Center for Reproductive Medicine

Brussels, Belgium

Center for Reproductive Medicine

Brussels, Belgium
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News Article | May 25, 2017
Site: www.eurekalert.org

The 22q11.2 region of human chromosome 22 is a hotspot for a variety of birth defects. Scientists learned about this region because it is deleted in about 1 in 4,000 births, causing the loss or duplication of up to 40 genes. This chromosome microdeletion or microduplication can result in a number of developmental abnormalities that vary greatly in severity among affected individuals. What many of the genes in this region do is not well understood, but when a set of these genes is absent it can cause havoc in the development and function of the heart, immune system and craniofacial features, as well as cognitive and behavioral issues. About 30 percent of individuals with the condition, called DiGeorge syndrome or 22q11.2 deletion syndrome, may also present with developmental abnormalities in the genitourinary system, both the upper- and the lower-tract defects. Congenital genitourinary birth defects, whether they occur as part of a syndrome such as DiGeorge syndrome or as isolated congenital abnormalities, are among the most common types of birth defects. Cryptorchidism, or undescended testis, occurs in about 6 percent of full-term male births, and hypospadias, a defect in which the opening of the urethra is not located at the tip of the penis, is seen in 1 in 250 male births. Defining the causes of genitourinary birth defects has been a focus of research investigations in Dr. Dolores Lamb's laboratory for many years. "About 12 years ago, we began studying genitourinary birth defects with a technique called array comparative genomic hybridization, which is essentially like a molecular karyotype that has very high resolution so we can see little gains or losses in regions of chromosomes," Lamb said. "We studied a number of unrelated children with cryptorchidism or hypospadias using this technology and found that about 20 percent of them had microdeletions or microduplications that clustered in specific regions of different chromosomes. One small deleted or duplicated chromosome region associated with these genitourinary conditions is 22q11.2. The children, however, were not diagnosed with DiGeorge syndrome." The researchers found that the changes were 'de novo,' or new in the children, meaning they were not present in the parents. Lamb and colleagues set out to identify which genes in 22q11.2 would be most likely involved in the abnormal development of the genitourinary system. If these genes were identified and their functions understood, researchers could then develop diagnostic tools and potential treatments for individuals affected by this condition. Finding genes involved in developmental disorders is like finding the missing or altered pieces in a complex, broken machine for which we don't have the blue print. Scientists use several strategies to find gene candidates and test their functions in the lab. In this case, Lamb and colleagues took a two-pronged approach. On one side, they looked at copy number variations, both duplications and deletions, of genes in the 22q11.2 region of patients with DiGeorge syndrome who also presented with genitourinary abnormalities. The analysis, together with creative thinking about potential pathways impacted by a gene dosage change, led the team to suspect a gene called CRKL was the most likely candidate at 22q11.2 to be involved in genitourinary abnormalities as a result of gene duplication or deletion. Further analysis showed that in humans CRKL is expressed in a variety of fetal tissues, including liver, lung, skeletal muscle, as well as in the heart, spleen, thymus, brain and kidney, which are relevant to DiGeorge syndrome. In the mouse and human, this gene is expressed modestly throughout development, including in the developing genitourinary tract. These results led the researchers to their next step toward determining CRKL's involvement in genitourinary defects. The researchers genetically engineered mice to lack crkl. One group of mice lacked both copies of the gene, the one received from the mother and the one passed on by the father, while another group lacked only one of the two crkl copies. Lacking both copies of the gene was lethal for the embryos, highlighting the importance of crkl in embryonic development. Analysis of both groups of embryos showed intrauterine growth restriction. In addition to having neural, heart and other congenital defects, about 23 percent of the mice exhibited severe kidney abnormalities. Like the human patients, the male mice lacking one copy of crkl had failure of testicular descent into the scrotum (cryptorchidism) resulting in fewer-than-average number of pups per litter, and with aging this sub-fertility progressed to male infertility. Further analysis showed that crkl regulates genitourinary development by altering expression of at least 52 DNA transcripts. "Our data show that having CRKL gene dosage changes in this region, including the loss of one copy of CRKL, can negatively affect normal genitourinary (specifically testicular descent) and kidney development," Lamb said. "CRKL has partial penetrance, so we see that some patients are affected while others aren't. There is a spectrum of severity between different individuals and this inter-individual variation was present even in the mouse model." "Our work has significant implications for initial patient diagnosis," Lamb said. "The research findings imply that patients with genitourinary birth defects due to 22q11.2 changes in gene dosage should also be evaluated for other potential birth defects seen in patients with DiGeorge syndrome that would affect the patient's future health. This is important because some of the genes in region 22q11.2 affect brain development and behavior and/or cognitive function, autism spectrum disorder, schizophrenia, bipolar disorder, heart, hearing or autoimmune defects depending on which gene in this region is affected. The genitourinary birth defect may not be the only health issue needing to be clinically evaluated." Read all the details about this study in the Proceedings of the National Academy of Sciences. Dr. Dolores Lamb is the director of the Center for Reproductive Medicine and a professor in the Scott Department of Urology and in the Department of Molecular and Cellular Biology at Baylor College of Medicine. She also is the Lester and Sue Smith Chair in Urologic Research. Dr. Meade Haller (who undertook these studies as part of her doctoral dissertation) and Dr. Qianxing Mo, from Baylor College of Medicine, and Dr. Akira Imamoto from the University of Chicago, also contributed to this work. This work was funded by National Institutes of Health Grants T32DK007763 and R01DK078121.


