At present, the methods of conservative treatment of endometrial atypical hyperplasia and early endometrial cancer have not been standardized. At present, the most commonly used and effective ones are mainly high-efficiency progestins. These include medroxyprogesterone acetate (MPA), medroxyprogesterone acetate (MA), levonorgestrel intrauterine device (LNG-IUD), progesterone, oral contraceptives, and progesterone caproate (28, 30). Oral progestogen treatment is the mainstay, most commonly Medroxyprogesterone acetate (MPA) 500-600mg once daily or Megestrol acetate (MA) 160-480mg once daily (31). Progestogen binding to the progesterone receptor (PR) delays DNA and RNA replication and decreases estrogen receptor (ER) expression, which in turn reduces endometrial cancer cell proliferation and promotes cell differentiation (32). The median duration of high-dose progestin treatment for endometrial atypical hyperplasia and early endometrial cancer CR is 6 months; if complete remission is not achieved after 9-12 months of treatment, it is recommended to change to surgical treatment, or the duration of the medication can be extended according to the therapeutic effect, but generally not more than 1 year (33); For persistent or progressive lesions, the treatment should be changed to surgery (34). Typically, patients who achieve CR with conservative treatment are advised to become pregnant as early as possible, and assisted reproduction is generally recommended as soon as possible, through which the risk of recurrence can be reduced (35).

In conclusion, compared with curettage, high-dose progestin oral therapy effectively avoids instrumental damage to the patient’s uterus, as well as the risk of intraoperative metastasis of cancer cells, and reduces the risk of recurrence while protecting the patient’s function. At the same time, progestogens mainly act on the patient’s endometrium, stimulating the proliferation and secretion of the endometrium, increasing the amount of negative feedback to the hypothalamus, thereby effectively inhibiting the production and release of luteinizing hormone in the anterior pituitary gland, inhibiting ovarian ovulation, and realizing treatment.

However, there are some problems associated with oral high-dose progestins. On the one hand, it can lead to common side effects such as breast pain, breast spillage, vaginal bleeding, weight gain, headaches, and mood changes, and on the other hand, since oral medications need to be taken over a long period of time, they require good self-consciousness and compliance on the part of the patient. To overcome this problem, intrauterine levonorgestrel intrauterine device (LNG-IUD) has also been used to treat early endometrial cancer and precancerous lesions (36).

Progestin-containing intrauterine devices (IUDs) offer an attractive method of delivering progestin to the localized endometrium and preventing atypical endometrial hyperplasia in patients with early-stage endometrial cancer who are being treated conservatively (37, 38). The LNG-IUD is a localized, sustained-release system of progestin, marketed and manufactured by Bayer AG, Germany (39–41). Currently commercially available progestin-containing intrauterine devices (IUDs) are categorized as Mirena, Jaydess, and Kyleena, depending on the dosage they contain (42, 43). In 1990, an intrauterine device (IUD) containing levonorgestrel (L-norgestrel) was introduced to the market under the name Mirena, which provides effective release for up to 5 years (44). The device releases up to 20 μg of levonorgestrel per day (average 14ug/24h) directly into the uterine cavity, creating a high concentration of progestin in the uterine cavity, strongly inhibiting atypical endometrial hyperplasia, generating high endometrial concentrations and low blood levels, with only minor adverse effects on body metabolism (45, 46). In 2013, a smaller IUD, marketed as Skyla or Jaydess, was introduced that contains 13.5 mg of levonorgestrel and releases approximately 10 μg of levonorgestrel per day, tapering down to 5 μg/d, which provides an effective release for 3 years (47). In 2016, Bayer of Germany received approval from the U.S. Food and Drug Administration (FAD) for its new IUD, Kyleena, which is the third IUD after Mirena and Jaydess. Each Kyleena contains 19.5 mg of the progestin hormone levonorgestrel, which provides effective release for up to five years after use (48).

Jaydess/Skyla and Kyleena are “low-dose” levonorgestrel-releasing intrauterine systems (LNG-IUS) compared to Mirena (49). Jaydess/Skyla and Kyleena have lower LNG content and smaller sizes, which make placement easier and less painful. placement while maintaining similar efficacy (43, 49, 50). The low-dose LNG system also reduces the incidence of overall adverse reactions, including obesity, metabolic disturbances, and other side effects of progestin overdose (51–53). However, the Mannheimer’s Ring, as a foreign body in the uterus, can still produce an inflammatory response, and patients may often present with irregular vaginal bleeding, lower abdominal pain, infections, and uterine perforation, and will need to go to the operating room to have it removed prior to a planned pregnancy (54).

