Use of hotalr-pcr2 blocker combined with progestogen in the preparation of a conservation therapy drug for endometrial cancer

Abstract

The application discloses a use of a HOTAIR-PRC2 blocking agent combined with a progestogen in preparation of a drug for conservation treatment of endometrial cancer. The application provides a use of a HOTAIR-PRC2 specific blocking agent combined with a progestogen, which can synergistically inhibit the progression of endometrial cancer. The HOTAIR-PRC2 specific blocking agent provided by the application can restore the expression of PR, and the combination of the progestogen can synergistically inhibit the proliferation, invasion and migration of tumors, promote cell apoptosis, block the cell cycle, and enhance the treatment effect of the progestogen, thereby providing a new treatment idea for the conservation treatment of endometrial cancer.

Description

Technical Field

[0001] This invention belongs to the field of new pharmaceutical applications, and particularly relates to the use of HOTAIR-PRC2 blockers in combination with progestins in the preparation of fertility-preserving drugs for endometrial cancer. Background Technology

[0002] Endometrial cancer (EC) is one of the most common malignant tumors in women, and its incidence and mortality rates have been rising globally over the past two decades. Statistics show that 14% of endometrial cancer patients are diagnosed in premenopausal women, and the proportion of women under 40 years old diagnosed with endometrial cancer is gradually increasing, indicating a trend towards younger onset. Currently, the main treatments for endometrial cancer are total hysterectomy and bilateral salpingo-oophorectomy. However, for women with early-stage endometrial cancer who have not yet given birth, the desire to preserve fertility is growing. Clinically, progestins are the first-line drugs for conservative treatment of early-stage endometrial cancer patients who wish to preserve their fertility. The most commonly used progestins include medroxyprogesterone acetate (MPA), medroxyprogesterone acetate (MA), and levonorgestrel-releasing intrauterine system (LNG-IUS). Progestins inhibit endometrial growth primarily by binding to the progesterone receptor (PR), thereby activating PR-mediated signaling pathways. The complete remission rate of progesterone therapy is approximately 70%, but 30% of individuals are insensitive to progesterone therapy, a condition known as progesterone resistance, which reduces the expected effectiveness of conservative progesterone treatment. Therefore, further expanding the range of drugs available for endometrial cancer treatment to enhance the effectiveness of progesterone therapy could contribute to improving the level of fertility care.

[0003] In recent years, the role of epigenetic dysregulation in cancer development and progression has been extensively studied, and the development of therapeutic drugs targeting epigenetic sites for endometrial cancer has become a new field in anti-tumor therapy research. Zeste enhancer homolog 2 (EZH2) is the core catalytic subunit of Polyco-mb Repressive Complex 2 (PRC2). Through trimethylation of lysine 27 on histone H3 (H3K27me3), it promotes transcriptional repression of related tumor suppressor genes and plays an important role in the development and progression of various tumors. HOTAIR (Homeobox(HOX) transcriptantisense RNA), as a member of long non-coding RNAs (lncRNAs), has a 5' functional domain that can recruit PRC2, enabling it to enter the nucleus and complete the H3K27me3 modification of specific genes, thus silencing the gene. Previous studies have shown that HOTAIR-PRC2 blockers can inhibit the proliferation, migration, and invasion of endometrial cancer and restore the expression of related tumor suppressor genes.

[0004] Multiple studies on breast cancer, recurrent miscarriage, and endometriosis have shown that progesterone therapy can upregulate EZH2 levels, and that EZH2 expression levels are negatively correlated with progesterone receptor (PR) expression levels. Therefore, the efficacy of progesterone therapy is limited. Summary of the Invention

[0005] Purpose of the invention: In view of the problems existing in the prior art, the present invention provides the use of HOTAIR-PRC2 blocker combined with progestin in the preparation of a fertility-preserving treatment for endometrial cancer.

[0006] Technical solution: To achieve the above-mentioned objectives, the present invention adopts the following technical solution:

[0007] In a first aspect, the present invention provides the use of a HOTAIR-PRC2 blocker in combination with a progestin in the preparation of a fertility-preserving treatment for endometrial cancer, wherein the chemical structural formula of the HOTAIR-PRC2 blocker is:

[0008]

[0009] Preferably, the progestin is medroxyprogesterone acetate.

