Treating PCOS With Semaglutide vs Active Lifestyle Intervention

Inclusion Criteria:

1. Sedentary- less than 2 hours of moderate (jogging, swimming etc) exercise a week.

2. BMI equal or greater than the 90th percentile for age and gender

3. PCOS per the most stringent NIH criteria adapted for adolescents (irregular menses >12 months post-menarche and clinical or biochemical hypertestosteronemia

4. Participants cannot be on hormonal contraception, so participants should remainabstinent or use reliable non-hormonal contraception (e.g. copper IUD) for theentire study period. For participants who receive semaglutide, they should avoidpregnancy for at least 2 months after stopping medication to avoid fetal exposure tothe medication.

Exclusion Criteria:

1. Diagnosed with or have a family history of medullary thyroid carcinoma (MTC) orMultiple Endocrine Neoplasia syndrome type 2 (MEN 2). Family history of medullarythyroid cancer or thyroid nodule palpated by endocrinologist at screening.

2. Use of medications known to affect insulin sensitivity: metformin (cannot have beenused in the 3 months prior to screening), oral glucocorticoids within 10 days,atypical antipsychotics, immunosuppressant agents, HIV medications, hormonalcontraception (cannot have been used in the 6 months prior to screening). Dermalpatch or vaginal ring contraception methods.Weight loss medications or stimulants.Use of other products containing other GLP-1 agonists.

3. Currently pregnant or breastfeeding women. Development of pregnancy during the studyperiod will necessitate withdrawal from the study.

4. Severe illness requiring hospitalization within 60 days.

5. Diabetes, defined as Hemoglobin A1C > 6.4%

6. BMI percentile less than the 90th percentile for age and sex. Weight >325 lbs. or <84 lbs.

7. Anemia, defined as Hemoglobin < 11 mg/dL

8. Diagnosed major psychiatric or developmental disorder limiting informed consent.

9. Implanted metal devices that are not compatible with MRI

10. Use of blood pressure medications.

11. Known liver disease other than NAFLD or AST or ALT >100 IU/L.

12. Personal history of pancreatitis

13. Known renal disease of any severity or an eGFR at screening of <45ml/min/1.73m2

14. History of severe GI disease (e.g. gastroparesis)

15. History of gallstones

16. Untreated thyroid disease

17. History of hypersensitivity to semaglutide

18. Other causes of hyperandrogenism (example: tumor, CAH) or amenorrhea (untreatedthyroid disease, tumor, primary ovarian failure, prolactinoma).

19. Active symptoms or undergoing treatment for anorexia nervosa or binging/purgingdisorder