This study is looking for a better way to treat pre-cancer or early-stage cancer in the lining of the uterus in women who are also overweight.

Everyone in the study will receive the standard treatment, a Progesterone IUD (LNG-IUD). This device is put in the uterus and releases hormones to help fight the disease. We will add a new medicine, Tirzepatide, for some people. Tirzepatide is a shot that helps with weight loss and overall health. You will be placed into one of two groups by chance (like flipping a coin):

1. Group 1: You get the Progesterone IUD PLUS the Tirzepatide shot.
2. Group 2: You get the Progesterone IUD ONLY (Standard Treatment).

During the study, you will be asked to fill out surveys often. These questions ask about your daily life, how you feel about your health and weight, and any side effects you might have. This helps us understand how the treatments affect you. You will have small tissue samples (biopsies) taken from your uterus at different times. This is how doctors check at 12 months (one year) if the pre-cancer or cancer cells are completely gone. The schedules for visits, tests, and monitoring will be identical for both groups to ensure fairness.

If this study is successful, it could mean that women who are overweight with these conditions can get a better treatment that gets rid of the disease and still allows them to keep their ability to have children (avoids surgery). It may also improve their overall health through weight loss.

This study is looking for a better way to treat early-stage uterine problems in women who are also overweight. These problems are called pre-cancer (EIN) or early cancer of the uterus.

The standard treatment we already use is a device called the LNG-IUD, which is placed in the uterus and releases hormones. This device helps many women avoid surgery and keep their ability to have children, but it doesn't always work well for women who are overweight. This is because being overweight causes other health problems, like problems with sugar and fat in the body, and inflammation, which can make the uterine problem worse.

We are testing a new medicine, Tirzepatide, in combination with the standard IUD treatment. Tirzepatide is a proven medicine that safely helps people lose significant weight and improve their health. We believe that by adding this weight-loss medicine, we can attack uterine disease from two sides:

1. Hormones: with the IUD.
2. Body Health: by improving weight, sugar levels, and inflammation with Tirzepatide.

Scientists have found that Tirzepatide might help slow down the growth of abnormal cells in the uterus. We hope that combining these two treatments will be much more effective at completely eliminating the cancerous or pre-cancerous cells (which we call a pathologic complete response).

In this study, we will carefully assess how well the medicine works on the tumor and how much weight loss and health improvement you experience. This will give us important information to help other women in the future.

Inclusion Criteria:

1. Histologically confirmed endometrial intraepithelial neoplasia (EIN), FIGO grade 1 or 2 endometrioid adenocarcinoma on a curette or endometrial biopsy. *EIN patients capped at a maximum of 50% of total enrollment ((≤10 patients). .
2. P53 wild-type and MMR proficient (or microsatellite stable) confirmed by immunohistochemistry.
3. Females with a BMI > 27 kg/m2 are at high risk of surgical complications due to comorbidities (diabetes, hypertension, cardiovascular disease, obstructive sleep apnea) or BMI > 30 kg/m2 with no comorbidities and have decided not to opt for immediate surgical intervention (having been advised that this is the standard of care);
4. Over 18 years of age at time of randomization;
5. CT scan of pelvis, abdomen, and chest (or chest X-Ray), suggesting the absence of extrauterine disease in patients with endometrial cancer only;
6. Myometrial invasion on MRI of not more than 50%;
7. No lymph vascular invasion on biopsy;
8. Serum CA125 ≤35 U/mL;
9. No known hypersensitivity or contraindications for LNG-IUD (severe liver disease, personal history of breast cancer, active pelvic inflammatory disease, congenital uterine abnormality) or GLP-1 agonist;
10. Ability to comply with endometrial biopsies at specified 3-monthly intervals;
11. Negative serum or urine pregnancy test in pre-menopausal women and women < 2 years after the onset of menopause;
12. No LNG-IUD or LNG-IUD inserted < 6 weeks prior to enrollment;
13. Subjects must be able and willing to give written informed consent and to comply with the requirements of this study protocol.

