Sub theme 1.8
Regulation of follicle development, oocyte and endometrial embryo quality


Goals of research: general outline
Scientific achievements
Future plans: special goals and approach
Running projects
Associated staff


Goals of research: general outline
  • Anovulatory infertility: Research focussing on classification of Anovulatory Infertility. Evidence Based approach of Anovulatory Infertility i.e. Prediction of Treatment and Pregnancy Outcome. Moreover, research is currently focussing on prevention and treatment of Obesity, Metabolic Syndrome, Cardio Vascular risks and Diabetes in these women. To this end longitudinal follow-up studies are performed in the largest meticulously phenotyped patient data base in the world which has been established in Erasmus MC within our department. Finally, genomic studies are focussing on genetic determinants of anovulatory infertility and treatment outcome in order to establish a more patient tailored individualised treatment.
  • Early Follicle Development: Research on Regulation of Early Follicle Development with special emphasis on the derangement of normal follicle development in Polycystic Ovary Syndrome (PCOS) and (premature) menopause. Clinical research is focussing on the incidence of infertility after childhood cancer treatment and prevention of ovarian dysfunction after cancer therapy during childhood and adulthood. The latter research is conducted in a large data set available within the local LATER outpatient clinic as well as within a national collaborative study of all LATER clinics in the Netherlands. 
  • Genetics of Infertility: Focussing on the genetic basis of complex diseases like PCOS and WHO II anovulatory Infertility as well as premature ovarian failure (POF). To this end we are using Genome Wide Association technology and micro-arrays as well as candidate gene approaches in the general-, patient- and founder-populations. This research is done in close collaboration with several international consortia with participants from the Netherlands, the United Kingdom, USA and Iceland. The future focus is to develop clinical applicable tests which can predict the individual risk of developing PCOS or POF. Moreover these instruments might gain insight in the pathophysiology and etiology of PCOS as well as POF. Valorisation of this knowledge is taken care of within a company called Genovum® in which erasmusMC and the department of OBGYN are the major shareholders.
  • Pregnancy outcome after ART: Strategies for optimizing patient selection as well as singleton pregnancies after ovulation induction. Cost effectiveness of different ovulation induction strategies. Optimization and simplification of IVF treatment and it’s perinatal- as well maternal-outcome.
Early Embryo development and early Stem cell development: Previous research from our group and others has shown that there is a high incidence of chromosomal abnormalities in human preimplantation embryos. Future research is directed at identifying underlying mechanisms for the lack of accuracy of chromosome segregation during cleavage divisions in human pre-implantation embryos in relation to oocyte and embryo quality. In later stages of in vitro embryo development, research is aimed at identifying signalling pathways involved in regulation of pluri-potency and differentiation within the developing human blastocysts, using extended culture of human surplus IVF embryos to the post-implantation stage.

Scientific achievements

Specific achievements in the fields of interest

Anovulatory infertility:

  • PCOS: The new definition of the diagnosis of PCOS is currently referred to as the Rotterdam consensus definition. This definition is still standing and being accepted widely as the best applicable diagnosis.
  • Several papers have been published assessing long term health risks resulting from PCOS in large patient and control populations establishing an increased risk for type II Diabetes and cardio vascular disease and Metabolic syndrome.
  • Ovarian reserve has been assessed in different populations at risk for early menopause or premature ovarian failure. These findings have been summarized in several original papers being the first to address these issues in well defined patient populations.

Early Follicle Development:

  • AMH seems to constitute the most promising and constant marker for ovarian ageing nowadays. During the last 5 years we have further elucidated how AMH is involved during early and late follicular recruitment and how it interacts with other known regulators of intra-ovarian response such as oestrogens and inhibins. Moreover, we have shown that expression and function in the human is very similar to that in rodents and other species. Finally, we have elucidated how genetic variation in either the AMH molecule itself or in the AMH type II receptor does affect the function of this intra-ovarian regulator of folliculogenesis.

