Comparing the Effects of Oral Contraceptive Pills Versus Metformin

Conditions

PCOS

Brief summary

To determine the effect of Oral Contraceptive Pills (OCP) verses Metformin verses OCP and Metformin on the prevalence of Metabolic Syndrome (MetS) and its components in overweight/obese women with Polycystic Ovary Syndrome (PCOS). The combination of OCP and metformin (OCP, through lowering androgens, and metformin, through improvement in insulin sensitivity) will affect the prevalence of MetS, thereby altering the risk profile for the development of diabetes and possible cardiovascular disease (CVD) in young women with PCOS.

Detailed description

The intervention will consist of randomizing subjects to one of three arms. Subjects will either be assigned to OCP + Placebo, Metformin + Placebo or OCP + Metformin. Metformin will be initiated in a step-up fashion on cycle day 1-3 of spontaneously or induced menses. Extended release pills will be utilized as they are associated with fewer gastrointestinal side effects. Subjects will begin with one tablet of metformin every night for 5 days, eventually building up to 4 tablets every night, with the maximum dose of metformin being 2000 mg. In regards to OCP, previous randomized clinical trials (RCTs) have shown that 20mcg ethinyl estradiol/norethindrone 1.0 mg was well tolerated. The study will utilize a 20mcg OCP but a less androgenic third generation progestin (desogestrel 0.15mg) with potentially lesser impact on lipids and insulin sensitivity. The OCP will be started on the first Sunday after spontaneous or induced menses. All subjects with no menses the 4 weeks before randomization will be given medroxyprogesterone acetate after a negative pregnancy test (in order to induce menses). Placebo pills will be administered to individuals randomized to OCP or metformin only in order to maintain study blinding. Subjects will undergo 6 in person study visits and life style modification counseling regarding diet and exercise. Phone contact will be made 2 weeks after randomization and at the end of each month when there is no in person visit to ensure study compliance with medications, keeping study logs and to review side effects

Dokras A, Coutifaris C, Remaley AT, Mehta NN, Playford MP, Kunselman AR, Stetter CC, Dodson WC, Legro RS.

2025-12-08

10.1371/journal.pmed.1004662

Protocol deviation report.

Anuja Dokras (8679261), Christos Coutifaris (245252), Alan T. Remaley (77852), Nehal N. Mehta (4588483), Martin P. Playford (3127800) et al. (9 authors)

OPAL (Open@LaTrobe) (La Trobe University)2025-12-08

10.1371/journal.pmed.1004662.s005

Study protocol with changes.

Anuja Dokras (8679261), Christos Coutifaris (245252), Alan T. Remaley (77852), Nehal N. Mehta (4588483), Martin P. Playford (3127800) et al. (9 authors)

OPAL (Open@LaTrobe) (La Trobe University)2025-12-08

10.1371/journal.pmed.1004662.s003

Serious adverse events.

Anuja Dokras (8679261), Christos Coutifaris (245252), Alan T. Remaley (77852), Nehal N. Mehta (4588483), Martin P. Playford (3127800) et al. (9 authors)

OPAL (Open@LaTrobe) (La Trobe University)2025-12-08

10.1371/journal.pmed.1004662.s013

Assessment of secondary outcomes.

Anuja Dokras (8679261), Christos Coutifaris (245252), Alan T. Remaley (77852), Nehal N. Mehta (4588483), Martin P. Playford (3127800) et al. (9 authors)

OPAL (Open@LaTrobe) (La Trobe University)2025-12-08

10.1371/journal.pmed.1004662.s007

Eligibility criteria.

Anuja Dokras (8679261), Christos Coutifaris (245252), Alan T. Remaley (77852), Nehal N. Mehta (4588483), Martin P. Playford (3127800) et al. (9 authors)

OPAL (Open@LaTrobe) (La Trobe University)2025-12-08

10.1371/journal.pmed.1004662.s006

Statistical analysis plan.

Anuja Dokras (8679261), Christos Coutifaris (245252), Alan T. Remaley (77852), Nehal N. Mehta (4588483), Martin P. Playford (3127800) et al. (9 authors)

OPAL (Open@LaTrobe) (La Trobe University)2025-12-08

10.1371/journal.pmed.1004662.s004

Interventions

DRUGOCP + Metformin

This will be a three-arm, double-blind, double-dummy, multicenter, prospective, randomized clinical trial comparing OCP vs. Metformin vs. OCP + Metformin on the prevalence of MetS in women with PCOS. This 6-month study will consist of a screening visit, followed by 6 study visits (Subjects will undergo 6 in person study visits and life style modification counseling regarding diet and exercise. Phone contact will be made 2 weeks after randomization and at the end of each month when there is no in person visit to ensure study compliance with medications, keeping study logs and to review side effects). No longer term follow-up is planned.

