Semaglutide, Weight Loss, and LNG-IUD for Conservative Treatment of Endometrial Atypical Hyperplasia and Grade 1 Endometrial Cancer

The goal of this clinical trial is to learn if a combination treatment of a hormonal intrauterine device (LNG-IUD), semaglutide, and a structured weight loss program can treat endometrial atypical hyperplasia or grade 1 endometrioid endometrial cancer while preserving fertility in women of reproductive age with endometrial atypical hyperplasia (EAH) or FIGO grade 1 endometrioid endometrial cancer who wish to preserve their fertility. The main questions it aims to answer are: * What proportion of participants achieve a complete pathological response after treatment? * How durable is the response at 12 months? * What effect does the treatment have on metabolic outcomes (weight, BMI, HbA1c) and quality of life? Participants will: * Receive an LNG-IUD * Receive semaglutide 2.4mg * Participate in a structured weight loss program * Undergo hysteroscopy with endometrial sampling to assess treatment response * Complete quality-of-life assessments at baseline, 6 months, and 12 months

Sex

Female

Minimum age

18 Years

Inclusion Criteria:

1. Histological Diagnosis: Histologically confirmed endometrial atypical hyperplasia or FIGO grade 1 endometrioid Endometrial Cancer
2. Imaging eligibility (for patients with endometrial cancer):

   1. Depth of myometrial invasion \<50% confirmed by MRI or disease limited to the endometrium
   2. No evidence of extrauterine or metastatic disease on imaging.
3. Treatment Rationale (at least one of the following must apply):

   1. Desire for future fertility: Patient expresses a documented desire to preserve the uterus and future reproductive function, with explicit acknowledgment that fertility-sparing treatment is not standard of care for endometrial cancer.
   2. Medical inoperability: patients are considered a poor surgical candidate due to:

   i. Class III obesity (BMI ≥40 kg/m²); or ii. ASA Physical Status Classification score ≥3.
4. Metabolic Profile: BMI ≥ 30 kg/m², or BMI 27-29.9 kg/m² with at least one weight-related comorbidity (hypertension, type 2 diabetes mellitus, dyslipidemia, obstructive sleep apnea, or non-alcoholic fatty liver disease).
5. Progestin washout: patients with prior progestin exposure are eligible provided the following minimum washout periods have been observed.

   1. Oral progestins: 7 days
   2. Injectable, short acting: 14 days
   3. Injectable, long acting: 6 months
   4. Contraceptive implant: 28 days
   5. LNG-IUD: 7 days after removal

Exclusion Criteria:

1. Age ≥18 years
2. Negative pregnancy test at screening
3. Ability to provide written informed consent and comply with study procedures
4. Willingness to undergo genetic counseling and MMR/IHC tumor profiling
5. Willingness and ability to participate in a structured weight loss program, including attendance at counseling sessions (in person or virtual) and adherence to dietary and physical activity goals.

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