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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
Epigenomic studies and critical windows for epigenetic alteration in reproductive processes, and epigenetic contributions to transgenerational phenotypes
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.
NIH NEWS IN HEALTH:
Pregnancy Problems? Boost the Chance of Having a Baby (Features FI Branch Chief Dr. Louis DePaolo)
U.S. Department of Agriculture/NIH Dual Purpose with Dual Benefit Program
Advances from the FI Branch-Funded National Centers for Translational Research in Reproduction and Infertility (NCTRI) (Formerly the Specialized Cooperative Centers Program in Reproduction and Infertility Research [SCCPIR])
- Naturally Occurring Molecules Stimulate Growth of Ovarian Follicles
For reasons that are not well understood, the removal of a small portion of the ovary or using a laser drill on the ovary sometimes stimulates ovulation in women who are infertile due to polycystic ovary syndrome (PCOS). Similarly, fragmenting mouse ovaries in a lab dish stimulates ovarian follicle growth. Branch-funded researcher Dr. Aaron Hsueh traced this effect to increased formation of large chains of the structural protein actin that disrupt the effects of a growth-regulating molecule called Hippo. When Hippo is disrupted, the ovarian cells accumulate proteins that stimulate cell growth, survival, and proliferation. This research shows that two different naturally occurring molecules, called JASP and S1P, increase the production of the form of actin which disrupts Hippo. Dr. Hsueh saw this effect in mouse ovaries cultured in a laboratory dish with JASP or S1P, and in mouse ovaries treated with JASP or S1P and transplanted into a recipient mouse. He also observed increased levels of growth promoting proteins in human ovarian strips cultured with JASP or S1P. These results suggest a new, non-surgical avenue of treatment for infertility in women with PCOS or other infertile women with reduced follicle growth. (PMID: 25690654)
- Technologies Used in Assisted Reproduction Found to Alter DNA Chemistry
Babies born as a result of assisted reproductive technologies (ART) have lower birth weight, more health problems just after birth, and are more likely to have long term neurological issues when compared to babies who were conceived naturally. These outcomes apply even to babies born from singleton ART pregnancies. Scientists have speculated that different levels of methylation—the addition of a chemical group to some DNA bases, which regulates gene expression—might be responsible for the short- and long-term health effects seen in ART babies. However, it is not known whether these DNA methylation differences are due to the underlying infertility of one or both parents, or if they result from laboratory conditions used in ART. To help resolve this question, Dr. Carmen Sapienza and his colleagues compared placental DNA methylation levels in 16 candidate genes in children conceived naturally (“fertile control” group) with ART-conceived children. Results strongly suggest that the DNA methylation differences are associated with some aspect of ART protocols, not simply the underlying infertility of the parents. Changes in ART procedures would hopefully minimize these methylation differences and lead to an improvement in neonatal and long-term outcomes of children conceived following ART. (PMID: 25901188)
Endometriosis is a poorly understood disorder of the female reproductive system in which tissue that normally lines the uterus also appears outside the uterus, often in the fallopian tubes and abdominal cavity. These abnormally placed tissue deposits (called lesions) can cause pain and inflammation and can interfere with normal fertility. Hormonal treatments, such as reducing the level of estrogen, for endometriosis are not always effective, have side-effects, and can make fertility problems worse. Recently, Dr. Katzenellenbogen and her team developed two compounds that bind to two different estrogen receptors ((thereby blocking the action of estrogen) and tested them in a mouse model of endometriosis. They found that the new compounds prevented the establishment of new tissue growths or caused the regression of established growths. The compounds also prevented/suppressed the nervous innervation and inflammation that accompany the abnormal tissue growth. Interestingly, the treatments had no effect on reproductive cyclicity or fertility. These results provide a new approach for the safe and effective treatment of endometriosis in women without altering fertility.
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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
- A Genetic Cause of Male Infertility
Almost one-half of all cases of male infertility are associated with genetic defects. Up to 20% of men who have no mature sperm in their seminal fluid, a condition called non-obstructive azoospermia (NOA), also have small DNA deletions on the Y chromosome. The rest of these men are typically given a diagnosis of idiopathic (“cause unknown”) azoospermia. To identify other genetic causes of idiopathic azoospermia, Dr. Alexander Yatsenko and his colleagues analyzed DNA from men with NOA and from normal, fertile men to identify genetic differences. They found that some patients with azoospermia lacked a small piece of DNA on the X chromosome. In normal men, this piece of DNA is transcribed in the testes as part of the TEX11 gene product, which is important in helping sperm to complete meiosis and maturation processes. These results suggest that TEX11 mutations are a common cause of azoopermia in infertile men. The finding is important for the diagnosis of azoospermia and for pre-conception testing in men whose partners are considering assisted reproductive technology. (PMID: 25970010)
- Overcoming Stress-Induced Infertility
It is well known that exposure to chronic stress can reduce fertility in women, yet we do not know exactly how the body's response to stress impacts reproductive function. NICHD-supported investigators found that chronic stress of female rats in the form of immobilization, even when followed by a stress-free recovery period, caused reduced fertility. However, when the research team blocked production of a brain peptide called RFRP3, the stressed rats became fully fertile, with normal mating behavior, number of pregnancies, and live births. These data provide the first evidence that RFRP3 mediates chronic stress-induced infertility and form the basis of a new approach that may alleviate infertility in women.
Diagnosing Disorders of Sex Development Is Facilitated by Genomic Sequencing
Babies can be born with a discrepancy between the apparent sex of their genitals or gonads, and the make-up of their sex chromosomes (XY = male, XX = female)—conditions called Disorders of Sex Development (DSD). Among DSD in chromosomal males with female-like genitals or gonads, in 85-90% of cases, the cause cannot be determined. Through the DSD Translational Research Network, Dr. Eric Vilain and his colleagues pioneered the use of exomic DNA sequencing to investigate the genetic cause of the condition in patients with 46 X,Y DSD. With exome sequencing, scientists can search all possible gene-coding regions of the genome at once for possible disease-causing mutations. In this case, Dr. Vilain analyzed the results against a list of all known human DSD-associated genes. He was able to identify a likely genetic diagnosis in more than one-third of the cases. Having a known genetic diagnosis is an enormous benefit to patients and families because it streamlines further clinical testing and directs potential treatments. http://press.endocrine.org/doi/full/10.1210/jc.2014-2605
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.
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
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.
- 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.
- 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:
. 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-14-272: Long-Term Outcomes of Medically Assisted Reproduction (R01) Expiration date: October 1, 2016
PAR-14-273: Long-Term Outcomes of Medically Assisted Reproduction (R21) Expiration date: October 1, 2016