134	A. Aluko and J. Stewart

Discussion

Successful implantation and placentation are important prerequisites for normal pregnancy [1]. The initial interaction between embryo and endometrium is complex, and even minor perturbations can derail this carefully choreographed process. It is, therefore, not surprising that the majority of spontaneously conceived embryos fail to implant. In fact, even with donor sperm insemination under optimal conditions, implantation rates rarely exceed 40% [2]. Although there is no standardized de nition for recurrent implantation failure (RIF), it is generally diagnosed after “three consecutive IVF attempts, in which one to two embryos of high-grade quality are transferred in each cycle” [3].

During implantation, the dialogue between the embryo and uterine wall is bi-­ directional and requires both a competent embryo and receptive endometrium. Embryos that are morphologically abnormal or aneuploid often struggle to implant, however, implantation failure after the transfer of high-quality, euploid blastocysts is concerning for an endometrial etiology. These cases are challenging and require careful examination of the uterine cavity for pathology—leiomyomas, endometrial polyps, uterine synechiae, and retained products of conception. In addition, the functional quality of the endometrium should be assessed. Inadequate endometrial proliferation in response to estrogen exposure, insuf cient progesterone effect during the luteal phase, and asynchrony between the embryo and endometrium can preclude normal implantation.

Intrauterine Pathology

Any distortion of normal uterine architecture has the potential to affect implantation by interfering with embryo transport, uterine peristalsis, and endometrial receptivity. In addition, space-occupying lesions diminish the surface area available for implantation. Leiomyomas, endometrial polyps, adenomyosis, uterine synechiae, and retained products of conception are examples of intrauterine pathology that can decrease the likelihood of achieving a successful pregnancy through IVF [4, 5]. Some of these structural abnormalities are discussed further in other chapters.

A variety of diagnostic modalities can identify intrauterine pathology. These include ultrasonography, three-dimensional (3D) ultrasonography, magnetic resonance imaging (MRI), hysterosalpingography (HSG), saline infusion sonohysterography (SIS), and hysteroscopy [6]. In our practice, less invasive methods such as ultrasonography, SIS, and HSG are often used as diagnostic tools. We perform an MRI when additional details for surgical planning are needed (ex: large leiomyomas) or when complex Mullerian anomalies are suspected. Hysteroscopy is reserved for patients with suspected intrauterine pathology requiring surgical correction or for diagnostic purposes in patients who have failed multiple IVF cycles.

21  Endometrial Factor

135

Thin Lining

It is well established that increasing endometrial thickness prior to embryo transfer correlates with implantation success in IVF cycles [7, 8]. In two studies of women undergoing IVF, a trilaminar appearance was favorable, and a minimum endometrial thickness of 6–7 mm was necessary for pregnancy [9, 10]. Interestingly, successful IVF pregnancies have been reported in patients with endometrial linings as thin as 3.5–4 mm, however, this clearly is not the norm [11–13]. At our institution, we rarely transfer embryos when the endometrium is either thin (de ned as less than 7 mm) or homogenous, as these appear to be suboptimal conditions for implantation.

Endometrial thinning can be a consequence of hormonal alterations from oral contraceptives, progestins, or clomiphene citrate or letrozole use [14, 15]. Furthermore, Asherman’s syndrome can render the endometrium unresponsive to estrogen exposure, and should be suspected in any patient with a history of uterine instrumentation. The impaired endometrial development associated withAsherman’s syndrome results not only from intrauterine scar formation, but also from myometrial brosis which reduces uterine perfusion and local delivery of hormones [14].

