Assessment of endometrial dating

Criteria for adequacy of endometrial biopsy specimens Previously, endometrial biopsy specimens were largely obtained by dilatation and curettage carried out under general anaesthesia. Open in a separate window. Diagnostic algorithm for examination of endometrial biopsies Tissues not derived from the endometrium are commonly represented in endometrial biopsies. Artefacts in endometrial biopsy specimens Several common artefacts are observed in endometrial biopsy specimens, which have received scant attention in the literature. Endometritis Endometritis may result in symptoms of abnormal uterine bleeding and the pathologist should always exclude this.

Endometrial polyps Polyps are a common cause of abnormal bleeding in premenopausal and postmenopausal women. The following points on endometrial polyps are worthy of mention: Proliferative activity is common in endometrial polyps, even in postmenopausal women. This is of no relevance, although I generally include a comment to this effect in the pathology report.

A diagnosis of simple hyperplasia should not be made in the case of an endometrial polyp, as a glandular architecture reminiscent of simple hyperplasia is a normal feature within a polyp. Focal mild glandular crowding is not uncommon and in my opinion does not warrant a diagnosis of complex endometrial hyperplasia. With considerable glandular crowding, however, a diagnosis of complex hyperplasia should be made.

In such circumstances, the gynaecologist should probably conduct a repeat biopsy of the endometrium. Obviously, if a cancer is identified in an endometrial polyp removed by biopsy, it is impossible to ascertain, without full evaluation of the surrounding endometrium, whether the cancer has arisen in or has secondarily involved the polyp.

Polyp cancers may be endometrioid in type, but serous proliferations, serous carcinoma or its precursor lesion endometrial intraepithelial carcinoma EIC , have a particular propensity to arise in or be associated with otherwise benign endometrial polyps. This is discussed more fully later. Endometrial polyps are particularly common in association with tamoxifen. This is also discussed later. Other benign endometrial lesions It is useful to have a checklist of benign lesions other than those listed earlier, including granulomas, placental site nodules and the various forms of epithelial and stromal metaplasias.

Epithelial metaplasias, especially squamous or mucinous in type, may coexist with hyperplasia or a carcinoma. In case of florid epithelial metaplasia, a hyperplastic or malignant process should be looked for and excluded. Assessing the glandular architecture and cytology may be difficult, as the squamous elements can be so extensive that the underlying glandular component is almost totally obliterated.

Indeed, in the setting of chronic obstruction, squamous carcinoma of the endometrium may develop from florid squamous metaplasia. Ciliated cells are common in a normal cyclical endometrium. Ciliated cells are normal in the lower uterine segment and should not be interpreted as ciliated metaplasia. When florid, this may be suggestive of a serous carcinoma or an EIC.


In this circumstance, attention should be paid to the background endometrium, which, in papillary syncytial metaplasia, usually shows features of breakdown. In problematic cases, p53 immunohistochemistry discussed below may be of value. Many endometrial epithelial metaplasias occur without obvious causation.

Epithelial metaplasias are, however, especially likely to be seen in endometrial polyps and in association with hormonal preparations. Mucinous proliferations of the endometrium, which are identified on biopsy, can be subdivided into categories based on the degree of architectural complexity, which correspond to an increasing risk of the presence of mucinous adenocarcinoma in subsequent hysterectomy. These are benign proliferations, and in this situation the presence of architectural complexity does not signify a hyperplastic process. By contrast, most metaplastic processes are oestrogen receptor positive and exhibit a weak heterogeneous pattern of p53 staining.

Effects of hormones on the endometrium Hormones have varying effects on the endometrium and it is essential that the clinician supplies details to the pathologist regarding any hormone treatment. Effects of tamoxifen on the endometrium Tamoxifen is widely used as adjuvant therapy in the management of breast cancer. Endometrial hyperplasia In my experience, various aspects related to endometrial hyperplasia commonly create problems for pathologists.

Potential benign mimics of endometrial hyperplasia Artefacts. Exclusion of benign mimics Before diagnosing an endometrial hyperplasia, it is important to exclude the many benign mimics. Classification of endometrial hyperplasia Endometrial hyperplasias should be classified according to the World Health Organization WHO scheme. Morphological features of endometrial hyperplasia In a simple hyperplasia, the normal gland to stroma ratio is maintained or there is slight increase.

