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Piergentili, R.; Gullo, G.; Basile, G.; Gulia, C.; Porrello, A.; Cucinella, G.; Marinelli, E.; Zaami, S. Etiology and Pathogenesis of EC in Fertile Women. Encyclopedia. Available online: (accessed on 01 December 2023).
Piergentili R, Gullo G, Basile G, Gulia C, Porrello A, Cucinella G, et al. Etiology and Pathogenesis of EC in Fertile Women. Encyclopedia. Available at: Accessed December 01, 2023.
Piergentili, Roberto, Giuseppe Gullo, Giuseppe Basile, Caterina Gulia, Alessandro Porrello, Gaspare Cucinella, Enrico Marinelli, Simona Zaami. "Etiology and Pathogenesis of EC in Fertile Women" Encyclopedia, (accessed December 01, 2023).
Piergentili, R., Gullo, G., Basile, G., Gulia, C., Porrello, A., Cucinella, G., Marinelli, E., & Zaami, S.(2023, July 24). Etiology and Pathogenesis of EC in Fertile Women. In Encyclopedia.
Piergentili, Roberto, et al. "Etiology and Pathogenesis of EC in Fertile Women." Encyclopedia. Web. 24 July, 2023.
Etiology and Pathogenesis of EC in Fertile Women

Endometrial cancer (EC) affects the lining of the uterus and is usually diagnosed in postmenopausal women, but about 5% of cases occur in women under 40, and approximately 20% of cases are diagnosed before menopause.

endometrial cancer (EC) assisted reproductive techniques (ART) miR-based

1. Introduction

Assisted reproductive technology (ART) refers to several techniques allowing women to achieve pregnancy in a non- (fully) natural way and include in vitro fertilization (IVF), intracytoplasmic sperm injection (ICSI), gamete intrafallopian transfer (GIFT), and preimplantation genetic diagnosis (PGD) [1]. ART is a viable option not only in couples with fertility impairment but also in women diagnosed with cancer set to undergo chemotherapy; such therapeutical approach, however, not only affects fertility by impairing the viability of gametes but could also alter their genome introducing deleterious mutations in the embryo. As such, ART is also a valuable option for EC patients to minimize those problems [2].
Endometrial cancer (EC) affects the lining of the uterus and is usually diagnosed in postmenopausal women, but about 5% of cases occur in women under 40, and approximately 20% of cases are diagnosed before menopause [3]. The most common type of endometrial cancer in premenopausal women is estrogen-sensitive adenocarcinoma (type I carcinoma), which has a better prognosis than more aggressive type II carcinoma. Several genes that play a central role in EC development and growth have been recognized in the last years, [4][5]; more recently, the epigenetics of EC has started to be unveiled. Micro RNAs (miRNAs or miRs) are short molecules of non-coding endogenous RNA that function as post-transcriptional regulators of gene expression [6]. In addition, in EC, miRs can play a role in the development and progression of cancer by modulating the expression of oncogenes and tumor suppressor genes. For example, some miRNAs have been reported to regulate the expression of PTEN, a tumor suppressor gene that is frequently mutated or deleted in EC (see below). In addition, miRs can also be associated with EC risk factors, such as insulin resistance and hyperinsulinemia, which can trigger cell proliferation and angiogenesis [7]. It is crucial to understand the molecular bases of EC and how it influences women’s fertility; of similar importance is the evaluation of who, how, and when can face oocyte preservation for ART procedures once EC is in remission.
Evaluation of female fertility is an important step for women who want to undergo ART or preserve their fertility after being diagnosed with EC. A pelvic examination should be performed to assess the uterus and adnexa for masses or other abnormalities. The gold standard method for diagnosing EC is hysteroscopy and endometrial biopsy, which have high sensitivity and specificity. Other imaging techniques, such as ultrasound, magnetic resonance imaging (MRI), or computed tomography (CT), can be used to evaluate the disease extent and plan the treatment [8].

