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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)
- A New Animal Model to Study PCOS
PCOS affects about 10% of reproductive-aged women and causes high androgen levels and other hormonal disturbances, failure to ovulate, and increased risk of metabolic syndrome. PCOS is a complex disease and, until now, animal models of PCOS were not optimal because they did not replicate all of the features seen in women with PCOS. Now, Dr. Kauffman and colleagues show that mice treated with the drug letrozole for 5 weeks at the time of puberty go on to develop both the reproductive and metabolic symptoms of PCOS. This new model could prove very useful in studying the genetic mechanisms that contribute to PCOS in women, and in developing new interventions to treat the disorder. (PMID: 26203175)
- Breast Cancer Treatment and Preserving Fertility
For premenopausal women with breast cancer, 5 years of tamoxifen therapy can reduce recurrence risk by almost 50% and mortality by more than 25%. Recent data indicates that continuing tamoxifen treatment for 10 years may be even more beneficial in preventing recurrence. Despite the benefits, many young breast cancer patients decide not to take tamoxifen, or stop using it soon after beginning. Dr. Llarena and colleagues hypothesized that young survivors might be reluctant to take tamoxifen because of concerns about their fertility. Tamoxifen can damage a fetus, so women need to wait to get pregnant until a few months after tamoxifen treatment has ended. Delaying a pregnancy for 5 to 10 years is not optimal for many breast cancer survivors, who might be nearing the end of their natural fertility. This study followed 515 women younger than age 45 with breast cancer for whom tamoxifen was recommended, and found that women with concerns about the effect on their fertility were 5 times more likely to never begin tamoxifen treatment or to stop it too early. The authors conclude that to optimize the use of tamoxifen in young women and reap its protective benefits against the recurrence of breast cancer, patients should receive information on options for preserving their fertility. (PMID: 26307641)
- Taming Endometriosis
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
- Advances from the FI Branch-Funded Reproductive Medicine Network (RMN)
- 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 )
- Chlamydia, Infertility, and Ectopic Pregnancy
Chlamydia is the most frequently reported bacterial sexually transmitted infection in the United States. If left untreated, this “silent,” often asymptomatic infection can spread into the uterus or fallopian tubes, either completely blocking the tubes or leaving them open but not functioning properly. Although fertility tests for women usually check for blocked tubes, less severe damage might not be detected even though tubal dysfunction could still be causing the infertility. In this study, Dr. Steiner and colleagues identified 1,250 infertile women known to have open fallopian tubes and found that 19% of them had anti-chlamydia antibodies, signaling past chlamydia infection. These women were significantly less likely to get pregnant after five cycles of fertility treatments and had a 2.7-fold increased risk of ectopic pregnancy. These results show that a simple blood test for anti-chlamydia antibodies can detect women at greater risk for ectopic pregnancy, allowing doctors to tailor the fertility treatments to optimize the likelihood of a successful pregnancy. (PMID 26413816)
- Personalizing Infertility Treatment to Increase Successful Pregnancies
In the standard treatment for unexplained infertility in women, doctors use the hormone gonadotropin or the drug clomiphene citrate to stimulate ovulation. However, for women with PCOS, the drug letrozole was more effective than clomiphene citrate in establishing pregnancies that end in a live birth. Some evidence suggested that letrozole might be better than clomiphene citrate for all infertile women, regardless of infertility cause, because letrozole has a lower risk of inducing twin or higher order pregnancies. However, this study by Dr. Diamond and colleagues showed that although using letrozole in women with unexplained infertility led to fewer multiple pregnancies, it also resulted in fewer live births when compared to the use of gonadotropins or clomiphene citrate. This study demonstrates that personalizing treatment to the underlying cause of infertility can increase the likelihood of a successful outcome. (PMID: 26398071)
- Branch-Supported Advances
- Weight Loss Improves Ovulation for Obese Women with PCOS
PCOS is the main cause of infertility in women who fail to ovulate. High levels of androgens, changes in the proportion of different types of ovarian follicles, and disruption of ovulation all might contribute to their infertility. Many women with PCOS are also overweight, which might worsen their infertility. Providers often recommend that women with PCOS lose weight if they want to conceive, but until now, there was not strong scientific evidence supporting increased fertility after weight loss. Dr. Legro and colleagues performed a randomized controlled clinical trial in which women with PCOS received continuous oral contraceptive pills (OCP) to lower androgen levels, were assigned to a diet and exercise regimen to lose weight, or received both continuous OCP and the weight loss intervention. After 16 weeks, women went through four cycles of ovarian stimulation to try to induce ovulation. Those who received continuous OCP alone fared worse than women in the other groups with an increased rate of metabolic syndrome. Women who had both interventions were protected from the rise in metabolic syndrome caused by continuous OCP alone. Women in the diet and exercise regimen, with or without continuous OCP, lost weight and had higher rates of ovulation than women who only used continuous OCP. This work shows that changes in lifestyle, like healthy dieting and exercise to induce weight loss, can help women with PCOS to overcome infertility. (PMID: 26401593)
- Early Exposure to Progesterone Programs Later Uterine Function
Progesterone is a critical hormone for reproduction, especially in the development and function of the uterus. Dr. Dhakal and colleagues found that female rats injected with progesterone for several days just after birth showed disturbances to uterine function when they matured. Neonatal exposure to progesterone disrupted the development of endometrial glands in the uterus, the timing of puberty, and fertility. As adults, the rats had decreased expression of some uterine genes involved in mediating the actions of progesterone, resulting in resistance to the effects of naturally circulating progesterone. These results are important because endometriosis, early pregnancy loss, leiomyoma, and endometrial cancer have all been linked to disruptions in the normal uterine response to progesterone. (PMID: 26204463)
- Changes to Genes Encoding Reproductive Hormones Might Cause PCOS
PCOS is the main cause of infertility in women who fail to ovulate, affecting between 7% and 15% of all women during their reproductive years. PCOS is often inherited, and studies have tried to determine which genes contribute to PCOS. In this study, Dr. Hayes and colleagues used a genome-wide association study (GWAS) in a large group of women with and without PCOS to look simultaneously at all possible genetic changes that might contribute to PCOS. Unlike other GWAS studies of PCOS, the affected women in this study had endocrine abnormalities that also put them at high risk for metabolic disorders. The authors found a new, highly significant genetic change on chromosome 11, very close to the gene that encodes follicle stimulating hormone B polypeptide (FSH-B). FSH-B forms part of the hormone FSH, which stimulates the growth of ovarian follicles; this change could explain why there are too many immature follicles in the ovaries of women with PCOS. Women with the genetic change near the FSH-B gene also had high levels of luteinizing hormone (LH) that adds to the abnormally high levels of androgens seen in women with PCOS. The authors conclude that this locus on chromosome 11 contains a gene variant which contributes to PCOS by changing the levels of FSH and LH that act on the ovary, altering follicle growth and increasing androgen production, respectively. (PMCID: PMC4557132)
- 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.
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