Suggested alternative terminology for classification of precursor lesions of endometrioid adenocarcinoma EIN terminology has been extensively championed by Mutter and coworkers. Briefly, five criteria must be fulfilled for a diagnosis of EIN: Cytology differing between architecturally crowded focus and background—that is, cytological demarcation. Atypical polypoid adenomyoma Only a few comments will be made regarding atypical polypoid adenomyoma APA , concentrating on those issues that are likely to pertain to endometrial biopsy specimens. Adenofibroma and adenosarcoma Adenofibroma, with a benign stromal component, and adenosarcoma, with a malignant one, are two of the mixed epithelial and mesenchymal mixed Mullerian tumours of the uterus.

Endometrial carcinoma Issues relevant only to the diagnosis of endometrial carcinoma on biopsy specimens will be considered. In a postmenopausal woman with an atrophic endometrium and no focal lesion on ultrasound scan, the presence of scant endometrial tissue in an outpatient biopsy is the norm. When an endometrial biopsy is carried out for abnormal uterine bleeding, the pathologist should always consider the possibility of a polyp. Serous proliferations, either serous carcinoma or endometrial intraepithelial carcinoma, have a propensity to arise in endometrial polyps.

All endometrial cancers should be typed and, if appropriate, graded, even for small biopsy specimens. Adv Anat Pathol 10 — Results of a questionnaire regarding criteria for adequacy of endometrial biopsies. J Clin Pathol 58 — Controlled analysis of factors associated with insufficient sample on outpatient endometrial biopsy. BJOG — Buckley C H, Fox H. Inflammation of the endometrium. Biopsy pathology of the endometrium.

Chapman and Hall, — Diagnosis of endometrial biopsies and curettings. Interpretation of endometrial biopsies and curettings. Int J Gynecol Pathol 18 — Euscher E, Nuovo G J. Int J Gynecol Pathol 21 — Appl Immunohistochem 5 — Mod Pathol 14 — Arch Pathol Lab Med — Histopathology 45 — J Clin Pathol 38 — Am J Obstet Gynaecol — An immunohistochemical study of lymphoid tissue in human endometrium. Int J Gynecol Pathol 7 — Kamat B R, Isacson P.

The immunohistochemical distribution of leucocyte subpopulations in human endometrium. Am J Pathol 66— Am J Surg Pathol 28 — Uterine serous carcinoma and endometrial intraepithelial carcinoma arising in endometrial polyps: Hum Pathol 34 — Silva E G, Jenkins R. Serous carcinoma in endometrial polyps. Mod Pathol 3 — Metaplasias in the female genital tract. Lowe D, Underwood J, eds.

Recent advances in histopathology. Royal Society of Medicine Press Ltd, Report of 89 cases and proposed classification. Am J Surg Pathol 4 — Endometrial papillary syncytial change: Am J Clin Pathol 99 — Mod Pathol 12 — Simple and complex hyperplastic papillary proliferations of the endometrium: Am J Surg Pathol 25 — Histopathology 35 44— Surface epithelial changes in endometrial adenocarcinoma: Int J Gynecol Pathol 14 — Feeley K M, Wells M. Hormone replacement therapy and the endometrium. J Clin Pathol 54 — A comparative study of endometrial biopsy, outpatient hysteroscopy and transvaginal ultrasound.

J Clin Pathol 56 — Mod Pathol 16 — Pathology of endometrium treated with tamoxifen. J Clin Pathol 47 — Lancet 1 [ PubMed ]. Tamoxifen and the endometrium. Int J Gynecol Pathol 17 — Tamoxifen and the endometrium: Int J Gynecol Pathol 8 — J Natl Cancer Inst 86 — J Natl Cancer Inst 87 — J Clin Oncol 11 — Malignant neoplasms of the uterine corpus in patients treated for breast carcinoma: Int J Gynecol Pathol 13 — Malignant biphasic uterine tumours: J Clin Pathol 55 — Uterine carcinosarcomas malignant mixed Mullerian tumors are metaplastic carcinomas.

Int J Gynecol Cancer 12 — A report of 19 cases. Int J Gynecol Cancer 10 — Int J Gynecol Cancer 5 — Page views in Accessed January 19th, To date endometrium, should see surface endometrium, but date based on most advanced area Must biopsy uterine corpus above the level of the isthmus; must also biopsy functionalis as basalis layer does not respond to progesterone Dating has low interobserver agreement, and may not have accuracy to diagnose luteal phase deficiency or to guide clinical management of women with reproductive failure Fertil Steril ; Images hosted on other servers: Mid proliferative endometrium and Ki67 staining.

