Study characteristics

Methods

Randomised controlled trial
Location of the trial: quote: Tabriz, Iran
Method of randomisation: unclear: quote: “Patients randomly divided in two equal groups.”
Method of allocation concealment: not stated.
Source of funding: Quote: "This study was financed by Research Vice Chancellor of Tabriz University of Medical Sciences."

Participants

Inclusion criteria: PCOS as per National Institutes of Health criteria.
Exclusion criteria: rheumatic disease, infective disease, therapy for hirsutism and scalp hair loss such as spironolactone and finasteride and therapy for acne such as antibiotics.
Number of women randomised: 70:

MET: 35
OCP: 35
Number of women analysed: 60:

MET: 30
OCP: 30
Number of withdrawal and reasons:

MET: Pregnancy: 3/ 8.6%
Epigastric pain: 2/ 5.7%
OCP: nausea, increased body weight drug intolerance: 5/ 14.3%
Summary characteristics: PCOS
Young patients: mean (+SD) age (years): 23.4 +/‐8.1
Mean weight ( +SD) kg: 63.4 +/‐ 14.7
Mostly hirsute (76.6%)
Age (years):
MET mean (+SD): 24.9 (11)
OCP mean (+SD): 22 (5.2)
BMI (kg/m²):

MET mean (+SD): 26.5 (5.7)
OCP mean (+SD): 24.6 (4.9)

Interventions

Treatment: MET 1000 mg/day
Control: OCP (Ethinyl Estradiol 35 Cyproterone acetate 2 mg) /days /21 days per months
Duration: 6 months
Co‐intervention(s): none

Outcomes

Primary outcomes: none
Secondary outcomes:

Body weight (kg)

BMI (kg/m²)
Serum total testosterone (nmol/L)

Subjective outcomes

None

Objective outcomes

(a) Clinical parameters

1. Body weight (kg)

2. BMI (kg/m²)

(b) Hormonal parameters
1. Serum total testosterone (nmol/L)

Notes

Power calculation: unclear

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: “Patients randomly divided in two equal groups.”

Insufficient information about the sequence generation process available to permit a judgement of 'low risk' or 'high risk'.

Allocation concealment (selection bias)

Unclear risk

Method of allocation concealment not stated.

Insufficient information available to permit judgement of ‘low risk’ or ‘high risk’.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Insufficient information available to permit a judgement of ‘low risk’ or ‘high risk’.
Blinding not stated.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Insufficient information available to permit a judgement of ‘low risk’ or ‘high risk’.
Blinding not stated.

Incomplete outcome data (attrition bias)
All outcomes

High risk

Reason for missing data imbalanced and related to intervention.
MET: epigastric pain 2/ 5.7%.
OCP: nausea, increased body weight drug intolerance 5/ 14.3%: more than twice.

Selective reporting (reporting bias)

Low risk

The study protocol is not available, but it is clear that the published reports include all expected outcomes, including those that were prespecified.

Other bias

Low risk

The study appears to be free of other sources of bias.

Study characteristics

Methods

Randomised controlled trial
Location of the trial: quote: San Diego, USA
Method of randomisation: quote: “Each patient was randomly assigned to group 1 or group 2 using concealed assignments from random numbers that were computer generated.”
Method of allocation concealment: not stated.
Source of funding: not stated.

Participants

Inclusion criteria: inclusion of patients in the study was based on the NIH criteria for the diagnoses of PCOS in this age group, which includes irregular menses or amenorrhoea and elevated free or total testosterone. Irregular menses or amenorrhoea was defined as less than or equal to eight menses per year. In addition, other causes of hyperandrogenism were excluded including: adrenal tumours, late congenital adrenal hyperplasia, and prolactinomas. Patients were only enrolled 2 years post‐menarche given the potential for menstrual irregularity in normal maturation post‐menarche.
Exclusion criteria: exclusion criteria included: current treatment or treatment within the last 3 months with metformin or OCP and personal or family history of blood clotting disorders, breast cancer, stroke, severe migraines with aura, elevated BP, defined as either systolic and/or diastolic BP ≥ 95th percentile measured upon three or more occasions, and smoking defined by more than one pack per day for the past 6 months.
Number of women randomised: 34

MET: 16

OCP: 18
Number of women analysed: 22

MET: 10

OCP: 12
Number of withdrawal and reasons:

MET: no shows and unreachable: 5 /31.2%
No insurance: 1/ 6.2%
OCP: no shows: 4/ 22.2%
No insurance: 1/ 5.6%
Decline treatment: 1/ 5.6%
Summary characteristics: PCOS, adolescent 12 to 18 years, 68% Hispanic
Age (years):
MET: range: 14 to 18

OCP: range: 15 to 17

BMI (kg/m²):

MET mean (+ SD): 33.7 (6)

OCP mean ( + SD): 33.4 (9)

Interventions

Treatment: MET 1g twice a day gradual increase maximum dose was reached over 3‐week period
Control: OCP (Ethinyl Estradiol 30mcg Noresthisterone 1mg)
Duration: 6 months
Co‐intervention(s): routine counselling about diet and exercise was done in clinic, but no specific exercise or diet prescription was offered.

Outcomes

Primary outcomes: Hirsutism score

Adverse events: severe (requiring stopping of medication) and minorSecondary outcomes:

Menstrual cyclicity, initiation of menses or significant shortening of cycles
BMI (kg/m²)
Serum total testosterone (nmol/L)

Fasting insulin (mIU/L)
Fasting HDL cholesterol (mmol/L)
Fasting triglycerides (mmol/L)

Subjective outcomes

(a) Clinical parameters

1. Hirsutism score

Objective outcomes

(a) Clinical parameters

1. Adverse events: severe (requiring stopping of medication) and minor

2. Menstrual cyclicity, initiation of menses or significant shortening of cycles
3. BMI ((kg/m²)

(b) Hormonal parameters
1. Serum total testosterone (nmol/L)

(c) Metabolic parameters

1. Fasting insulin (mIU/L)
2. Fasting HDL cholesterol (mmol/L)
3. Fasting triglycerides (mmol/L)

Notes

Power calculation: yes, a priori, on FT and BMI (secondary outcomes)

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: “Each patient was randomly assigned to group 1 or group 2 using concealed assignments from random numbers that were computer generated.”

Allocation concealment (selection bias)

Unclear risk

Method of allocation concealment not stated.
Insufficient information available to permit a judgement of ‘low risk’ and ‘high risk’.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Insufficient information available to permit a judgement of ‘low risk’ or ‘high risk’.

Blinding not stated.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Insufficient information available to permit a judgement of ‘low risk’ or ‘high risk’.

Blinding not stated.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Quote: "No show, unreachable" unclear reasons for withdrawal and could be related to the intervention.
Insufficient report of attrition/exclusions to permit a judgement of ‘low risk’ or ‘high risk’.

Selective reporting (reporting bias)

High risk

Measurement of hirsutism and improvement in menstrual pattern described in methods but not reported in the result or reported without giving the number of patient with improvement in menstrual pattern.

HDL cholesterol, SD not reported for OCP group therefore could not be included in the meta‐analysis.
Hirsutism is one of our primary outcomes, not all of the study's prespecified primary outcomes have been reported.

Other bias

Low risk

The study appears to be free of other sources of bias.

Study characteristics

Methods

Randomised controlled trial
Location of the trial: quote: Massachussets, USA
Method of randomisation: quote: "Random numbers table"
Method of allocation concealment: not stated
Source of funding: not stated

Participants

Inclusion criteria: hyperandrogenaemia (total T > 60 ng/dL and free T > 1.1 pg/mL), no evidence of androgen secreting tumour, oligomenorrhoea (< 6 menses in the previous 6 months) and obesity (> 95th percentile BMI for age), hyperinsulinaemic (fasting insulin > 20 µU/mL) but not diabetic (fasting glucose < 126 mg/dL). PCOS diagnosis consistent with NIH.
Exclusion criteria: reported current or past sexual activity, OCP use within previous 6 months, positive urine pregnancy test (performed on all participants at baseline), abnormal BUN, Cr, AST or positive personal or family history of thrombosis, primary adrenal source of androgeneses.
Number of women randomised: 35

MET: 18

OCP: 17
Number of women analysed: 31

MET: 16

OCP: 15
Number of withdrawal and reasons:
MET: 2/ 11%
OCP: 2/ 12%
All unreachable or refused to come to further visits. No breakdown by MET versus OCP.
Summary characteristics: PCOS, 12 to 21 years, obese, hyperinsulinaemic, oligoamenorrhoeic and hyperandrogenaemia
Age (years):

MET Mean (range): 15.4 years (13.1 to 18.4)

OCP Mean (range): 15.3 years (12.5 to 21)
BMI (kg/m²):

MET (mean ± SEM): 37.3 (1.3)

OCP (mean ± SEM): 40.1 (2.1)

Interventions

Treatment: MET 500 mg twice a day 2 weeks and dose increased to 1 g twice a day if tolerated
Control: OCP (Ethinyl Estradiol 35mcg norgestimate 0.25 mg)
Duration: 6 months
Co‐intervention(s): none

Outcomes

Primary outcomes:
Hirsutism score
Secondary outcomes:

Menstrual cyclicity, initiation of menses or significant shortening of cycles

Acne score
Body weight (kg)

BMI (kg/m²)

Serum total testosterone (ng/dL)
Fasting insulin (µU/L)
Fasting glucose (mmol/L)
Fasting total cholesterol (mg/dL)
Fasting HDL cholesterol (mg/dL)
Fasting LDL cholesterol (mg/dL)
Fasting triglycerides (mg/dL)

Subjective outcomes

(a) Clinical parameters

1. Hirsutism score
2. Acne score

Objective outcomes

(a) Clinical parameters

1. Menstrual cyclicity, initiation of menses or significant shortening of cycles
2. Body weight (kg) and/or BMI (kg/m²)

(b) Hormonal parameters

1. Serum total testosterone (ng/dL)
(c) Metabolic parameters

1. Fasting insulin (µU/L)
2. Fasting glucose (mmol/L)
3. Fasting total cholesterol (mg/dL)
4. Fasting HDL cholesterol (mg/dL)
5. Fasting LDL cholesterol (mg/dL)
6. Fasting triglycerides (mg/dL)

Notes

Authors contacted about: Ferriman‐Gallwey score, menstrual rate and acne score because expressed with graph.

Authors were also contacted to ask about free testosterone because calculated in the methods as total testosterone/SHBG.

Power calculation: yes, a priori on free testosterone

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Random numbers table".

Allocation concealment (selection bias)

Unclear risk

Method of allocation concealment not stated.

Insufficient information available to permit judgement of ‘low risk’ or ‘high risk’.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Insufficient information available to permit a judgement of ‘low risk’ or ‘high risk’.

Blinding not stated.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Insufficient information available to permit a judgement of ‘low risk’ or ‘high risk’.

Blinding not stated.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Quote: "All unreachable or refused to come to further visits" unclear reason for withdrawal could be related to intervention. Insufficient reporting of attrition/exclusions to permit a judgement of 'low risk' or 'high risk.

Selective reporting (reporting bias)

High risk

From results section of paper, all of the studies pre‐specified (primary and secondary) outcomes that are of interest in the review have been reported in the pre‐specified way with the exception of blood pressure, Ferriman‐Gallwey score, acne score, menstrual improvement. These 3 last outcomes are presented with graphs.
One or more outcomes of interest in the review have been reported incompletely so that they cannot be entered in a meta‐analysis.

Other bias

Low risk

The study appears to be free of other sources of bias.

Study characteristics

Methods

Randomised controlled trial
Location of the trial: quote: Kolkata, India

Method of randomisation: quote: "Computer‐generated randomization table, interventions were sealed in sequentially numbered identical opaque containers."

Method of allocation concealment: quote: "Interventions were sealed in sequentially numbered identical opaque containers"

Source of fundings: not stated

Participants

Inclusion criteria: PCOS 2003 Rotterdam criteria
Exclusion criteria: not stated
Number of women randomised: 129:

OCP + MET arm: 63
OCP arm: 66
Number of women analysed: 85:

OCP + MET : 46
OCP: 39
Number of withdrawal and reasons:

OCP + MET: Lost to F/U: 17/ 27%
OCP: Lost to F/U: 27/ 41%
Summary characteristics: PCOS

Age (years):

OCP + MET mean (+ SD):
20.68 (3.36)

OCP mean (+ SD):
21.24 (4.01)
BMI (kg/m²):

OCP + MET mean (+ SD)

26.23 (4.06)

OCP mean (+ SD):

25.11 (4.33)

Interventions

Treatment: OCP (Ethinyl Estradiol 20 mcg Drospirenone 3 mcg) daily cyclically 24/4 + MET 500 mg/day
Control: OCP (Ethinyl Estradiol 20 mcg Drospirenone 3 mcg) daily cyclically 24/4
Duration: 12 months
Co‐intervention(s): none

Outcomes

Primary outcomes:

Hirsutism score

Secondary outcomes:

Acne
BMI (kg/m²)
Blood pressure (systolic) (mm Hg)

Blood pressure (diastolic) (mm Hg)
Serum total testosterone (nmol/L)
Sex hormone‐binding globulin (SHBG)

Free androgen index (FAI) (%)

Subjective outcomes

(a) Clinical parameters
1. Hirsutism score

2. Acne

Objective outcomes

(a) Clinical parameters
1. BMI (kg/m²)

2. Blood pressure (systolic) (mm Hg)

3. Blood pressure (diastolic) (mm Hg)
(b) Hormonal parameters
1. Serum total testosterone (nmol/L)
2. Free androgen index (FAI) (%)

Notes

Abstract only

Authors contacted about: their results

Power calculation: done, a priori, unclear on FAI (secondary outcome)

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: “Computer‐generated randomization table”.