Conservative treatment of early endometrial cancer by scraping to achieve removal of the cancer was first reported in the 1960s (55). With the rapid development of medical science and technology and the rapid maturation of gynecological endoscopy technology, hysteroscopy has been rapidly applied to all aspects of the diagnosis and treatment of gynecological diseases in recent decades.Gonthier C proposes a new idea of hysteroscopic lesion electrosurgery combined with high-efficiency progestin for the treatment of early EC with preservation of reproductive function (56). Hysteroscopic Focal Electrodessication (HFE) is the procedure of removing the lesion in the uterine cavity and its surrounding tissues under the direct vision of the hysteroscope to minimize the cancerous foci and protect other normal tissues and endothelial lining from being damaged, so as to achieve the optimization of the cure of the disease and the protection of the reproductive function (57, 58). The resected tissues are sent for pathologic examination, and if they meet the indications of preserving reproductive function, they are combined with high-efficiency progestin for postoperative maintenance therapy, and progestin acts on the endometrium to further inhibit and eliminate the remaining cancer foci (59).

Crosbie et al. concluded that hysteroscopic lesion electrosurgery combined with high-efficiency progestins not only reduces the tumor load of subsequent drug therapy but also effectively reduces the application of progestins, decreases the side effects of progestins, improves the efficacy of treatment, and shortens the treatment period at the same time (20). Study demonstrates high complete remission rates in patients with fertility-preserving early-stage endometrial cancer treated with hysteroscopic lesion electrodesiccation and subsequent high-potency progestin therapy (60, 61). However, the application of hysteroscopy is easy to cause damage to the endometrium, after the operation, the patient may be complicated by uterine deformity, endometrial thinning, endometrial inflammation of the uterine cavity adhesions and other changes that lead to a decrease in the endometrial tolerance, which is not conducive to embryo implantation, and is prone to miscarriage, preterm labor, and so on (62, 63). In addition, Kandoth et al. suggested that the application of hysteroscopy may cause intraperitoneal dissemination of cancer cells, but no study has shown that the prognosis of patients is affected by it (62, 64).

In conclusion, whether hysteroscopic lesion electrodesiccation has a better oncologic prognosis in the management of patients with EC, and the impact of postoperative complications such as the occurrence of uterine adhesions on pregnancy outcomes is unclear, and the controversial nature of its application suggests that a large number of prospective studies with large samples are still needed for further exploration.

GnRH is a peptide hormone secreted by the hypothalamus that stimulates the pituitary gland to synthesize gonadotropins, thereby promoting the secretion of sex hormones by the ovaries (65). Gonadotropin-releasing hormone agonist (GnRH agonist, GnRH-a) is a synthetic derivative of GnRH-a,by altering amino acids 6 and 10 of GnRH-a, the newly produced skin chain is structurally stabilized, the half-life is extended (1-6h), and the binding capacity to the corresponding receptor is increased 100-200-fold, which enables GnRH-a to inhibit the secretion of pituitary gonadotropins (66). The mechanism of action of GnRH-a in the treatment of EC is mainly desensitization, i.e., when the patient first uses the drug for 7-14 days, it will make the pituitary gonadotropin transiently elevated, and if it is used continuously, the pituitary function will be inhibited to appear down-regulation, which will result in a significant decrease in the levels of serum follicular spiking (folliclestimulating hormone (FSH), luteinizing hormone (LH), and ovarian sex hormones, and thus achieve the effect of inhibiting endometrial hyperplasia. Luteinizing hormone (LH), ovarian sex hormone levels decreased significantly, thus achieving the effect of inhibiting endothelial hyperplasia (65, 67–69); In addition, GnRH-a can directly bind to GnRH receptors on tumor cells, interfering with mitotic signaling, inducing a decrease in c-fos expression of oncogenes, and inhibiting tumor cell proliferation, thus inhibiting tumor growth (70, 71). Tang et al. found that GnRH-a inhibited the proliferation of EC cells in in vitro experiments (72). Pashov et al. reported 9 patients with early EC who were given 9 consecutive injections of GnRH-a and placed on LNG-IUS for at least 1 year after the 3rd injection, and achieved a favorable outcome (73). Sallam et al. showed that the use of GnRH-a for 3-6 months resulted in a 4-fold increase in the clinical pregnancy rate, which may improve the conception rate of patients while treating endothelial pathologies (74). Since its reversal rate can reach 35%, it has been proposed for the treatment of endometrial cancer due to atypical endometrial hyperplasia.

