Fertility and Infertility Branch (FIB)

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 normal 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.

Fertility Preservation: Supports basic, clinical, and translational research designed to preserve reproductive capacity in individuals who are or may become infertile
Male Reproductive Health: Supports research on the physiology and pathophysiology of male reproduction
Ovarian Function and Dysfunction: Supports research on the function of the ovary
Preimplantation Genetics and Development: Studies the genetic and epigenetic control mechanisms that affect the quality of oocytes and preimplantation embryos
Embryonic Gonad and Germ Cell Development: Examines embryonic development of the gonads and germ cells
Reproductive Medicine Infertility: Studies etiology and pathophysiology of diseases and disorders that cause human infertility and impaired fecundity
Reproductive Neuroendocrinology: Addresses the central neurobiological mechanisms governing gametogenesis and ovulation
Uterine Function and Implantation Biology: Supports basic research studies on uterine function involving molecular-, cellular-, tissue-, and organ-level approaches
Dual Purpose with Dual Benefit: Research in Biomedicine and Agriculture Using Agriculturally Important Domestic Animal Species (An Interagency Partnership): Promotes the use of agriculturally important domestic animal species in basic and translational research relevant to both biomedicine and agriculture
National Centers for Translational Research in Reproduction and Infertility (NCTRI): Promotes multidisciplinary interactions between basic and clinical scientists interested in establishing high-quality translational research programs in the reproductive sciences
Reproductive Medicine Network (RMN): Conducts large, multicenter clinical trials of diagnostic and therapeutic interventions for male and female infertility and reproductive diseases and disorders
Clinical Reproductive Scientist Training (CREST) Program: In partnership with American Society for Reproductive Medicine, trains reproductive endocrinology and infertility specialists in the conduct of clinical research
Reproductive Scientist Development Program (RSDP): Develops a cadre of reproductive physician-scientists based in academic departments to address important problems in the field of obstetrics and gynecology

Branch-Funded Projects

Now in NICHD's Data and Specimen Hub (DASH): Reproductive Medicine Network Data
University of Virginia Ligand Assay and Analysis Core : Provides high-quality and cost-effective assay services
RMN Data and Specimen Repository : Stores data and specimens of completed RMN trials that may be used by researchers
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
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. The full text of the guideline is available at https://www.monash.edu/medicine/sphpm/mchri/pcos/guideline .

Louis DePaolo, Branch Chief
Main Research Areas: CREST program; RSDP; translational research in reproduction
Clara Cheng, Program Officer
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
Esther Eisenberg, Program Director and Project Scientist
Main Research Areas: Assisted reproductive technology; reproductive medicine and infertility (includes infertility disorders and reproductive disorders that impact fertility such as endometriosis); RMN; polycystic ovary syndrome; female reproductive tract (oviduct, uterus, vagina); endometrial function and implantation biology; clinical trials
Stuart Moss, Program Director
Main Research Areas: Male reproductive health (includes testis biology, sperm development and function, and hormone production); NCTRI
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
Susan Taymans, 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; sex determination and differentiation (in the context of fertility and infertility); training for graduate students and postdoctoral fellows in reproductive health

Highlights

Human Infertility Allele Database . This NICHD-funded resource lists experimentally validated benign and deleterious single nucleotide polymorphisms in genes associated with human infertility (site works best in Firefox and Chrome).

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 of 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)

TEAD4 and early pregnancy loss. Reproductive success in placental mammals relies on proper development of the trophoblast lineage. A proper balance of self-renewal versus differentiation of trophoblast progenitors is particularly critical for establishment of pregnancy. Dr. Soumen Paul and colleagues at the University of Kansas studied the role of TEAD4, a Hippo signaling effector, on trophoblast development in early post-implantation mouse embryos. They showed that loss of the Tead4 gene in trophoblast progenitors of mutant mice resulted in insufficient numbers of post-implantation trophoblasts, leading to embryo death at the developmental stage equivalent to the first trimester of human gestation. They also found that a subset of patients with unexplained recurrent pregnancy loss had attenuated TEAD4 expression. The trophoblast progenitor cells derived from the patients’ placentae were defective in self-renewal, but rescue of TEAD4 expression restored it. Taken together, these data revealed an evolutionarily conserved mechanism whereby TEAD4 maintains the stem-ness and promotes self-renewal of trophoblast progenitors in post-implantation embryos to ensure successful placentation and progression of pregnancy. (PMID: 32669432)