Allocation concealment (selection bias)

Low risk

Quote: “Interventions were sealed in sequentially numbered identical opaque containers”.

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Quote: "Patients were masked but investigator and data analysis not”.

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Quote: "Patients were masked but investigator and data analysis not”.

Incomplete outcome data (attrition bias)
All outcomes

High risk

Reason for missing data unclear quote: "lost to F/U".

Missing values were imputed by carrying last observation forward. Quote: “use of LOCF might be appropriate if most people for whom outcomes are carried forward had a genuine measurement relatively recently.” 6 months to 12 is not judged as “recently” by the authors: inappropriate use of imputation

Selective reporting (reporting bias)

Low risk

The study protocol is not available but it is clear that the published reports include all expected outcomes, including those that were pre‐specified.

Other bias

Unclear risk

Insufficient information.
Abstract only.

Study characteristics

Methods

Randomised controlled trial
Location of the trial: quote: Istanbul, TurkeyMethod of randomisation: quote: "The remaining subjects were randomized into four subgroups by a computerized method"Method of allocation concealment: Not statedSource of funding: Quote: "This study was financially supported by Gulhane Military Medical Academy as it was originally conducted as a graduation thesis in obstetrics and gynaecology."

Participants

Inclusion criteria: the diagnosis of PCOS was made according to the Rotterdam criteria. Clinical or biochemical hyperandrogenism was detected if the modified Ferriman‐Gallwey score was higher than 8, acne was present and serum concentrations of total and/or free testosterone were increased. Oligomenorrhoea was defined when menstruation occurred six times a year at most. Polycystic ovaries were visualised by ultrasonography when increased stromal echogenicity was peripherally surrounded by more than 10 follicles with a diameter of 2 mm to 8 mm.
Exclusion criteria: those patients who had systemic disorders and were receiving therapies that could affect carbohydrate and lipid metabolism were excluded from the study. Patients reporting contraindications for oral contraceptives and metformin were also excluded from the study.
Number of women randomised: 87/70

MET + OCP: 20

MET: 29

OCP: 21
Number of women analysed: 63/46

MET+ OCP: 12

MET: 17

OCP: 17
Number of withdrawal and reasons:
MET + OCP: severe nausea: 1/ 5%
Headache: 1 / 5%
Dizziness: 2 / 10%
Unknown: 2 / 10%
Hirsutism: 1/ 5%
Unwilling weight loss: 1/ 5%
MET: pregnancy: 4/ 13.8%
Severe nausea: 2/ 6.9%
Feeling hunger: 1 / 3.4%
Unknown: 1/ 3.4%
Hirsutism: 1 / 3.4%
Unwilling weight loss: 1/ 3.4%
Dizziness: 1 / 3.4%
Hypothyroidism: 1 / 3.4%
OCP: pregnancy: 1 / 4.8%
Severe nausea: 1/ 4.8%
Sexual reluctant: 1/ 4.8%
Hirsutism: 1/ 4.8%
Summary characteristics: PCOS, 18 to 39, non‐obese
Age (years):
MET + OCP mean (+ SD): 27.35 (5.65)
MET mean (+ SD): 26.2 (3.96)
OCP mean (+ SD): 26.6 (4.92)
BMI (kg/m²):

MET + OCP mean (+ SD): 25.11 (3.75)
MET mean (+ SD): 25.06 (3.08)
OCP mean (+ SD): 23.45 (3.4)

Interventions

MET 1700 mg/day (850 mg twice a day) + OCP (Ethinyl Estradiol 30 mcg Drospirenone 3 mg)

MET 1700 mg/day (850mg twice a day)

OCP (Ethinyl Estradiol 30 mcg / Drospirenone 3mg)

Duration: 6 months
Co‐intervention(s): none

Outcomes

Primary outcomes:

Adverse events: severe (requiring stopping of medication) and minor
Secondary outcomes:

BMI (kg/m²)

Fasting glucose (mmol/L)

Subjective outcomes

None

Objective outcomes

(a) Clinical parameters

1. Adverse events: severe (requiring stopping of medication) and minor

2. BMI (kg/m²)

(c) Metabolic parameters

2. Fasting glucose (mmol/L)

Notes

Power calculation: unclear

3‐arm study: OCP V MET V MET + OCP

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "The remaining subjects were randomized into four subgroups by a computerized method"

Allocation concealment (selection bias)

Unclear risk

Method of allocation concealment not stated.
Insufficient information available to permit a judgement of ‘low risk’ or ‘high risk’.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Insufficient information available to permit a judgement of ‘low risk’ or ‘high risk’.

Blinding not stated.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Insufficient information available to permit a judgement of ‘low risk’ or ‘high risk’.

Blinding not stated.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Missing outcome data well described, and percentage of missing data related to intervention low.

Selective reporting (reporting bias)

Unclear risk

BMI described in the method not reported in the results.
But not a primary or key outcomes.

Insufficient information available to permit a judgment of 'low risk' or 'high risk'.

Other bias

Low risk

The study appears to be free of other sources of bias.

Study characteristics

Methods

Randomised controlled trial
Location of the trial: quote: Izmir, TurkeyMethod of randomisation: quote: "Patients were randomized".Method of allocation concealment: nNot statedSource of funding: not stated

Participants

Inclusion criteria: Rotterdam PCOS Consensus criteriaExclusion criteria: DM, hyperprolactinaemia, congenital adrenal hyperplasia (through ACTH test), thyroid disorders, Cushing syndrome, hypertension, hepatic or renal dysfunction, confounding medications (OCP), antihypertensive medications, insulin sensitising drugs)Number of women randomised: unclear: 100/ 99/ 94

MET: 47

OCP: 33Number of women analysed: 94

MET: 47

OCP: 33Number of withdrawal and reasons: unclear. Could be 0/94 (0%), 5/99 (5%) or 6/100 (6%). Summary characteristics: PCOS, lean young women BMI (kg/m²):
MET Mean (± SEM): 25.82 (6.12)

OCP Mean (±S EM): 24.72 (4.1)

Interventions

Treatment: MET 2g/day
Control: OCP (Ethinyl Estradiol 35 mcg Cyproterone acetate 2 mg)
Duration: 4 months
Co‐intervention(s): none

Outcomes

Primary outcomes:

Hirsutism score
Secondary outcomes:

Menstrual cyclicity, initiation of menses or significant shortening of cycles

Acne – subjective
Body weight (kg)

BMI (kg/m²)

Blood pressure (systolic) (mm Hg)

Blood pressure (diastolic) (mm Hg)

Serum total testosterone (ng/mL)

Fasting insulin (mIU/mL)
Fasting glucose (mg/dL)
Fasting total cholesterol (mg/dL)
Fasting HDL cholesterol (mg/dL)
Fasting LDL cholesterol (mg/dL)
Fasting triglycerides (mg/dL)

Subjective outcomes

(a) Clinical parameters

1. Acne – subjective

2. Hirsutism score

Objective outcomes

(a) Clinical parameters

1. Menstrual cyclicity, initiation of menses or significant shortening of cycles
2. Body weight (kg)

3. BMI (kg/m²)
4. Blood pressure (systolic) (mm Hg)

5. Blood pressure (diastolic) (mm Hg)

(b) Hormonal parameters

1. Serum total testosterone (ng/mL)

(c) Metabolic parameters

1. Fasting insulin (mIU/mL)
2. Fasting glucose (mg/dL)
3. Fasting total cholesterol (mg/dL)
4. Fasting HDL cholesterol (mg/dL)
5. Fasting LDL cholesterol (mg/dL)
6. Fasting triglycerides (mg/dL)

Notes

Authors contacted about: fasting insulin because expressed in wrong unit.

Power calculation: unclear

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: "Patients were randomized".

Insufficient information about the sequence generation process available to permit judgement of ‘low risk’ or ‘high risk’.

Allocation concealment (selection bias)

Unclear risk

Method of allocation concealment not stated.

Insufficient information available to permit judgement of ‘low risk’ or ‘high risk’.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Insufficient information available to permit a judgement of ‘low risk’ or ‘high risk’.

Blinding not stated.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Insufficient information available to permit a judgement of ‘low risk’ or ‘high risk’.

Blinding not stated.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

States both n = 100, n = 99 and n = 94 randomised (n = 47 metformin, n = 14 rosiglitazone, n = 33 OCP). Withdrawal could be (0% or n = 5 (5%) or n = 6 (6%), no reasons provided for any withdrawals. Insufficient reporting of attrition/exclusions to permit a judgement of 'low risk' or 'high risk'

Selective reporting (reporting bias)

High risk

Acne, hirsutism and improvement of menstrual patterns are described in the results but not in the methods.

One or more primary outcomes have been reported using measurements, analysis methods or subset data THAT WERE NOT PRE‐SPECIFIED.

Moreover, from results section of paper, all of the studies pre‐specified (primary and secondary) outcomes that are of interest in the review have been reported in the pre‐specified way with the exception of BP, but not a primary or key outcomes.

Other bias

High risk

Baseline imbalance, MET n = 47, rosiglitazone n = 14, OCP n = 33 which cannot be explained by method of randomisation or allocation concealment or incomplete outcome data.

Study characteristics

Methods

Randomised controlled trial
Location of the trial: quote: Thessaloniki, Greece
Method of randomisation quote: "Randomization was performed by random number tables"
Method of allocation concealment: quote: "The patient number treatment codes were held by a third party"
Source of funding: None

Participants

Inclusion criteria: the diagnosis of PCOS was based on the presence of irregular menstrual cycles (eight or fewer menses per year) as well as elevated serum levels of testosterone and/or clinical symptoms of hyperandrogenism, according to the National Institute of Child Health and Human Development conference.
Exclusion criteria: non‐classical congenital adrenal hyperplasia, androgen‐secreting neoplasms, hyperprolactinaemia and thyroid disease were excluded by appropriate tests in all women. Patients were excluded from participation if they were pregnant or planning to become pregnant, were breastfeeding, had a history of current or recent (within 6 months) use of oral contraceptives, antidiabetics, or antiandrogens, or had any contraindications to metformin therapy including renal or hepatic impairment.
Number of women randomised: 120

MET: 40

OCP 1: 40

OCP 2: 40
Number of women analysed: 109

MET: 35

OCP 1: 38

OCP 2: 36
Number of withdrawal and reasons:
MET: GI side effect 5/ 12.5%
OCP 1: loss to F/U 2 /10%

OCP 2: loss to F/U 4/10%
Summary characteristics: PCOS
All the participants were lean (BMI < 25 kg/m²), in good health and nonsmokers or had quit smoking for more than a year at baseline.
Age (years):
MET mean (+ SE): 21.5 (0.5)

OCP 1 mean (+ SE): 22 (0.6)

OCP 2 mean (+ SE): 23.2 (0.6)
BMI (kg/m²):

MET mean (+ SE): 23.03 (0.67)

OCP 1 mean (+ SE): 21.8 (0.35)

OCP 2 mean (+SE): 22.37 (0.48)

Interventions

Treatment: MET 425 mg twice a day one week then 850 mg twice a dayControl: OCP 1 (Ethinyl Estradiol 35 mcg / Cyproterone acetate 2 mg) 21 days stop 7 days

OCP 2 (Ethinyl estradiol 30 mcg / drospirenone 3 mg) 21 days stop 7 daysDuration: 6 monthsCo‐intervention(s): none

Outcomes

Primary outcomes:

Adverse events: severe (requiring stopping of medication) and minorSecondary outcomes:

BMI (kg/m²)

Serum total testosterone (nmol/L)
Free androgen index (FAI) (%)

Subjective outcomes

None

Objective outcomes

(a) Clinical parameters

1. Adverse events: severe (requiring stopping of medication) and minor

2.BMI (kg/m²)

(b) Hormonal parameters

1. Serum total testosterone (nmol/L)
2. Free androgen index (FAI) (%)

Notes

Power calculation: unclear

3 arms study MET V OCP (drospirenone) V OCP (cyproterone acetate), authors have decided to combine both OCP versus MET

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Randomization was performed by random number tables."

Allocation concealment (selection bias)

Low risk

Quote: "The patient number treatment codes were held by a third party."

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Insufficient information available to permit a judgement of ‘low risk’ or ‘high risk’.

Blinding not stated.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Insufficient information available to permit a judgement of ‘low risk’ or ‘high risk’.

Blinding not stated.

