Endometrial Receptivity and RIF
The uterus, aka the ‘womb’, is an incredible organ that carries a growing baby, providing it with all of the necessary nutrients it requires. It is held in place by strong ligaments, and it is remarkably elastic, stretching to about 500 times its pre pregnancy size (from the size of a clenched fist to the size of a water melon). It grows in weight too, from a couple of ounces to more than 2 pounds. When your pregnancy is over, the uterus returns to its original size.
The menstrual cycle has three phases, menses (your period), the proliferative phase (egg growth and endometrial growth) and the secretory phase (endometrial maintenance).
The tissue of the endometrium grows and develops to become thick and hospitable for an embryo to implant. Following ovulation, there is a transformation of the endometrial cells. The key function of the endometrium is that it needs to support and ongoing pregnancy. Studies have shown that the timing of endometrial receptivity is very important as if implantation occurs too early it can result in miscarriage, and if delayed can cause problems with implantation.
Fertility - a time sensitive implantation ‘window’
The other dynamic change that occurs is that when fertility is not achieved, breakdown and shedding of the lining occurs at time of menstruation.
“Did you know that a woman will typically shed her uterine lining 400 times in her life time? 400 periods = 400 times the uterus sheds the lining and rebuilds itself”
The endometrium has a diverse and dynamic population of immune cells that play key roles in preparation for pregnancy and menstruation. The immune cells become embedded within the endometrial cells in the uterine lining. An important feature is the rapid increase in the number of immune cells throughout the cycle that when menstruation does occur, almost 30% of the stromal volume (endometrium) is lost - which was made up of these immune cells (Macrophages, Neutrophils, uNK, Eosinophils, and T Lymphocytes cells).
The below diagram shows nicely how the immune cells (Macrophages, Neutrophils, uNK, Eosinophils, and T Lymphocytes cells) are present within the different stages of the cycle.
Sex Steroids: Estrogen and Progesterone
The uterus has estrogen and progesterone receptors meaning it responds to both hormones. Both hormones are crucially important. Progesterone is required for implantation but estrogen is fundamental to opening this ‘window’ of implantation.
During the menstrual cycle, ovulation occurs, the follicle ruptures to release the egg and the corpus luteum produces progesterone. This progesterone maintains the uterine lining. Therefore, the health of the follicle will influence the health of the corpus luteum and the progesterone being released.
Once ovulation occurs the egg survives 12-24 hours. If fertilisation occurs, the uterine lining is receptive to an embryo implanting within the next 5-6 days. This is called the ‘window’ of implantation. The time it will take for the egg to be fertilised, for the embryo to travel through the Fallopian tube and to implant into the uterine lining. If this doesn’t occur, menstruation ensues.
What causes implantation failure?
Implantation does not always happen and when it does not, it can result in what we call ‘implantation failure’. Repeated implantation failure (RIF) is determined when embryos of good quality fail to implant following several in vitro fertilization (IVF) treatment cycles. The causes of implantation failure are diverse and especially due to different maternal factors as uterine abnormalities, hormonal or metabolic disorders, infections, immunological factors, thrombophilias as well as other less common ones. Below is an outline of some of the maternal factors that can be underlying in someone who is experiencing recurrent implantation failures (RIF) and some of the treatment options that can be offered.
Anatomical Factors (Uterine anomalies)
Endometrial thickness and receptivity
Thrombophilia and Connective Tissue Disease
Immunological Factors
Successful implantation is a complex process involving two main players, the mother and the embryo. Problems originated from the maternal environment, such as abnormal uterine anatomy, non-receptive endometrium and the medical condition of the mother (such as thrombophilia and abnormal immunologic response) can adversely affect the cross-talk between the embryo and the endometrium that is crucial for successful implantation. Successful implantation requires a cascade of events that all need to be perfectly aligned.
Similarly, this endometrium—embryo interaction may be hampered if the embryo is disordered. Embryo abnormality can originate from either paternal sperm factors (the father), or from the oocyte and its capability of being fertilized normally and cleave/grow.
Therefore, the investigation and treatment of RIF should focus on both male and female risk factors that once identified should be managed and treated appropriately.
Following three consecutive IVF failures, it is recommended that patients should undergo hysteroscopy to assess the uterine cavity. A hysteroscopy is a day case procedure where a small camera is directed through the vagina and cervix in order to be able to visualise the inside of the uterus on camera. Three dimensional ultrasonographies, as well as hysterosalpingography, are complimentary tests that can also be performed. Once an abnormality associated with implantation failure is recognized, treatment options can include
uterine septectomy,
removal of intra-uterine adhesions,
endometrial polypectomy (removal of a polyp) or
myomectomy (removal of a fibroid- particularly the submucous type impinging on the inside of the uterine lining), and
excision of hydrosalpinx (blocked Fallopian tube).
A thin unresponsive endometrium can be difficult to manage. High dose estrogen, the application of vaginal estrogen pills, aspirin and other medications that may increase blood flow to the endometrium, as well as mechanical endometrial stimulation by mean biopsy sampling can be offered however if all available treatments are unsuccessful, then surrogacy can sometimes be offered as reasonable option.
In recurrent miscarriages, women are advised to undergo blood tests for thrombophilia as well as for connective tissue diseases that involve antiphospholipide antibodies.
However, as mentioned earlier, thrombophilia and antiphospholipids antibodies may also be associated with risk of RIF. Once detected, a consultation with a hematologist and connective tissue disease specialist is advised and treatment with low molecular weight heparin (LMWH) is recommended. When thrombophilic trait is detected, treatment with prophylactic dose of LMWH is sufficient and seems to improve IVF outcome. However, when anti phospholipids antibodies (APLA) syndrome is diagnosed, a concomitant treatment with mini dose aspirin and/or corticosteroids should be considered.
It’s really important that once this is diagnosed, the appropriate treatment protocol for ovarian stimulation should be implemented to minimize the risk of ovarian hyperstimulation sysndrome (OHSS). Initiation of LMWH should be considered from the early stimulation period or from the day of embryo transfer. A patient’s family and personal medical history, particularly her previous IVF experience, are important for reaching a decision on this. Patients with no history of thrombotic events, personally or among close relatives, and who already experienced several uneventful IVF treatments, may be considered suitable to start LMWH on the day of ET. Patient with APLA syndrome, or with a history of a disease that can be attributed to a hypercoagulability trait, should start anticoagulation alongside gonadotropin administration.
Treatment with LMWH should be stopped 24 h before egg retrieval and reinitiated the day following ovum pick-up. LMW should not be advised for everyone as treatment with LMWH, aspirin or corticosteroids was not found to be effective, and is not advocated for women with RIF who were negative for thrombophilic tests.