The incidence of endometrial cancer is increasing at an alarming rate. This trend parallels the rising rate of obesity, the most significant risk factor for endometrial cancer. Young women with obesity and endometrial cancer or atypical hyperplasia who want to maintain their fertility are treated with progestin therapy, such as progestin intra-uterine device (pIUD), which is associated with a mediocre response rate and high recurrence rate, and does not address the underlying cause, obesity. Therefore, the investigators want to assess whether the addition of a weight-loss drug to pIUD will improve their oncologic, reproductive and metabolic outcomes.

The research aims to answer the question: "Does the addition of a Glucose-dependent Insulinotropic Polypeptide (GIP)/Glucagon-like Peptide-1 (GLP-1) co-agonist to standard progestin treatment lead to a higher complete response rate compared to historical response rates using progestin alone in young patients with endometrial cancer/atypical hyperplasia who wish to preserve their fertility?".

This is a multicentre single arm open-label phase II clinical trial to assess the complete pathologic response as determined by endometrial sampling after 48 weeks of tirzepatide (GIP/GLP-1 co-agonist) and progestin therapy in patients with BMI ≥ 27 who have endometrial cancer/atypical hyperplasia and desire fertility preservation.

Inclusion Criteria:

• BMI ≥ 27
• Diagnosis of grade 1 or 2 endometrioid endometrial cancer or atypical hyperplasia made by either endometrial biopsy or dilation and curettage
• For those with endometrial cancer, clinical FIGO 2009 stage 1A disease without evidence of metastatic disease beyond the uterus and no myometrial invasion by MRI or CT
• ECOG status <2
• Desire for fertility preservation
• Ability to understand and willing to sign a written informed consent document

Exclusion Criteria:

• Evidence of myometrial invasion or extra-uterine disease on imaging
• High grade or p53 mutated (p53mut) endometrial cancer
• Estrogen receptor negative endometrial cancer (positivity defined as moderate/strong staining>10%)
• Mismatch repair deficient (MMRd) endometrial cancer
• History of other malignancies except if curatively treated with no evidence of disease for >5 years
• Previous surgical treatment of obesity
• Current use of weight loss medication (no use in last 2 months)
• Medical co-morbidity with end-organ dysfunction
• Contraindications to pIUD or tirzepatide.
• Any other condition that would, in the Investigator's judgment, contraindicate the patient's participation in the clinical study due to safety concerns or compliance with clinical study procedures.