15% of American couples. Male infertility sometimes results from partial deletions on the Y chromosome; these deletions remove genes that function in the production of sperm. Men with this condition produce very few, if any, mature and viable sperm, but it's not clear exactly where in the process the sperm development fails. Because the human Y chromosome is unique, until now it has not been possible to study the process of sperm development in men with these deletions. Dr. Renee Reijo-Pera and her colleagues took skin cells from infertile men with Y chromosome deletions and transformed them into induced pluripotent stem cells (iPSCs), cells with the ability to form almost any specialized cell type. In this case, when they were transplanted into the testes of mice, the iPSCs differentiated into cells that looked and acted like very early germ cells—the cells that go on to become sperm. By studying the fate of these early germ cells derived from infertile men transplanted into the mice, scientists can begin to understand exactly what goes wrong with spermatogenesis in infertile men with Y chromosome deletions. (PMID: 24794432)
- 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 who have undergone cancer treatments have reduced 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
- 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
- Lifting the Brakes on Meiosis
Oocytes (eggs) and sperm must complete the process of meiosis—the cell divisions that halve the number of chromosomes—to prepare for fertilization. Unlike sperm, which continually mature and complete meiosis, all oocytes fall dormant midway through the process and will only resume meiosis if they are selected for ovulation. This state of suspended animation is maintained by the constant production of the molecule cGMP, which acts as a brake on meiosis. During each cycle, a surge of luteinizing hormone (LH) temporarily reduces cGMP production, allowing meiosis to resume in the oocyte that will be ovulated. Using rat follicles matured and grown in culture dishes, Dr. Laurinda Jaffe and her colleagues found that LH inhibits cGMP by inactivating NPR2, a receptor in the cells that surround the oocyte and produce cGMP. Within 10 minutes of LH signaling, enzymes called phosphoprotein phosphatases inactivate NPR2. In addition to decreasing cGMP production, LH might also increase the break-down of previously produced cGMP, according to this research. The research also confirmed that there is a slower but longer lasting inhibition of cGMP, as a molecule that binds to NPR2 to prompt production of cGMP decreases. These discoveries enhance our understanding of the oocyte maturation process and provide potential new approaches to regulate fertility without using hormones. PMID: 25183874
- Decoys in Blood Vessel Development
Abnormal implantation in the uterus, or improper development of the placenta, can cause serious cardiovascular problems in the fetus, often due to inadequate action of the hormone adrenomedullin. Adrenomedullin binds to receptors in cells that line the circulatory system to promote the development of blood vessels. Dr. Caron and her co-workers found that the level of receptors for adrenomedullin act as a “molecular rheostat” to precisely determine the degree of action of adrenomedullin. They found that there are two types of receptors: one that promotes normal activity of adrenomedullin; and another that acts as a “decoy,” binding adrenomedullin but preventing its normal cellular effects. With high levels of the decoy receptor, CXCR7, less adrenomedullin is available to bind to the active type of receptors. The balance of decoy and regular receptors thus determines the total activity of adrenomedullin to precisely regulate blood vessel development, and in turn, placental function. PMID: 25203207
- New Treatment for Anovulatory Infertility in PCOS
PCOS is the most common cause of infertility in women who don't ovulate. Doctors often use a drug called clomiphene citrate to stimulate ovulation in women with PCOS, but it had a low success rate along with some side effects like mood changes and hot flashes. The FI Branch's Reproductive Medicine Network ran a clinical trial to compare the use of clomiphene citrate and another drug called letrozole, to treat infertility in women with PCOS. The drugs work differently: clomiphene changes the function of estrogen receptors, while letrozole inhibits the enzyme aromatase, which converts androgens to estrogens. In their study published in the New England Journal of Medicine, they reported that women with PCOS who took letrozole over 5 menstrual cycles were more likely to ovulate and had 44% more live births then women who took clomiphene. Letrozole was also just as safe to mothers and babies as clomiphene. This study shows that letrozole is superior to clomiphene in treating anovulatory women with PCOS. (PMID: 25006718 or see the press release at http://www.nichd.nih.gov/news/releases/Pages/070914-PCOS.aspx )
- In Vitro Fertilization (IVF) and Long-Term Health of Offspring
Many infertile couples turn to IVF to conceive a child. In IVF, fertilization and the very early stages of embryo development occur outside the body, and then the embryo is transferred to the uterus. While most babies born from IVF seem to be healthy, people remain concerned about possible long-term effects on the health of those children. A recent study by Dr. Paolo Rinaudo and his colleagues looked at the long-term effects of IVF on the health of mice born from IVF, using "optimal" conditions for fertilization and embryo culture. They found that even under these optimal conditions, the resulting mice had altered growth, fat accumulation and glucose metabolism, postnatally and as adults. Their data suggest that even optimal conditions for IVF can reprogram the body and cause life-long changes to growth and overall health. These results show that very early embryos are vulnerable to conditions in their surroundings, and those conditions can alter the body in permanent ways, highlighting the need for studies to follow up the health of children born from IVF. (PMID: 24684304)
- Mutation in Meiosis Gene Results in Ovarian Failure
Premature ovarian failure (POF), also known as Primary Ovarian Insufficiency (POI), is associated with the cessation of fertility in women 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.
- 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
- Scientific Article from FI Branch Staff:
- Legro, R.S., Brzyski, R.G., Diamond, M.P., Coutifaris, C., Schlaff, W.D., Casson, P., Christman, G.M., Huang, H., Yan, Q., Alvero, R., Haisenleder, D.J., Barnhart, K.T., Bates, G.W., Usadi, R., Lucidi, S., Baker, V., Trussell, J.C., Krawetz, S.A., Snyder, P., Ohl, D., Santoro, N., Eisenberg, E., Zhang, H. (2014). Letrozole Versus Clomiphene for Infertility in the Polycystic Ovary Syndrome. New England Journal of Medicine 371:371:119-29. PMID: 25006718
- Tamaresis, J.S., Irwin, J.C., Goldfien, G.A., Rabban, J.T., Burney, R.O., Nezhat, C., DePaolo, L.V., Giudice, L.G. (2014). Molecular Classification of Endometriosis and Disease Stage Using High-Dimensional Genomic Data. Endocrinology 55:4986-4999. PMID: 25243856
- 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
- PAR-14-272: Long-Term Outcomes of Medically Assisted Reproduction (R01)
- PAR-14-273: Long-Term Outcomes of Medically Assisted Reproduction (R21)