My approach to the interpretation of endometrial biopsies and curettings

Day 10 - 12 endometrium shows glands that are more tortuous and crowded; intraglandular nuclear pseudo- stratification and mitotic activity are more prominent see inset and the stroma is edematous and mitotically active. The glands exhibit a regular tortuosity and are clearly oriented from the base to the surface of the endometrium; subnuclear glycogen vacuoles are clearly visible.

Also, at the time of decidualization, increased cytokine production leads to the migration of immune cells into the endometrium, of which the most important are monocytes and uterine natural killer NK cells King, Immune competent cells have their specific role in the preparation of endometrial receptivity. Besides cellular changes, decidualization creates an extracellular matrix ECM composition of utmost importance. This matrix is composed mainly of laminin, heparan sulphate proteoglycans and type IV collagens Ferenczy and Giudice, In the last two decades, a large number of proteins and other molecules, which are expressed in the endometrium in a cycle-dependent manner, have been described.

Some of them, such as the insulin-like growth factor binding protein-1 IGFBP-1 , are used as a marker for decidualization at least in in vitro experiments. Nevertheless, the importance of these factors for endometrial regulation, and the interaction of these factors, is far from being understood. Furthermore, new technologies of molecular genetics, in particular the microarrays Popovici et al.

However, the actual functions of these individual genes often remain to be determined. Although knowledge on molecular mechanisms in the endometrium has increased tremendously, translation of this basic research into daily clinical routine is rather limited. Therapeutic options remain poor. Therefore, the main purpose of this review is the re-evaluation of the endometrial contribution to fertility.

The first section focuses on the endometrial development towards a receptive milieu. To elucidate the possible function of regulatory factors for each phase of endometrial development, we have used a cycle-dependent description. The second section is dedicated to the actual clinical evaluation of endometrial receptivity, possible therapeutic strategies and, in particular, the evaluation of endometrial function in the non-natural situation of hormonal stimulation.

Every phase of the endometrial cycle is precisely tuned by many known and unknown genes that are regulated by endocrine, paracrine and autocrine factors. In this section, we have concentrated on some of the more important factors, many of which have been shown to be of relevance in humans.

These factors are summarized in Figure 1. Microarray profiling of endometrial genes may allow a more comprehensive overview of gene encoding factors that are involved in endometrial differentiation. Furthermore, expression profiling of genes during the WOI in endometriosis may be helpful in identifying genes responsible for implantation failure Kao et al.

The main feature of the endometrial tissue during the proliferative phase is active proliferation and angiogenesis to ensure nutrition of the developing new tissue, while suppressing apoptotic factors. Adequate development of endometrial tissue during this phase of the cycle is crucial for synchronization of the maturation process necessary for implantation during the secretory phase endometrium Hoozemans et al. One of the key players during the proliferative phase is the rising female hormone estrogen. Estrogen is found to induce the proliferation of cells and demonstrates an indirect effect by stimulating the expression of steroid receptors such as the progesterone receptor PR , which is crucial for progesterone action during the secretory phase, and ERs ERa, ERb Chauchereau et al.

Estrogen also acts as a cell survival factor in the late proliferative phase via inhibition of the tumour suppressor gene phosphatase and tensin homologue PTEN. This gene is found to increase apoptosis and contact inhibition in endometrial cells by regulating various factors. PTEN inhibition on the other hand leads to elevated expression of such factors, e. Akt, a cell survival factor which acts via down-regulation of FasL, cell cycle inhibitor p27, cytochrome C release and many others Uegaki et al.

Anti-apoptotic genes like Bcl-2 are also up-regulated in the proliferative phase Kayisli et al. These changes partially reflect the interaction between immune cells and the endometrial cells during this phase. Furthermore, ovarian hormones extensively regulate the growth factor system of insulin-like growth factor IGF and IGF-binding protein; induction of IGF-I by estrogen during the proliferative phase Giudice et al. In a recent microarray analysis, additional genes within the human endometrium were discovered to be regulated by estrogen Punyadeera et al.

These include the trefoil peptides, mammaglobins, wnt family and more. They include the genes for many cytokines, enzymes involved in eicosanoid biosynthesis and immunomodulators and their receptors, all of which are active during the menstruation process via tissue degeneration, inflammation, hypoxia, epithelial repair and angiogenesis Punyadeera et al. The macrophage migration inhibitory factor MIF is predominantly expressed in glands and surface epithelium in the late proliferative phase and premenstrual phase when architectural changes of the endometrium take place Kats et al.