DRUGOCP + Placebo

This will be a three-arm, double-blind, double-dummy, multicenter, prospective, randomized clinical trial comparing OCP vs. Metformin vs. OCP + Metformin on the prevalence of MetS in women with PCOS. This 6-month study will consist of a screening visit, followed by 6 study visits (Subjects will undergo 6 in person study visits and life style modification counseling regarding diet and exercise. Phone contact will be made 2 weeks after randomization and at the end of each month when there is no in person visit to ensure study compliance with medications, keeping study logs and to review side effects). No longer term follow-up is planned.

DRUGMetformin + Placebo

This will be a three-arm, double-blind, double-dummy, multicenter, prospective, randomized clinical trial comparing OCP vs. Metformin vs. OCP + Metformin on the prevalence of MetS in women with PCOS. This 6-month study will consist of a screening visit, followed by 6 study visits (Subjects will undergo 6 in person study visits and life style modification counseling regarding diet and exercise. Phone contact will be made 2 weeks after randomization and at the end of each month when there is no in person visit to ensure study compliance with medications, keeping study logs and to review side effects). No longer term follow-up is planned.

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

TRIPLE (Subject, Caregiver, Investigator)

Intervention model description

This will be a three-arm, double-blind, double-dummy, multicenter, prospective, randomized clinical trial comparing OCP vs. Metformin vs. OCP + Metformin on the prevalence of MetS in women with PCOS. This 6-month study will consist of a screening visit, followed by 6 study visits. No longer term follow-up is planned.

Eligibility

Sex/Gender

FEMALE

Age

18 Years to 40 Years

Healthy volunteers

No

Inclusion criteria

1. Women ≥ 18 to ≤ 40 years of age (at the time of screening), with hyperandrogenic PCOS. 2. Subjects will be diagnosed with PCOS defined by the most recent Rotterdam criteria based on: 1. androgen excess (defined as an elevated serum T level or hirsutism, based on a Ferriman Gallwey score \> 8 (note: \> 2 for women of Asian descent) AND either: 2. history of chronic anovulation (8 or fewer periods per year) AND/OR 3. polycystic ovaries. 3. BMI ≥ 25 kg/m² to ≤ 48 kg/m² obtained at screening visit. 4. In good general health. 5. Willing to avoid pregnancy for the duration of the study.

Exclusion criteria

1. Current pregnancy or desire of pregnancy during course of study 2. Currently breastfeeding 3. Known 21 hydroxylase deficiency 4. Untreated thyroid disease (TSH \<0.45 mlU/mL and \> 4.5 mlU/mL) 5. Untreated hyperprolactinemia (2 Levels\>30 ng/ml at least one week apart) 6. Type 1 or type 2 Diabetes Mellitus (elevated fasting serum glucose \>126mg/dL on two occasions, poorly controlled diabetes (HgbA1C\>6.5%), currently receiving anti-diabetic agents, or currently receiving metformin for treatment of diabetes 7. Liver disease (AST/ALT\>2 times normal or a total bilirubin \>2.5 mg/dL) 8. Renal disease (BUN\>30 mg/dL or serum creatinine \>1.4 mg/dL) 9. Anemia (hemoglobin \<10 mg/dL) 10. History of deep venous thrombosis, pulmonary embolus, or cerebrovascular accident 11. Current history of alcohol abuse (\>14drinks/week) 12. Poorly controlled hypertension defined as average systolic blood pressure \>= 150 mm Hg or average diastolic \>=100 mm Hg obtained on three measurements obtained 5 minutes apart. If treated, average systolic blood pressure \>=140 mm Hg or average diastolic \>=90 mm Hg 13. Patients with a history of, or suspected cervical carcinoma, endometrial carcinoma, or breast carcinoma 14. TG\>200mg/dl 15. Use of lipid lowering or weight loss agents (subjects may wash out from weight loss agents) 16. Current use of oral contraceptives, depo progestin, or hormonal implants 17. Participation in any study of an investigational drug or device or biological agent within 30 days 18. Suspected adrenal or ovarian tumor secreting androgens 19. Suspected Cushing's syndrome 20. Bariatric surgery procedure in the recent past (\<12 months) 21. Absolute contraindications to the use of hormonal contraceptives or metformin, 23\. Subjects who are unable to comply with the study procedures, for instance due to mental illness, substance abuse, or participation in other studies.

