Tuesday, July 19, 2011

Endometrial injury subfertility and superfertility: a decidual link.

Miscarriages occur in approximately 20% of pregnancies. Recurrent pregnancy loss (RPL), affects 1-2% of couples and is defined as three or more consecutive miscarriages. Broadly speaking, the most common cause is chromosomal abnormalities of the embryo. Other causes of RPL include immunological factors (e.g. Lupus), blood clotting disorders a.k.a. thrombophilias (e.g. antiphospholipid syndrome) and uterine factors which are less well understood. The authors of the review article, The molecular basis of recurrent pregnancy loss: impaired natural embryo selection, examine uterine factor infertility and its relation to recurrent miscarriage. 

Researchers have noted that many women with recurrent and consecutive miscarriages, have unusually high pregnancy rates, conceiving within an average of 3 months or less. These women are dubbed ‘superfertile’, though the concept of superfertility in humans is anecdotal and not based on clinical diagnostic testing. Three percent of the population is estimated to be superfertile, compared to 18% estimated to be subfertile (Tietz, 1950; Evers, 2002). It has already been hypothesized that recurrent miscarriage is a consequence of impaired natural embryo selection, in other words, the inability of the uterus to filter out poor quality embryos destined to miscarry (Quenby, 2002). In their review, Teklenburg et al examine the biological plausibility of superfertility as a pathological entity leading to apparent infertility. They use results from their own studies and others to lead to the hypothesis that cyclic changes in the endometrium ensure normal implantation, and that a dysfunctional endometrium associated with superfertility will lead to perturbations in the endometrial decidual response, delayed implantation and poor embryo selection resulting in defective placental formation and miscarriage, regardless of embryo karyotype. This would explain why karyotype analysis of miscarried embryos from superfertile women reveal both chromosomally normal and abnormal embryos. 

To arrive at this theory, they examined the implantation window of the embryo and its coordination with endometrial development. There is clinical evidence that an unresponsive endometrium during the window of implantation is a cause of subfertility. Thus, one would expect that persistent endometrial receptivity will result in higher implantation rates but would also include embryos of poor quality (i.e. superfertility). Central to the process of implantation is decidualization, which occurs about 10 days after ovulation regardless of pregnancy status. This is the process by which endometrial stromal cells differentiate into decidual cells giving the endometrium properties necessary for placenta formation. Inadequate decidualization leads to miscarriage or obstetric complications such as preterm birth. Underlying implantation is a complex molecular cross-talk between the embryo and the endometrium, a process triggered by the hormone progesterone which is responsible for maintaining the endometrium’s integrity during a viable pregnancy. Several types of molecular regulators including growth hormones, transcription factors, and cytokines are needed to mediate the implantation process. The window during which the endometrium is receptive to embryo implantation occurs approximately 6 days after ovulation, lasting for around 5 days. The proposals that miscarriages may be caused by impaired embryo selection or conception outside of the normal implantation window are not new. There is already some evidence from studies to support that impaired embryo selection underlying a short time to pregnancy is a cause of sporadic miscarriages.

Cyclic decidualization in the absence of pregnancy results in menstruation. Researchers have tried to explain from an evolutionary standpoint, why a process which results in the ‘punitive’ occurrence of repeated menstruation arose. One possible explanation is uterine preconditioning which protects the uterine tissues from hyperinflammation and oxidative stress resulting from deep trophoblast invasion during pregnancy.  Another possible explanation put forth by Teklenburg et al in this review is embryo natural selection.  In human co-culture studies, their group recently observed that blastocysts were unable to trigger a maternal response in endometrial stromal cells which had not been decidualized, yet they were able to in decidualizing cells. This led them to hypoethsize that an important function of decidualization is to provide endometrial stromal cells the ability to act as biosensors of embryo quality (Teklenburg et al, 2010a). Therefore the failure of the endometrial stromal cells to undergo an appropriate decidualization would lead not only to late implantation of poorer quality embryos but also to early placental failure regardless of embryonic karyotype. Thus, the ability of the decidualized endometrium to terminate the window of implantation could be just as important for a viable pregnancy as its ability to become receptive.