Incomplete outcome data (attrition bias)
All outcomes

High risk

MET: GI side effect 5/ 12.5% versus OCP 1: loss to F/U 2 /10% and OCP 2 loss to F/U 4/10%. Reason for missing outcome data is likely to be related to true outcome, with imbalance reasons for missing data across intervention group.
Loss to F/U versus GI adverse events.

Selective reporting (reporting bias)

Unclear risk

Fasting glucose and fasting insulin pre‐specified in the methods not stated in the results.

But not a primary or key outcomes.

Insufficient information available to permit a judgment of 'low risk' or 'high risk'.

Other bias

Low risk

The study appears to be free of other sources of bias.

Study characteristics

Methods

Randomised controlled trial
Location of the trial: quote: Prague, Czech Republic

Method of randomisation: quote: "All patients were randomly assigned to two groups using a computer generator of random values with a uniform distribution within the interval 0 to 1. The values obtained were transformed into rank values, ranks 1‐15 were assigned to the OCP group and remaining 15 were assigned to identical OCP in combination with metformin"

Method of allocation concealment: not stated

Source of funding: not stated

Participants

Inclusion criteria: PCOS: (i) oligomenorrhoea from menarche (menstrual cycle > 35 days); (ii) an increased concentration of at least one androgen above the upper reference limit (testosterone 0.5 to 2.63 n mol/L, androstenedione 1.57 to 5.4 n mol/L, dehydroepiandrosterone (DHEA) 0.8 to 10.5 n mol/L); and (iii) clinical manifestation of hyperandrogenism (acne, hirsutism or both).
Exclusion criteria: secondary endocrine disorder, such as hyperprolactinaemia, thyroid dysfunction or a non‐classical form of congenital adrenal hyperplasia, those wishing to conceive within the next 6 months, or contraindications to oral contraceptive use.
Number of women randomised: 30:

OCP + MET arm: 15

OCP arm: 15

Number of women analysed: 28:

OCP + MET: 13

OCP 15
Number of withdrawal and reasons:

OCP + MET: 2: GIT problem: 1/ 6.7%

Non compliance: 1/ 6.7%

OCP: 0
Summary characteristics: PCOS
Age (years):

MET + OCP Mean (± SD):

23.8 (5.4)

OCP Mean (+ SD)

23.2 (4.6)
BMI (kg/m²):

MET + OCP Mean (± SD):

24.7(4.9)

OCP Mean (+ SD):

22.1(3.1)

Interventions

Treatment(s): MET 500 mg three times a day + OCP (Ethinyl estradiol 35 mcg norgestimate 250 mcg) once daily (21 days per month followed by 7 days pill‐free period)

Control: OCP (Ethinyl estradiol 35 mcg norgestimate 250 mcg) once daily (21 days per month followed by 7 days pill‐free period)

Duration: 6 months

Co‐intervention(s): none

Outcomes

Primary outcomes:

Adverse events: severe (requiring stopping of medication) and minor
Secondary outcomes:

Body weight (kg)

BMI (kg/m²))

Serum total testosterone (nmol/L)
Free androgen index (FAI) (%)

Fasting insulin (pmol/L)
Fasting glucose (mmol/L)
Total Cholesterol (mmol/L)
HDL Cholesterol (mmol/L)
LDL Cholesterol (mmol/L)
Triglycerides (mmol/L)

Subjective outcomes

None

Objective outcomes

(a) Clinical parameters

1. Adverse events: severe (requiring stopping of medication) and minor
2. Body weight (kg)
3. (BMI (kg/m²)

(b) Hormonal parameters
1.Serum total testosterone (nmol/L)
3.Free androgen index (FAI) (%)

(c) Metabolic parameters
1. Fasting insulin (pmol/L)
2. Fasting glucose (mmol/L)
3. Total Cholesterol (mmol/L)
4. HDL Cholesterol (mmol/L)
5. LDL Cholesterol (mmol/L)
6. Triglycerides (mmol/L)

Notes

Authors contacted about power calculation, method of randomisation and co‐intervention:
Calculated statistical power of study not sufficient as due to wide physiological range for insulin sensitivity the sufficient number is extremely high (personal communication with author).

Method of randomisation and co intervention kindly provided by the authors that was not in the original paper

Power calculation: unclear

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "All patients were randomly assigned to two groups using a generator of random values with a uniform distribution within the interval 0 to 1 (statistical software NCSS 2002). The values obtained were transformed into rank values. The subjects with ranks 1–15 were assigned to the COC group and received a monophasic COC (EE 35 mg/NGM 250mg) in a cyclic regimen (21 days of active pills followed by 7 days of pill‐free interval) for 6 months. The remaining 15 subjects received an identical COC in combination with metformin (1500 mg/day) for 6 months (METOC group)."

Allocation concealment (selection bias)

Unclear risk

Method of allocation concealment not stated. Insufficient information to permit judgement of ‘Yes’ or ‘No’.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Insufficient information available to permit a judgement of ‘low risk’ or ‘high risk’.

Blinding not stated.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Insufficient information available to permit a judgement of ‘low risk’ or ‘high risk’.

Blinding not stated.

Incomplete outcome data (attrition bias)
All outcomes

High risk

Withdrawal OCP 0% versus metformin + OCP 13% due to n = 1 GIT problem and n = 1 study protocol non‐compliance. Reason for missing outcome data is likely to be related to true outcome, with either imbalance in numbers or reasons for missing data across intervention.

Selective reporting (reporting bias)

Low risk

From results section of paper, all of the studies pre‐specified (primary and secondary) outcomes that are of interest in the review have been reported in the pre‐specified way.

Other bias

Low risk

The study appears to be free of other sources of bias.

Study characteristics

Methods

Randomised controlled trial, cross‐over study

Location of the trial: quote: Gdynia, Poland

Method of randomisation: quote: "Women were treated in a computer‐randomized order"

Method of allocation concealment: not stated

Sources of fundings: Quote: "This study has been founded by the Polish National Centre of Science (grant number 2 P05E 077 30) and the Medical University of Gdańsk Grant (ST‐101)"

Participants

Inclusion criteria: the diagnosis of PCOS was made according to the Rotterdam criteria where the study participants had to present at least 2 of the 3 following features: oligo‐/amenorrhoea, clinical/biochemical indices of hyperandrogenism or polycystic ovaries on transvaginal ultrasonography.
Exclusion criteria: hyperprolactinaemia, non‐classical congenital adrenal hyperplasia and androgen producing neoplasms. Participants who had received any medication such as oral contraceptives, antiandrogens, neuroleptics, antidepressants or corticosteroids in the preceding 3 months were not included into the study. Furthermore, women with diagnosed diabetes, overt thyroid disease, chronic inflammatory disorders or a history of infection preceding 1 month before the study were also excluded. Pregnancy, age more than 40 years and contraindications to oral contraception or metformin were additional exclusion criteria.
Number of women randomised: 42

OCP arm: 24
MET arm: 18
Number of women analysed: 34

OCP: 21
MET: 13
Number of withdrawal and reasons:

OCP: 3: Loss to F/U: 1/ 4.2%
Intolerance: 2/ 8.3%
MET: 5 Loss to F/U: 4/ 22%
Depression: 1/ 5.5%
Summary characteristics: PCOS, age range 18 to 36, 20% smokers
Age (years):

OCP mean (95%CI):

24.9 (23.5; 26.4)
MET mean (95%CI):

24.6 (23.0; 26.3)
BMI (kg/m²):

OCP: mean (+SD):

24.9 (4.4)

MET: mean (+SD):

25.1 (9.8)

Interventions

Treatment: MET 850 mg twice a day

Control: OCP (Ethinyl Estradiol 35 mcg Cyproterone acetate 2mg)

Duration: 4 months

Co‐intervention(s): none

Outcomes

Primary outcomes:

Hirsutism score

Adverse events: severe (requiring stopping of medication) and minor
Secondary outcomes:

Body weight (kg)

BMI (kg/m²)

Blood pressure (systolic) (mm Hg)

Blood pressure (diastolic) (mm Hg)

Serum total testosterone (nmol/L)
Free androgen index (FAI) (%)

Fasting glucose (mmol/L)
Fasting total cholesterol (mmol/L)
Fasting HDL cholesterol (mmol/L)
Fasting LDL cholesterol (mmol/L)
Fasting triglycerides (mmol/L)

Subjective outcomes

(a) Clinical parameters

1. Hirsutism score

Objective outcomes

(a) Clinical parameters

1. Adverse events: severe (requiring stopping of medication) and minor

2. Body weight (kg)

3. BMI (kg/m²)
4. Blood pressure (systolic) (mm Hg)

5. Blood pressure (diastolic) (mm Hg)

(b) Hormonal parameters

1. Serum total testosterone (nmol/L)
2. Free androgen index (FAI) (%)

(c) Metabolic parameters

1. Fasting glucose (mmol/L)
2. Fasting total cholesterol (mmol/L)
3. Fasting HDL cholesterol (mmol/L)
4. Fasting LDL cholesterol (mmol/L)
5. Fasting triglycerides (mmol/L)

Notes

Authors contacted about the results, they send us the results before cross‐over

Power calculation: unclear

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: “Women were treated in a computer‐randomized order”.

Allocation concealment (selection bias)

Unclear risk

Method of concealment not stated. Insufficient information available to permit a judgement of ‘low risk’ or ‘high risk’.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Insufficient information available to permit a judgement of ‘low risk’ or ‘high risk’.

Blinding not stated.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Insufficient information available to permit a judgement of ‘low risk’ or ‘high risk’.

Blinding not stated.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

“loss of F/U” unclear reason for withdrawal could be related to intervention. 2 “intolerance” in OCP group so related to the intervention, 1 “depression” in MET group unlikely related to the intervention.
Insufficient reporting of attrition/ exclusions to permit a judgement of 'low risk' or 'high risk'.

Selective reporting (reporting bias)

Unclear risk

Fasting glucose pre‐specified in the methods not stated in the results.

But not a primary or key outcomes.

Insufficient information available to permit a judgment of 'low risk' or 'high risk'.

Other bias

High risk

Number of patients randomised in each group is different 24 versus 18 and more withdrawal in the smallest group.
Baseline imbalance.

Study characteristics

Methods

Randomised controlled trial
Location of the trial: quote: Alexandria, EgyptMethod of randomisation: quote: "computer‐generated random‐number tables"Method of allocation concealment: not statedSource of funding: Not stated

Participants

Inclusion criteria: PCOS was defined in these girls by the presence of oligomenorrhoea (< 6 cycles/year) and serum testosterone >1 mcg/mL (The Rotterdam consensus workshop group, 2004).
Exclusion criteria: suprarenal dysfunction, hyperprolactinaemia, thyroid dysfunction, or recent intake of medications likely to affect hormonal profile was a reason for exclusion from the study.
Number of women randomised: 80

MET: 40

OCP: 40
Number of women analysed: 65

MET: 32

OCP: 33
Number of withdrawal and reasons:

MET: adverse events 4/ 10%
Non compliant 2 /5%
Not satisfied 1 / 2.5%
Loss F/U 1 / 2.5%
OCP: side effect 2 / 5%
Non compliant 1/ 2.5%
Weight gain 4 / 10%
Summary characteristics: PCOS, adolescent 15 to 20 years, all presented with hirsutism, acne and menstrual disorder
Age (years):

MET mean (+SD):
17.2 (2)

OCP mean (+SD):

16.9 (1.6)

Interventions

Treatment: MET 1700 mg/dayControl: OCP (Ethinyl Estradiol 30 mcg progestin 15 mg)Duration: 24 monthsCo‐intervention(s): none

Outcomes

Primary outcomes: Hirsutism score

Adverse events: severe (requiring stopping of medication) and minorSecondary outcomes:

Menstrual cyclicity, initiation of menses or significant shortening of cycles

Body weight (kg)

Serum total testosterone (nmol/L)

Fasting insulin (mIU/L)
Fasting glucose (mmol/L)

Subjective outcomes

(a) Clinical parameters

1. Hirsutism score

Objective outcomes

(a) Clinical parameters

1. Adverse events: severe (requiring stopping of medication) and minor

2. Menstrual cyclicity, initiation of menses or significant shortening of cycles
3. Body weight (kg)

(b) Hormonal parameters

1. Serum total testosterone (nmol/L)

(c) Metabolic parameters

1. Fasting insulin (mIU/L)
2. Fasting glucose (mmol/L)

Notes

Authors contacted about: results, because total testosterone and fasting insulin were in wrong unit. Power calculation: done, a priori, on glucose/insulin ratio outcome

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: “computer‐generated random‐number tables”

Allocation concealment (selection bias)

Unclear risk

Method of concealment not stated.
Insufficient information available to permit a judgement of ‘low risk’ or ‘high risk’.

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Quote: "The study was not blinded”.

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Quote: "The study was not blinded”.

Incomplete outcome data (attrition bias)
All outcomes

High risk

10% drop out for side effect in MET group/ 10% drop out for weight gain in OCP group, both different yet related to intervention. Quote “statistical analysis of data was done on an intention‐to‐treat basis” but method used not described.