Genetics of Infertility:

  • Research trying to identify genomic markers of this complex disease was quite successful during the past 5 years. Several new markers (GnRH, FSH and LH, and glucocorticoid receptor polymorphisms) which affect treatment outcome significantly have been identified and will be incorporated in newer patient tailored treatment algorithms in the near future.

Pregnancy outcome after ART:

  • During the last 5 years we have contributed largely to a new paradigm shifting from diagnosis to prognosis. Hence we have accomplished that newer treatment regimens are based on recent research findings of our group and have become more patient tailored. Based on (bio)clinical markers treatment regimens can be adjusted nowadays to meet the specific needs of individual patients. Predictors of treatment outcome have been identified and individualized costs effective treatment modalities have been developed.
  • A new prediction model has been developed which is currently accepted as the best prediction model to assess a couples chance on a spontaneous pregnancy and is this model is used worldwide on a large scale.

Early Embryo development and early Stem cell development:

  • Recently our group was the first to prove that in early human embryo’s paternal X inactivation takes place. Similarly, during meiosis sex chromosome inactivation has been elucidated in other species. And the process of meiotic silencing of heterologous chromatin has been studies in detail. These papers have contributed to the further understanding of these complex processes involved in spermato- as well as folliculogenesis.

Future plans: special goals and approach

Anovulatory infertility

  • Prevention and treatment of Obesity, Metabolic Syndrome, Cardio Vascular risks and Diabetes in women with PCOS. To this end longitudinal follow-up studies are performed in the largest meticulously phenotyped patient data base in the world which has been established in Erasmus MC within our department. This research will be conducted within local, national and international collaborations.

Genomic studies are focussing on genetic determinants of anovulatory infertility and treatment outcome in order to establish a more patient tailored individualised treatment.

 

Early Follicle Development

  • Clinical research is focussing on the incidence of infertility after childhood cancer treatment and prevention of ovarian dysfunction after cancer therapy during childhood and adulthood. The latter research is conducted in a large data set available within the local LATER outpatient clinic of Erasmus MC as well as within a national collaborative study of all LATER clinics in the Netherlands.

Genetics of infertility

  • Genome Wide Association technology and micro-arrays as well as candidate gene approaches in the general-, patient- and founder-populations. This research is done in close collaboration with several international consortia with participants from the Netherlands, the United Kingdom, USA and Iceland. The future focus is to develop clinical applicable tests which can predict the individual risk of developing PCOS or POF. Moreover these instruments might gain insight in the pathophysiology and etiology of PCOS as well as POF.
  • Valorisation of this knowledge is taken care of within a company called Genovum® in which erasmusMC and the department of OBGYN are the major shareholders.

Pregnancy outcome after ART

  • Strategies for optimizing patient selection as well as singleton pregnancies after ovulation induction. Cost effectiveness of different ovulation induction strategies. Optimization and simplification of IVF treatment and it’s perinatal- as well maternal-outcome. This research will be conducted within local, national and international collaborations.

Early Embryo development and early Stem cell development

  • Future research is directed at identifying underlying mechanisms for the lack of accuracy of chromosome segregation during cleavage divisions in human pre-implantation embryos in relation to oocyte and embryo quality. This research will be predominantly conducted within local collaborations.
  • Research in later stages of in vitro embryo development is aimed at identifying signalling pathways involved in regulation of pluripotency and differentiation within the developing human blastocysts, using extended culture of human surplus IVF embryos to the post-implantation stage. This research will be predominantly conducted within local collaborations.

Most recent publications

1.      De Vet, A., Laven, J.S.E., De Jong, F.H., Themmen, A.P.N., Fauser, B.C.J.M. Antimüllerian hormone serum levels: A putative marker for ovarian aging (2002) Fertility and Sterility, 77, pp. 357-362. Cited 180 times. IF: 3.168

2.       Balen, A.H., Laven, J.S.E., Tan, S.-L., Dewailly, D. Ultrasound assessment of the polycystic ovary: International consensus definitions (2003). Human Reproduction Update, 9, pp. 505-514. Cited 163 times. IF: 7.257