This is not surprising as MIF is a multifunctional cytokine that is involved in angiogenesis and tissue remodelling. In a highly proliferating tissue like the endometrium during the proliferative phase, angiogenesis is mandatory to supply the tissue with sufficient nutrients.

The Endometrial Cycle

Angiogenesis takes place throughout the menstrual cycle with a significant increase in the basal layer and in the subepithelial plexus during the first part of the cycle. Angiogenesis changes in aspect during the cycle: Not surprisingly, angiogenesis is regulated by many factors, such as nitric oxide, matrix metalloproteinases MMPs and many growth factors, including fibroblast growth factor, epidermal growth factor and vascular endothelial growth factor VEGF , which is one of the key players in angiogenesis Print et al.

The angiogenic factor VEGF seems to have additional functions in epithelial cells late in the proliferative phase, where it is found to have a proliferative effect Hastings et al. This effect could potentially be transmitted via an atypical VEGF receptor called neuropilin, which is simulanteously up-regulated within these cells Germeyer et al.

In addition to their effect during menstruation, MMPs are thought to be relevant in tissue regeneration. MMP-7, for example, is up-regulated during the early proliferative phase Hirota et al. Finally, several factors that are up-regulated during menstruation need to be eliminated in the proliferative phase.

To summarize, the proliferative phase is characterized by a concert of factors directed towards tissue remodelling, proliferative and anti-apoptotic processes, and stimulated angiogenesis. In humans, during the late secretory phase of normal menstrual cycles, the morphological changes that characterize decidualization are taking place independently of conception.

All cell types in the endometrium are affected, with the functionally distinct tissue showing characteristic endometrial cell differentation and an infiltration by large numbers of immune cells. Progesterone, which suppresses proliferation and induces cell differentiation, is the major player during this second half of the menstrual cycle, and acts at least partially via the progesterone type A receptor PR A, Wang et al.

PR B is diminished in the glandular epithelial cells, but is still present in the stroma Mote et al. Therefore, the action of progesterone during the implantation window is most likely through PR B in the stromal compartment. Recently, membrane progestin receptors have been described in the endometrium, indicating a possible action of progesterone in the endometrial glands via these membrane receptors Fernandes et al.

Epithelial cells are characterized by their glandular secretory transformation. Stromal cell decidualization is accompanied by the production and secretion of distinct decidual proteins such as prolactin, IGFBP-1 and tissue factor Irwin et al. The endometrium in the mid- to late-secretory phase, as well as the decidua, is also infiltrated by a variety of bone marrow-derived immune cells.

Clinical history

During the secretory phase, vascular remodelling occurs, with the main angiogenic mechanism being coiling and intussusception of the spiral arteries Gambino et al. With these distinct morphological and biochemical changes, the endometrium is prepared for the implantation of the blastocyst. The embryo apposes and attaches to the endometrial epithelial cells and invades the endometrial stroma.

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Pinopodes might influence the concentration of endometrial fluids near the implantation site, thus facilitating the process of adhesion and invasion Stavreus-Evers et al. They can be found on the apical surface of the luminal endometrial epithelium and are strictly progesterone dependent. The determination of the day on which fully developed pinopodes can be demonstrated in patients with repeated implantation failure in assisted reproductive cycles showed an increase in pregnancy rates when transfer cycles are modified accordingly Nikas et al.

This suggests pinopod formation as a possible, although because of the necessity of an invasive biopsy, impractical marker of receptivity Bentin-Ley, ; Adams et al.

Confocal microscopy experiments revealed the presence of HB-EGF both inside the luminal epithelial cells and on the surface of pinopodes, suggesting a possible role of HB-EGF in the attachment process. There is a remarkable shift in HB-EGF expression during the menstrual cycle with maximal stromal expression in the proliferative phase and, in contrast, peak expression during the WOI in luminal and glandular epithelial cells Leach et al.

The role of the EGF system in endometrium is not fully understood. Data on EGF expression in the human endometrium throughout the cycle are contradictory. Whereas some groups were not able to demonstrate EGF in the endometrium regardless of the cycle phase Ejskjaer et al.

human endometrium as a fertility-determining factor | Human Reproduction Update | Oxford Academic

Mucins, in particular MUC1, are candidates for selection of the implantation site. A MUC1 barrier on the luminal epithelium impairs interactions between the embryo and the endometrium by anti-adhesive properties. Changes of MUC1 glycoforms and interactions with integrins may allow for a selected site of facilitated adhesion DeLoia et al. Furthermore, the blastocyst itself cleaves MUC1 very locally and might influence the most appropriate site of implantation. In a clinical study, endometrial samples from women with idiopathic infertility have shown a reduced expression of the MUC1 D9B1 epitope compared with samples from normal fertile women Aplin, This epitope was also reduced in women with the endometrium out of phase LPD as well as in women using an intrauterine device IUD Aplin, , suggesting that certain parts of the MUC1 glycoprotein are more important for implantation than others.

