Fertility and Infertility Branch (FIB)

Fertilization

Overview/Mission

FIB’s mission is to encourage, enable, and support 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, FIB funds basic, clinical, and translational studies to enhance our understanding of typical reproduction and reproductive pathophysiology, as well as to enable the development of more effective strategies for the diagnosis, management, and prevention of conditions that compromise male and female fertility.

FIB is interested in applications that align with the five following research priorities. In addition, applications for FIB that propose technical innovations or that address health disparities or involve diverse populations (race, ethnicity, disability, or patients with diseases not previously recognized to have a fertility/infertility component) will have higher priority, even if they do not address one of the science areas listed in the following priorities. For more information about NICHD’s research themes, cross-cutting topics, and aspirational goals, visit the plan’s Scientific Research Themes and Objectives.

Early Pregnancy Loss and Predictors of Pregnancy Outcome

Strategic Plan Theme 2: Promoting Gynecologic, Andrologic, and Reproductive Health
Strategic Plan Cross-Cutting Topic: Infectious Disease

Gap: It is known that about 50% of conceptions advance beyond 20 weeks of gestation. Moreover, approximately 50% to 70% of early pregnancy losses (<20 weeks) result from lethal numeric chromosome errors (i.e., aneuploidy), and up to 75% result from implantation failure as a result of embryo and/or uterine factors, while the etiology of the remaining losses is poorly understood. It has become apparent, however, that immune system dysfunction as a result of either impaired innate immunity or infections can affect various aspects of pregnancy establishment, such as implantation and early placentation. Endometrial differentiation and the nature of embryo-uterine communication in early pregnancy establishment are critical to ensuring normal maternal-fetal interaction later in pregnancy, but currently there are no early predictors of pregnancy outcome.

Priority: Research that addresses the etiology of unexplained early pregnancy loss and the potential role of biological factors involved in pregnancy establishment in predicting adverse pregnancy outcomes (i.e., preeclampsia, preterm birth, placenta previa, etc.), with an emphasis on the role of endometrial differentiation, innate immune factors, the impact of infections, and embryo-uterine communication. Due to the heterogeneity of tissues and cell types involved in early pregnancy establishment (i.e., gametes, embryo, uterus, immune cells, endocrine cells, endothelial cells, stromal cells, etc.), use of ‘omics approaches at the single-cell level is particularly encouraged.

Fertility and Overall Health

Strategic Plan Theme 2: Promoting Gynecologic, Andrologic, and Reproductive Health
Strategic Plan Cross-Cutting Topic: Disease Prevention

Gap: Evidence over the past decade indicates that an individual's fertility/reproductive health status correlates with and potentially predicts their risk of developing several chronic, life-threatening health conditions, such as cancer, diabetes, cardiovascular disease, and metabolic dysfunction. Additional work is needed to understand this link for infertile men and women and to begin to investigate the possible biological basis for this association with the goal of early detection of disease, prevention of adverse health outcomes, and optimal timing for intervention and prevention efforts.

Priority: Research that investigates the biological bases of fertility status in women and men as a biomarker for future health outcomes, with emphasis on the use of predictive models (using artificial intelligence, for example) based on existing longitudinal data sets with secondary analyses, such as electronic health record or fertility clinic data integrated with other health data.  

‘Omic Approaches to Investigate Infertility Pathogenesis

Strategic Plan Theme 2: Promoting Gynecologic, Andrologic, and Reproductive Health

Gap: Progress has stalled in the treatment of many types of infertility with known causes, while many more cases of infertility cannot be ascribed to a specific cause (i.e., idiopathic). The estimate that 1,000 to 2,000 genes are involved in sperm production makes it difficult to ascribe specific genetic causes to male infertility. However, the use of powerful ‘omics approaches (including genomics, epigenomics, metabolomics, microbiomics, and transcriptomics) could greatly advance our understanding of infertility disease pathogenesis resulting in novel diagnostic, treatment, and prevention strategies that could potentially evaluate the risk that the condition would be passed on to offspring and future generations (transgenerational inheritance). 

Priority: ‘Omics-based research that helps elucidate the pathogenesis of infertility, particularly idiopathic infertility, with the goal of providing novel approaches for diagnosis, treatment, and prevention of male and female infertility.

Nutrition, Metabolism, Circadian Rhythms, and Reproduction

Strategic Plan Theme 2: Promoting Gynecologic, Andrologic, and Reproductive Health
Strategic Plan Cross-Cutting Topic: Nutrition

Gap: The individual contributions of nutrition, metabolism, and circadian rhythms to the regulation of reproduction are known. Recently, conditions such as polycystic ovary syndrome (PCOS) illustrate the inter-relationship of metabolic disturbances and sleep disorders in the dysregulation of normal reproductive function. Additional systematic and integrated studies of the roles of these various inputs in the maintenance of normal reproductive function are needed to better understand the potential involvement of these collective inputs to the etiology of some fertility-related disorders such as PCOS.

