**1. Morphological Features of the Human Endometrium**

The uterine endometrium is an inner mucosal layer of the uterine cavity with the unique ability to regenerate or shed depending on the phases of the menstrual cycle and hormonal levels [1,2]. The human endometrium consists of two layers: functional (stratum functionalis) and basal (stratum basalis). The endometrium undergoes structural modification and changes in specialized cells in response to fluctuations of estrogen and progesterone during the menstrual cycle [3]. The basal layer of the endometrium is responsible for the regeneration of functional layer during the proliferative phase [4–6]. A hypothesis on the regeneration process of the endometrium suggests that the functional layer quality depends on endometrial progenitors/stem cells located in the basal layer [7–9]. However, understanding of the regenerative mechanism of the endometrium during the menstrual cycle and the location of endometrial progenitor/stem cells have not been fully elucidated [10–12]. The traditional morphological theory of the endometrium describes it as two-dimensional (2D) histological structure [13–15]. However, due to the complexity of the morphology of the endometrial glands, the technical characteristics of 2D histopathological imaging have been found to be insufficient [4].

It was hypothesized that clonal genomic alterations in histologically normal endometrial glands may change the stereoscopic structure of the endometrial glands. Threedimensional (3D) pathological morphology of tissue affected by adenomyosis and 3D

**Citation:** Terzic, M.; Aimagambetova, G.; Kunz, J.; Bapayeva, G.; Aitbayeva, B.; Terzic, S.; Laganà, A.S. Molecular Basis of Endometriosis and Endometrial Cancer: Current Knowledge and Future Perspectives. *Int. J. Mol. Sci.* **2021**, *22*, 9274. https://doi.org/ 10.3390/ijms22179274

Academic Editors: Maurizio Battino and Alfonso Baldi

Received: 22 July 2021 Accepted: 25 August 2021 Published: 27 August 2021

**Publisher's Note:** MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

**Copyright:** © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

morphology of the normal endometrial glands was compared using 3D full-thickness images of the human uterine endometrium with microscopy [4]. 3D imaging revealed a more complex network of endometrial glands in human endometrium than was observed with traditional 2-dimensional (2D) imaging [4]. Using 3D imaging, Yamaguchi and co-authors (2021) found specific morphological features of human endometrial glands, including occluded glands, the plexus of the basal glands, and the gland-sharing plexus with other glands, which were not observed in the past using 2D histological methods [4]. The 3D analysis of the endometrial layers clarified that the plexus structure of the glands expanded horizontally along the muscular layer. Furthermore, these morphological features were detected regardless of age or phase of the menstrual cycle, suggesting that they are basic components of the normal human endometrium [4]. These novel findings suggest that 2D histology, which has been in use for more than 100 years, does not adequately depict the morphology of the endometrium. A clearer picture of the structure of the human could develop our understanding of various endometrial conditions and the etiology of endometriosis and endometrial cancer (EC). These diseases significantly affect reproductive age women and impact their quality of life [16–18]. Understanding the pathogenesis, immunohistochemical and molecular mechanisms of these conditions could improve the management of patients with endometriosis and EC [19–22].
