Treating PCOS With Semaglutide vs Active Lifestyle Intervention

In obese girls with polycystic ovarian syndrome, testosterone and obesity combine to create unique pathology to increase metabolic disease including fatty liver and insulin resistance, which may be mediated by altered glucagon like peptide-1 activity. The investigators will treat girls with obesity and polycystic ovarian syndrome for 4 months with a glucagon like peptide-1 receptor agonist compared to dietary intervention to primarily lower hepatic fat and secondarily improve whole body and adipose insulin sensitivity. Mechanisms of hepatic metabolism, including rates of de novo lipogenesis and relative mitochondrial flux will also be assessed.

Inclusion criteria

• Sedentary- less than 2 hours of moderate (jogging, swimming etc) exercise a week.
• BMI equal or greater than the 90th percentile for age and gender
• PCOS per the most stringent NIH criteria adapted for adolescents (irregular menses >12 months post-menarche and clinical or 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.

Exclusion criteria

• Diagnosed with or have a family history of medullary thyroid carcinoma (MTC) or Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Family history of medullary thyroid cancer or thyroid nodule palpated by endocrinologist at screening.
• Use of medications known to affect insulin sensitivity: metformin (cannot have been used in the 3 months prior to screening), oral glucocorticoids within 10 days, atypical antipsychotics, immunosuppressant agents, HIV medications, hormonal contraception (cannot have been used in the 6 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.
• Currently pregnant or breastfeeding women. Development of pregnancy during the study period will necessitate withdrawal from the study.
• Severe illness requiring hospitalization within 60 days.
• Diabetes, defined as Hemoglobin A1C > 6.4%
• BMI percentile less than the 90th percentile for age and sex. Weight >325 lbs. or <84 lbs.
• Anemia, defined as Hemoglobin < 11 mg/dL
• Diagnosed major psychiatric or developmental disorder limiting informed consent.
• Implanted metal devices that are not compatible with MRI
• Use of blood pressure medications.
• Known liver disease other than NAFLD or AST or ALT >100 IU/L.
• Personal history of pancreatitis
• Known renal disease of any severity or an eGFR at screening of <45ml/min/1.73m2
• History of severe GI disease (e.g. gastroparesis)
• History of gallstones
• Untreated thyroid disease
• History of hypersensitivity to semaglutide
• Other causes of hyperandrogenism (example: tumor, CAH) or amenorrhea (untreated thyroid disease, tumor, primary ovarian failure, prolactinoma).
• Active symptoms or undergoing treatment for anorexia nervosa or binging/purging disorder