Selective reporting (reporting bias)

High risk

Fasting glucose and Ferriman‐Gallwey score not reported in the results. Instead of Ferriman‐Gallwey score: subjective assessment of hirsutism.

Total testosterone and fasting insulin cannot be used because are expressed with wrong units.
Not all of the study's prespecified primary outcomes have been reported.

Other bias

Low risk

The study appears to be free of other sources of bias.

Study characteristics

Methods

Randomised controlled trial

Location of the trial: quote: Istanbul, Turkey

Method of randomisation: quote: "Randomization was produced from a computer‐generated random list, where even and odd numbers were allocated OCP and OCP+metformin treatments respectively."

Method of allocation concealment: not stated

Source of fundings: not stated

Participants

Inclusion criteria: PCOS defined as the presence of (i) bilateral polycystic ovaries on ultrasound examination (multiple >10, small 2 mm to 8 mm diameter in 1 plane in the periphery and increased stromal echogenicity); (ii) chronic oligomenorrhoea (< 6 menstrual periods in the previous year) or amenorrhoea; and (iii) manifestations of hyperandrogenism and/or hyperandrogaenemia, such as a hirsutism score of > 8 Ferriman‐Gallwey); acne; elevated serum testosterone and/or androstenedione and/or free testosterone levels.
All women were either of normal weight or thin (BMI = 26 kg/m²).
Exclusion criteria: not euthyroid, hyperprolactinaemia, serum testosterone = 7 n mol/L, serum DHEAS = 19 µmol/L, late‐onset congenital adrenal hyperplasia, Cushing syndrome, adnexal mass seen during pelvic sonography, diabetes, any other known endocrinological disease, those taking drugs known to affect carbohydrate or lipid metabolism and OGTT results during the 6 months preceding the study
Number of women randomised: 40:

MET + OCP arm: 20

OCP arm: 20
Number of women analysed: 40:

MET+ OCP arm: 20

OCP arm: 20

Number of withdrawal and reasons: 0
Summary characteristics: PCOS, normal or thin women.
Age (years):

MET+OCP Mean (± SD):

24.9 (6.62)

OCP Mean (± SD)

23.45 (6.07)
BMI (kg/m²):

MET+OCP Mean (± SD):

22.74(2.66)

OCP Mean (± SD):

21.83(1.4)

Interventions

Treatment(s): MET 500 mg three times a day (for the first 15 days, MET 500 mg twice a day for adequate compliance) + OCP (Ethinyl estradiol 35 mcg Cyproterone acetate 2 mg) once daily (21 days per month followed by 7 days pill‐free period)

Control: OCP (Ethinyl estradiol 35 mcg Cyproterone acetate 2 mg) once daily (21 days per month followed by 7 days pill‐free period)

Duration: 4 months

Co‐interventions: None

Outcomes

Primary outcomes:

Hirsutism score

Adverse events: severe (requiring stopping of medication) and minor

Secondary outcomes:

BM (kg/m²)

Serum total testosterone (nmol/L)

Fasting insulin (pmol/L)
Fasting glucose (mmol/L)
Total Cholesterol (mmol/L)
HDL Cholesterol (mmol/L)
LDL Cholesterol (mmol/L)
Triglycerides (mmol/L)

Subjective outcomes

(a) Clinical parameters
1. Hirsutism score (Ferriman‐Gallwey)

Objective outcomes

(a) Clinical parameters

1. Adverse events: severe (requiring stopping of medication) and minor
2. (BMI (kg/m²)

(b) Hormonal parameters
1. Serum total testosterone (n mol/L)

(c) Metabolic parameters
1. Fasting insulin (pmol/L)
2. Fasting glucose (mmol/L)
3. Total Cholesterol (mmol/L)
4. HDL Cholesterol (mmol/L)
5. LDL Cholesterol (mmol/L)
6. Triglycerides (mmol/L)

Notes

Power calculation: done, a priori, on BMI (secondary outcome)

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Randomization was produced from a computer‐generated random list where even and odd numbers were allocated OCP and OCP + metformin treatments respectively"

Allocation concealment (selection bias)

Unclear risk

Method of allocation concealment not stated.

Insufficient information to permit judgement of ‘low risk’ or ‘high risk’.

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Quote: "No attempt was made to mask the treatments from the subjects, and placebo was not used."

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "Clinical parameters of the subjects were evaluated by the same person, who was blind to the type of treatment"

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No missing outcome data.

Selective reporting (reporting bias)

Low risk

From results section of paper, all of the studies pre‐specified (primary and secondary) outcomes that are of interest in the review have been reported in the pre‐specified way.

Other bias

Low risk

The study appears to be free of other sources of bias.

Study characteristics

Methods

Randomised controlled trial

Location of the trial: quote: Virginia, USA

Method of randomisation: quote: "The VCU Investigational Pharmacy prepared metformin and matched placebo capsules, randomized the women with a computerized random number generator using a 1:1 allocation ratio with blocks of random size (three and four women in a block) and concealed the allocation."

Method of allocation concealment: not stated

Source of fundings: quote:"NIH grant and clinical research centre grant"

Participants

Inclusion criteria: PCOS described by the modified Rotterdam criteria, after excluding other endocrine disorders, as 1) the presence of clinical and/or biochemical signs of hyperandrogenism, and 2) at least one of the following: oligo‐ ovulation or anovulation or polycystic ovaries. All participants in the study had hyperandrogenaemia.
Exclusion criteria: women were excluded from the study if they were pregnant; had diabetes or history of thromboembolism; had used tobacco within the previous 6 months; or had used OCs, diabetes/hyperlipidaemia medications, or antiandrogens within the previous 3 months.
Number of women randomised: 23:

OCP + MET arm: 11
OCP + PBO arm: 12

Number of women analysed: 19:
OCP + MET: 9
OCP + PBO: 10
Number of withdrawal and reasons:

OCP + MET: 2: Loss of F/U 1/ 9%

Moving away: 1/ 9%

OCP + PBO: 2: Loss of F/U 1/ 8.3%
Menorrhagia: 1/ 8.3%

Summary characteristics: PCOS, all participants of the study had hyperandrogenaemia
BMI (kg/m²):

OCP + PBO mean (+SD):
32.6 (2.3)

OCP + MET mean (+SD):
36.2 (2.5)

Interventions

Treatment: OCP (Ethinyl estradiol 35 norgestimate 0.18/0.215/0.25) + MET 500 mg/day/1 week then twice a day/1 week then three times a day

Control: OCP (Ethinyl estradiol 35 norgestimate 0.18/0.215/0.25) + PBO

Duration: 3 months

Co‐intervention(s): none

Outcomes

Primary outcomes:

Adverse events: severe (requiring stopping of medication) and minor

Secondary outcomes:

Body weight (kg)

BMI (kg/m²)
Blood pressure (systolic) (mm Hg)

Blood pressure (diastolic) (mm Hg)

Serum total testosterone (nmol/L)

Fasting insulin (mIU/L)
Fasting glucose (mmol/L)
Fasting total cholesterol (mmol/L)
Fasting HDL cholesterol (mmol/L)
Fasting LDL cholesterol (mmol/L)
Fasting triglycerides (mmol/L)

Subjective outcomes

None

Objective outcomes

(a) Clinical parameters:

1. Adverse events: severe (requiring stopping of medication) and minor

2. Body weight (kg) and BMI (kg/m²)
3. Blood pressure (systolic, diastolic) (mm Hg)

(b) Hormonal parameters:

1. Serum total testosterone (nmol/L)

(c) Metabolic parameters:

1. Fasting insulin (mIU/L)
2. Fasting glucose (mmol/L)
3. Fasting total cholesterol (mmol/L)
4. Fasting HDL cholesterol (mmol/L)
5. Fasting LDL cholesterol (mmol/L)
6. Fasting triglycerides (mmol/L)

Notes

Power calculation: done, a priori, on insulin sensitivity

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "The VCU Investigational Pharmacy prepared metformin and matched placebo capsules, randomized the women with a computerized random number generator using a 1:1 allocation ratio with blocks of random size (three and four women in a block), and concealed the allocation."

Allocation concealment (selection bias)

Unclear risk

Quote: "The VCU Investigational Pharmacy prepared metformin and matched placebo capsules, randomized the women with a computerized random number generator using a 1:1 allocation ratio with blocks of random size (three and four women in a block), and concealed the allocation".

Method of allocation concealment not stated. Insufficient information available to permit a judgement of "low risk" or "high risk"

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Quote: “single‐center, randomized, double‐blind, placebo‐ controlled trial” but did not state who was double blinded "matched placebo capsule"
Insufficient information available to permit a judgement of “low risk” or “high risk”.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Quote: “single‐center, randomized, double‐blind, placebo‐ controlled trial” but did not state who was double blinded "matched placebo capsule"
Insufficient information available to permit a judgement of “low risk” or “high risk”.

Incomplete outcome data (attrition bias)
All outcomes

High risk

One withdrawal/ 12: 8% in OCP+ PBO is menorrhagia which is a serious adverse event which can have clinical impact.

Selective reporting (reporting bias)

High risk

Except for fasting insulin and fasting glucose all the other outcomes are not described in the methods and given in an “annexe”.
One or more primary outcomes have been reported using measurements, analysis, methods or subset of the data THAT WERE NOT PRE‐SPECIFIED

Other bias

Low risk

The study appears to be free of other sources of bias.

Study characteristics

Methods

Randomised controlled trial

Location of the trial: quote: Zhengzhou, China

Method of randomisation: quote: "The study participators were randomly divided into two groups using a table of random numbers."

Method of allocation concealment: quote: "Preparation of the medication was performed in a centralized manner, and labeling, with the exception of the relevant randomization code, was identical in all presentations."

Source of fundings: not stated

Participants

Inclusion criteria: PCOS: Rotterdam criteria: (1) oligo/anovulation, (2) signs of hyperandrogenism (i.e. hirsutism and acne) or (3) enhanced ovaries (at least 12 discrete follicles of 2 mm to 9 mm in diameter in one ovary or the ovarian volume > 10 cm3 observed by transvaginal ultrasonography)Exclusion criteria: women with androgen‐excess disorders or patients with specific aetiologies such as congenital adrenal hyperplasia, Cushing’s syndrome, thyroid hormone abnormalities, hyperprolactinaemia, or ovarian/adrenal tumours. Furthermore, all patients had no history of previous first‐trimester miscarriage or pregnancy. The patients with more than one outlier baseline parameter data using the Grubbs test were also excluded in the following clinical trial study.Number of women randomised: 82:

OCP + MET arm: 41
OCP arm: 41Number of women analysed: not statedNumber of withdrawal and reasons: not statedSummary characteristics: PCOS, mean age for the whole cohort: 29.0 yearsAge (years):

OCP + MET mean (+ SD):
27.86 (3.79)

OCP mean(+ SD):
28.57 (3.04)BMI (kg/m²):

OCP + MET mean (+ SD)

29.46 (4.43)

OCP mean(+ SD)

27.77 (4.23)

Interventions

Treatment: OCP (Ethinyl Estradiol 35 mcg Cyproterone acetate 2 mg) cyclically 21 days stop 7 days + MET 425 mg twice a day then 850 mg twice a day

Control: OCP (Ethinyl Estradiol 35 mcg Cyproterone acetate 2 mg) cyclically 21 days stop 7 days

Duration: 3 months

Co‐intervention(s): none

Outcomes

Primary outcomes:

Hirsutism score

Secondary outcomes:

Acne score

BMI (kg/m²)
Blood pressure (systolic) (mm Hg)

Blood pressure (diastolic) (mm Hg)

Serum total testosterone (nmol/L)

Fasting insulin (mIU/L)
Fasting glucose (mmol/L)
Fasting total cholesterol (mmol/L)
Fasting HDL cholesterol (mmol/L)
Fasting LDL cholesterol (mmol/L)
Fasting triglycerides (mmol/L)

Subjective outcomes

(a) Clinical parameters

1.Hirsutism score
2.Acne score

Objective outcomes

(a) Clinical parameters

1. BMI (kg/m²)
2. Blood pressure (systolic) (mm Hg)

3. Blood pressure (diastolic) (mm Hg)

(b) Hormonal parameters

1.Serum total testosterone (nmol/L)

(c) Metabolic parameters

1. Fasting insulin (mIU/L)
2. Fasting glucose (mmol/L)
3. Fasting total cholesterol (mmol/L)
4. Fasting HDL cholesterol (mmol/L)
5. Fasting LDL cholesterol (mmol/L)
6. Fasting triglycerides (mmol/L)

Notes

Authors contacted about the number of patient randomised in each group and number of withdrawal

Power calculation: unclear

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: “The study participators were randomly divided into two groups using a table of random numbers”

Allocation concealment (selection bias)

Low risk

Quote: “Preparation of the medication was performed in a centralized manner, and labelling, with the exception of the relevant randomization code, was identical in all presentations”

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Quote: "This study was carried out in double‐blind conditions, so neither the patient nor the doctor was aware of the composition of the treatment administered.” The “doctor” could be the clinician or outcome assessor.
Insufficient information available to permit a judgement of “low risk” or “high risk”.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Quote: “This study was carried out in double‐blind conditions, so neither the patient nor the doctor was aware of the composition of the treatment administered.” The “doctor” could be the clinician or outcome assessor.

