Fertility and Infertility Branch (FIB)

FertilizationOverview/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.


Highlights

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 (site works best in Firefox and Chrome).

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

  • 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)

  • High-fat diet in polycystic ovary syndrome (PCOS) women is linked to defects in placenta. PCOS affects 5-15% of reproductive-age women in the United States, often causing subfertility because of the endocrine and metabolic dysfunction that occur with the syndrome. Dr. Antonio Frias and colleagues studied a primate (macaque) model of PCOS to examine how high levels of maternal testosterone and nutrition interact to influence the placenta. They found that a high-fat, Western-style diet (WSD) had significant deleterious effects on placental blood flow as compared to animals receiving a normal diet, while testosterone had negative effects on the formation of fetal blood vessels. The combination of WSD and high testosterone levels act through different mechanisms but, together, have large negative effects on overall placenta function. (PMID: 31180495)

  • Primate born using sperm from frozen juvenile testicular tissue. Cancer treatment can spare a young boy’s life, at the cost of his future fertility. Currently, no options exist for fertility preservation for boys who are too young to produce sperm. Dr. Kyle Orwig and his colleagues grafted cryopreserved testicular sections taken from juvenile rhesus macaques back into the original donors after puberty. The grafts grew and made testosterone and sperm, which in one case resulted in a successful pregnancy and live birth. This is the first proof that immature testicular tissue can be preserved and used later to restore fertility. (PMID: 30898927)
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