[0010] The molar ratio of the HOTAIR-PRC2 blocker to progesterone is (17.5-320):(5-80). Preferably, the molar ratio of the HOTAIR-PRC2 blocker to progesterone is (2.3:1)–(32:1); more preferably, the molar ratio of the HOTAIR-PRC2 blocker to progesterone is (1.14:1)–(28:1); even more preferably, the molar ratio of the HOTAIR-PRC2 blocker to progesterone is (0.57:1)–(20:1); and most preferably, the molar ratio of the HOTAIR-PRC2 blocker to progesterone is 10:1.

[0011] Preferably, the endometrial cancer is mammalian endometrial cancer; more preferably, the mammal is selected from rodents, even-toed ungulates, perissodactyls, lagomorphs, or primates.

[0012] In a second aspect, the present invention provides a composition comprising a HOTAIR-PRC2 blocker and a progestin, wherein the chemical structural formula of the HOTAIR-PRC2 blocker is:

[0013]

[0014] Preferably, the composition of this application uses an inhibitor targeting the HOTAIR-PRC2 linkage and a progestin as active ingredients, and may also include other pharmacologically active ingredients that have a therapeutic effect on tumors.

[0015] Preferably, the composition of this application uses a blocker targeting the HOTAIR-PRC2 linkage and a progestin as active ingredients, and may also include pharmaceutically acceptable adjuvant ingredients.

[0016] Preferably, the progestin is medroxyprogesterone acetate.

[0017] The molar ratio of the HOTAIR-PRC2 blocker to progesterone is (17.5-320):(5-80). Preferably, the molar ratio of the HOTAIR-PRC2 blocker to progesterone is (2.3:1)–(32:1); more preferably, the molar ratio of the HOTAIR-PRC2 blocker to progesterone is (1.14:1)–(28:1); even more preferably, the molar ratio of the HOTAIR-PRC2 blocker to progesterone is (0.57:1)–(20:1); and most preferably, the molar ratio of the HOTAIR-PRC2 blocker to progesterone is 10:1.

[0018] Thirdly, the present invention provides the use of the described composition in the preparation of a medicament for the treatment of endometrial cancer.

[0019] The name of the HOTAIR-PRC2 blocker described in this application is compound 36806 or AC1Q3QW B (abbreviated as AQB).

[0020] PubChem CID:36806;

[0021] ChemicalNames:N-[(5,7-dichloro-2,3-dihydro-1-benzofuran-2-yl)methyl]propan-2-amine;

[0022] The English name of medroxyprogesterone acetate mentioned in this application is medroxyprogesterone acetate, and its molecular formula is C. 24 H 34 O4, with a molecular weight of 386.52 g / mol and CAS number 71-58-9, has the following chemical structural formula:

[0023]

[0024] The drug for treating endometrial cancer in this application can be administered to mammals or mammalian tumor cells. The mammals are selected from rodents, even-toed ungulates, perissodactyls, lagomorphs, primates, etc.; the primates are selected from monkeys, apes, or humans. The tumor cells can be isolated tumor cells. Furthermore, the administration target can be a patient suffering from a tumor or an individual expecting treatment for a tumor, or the administration target can be isolated tumor cells from a patient or an individual expecting treatment for a tumor.

[0025] The drug for treating endometrial cancer described in this application can be administered to the patient before, during, and after tumor treatment.

[0026] Beneficial Effects: The HOTAIR-PRC2 specific blocker of this application can increase the expression of progesterone receptor PR, thereby enhancing the efficacy of progesterone in inhibiting endometrial cancer. The HOTAIR-PRC2 specific blocker combined with progesterone can synergistically inhibit the proliferation, migration, and invasion of endometrial cancer, arrest the cell cycle, and promote apoptosis. Compared with monotherapy, the combination of the two drugs can more significantly inhibit the biological behavior of endometrial cancer, increasing the efficacy of progesterone-only treatment for endometrial cancer. Attached Figure Description

[0027] Figure 1This invention presents graphs illustrating the effects of AQB, progesterone, and the combined use of AQB and progesterone on the in vitro proliferation of endometrial cancer cells. Specifically: A: Bliss model color gradient graph showing the inhibition of HEC-1A cell proliferation by different concentration gradients of AQB and progesterone; B: Line graph showing the inhibition of HEC-1A cell proliferation by AQB and progesterone; C: Bliss model color gradient graph showing the inhibition of Ishikawa cell proliferation by different concentration combinations of AQB and progesterone; D: Line graph showing the inhibition of Ishikawa cell proliferation by AQB and progesterone; E: Graph showing the effects of AQB, progesterone, and the combined use of AQB and progesterone on the monoclonal formation ability of HEC-1A cells; F: Statistical graph of HEC-1A cell monoclonal formation ability; G: Graph showing the effects of AQB, progesterone, and the combined use of AQB and progesterone on the monoclonal formation ability of Ishikawa cells; H: Statistical graph of Ishikawa cell monoclonal formation ability.

