In this Update, the authors discuss 2 important areas that impact fertility. First, with in vitro fertilization (IVF), successful implantation that leads to live birth requires a normal embryo and a receptive endometrium. While research using advanced molecular array technology has resulted in a clinical test to identify the optimal window of implantation, recent evidence has questioned its clinical effectiveness. Second, recognizing the importance of endometriosis—a common disease with high burden that causes pain, infertility, and other symptoms—the World Health Organization (WHO) last year published an informative fact sheet that highlights the diagnosis, treatment options, and challenges of this significant disease.
Endometrial receptivity array and the quest for optimal endometrial preparation prior to embryo transfer in IVF
Bergin K, Eliner Y, Duvall DW Jr, et al. The use of propensity score matching to assess the benefit of the endometrial receptivity analysis in frozen embryo transfers. Fertil Steril. 2021;116:396-403.
Riestenberg C, Kroener L, Quinn M, et al. Routine endometrial receptivity array in first embryo transfer cycles does not improve live birth rate. Fertil Steril. 2021;115:1001-1006.
Doyle N, Jahandideh S, Hill MJ, et al. A randomized controlled trial comparing live birth from single euploid frozen blastocyst transfer using standardized timing versus timing by endometrial receptivity analysis. Fertil Steril. 2021;116(suppl):e101.
A successful pregnancy requires optimal crosstalk between the embryo and the endometrium. Over the past several decades, research efforts to improve IVF outcomes have been focused mainly on the embryo factor and methods to improve embryo selection, such as extended culture to blastocyst, time-lapse imaging (morphokinetic assessment), and more notably, preimplantation genetic testing for aneuploidy (PGT-A). However, the other half of the equation, the endometrium, has not garnered the attention that it deserves. Effort has therefore been renewed to optimize the endometrial factor by better diagnosing and treating various forms of endometrial dysfunction that could lead to infertility in general and lack of success with IVF and euploid embryo transfers in particular.
Historical background on endometrial function
Progesterone has long been recognized as the main effector that transforms the estrogen-primed endometrium into a receptive state that results in successful embryo implantation. Progesterone exposure is required at appropriate levels and duration before the endometrium becomes receptive to the embryo. If implantation does not occur soon after the endometrium has attained receptive status (7–10 days after ovulation), further progesterone exposure results in progression of endometrial changes that no longer permit successful implantation.
As early as the 1950s, “luteal phase deficiency” was defined as due to inadequate progesterone secretion and resulted in a short luteal phase. In the 1970s, histologic “dating” of the endometrium became the gold standard for diagnosing luteal phase defects; this relied on a classic histologic appearance of secretory phase endometrium and its changes throughout the luteal phase. Subsequently, however, results of prospective randomized controlled trials published in 2004 cast significant doubt on the accuracy and reproducibility of these endometrial biopsies and did not show any clinical diagnostic benefit or correlation with pregnancy outcomes.
21st century advances: Endometrial dating 2.0
A decade later, with the advancement of molecular biology tools such as microarray technology, researchers were able to study endometrial gene expression patterns at different stages of the menstrual cycle. They identified different phases of endometrial development with molecular profiles, or “signatures,” for the luteal phase, endometriosis, polycystic ovary syndrome, and uterine fibroids.
In 2013, researchers in Spain introduced a diagnostic test called endometrial receptivity array (ERA) with the stated goal of being able to temporally define the receptive endometrium and identify prereceptive as well as postreceptive states.1 In other words, instead of the histologic dating of the endometrium used in the 1970s, it represented “molecular dating” of the endometrium. Although the initial studies were conducted among women who experienced prior unsuccessful embryo transfers (the so-called recurrent implantation failure, or RIF), the test’s scope was subsequently expanded to include any individual planning on a frozen embryo transfer (FET), regardless of any prior attempts. The term personalized embryo transfer (pET) was coined to suggest the ability to define the best time (up to hours) for embryo transfers on an individual basis. Despite lack of independent validation studies, ERA was then widely adopted by many clinicians (and requested by some patients) with the hope of improving IVF outcomes.
However, not unlike many other novel innovations in assisted reproductive technology, ERA regrettably did not withstand the test of time. Three independent studies in 2021, 1 randomized clinical trial and 2 observational cohort studies, did not show any benefit with regard to implantation rates, pregnancy rates, or live birth rates when ERA was performed in the general infertility population.2-4
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