NORWALK, Conn.--(BUSINESS WIRE)--The Multiple Myeloma Research Foundation (MMRF) today announced that Ronald O. Perelman and Dr. Anna Chapman, through the Perelman Family Foundation, have committed more than $4 million in funding to launch the first ever research program solely dedicated to the early detection and prevention of multiple myeloma. This generous donation will seed the launch of the groundbreaking Perelman Family Foundation Early Disease Translational Research Program, part of the MMRF Prevention Project, to speed efforts toward early detection, delayed disease progression, and eventually, ultimately, prevention of this incurable disease. “The goal of this initiative is to develop a completely new paradigm for research in multiple myeloma, focusing on early detection and ultimately, prevention. Right now, detection of this terrible disease often comes too late. Unlike most cancers, early detection of multiple myeloma doesn't increase a person’s chance of survival under current treatment options. The Perelman Family Foundation Early Disease Translational Research Program will support research focused on improving outcomes after early detection. With the MMRF and our university partners, we are confident that we will be able to make breakthroughs for multiple myeloma patients, and that the program will serve as a model for future initiatives,” said Dr. Anna Chapman. The gift from the Perelman Family Foundation provides a catalyst for essential research focused on: better understanding genomic determinants of early disease progression; how microenvironment factors influence early disease progression; and enhancing patient tumor immunity. Perelman Family Foundation Early Disease Translational Research Program brings together six leading cancer research centers: Dana-Farber Cancer Institute, Memorial Sloan Kettering Cancer Center, MD Anderson Cancer Center, Rockefeller University, University of Arkansas for Medical Science, Yale University, as well as the MMRF. The studies conducted by these teams will identify novel targets and biomarkers of disease progression and enable the development of therapeutic approaches to delay or even stop progression to myeloma. “We are so thankful to Ronald and Anna for supporting our vision for a bold program that will take us one step closer to a future where our children and grandchildren will never need to worry about incurable cancers,” said the Multiple Myeloma Research Foundation Founder Kathy Giusti. “Not only does the MMRF answer the questions of patients today and urgently deliver them the precise information and treatment they need to fight their multiple myeloma, but, with this generous donation, we will now also be able to focus on the patients of tomorrow.” Inspired by the dedication and vision of its Chairman and CEO Ronald O. Perelman and his family, the Perelman Family Foundation is firmly committed to philanthropy, focusing on women’s health, education and the arts. Ranked among the top philanthropists in the United States, Mr. Perelman is the founder of the Revlon/UCLA Women’s Cancer Research Program, which analyzes the causes of and develops groundbreaking treatment for breast and ovarian cancer. Launched in 1994, the program was responsible for the development of Herceptin, the first genetically-based treatment for a major cancer to be approved by the FDA, which currently cures more than thirty percent of breast cancer cases in women. In 2014, he co-founded, along with Barbra Streisand, the Women’s Heart Alliance to raise awareness, encourage action and drive new research to fight heart disease in women. Through the Perelman Family Foundation, Mr. Perelman supports the Ronald O. Perelman Center for Emergency Services and the Ronald O. Perelman Department of Dermatology at NYU Langone Medical Center; the Ronald O. Perelman Heart Institute at New York Presbyterian Hospital, an internationally-recognized center offering comprehensive, innovative, and world-class cardiovascular care and heart health education; and the Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine at Weill Cornell Medicine. Multiple myeloma is a cancer of the plasma cell. It is the second most common blood cancer. An estimated 30,280 adults will be diagnosed this year and 12,590 people are predicted to die from the disease. The mission of the Multiple Myeloma Research Foundation (MMRF) is to find a cure for multiple myeloma by relentless pursuing innovation that accelerates the development of next-generation treatments to extend the lives of patients. Founded in 1998 by Kathy Giusti, a multiple myeloma patient, and her twin sister Karen Andrews as a 501 (c) (3) nonprofit organization, the MMRF is a world-recognized leader in cancer research. Together with its partners, the MMRF has created the only end-to-end solution in precision medicine and the single largest genomic dataset in all cancers. The MMRF continues to disrupt the industry today, as a pioneer and leader at the helm of new research efforts. Since its inception, the organization has raised over $350 million and directs nearly 90% of the total funds to research and related programs. As a result, the MMRF has been awarded by Charity Navigator’s coveted four-star rating for 12 years, the highest designation for outstanding fiscal responsibility and exceptional efficiency.


