Does Vaginal Delivery of Combined Hormonal Contraception Affect the Risk of Metabolic Syndrome in Overweight/Obese Women With PCOS

• Etonogestrel/ethinyl estradiol vaginal ring (Drug), also known as NuvaRing: 16 weeks of continuous use of contraceptive vaginal ring

Primary outcomes

• Incidence of Metabolic Syndrome [4 months]: Metabolic Syndrome defined according to the updated Adult Treatment Panel III as 3 or more of the following criteria: blood pressure ≥130/85 mm Hg, waist circumference >35 inches, fasting glucose ≥110 mg/dL, TG ≥150 mg/dL, HDL-C <50 mg/dL.

Secondary outcomes

• Change in low-density lipoprotein (LDL) measure [4 months]
• Change in high-density lipoprotein (HDL) measure [4 months]
• Change in triglycerides measure [4 months]
• Change in apolipoprotein A [4 months]
• Change in apolipoprotein B [4 months]
• Change in advanced lipid testing measure [4 months]
• Change in cholesterol efflux capacity [4 months]
• Change in fasting insulin level [4 months]
• Change in fasting 2 hour oral Glucose Tolerance Test result [4 months]
• Change in Testosterone [4 months]
• Change in Ferriman-Gallwey Hirsutism score [4 months]: A lower score indicates less hirsutism. The F-G scoring system has a minimum value of 0, and a maximum value of 36.
• Body Mass Index [4 months]
• Change in scoring on the Center for Epidemiologic Studies Depression Scale [4 months]: The range of values is zero to 60, with the higher scores indicating the presence of more depressive symptoms.
• Change in scoring on the State-Trait Anxiety Inventory [4 months]: The State-Trait Anxiety Inventory measures both state and trait anxiety, the scores range from 20 to 80, with higher scores correlating with greater anxiety.
• Change in scoring on Polycystic Ovary Syndrome Quality of Life Questionnaire [4 months]: Worse quality of life is associated with a lower score on the questionnaire, with a range score from 30 to 210.

Sex: Female, ages: 18 Years to 40 Years

Inclusion Criteria:

* Diagnosis of PCOS according to Rotterdam criteria, with at least 2 of 3 of the following criteria: oligomenorrhea (≤8 periods per year), clinical or biochemical hyperandrogenism, and polycystic ovaries on ultrasound
* Body mass index ≥25 and ≤45 kg/m2
* In good general health according to the investigators' discretion
* Willing to avoid pregnancy for the duration of the study

Exclusion Criteria:

* Current pregnancy or desire for pregnancy during course of study
* Current breastfeeding
* Second-trimester pregnancy within four weeks prior to initiation of NuvaRing or third-trimester pregnancy within 6 months prior to initiation of NuvaRing
* Use of hormonal contraception within four weeks prior to initiation of NuvaRing
* Diagnosis of metabolic syndrome. Metabolic syndrome will be defined according to the updated Adult Treatment Panel III as 3 or more of the following criteria: blood pressure ≥130/85 mm Hg, waist circumference >35 inches, fasting glucose ≥110 mg/dL, TG ≥150 mg/dL, HDL-C <50 mg/dL.
* Contraindications to NuvaRing use:

  * Age ≥ 35 plus tobacco use
  * Current or past deep vein thrombosis or pulmonary embolism
  * Cerebrovascular disease
  * Coronary artery disease
  * Thrombogenic valvular or rhythm diseases of the heart (such as subacute bacterial endocarditis with valvular disease or atrial fibrillation)
  * Inherited or acquired coagulopathy
  * Headaches with focal neurological symptoms or migraine headaches with aura
  * Age ≥ 35 plus any migraine headaches
  * Liver tumors, benign or malignant
  * Undiagnosed abnormal uterine bleeding
  * Current or past breast cancer or other estrogen- or progestin-sensitive cancer
  * Hypersensitivity to any of the components of NuvaRing
  * Use of hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir
* Medical comorbidities:

  * 21-hydroxylase deficiency, congenital adrenal hyperplasia
  * Untreated thyroid disease
  * Untreated hyperprolactinemia
  * Type 1 or 2 diabetes mellitus
  * Uncontrolled liver disease
  * Uncontrolled renal disease
  * Current alcohol abuse
  * Hypertension ≥ 140 mm Hg average systolic or ≥ 90 mm Hg average diastolic in women using anti-hypertensive medication
  * Hypertension ≥ 150 mm Hg average systolic or ≥ 100 mm Hg average diastolic in women not using anti-hypertensive medication
  * History of or current gynecologic cancer
  * Triglycerides >=250 mg/dL
  * Current use of lipid-lowering or weight loss agents
  * Participation in any study of an investigational drug or device or biologic agent within 30 days
  * Suspected adrenal or ovarian tumor secreting androgens
  * Suspected Cushing's syndrome
  * Bariatric surgery within 12 months
  * Other medical concerns that in the judgment of the investigator may compromise safety of the participant or confound the reliability of compliance and information acquired in this study

• Andrea Roe, MD MPH, Principal investigator, University of Pennsylvania