Human Reproduction Update - Advance Access

Trophoblast invasion: the role of intracellular cytokine signalling via signal transducer and activator of transcription 3 (STAT3)

Fitzgerald, J. S., Poehlmann, T. G., Schleussner, E., Markert, U. R. — 2008-04-17

Trophoblast cells display a very unique capability: they physiologically invade into the surrounding tissue. This capability is widely associated with tumours, and, indeed, the invasive behaviour of both is rather similar. The imposing difference is that trophoblast cell invasion is temporally and locally controlled in contrast to unlimited tumour invasion. It initiates immediately after embryo implantation into the endometrium. Parallel to tumours, trophoblasts secrete proteases, such as matrix metalloproteinases, which dissolve the extracellular matrix and the surrounding tissue. Thereby, these proteases prepare and allow true invasion of trophoblasts. The invasive capacities of trophoblasts are positively and negatively regulated by numerous cytokines including leukaemia inhibitory factor (LIF), interleukin-6, hepatocyte growth factor, granulocyte macrophage–colony stimulating factor and others. They interact via specific receptors with the trophoblast cells, in which they activate intracellular signalling cascades. These will then induce expression of invasion relevant genes. One of these signalling pathways is the Janus kinase/signal transducers and activators of transcription (STAT) pathway. Especially phosphorylated STAT3 enhances invasiveness of tumours and trophoblast cells, where it is mainly activated by LIF. One of its most efficient physiological antagonists is suppressor of cytokine signalling 3. The balance of these two intracellular molecules seems to be a key regulator of tumour and trophoblast invasion.

Genetic aspects of female reproduction

The ESHRE Capri Workshop Group — 2008-04-02

BACKGROUND

Sexual reproduction provides the means for preserving genetic identity and in turn, genetic variability may affect the ability to reproduce. This review aims to summarize current research on genetic diagnosis and genetic causes of reproductive disorders.

METHODS

Searches were done by subject in Medline and other databases, and each subject summary was presented to the Workshop Group and omissions or disagreements were resolved by discussion.

RESULTS

Single-gene defects are most likely to be found among patients with hypogonadotropic hypogonadism, which may be due to defects in the KAL genes or the gonadotrophin-releasing hormone receptor genes. With premature ovarian failure there is an increased risk of having a premutation of the Fragile X syndrome gene. Complex genetic inheritance may explain the variable familial links in polycystic ovary syndrome and endometriosis, but no definitive genetic pathways are as yet known. With recurrent miscarriage, genetic defects causing thrombophilias are 2-fold more likely. Chromosome abnormalities account for ~60% of all spontaneous abortions, and the most common type, trisomy, is closely associated with advanced maternal age. Three percent of couples have a balanced chromosome abnormality, but live birth rates are better with natural conception than with preimplantation genetic diagnosis.

CONCLUSIONS

Understanding of the methods used for genetic diagnosis and research is becoming a standard requirement for the clinical practice of reproductive medicine.

Targeting the vascular endothelial growth factor system to prevent ovarian hyperstimulation syndrome

Soares, S. R., Gomez, R., Simon, C., Garcia-Velasco, J. A., Pellicer, A. — 2008-04-02

BACKGROUND

Ovarian hyperstimulation syndrome (OHSS) typically occurs when ovaries are primed with FSH/LH and subsequently exposed to hCG. The ultimate pathophysiological step underlying this clinical picture is increased vascular permeability (VP).

METHODS

A search of the literature was carried out using PubMed and the authors’ files.

RESULTS

In rodents and humans, the expression of vascular endothelial growth factor (VEGF) and VEGF receptor 2 (VEGFR-2) mRNA increases during ovarian stimulation. With the administration of hCG, the expression of each rises to a maximum. Expression of VEGF/VEGFR-2 mRNAs correlates with enhanced VP, with both peaking 48 h following an injection of hCG. Immunohistochemistry shows the presence of VEGF and VEGFR-2 proteins in the granulosa-lutein and endothelial cells of the entire corpus luteum. Increased VP may be mediated through adhesion molecules such as VE-cadherin, which is involved in the loosening of endothelial intercellular junctions. These findings regarding the pathophysiology of OHSS suggest that the syndrome can be prevented by inducing ovulation with LH or GnRH analogues, which prevent VEGF overexpression. Also, co-administration of a dopamine agonist inhibits phosphorylation of the receptor VEGFR-2. In a trial of 69 oocyte donors, the incidence of moderate OHSS was 20% with the dopamine agonist cabergoline and 44% with a placebo (P = 0.04).

CONCLUSIONS

The pathophysiological mechanisms involved in OHSS suggest potential preventive approaches, but larger trials are necessary for evaluating the efficacy and safety of the pharmaco-prevention of OHSS.