Design outcomes

Primary

Measure	Time frame	Description
Number of Participants With Metabolic Syndrome After 6 Months of Treatment Metformin or OCP+Metformin for 6 Months.	Baseline and 6 months	Our primary goal is to determine the effect of 6 months' treatment with OCP vs. metformin vs. OCP + metformin on prevalence of MetS and its components in overweight / obese women. Implicit in the primary aim is clearly defining MetS, by NCEP ATPIII criteria as the presence of at least 3 of the following 5 criteria: TG≥150mg/dl, HDL-C\<50mg/dl, BP≥130/≥85mmHg, WC\>88cm and fasting glucose≥100mg/dl; and the goal of tracking safety of our interventions at all Phases of the study (through safety lab evaluations, vital signs and diaries)

Secondary

Measure	Time frame	Description
Changes in Serum Adipokines in the 3 Arms	Baseline and 6 months	Serum adipokines to be measured are adiponectin and leptin. These changes will be correlated with changes in serum and androgens and markers of insulin sensitivity.
Changes in Total Body Fat Distribution in the 3 Arms From Baseline to 6 Months	Baseline and 6 months	Body fat distribution will be measured by DXA. These changes will be correlated with changes in serum and androgens and markers of insulin sensitivity
Changes in Total Triglyceride-Rich Lipoprotein (TRLP) From Baseline to 6 Months	Baseline and 6 months	This will be measured by NMR spectroscopy
Changes in Serum Marker of Inflammation: Free Fatty Acids.	Baseline and 6 months	Measured by change in Free Fatty Acids
Changes in Serum Apoliprotein B From Baseline to 6 Months	Baseline and 6 months	This will be measured by NMR spectroscopy
Changes in Visceral Body Fat Distribution in the 3 Arms	Baseline and 6 months	Body fat distribution will be measured by DXA. These changes will be correlated with changes in serum and androgens and markers of insulin sensitivity
Changes in Quality of Life Parameters for Weight in All 3 Arms as Assessed by PCOSQ From Baseline to 6 Months	Baseline and 6 months	QOL will be measured by the Polycystic Ovary Syndrome Questionnaire (PCOSQ) Weight domain which has 5 items rated on a 7 point likert scale with a lower score representing a decreased quality of life. The total range is 7 to 35.
Change in HDL-C Function	Baseline and 6 months	This will be assessed by measuring reverse cholesterol efflux capacity using validated ex vivo system.
Changes in Quality of Life Parameters for Body Hair in All 3 Arms as Assessed by PCOSQ From Baseline to 6 Months	Baseline and 6 months	QOL will be measured by the Polycystic Ovary Syndrome Questionnaire (PCOSQ) Body Hair domain which has 5 items rated on a 7 point likert scale with a lower score representing a decreased quality of life. The total range is 7 to 35.

Countries

United States

Participant flow

Participants by arm

Arm	Count
OCP + Placebo The OCP will be started on the first Sunday after spontaneous or induced menses. All subjects with no menses the 4 weeks before randomization will be given medroxyprogesterone acetate after a negative pregnancy test (in order to induce menses). Placebo pills will be administered to individuals randomized to OCP only in order to maintain study blinding. OCP + Placebo: This will be a three-arm, double-blind, double-dummy, multicenter, prospective, randomized clinical trial comparing OCP vs. Metformin vs. OCP + Metformin on the prevalence of MetS in women with PCOS. This 6-month study will consist of a screening visit, followed by 6 study visits (Subjects will undergo 6 in person study visits and life style modification counseling regarding diet and exercise. Phone contact will be made 2 weeks after randomization and at the end of each month when there is no in person visit to ensure study compliance with medications, keeping study logs and to review side effects). No longer term follow-up is planned.	79
Metformin + Placebo Metformin will be initiated in a step-up fashion on cycle day 1-3 of spontaneously or induced menses. Extended release pills will be utilized as they are associated with fewer gastrointestinal side effects. Subjects will begin with one tablet of metformin every night for 5 days, eventually building up to 4 tablets every night, with the maximum dose of metformin being 2000 mg. Placebo pills will be administered to individuals randomized to metformin only in order to maintain study blinding. Metformin + Placebo: This will be a three-arm, double-blind, double-dummy, multicenter, prospective, randomized clinical trial comparing OCP vs. Metformin vs. OCP + Metformin on the prevalence of MetS in women with PCOS. This 6-month study will consist of a screening visit, followed by 6 study visits (Subjects will undergo 6 in person study visits and life style modification counseling regarding diet and exercise. Phone contact will be made 2 weeks after randomization and at the end of each month when there is no in person visit to ensure study compliance with medications, keeping study logs and to review side effects). No longer term follow-up is planned.	81
OCP + Metformin The OCP will be started on the first Sunday after spontaneous or induced menses. All subjects with no menses the 4 weeks before randomization will be given medroxyprogesterone acetate after a negative pregnancy test (in order to induce menses). Metformin will be initiated in a step-up fashion on cycle day 1-3 of spontaneously or induced menses. Extended release pills will be utilized as they are associated with fewer gastrointestinal side effects. Subjects will begin with one tablet of metformin every night for 5 days, eventually building up to 4 tablets every night, with the maximum dose of metformin being 2000 mg. OCP + Metformin: This will be a three-arm, double-blind, double-dummy, multicenter, prospective, randomized clinical trial comparing OCP vs. Metformin vs. OCP + Metformin on the prevalence of MetS in women with PCOS. This 6-month study will consist of a screening visit, followed by 6 study visits (Subjects will undergo 6 in person study visits and life style modification counseling regarding diet and exercise. Phone contact will be made 2 weeks after randomization and at the end of each month when there is no in person visit to ensure study compliance with medications, keeping study logs and to review side effects). No longer term follow-up is planned.	80
Total	240