Integrins are the best-studied group of cell adhesion molecules in the endometrium. Their extracellular domain serves as a receptor for various ECM ligands such as fibronectin, collagen and laminin Albelda and Buck, Many integrins show a cycle-dependent expression. It is co-localized with osteopontin and appears to be stimulated by EGF Lessey, Osteopontin is an important receptor for the integrins and indeed a possible function for embryonic implantation seems obvious.

Osteopontin has been detected during the mid- to late-secretory phase Apparao et al. Consolidating its role in endometrial receptivity, microarrays analysing the WOI have shown that osteopontin is consistently up-regulated during the WOI when compared with both the late proliferative phase and the early secretory phase Horcajadas et al. The role of leukaemia-inhibitory factor LIF in implantation has been shown in a mouse model lacking a functional LIF gene; although the homozygous female mouse mated with a wild-type male the embryos did not attach and implant Stewart, Data on humans, however, are still scarce.

Clinically, more women with idiopathic infertility have undetectable levels of LIF in their uterine flushing in contrast with fertile women Laird et al. LIF mRNA expression is 3-fold higher in glandular epithelium compared with stroma and is cycle dependent with preferential expression in the secretory compared with the proliferative phase Kojima et al.

The embryo expresses l -selectin after it hatches from the zona pellucida Genbacev et al. A similar process was postulated when Genbacev et al. The hypothesis postulates that the embryo is transported through the uterine cavity by mucin flow. When it hatches, l -selectin binds oligosaccharides on the epithelial surface, slows down the blastocyst and enables a firm interaction with integrins, leading to embryo adhesion.

Furthermore, a large number of chemokines have been described at the embryo—maternal interface Dimitriadis et al. For example the chemokine receptor CXCR1 is upregulated in epithelial cells in the presence of a blastocyst Dominguez et al. Factors regulating the trophoblast. After traversing the epithelial cell layer, trophoblast cells of the implanting embryo invade the endometrial stroma with the goal of anchoring themselves tightly and invading the maternal vasculature in order to create a low-pressure circulation thereby accessing nutrients.

Interactions of the invading trophoblast occur with the ECM and result in changes in trophoblast invasiveness.

Histopathology Uterus, endometrium--Proliferative endometriu

Both laminin and fibronectin, proteins of the ECM, are secreted by endometrial stromal cells predominantly in the secretory endometrium and decidua Irwin et al. Fibronectin has an RGD amino acid sequence, which enables it to bind to the fibronectin receptor on the differentiating invasive cytotrophoblast, probably also inhibiting its invasion Damsky et al. Women with otherwise unexplained infertility or repeated abortions show different patterns of MMPs, tissue inhibitors of metalloproteinases TIMPs and cathepsin from normal controls Jokimaa et al.

Another restraining endometrial factor which is secreted by decidualized endometrial stromal cells under the influence of progesterone is IGFBP-1 Zhou and Bondy, IGFBP-1 is the best-characterized endometrial marker of decidualization besides prolactin. It is equally produced in stromal and in epithelial cells Chegini et al.

Factors regulating immune cells. Colony stimulating factor-1 CSF-1 is produced by endometrial epithelial glands as well as by macrophages during the mid-proliferative phase up to the mid-secretory phase Tsoukatos et al. Its production declines during the WOI Pampfer et al. Its known function is in the development and growth of the decidual macrophages.

It seems, however, to also have a differentiating effect on the first trimester trophoblast causing them to form a villous syncytial phenotype Morrish et al. In patients, CSF-1 has been shown to vary largely in the serum of different individuals, making it difficult to compare with patient groups. Glycodelin A is one of the most abundantly secreted glycoproteins in the secretory endometrium and early pregnancy decidua. It is produced by the endometrial glands and secreted into their lumen as well as into the circulation.

Even though serum levels of glycodelin do not accurately reflect histological changes in the endometrium McRae et al. Its known function is to suppress the activity of NK cells Okamoto et al. Multiple studies have been performed measuring glycodelin in infertile patients either in serum or in uterine flushings.

Uterine flushings seem to be more useful in assessing endometrial function than serum samples. However, standardizations and further investigations are needed to establish its future use in clinical practice see Lindhard et al.