Insufficient information available to permit a judgement of “low risk” or “high risk”.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Paper does not provide any information on participant after randomisation.

Selective reporting (reporting bias)

Unclear risk

Body weight prespecified in the methods not reported in the results.

But not a primary or key outcomes.

Insufficient information available to permit a judgment of 'low risk' or 'high risk'.

Other bias

Low risk

The study appears to be free of other sources of bias.

Study characteristics

Methods

Randomised controlled trial
Location of the trial: quote: Odense, DenmarkMethod of randomisation: not statedMethod of allocation concealment: not statedSource of funding: quote: "This work was supported by the Jacob Madsen’s and Olga Madsen’s Foundation, the Institute of Clinical Research, the Odense University Hospital, Kolding Hospital, the A. P. Møller’s Foundation, the Bernhard and Marie Kleins Foundation, The Novo Nordisk Foundation, and The Danish Medical Association. Oral contraceptive pills and metformin tablets were sponsored by Sandoz."

Participants

Inclusion criteria: aged 18 to 39 years fulfilling the Rotterdam criteria for PCOS were included in the study. The included patients fulfilled two of the criteria:
1) irregular periods during more than a year in combination with a cycle length longer than 35 days;
2) total‐ or free‐T levels above the reference interval (upper limits: total T >1.8 nmol/L, free T >0.035 nmol/L) and/or hirsutism; and
3) transvaginal ultrasound with polycystic ovaries.
Exclusion criteria:
Serious endocrine diseases were excluded. Patients with diabetes (fasting plasma glucose ≥ 7.0 mmol/L and/or HbA1c ≥ 44 mmol/mol), elevated liver enzymes, renal dysfunction, congestive heart disease, depression, and eating disorders were not included in the study. Obese patients (BMI) ≥ 35 kg/m²) and patients with other contraindications for OCP(previous or family history of thrombosis or breast cancer, coagulatory defects, and heavy smokers) were not included in the study. Patients were not included if they were pregnant or expressed a wish for conception during the study period. Patients paused OCP for at least 3 months and metformin for at least 1 month before evaluation, and no patients were treated with medicine known to affect hormonal or metabolic parameters.
Number of women randomised: 90

MET + OCP: 30

MET: 30

OCP: 30
Number of women analysed: 65

MET + OCP: 23

MET: 19

OCP: 23
Number of withdrawal and reasons:

MET + OCP: 7
Nausea: 3/ 10%
Regrets: 2/ 6.7%
Lost F/U: 2/ 6.7%
MET:11
pregnant: 1/ 3.3%
wants OCP: 2/ 6.7%
depression: 1/ 3.3%
nausea: 1/3.3%
regrets: 4/ 13.3%
lost F/U: 2/ 6.7%

OCP: 7
wants pregnancy: 2/ 6.7%
adverse events: 3/ 10%
lost F/U: 2/ 6.7%
Summary characteristics: PCOS, aged 18 to 39 years
Age (years):

MET + OCP mean (+SD): 28 (4.9)

MET mean (+SD): 28 (4.8)
OCP mean (+)SD: 28 (4.7)
BMI (kg/m²):

MET + OCP mean (+SD): 27.6 (3.9)

MET mean (+SD): 25.9 (4.4)
OCP mean (+SD): 27.2 (4.8)

Interventions

MET 1000 mg twice a day + OCP (Ethinyl estradiol 30 mcg desogestrel 150 mg) Metformin 1000 mg twice a day

OCP (Ethinyl estradiol 30 mcg desogestrel 150 mg)

Duration: 12 monthsCo‐intervention(s): general advice on lifestyle intervention, laser treatment was offered to patient with moderate or severe facial hirsutism and patients were allowed to shave/wax

Outcomes

Primary outcomes:
Hirsutism score

Adverse events: severe (requiring stopping of medication) and minor
Secondary outcomes:

Body weight (kg)

BMI (kg/m²)

Blood pressure (systolic) (mm Hg)

Blood pressure (systolic) (mm Hg)

Serum total testosterone (nmol/L)

Fasting insulin (mIU/L)

Subjective outcomes

(a) Clinical parameters

1. Hirsutism score

Objective outcomes

(a) Clinical parameters

1. Adverse events: severe (requiring stopping of medication) and minor

2. Body weight (kg)

3. BMI (kg/m²)

4. Blood pressure (systolic) (mm Hg)

5. Blood pressure (diastolic) (mm Hg)

(b) Hormonal parameters

1. Serum total testosterone (nmol/L)

2. FAI

(c) Metabolic parameters

1. Fasting insulin (mIU/L)

2. Fasting glucose (mmol/L)
3. Fasting total cholesterol (mmol/L)
4. Fasting HDL cholesterol (mmol/L)
5. Fasting LDL cholesterol (mmol/L)
6. Fasting triglycerides (mmol/L)

Notes

Authors contacted about: their results because they were expressed in median (25th and 75th quartiles) therefore not applicable, they kindly gave us theirs results presented in the study and a few more outcomes: blood pressure, FAI, fasting glucose, fasting total cholesterol (mmol/L), fasting HDL cholesterol (mmol/L), fasting LDL cholesterol (mmol/L), fasting triglycerides (mmol/L). We could finally calculate the mean + SD.
Power calculation: no

3 arms study MET versus OCP versus OCP + MET

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: “Included patients were randomized to 12 months of treatment with metformin (10001000 mg/d) or OCP (150 mg desogestrel/ 30 mcg ehinylestradiol) or combined treatment (metformin OCP)”. Method of randomisation not stated.
Insufficient information available to permit a judgement of ‘low risk’ or ‘high risk’.

Allocation concealment (selection bias)

Unclear risk

Method of allocation concealment not stated.

Insufficient information available to permit a judgement of ‘low risk’ or ‘high risk’.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Insufficient information available to permit a judgement of ‘low risk’ or ‘high risk’.

Blinding not stated.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Insufficient information available to permit a judgement of ‘low risk’ or ‘high risk’.

Blinding not stated.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Reason for missing outcome data "regrets, lost F/U, wants OCP" are unclear and could be related to intervention. insufficient reporting of attrition/exclusions to permit a judgement of 'low risk' or 'high risk'.

Selective reporting (reporting bias)

Unclear risk

Total cholesterol, HDL and triglycerides described in the method not stated in the results part. Improvment of menstrual cycles described for MET group not for OCP group.

But not a primary or key outcomes.

Insufficient information available to permit a judgment of 'low risk' or 'high risk'.

Other bias

High risk

The use of laser treatment, shaving or waxing to treat hirsutism is an important confounding factor to evaluate Ferriman‐Gallwey score.

Study characteristics

Methods

Randomised controlled trial
Location of the trial: quote: Glasgow, Scotland, UK

Method of randomisation: quote "Block‐randomized (n = 10/block) in a 1:1 ratio to receive either OCP or metformin. Randomization was by random number tables, the patient number treatment codes were held by a third party."

Method of allocation concealment:quote "The patient number treatment codes were held by a third party and were allocated individually after obtaining written consent"

Source of fundings: not stated

Participants

Inclusion criteria: women with PCOS, whose primary complaint was hirsutism (Ferriman‐Gallwey score > 8). PCOS: at least two of the three following features: oligomenorrhoea/ amenorrhoea, polycystic ovaries on ultrasound, or an elevated FAI.
Exclusion criteria: Contraindications to either metformin or Dianette (including BMI > 38), use of oral contraception or metformin within the previous 3 months, and those taking medication known to affect gonadal or adrenal function, or carbohydrate or lipid metabolism. Thyroid dysfunction, hyperprolactinaemia, diabetes mellitus, or late‐on‐set congenital adrenal hyperplasia
Number of women randomised: 52:

MET arm: 26

OCP arm: 26
Number of women analysed: 34:

MET: 18

OCP: 16
Number of withdrawal and reasons: 18

MET: 8: Pregnant 3/ 11.5%

GI 3/ 11.5%

Lost of F/U 2/ 7.7%

OCP: 10: Weight gain 5/ 19%

BP 1/ 3.8%

Depression 1/ 3.8%

Chest pain 1/ 3.8%

Loss of F/U 2/ 7.7%
Summary characteristics: PCOS, hirsute women
Age (years):
MET mean (95% CL):

31.3 (27.9‐34.7)

OCP mean (95% CL):

31.7 (26.8‐36.5)

BMI (kg/m²):

MET mean (95% CL):

31.7 (29.5‐35.5)

OCP mean (95% CL)

31.8 (28.4‐34.4)

Interventions

Treatment(s): MET 500 mg three times a day

Control: OCP (Ethinyl estradiol 35 mcg Cyproterone acetate 2mg) once daily (21 days per month followed by 7 days pill‐free period)

Duration: 12 months

Co‐intervention: none

Outcomes

Primary outcomes:

Hirsutism score (Ferriman‐Gallwey)

Hirsutism ‐ subjective (VAS)

Adverse events: severe (requiring stopping of medication) and minor

Secondary outcomes:

Acne ‐ subjective (VAS)

BMI (kg/m²)
Blood pressure (systolic) (mm Hg)

Blood pressure (diastolic) (mm Hg)
Serum total testosterone (nmol/L)
Free androgen index (FAI) (%)
Fasting insulin (pmol/L)
Fasting glucose (mmol/L)
Total Cholesterol (mmol/L)
HDL Cholesterol (mmol/L)
LDL Cholesterol (mmol/L)
Triglycerides (mmol/L)

Subjective outcomes

(a) Clinical parameters
1. Hirsutism ‐ subjective (VAS)

2. Hirsutism score (Ferriman‐Gallwey)
3. Acne ‐ subjective (VAS)

Objective outcomes

(a) Clinical parameters

1. Adverse events: severe (requiring stopping of medication) and minor

2. BMI (kg/m²)
3. Blood pressure (systolic) (mm Hg)

4. Blood pressure (diastolic) (mm Hg)

(b) Hormonal parameters
1. Serum total testosterone (n mol/L)
2. Free androgen index (FAI) (%)

(c) Metabolic parameters
1. Fasting insulin (pmol/L)
2. Fasting glucose (mmol/L)
3. Total Cholesterol (mmol/L)
4. HDL Cholesterol (mmol/L)
5. LDL Cholesterol (mmol/L)
6. Triglycerides (mmol/L)

Notes

Authors contacted about: BMI result and co intervention kindly provided by the authors that was not in the original paper.

Power calculation: unclear

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Patients were block‐randomized (n=10/block) in a 1:1 ratio. Randomization was by random number tables"

Allocation concealment (selection bias)

Low risk

Quote: "The patient number treatment codes were held by a third party and were allocated individually after obtaining written consent."

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Insufficient information available to permit a judgement of ‘low risk’ or ‘high risk’.

Blinding not stated.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Insufficient information available to permit a judgement of ‘low risk’ or ‘high risk’.

Blinding not stated.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

"Loss to F/U" reason is unclear and could be related to intervention. Insufficient reporting of attrition/exclusions to permit a judgement of 'low risk' or 'high risk'.

Selective reporting (reporting bias)

Low risk

From results section of paper, all of the studies pre‐specified (primary and secondary) outcomes that are of interest in the review have been reported in the pre‐specified way.

Other bias

Low risk

The study appears to be free of other sources of bias.

Study characteristics

Methods

Randomised controlled trial
Location of the trial: quote: New York, USA
Method of randomisation: quote:"‘Subjects were randomized to one of four arms by random number assignment: placebo, metformin, OC, or lifestyle management"
Method of allocation concealment: not stated
Source of funding: this work was supported by Grants K23 HD043881‐01A1 and 5R03 HD41989‐02 from the National Institutes of Health (NIH), and Grant UL1RR024160 from the National Center for Research Resources
(NCRR), a component of the NIH and NIH Roadmap for Medical Research.
Desogen was supplied by Organon Pharmaceuticals, Inc.

Participants

Inclusion criteria: from methods section of paper and Clinical Trial Registry
Postmenarchal adolescent women between the ages of 12 and 18 years withBMI above the 95th percentile (or BMI > 25 kg/m²) and evidence of menstrual irregularity (fewer than eight menses in the preceding year or cycle length > 45 days) and clinical or biochemical evidence of hyperandrogenism (testosterone > 50 ng/dL), currently healthy, studied off any hormonal therapy or insulin sensitisers for at least 2 months, non‐smokers.
PCOS: Consistent with NIH.
Exclusion criteria: from methods section of paper and Clinical Trial Registry
Exclusion of other causes of hyperandrogenism and menstrual irregularity
Exclusion of diabetes mellitus, Cushing’s disease, hyperprolactinaemia, untreated hypo or hyperthyroidism, history of adrenal hyperplasia, significant renal impairment, received oral contraceptives, oestrogen or progestin or other drugs known to effect lipoprotein metabolism within 2 months of starting study, exercise > 10 hours/week.
Number of women randomised: 21

MET: 10

OCP: 11
Number of women analysed: 16

MET: 6

OCP: 10
Number of withdrawal and reasons:

MET: 4 lost to follow‐up: 2/ 20%

personal reasons: 2/ 20%
OCP: 1 lost to follow‐up: 1/ 9%
Summary characteristics: PCOS, young (12 to 18years), obese
Age (years):

MET mean (±SD): 16 (1.7)

OCP mean (±SD): 15.4 (1.4)
BMI (kg/m²):

MET mean (± SD): 34.3 (6.5)

OCP mean (± SD): 37.8 (6.1)

Interventions

Treatment: MET 850 mg twice a day, starting as single doses of 425 mg and building gradually to two capsules twice a day.
Control: OCP (Ethinyl estradiol 30 mcg desogestrel 0.15 mg ) taken in a cyclic fashion.
Duration: 6 months
Co‐intervention(s): "Subjects who were not assigned to lifestyle treatment received standard office advice on nutrition and exercise for healthy living and were seen monthly."

