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

Prior treatment

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

Other illness

• Diagnosed with or have a family history of medullary thyroid carcinoma (MTC) or Multiple Endocrine Neoplasia syndrome type 2 (MEN2). Family history of medullary thyroid cancer or thyroid nodule palpated by endocrinologist at screening. - Per approved drug label
• Severe illness requiring hospitalization within 60 days.

Lab values

• Diabetes, defined as Hemoglobin A1C ≥6.5%
• Anemia, defined as Hemoglobin \< 12 mg/dL
• 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 17) Other causes of hyperandrogenism (example: tumor, CAH) or amenorrhea (untreated thyroid disease, tumor, primary ovarian failure, prolactinoma).
  • 18\) 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.

Other

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

• Female
• Ages 12-35 years
• Sedentary- less than 2 hours of moderate (jogging, swimming etc.) exercise a week.
• Oligomenorrhea, on or off metformin, as defined per age category in the most recent 2018 PCOS international guidelines
• Initial BMI based on age and weight:
  • If \<18 years, initial BMI percentile ≥95
  • If 18-35 years, initial BMI ≥30 kg/m2 OR initial BMI ≥27 kg/m2 with at least one weight-related comorbid condition, e.g., hypertension or dyslipidemia
  • Must be weight stable within ±5kg in the 3 months prior to enrollment
• Diagnosed with PCOS per the most stringent NIH criteria with adaptation for adolescents (oligomenorrhea \>24 months post-menarche or primary amenorrhea after age 15 years and clinical/ biochemical hypertestosteronemia
• Participants cannot be on hormonal contraception, so participants should remain abstinent or use reliable non-hormonal contraception (e.g., copper IUD) for the entire study period. For participants who receive semaglutide, they should avoid pregnancy for at least 2 months after stopping medication to avoid fetal exposure to the medication.
• For participants in the metformin + semaglutide group, participants must have been stable on ≥ 1500 mg of metformin a day for at least 3 months by time of screening