[0028] Figure 2 This invention presents graphs illustrating the effects of AQB, progesterone, and the combined intervention of AQB and progesterone on the in vitro migration and invasion of endometrial cancer cells. Specifically: A: Effects of AQB, hormones, and the combined intervention of AQB and progesterone on the migration and invasion abilities of HEC-1A cells; B: Effects of AQB, progesterone, and the combined intervention of AQB and progesterone on the migration and invasion abilities of Ishikawa cells; C: Effects of AQB, progesterone, and the combined intervention of AQB and progesterone on the expression levels of E-cadherin, N-cadherin, and Vimentin proteins in HEC-1A cells, along with statistical data; D: Effects of AQB, progesterone, and the combined intervention of AQB and progesterone on the expression levels of E-cadherin, N-cadherin, and Vimentin proteins in Ishikawa cells, along with statistical data.

[0029] Figure 3This invention presents graphs illustrating the effects of AQB, progesterone, and the combined intervention of AQB and progesterone on the cell cycle of endometrial cancer cells. A: Flow cytometry analysis of the effects of AQB, progesterone, and the combined intervention of AQB and progesterone on the cell cycle of HEC-1A cells; B: Flow cytometry analysis of the effects of AQB, progesterone, and the combined intervention of AQB and progesterone on the cell cycle of Ishikawa cells; C: Western blot analysis of the effects of AQB, progesterone, and the combined intervention of AQB and progesterone on the expression levels of p21, CDK4, and CDK6 proteins in HEC-1A cells, along with statistical graphs; D: Western blot analysis of the effects of AQB, progesterone, and the combined intervention of AQB and progesterone on the expression levels of p21, CDK4, and CDK6 proteins in Ishikawa cells, along with statistical graphs; E: Western blot analysis of the effects of AQB, progesterone, and the combined intervention of AQB and progesterone on the expression levels of Cyclin D1 and Cyclin D1 proteins in HEC-1A cells. Effects and statistical graphs of E1 protein expression levels; F: Effects and statistical graphs of Western blot analysis of AQB, progesterone and combined intervention of AQB and progesterone on Cyclin D1 and Cyclin E1 protein expression levels in Ishikawa cells.

[0030] Figure 4 This invention presents the effects of AQB, progesterone, and the combined intervention of AQB and progesterone on apoptosis of endometrial cancer cells. Specifically, A: Effect of AQB, progesterone, and the combined intervention of AQB and progesterone on apoptosis of HEC-1A cells; B: Effect of AQB, progesterone, and the combined intervention of AQB and progesterone on apoptosis of Ishikawa cells; C: Effect of Western blot analysis on the protein expression levels of Caspase-7, Cleaved Caspase-7, and Bcl2 in HEC-1A cells, along with statistical data; D: Effect of Western blot analysis on the protein expression levels of Caspase-7, Cleaved Caspase-7, and Bcl2 in Ishikawa cells, along with statistical data.

[0031] Figure 5This invention presents the effects of progesterone intervention on EZH2 and AQB intervention on the protein expression of progesterone receptor PR in endometrial cancer cells. A: Western blot analysis of the effect of different concentrations of progesterone on cytoplasmic EZH2 protein expression in HEC-1A cells and statistical graph; B: Western blot analysis of the effect of different concentrations of progesterone on cytoplasmic EZH2 protein expression in Ishikawa cells and statistical graph; C: Western blot analysis of the effect of different concentrations of progesterone on nuclear EZH2 protein expression in HEC-1A cells and statistical graph; D: Western blot analysis of the effect of different concentrations of progesterone on nuclear EZH2 protein expression in Ishikawa cells. E: Effects and statistical graphs of H2 protein expression on total EZH2 protein expression in HEC-1A cells treated with different concentrations of progesterone, as detected by Western blot; F: Effects and statistical graphs of total EZH2 protein expression in Ishikawa cells treated with different concentrations of progesterone, as detected by Western blot; G: Effects and statistical graphs of progesterone receptor PR and H3K27me3 protein expression in HEC-1A cells treated with different concentrations of AQB, as detected by Western blot; H: Effects and statistical graphs of progesterone receptor PR and H3K27me3 protein expression in Ishikawa cells treated with different concentrations of AQB, as detected by Western blot.