Outcomes

Primary outcomes:

Hirsutism score
Secondary outcomes:

Menstrual cyclicity, initiation of menses or significant shortening of cycles
BMI (kg/m²)
Blood pressure (systolic, diastolic) (mm Hg)

Serum total testosterone (ng/dL)
Free androgen index (FAI) (%)

Fasting insulin (IU/mL)
Fasting glucose (mmol/L)
Fasting total cholesterol (mmol/L)
Fasting HDL cholesterol (mmol/L)
Fasting LDL cholesterol (mmol/L)
Fasting triglycerides (mmol/L)

Subjective outcomes

(a) Clinical parameters

1. Hirsutism score

Objective outcomes

(a) Clinical parameters

1. Menstrual cyclicity, initiation of menses or significant shortening of cycles
2. BMI (kg/m²)
3. Blood pressure (systolic, diastolic) (mm Hg)

(b) Hormonal parameters

1. Serum total testosterone (ng/dL)
2. Free androgen index (FAI) (%)

(c) Metabolic parameters

1. Fasting insulin (IU/mL)
2. Fasting glucose (mmol/L)
3. Fasting total cholesterol (mmol/L)
4. Fasting HDL cholesterol (mmol/L)
5. Fasting LDL cholesterol (mmol/L)
6. Fasting triglycerides (mmol/L)

Notes

Authors contacted about: fasting insulin because expressed in wrong unit.

Power calculation: unclear

4 arms treatment: PBO V MET versus OCP versus LS

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Subjects were randomized to one of four arms by random number assignment: placebo, metformin, OC, or lifestyle management"

Allocation concealment (selection bias)

Unclear risk

Method of allocation concealment not stated.

Insufficient information to permit judgement of ‘low risk’ or ‘high risk’

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "Assignment to metformin or placebo was blinded to subject and investigator." "outcome assessors and data analysts were unaware of study assignment"

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "Assignment to metformin or placebo was blinded to subject and investigator." "outcome assessors and data analysts were unaware of study assignment"

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Quote: "Lost F/U, personal reason" are both unclear reason of withdrawal and could be related to intervention. Insufficient reporting attrition/exclusions to permit a judgement of 'low risk' or 'high risk'.

Selective reporting (reporting bias)

Unclear risk

From results section of paper and clinical trial registry, all of the studies pre‐specified (primary and secondary) outcomes that are of interest in the review have been reported in the pre‐specified way with the exception of weight which was only reported as part of BMI and menstrual rate which was not reported for OCP.

But not a primary or key outcomes.

Insufficient information available to permit a judgment of 'low risk' or 'high risk'.

Other bias

Low risk

The study appears to be free of other sources of bias.

Study characteristics

Methods

Randomised controlled trial
Location of the trial: quote: New York, USA
Method of randomisation: quote: "Subjects were assigned by a random number table."
Method of allocation concealment: not stated
Source of funding: this work was supported by Grants K23 HD043881‐01A1 and 5R03 HD41989‐02 from the National Institutes of Health (NIH), and Grant UL1RR024160 from the National Center for Research Resources
(NCRR), a component of the NIH and NIH Roadmap for Medical Research.
Desogen was supplied by Organon Pharmaceuticals, Inc..

Participants

Inclusion criteria: Postmenarchal adolescent women between the ages of 12 and 18 yr with BMI above the 95th percentile and evidence of menstrual irregularity (fewer than eight menses in the preceding year) and clinical or biochemical evidence of hyperandrogenism, currently healthy, studied off any hormonal therapy or insulin sensitisers for at least 2 months, non‐smokers, must be able to swallow capsules, at least 6 months since onset of first menstrual cycle.
PCOS diagnosis consistent with NIH.
Exclusion criteria: exclusion of other causes of hyperandrogenism and menstrual irregularity; diabetes; kidney or lLiver disease; tobacco use; depression or bipolar disease; contraindication to exercise; weight > 300 lbs
Number of women randomised: 36

MET + OCP: 18

OCP: 18
Number of women analysed: 32

MET + OCP: 16

OCP: 16
Number of withdrawal and reasons:

MET + OCP: 2, GI symptoms: 1/ 5.6%

not stated: 1/ 5.6%
OCP: 2, GI symptoms: 1/ 5.6%

not stated: 1/ 5.6%
Summary characteristics: PCOS, young (12 to 18years), obese
Age (years):

MET + OCP mean(± SD): 14.7 (1.6)

OCP mean(± SD): 15.8 (1.6)
BMI (kg/m²):

MET + OCP OCP mean (± SD): 34.1 (4.3)

OCP mean (± SD): 35.7 (4.9)

Interventions

Treatment: MET 2000 mg/day (divided into four doses with a gradual build up at study start) + OCP (Ethinyl estradiol 30 mcg drosporenone 3 mg)
Control: OCP (Ethinyl estradiol 30 mcg drospirenone 3 mg) + PBO
Duration: 6 months
Co‐intervention(s): co‐intervention with lifestyle (24‐week program with adult family member in classes for training for diet, exercise and behaviour modification skills in open group format with rolling admission). Frequent contact with participants and a combination of structured lectures and flexible personal strategies emphasised self‐esteem and social support. The format included a core curriculum taught in separate adolescent and parent groups repeated over the 24 weeks, interspersed with individual appointments. Exercise was monitored in a group setting on a weekly basis. Contact between participants was encouraged outside the weekly setting with electronic communications such as Internet chat groups to support continued lifestyle changes. Structured group exercise was included weekly. Goals of therapy were based on initial caloric intake by diet record aiming for a 500 kcal/day deficit. Exercise was recommended to include 30 minutes/day of moderate to intense activity.

Outcomes

Primary outcomes:

Hirsutism score

Adverse events: severe (requiring stopping of medication) and minor
Secondary outcomes:

Menstrual cyclicity, initiation of menses or significant shortening of cycles
Body weight (kg)

BMI (kg/m²)
Blood pressure (systolic) (mm Hg)

Blood pressure (diastolic) (mm Hg)

Serum total testosterone (nmol/L)
Free androgen index (FAI) (%)

Fasting insulin (IU/mL)
Fasting glucose (mmol/L)
Fasting total cholesterol (mmol/L)
Fasting HDL cholesterol (mmol/L)
Fasting LDL cholesterol (mmol/L)
Fasting triglycerides (mmol/L)

Subjective outcomes

(a) Clinical parameters

1. Hirsutism score

Objective outcomes

(a) Clinical parameters

1. Adverse events: severe (requiring stopping of medication) and minor

2. Menstrual cyclicity, initiation of menses or significant shortening of cycles
3. Body weight (kg) and/or BMI (kg/m²)
4. Blood pressure (systolic, diastolic) (mm Hg)

(b) Hormonal parameters

1. Serum total testosterone (nmol/L)
2. Free androgen index (FAI) (%)

(c) Metabolic parameters

1. Fasting insulin (IU/mL)
2. Fasting glucose (mmol/L)
3. Fasting total cholesterol (mmol/L)
4. Fasting HDL cholesterol (mmol/L)
5. Fasting LDL cholesterol (mmol/L)
6. Fasting triglycerides (mmol/L)

Notes

Authors contacted about: fasting insulin because expressed in wrong unit.

Power calculation: unclear

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Subjects were assigned by a random number table to metformin or placebo."

Allocation concealment (selection bias)

Unclear risk

Method of allocation concealment not stated.

Insufficient information to permit judgement of ‘low risk’ or ‘high risk’

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Quote: "Double Blind (Subject, Investigator)".

Unclear if investigator blinding refers to blinding for clinician reported outcomes. Potential for lack of clinician blinding to impact on results reporting and result in bias for clinician reported outcomes.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Quote: "Double Blind (Subject, Investigator)".

Unclear if investigator blinding refers to blinding for clinician reported outcomes. Potential for lack of clinician blinding to impact on results reporting and result in bias for clinician reported outcomes.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Reason for missing outcome data "not stated" in 2 cases could be related to intervention. Insufficient reporting of attrition/exclusion to permit a judgement of 'low risk' or 'high risk'.

Selective reporting (reporting bias)

Unclear risk

From results section of paper and clinical trial registry, all of the studies pre‐specified (primary and secondary) outcomes that are of interest in the review have been reported in the pre‐specified way with the exception of weight which was only reported as part of BMI, menstrual rate.

But not a primary or key outcomes.

Insufficient information available to permit a judgment of 'low risk' or 'high risk'.

Other bias

Low risk

The study appears to be free of other sources of bias.

Study characteristics

Methods

Randomised controlled trial
Location of the trial: quote: Beijing, China
Method of randomisation: quote: "Randomly divided into 4 groups"
Method of allocation concealment: not stated
Source of funding: Not stated

Participants

Inclusion criteria: women with PCOS according to Rotterdam criteria, normal liver and kidney function, no treatment provided 3 months prior to the study.
Exclusion criteria: congenital adrenal hyperplasia (CAH); Cushing's syndrome; hyperprolactinaemia; thyroid disease; hormone‐secreting tumours.
Number of women randomised: 24

MET: 15

OCP: 10
Number of women analysed: 24

MET: 15

OCP: 10
Number of withdrawal and reasons: 0
Summary characteristics: PCOS
Age (years):

MET mean (+SD): 23.3 (6.53)

OCP mean (+SD): 23 (6.11)

Interventions

Treatment: MET oral, 500 mg/time, three times a day
Control: OCP (Ethynil Estradiol 35 mcg/ Cyproterone acetate 25 mg) start on day 5 of menstrual cycle, continued for 21 days; one pill a day
Duration: 3 months
Co‐intervention(s): none

Outcomes

Primary outcomes:

Hirsutism (assessed clinically and subjectively)
Secondary outcomes:

Improved menstrual pattern (i.e. an initiation of menses or significant shortening of cycles or intermenstrual days)

Acne (assessed clinically and subjectively)

BMI (kg/m²)

Serum total testosterone (n mol/L)

Fasting insulin (mIU/L)

Subjective outcomes

(a) Clinical parameters

Hirsutism (assessed clinically and subjectively)

Acne (assessed clinically and subjectively)

Objective outcomes

(a) Clinical parameters

Improved menstrual pattern (i.e. an initiation of menses or significant shortening of cycles or intermenstrual days)

BMI (kg/m²)

(b) Hormonal parameters

Serum total testosterone (n mol/L)

(c) Metabolic parameters

Fasting insulin (mIU/L)

Notes

Power calculation: no

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: "Randomly divided into 4 groups"

Insufficient information about the sequence generation process available to permit a judgement of 'low risk' or 'high risk'

Allocation concealment (selection bias)

Unclear risk

Method of allocation concealment not stated.

Insufficient information available to permit a judgement of 'low risk' or 'high risk'

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Insufficient information available to permit a judgement of ‘low risk’ or ‘high risk’.

Blinding not stated.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Insufficient information available to permit a judgement of ‘low risk’ or ‘high risk’.

Blinding not stated.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No missing outcome data.

Selective reporting (reporting bias)

High risk

Hirsutism and acne described with score in the methods (Ferriman‐Gallwey score; acne score) but reported in the results as number of patients who had an improvement.

BMI not reported in the results.

One or more primary outcomes have been reported using measurements, analysis methods or subset of the data that were not prespecified.

Other bias

High risk

Baselin imbalance.