Stoop D.,Center for Reproductive Medicine | Cobo A.,IVI Valencia | Silber S.,St Lukes Hospital
The Lancet | Year: 2014

Cryopreservation of eggs or ovarian tissue to preserve fertility for patients with cancer has been studied since 1994 with R G Gosden's paper describing restoration of fertility in oophorectomised sheep, and for decades previously by others in smaller mammals. Clinically this approach has shown great success. Many healthy children have been born from eggs cryopreserved with the Kuwayama egg vitrifi cation technique for non-medical (social) indications, but until now very few patients with cancer have achieved pregnancy with cryopreserved eggs. Often, oncologists do not wish to delay cancer treatment while the patient goes through multiple ovarian stimulation cycles to retrieve eggs, and the patient can only start using the oocytes after full recovery from cancer. Ovarian stimulation and egg retrieval is not a barrier for patients without cancer who wish to delay childbearing, which makes oocyte cryopreservation increasingly popular to overcome an age-related decline in fertility. Cryopreservation of ovarian tissue is an option if egg cryopreservation is ruled out. More than 37 babies have been born so far with cryopreserved ovarian tissue in patients with cancer who have had a complete return of hormonal function, and fertility to baseline. Both egg and ovarian tissue cryopreservation might be ready for application to the preservation of fertility not only in patients with cancer but also in countering the increasing incidence of age-related decline in female fertility.


De Vos M.,Center for Reproductive Medicine | Devroey P.,Center for Reproductive Medicine | Fauser B.C.,University Utrecht
The Lancet | Year: 2010

Primary ovarian insufficiency is a subclass of ovarian dysfunction in which the cause is within the ovary. In most cases, an unknown mechanism leads to premature exhaustion of the resting pool of primordial follicles. Primary ovarian insufficiency might also result from genetic defects, chemotherapy, radiotherapy, or surgery. The main symptom is absence of regular menstrual cycles, and the diagnosis is confirmed by detection of raised follicle-stimulating hormone and declined oestradiol concentrations in the serum, suggesting a primary ovarian defect. The disorder usually leads to sterility, and has a large effect on reproductive health when it arises at a young age. Fertility-preservation options can be offered to some patients with cancer and those at risk of early menopause, such as those with familial cases of primary ovarian insufficiency. Long-term deprivation of oestrogen has serious implications for female health in general; and for bone density, cardiovascular and neurological systems, wellbeing, and sexual health in particular. © 2010 Elsevier Ltd.