[0032] Figure 6 This is a diagram illustrating the effects of AQB, progesterone, and the combined intervention of AQB and progesterone on gene expression and molecular pathways in endometrial cancer cells. A: Volcano diagram of gene expression in HEC-1A cells treated with AQB using RNA-secquence assays; B: Volcano diagram of gene expression in HEC-1A cells treated with progesterone using RNA-secquence assays; C: Volcano diagram of gene expression in HEC-1A cells treated with the combined intervention of AQB and progesterone using RNA-secquence assays; D: Differentially expressed molecules in HEC-1A cells treated with AQB. E: KEGG enrichment analysis diagram of differentially expressed molecules in HEC-1A cells after progesterone intervention; F: Effects of AQB, progesterone, and AQB combined with progesterone on the expression of T-ERK1 / 2, P-ERK1 / 2, T-JNK, and P-JNK proteins in the MAPK pathway in HEC-1A cells; G: Effects of AQB, progesterone, and AQB combined with progesterone on the expression of T-ERK1 / 2, P-ERK1 / 2, T-JNK, and P-JNK proteins in the MAPK pathway in Ishikawa cells. Detailed Implementation

[0033] The technical solution of the present invention will be further described in detail below with reference to the accompanying drawings and embodiments.

[0034] The chemical structural formula of the HOTAIR-PRC2 blocker in this application is as follows:

[0035]

[0036] The name is compound 36806 or AC1Q3QWB (abbreviated as AQB);

[0037] PubChem CID:36806;

[0038] Chemical Names: N-[(5,7-dichloro-2,3-dihydro-1-benzofuran-2-yl)methyl]propan-2-amine; synthesized by WuXi AppTec.

[0039] The progestin used in this application is medroxyprogesterone acetate. Medroxyprogesterone acetate has the English name C24H34O44, a molecular weight of 386.52 g / mol, CAS number 71-58-9, and was purchased from Selleck, catalog number S2567. Its chemical structure is as follows:

[0040]

[0041] The endometrial cancer cells used in this application were HEC-1A cells and Ishikawa cells.

[0042] Application Example 1

[0043] To observe whether the combination of different concentrations of AQB and progesterone has a synergistic inhibitory effect on endometrial cancer cells.

[0044] HEC-1A cells were treated with different concentrations of AQB (0 μM, 17.5 μM, 35 μM, 70 μM, 140 μM, 280 μM) and progesterone (0 μM, 5 μM, 10 μM, 20 μM, 40 μM) alone or in combination for 48 h, and cell viability was assessed using the CCK-8 assay. Ishikawa cells were also treated with different concentrations of AQB (0 μM, 20 μM, 40 μM, 80 μM, 160 μM, 320 μM) and progesterone (0 μM, 10 μM, 20 μM, 40 μM, 80 μM) alone or in combination for 48 h, and cell viability was assessed using the CCK-8 assay.

[0045] Substituting the measured CCK-8 values ​​into the Bliss-independent model calculation, the results showed that after combined treatment of HEC-1A and Ishikawa cells with AQB and progesterone, the Bliss value was greater than 0 over a large range, indicating that the combination of the two in HEC-1A cells (e.g., Figure 1 A, Figure 1 (as shown in C) and Ishikawa cells (e.g.) Figure 1 B. Figure 1 (As shown in D) exhibits a synergistic inhibitory effect.

[0046] Observe the effect of combined use of AQB and progesterone on the proliferation of endometrial cancer cells.

[0047] HEC-1A cells and Ishikawa cells were treated with a control group, an AQB 100μM group, a progesterone 10μM group, and a combination of AQB 100μM and progesterone 10μM. Cell viability was measured by the CCK-8 assay for 5 consecutive days.

