Role of Semaglutide in Restoring Ovulation in Youth and Adults With Polycystic Ovary Syndrome

Inclusion Criteria

1. Female

2. Ages 12-35 years

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

4. Oligomenorrhea, on or off metformin, as defined per age category in the most recent 2018 PCOS international guidelines

5. Initial BMI based on age and weight:

6. If <18 years, initial BMI percentile ≥95

7. If 18-35 years, initial BMI ≥30 kg/m2 OR initial BMI ≥27 kg/m2 with at leastone weight-related comorbid condition, e.g., hypertension or dyslipidemia

8. Must be weight stable within ±5kg in the 3 months prior to enrollment

9. Diagnosed with PCOS per the most stringent NIH criteria with adaptation foradolescents (oligomenorrhea >24 months post-menarche or primary amenorrhea after age 15 years and clinical/ biochemical hypertestosteronemia

10. 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.

11. For participants in the metformin + semaglutide group, participants must have beenstable on ≥ 1500 mg of metformin a day for at least 3 months by time of screening

Exclusion Criteria:

1. Diagnosed with or have a family history of medullary thyroid carcinoma (MTC) orMultiple Endocrine Neoplasia syndrome type 2 (MEN2). Family history of medullarythyroid cancer or thyroid nodule palpated by endocrinologist at screening. - Perapproved drug label

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

3. Weight loss medications in the last 6 months

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

5. Severe illness requiring hospitalization within 60 days.

6. Diabetes, defined as Hemoglobin A1C ≥6.5%

7. Anemia, defined as Hemoglobin < 12 mg/dL

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

10. Known liver disease other than NAFLD, or AST or ALT >125 IU/L. 11) Personal history of pancreatitis 12) Known renal disease of any severity or an eGFR at screening of <45ml/min/1.73m2 13) History of severe GI disease (e.g., gastroparesis) 14) History of gallstones 15) Untreated thyroid disease 16) History of hypersensitivity to semaglutide

11. Other causes of hyperandrogenism (example: tumor, CAH) or amenorrhea (untreated thyroid disease, tumor, primary ovarian failure, prolactinoma).

12. Active symptoms or undergoing treatment for anorexia nervosa or binging/purging disorder 19) Desiring pregnancy in the next 12-18 months. 20) Bariatric surgery 21) Use of THC (smoking or edible) more than 3 days a week 22) Alcohol use-drinking more than 2 drinks, more than 3 days a week 23) Any potential participants who cannot/will not commit to abstinence, use of a copper intrauterine device (IUD), or use of double barrier forms of contraception.