In patients who have a thin endometrium during the late follicular phase of their natural cycles, we opt for transfer of embryos in a medicated cycle, where both exogenous estrogen and progesterone are administered in order to prepare the uterine lining for implantation. If the endometrium remains refractory to exogenous estrogen in our standard medicated protocols, we typically increase the estradiol dose and consider alterations in the route of administration. If these measures fail to produce a desired effect, a diagnostic hysteroscopy should be considered. If this is unrevealing, we offer adjunctive treatment in select cases with vasoactive medications such as sildena l, in an effort to facilitate endometrial perfusion by increasing uterine blood fow. Initial studies on vaginal sildena l citrate by Sher et al. were able to demonstrate an improvement in endometrial thickness, as well as implantation and ongoing pregnancy rates in women with IVF failures attributed to poor endometrial development [16, 17]. Other vasoactive medications have also been studied, including low dose aspirin, pentoxifylline, and vitamin E [14, 15], however, the bene t of using these substances in RIF patients remains to be determined.

Endometrial Receptivity Analysis (ERA)

It is imperative that the embryo makes contact with the uterine wall during the fertile window of implantation, which occurs for only a few days during the luteal phase [1, 18]. The transition from proliferative to secretory endometrium, under the infuence of rising progesterone levels, plays a critical role in establishing endometrial receptivity. A host of cytokines, growth factors, and lipids are also involved, which is refected by the fact that certain genes are differentially expressed in receptive endometrium [1]. The Endometrial Receptivity Analysis (ERA) capitalizes on

Данная книга находится в списке для перевода на русский язык сайта https://meduniver.com/

136	A. Aluko and J. Stewart

this unique gene expression pro le, or “transcriptomic signature,” in order to determine the optimal timing for embryo transfer [19]. An ERA is typically performed through an endometrial biopsy obtained after 5 full days of progesterone exposure in a mock medicated frozen embryo transfer cycle [4]. When there is a “receptive” ERA result, such as in our patient’s case, a frozen embryo transfer can be performed in a subsequent medicated cycle 5 days after initiation of progesterone. In patients with a “non-receptive” result, the day of transfer can be adjusted based on whether the endometrium was “pre-” or “post-receptive” on the day of biopsy.

ERA studies suggest that one in four women with recurrent implantation failure have a displaced window of implantation [20]. In this subset of patients, the ERA allows for individualization of embryo transfer protocols [21]. Although personalized embryo transfer in patients with recurrent implantation failure has been found to improve implantation and ongoing pregnancy rates in some patients [22, 23], there are studies that have failed to nd any signi cant bene t to using the ERA [24]. In our practice, patients who have failed two or more frozen embryo transfer cycles with high-quality, euploid blastocysts are at least offered an ERA in an attempt to optimize timing of subsequent embryo transfers.

Chronic Endometritis

As part of her workup after two failed frozen embryo transfers, our patient had an endometrial biopsy to rule out chronic endometritis. Although chronic endometritis has long been considered a potential cause of reproductive failure, the extent to which this condition impacts fertility remains poorly understood [1]. Though often asymptomatic, chronic endometritis can present with abnormal uterine bleeding, pelvic discomfort, and leukorrhea [25]. Histologically, chronic endometritis is characterized by super cial stromal edema, increased stromal density, and plasma cell in ltration [26]. In vitro studies suggest that chronic endometritis refects an aberrant immune response to microbial antigens, resulting in the excessive recruitment of lymphocytes to the endometrial stroma, which produce antibodies that negatively impact endometrial receptivity and implantation [27]. The abnormal infammatory microenvironment of chronic endometritis has been associated with delayed differentiation of mid-secretory endometrium [28] and linked to altered endometrial gene expression during the implantation window [29].

Although there are no standardized criteria for diagnosing chronic endometritis, the presence of endometrial stromal plasma cells is both highly sensitive and speci c [27]. Unfortunately, plasma cells can be dif cult to detect using conventional hematoxylin and eosin (H&E) staining, even by skilled pathologists. Immunohistochemical staining for syndecan-1 (CD138), a plasma cell surface proteoglycan, can enhance identi cation of plasma cells within an endometrial biopsy specimen and is frequently utilized as an adjunct to improve the sensitivity of pathologic diagnosis [30, 31]. At our institution, we frequently request CD138 immunohistochemical staining in addition to H&E staining but recognize the many