ERA in adenomyosis

Question

Answer

Herewith my response on both issues;

A: ADENOMYOSIS:

Adenomyosis is a condition where endometrial glands develop outside the uterine lining (endometrium), within the muscular wall of the uterus (myometrium). Definitive diagnosis of adenomyosis is difficult to make. The condition should be suspected when a premenopausal woman (usually>25 years of age) presents with pelvic pain, heavy painful periods, pain with deep penetration during intercourse, “unexplained infertility” or repeated miscarriages and thereupon, when on digital pelvic examination she is found to have an often smoothly enlarged (bulky) soft tender uterus. Previously, a definitive diagnosis was only possible after a woman had her uterus removed (hysterectomy) and it this was inspected under a microscope. However the use of uterine magnetic resonance imaging (MRI) now permits reliable diagnosis. Ultrasound examination of the uterus on the other hand , while not permitting definitive diagnosis, is a very helpful tool in raising a suspicion of the existence of adenomyosis.

Criteria used to make a diagnosis of adenomyosis on transvaginal ultrasound:

• Smooth generalized enlargement of the uterus.
• Asymmetrical thickening of one side of the (myometrium) as compared to another side.
• Thickening (>12mm) of the junctional zone between the endometrium and myometrium with increased blood flow.
• Absence of a clear line of demarcation between the endometrium and the myometrium
• Cysts in the myometrium
• One or more non discrete (not encapsulated) tumors (adenomyomas) in the myometrium.

Since there is no proven independent relationship between adenomyosis and egg/embryo quality any associated reproductive dysfunction (infertility/miscarriages) might be attributable to an implantation dysfunction. It is tempting to postulate that this is brought about by adenomyosis-related anatomical pathology at the endometrial-myometrial junction. However, many women with adenomyosis, do go on to have children without difficulty. Given that 30%-70% of women who have adenomyosis also have endometriosis…. a known cause of infertility, it is my opinion that infertility caused by adenomyosis is likely linked to endometriosis where infertility is at least in part due to a toxic pelvic environment that compromises egg fertilization potential and/or due to an immunologic implantation dysfunction (IID) linked to activation of uterine natural killer cells (NKa). Thus, in my opinion all women who are suspected of having adenomyosis-related reproductive dysfunction (infertility/miscarriages) should be investigated for endometriosis and for IID. The latter, if confirmed would make them candidates for selective immunotherapy (using intralipid/steroid/heparin) in combination with IVF.

Surgery: Conservative surgery to address adenomyosis-related infertility involves excision of portions of the uterus with focal or nodular adenomyosis and/or excision of uterine adenomyomas. It is very challenging and difficult to perform because adenomyosis does not have distinct borders that distinguish normal uterine tissue from the lesions. In addition, surgical treatment for adenomyosis-related reproductive dysfunction is of questionable value and of course is  not an option for diffuse adenomyosis.

Medical treatment: There are three approaches.

• GnRH agonists (Buserelin/Lupron) which is thought to work by lowering estrogen levels.
• Aromatase inhibitors such as Letrozole have also been tried with limited success
• Inhibitors of angiogenesis: The junctional zone in women with adenomyosis may grow blood vessels more readily that other women (i.e. angiogenesis). A hormone known as VEGF can drive this process. It is against this background that it has been postulated that use of drugs that reduce the action of VEGF and thereby counter blood vessel proliferation in the uterus could have a therapeutic benefit. While worth trying in some cases, thus far such treatment has been rather disappointing
• Immunotherapy to counter IID: The use of therapies such as Intralipid (or IVIG)/steroids/heparin in combination with IVF might well hold promise in those women with adenomyosis who have NKa.

Fortunately, not all women with adenomyosis are infertile. For those who are, treatment presents a real problem. Even when IVF is used and the woman conceives, there is still a significant risk of miscarriage. Since the condition does not compromise egg/embryo quality, women with adenomyosis-related intractable reproductive dysfunction who fail to benefit from all options referred to above…(including IVF) might as a last resort consider  Gestational surro resort consider  Gestational surrogacy.

B: ERA

The blastocyst and the endometrium are in a constant state of cross-talk. In order for successful implantation to take place, the blastocyst must be at the appropriate stage of development, and needs to signal a well synchronized endometrium to ‘accept it”. This dialogue between embryo and endometrium involves growth factors, cytokines, immunologic accommodations, cell adhesion molecules, and transcription factors. These are all mostly genetically driven but are also heavily influenced by numerous physiologic, pathophysiologic, hormonal and molecular mechanisms capable of profoundly affecting the receptivity of the secretory endometrium to the overtures made by the embryo, to implant. 

