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

Girls and women 12-35 years old with obesity and polycystic ovarian syndrome who are on or off metformin, will receive a glucagon like peptide-1 receptor agonist intervention for 10 months to induce metabolic changes, weight loss and improve reproductive abnormalities.

Study Overview

• Status: Recruiting
• Conditions: Obese; PCOS (Polycystic Ovary Syndrome) of Bilateral Ovaries
• Intervention / Treatment: Drug: Semaglutide Injectable Product (Wegovy and/or Ozempic)

Detailed Description

Polycystic ovary syndrome is one of the most common endocrinopathies in women, presents with anovulation in adolescence, and reproductive dysfunction is related to excess weight. After a 4-month observation period of either no medication or metformin treatment, females aged 12-35 years with obesity and polycystic ovary syndrome will receive 10 months of a glucagon-like peptide-1 receptor agonist to induce metabolic changes, weight loss and improve reproductive abnormalities. We will assess the relationship between weight loss and reproductive function, as well as identify if age, hormonal and metabolic measures and such insulin sensitivity and insulin secretion predict the response to glucagon-like peptide-1 receptor agonist therapy.

• Study Type: Interventional
• Enrollment (Estimated): 80
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Yesenia Garcia-Reyes, MS; Phone Number: 720-777-6984; Email: PCOSresearch@cuanschutz.edu

Study Locations

• United States
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Recruiting
      • University of Colorado Anschutz/Children's Hospital Colorado Aurora
      • Contact: Yesenia Garcia Reyes; Phone Number: 720-777-6984; Email: PCOSresearch@cuanschutz.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult
• Accepts Healthy Volunteers: No

Description

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:

   1. If <18 years, initial BMI percentile ≥95
   2. 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
   3. Must be weight stable within ±5kg in the 3 months prior to enrollment
6. 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
7. 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.
8. 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

Exclusion Criteria:

1. 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
2. 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.
3. Weight loss medications in the last 6 months
4. Currently pregnant or breastfeeding women. Development of pregnancy during the study period 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 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Untreated PCOS; Participants with PCOS who are not on metformin or hormonal therapy, will receive 10-months of semaglutide intervention. Participants will get either semaglutide as either: Wegovy: 0.25mg for 4 weeks, 0.5mg for 4 weeks, 1mg 4-weeks, and 1.7mg for the remainder of the study. or Ozempic: 0.25mg for 4 weeks, 0.5mg for 4 weeks, 1mg 4-weeks, and Wegovy for 1.7mg for the remainder of the study.	Drug: Semaglutide Injectable Product (Wegovy and/or Ozempic); 10 months of semaglutide, with dose escalation as recommended by manufacturer. Maximum dose used will be 1.7mg; Other Names: Semaglutide (Wegovy and/or Ozempic)
Experimental: PCOS on Metformin; Participants with PCOS who are currently on metformin and still not having regular menses, will receive 10-months of semaglutide intervention. Participants in this arm will continue to take their metformin throughout the trial. Participants will get either semaglutide as either: Wegovy: 0.25mg for 4 weeks, 0.5mg for 4 weeks, 1mg 4-weeks, and 1.7mg for the remainder of the study. or Ozempic: 0.25mg for 4 weeks, 0.5mg for 4 weeks, 1mg 4-weeks, and Wegovy for 1.7mg for the remainder of the study.	Drug: Semaglutide Injectable Product (Wegovy and/or Ozempic); 10 months of semaglutide, with dose escalation as recommended by manufacturer. Maximum dose used will be 1.7mg; Other Names: Semaglutide (Wegovy and/or Ozempic)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in ovulation frequency before and after semaglutide in females with PCOS	The change in ovulation will be measured at baseline and 6-10 months post treatment with semaglutide from 4 months daily urinary progesterone metabolites	14 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Whole Body Insulin Sensitivity	Participants will undergo a 75 gram oral glucose tolerance test, and whole body insulin sensitivity will be expressed as Si, calculated via the oral minimal model using SAMM II software. This software uses participant weight, glucose and insulin concentrations at various time points during the oral glucose tolerance test to calculate the participant's insulin sensitivity. A positive Si value means an improvement in insulin sensitivity.	Baseline and 10 months
Change in ovarian morphology	Participants will have an ovarian ultrasound performed to measure change in ovarian morphology: ovarian size and number of follicles pre/post treatment with semaglutide	Baseline and 10 months

Collaborators and Investigators

• Sponsor: University of Colorado, Denver
• Collaborators: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
• Investigators: Principal Investigator: Melanie Cree-Green, MD,PhD, University of Colorado Anschutz/Children's Hospital Colorado

Study record dates

Study Major Dates

• Study Start (Actual): November 3, 2023
• Primary Completion (Estimated): February 1, 2028
• Study Completion (Estimated): June 30, 2028

Study Registration Dates

• First Submitted: April 6, 2023
• First Submitted That Met QC Criteria: April 6, 2023
• First Posted (Actual): April 19, 2023

Study Record Updates

• Last Update Posted (Estimated): August 28, 2025
• Last Update Submitted That Met QC Criteria: August 21, 2025
• Last Verified: August 1, 2025

More Information

Terms related to this study

• Keywords: semaglutide; PCOS
• Additional Relevant MeSH Terms: Urogenital Diseases; Genital Diseases; Endocrine System Diseases; Nutrition Disorders; Neoplasms; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Overnutrition; Body Weight; Genital Diseases, Female; Ovarian Diseases; Adnexal Diseases; Gonadal Disorders; Overweight; Ovarian Cysts; Cysts; Pathological Conditions, Signs and Symptoms; Nutritional and Metabolic Diseases; Signs and Symptoms; Obesity; Polycystic Ovary Syndrome; Hypoglycemic Agents; Physiological Effects of Drugs; Glucagon-Like Peptide-1 Receptor Agonists; semaglutide
• Other Study ID Numbers: 21-4941; R01HD108340 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No