Study characteristics

Methods

Randomised controlled trial
Location of the trial: quote: Kayseri, TurkeyMethod of randomisation: quote: "The study population randomized into two different groups.”Method of allocation concealment: not statedSource of funding: Not stated

Participants

Inclusion criteria: PCOS was defined as the presence of two of the following criteria after the exclusion of other aetiologies: (i) polycystic ovaries on ultrasound examination, (ii) chronic oligomenorrhoea or amenorrhoea, (iii) clinical or biochemical evidence of hyperandrogenism
Exclusion criteria: exclusion criteria included diabetes mellitus, corticosteroid use, use of drugs affecting insulin resistance, hyperlipidaemia, hypertension, oral contraceptive use, evidence of ongoing infection, presence of severe valve disease, pregnancy, systemic disease (hepatic, renal, cardiac), smoking, aortic disease (coarctation, aneurism, Marfan syndrome or history of aortic surgery).
Number of women randomised: 50

MET + OCP: 25

OCP: 25
Number of women analysed: 50

MET + OCP: 25

OCP: 25

Number of withdrawal and reasons: 0
Summary characteristics: PCOS, aged 17‐37 years

Age (years):
MET + OCP mean (+SD): 24 (4)

OCP mean (+SD): 23 (5)

BMI (kg/m²):

MET + OCP mean (+SD): 29.8 (6.9)

OCP mean (+SD): 26.7 (5.7)

Interventions

Treatment: MET 850 mg twice a day + OCP (Ethinyl estradiol 3mcg drospirenone 3 mg) 21days then 7 days placebo
Control: OCP (Ethinyl estradiol 3 mcg drospirenone 3 mg) 21days then 7 days placebo
Duration: 6 months
Co‐intervention(s): none

Outcomes

Primary outcomes:

None
Secondary outcomes:

Body weight (kg)

BMI (kg/m²)
Blood pressure (systolic) (mm Hg)

Blood pressure (diastolic) (mm Hg)

Serum total testosterone (nmol/L)
Free androgen index (FAI) (%)

Fasting total cholesterol (mmol/L)
Fasting HDL cholesterol (mmol/L)
Fasting LDL cholesterol (mmol/L)
Fasting triglycerides (mmol/L)

Subjective outcomes

None

Objective outcomes

(a) Clinical parameters

1. Body weight (kg)

2. (BMI (kg/m²)
3. Blood pressure (systolic) (mm Hg)

4. Blood pressure (diastolic) (mm Hg)

(b) Hormonal parameters

1. Serum total testosterone (nmol/L)
2. Free androgen index (FAI) (%)

(c) Metabolic parameters

1. Fasting total cholesterol (mmol/L)
2. Fasting HDL cholesterol (mmol/L)
3. Fasting LDL cholesterol (mmol/L)
4. Fasting triglycerides (mmol/L)

Notes

Authors contacted about: testosterone because expressed in the wrong unit.
Power calculation: unclear

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: “Then, the study population randomized into two different groups.”
Method of randomisation not described.
Insufficient information about the sequence generation process available to permit a judgment of ‘low risk’ or ‘high risk’.

Allocation concealment (selection bias)

Unclear risk

Method of concealment not stated.
Insufficient information available to permit a judgement of ‘low risk’ or ‘high risk’.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Insufficient information available to permit a judgement of ‘low risk’ or ‘high risk’.

Blinding not stated.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Insufficient information available to permit a judgement of ‘low risk’ or ‘high risk’.

Blinding not stated.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No missing outcome data.

Selective reporting (reporting bias)

Unclear risk

Insufficient information available to permit a judgement of ‘low risk’ and ‘high risk’.
Protocole not available and measurements are not described in the methods.

Other bias

Low risk

The study appears to be free of other sources of bias.

Study characteristics

Methods

Randomised controlled trial
Location of the trial: quote: Izmir, TurkeyMethod of randomisation: unclear, quote: “Patients were randomly assigned to one of four treatment groups and each group contained 12 participants.”Method of allocation concealment: not statedSource of funding: none

Participants

Inclusion criteria: PCOS was diagnosed according to the criteria of the Rotterdam European Society of Human Reproduction and Embryology–American Society for Reproductive Medicine PCOS consensus workshop group. All patients fulfilled the PCOS criteria. All women had normal thyroid, renal and hepatic functions.
Exclusion criteria: None of them had late‐onset congenital adrenal hyperplasia.
Women who had any medication (e.g., antihypertensives, oral anti‐diabetics, oral contraceptives, antiandrogens, statins, warfarin, antidepressant medication, and GnRH agonists and antagonists) in the preceding 3 months were not included. Women who are current smokers and with hypertension, diabetes, history of coronary heart disease, known coagulation abnormalities were also excluded. Fasting glucose levels were normal in all patients (< 100 mg/dL). None of the participants had chronic alcohol consumption.
Number of women randomised: 36

OCP + MET: 12

OCP: 12

MET: 12Number of women analysed: 36

OCP + MET: 12

OCP: 12

MET: 12

Number of withdrawal and reasons: 0Summary characteristics: PCOS, 24.0 + 5.4 years; BMI 27.9 + 5.28 kg/m²
Age (years): MET+ OCP mean (+ SD): 24.9 (4.8)
MET mean (+ SD): 24.4 (6.2)
OCP mean (+ SD): 23.2 (5.1)BMI (kg/m²):

MET+ OCP mean (+ SD): 27.6 (3)
MET mean (+ SD): 27.8 (4)
OCP mean (+ SD): 28.7 (6)

Interventions

MET 850 mg twice a day + OCP (Ethinyl estradiol 35 mcg Cyproterone acetate 2 mg) 21days stop 7 days OCP (Ethinyl estradiol 35 mcg Cyproterone acetate 2 mg) 21days stop 7 days

MET 850 mg twice a day

Duration: 3 monthsCo‐intervention(s): the participants were instructed to limit fat intake and improve dietary behaviour without giving any calory restricted diet program.

Outcomes

Primary outcomes:

Adverse events: severe (requiring stopping of medication) and minorSecondary outcomes:

BMI (kg/m²)

Fasting insulin (mIU/L)
Fasting total cholesterol (mmol/L)
Fasting HDL cholesterol (mmol/L)
Fasting LDL cholesterol (mmol/L)
Fasting triglycerides (mmol/L)

Subjective outcomes

None

Objective outcomes

(a) Clinical parameters

1. Adverse events: severe (requiring stopping of medication) and minor

2. BMI (kg/m²)

(c) Metabolic parameters

1. Fasting insulin (mIU/L)
2. Fasting total cholesterol (mmol/L)
3. Fasting HDL cholesterol (mmol/L)
4. Fasting LDL cholesterol (mmol/L)
5. Fasting triglycerides (mmol/L)

Notes

Power calculation: yes, a priori, on fasting insulin

3 arms study MET versus OCPversusV OCP + MET

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: “Patients were randomly assigned to one of four treatment groups and each group contained 12 participants.”
Insufficient information about the sequence generation process available to permit a judgement of ‘low risk’ or ‘high risk’

Allocation concealment (selection bias)

Unclear risk

Method of concealment not stated.
Insufficient information available to permit a judgment of ‘low risk’ or ‘high risk’

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Insufficient information available to permit a judgement of ‘low risk’ or ‘high risk’.

Blinding not stated.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Insufficient information available to permit a judgement of ‘low risk’ or ‘high risk’.

Blinding not stated.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No missing outcome data.

Selective reporting (reporting bias)

Unclear risk

The study protocol is not available and clinical measurements are not described in the methods.

Other bias

Low risk

The study appears to be free of other sources of bias.

Study characteristics

Methods

Randomised controlled trial
Location of the trial: quote: Izmir, TurkeyMethod of randomisation: quote: "Patients were randomly assigned"Method of allocation concealment: not statedSource of funding: not stated

Participants

Inclusion criteria: PCOS consistent with Rotterdam criteria
PCOS according to the criteria of the Rotterdam European Society of Human Reproduction and Embryology– American Society for Reproductive Medicine 1) oligomenorrhoea or amenorrhoea, 2) clinical (hirsutism, acne) and/ or biochemical signs of hyperandrogenism, and 3) polycystic ovaries)
All women had normal thyroid, renal and hepatic functions. None of them had late‐onset congenital adrenal hyperplasia. All patients were normal (< 100 mg/dL) fasting glucose levels.Exclusion criteria: any medication (e.g., antihypertensives, oral antidiabetics, oral contraceptives, antiandrogens, statins, vitamins, warfarin, antidepressant medication, and GnRH agonists and antagonists) in the preceding 3 months.
Hypertension, diabetes, history of coronary heart disease, known coagulation abnormalities and current smokers and chronic alcohol users.Number of women randomised: 43

MET + OCP: 21

OCP: 22Number of women analysed: 43

MET + OCP: 21

OCP: 22Number of withdrawal and reasons: 0Summary characteristics: PCOS, mean age 24.6 (5) / mean BMI 27.9 (5.4) Age (years):

MET + OCP mean (±SD): 26.1 (4.4)

OCP mean (±SD): 24.1(5.6)

BMI (kg/m²):

MET + OCP mean (± SD): 28.7(4.4)

OCP mean (± SD): 27.2 (6.2)

Interventions

Treatment: MET 850 mg three times a day + OCP (Ethynil Estradiol 35 mcg Cyproterone acetate 2 mg) 21 days per month followed by a 7‐day pill‐free period Control: OCP (Ethynil estradiol 35 mcg Cyproterone acetate 2 mg) for 3 months 21 days per month followed by a 7‐day pill‐free periodDuration: 3 months.Co‐intervention(s): none

Outcomes

Primary outcomes:

Adverse events: severe (requiring stopping of medication) and minorSecondary outcomes:

BMI (kg/m²)

Fasting insulin (µIU/L)
Fasting glucose (mg/dL)
Fasting total cholesterol (mg/dL)
Fasting HDL cholesterol (mg/dL)
Fasting LDL cholesterol (mg/dL)
Fasting triglycerides (mg/dL)

Subjective outcomes

None

Objective outcomes

(a) Clinical parameters

1. Adverse events: severe (requiring stopping of medication) and minor

2. BMI (kg/m²)

(c) Metabolic parameters

1. Fasting insulin (µIU/L)
2. Fasting glucose (mg/dL)
3. Fasting total cholesterol (mg/dL)
4. Fasting HDL cholesterol (mg/dL)
5. Fasting LDL cholesterol (mg/dL)
6. Fasting triglycerides (mg/dL)

Notes

Power calculation: unclear

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: "Patients were randomly assigned".

Insufficient information about the sequence generation process available to permit a judgement of ‘low risk’ or ‘high risk’

Allocation concealment (selection bias)

Unclear risk

Method of allocation concealment not stated.

Insufficient information to permit judgement of ‘low risk’ or ‘high risk’

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Insufficient information available to permit a judgement of ‘low risk’ or ‘high risk’.

Blinding not stated.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Insufficient information available to permit a judgement of ‘low risk’ or ‘high risk’.

Blinding not stated.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Quote: "no subject were lost during the F/U and none of the 43 patients had stopped the therapies because of adverse effects"

No missing outcome data.

Selective reporting (reporting bias)

Unclear risk

From results section of paper, all of the studies pre‐specified (primary and secondary) outcomes that are of interest in the review have been reported in the pre‐specified way with the exception of glucose which was only reported as HOMA.

But not a primary or key outcomes.

Insufficient information available to permit a judgment of 'low risk' or 'high risk'.

Other bias

Low risk

The study appears to be free of other sources of bias.

Study characteristics

Methods

Randomised controlled trial
Location of the trial: quote: Ankara, Turkey
Method of randomisation: quote: "computer‐based randomized prospective analyses"
Method of allocation concealment: not stated
Source of funding: not stated

Participants

Inclusion criteria: PCOS according to the menstrual, laboratory, and ultrasonographic criteria of Rotterdam 2003. (Menstrual criteria included oligo‐ or amenorrhoea, irregular cycle length, > 45 days or less than six periods a year, ultrasound criteria used for diagnosis). Patients with normal androgen levels (the normal range values for serum‐free testosterone in our laboratory <3.17 ng/mL) with non obese and obese women with PCOS were selected.
Exclusion criteria: for all participants included age less than 18 years or greater than 35 years, smoking, folic acid and vitamin B12 deficiency, pregnancy, hypothyroidism, hyperprolactinaemia, Cushing’s syndrome, nonclassical congenital adrenal hyperplasia (17 OHP <5 ng/dl) and current or previous (within the last 6 months) use of oral contraceptives, glucocorticoids, antiandrogens, ovulation induction
agents, antidiabetic and anti‐obesity drugs, or other hormonal drugs. Women with clinical and/or biochemical hyperandrogenism alone were excluded from the study.
Number of women randomised: 105

MET: 54: 28 BMI ≥ 25 / 26 BMI < 25
OCP: 51: 26 BMI ≥ 25 / 25 BMI < 25

Number of women analysed: 96

MET: 47
OCP: 49
Number of withdrawal and reasons: MET:
Loss of F/U: 5 / 9.3%
Discontinu: 2 / 3.7%
OCP:
Discontinu: 2 / 3.9%
Summary characteristics: PCOS, normoandrogenaemic and oligoamenorrhoeic with impaired glucose tolerance
Age (years):

MET mean (+ SD):
BMI ≥ 25: Age (years): 28.7 (3.7)
BM I< 25: Age (years): 26.3 (3)

OCP mean (+ SD):
BMI ≥ 25: Age (years): 29 (3.5)
BMI < 25: Age (years): 26.7 (3.8)
BMI (kg/m²):

MET mean (+ SD):
BMI ≥ 25 BMI (kg/m²): 31.5 (2.1)
BMI < 25 BMI (kg/m²): 23,37 (1.64)

OCP mean (+ SD):
BMI ≥ 25 BMI (kg/m²): 27.7 (0.9)
BM I< 25 BMI (kg/m²): 21.63 (1.47)

Interventions

Treatment: MET 850 mg twice a day
Control: OCP (Ethinyl estradiol 30 mcg desogestrel 0.15 mg)
Duration: 6 months
Co‐intervention(s): B‐groups vitamins vitamin B1.250 mg; vitamin B6.250 mg; vitamin B12.1000 mg, twice daily

Outcomes

Primary outcomes:

Adverse events: severe (requiring stopping of medication) and minor
Secondary outcomes:

BMI (kg/m²)

Subjective outcomes

None

Objective outcomes

(a) Clinical parameters

1. Adverse events: severe (requiring stopping of medication) and minor
2. BMI (kg/m²)

Notes

Power calculation: unclear

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: “computer‐based randomized prospective analyses”.