[0048] The results showed statistically significant differences in cell proliferation among different treatment groups (p<0.05). Compared with the control group, the OD values ​​of HEC-1A cells significantly decreased after treatment with either AQB or progestin alone, with the decrease in OD values ​​being more significant in the combined group (e.g., ...). Figure 1 (As shown in B). Compared with the control group, the cell proliferation capacity of Ishikawa cells was significantly reduced after treatment with AQB alone or progesterone, with the most significant decrease in cell proliferation capacity observed in the combined group (e.g., ...). Figure 1 (as shown in D).

[0049] Observe the effect of combined use of AQB and progesterone on the clonogenic ability of endometrial cancer cells.

[0050] HEC-1A cells and Ishikawa cells were treated with the following methods: control group, AQB 100μM group, progesterone 10μM group, and AQB 100μM + progesterone 10μM combination group. After treatment with the drugs for about 2 weeks, the cells were fixed with 4% paraformaldehyde, stained with crystal violet, photographed, and counted.

[0051] The results showed that the combination of AQB and progesterone significantly inhibited the colony formation of HEC-1A and Ishikawa cells compared with AQB or progesterone alone, and the cell colony counts in different treatment groups were statistically significant (p<0.05). Compared with the control group, the cell colony counts in the AQB group and the progesterone group were reduced, and the reduction in cell colony counts in the combination group was more significant (e.g., ...). Figure 1 (as shown in E, 1F).

[0052] Application Example 2

[0053] Observe the effects of combined use of AQB and progesterone on the migration and invasion abilities of endometrial cancer cells.

[0054] The experiment was divided into a control group, an AQB monotherapy group, a progestin monotherapy group, and a two-drug combination group. After 48 hours of drug treatment, HEC-1A and Ishikawa cells were removed from the Transwell chambers, unpenetrated cells were wiped away with cotton swabs, fixed with 4% paraformaldehyde, stained with crystal violet, photographed, and counted. After 48 hours of drug treatment, HEC-1A and Ishikawa cells were used to extract cellular proteins for Western blotting experiments.

[0055] Experimental results showed that at concentrations that did not significantly affect cell proliferation, AQB, progesterone, and the combination of AQB and progesterone all significantly inhibited the migration and invasion of endometrial cancer cells. Furthermore, the combination of AQB and progesterone showed a more significant inhibitory effect than either AQB or progesterone alone (e.g., Figure 2 A, Figure 2 As shown in Figure B), this study demonstrates that the combined use of AQB and progesterone has a synergistic effect in inhibiting the migration and invasion of endometrial cancer cells. Western blot analysis showed that the combined use of AQB and progesterone inhibited the protein expression levels of N-cadherin and Vimentin, while promoting the protein expression of E-cadherin; the differences were statistically significant (p < 0.05). Figure 2 C Figure 2 (as shown in D).

[0056] Application Example 3

[0057] Observe the effect of combined use of AQB and progesterone on the cell cycle of endometrial cancer cells.

[0058] The experiment was divided into a control group, an AQB monotherapy group, a progestin monotherapy group, and a two-drug combination group. Cells were collected for flow cytometry 48 hours after drug treatment.

[0059] Flow cytometry results showed that the combination of AQB and progesterone significantly arrested the cell cycle in the G1 phase more effectively than either AQB or progesterone alone (e.g., Figure 3 A, Figure 3 (As shown in B). Western blot results showed that the combined intervention of AQB and progesterone had a synergistic inhibitory effect on the expression levels of CDK4, CDK6, Cyclin D1, and Cyclin E1 proteins, and the differences were statistically significant (p<0.05, e.g., ...). Figure 3 E, Figure 3 (As shown in F). Combined intervention with AQB and progesterone synergistically promoted p21 protein expression levels, with statistically significant differences (p < 0.05). Figure 3 C Figure 3 (as shown in D).

[0060] Application Example 4

[0061] Observe the effect of combined use of AQB and progesterone on apoptosis of endometrial cancer cells.

[0062] The experiment was divided into a control group, an AQB monotherapy group, a progesterone monotherapy group, and a two-drug combination group. Cells were collected 48 hours after drug treatment for Annexin V-FITC apoptosis assays.

[0063] Apoptosis experiments showed that both AQB and progesterone treatment significantly promoted apoptosis, and the combination of the two drugs synergistically promoted apoptosis (e.g., Figure 4 A, Figure 4 (As shown in B). Western blot results showed that the combination of the two drugs promoted the protein expression of cleaved caspase-7 and inhibited the protein expression of Bcl-2, with statistically significant differences (p<0.05). Figure 4 C Figure 4 (as shown in D).