De Vos M.,Center for Reproductive Medicine | Smitz J.,Laboratory of Clinical Chemistry and Radioimmunology | Woodruff T.K.,Northwestern University
The Lancet | Year: 2014

Enhanced long-term survival rates of young women with cancer and advances in reproductive medicine and cryobiology have culminated in an increased interest in fertility preservation methods in girls and young women with cancer. Present data suggest that young patients with cancer should be referred for fertility preservation counselling quickly to help with their coping process. Although the clinical application of novel developments, including oocyte vitrification and oocyte maturation in vitro, has resulted in reasonable success rates in assisted reproduction programmes, experience with these techniques in the setting of fertility preservation is in its infancy. It is hoped that these and other approaches, some of which are still regarded as experimental (eg, ovarian tissue cryopreservation, pharmacological protection against gonadotoxic agents, in-vitro follicle growth, and follicle transplantation) will be optimised and become established within the next decade. Unravelling the complex mechanisms of activation and suppression of follicle growth will not only expand the care of thousands of women diagnosed with cancer, but also inform the care of millions of women confronted with reduced reproductive fitness because of ageing.


Roque M.,Center for Reproductive Medicine | Esteves S.C.,Center for Male Reproduction
Asian Journal of Andrology | Year: 2016

A systematic review was conducted to identify and qualitatively analyze the methods as well as recommendations of Clinical Practice Guidelines (CPG) and Best Practice Statements (BPS) concerning varicocele in the pediatric and adolescent population. An electronic search was performed with the MEDLINE, EMBASE, Science Direct, and Scielo databases, as well as guidelines′ Web sites until September 2015. Four guidelines were included in the qualitative synthesis. In general, the recommendations provided by the CPG/BPS were consistent despite the existence of some gaps across the studies. The guidelines issued by the American Urological Association (AUA) and American Society for Reproductive Medicine (ASRM) did not provide evidence-based levels for the recommendations given. Most of the recommendations given by the European Association of Urology (EAU) and European Society of Pediatric Urology (ESPU) were derived from nonrandomized clinical trials, retrospective studies, and expert opinion. Among all CPG/BPS, only one was specifically designed for the pediatric population. The studied guidelines did not undertake independent cost-effectiveness and risk-benefit analysis. The main objectives of these guidelines were to translate the best evidence into practice and provide a framework of standardized care while maintaining clinical autonomy and physician judgment. However, the limitations identified in the CPG/BPS for the diagnosis and management of varicocele in children and adolescents indicate ample opportunities for research and future incorporation of higher quality standards in patient care. © 2016 AJA, SIMM & SJTU.


Devroey P.,Center for Reproductive Medicine | Polyzos N.P.,Center for Reproductive Medicine | Blockeel C.,Center for Reproductive Medicine
Human Reproduction | Year: 2011

Published data indicate a significant increase in ovarian hyperstimulation syndrome globally. The occurrence of approximately three maternal deaths per 100 000 stimulated women has been reported, and extrapolation of these figures to a global situation would give an impressive number. The syndrome can be erased by applying ovarian stimulation using the combination of GnRH antagonist with GnRH agonist to trigger ovulation. In this case, the strategy is to freeze all of the oocytes or embryos for later use. © 2011 The Author.


Goossens E.,Vrije Universiteit Brussel | Van Saen D.,Center for Reproductive Medicine | Tournaye H.,Vrije Universiteit Brussel | Tournaye H.,Center for Reproductive Medicine
Human Reproduction | Year: 2013

STUDY QUESTION: What issues remain to be solved before fertility preservation and transplantation can be offered to prepubertal boys? SUMMARY ANSWER: The main issues that need further investigation are malignant cell decontamination, improvement of in vivo fertility restoration and in vitro maturation.WHAT IS KNOWN ALREADYPrepubertal boys who need gonadotoxic treatment might render sterile for the rest of their life. As these boys do not yet produce sperm cells, they cannot benefit from sperm banking. Spermatogonial stem cell (SSC) banking followed by autologous transplantation has been proposed as a fertility preservation strategy. But before this technique can be applied in the clinic, some important issues have to be resolved.STUDY DESIGN, SIZE DURATIONOriginal articles as well as review articles published in English were included in a search of the literature.PARTICIPANTS/MATERIALS, SETTING, METHODSRelevant studies were selected by an extensive Medline search. Search terms were fertility preservation, cryopreservation, prepubertal, SSC, testis tissue, transplantation, grafting and in vitro spermatogenesis. The final number of studies selected for this review was 102. MAIN RESULTS AND THE ROLE OF CHANCE: Cryopreservation protocols for testicular tissue have been developed and are already being used in the clinic. Since the efficiency and safety of SSC transplantation have been reported in mice, transplantation methods are now being adapted to the human testes. Very recently, a few publications reported on in vitro spermatogenesis in mice, but this technique is still far from being applied in a clinical setting. LIMITATIONS, REASONS FOR CAUTION: Using tissue from cancer patients holds a potential risk for contamination of the collected testicular tissue. Therefore, it is of immense importance to separate malignant cells from the cell suspension before transplantation. Because biopsies obtained from young boys are small and contain only few SSCs, propagation of these cells in vitro will be necessary. WIDER IMPLICATIONS OF THE FINDINGS: The ultimate use of the banked tissue will depend on the patient's disease. If the patient was suffering from a non-malignant disease, tissue grafting might be offered. In cancer patients, decontaminated cell suspensions will be injected in the testis. For patients with Klinefelter syndrome, the only option would be in vitro spermatogenesis. However, at present, restoring fertility in cancer and Klinefelter patients is not yet possible. STUDY FUNDING/COMPETING INTEREST(S): Research Foundation, Flanders (G.0385.08 to H.T.), the Institute for the Agency for Innovation, Belgium (IWT/SB/111245 to E.G.), the Flemish League against Cancer (to E.G.), Kom op tegen kanker (G.0547.11 to H.T.) and the Fund Willy Gepts (to HT). E.G. is a Postdoctoral Fellow of the FWO, Research Foundation, Flanders. There are no conflicts of interest. © 2013 The Author.