Priority: Research that examines integration of nutritional, metabolic, and circadian cues in regulating fertility, with emphasis on the use of ‘omics technologies, including microbiomics and metabolomics.

Early Reproductive Transitions

Strategic Plan Theme 1: Understanding the Molecular, Cellular and Structural Basis of Development
Strategic Plan Theme 2: Promoting Gynecologic, Andrologic, and Reproductive Health
Strategic Plan Theme 4: Improving Child and Adolescent Health and the Transition to Adulthood
Strategic Plan Cross-Cutting Topic: Disease Prevention

Gap: The reproductive system is unique in that it undergoes profound functional and structural changes at different points in the normal lifespan, yet strong indicators of the onset or completion of those changes are lacking. Studies to identify novel markers and key regulators of embryonic gonad and reproductive tract development, pubertal maturation, and the adolescent transition to adulthood are critical to distinguish normal transitional development from atypical development. Identification of potential problems with reproductive tract development, such as cryptorchidism or hypospadias, or early diagnosis of reproductive diseases and disorders that can affect fertility in adulthood would facilitate prevention and/or treatment strategies.

Priority: Identify reliable biomarkers and key regulators of reproductive transitions with emphasis on typical and atypical embryonic development of the reproductive tract, gonads and gametes, pubertal maturation, and the adolescent transition, particularly among diverse populations.

  • Researchers: RMN data is now available in NICHD's Data and Specimen Hub (DASH)
  • University of Virginia Ligand Assay and Analysis Core external link: Provides high-quality and cost-effective assay services
  • Trans-NIH Strategic Plan for Women’s Health Research: This 5-year plan highlights a multipronged pathway to advance a vision in which sex and gender influences are integrated into the biomedical research enterprise; every woman receives evidence-based disease prevention and treatment tailored to her own needs, circumstances, and goals; and women in science careers reach their full potential
  • Human Infertility Allele Database external link: This NICHD-funded resource lists experimentally validated benign and deleterious single nucleotide polymorphisms in genes associated with human infertility
  • Interlome Gene List external link : This gene variant database presents NICHD-funded research on pathogenic variants of human genes that are associated with fetal lethality, spontaneous pregnancy loss, recurrent pregnancy loss, intrauterine fetal demise, stillbirth, and neonatal mortality.
  • Recurrent Pregnancy Loss Data Sets external link: This -omics data repository presents NICHD-funded research on recurrent pregnancy loss. It integrates genetic, clinical, and molecular phenotypic data to discover novel genes and genetic variants that contribute to pregnancy loss and to improve prediction of the loss.
  • Teede, H. J., Misso, M. L., Costello, M. F., Dokras, A., Laven, J., Piltonen, T., Normal, R. J., and the International PCOS Network. (2018). Recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome. Clinical Endocrinology, 89, 3 251–268. PMID: 30024653.

  • Daniel Johnston, Acting Branch Chief
    Main Research Areas: Epididymis; sperm; testis; contraception
  • Susan Taymans, Deputy Branch Chief and Program Director
    Main Research Areas: Genetic and epigenetic control of early germ cell development and meiosis; fertility preservation; ovarian function and dysfunction; primary ovarian insufficiency; fertility status and overall health; sex determination and differentiation (in the context of fertility and infertility); training for graduate students and postdoctoral fellows in reproductive health
  • Clara Cheng, Program Director
    Main Research Areas: Trophoblast development and differentiation; early placental formation; female reproductive tract (oviduct, uterus, vagina); uterine function and implantation biology; implantation-based early pregnancy loss; interplay of immune and endocrine systems in blastocyst-uterine interaction
  • Emily Jay, Staff Assistant
  • Travis Kent, Program Officer
    Main Research Areas: Spermatogenesis; testis biology; sperm function; male reproductive tract (including epididymis and seminal vesicles); semen content; fertilization; sperm/semen contribution to offspring fitness; NCTRI
  • Ying Liu, Program Analyst
  • Ravi Ravindranath, Program Director
    Main Research Areas: Totipotent and pluripotent stem cells; embryonic and induced pluripotent stem cells; reprogramming; oocyte quality and developmental competence; genetics and epigenetics of preimplantation embryo; reproductive neuroendocrinology; gonadotropins; metabolic signals and reproduction; reproductive behavior
  • Aritro Sen, Program Officer
    Main Research Areas: Reproductive medicine and infertility; infertility and disease disorders; assisted reproductive technology; strategies for diagnosis and management of infertility; polycystic ovary syndrome; training of clinical scientists in reproductive health; Small Business Innovation Research/Small Business Technology Transfer

Highlights

Our branch is hiring! Visit our Jobs page to learn more about our listing for FIB chief.