Compared with oral progestogen, this drug is injected once a month, avoiding the disadvantage of progestogen needing to be taken orally every day, which can improve patient compliance, and the chance of liver and kidney function damage is small, but the price is relatively high.The main adverse effects are menopausal symptoms associated with reduced estrogen and progestogen levels, which can be relieved by oral medication such as Livastigmine.

In patients with polycystic ovary syndrome (PCOS), the body is in a progesterone-deficient state and the endometrium is in a state of estrogen-mediated proliferation for a long period of time due to prolonged anovulation or reduced ovulation, which may be an important reason for the high incidence of endometrial cancer in patients with polycystic ovary syndrome (75–77). Most clinical features of patients with polycystic ovary syndrome are characterized by hyperandrogenism, scanty or amenorrhea, anovulatory infertility, hirsutism, insulin resistance, and type II diabetes mellitus (78–80). Meanwhile, studies have shown that obesity, diabetes, and insulin resistance are risk factors for the development and progression of endometrial cancer (81, 82). Metformin, an oral hypoglycemic agent of the biguanide class, is now widely used in the treatment of type II diabetes mellitus to improve insulin resistance (83). Therefore, metformin can also be used in the conservative treatment of patients with early-stage endometrial cancer due to PCOS.

The study showed that the combination of metformin and oral progestins not only modified the insulin resistance status, but also that the combination of metformin and oral progestins remained effective in patients with atypical endometrial hyperplasia combined with polycystic ovary syndrome, even if oral progestins alone failed to treat the disease (84). Meanwhile, Shan et al (85). reported 2 cases (25%) in which combined metformin administration still failed to reverse endometrial histology to normal. However, the mechanism of action of metformin is very complex, and the more clearly studied mechanism is the activation of mitogen-activated protein kinase (AMPK), which in turn inhibits tumor suppressor genes such as PTEN/AKT and TSC2/TSC1 (86). The end result of these effects is the indirect inhibition of mTOR, a central cell growth activator, through the PI3K/Akt pathway (86–89), and through the induction of caspases 3/7, 8, 9 and proteins that regulate autophagy and cell death (e.g. bcl2 and beclin 1) leading to apoptosis (90–92). In endometrial cancer, metformin decreases cell viability and proliferation in a human endometrial cancer cell line (Ishikawa cells) through activation of pAMPK, induction of beclin 1, down-regulation of IGF, and increased autophagy and apoptosis (92).

Estrogen overstimulation is the main cause of EC. Progesterone antagonizes estrogenic activity by competitively blocking estrogen receptors and is the basic treatment for EC (93). However, prolonged progesterone therapy leads to decreased regulation of cytoplasmic and nuclear receptors, as well as lack of functional progesterone receptor expression in some patients, which in turn affects the anti-endothelial cell proliferation and differentiation effects of progesterone.

Tamoxifen (TAM) belongs to the group of estrogen receptor modulators and acts as both an antagonist and an agonist of the estrogen receptor, depending on the target tissue. As early as 1985, Killackey et al. suggested a possible link between tamoxifen use and the development of endometrial cancer (94). This was confirmed by a series of later studies that showed tamoxifen users had a 1.5 to 6.9 times increased risk of EC (95). However, the risk of tamoxifen-associated EC was not related to the daily dose of the medication, but rather to the duration of the medication and cumulative dose (96–99). Postmenopausal and elderly patients have a higher risk of EC than premenopausal and younger women, and it increases with weight gain (95, 96, 100). Therefore, in young patients with endometrial cancer, tamoxifen alone or in combination with progesterone can be used in the short term as an effective adjuvant therapy with low toxicity (101–103). Because TAM has a composition structure similar to that of estrogen, it can competitively bind with estrogen receptor in the body after entering the human body, thus inhibiting estrogen from binding to it, and at the same time it can stimulate the excitation of progesterone receptor and improve its activity, effectively regulating the estrogen and progestogen levels in the patient’s body, inhibiting the growth and proliferation of tumor cells, and further enhancing the clinical efficacy of the treatment after being used in conjunction with MA.

As the preferred second-line hormone therapy after first-line progestogen therapy, especially for endometrial tumors and estrogen receptor-positive patients, it is effective in 10%-53% of cases (102). Thus, tamoxifen is a dual drug with regard to EC: on the one hand, it increases the risk of the development of this disease, and on the other hand, it acts as a remedy that somehow slows down the development of the tumor. Thus, tamoxifen is a dual drug with regard to EC: on the one hand, it increases the risk of the development of this disease, and on the other hand, it acts as a remedy that somehow slows down the development of the tumor.