3.      Weenen, C., Laven, J.S.E., von Bergh, A.R.M., Cranfield, M., Groome, N.P., Visser, J.A., Kramer, P., Fauser, B.C.J.M., Themmen, A.P.N. Anti-Müllerian hormone expression pattern in the human ovary: Potential implications for initial and cyclic follicle recruitment (2004). Molecular Human Reproduction, 10, pp. 77-83. Cited 125 times. IF: 2.871

4.      Laven, J.S.E., Mulders, A.G.M.G.J., Visser, J.A., Themmen, A.P., De Jong, F.H., Fauser, B.C.J.M. Anti-Müllerian Hormone Serum Concentrations in Normoovulatory and Anovulatory Women of Reproductive Age (2004). Journal of Clinical Endocrinology and Metabolism, 89 (1), pp. 318-323. Cited 76 times. IF: 5.493

5.      Laven, J.S.E., Imani, B., Eijkemans, M.J.C., Fauser, B.C.J.M. New approach to polycystic ovary syndrome and other forms of anovulatory infertility (2002). Obstetrical and Gynecological Survey, 57 (11), pp. 755-767. Cited 73 times. IF: 2.395

6.      Visser, J.A., de Jong, F.H., Laven, J.S.E., Themmen, A.P.N. Anti-Müllerian hormone: A new marker for ovarian function (2006). Reproduction, 131 (1), pp. 1-9. Cited 67 times. IF: 2.962

7.      Mulders, A.G.M.G.J., Laven, J.S.E., Eijkemans, M.J.C., Hughes, E.G., Fauser, B.C.J.M. Patient predictors for outcome of gonadotrophin ovulation induction in women with normogonadotrophic anovulatory infertility: A meta-analysis (2003) Human Reproduction Update, 9 (5), pp. 429-449. Cited 35 times. IF: 7.257

8.      Laven, J.S.E., Imani, B., Eijkemans, M.J.C., De Jong, F.H., Fauser, B.C.J.M. Absent biologically relevant associations between serum inhibin B concentrations and characteristics of polycystic ovary syndrome in normogonadotrophic anovulatory infertility (2001). Human Reproduction, 16, pp. 1359-1364. Cited 32 times. IF: 3.543

9.      Hohmann, F.P., Laven, J.S.E., De Jong, F.H., Eijkemans, M.J.C., Fauser, B.C.J.M. Low-dose exogenous FSH initiated during the early, mid or late follicular phase can induce multiple dominant follicle development (2001).  Human Reproduction, 16, pp. 846-854. Cited 30 times. IF: 3.543

10.  Jansen, E., Laven, J.S.E., Dommerholt, H.B.R., Polman, J., Van Rijt, C., Van Den Hurk, C., Westland, J., Mosselman, S., Fauser, B.C.J.M. Abnormal gene expression profiles in human ovaries from polycystic ovary syndrome patients (2004) Molecular Endocrinology, 18, pp. 3050-3063. Cited 29 times. IF: 5.337


People associated with sub theme 1.8: Regulation of follicle development, oocyte and endometrial embryo quality
Name Position Department
Public pictures  Tmmaverick  bessiely2 Professor not being a workgroup leader General Surgery
B.J.B.  Beudeker PhD-candidate Virology
S.H.  Donze PhD-candidate Pediatrics Endocrinology
MSc.  K.  Holleman PhD-candidate Obstetrics and Gynaecology
Ре&  Paulpeter  Kjangongtery Senior researcher not being a workgroup leader General Surgery
Drs.  ALF  van der  Kooi PhD-candidate Obstetrics and Gynaecology
Dr  w  liu Postdoc/junior researcher Internal Medicine
Drs.  C.M.  Meun PhD-candidate Obstetrics and Gynaecology
Drs  H.  Pastoor PhD-candidate Obstetrics and Gynaecology
QettoE  Progonmab Physician (MD) General Surgery
Smooveb73  richeventkaluga Other as mentioned (please specify in remarks) General Surgery
Paulpeter  richeventrzn Other as mentioned (please specify in remarks) General Surgery
ŠæŠµŠ½Š¾Š±ŠµŃ‚Š¾Š½  Paulpeter  SheltonPar PhD-candidate General Surgery