2. Etiology and Pathogenesis of EC in Fertile Women

2.1. Clinical and Endocrinological Characteristics of EC

EC has long been known as one of the most widespread gynecologic cancers worldwide; it is also the most common cancer affecting the female genital tract in developed countries. This malignancy is localized to the uterus in most patients (reportedly, as many as 67%) [9].
While uterine corpus cancer is currently the most common gynecologic malignancy, endometrial carcinomas constitute the majority of such diagnoses; sarcoma accounts for less than 10% of uterine corpus cancers. As many as 83% of uterine corpus cancers are endometrioid carcinomas. In addition, 4% to 6% of endometrial carcinomas consist of serous and papillary serous carcinomas, while clear cell carcinomas account for 1% to 2%. For a thorough analysis and better management and prevention of such conditions, it is worth drawing a distinction among type 1 endometrioid, type 2 serous endometrial carcinomas, and other highly aggressive non-endometrioid carcinoma histotypes [10][11].
Abnormal uterine bleeding or postmenopausal bleeding constitutes typical EC presentations. A diagnostic evaluation should be made available to any patient having EC risk factors, which should include the assessment of clinical history, imaging, and endometrial sampling. Standard EC therapeutic pathways may entail hysterectomy, bilateral salpingo-oophorectomy, and surgical staging. Hysterectomy is instrumental in accurately assessing EC prognostic factors, such as stage, grade, myometrial invasion, lymphovascular space invasion, and lymph node status [12][13][14].
ECs have been found to begin as preinvasive intraepithelial lesions transitioning into full-blown invasive cancers affecting endometrial stroma. A progressive penetration into the myometrium occurs through the lymphatic capillaries, thus spreading cancerous cells into regional lymph nodes. Then, the metastasizing process unfolds via vascular channels. The uterine cervix and stroma are likely affected by tumor progression through lymphatic channels, even if surface spread has been observed to take place from ECs manifesting in the lower uterine segment (LUS). LUS involvement in endometrial carcinoma has often been reported to result in lower survival rates and higher recurrence rates [15].
High levels of free estrogens leading to endometrial hyperplasia have been linked to estrogen-secreting, ovarian tumors, and polycystic ovaries (PCO); both conditions can adversely affect regular ovulation and menstruation. While anovulation obviously results in infertility, nulliparity is linked to a higher EC risk, even after adjusting for infertility [16].
Potential precursors of type I EC (which has been linked to a tumoral environment with excess estrogen) have been found to be atypical endometrial hyperplasia or endometrial intraepithelial neoplasia (EIN). Such dynamics often manifest at an early stage, with rather favorable outcomes. Serous, clear cell, mixed cell, and undifferentiated histologies are all elements reportedly associated with type II ECs, which are estrogen-independent and manifest at an already advanced stage with unfavorable prognosis [17]. The validation of genes or biomolecular factors is instrumental for an accurate prognosis assessment [18].
Such clinical dynamics entail medical as well as ethical and social concerns: fertility-sparing treatment (FST) can in fact forgo more radical care procedures by prioritizing the patient’s reproductive capabilities. ARTs are often required to that end, which means that EC treatment in patients of reproductive age is uniquely challenging, due to the need to strike a balance between “competing interests” of cancer care and the determination of patients to maintain their reproductive potential. Early menarche and late menopause, with higher levels of lifetime exposure to endogenous estrogens, have been found to lead to higher EC risks.

2.2. Challenges Arising from Fertility-Sparing Approaches in EC Patients

EC type and fundamental traits ought to be thoroughly assessed in order to choose the therapeutic pathway, which best suits each patient, particularly when weighing a conservative management opportunity.
Fertility-sparing procedures need to be weighed and counseled when making treatment decisions. That is even truer in light of the potentially harmful psychological dynamics that may be triggered by the loss of fertility following aggressive therapeutic approaches [19][20].
EC risk of extrauterine spread is an essential aspect to evaluate when assessing patient eligibility for fertility-sparing procedures. For patients who have an interest in preserving their fertility and plan to conceive as soon as possible after remission, fertility-sparing should be always considered, in the absence of contraindications and when there is favorable histopathological cancer makeup [21].
The fertility-sparing decision-making process needs to be weighed against various EC risk factors, such as obesity and polycystic ovary syndrome; such factors are linked to infertility as well; hence, any ART consideration may well be influenced by them. EC stage Ia grade 1 (G1) and EEC are the malignancies for which fertility-sparing treatment is most often chosen. EC type II, on the other hand, often makes patients ineligible for conservative treatments, due to its high level of invasiveness and poor differentiation. Young women with G1, no myometrium and/or adnexal invasion, and without lymphvascular space involvement, are therefore deemed the best candidates for fertility preservation approaches [22][23]).
When outlining any such pathway, it is worth taking into account updated guidelines by scientific societies such as ESGO-ESHRE-ESGE (the European Society of Gynaecological Oncology, the European Society of Human Reproduction and Embryology, and the European Society for Gynaecological Endoscopy, respectively), which have issued specific, evidence-based guidance for fertility-sparing treatment of EC patients, by focusing on the fundamental traits of fertility-sparing treatments. Particularly relevant is the recommendation that EC patients undergoing fertility-sparing procedures are counseled and cared for by a multidisciplinary team relying on oncologists and fertility specialists [24].
Progestin therapies (e.g., medroxyprogesterone acetate, MPA), megestrol acetate (MA), and progesterone-releasing intrauterine device (IUD) are the most widespread and validated EC hormonal treatment (HT) options and constitute the bedrock of the conservative fertility-sparing toolbox. MPA at 250–600 mg daily and MA at 160–480 mg daily are the most widely used regimens and rely on similar potency levels [25]. A 2016 meta-analysis by Qin et al., accounting for 25 sources comprising 445 women with early-stage EC treated with an oral progestin, has found an 82.4% regression rate, a 25% relapse rate, and a 28.8% pregnancy rate. Such findings point to the high degree of safety of oral progestins for early-stage EC patients who wish to have their fertility preserved [26].
Recent data have pointed to the novel levonorgestrel intrauterine device (LNG-IUD) as a solid fertility preservation option as well [27]. This device elicits a local hormonal surge in higher amounts and has efficacy rates similar to oral formulation, although conclusive comparative studies are not yet available [28].


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