Embryo implantation takes place 6-9 days after ovulation. This period is commonly referred to as the “window of implantation (WOI)”. In the past it was believed that as long as the embryo reached the uterus in this 4 day time frame, its chance of implanting would not be affected.

In 2013, after evaluating 238 genes in the secretory endometrium and applying bioformatics, Ruiz-Alonzo, et all introduced the Endometrial Receptivity Array (ERA) . Using this test, they categorized mid-secretory endometria into 4 categories: “a) proliferative, b) pre-receptive, c) receptive or d) post-receptive”. They claimed that women with pre-receptive or post-receptive endometria were more likely to experience failed implantation post-embryo transfer (ET).

It was in large part this research which suggested that the concept of a relatively “wide” (4day) WOI, was flawed, that an optimal WOI is likely much narrower and could be a critical factor in determining the success or failure of implantation post-ET. Ruiz-Alonzo also  reported that about 25% of women with recurrent IVF failure (RIF), have pre, or post-receptive endometria. They presented data suggesting that  viable IVF pregnancy rates could be enhanced,

by deferring FET by about 24 hours in women who had pre-receptive endometria and bringing ET forward by the same amount of time, in women with post-receptive endometria,

There is no doubt that ERA testing has opened the door to an intriguing arena for research. Presently however, available data is inconclusive. Here, following  recent studies are 2 dissenting opinions regarding  the value for ERA:

• Basil and Casper (2018) state: “Performing the ERA test in a mock cycle prior to a FET does not seem to improve the ongoing pregnancy rate in good prognosis patients. Further large prospective studies are needed to elucidate the role of ERA testing in both good prognosis patients and in patients with recurrent implantation failure”
• Churchill and Comstock (2017)  conclude:” In our preliminary observations, the non-receptive ERA group had similar live birth rates compared to the receptive ERA group. It appears the majority of the pregnancies conceived in the non-receptive group occurred during ovulatory cycles and thus a non-receptive ERA in a medicated cycle likely does not have prognostic value for ovulatory cycles. Larger studies are needed to assess the prognostic value of ERA testing in the gen-eral infertility population.”

There are additional negatives that relate to the considerable emotional and financial cost of doing ERA testing:

1. First, the process costs $600-$1000 to undertake
2. , Second, it requires that the patient undergo egg retrieval, vitrify (cryobank) all blastocysts, res for 1 or more cycles to allow their hormonal equilibrium to restore, do an ERA biopsy to determine the synchronicity of the endometrium, wait a few weeks for the results of the test and thereupon engage in undertaking an additional natural or hormonal preparation cycle for timed FET. This represents a significant time lapse, emotional cost and additional expense.

Presently, ERA testing is only advocated for women who have experienced several IVF failures. However, some authorities are beginning to advocate that it become routine for women undergoing all IVF.

The  additional financial cost inherent in the performance of the ERA test ($600-$1000), the considerable time delay in getting results, the fact that awaiting results of testing and preparing the patient for FET, of necessity extends the completion of the IVF/ET process by at least a few months, all serve to increase the emotional and financial hardship confronting patients undergoing ERA. Such considerations, coupled with the current absence of conclusive data that confirm efficacy, are arguments against the widespread use of ERA . In my opinion, ERA testing should presently be considered as being  one additional diagnostic and be confined to women with “unexplained” RIF.

Gold standard statistical analyses require that all confounding variables be controlled while examining the effect of altering the one under assessment. There is an obvious interplay of numerous, ever changing variables involved in outcome following ET,  e.g. embryo competency, anatomical configuration of the uterus and the contour of the endometrial cavity, endometrial thickness, immunologic and molecular factors as well as the very important  effect of technical skill/expertise in performing the  ET procedure …(to mention but a few). It follows that it is virtually impossible to draw reliable conclusions from IVF-related randomized controlled studies that use outcome as the end-point. This applies equally to results reported following “ gold standard”  testing on the efficacy of ERA and, is one of the main reasons why I question the reliability of reported data (positive or negative).

The fact is that IVF (and related technologies) constitute neither a “pure science” nor a “pure art”. Rather they represent an “art-science blend”, where scientific principles applied to longitudinal experience and technical expertise coalesce to produce a biomedical product that will invariably differ (to a greater or lesser degree) from one set of clinical circumstances to another.

Since, the ultimate goal of applied Assisted Reproductive Medicine is to safely achieve the birth of a viable and healthy baby, the tools we apply, that are aimed at achieving this end-point, are honed through the adaptation of scientific principles and concepts, experience and expertise, examined and tested longitudinally over time. Needless to say, the entire IVF/ET process is of necessity subject to change and adaptation as new scientific and technical developments emerge.

This absolutely applies to the ERA as well!

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