Can there be a genetic background of the primary idiopathic infertility? The leukemia-inhibitory factor gene mutations in the population of infertile women

Z. Rokyta (1), M. Králícková (1), Z. Ulcová-Gallová (1), P. Síma (2), T. Vanecek (3), R. Síma (3), O. Hes (3)

Department of Obstetrics and Gynecology, University Hospital, Faculty of Medicine, Charles University, Pilsen (1); Department of Immunology and Gnothobiology, Institute of Microbiology, Czech Academy of Sciences, Prague (2); Department of Pathology, University Hospital, Faculty of Medicine, Charles University, Pilsen, Czech Republic (3)

Objective: Since the first successful In Vitro Fertilization (IVF) in human and birth of Louise Joy Brown, the world's first testtube baby (in 1978), the number of patients using Assisted Reproductive Technologies (ART) has increased tremendously. But ART are still not efficient enough - approximately half of the women who seek medical treatment for infertility never give birth to a child. During the past decade only one in six cycles of assisted conception has resulted successfully in a live birth. As it was shown previously, leukemia inhibitory factor (LIF) is one of the essential cytokines in molecular crosstalk that influences the embryo implantation. 'Errors' in the embryo-endometrium communication leading to difficulties with the embryo implantation are supposed to be one of the causes of the relatively low pregnancy rates of ART and also one of the causes of the primary idiopathic infertility (PII). We designed a LIF gene mutation screening method that is based on the temperature-gradient gel electrophoresis (TGGE) and subsequent sequencing.

Design & Methods: The population to screen consists of 105 clinically characterised group of women with diagnosed infertility including a subgroup of 40 women with idiopathic primary infertility. The control population comprises of 55 healthy control subjects that conceived spontaneously and delivered successfully.

Results: Four LIF gene mutations were detected. In all cases the G to A transition at the position 3400 of the human LIF gene was identified. This position corresponds to region of the lif protein (AB loop) that is supposed to be highly important for the LIF and LIF-receptor interaction. All positive women were infertile. Three of them were diagnosed with primary idiopathic infertility and had history of at least one unsuccessful in vitro fertilisation (IVF) cycle. One of them got pregnant once (spontaneously) but suffered by spontaneus abortion at the 6th week of her pregnancy. No positive TGGE samples were identified in the control group.

Conclusions: Our results suggest that LIF gene mutations can lead to embryo implantation failure and that way to infertility and decreased pregnancy rates in assisted reproduction techniques. We believe that better understanding of the genetic background of infertility belongs to the holistic approach to reproductive health.

This study was supported by:Grant Agency of the Czech Republic, Grant No. 301/02/1232, Charles University, Institutional Research Concept No. VZ 111400005(6035).