Endometrial Effects of Metformin Action in Women With Polycystic Ovarian Syndrome (PCOS)

The investigators aim is to conduct a prospective un-blinded pilot study of premenopausal women diagnosed with Polycystic Ovarian Syndrome (PCOS), defined using criteria developed at the 1990 NICHD conference on PCOS, undergoing treatment for ovulation induction with Metformin. We propose that improving insulin sensitivity with use of Metformin in women diagnosed with PCOS has facilitatory influences on the uterine endometrium.

Study Overview

• Status: Completed
• Conditions: Polycystic Ovarian Syndrome
• Intervention / Treatment: Drug: Endometrin (progesterone 100mg vaginal inserts); Drug: Metformin

Detailed Description

Endometrial assessments are proposed following three month and then nine month treatment with metformin; expression of specified markers at respective time points will be compared to baseline.

Visit 1: Screening

• Signed informed consent
• Comprehensive history intake
• Physical exam: Vital signs, height, weight, waist circumferences, waist : hip ratio
• Urine pregnancy test
• Subjects provided with a 10 day supply of vaginal progesterone and EMBx will be scheduled between days 6-8 of progesterone use.

Visit 2: Baseline

• Urine pregnancy test
• Endometrium thickness will be measured via transvaginal ultrasound
• EMBx: sample of endometrial tissue will be sent for histopathology to rule out endometrial hyperplasia or cancer
• 20cc blood
• Metformin prescription and dispensing will be as per clinical care.
• Women will be advised to use barrier method of contraception (ie; condoms, contraceptive jellies or foam, sponge, diaphragm, or cervical cap) for the duration of the study.

Visits 3 and 5 (Weeks 8-10 and 30-34, respectively)

• Urine pregnancy test
• A 10 day course of vaginal progesterone to allow scheduling of EMBx's time points specified under visit 1

Visits 4 and 6 (Weeks 12 ± 1 week and 36 ± 1 week respectively)

- The procedure specified for baseline (Visit 2) will be repeated.

• Study Type: Observational
• Enrollment (Actual): 14

Contacts and Locations

Study Locations

• United States
  • Connecticut
    • New Haven, Connecticut, United States, 06520-8063
      • Yale-New Haven Hospital Women's Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 42 years (ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

• Sampling Method: Probability Sample

Study Population

Women will be recruited from the multi-physician Yale Reproductive Endocrinology clinical practice and Yale Fertility Center. Metformin is a routinely employed therapeutic strategy utilized for managing PCOS by practitioners at YFC. Almost 1/3 of the patients with PCOS are not interested in pursuing fertility in the immediate future and it is these patients who will be offered participation in the trial.

Description

Inclusion Criteria:

• Premenopausal between 18-42 years of age
• Diagnosed with PCOS as defined by chronic oligo- or amenorrhea (8 menstrual periods annually); biochemical hyperandrogenemia (elevated total or free testosterone) and /or clinical hyperandrogenism (excessive facial hair &/or acne); exclusion of common medical disorders (normal thyroid function tests and serum prolactin and exclusion of 21-hydroxylase deficiency by a fasting 17-hydroxyprogesterone <200 ng/dl).
• Acceptable health on the basis of interview, medical history, physical examination, and laboratory tests (CBC, SMA20, urinalysis) performed within the past 6 months
• Able to provide signed informed consent
• Able to comply with study requirements
• Willing to delay the start of clinically prescribed metformin treatment

Exclusion Criteria:

• Known diabetics or those with clinically significant and known pulmonary, cardiac, renal, hepatic, neurologic, psychiatric, infectious, neoplastic and malignant disease (other than non-melanoma skin cancer)
• Current use of hormonal contraceptives
• Seeking pregnancy; use of fertility drugs within 6 months of study
• Current or recent (within 3 months) use of metformin
• Ingestion of any investigational drug within two months prior to study onset
• Evidence of endometrial hyperplasia or cancer upon baseline EMBx

Study Plan

How is the study designed?

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
A; Women with PCOS initiating Metformin and exposure to vaginal progesterone for 6-8 days prior ro Endometrium Biopsy	Drug: Endometrin (progesterone 100mg vaginal inserts); once a day, 6-8 days as specified (prior to each EMBx); Drug: Metformin; per clinical care guidelines
B; Women with PCOS not planning initiating Metformin and exposure to vaginal progesterone for 6-8 days prior to Endometrium Biopsy	Drug: Endometrin (progesterone 100mg vaginal inserts); once a day, 6-8 days as specified (prior to each EMBx)
Women with PCOS who previously initiated metformin; Women with PCOS who initiated metformin at least 3 months prior to enrollment who have completed a 6-10 day course of progesterone

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
It is anticipated that endometrial expression of implantation markers will be upregulated by metformin treatment compared to baseline and improved parameters will be identified with longer duration of metformin exposure. endometrium biopsy	baseline
It is anticipated that endometrial expression of implantation markers will be upregulated by metformin treatment compared to baseline and improved parameters will be identified with longer duration of metformin exposure. endometrium biopsy	3 months
It is anticipated that endometrial expression of implantation markers will be upregulated by metformin treatment compared to baseline and improved parameters will be identified with longer duration of metformin exposure. endometrium biopsy	9 months

Secondary Outcome Measures

Outcome Measure	Time Frame
blood draw (20mL)	on day of EMBx
A combination of quantitative real time PCR, immunohistochemistry, and Western Blot techniques will be utilized for studying endometrial markers of receptivity in the endometrial tissue	9 months

Collaborators and Investigators

• Sponsor: Yale University
• Collaborators: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
• Investigators: Principal Investigator: Lubna Pal, MBBS MRCOG MSc, Yale University

Publications and helpful links

Helpful Links

• MedlinePlus related topics: Polycystic Ovary Disease
• Drug Information available for: Metformin

Study record dates

Study Major Dates

• Study Start: June 1, 2009
• Primary Completion (ACTUAL): July 1, 2013
• Study Completion (ACTUAL): July 1, 2013

Study Registration Dates

• First Submitted: February 16, 2010
• First Submitted That Met QC Criteria: February 16, 2010
• First Posted (ESTIMATE): February 17, 2010

Study Record Updates

• Last Update Posted (ACTUAL): March 30, 2020
• Last Update Submitted That Met QC Criteria: March 27, 2020
• Last Verified: June 1, 2014

More Information

Terms related to this study

• Keywords: Metformin; Endometrin; Polycystic Ovarian Syndrome (PCOS)
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms; Endocrine System Diseases; Disease; Ovarian Cysts; Cysts; Ovarian Diseases; Adnexal Diseases; Gonadal Disorders; Polycystic Ovary Syndrome; Syndrome; Hypoglycemic Agents; Physiological Effects of Drugs; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Progestins; Metformin; Progesterone
• Other Study ID Numbers: 0905005203; U54HD052668-02 (NIH)