Road to Prevention of Stillbirth Requests for Applications (RFAs). NIH has published two RFAs to fund research centers and a data coordinating center that will form an integrated and collaborative Stillbirth Research Consortium. This consortium will support stillbirth-relevant basic, translational, clinical, and/or data sciences research across the United States, with a particular emphasis on ways to decrease the incidence of stillbirth in vulnerable populations. 

Uterine Fibroids and Women’s Health. Learn about NICHD support of research on uterine fibroids and women's health, and review some recent advances in understanding, diagnosing, and treating them.

Assisted Reproductive Technology (ART) and Women's Health. Learn about NICHD support of research on ART and women's health, and review some recent advances in advancing ART methods, achieving optimal conditions for ART, and understanding its long-term effects.

Polycystic Ovary Syndrome (PCOS) and Women's Health. Learn about NICHD support of research on PCOS and women's health, and review some recent advances in understanding, diagnosing, and treating this condition.

Infertility and Women's Health. Learn about NICHD support of research on infertility and learn about some recent advances in understanding, diagnosing, and treating this common condition in males and females.

Endometriosis and Women's Health. Learn about NICHD support of research on endometriosis and learn about some recent advances in understanding, diagnosing, and treating this common gynecologic condition.

Get to Know NICHD! Learn more about what inspired FIB Acting Chief Dr. Daniel Johnston and Program Officer Dr. Travis Kent to pursue science and how their decisions and experiences led them to their careers with NICHD.

Workshop on Idiopathic/Non-Aneuploid Early Pregnancy Loss (EPL): The State of the Science. This workshop, held July 22-23, 2021, included discussions of knowledge gaps, barriers to advancing the science, promising approaches, and needed tools for EPL research. Access recordings from Day 1 and Day 2, or the workshop program (PDF 160 KB) for additional information.

Physiomimetics and Organoids for Reproductive Health. This workshop, held September 23-24, 2021, focused on physiomimetics, sometimes called “organs-on-a-chip,” and organoids, and applications of these technologies for reproductive health research. Access recordings from Day 1 and Day 2, or the meeting summary (PDF 469 KB) for additional information.

 

Advancing Bioprinting and Regenerative Medicine Solutions for Obstetric, Gynecologic, and Pediatric Applications Workshop. This workshop, held November 16-17, 2021, was a transdisciplinary discussion on the state-of-the-science of tissue-construct manufacturing using 3D printing of biological, cellular, and tissue-based products (a.k.a., bioprinting) and regenerative medicine in the context of obstetric, gynecologic, and pediatric applications. Access recordings from Day 1 and Day 2.

Some recent findings from FIB-supported researchers include the following:

  • Gene variant involved in genome integrity and male infertility. Even though male infertility affects millions of couples, the cause of primary infertility in males remains largely unknown. In a genomic study of spermatogenic failure, FIB-funded scientists from the GEnetics of Male INfertility Initiative identified single nucleotide variants (SNVs) in germ-cell nuclear antigen (GCNA), a gene on the X chromosome critical for genome integrity in male meiosis. All the identified SNVs had an extremely low minor allele frequency in the general population but were found in 7 men with spermatogenic failure in the cohort of approximately 2,200 participants. Five identified SNVs occur in key functional regions, suggesting that they disrupt structure and function of the GCNA protein, ultimately arresting germ-cell division. This is the first study implicating GCNA, a key genome integrity factor, in human male infertility. (PMID: 33963445)
  • New in vitro system for mammalian meiosis. Despite conservation from yeast to humans of the chromosome structures and the fundamental molecules involved in meiosis, the trigger for meiosis differs across species, and for humans, is still unknown. In yeast, nutrient deprivation triggers meiosis; in mammals, retinoic acid (RA) and its downstream targets, while necessary for meiosis, are not sufficient to trigger it. This knowledge gap prevented scientists from initiating mammalian meiosis and spermatogenesis in vitro. In this FIB-funded study, Dr. Ning Wang and colleagues showed that nutrient deprivation plus RA, but neither alone, induced meiosis in primary mouse spermatocytes cultured without somatic cells. The combination induced both the expression of meiosis-specific genes and DNA double strand breaks. Switching these induced cells to a "meiotic progression" medium allowed them to develop to the early pachytene stage, and to form chromosomal synapses. Transcriptomic analysis of the nutrient-deprived cells identified 11 transcription factor genes that were upregulated, and associated with early meiosis in vivo, independently of RA. In addition to identifying key players in meiotic initiation, this work also establishes a valuable in vitro system for studying meiosis and producing male haploid gametes. (PMID: 33741948)
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