Advances in understanding the timing of puberty. The mechanism through which genetic, nutritional, and environmental factors interact to control the onset of puberty is not well understood, and doctors often struggle to manage patients whose puberty is atypically early or late. Now, two new FIB-funded studies provide important insights into the mechanistic underpinnings of early puberty and possible detection of children whose puberty may be delayed.
- In one study, Dr. Ursula Kaiser and her colleagues investigated how expression of the kisspeptin gene is regulated. They found that the protein encoded by the MKRN3 gene acts as a "brake" on puberty by ubiquitinating the promoters of KISS1 (encoding kisspeptin), and another gene called TAC3, preventing their expression. When Mkrn3 levels fall, which normally occurs as puberty approaches, the lack of ubiquitination allows expression of KISS1 and TAC3, which in turn stimulate gonadotropin-releasing hormone (GnRH) and luteinizing hormone (LH) release. This suggests that mutations in the gene encoding Mkrn3 could cause precocious (early onset) puberty in children. (PMID: 32407292)
- In a second study supported through the National Center for Translational Research in Reproduction and Infertility (NCTRI) at Harvard University, Dr. Stephanie Seminara and her colleagues tested whether injection of kisspeptin, which stimulates GnRH release, can be used to predict outcomes for individuals with pubertal delay. Among 3 girls and 13 boys followed longitudinally, one-half had a rise in LH in response to kisspeptin and subsequently progressed through puberty. In contrast, the other one-half had low LH responses to kisspeptin and showed no physical signs of puberty by the time they turned 18. The authors conclude that kisspeptin stimulation is a promising novel tool for predicting pubertal outcomes for children with delayed puberty. (PMID: 32232399)

Use of assisted reproductive technologies (ART) related to placenta defects in mice. Even though millions of ART-aided births occur every year, these procedures are associated with increased risks of preeclampsia, development of an abnormal placenta, and abnormal fetal growth. Dr. Marisa Bartolomei and her colleagues at the University of Pennsylvania NCTRI tested the effects of four individual ART procedures, hormone stimulation, in vitro fertilization (IVF), embryo culture, and embryo transfer, on placental development and fetal growth in mice. All four procedures led to reduced fetal weight (with some later recovery, however), and increased placental weight, with abnormalities in the blood supply that improve during development. The IVF treatment increased levels of an anti-angiogenic factor implicated in preeclampsia, and embryo culture caused hypomethylation of placental DNA. The results support the idea that ART procedures themselves cause pregnancy complications unrelated to underlying infertility. As embryo culture had the strongest effects, future studies should focus on optimizing embryo culture to ensure healthy outcomes for both mothers and offspring. (PMID: 32471820)

Inflammation of ovarian tissue surrounding oocytes may be related to female reproductive aging. As women age, their un-replenishable supply of oocytes declines, and the quality of their remaining oocytes declines, too. The underlying reason for these changes, however, is not clear. Dr. Francesca Duncan and her colleagues tested the novel hypothesis that the ovarian stroma, the environment surrounding the eggs, plays a key role in oocyte quality and quantity. Specifically, they hypothesized that with age, hyaluronan, a normal component of the stroma, fragments into damaging particles that drive inflammation in the stroma, which in turn compromises oocytes. They found that treating isolated ovarian stroma containing hyaluronan fragments drove accumulation of inflammatory cytokines, decreased estrogen production, damaged oocytes, and disrupted meiosis. These data demonstrate that hyaluronan fragments could contribute to female reproductive aging. (PMID: 32033185)

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Fertility and Infertility Branch (FIB)

Overview/Mission

Branch Research Priorities