[0064] Application Example 5

[0065] Observe the effects of progesterone treatment on EZH2 protein expression in endometrial cancer cells, and AQB treatment on progesterone receptor PR protein expression in endometrial cancer cells.

[0066] HEC-1A and Ishikawa cells were treated with a control group, a 5μM progesterone group, a 10μM progesterone group, and a 20μM progesterone group. Cytoplasmic proteins, nuclear proteins, and total cellular proteins were collected for Western blotting experiments. For HEC-1A cells, a control group and AQB groups of 60μM, 80μM, 100μM, and 120μM were also included. Cells were treated with the drug for 48 hours, and proteins were extracted for Western blotting. For Ishikawa cells, a control group and AQB groups of 70μM, 100μM, 130μM, and 160μM were also included. Cells were treated with the drug for 48 hours, and proteins were extracted for Western blotting.

[0067] The results showed that after progesterone treatment of HEC-1A cells and Ishikawa cells, the protein expression levels of nuclear and total EZH2 increased, and the differences were statistically significant (p<0.05). Figure 5 (As shown in A, 5C, and 5E); the protein expression of EZH2 in the cytoplasm decreased after treatment with 20 μM progesterone, and the difference was statistically significant (p < 0.05). Figure 5(As shown in B, 5D, and 5F). After AQB treatment of HEC-1A and Ishikawa cells, the protein expression level of progesterone receptor PR increased, while the protein expression level of H3K27me3 decreased, and the differences were statistically significant (p<0.05). Figure 5 (As shown in G, 5H).

[0068] Application Example 6

[0069] The experiment to observe the effects of combined AQB and progesterone on gene expression and molecular pathways in endometrial cancer cells was divided into a control group, an AQB monotherapy group, a progesterone monotherapy group, and a combined AQB and progesterone group. Each group was performed in triplicate. After 48 hours of drug treatment, total RNA was extracted from HEC-1A cells in each group, and RNA-secquence sequencing was performed by Tianjin Novogene Technology Co., Ltd., followed by data processing and plotting. Cells were collected for Western blotting experiments after 48 hours of drug treatment to extract cellular proteins.

[0070] The results showed that AQB combined with progesterone caused upregulation or downregulation of more genes than AQB or progesterone alone (e.g., Figure 6 As shown in A, 6B, and 6C), enrichment analysis of differentially expressed molecules after AQB and progesterone treatment of HEC-1A cells both enriched the MAPK pathway (e.g., ...). Figure 6 (As shown in D, 6E). Western blot results showed that combined intervention with AQB and progesterone synergistically inhibited the protein expression of P-ERK1 / 2 and P-JNK, with statistically significant differences (p<0.05, e.g., ...). Figure 6 (as shown in F, 6G).

[0071] The embodiments described herein are preferred embodiments of the present invention and are not intended to limit the scope of protection of the present invention. Therefore, all equivalent changes made in accordance with the structure, shape and principle of the present invention should be covered within the scope of protection of the present invention.

Claims

1. The use of HOTAIR-PRC2 blocker in combination with progestin in the preparation of a fertility-preserving treatment for endometrial cancer, wherein the chemical structural formula of the HOTAIR-PRC2 blocker is: The molar ratio of the HOTAIR-PRC2 blocker to progestin is (17.5-320):(5-80).

2. The use according to claim 1, characterized in that, The progestin mentioned is medroxyprogesterone acetate.

3. The use according to claim 1, characterized in that, The endometrial cancer mentioned refers to endometrial cancer in mammals.

4. The use according to claim 3, characterized in that, The mammals are selected from rodents, even-toed ungulates, odd-toed ungulates, lagomorphs, or primates.

5. A composition comprising a HOTAIR-PRC2 blocker and a progestin, wherein the chemical structural formula of the HOTAIR-PRC2 blocker is: The molar ratio of the HOTAIR-PRC2 blocker to progestin is (17.5-320):(5-80).

6. The composition according to claim 5, characterized in that, The progestin mentioned is medroxyprogesterone acetate.

7. Use of the composition of claim 5 in the preparation of a fertility-preserving treatment for endometrial cancer.

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