They propose that this instrinsic failure of endometrial stromal cells to mount an appropriate decidual response is due to a reversible programming of endometrial cells, most likely epigenetic changes such as DNA methylation. 

Implications for Asherman's syndrome?
This hypothesis can potentially explain many causes of uterine factor infertility as well as their current treatments. For example, inflammatory signals are important epigenetic modifiers (Backdahl et al, 2009). Although the review does not mention Asherman's syndrome, it could be speculated that tissue injury from D&Cs resulting in inflammation can lead to epigenetic modification that underlies recurrent miscarriage. Of course this may happen even if the injury does not lead to intrauterine adhesion formation. The persistence of epigenetic modification from the initial trauma could also explain why even after corrective surgery women who had Asherman's syndrome may continue to experience miscarriage or perhaps even become ‘superfertile’ from a defective decidual response. Although superfertility in Asherman’s syndrome has not been previously reported to my knowledge, it is biologically plausible if the theory about epigenetic modification subsequent to endometrial injury is correct. It could also explain why women may become infertile even in the presence of few intrauterine adhesions. Conversely, local injury using endometrial biopsy has been used to improve pregnancy rates in subfertile women, lending support to the theory that tissue injury can modify the decidual response (for the better in this case). How injury can increase fertility in some cases or reduce it in others is unclear, but would probably be related to the extent and location of the injury and baseline fertility characteristics specific to the woman. An interesting study would be to compare decidualization in women with and without Asherman’s syndrome through the expression of uterine proteins and factors involved in decidualization. The potential link between endometrial injury and superfertility may also explain the obstetric complications encountered in women with a history of Asherman’s syndrome such as placenta accreta and percreta, intrauterine growth restriction and preterm birth since these are all related to impaired placental function. 

If the above hypothesis is correct, the bad news is that prenatal genetic diagnosis (PGD) and comparative genomic hybridization (CGH) would not be effective treatments for recurrent miscarriage since even chromosomally normal embryos would abort in the presence of a defective decidual response. Variations in the prevalence of superfertile versus subfertile or infertile patients in different studies could explain the conflicting  efficacies reported for these techniques. There is at least some hope for women with recurrent miscarriage; the authors point out that even after 3 consecutive miscarriages many women with RPL go on to have a successful pregnancy. (Rai and Regan, 2006). The authors also noted that many of the drugs used in the management of RPL (progesterone, DHEA, glucocorticoids and heparin) directly modulate the decidual response and that the timing of their administration could be the critical factor in their outcome.

A better understanding of the endometrium and its decidual response may hold the key to preventing recurrent miscarriage and future obstetric complications. Perhaps the confirmation of an association between endometrial injury, defective decidualization and recurrent pregnancy loss would further support the need to switch to non-invasive and minimally invasive gynecological and obstetric treatments. 


Backdahl L, Bushell A, Beck S. Inflammatory signalling as mediator of epigenetic modulation in tissue-specific chronic inflammation. Int J Biochem Cell Biol 2009;41:176 – 184.

Evers JL. Female subfertility. Lancet 2002;360:151 – 159.
Quenby S, Vince G, Farquharson R, Aplin J. Recurrent miscarriage: a defect in nature’s quality control? Hum Reprod 2002;17:1959 – 1963.

Rai R, Regan L. Recurrent miscarriage. Lancet 2006;368:601 – 611.

a. Teklenburg G, Salker M, Molokhia M, Lavery S, Trew G, Aojanepong T, Mardon HJ, Lokugamage AU, Rai R, Landles C et al. Natural selection of human embryos: decidualizing endometrial stromal cells serve as
sensors of embryo quality upon implantation. PLoS ONE 2010;5:e10258.

Teklenburg G, Salker M, Heijnen C, Macklon NS, Brosens JJ. The Molecular basis of recurrent pregnancy loss: impaired natural embryo selection. Mol Human Reprod. 2010;16(12): 886-895.

Tietze C, Guttmacher AF, Rubin S. Time required for conception in 1727 planned pregnancies. Fertil Steril 1950;1:338– 346.