WRITE UPS - PERI-CONCEPTION - Look The Blastocyst Is Talking


Look The Blastocyst Is Talking


Immunology and genetics are two subjects in clinical practice that have a widespread subtle bearing but are always given a “step motherly” treatment. This is not because they are unimportant but because they are difficult to understand. Over the period of time our group has felt that not only are these areas cardinal in understanding the physiology of many obstetric conditions, but they can be wisely used to treat a series of clinical situations. Peri-conception care is rapidly becoming a specialized area in obstetrics. It has got many new developments and thanks to a high failure rate of nidation and sustenance of pregnancy in ART, this subject has become all the more important.


Blastocyst - Endometrium Cross Talk:

A blastocyst is a friendly being. It loves to make friends with many a mucosa. Its friendliness also causes ectopic pregnancies. It has got a great enticing capacity. It lures the mucosa to allow it not only to stick to the mucosa but also burrow through. It is not an encroacher however. It is a nice being that knows its limitations and stops burrowing at a particular point. This has got clinical bearings. The entire process of cross talk to burrowing and right up to the stoppage of any further progress, once the limit has reached, is all a series of immunological changes.


Embryonic implantation requires coordinated development of the blastocyst and the maternal endometrium. Nevertheless, communication between these tissues and the reciprocal effects of these tissues on each other constitutes an exciting and as yet unsolved paradigm in reproductive medicine. Crosstalk between the embryo, endometrium and the corpus luteum is known to occur.


As the conductor of the orchestra, HCG generates a series of immunologicaly active substances that act like messengers and ambassadors of the blastocyst going to the endometrium (now the decidua) queering the pitch for a successful and lasting nidation. Clinical result is a successful pregnancy outcome. This could be one of the bases of the use of HCG in clinical practice for cases of pregnancy loss.

Not only do levels of HCG rise in very early days of pregnancy but also this rise is rapid and calibrated. Not only a deficiency in the quantitative level is detrimental to healthy nidation but also the rapidity of the rise is equally important. Either of them failing generates a deficient cross talk and the conceptus doesn’t nidate well. Clinical result: menstrual abortions and spontaneous early first trimester abortion.


The normal hormonally regulated human endometrium is the trigger of molecular events preparing the blastocyst to efficiently communicate and regulate endometrial adhesion molecules in order to implant. The embryo is able to modulate endometrial molecules during the apposition phase (chemokines) and the adhesion phase (adhesion and anti-adhesion molecules). Here, we report a coordinated embryonic regulation of hEEC apoptosis. In the apposition phase, the presence of a blastocyst rescues hEEC from the apoptotic pathway. However, when the human blastocyst adheres to the hEEC monolayer, it induces a paracrine apoptotic reaction. Neutralizing adhesion assays revealed that the Fas/Fas-L death system may be an important mechanism to cross the epithelial barrier, which is crucial for embryonic adhesion, and the manipulation of this system could have potential clinical implications as an interceptive mechanism.


Recently, a major break through was made in this area: A discovery of a novel cell adhesion molecule complex mediating the initial attachment of trophoblast to the endometrial epithelium: trophinin and tastin. The human endometrium is an extremely sensitive target for steroid hormones. During the menstrual cycle, this tissue undergoes dynamic changes that are reflected on the surface morphology of the epithelium. The morphologic changes peak at the mid-secretory phase, with the formation of the so-called pinopodes. Clinical evidence indicates the existence in the human of a narrow window of uterine receptivity, which opens during the mid-luteal phase. At the same time, formation of pinopodes on the apical membranes of the endometrial epithelial cells occurs.

To develop a specific marker for receptivity in clinical practice, the kinetics of pinopode formation has been investigated through sequential endometrial biopsy in natural, hormone replacement and stimulated cycles. The results show that pinopodes last <48 h in all cycles, and the timing of their formation depends both on the hormonal treatment applied and on the patient's individual response.

On an average, pinopodes form earlier in stimulated cycles and later in hormone replacement cycles, compared with natural cycles. Pinopode expression is strongly correlated with implantation following embryo transfer and furthermore, detection of pinopodes in assessment cycles may be extremely useful for the assessment of receptivity on an individual basis to optimize embryo transfer, resulting in increased implantation rates. One of the most puzzling problems of endometriosis is determining which mechanisms link this spectrum of conditions to infertility. Clinical studies reveal that implantation rates seem to be lower in women with endometriosis, while spontaneous abortion rates show variable results.

Biochemical markers (integrins and other cell adhesion molecules), morphological markers (pinopodes), apoptosis and ultrasound studies confirm that not only does the endometrium from women with endometriosis behave differently from the endometrium of women without endometriosis, but ectopic endometrium also behaves differently from eutopic endometrium.
Many controlled ovarian hyperstimulation cycles are associated with synchronous early expression of the expected pattern of histologic features, estrogen and progesterone receptors, and pinopodes. The most predictive feature of this premature expression was the level of progesterone the day after HCG administration.

Pinopode formation was more pronounced in endometrial biopsies than in cell cultures. All blastocysts adhered to pinopode presenting cells. Furthermore, endometrial epithelial pinopodes, generally considered as a marker of endometrial receptivity, seem to be directly involved in the adhesion of the blastocyst to the endometrial surface.


Current clinical studies indicate the existence in the human of an "implantation/nidation window." The implantation window in humans, according to this marker, lasts less than 48 hours, and the timing of its opening is dependent on the hormonal treatment applied, occurring earlier in cycles following ovarian stimulation and later in cycles induced by hormone replacement treatment. Furthermore, the timing varies among different individuals under the same treatment.

The appearance of pinopodes was found to be strictly progesterone dependent. When given together with progesterone, before the development of pinopodes, high doses of estradiol (plasma level approximately 300 pmol/l) inhibited pinopode formation; on the contrary, low doses of estradiol (nidatory doses) did not interfere with the process until the 4th day of treatment. Pinopodes could be an extremely useful tool to estimate uterine receptivity. The hormonal treatment applied to induce ovulation (clomiphene citrate, hMG and hCG) can modify the normal development of the prenidatory endometrium, and may thus have a negative effect on the rate of egg implantation.

   Endometrial progesterone-induced uterine protein-1 localization shifts from stromal to epithelial, coinciding with the time of ovulation, fertilization, and implantation. This observation, combined with the disappearance of progesterone-induced uterine protein-1 in late-secretory, non-pregnant endometrium and its presence in decidua and trophoblast, suggests that progesterone-induced uterine protein-1 may play a role in decidualization, endometrial or embryo cross-talk, or placental physiologic features. 



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