Exclusion Criteria:

1. ECOG performance status ≥3 (Appendix II); 2. Grade 1 or 2 endometrioid adenocarcinoma of the endometrium with myometrial invasion deeper than 50% on MRI, or any patients with grade 3 endometrioid adenocarcinoma; 3. MMR deficient or p53 mutated endometrial cancer; 4. Histological (cell) type other than endometrioid adenocarcinoma (sarcomas or high-risk endometrial e.g., papillary serous, clear cell); 5. Pregnant or planning to become pregnant during trial period; 6. Prior treatment for EAC; 7. Patients with a history of pelvic or abdominal radiotherapy; 8. Unwilling to have additional endometrial biopsies or unable to attend monthly clinical assessments; 9. Unable to provide informed consent or complete questionnaires; 10. Evidence of extra-uterine extension on cross-sectional imaging; 11. Congenital or acquired uterine anomaly that distorts the uterine cavity; 12. Acute pelvic inflammatory disease; 13. Genital actinomycosis; 14. History of pancreatitis; 15. Diagnosis of Type 1 diabetes; 16. Previous treatment with GLP-1 receptor agonists within the last 3 months; 17. Visit 1 thyroid-stimulatory hormone outside of the range of 0.4-6.0 mL/uL; 18. Obesity induced by other endocrine disorders (e.g., Cushing syndrome); 19. Current or history of treatment with medications that may cause significant weight gain within 3 months prior to screening visit, including systemic corticosteroids (except for a short course of treatment, i.e., 7-10 days or physiologic replacement doses ≤10 mg/day prednisone equivalent), tri-cyclic antidepressants, atypical antipsychotic and mood stabilizers (e.g., imipramine, amitriptyline, mirtazapine, phenelzine, chlorpromazine, thioridazine, clozapine, olanzapine, valproic acid and its derivatives, and lithium); 20. Participation in a clinical trial of weight control within the last 3 months before screening for this trial; 21. Previous surgical treatment for obesity (excluding liposuction if performed >1 year before study entry); 22. History of major depressive disorder or a PHQ-9 >15 within the last 2 years (completed at visit 1) or history of other severe psychiatric disorders (e.g., schizophrenia or bipolar disorder) or diagnosis of an eating disorder such as restrained eating, binge eating, or bulimia (based on Questionnaire for Diagnosing Binge Eating Disorder and Bulimia Nervosa completed at visit 1); 23. Participants with a lifetime history of a suicide attempt or history of any suicidal behavior within the past month before entry into the trial; 24. Surgery scheduled for the trial duration period, except for minor surgical procedures, at the discretion of the Investigator; 25. Impaired liver function, defined as screening aspartate aminotransferase or alanine aminotransferase ≥ 2.5 times the upper normal range (one re-test analyzed at the local laboratory within 1 week prior to screening is permitted, with the last sample being conclusive); 26. Impaired renal function is defined as serum creatinine ≥ 1.72 mg/dl (1 retest within 1 week prior to screening through the local laboratory is permitted, with the result of the last sample conclusive); 27. Known clinically significant active cardiovascular disease, including history of unstable angina, acute coronary event, other significant cardiac events (including history of arrhythmias, myocardial infarction (MI), or conduction delays on electrocardiogram [ECG]), or cerebral stroke within the past 6 months and/or heart failure (New York Heart Association [NYHA] Class III or IV) at the discretion of the Investigator; 28. Uncontrolled treated/untreated hypertension (systolic blood pressure ≥160 mmHg and/or diastolic blood pressure ≥100 mmHg). If white-coat hypertension is suspected at the screening visit, a repeated measurement at run-in before other trial-related activities is allowed; 29. Known history of substance abuse; 30. Language barrier, mental incapacity, unwillingness, or inability to understand and complete the mental health questionnaire in the provided language; 31. History of breast, thyroid or colon cancer. Patients with any prior diagnosis of thyroid cancer are not eligible for this study 32. Current other cancer. Patients with any current malignancy or past malignancy in the past 5 years are not eligible. Excluded are treated basal cell carcinoma or squamous cell carcinoma. (past or present, except basal cell skin cancer or squamous cell skin cancer). Patient who have received any active treatment for another malignancy within 2 years prior to enrollment are not eligible); 33. Breastfeeding mothers

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