Abstract
“… the benefits of endometrial scratching have reawakened an interest in endometrial assessment, particularly since the improvement in pregnancy rates after biopsy appears to be a robust and reproducible finding.”
The endometrium is a hormone-dependent tissue that forms the mucosal lining of the inside of the uterus. It is not only an interface between the internal and external environment of a woman's body, but philosophically speaking, it is the interface to our own existence, as all of us required the endometrium to begin our journey as human beings. For those of us that study the endometrium, we are in awe of its abilities to grow, develop, shed and grow again some 400-times during a woman's lifespan. It serves as a conduit for sperm, it prevents infection, is an outpost for the immune cells and in the event of a fertilization of an oocyte, acts as a gatekeeper for the initiation of pregnancy and maintains that pregnancy for 8–9 months. It establishes that delicate balance between allowing invasion of the trophoblast (placenta) into the maternal vasculature while at the same time controlling that invasion so it does not jeopardize maternal health. The endometrium appears virtually immortal usually with an unparalleled ability to renew itself without being neoplastic.
This protean ability of the endometrium to multitask can lead to excessive growth that with time or circumstance can lead to a multitude of gynecologic conditions, some of which can be life threatening [1]. Fortunately, the endometrium is one of the most accessible of all tissues and can be monitored by endometrial biopsy, ultrasound and MRI to monitor its status. For reproductive-aged women, the endometrium is often examined when periods become irregular or abnormally heavy or light. For those with infertility, the endometrium can tell a great deal about the presence of endometriosis, infection or inflammation (endometritis), and hormonal imbalance (polycystic ovary syndrome [PCOS]). Endometrial assessment is essential for women with vaginal bleeding around or after menopause to assess the presence of endometrial hyperplasia or cancer and newer techniques involving proteomics and DNA microarray promise to streamline the diagnostic accuracy and sensitivity for a variety of gynecologic conditions involving the endometrium. All of these approaches require an endometrial biopsy.
Historically, much of the basis for endometrial assessment originated in the 1940s and 1950s when endometrial ‘dating’ was established based on histological characteristics [2]. The fact that the endometrium develops in a cyclic and organized way provided a road map to what is considered normal development. Jones used this technique to suggest that endometrial dating based on endometrial biopsies could point to a cause of infertility that became known as luteal phase defect, which she first suggested in 1949 [3]. This topic is still considered controversial after 60 years of debate and consideration [4]. Techniques to improve on histological dating criteria have evolved, including the use of progesterone in the blood as a surrogate marker [5], the use of endometrial adhesion molecules to ‘date’ the endometrium [6] and, most recently, DNA microarray that examines the entire human genome to dissect and divide endometrial development each month into its four stages (proliferative phase, early-, mid- and late-secretory) [7,8].
The assessment of the endometrium is most important when applied to diseases affecting women. One of the most significant is endometriosis, which affects an estimated 176 million woman worldwide [9]. A systematic review of endometrial biomarkers associated with endometriosis was recently published highlighting the expansive and baffling array of approaches being applied to the diagnosis of this disease [10]. The presence of sensory nerve fibers in the endometrium appears to be a highly specific and sensitive novel finding in women with endometriosis and may provide an understanding of dysmenorrhea as well as serving as a new diagnostic marker for this disease [11].
The most significant concept relating the endometrium to the disease of endometriosis, in my opinion, is that of progesterone resistance [12]. A key unanswered question in endometrial research today is how endometriosis, which resides outside of the uterus, causes progesterone resistance in the eutopic endometrium. A lack of progesterone action contributes significantly to the pathophysiology of this disease, affecting women from adolescence to menopause. Progesterone is required for pregnancy, is anti-inflammatory, antiproliferative and promotes immune tolerance. Suboptimal responses to progesterone allow estrogen to become the dominant driving force during the menstrual cycle, leading to poor implantation, inflammation and excessive cell proliferation. That imbalance in estrogen and progesterone, associated with progesterone resistance, has been studied at the molecular level showing hundreds of genes that are affected [13].
“The most significant concept relating the endometrium to the disease of endometriosis … is that of progesterone resistance.”
Assessment of the endometrium as part of infertility workup remains an active area for research. It has been reported that endometrial integrin (cell adhesion molecules) expression can predict not only endometriosis but also success as part of in vitro fertilization [14,15]. Loss of integrins appears to be associated with an overexpression of endometrial aromatase (an enzyme that converts androgens to estrogens) that has also been associated with poor IVF outcomes [16]. The blockade of this enzyme using aromatase inhibitors improves IVF success suggesting the primary importance of this aberrant expression of aromatase [14]. Interestingly, endometrial biopsy prior to IVF has been shown, by systematic review, to be beneficial for implantation, suggesting that the endometrial injury sustained during endometrial biopsy activates the endometrium and restores its function in some women with infertility [17]. Ongoing studies suggest that recruitment of specific immune cells as part of the healing process may contribute to that improvement in receptivity [18].
The endometrium of women with PCOS is also abnormal. Women with PCOS have menstrual irregularity and infertility but we found, using DNA microarray, disturbance in the expression of hundreds of endometrial genes compared to normal women, reminiscent of the changes we found in women with endometriosis and progesterone resistance [19]. As women with PCOS bleed heavily and do not ovulate regularly, endometriosis may be more common in this group of women as well, although the association is rarely studied.
Less invasive methods for endometrial assessment are available. Transvaginal sonography has become widely accepted as a tool for high-resolution imaging of the uterus and endometrium. Growth of the endometrium can easily be measured using ultrasound. The endometrial thickness and texture can be indicators of normal development or be used as a sign of disease. Endometrium in the early proliferative phase immediately following menses is typically thin; in response to estrogen, the endometrium thickens and becomes trilaminar in appearance, growing between 0.1 and 0.5 mm daily. Following ovulation, the endometrium becomes hyperechoic as secretory changes ensue. Transvaginal pulsed Doppler ultrasound measures uterine artery blood flow expressed as the pulsutility index (PI). The PI varies across the menstrual cycle and may used to predict implantation after assisted reproductive techniques. Aside from endometrial thickness, morphology, blood flow and uterine artery pulsatility have all been examined as possible markers of a receptive endometrium and increased PI has been associated with elevated markers of pregnancy loss, including anticardiolipin antibodies. An interesting future area of research will be the correlation of PI and other ultrasound characteristics with traditional and advanced assessment of endometrial biomarkers.
“Assessment of the endometrium as part of infertility workup remains an active area for research.”
Assessment of the endometrium is becoming a routine part of healthcare for women. In fact, the benefits of endometrial scratching have reawakened an interest in endometrial assessment, particularly since the improvement in pregnancy rates after biopsy appears to be a robust and reproducible finding. The accessibility to the endometrial cavity combined with the increasing number of biomarkers available, promises increasingly sophisticated methods for determining the state of the endometrium in both health and disease. Immune-based assays that examine resident leukocytes are increasingly important for the prediction of fertility as well as diagnostics for endometriosis [4]. Microarray and proteomic approaches will soon provide fingerprinting for any number of conditions involving the endometrium, while genetic assessment is currently being developed for the diagnosis and assessment of risk for diseases such as endometriosis [20]. While reluctant to give up its secrets, the endometrium with all its complexity is providing increasing insight into how life begins and how gynecological health can be shaped by this amazing endocrine tissue.
Financial & competing interests disclosure
The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.