The introduction of the technique of intracytoplasmic sperm injection to achieve fertilization, especially using surgically retrieved testicular or epididymal sperm from men with obstructive or non-obstructive azoospermia, has revolutionized the field of assisted reproduction. The techniques for the retrieval of spermatozoa vary from relatively simple percutaneous sperm aspiration to open excision (testicular biopsy) and the more invasive Micro-TESE. The probability of retrieving spermatozoa can be as high as 100% in men with obstructive azoospermia (congenital bilateral absence of the vas deferens, status post-vasectomy). However, in nonobstructive azoospermia, successful sperm retrieval has been reported in 10-100% of cases by various investigators. The surgical retrieval and cryopreservation of sperm, especially in men with non-obstructive azoospermia, to some extent ensures the availability of sperm at the time of intracytoplasmic sperm injection. In addition, this strategy can avoid unnecessary ovarian stimulation in those patients intending to undergo in vitro fertilization-intracytoplasmic sperm injection with freshly retrieved testicular sperm when an absolute absence of sperm in the testis is identified. Several different methods for the cryopreservation of testicular and epididymal sperm are available. The choice of the container or carrier may be an important consideration and should take into account the number or concentration of the sperm in the final preparation. When the number of sperm in a testicular biopsy sample is extremely low (e.g., 1-20 total sperm available), the use of an evacuated zona pellucida to store the cryopreserved sperm has been shown to be an effective approach. © 2013 CLINICS.


Roque M.,Center for Reproductive Medicine
Journal of Assisted Reproduction and Genetics | Year: 2015

Purpose: This publication will evaluate the available evidence in the literature comparing fresh embryo transfer (ET) and elective frozen-thawed embryo transfer (FET) regarding the possible interference of controlled ovarian stimulation (COS) in implantation and endometrial receptivity, IVF safety, and obstetric and perinatal outcomes.Methods: We performed a review in the literature of the available evidence comparing fresh to elective FET (freeze-all policy).Results: The improvements made in cryopreservation techniques have led to few or no detrimental effects to the embryo and have resulted in no consequences to the offspring when compared to fresh embryos; this has allowed reproductive practitioners to create the freeze-all policy (when all viable embryos are electively cryopreserved in the fresh cycle and transferred in a posterior cycle). There are increasing concerns about the adverse effects associated with COS over the endometrial and uterine environments, as well as with the safety of COS in pregnancies that have originated from fresh ET during in vitro fertilization (IVF) treatments. COS may contribute to modifications in the endometrium, which might be related to poorer outcomes when fresh ET is performed. It has been suggested that obstetric and perinatal outcomes in pregnancies resulting from fresh ET are poorer when compared with those that occur after FET. In cycles with fresh ET, there is still a risk of ovarian hyperstimulation syndrome (OHSS).Conclusion: There is growing evidence in the literature suggesting better IVF outcomes, and decreased obstetric and perinatal morbidity when adopting the freeze-all policy instead of fresh ET. © 2014, Springer Science+Business Media New York.

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