Baseline characteristics

Characteristic	Metformin + Placebo	OCP + Metformin	Total	OCP + Placebo
Age, Continuous	30.1 years STANDARD_DEVIATION 5.3	29.2 years STANDARD_DEVIATION 5.4	29.5 years STANDARD_DEVIATION 5.2	29.1 years STANDARD_DEVIATION 4.8
Count of Current Smokers	5 Participants	5 Participants	16 Participants	6 Participants
Diastolic Blood Pressure	77.7 mmHG STANDARD_DEVIATION 6.4	76.9 mmHG STANDARD_DEVIATION 6.3	77.1 mmHG STANDARD_DEVIATION 6.8	76.8 mmHG STANDARD_DEVIATION 7.3
Ethnicity (NIH/OMB) Hispanic or Latino	17 Participants	14 Participants	42 Participants	11 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	64 Participants	66 Participants	198 Participants	68 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants	0 Participants
Fasting glucose value from safety labs	77.6 mg/dL STANDARD_DEVIATION 17	74.2 mg/dL STANDARD_DEVIATION 15.8	76.6 mg/dL STANDARD_DEVIATION 15.9	78.1 mg/dL STANDARD_DEVIATION 14.7
Menses per year	5.7 menses per year STANDARD_DEVIATION 3.8	4.8 menses per year STANDARD_DEVIATION 3.3	5.1 menses per year STANDARD_DEVIATION 3.4	4.7 menses per year STANDARD_DEVIATION 3.2
Percentage of Nulliparous	57 Participants	58 Participants	171 Participants	56 Participants
Percentage of Participants on Hypertension Medications	2 Participants	2 Participants	11 Participants	7 Participants
Percentage of Participants with Prediabetes, based on HbA1C	27 Participants	27 Participants	81 Participants	27 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	3 Participants	3 Participants	11 Participants	5 Participants
Race (NIH/OMB) Black or African American	16 Participants	19 Participants	54 Participants	19 Participants
Race (NIH/OMB) More than one race	2 Participants	1 Participants	5 Participants	2 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	1 Participants	0 Participants	1 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) White	59 Participants	57 Participants	169 Participants	53 Participants
Sex: Female, Male Female	81 Participants	80 Participants	240 Participants	79 Participants
Sex: Female, Male Male	0 Participants	0 Participants	0 Participants	0 Participants
Systolic Blood Pressure	116.9 mmHg STANDARD_DEVIATION 10.1	117.0 mmHg STANDARD_DEVIATION 8.4	116.9 mmHg STANDARD_DEVIATION 9.5	116.8 mmHg STANDARD_DEVIATION 9.8
Triglycerides	90.0 mg/dL	97.0 mg/dL	97.5 mg/dL	102.0 mg/dL
Waist measurement	107.4 cm STANDARD_DEVIATION 15.6	109.0 cm STANDARD_DEVIATION 16.4	108 cm STANDARD_DEVIATION 15	108.0 cm STANDARD_DEVIATION 12.8

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk
deaths Total, all-cause mortality	0 / 79	0 / 81	0 / 80
other Total, other adverse events	71 / 79	76 / 81	78 / 80
serious Total, serious adverse events	2 / 79	3 / 81	3 / 80

Outcome results

Primary

Number of Participants With Metabolic Syndrome After 6 Months of Treatment Metformin or OCP+Metformin for 6 Months.

Our primary goal is to determine the effect of 6 months' treatment with OCP vs. metformin vs. OCP + metformin on prevalence of MetS and its components in overweight / obese women. Implicit in the primary aim is clearly defining MetS, by NCEP ATPIII criteria as the presence of at least 3 of the following 5 criteria: TG≥150mg/dl, HDL-C\<50mg/dl, BP≥130/≥85mmHg, WC\>88cm and fasting glucose≥100mg/dl; and the goal of tracking safety of our interventions at all Phases of the study (through safety lab evaluations, vital signs and diaries)