BioWorld International Correspondent

LONDON - A small signalling molecule in mice that is essential for embryos to implant in the uterus could lead to novel forms of non-steroidal contraception, said a team of researchers in Cambridge, UK.

Their work proves that inhibiting the molecule, called STAT3, can reduce the rate at which embryos implant by 70 percent. If STAT3 also is essential for implantation of embryos in humans, it could provide a promising target for the development of new types of contraceptives.

Andrew Sharkey, senior research associate in the department of pathology at the University of Cambridge, told BioWorld International: "At present, we just have proof of principle that STAT3 is a drug target. But before any inhibitor of STAT3 could be developed as a contraceptive, work would need to be done to find out if there are ways of delivering the inhibitor at low-level doses in order to bring about an ongoing contraceptive effect, and whether there are any side effects."

The study is reported in the May 30, 2005, issue of Proceedings of the National Academy of Sciences in a paper titled "Inhibition of Stat3 activation in the endometrium prevents implantation: A novel approach to contraception."

The World Health Organization has funded the work. Many existing methods of contraception have disadvantages, such as side effects, or the need to monitor blood pressure, for example, which presents a problem in parts of the world where primary health care is poor.

Furthermore, since the main methods of contraception were discovered, Sharkey pointed out, knowledge of the process of embryo attachment and implantation has expanded greatly, giving rise to hopes that new types of contraceptives are simply waiting to be discovered with the help of new molecular biological techniques.

Sharkey's group has concentrated on the process that allows the endometrium of the uterus to become receptive to an embryo: In mice, the period lasts only 24 hours. Embryos that enter the uterus outside the period of receptivity cannot implant.

Research already had shown that a cytokine called leukemia inhibitory factor (LIF) was essential for implantation of the embryos in mice. The endometrium of the uterus secretes LIF into the lumen of the uterus in response to the peak in the level of oestrogen. Knockout mice lacking a functional copy of the gene encoding LIF produce normal embryos, but those fail to attach. If LIF is injected into the uteri of those mice, however, implantation will go ahead.

Sharkey and colleagues wanted to investigate how LIF influenced implantation in that way, and, in particular, exactly what happened when LIF binds to its receptor, activating a cascade of signalling pathways.

They knew that STAT3 was one of the molecules released after LIF bound to its receptor, and some studies had suggested that the pathway was the main one responsible for making the endometrium receptive.

"We have now formally proved that, by blocking it with a membrane-soluble STAT3 inhibitor," Sharkey said. The team injected either the STAT3 inhibitor or a control peptide into the uterine lumen of female mice on day three of pregnancy, 24 hours before implantation normally occurs. The number of embryos that implanted was counted on days eight to 10 of pregnancy.

In the control group, the mean number of implanted embryos per uterine horn was 3.7, compared to 1.1 in the group treated with the inhibitor - a reduction of 70 percent, statistically significant (p < 0.001).

Further experiments showed that exposure to the STAT3 inhibitor did not affect the immediate subsequent development of the embryos, or the embryos' ability to implant.

Sharkey emphasized that little is known about the importance of signalling via the LIF receptor in bringing about implantation in humans, although there is "good evidence" that LIF is important in non-human primates.

"We need to know if LIF is important in human implantation, and, if so, is it acting through STAT3? Does STAT3 play a similarly important role?" Sharkey said. Many companies are working on producing STAT3 antagonists to treat diseases such as cancer and diabetes - and it would be interesting to know whether those compounds have any effect on the pregnancy rate of women who are trying to get pregnant, he added.