Allocation concealment (selection bias)

Unclear risk

Method of allocation concealment not stated.
Insufficient information available to permit a judgement of ‘low risk’ or ‘high risk’.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Insufficient information available to permit a judgement of ‘low risk’ or ‘high risk’.

Blinding not stated.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Insufficient information available to permit a judgement of ‘low risk’ or ‘high risk’.

Blinding not stated.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

"Loss of F/U" or "discontinue treatment" unclear reason of withdrawal and could be related to intervention.
Insufficient report of attrition/ exclusions to permit a judgement of ‘low risk’ or ‘high risk’

Selective reporting (reporting bias)

Unclear risk

Testosterone is not reported in the results.

But not a primary or key outcomes.

Insufficient information available to permit a judgment of 'low risk' or 'high risk'.

Other bias

High risk

Baseline characteristic were not similar: BMI in metformin group higher than in OCP group in the subgroup BM I≥ 25kg/m²

MET mean (+ SD): 31.5 (2.1) / OCP mean (+SD): 27.7 (0.9)

Study characteristics

Methods

Randomised controlled trial
Location of the trial: quote: Shanghai, China
Method of randomisation: unclear quote: “randomly assigned”
Method of allocation concealment: not stated
Source of funding: not stated

Participants

Inclusion criteria: Rotterdam criteria of PCOS, the diagnostic and inclusion criteria are as follows. (1) irregular ovulation: oligomenorrhoea, amenorrhoea or irregular menstrual cycle. (2) obvious signs of hyperandrogen or increased androgen level or anomalies of circulation androgens. (3) polycystic ovary: ultrasound showed more than 12 follicles of 2 mm to 9 mm in diameter per side or 10 cm3 of ovarian volume in 3 to 5 days of menstruation. Patient with any 2 of the above‐mentioned signs or symptoms are then diagnosed with PCOS.
Exclusion criteria: (1) not meeting the above diagnostic criteria for PCOS. (2) other reasons causing hyperandrogenism: late‐onset congenital hyperplasia, Cushing’s syndrome, androgen secretion of ovarian or adrenal tumours. (3) hyperprolactinaemia or hypothalamic amenorrhoea. (4) thyroid dysfunction.
Number of women randomised: 28

MET: 17

OCP: 11
Number of women analysed: 28

MET: 17

OCP: 11
Number of withdrawal and reasons: 0
Summary characteristics: PCOS, aged from 15 to 40 years old
BMI (kg/m²):

MET mean (+ SD):

25.7 (2.96)

OCP mean (+ SD):

19.27 (10.46)

Interventions

Treatment: MET 500 mg twice a day
Control: OCP (Ethinyl Estradiol 35 Cyproterone acetate 2 mg)/day, 21days on the 5th day of menstruations
Duration: 3 months
Co‐intervention(s): quote: “patient in group A and B who faced amenorrhoea within 60d during treatment were given medroxyprogesterone acetate for a total of 5 days to induce menstruation”

Outcomes

Primary outcomes: none
Secondary outcomes:

Body weight (kg)

BMI (kg/m²)

Serum total testosterone (nmol/L)

Free androgen index (FAI) (%)

Fasting insulin (mIU/L)
Fasting glucose (mmol/L)

Subjective outcomes

None

Objective outcomes

(a) Clinical parameters

1. Body weight (kg)

2. BMI (kg/m²)

(b) Hormonal parameters

1. Serum total testosterone (nmol/L)

2. Free androgen index (FAI) (%)

(c) Metabolic parameters

1. Fasting insulin (mIU/L)
2. Fasting glucose (mmol/L)

Notes

Authors contacted about: the outcome fasting insulin because expressed in a wrong unit.
Power calculation: unclear

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: “randomly assigned”.
insufficient information available to permit a judgement of “low risk” or “high risk”.

Allocation concealment (selection bias)

Unclear risk

Method of allocation concealment not stated.
Insufficient information available to permit a judgement of “low risk” or “high risk”.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Insufficient information available to permit a judgement of ‘low risk’ or ‘high risk’.

Blinding not stated.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Insufficient information available to permit a judgement of ‘low risk’ or ‘high risk’.

Blinding not stated.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No missing outcome data.

Selective reporting (reporting bias)

Low risk

The study protocol is not available but it is clear that the published reports include all expected outcomes, including those that were pre‐specified.

Other bias

High risk

Number of patients randomised in each group is different 17 versus 11.
Baseline imbalance.

Study characteristics

Methods

Randomised controlled trial

Locationof the trial: quote: New Delhi, India

Method of randomisation: quote: "Computer‐generated random sequence numbering based on the intervention received"

Method of concealment: not stated

Source of fundings: none

Participants

Inclusion criteria: PCOS Rotterdam criteria for the diagnosis, aged between 18 and 40 years, symptom duration > 6 months, premenopausal, normal thyroid function.
Exclusion criteria: patients with a history of using any drug therapy (insulin sensitisers, hormone therapy, calcium, and Vitamin D), use of other drugs that affect the body composition and androgen levels (insulin, glucocorticoids)
pregnancy or lactation
Number of women randomised: 90

OCP + MET arm: 30

MET arm: 30

OCP arm: 30
Number of women analysed: 87

OCP + MET: 29

MET: 30

OCP: 28

Number of withdrawal and reasons: 3
OCP + MET: 1 reason NA

OCP: 2 reason NA

Summary characteristics: The study population had a mean age 23.2 ± 4.4 year and BMI of 28.4 ± 6.1 kg/m². The entire study population falls into the obese category and had significant hirsutism.
Age (years):

OCP + MET mean (+ SD):
24.1 (5.9)
MET mean (+ SD):
22 (5.2)

OCP mean (+ SD):
22.9 (5)

BMI (kg/m²):

OCP + MET mean (+ SD):
30.1 (5.5)

MET mean (+ SD):
27.14 (6)

OCP mean (+ SD):
26.15 (4.9)

Interventions

OCP (Ethinyl estradiol 35 mcg, Cyproterone acetate 2 mg) standard combination pill

MET 500 mg/day gradually increased to 2000 mg

MET 500 mg/day gradually increased to 2000 mg + OCP (Ethinyl estradiol 35 mcg, Cyproterone acetate 2 mg) standard combination pill

Duration: 6 months

Co‐intervention(s): all the patients were explained about healthy lifestyle measures and dietary advice to reduce weight

Outcomes

Primary outcomes:

Hirsutism score

Secondary outcomes:

Menstrual cyclicity, initiation of menses or significant shortening of cycles

Acne score
Body weight (kg) and/or BMI (kg/m²)

Serum total testosterone (nmol/L)

Fasting insulin (mIU/L)
Fasting glucose (mmol/L)
Fasting total cholesterol (mmol/L)
Fasting HDL cholesterol (mmol/L)
Fasting LDL cholesterol (mmol/L)
Fasting triglycerides (mmol/L)

Subjective outcomes

(a) clinical parameters

1.Hirsutism score
2.Acne score

Objective outcomes

(a) clinical parameters

1.Menstrual cyclicity, initiation of menses or significant shortening of cycles
2.Body weight (kg) and/or BMI (kg/m²)

(b) hormonal parameters

1.Serum total testosterone (nmol/L)

(c) metabolic parameters

1.Fasting insulin (mIU/L)
2.Fasting glucose (mmol/L)
3.Fasting total cholesterol (mmol/L)
4.Fasting HDL cholesterol (mmol/L)
5.Fasting LDL cholesterol (mmol/L)
6.Fasting triglycerides (mmol/L)

Notes

Power calculation: unclear

3 arms study MET versus OCP versus OCP + MET

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: “computer‐generated random sequence numbering based on the intervention received”

Allocation concealment (selection bias)

Unclear risk

Method of allocation concealment not stated
Insufficient information available to permit a judgement of “low risk” or “high risk”

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Insufficient information available to permit a judgement of ‘low risk’ or ‘high risk’.

Blinding not stated.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Insufficient information available to permit a judgement of ‘low risk’ or ‘high risk’.

Blinding not stated.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Reason of the dropout of the patient in the MET + OCP and OCP group not stated. Insufficient reporting of attrition/exclusions to permit a judgement of 'low risk' or 'high risk'.

Selective reporting (reporting bias)

Unclear risk

Regarding acne score the results are given only for severe acne score not for all the patients.
Regarding the menstrual cyclicity described in the methods but nothing is described in the results

But not a primary or key outcomes.

Insufficient information available to permit a judgment of 'low risk' or 'high risk'.

Other bias

Low risk

The study appears to be free of other sources of bias.

Study characteristics

Methods

Randomised controlled trial
Location of the trial: quote: Nanjin, China
Method of randomisation: quote: "randomly assigned to three groups"
Method of allocation concealment: not stated
Source of funding: not stated

Participants

Inclusion criteria: Women with PCOS without any precision
Exclusion criteria: no hormonal or insulin secretion treatment three months prior entering study.
Number of women randomised: 40

MET: 20

OCP: 20
Number of women analysed: 40

MET: 20

OCP: 20
Number of withdrawal and reasons: 0
Summary characteristics: PCOS, age: 28.4 +/‐ 3.5 years

Interventions

Treatment: MET 0.25 g three times a day + OCP (Ethinyl Estradiol 35 mcg/ Cyproterone acetate 25 mg),1pill/day, 21 days, starts day 5 of the menstrual cycle.
Control: MET only for 6 month: 0.25 g, three times a day
Duration: 6 months
Co‐intervention(s):nNone

Outcomes

Primary outcomes: none
Secondary outcomes:

BMI (kg/m²)

Serum total testosterone (nmol/L)
Free androgen index (FAI) (%)

Fasting insulin (mIU/L)
Fasting glucose (mmol/L)
Total cholesterol (mmol/L)
HDL cholesterol (mmol/L)
Triglycerides (mmol/L)

Subjective outcomes

None

Objective outcomes

(a) Clinical parameters

BMI (kg/m²)

(b) Hormonal parameters

Serum total testosterone (nmol/L)
Free androgen index (FAI) (%)

(c) Metabolic parameters

Fasting insulin (mIU/L)
Fasting glucose (mmol/L)
Total cholesterol (mmol/L)
HDL cholesterol (mmol/L)
Triglycerides (mmol/L)

Notes

Power calculation: no

Third arm treatment not included: MET (6 months) + OCP only 3 months

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: "Randomly divided into 4 groups"

Insufficient information about the sequence generation process available to permit a judgement of 'low risk' or 'high risk'

Allocation concealment (selection bias)

Unclear risk

Method of allocation concealment not stated.

Insufficient information available to permit a judgement of 'low risk' or 'high risk'

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Insufficient information available to permit a judgement of ‘low risk’ or ‘high risk’.

Blinding not stated.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Insufficient information available to permit a judgement of ‘low risk’ or ‘high risk’.

Blinding not stated.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No missing outcome data.

Selective reporting (reporting bias)

Low risk

The study protocol is not available, but it is clear that the published reports include all expected outcomes, including those that were pre‐specified.

Other bias

Low risk

The study appears to be free of other sources of bias.

Study characteristics

Methods

Randomised controlled trial
Location of the trial: quote: Madrid, SpainMethod of randomisation: quote: “Simple randomization was conducted using blocks of 10 sealed opaque envelopes assigning five patients to receive Diane35 Diario and five patients to receive metformin”Method of allocation concealment: “One investigator generated the randomization envelopes, whereas another enrolled and assigned the participants to their arm of treatment”, “sealed opaque envelopes”
Source of funding: "This study was supported by the Spanish Ministry of Health and Consumer Affairs, Instituto de Investigacion Carlos III Grants Fondo de Investigacion Sanitaria and Red de Diabetes Enfermedades Metabolicas Asociadas; Ministry of Education and Science Grant; and by economic aid from Hospital Ramon y Cajal."

Participants

Inclusion criteria: the diagnosis of PCOS was based on the presence of clinical and/or biochemical hyperandrogenism, oligo‐ovulation, and exclusion of secondary aetiologies. Hirsutism was defined by a modified Ferriman‐Gallwey score above 7 and oligomenorrhoea (more than six cycles longer than 36 days in the previous year) or amenorrhoea (absence of menstruation for three consecutive months), or luteal phase progesterone measurements less than 4 ng/ml (12.72 nmol/L) in women with regular menstrual cycles were considered indicative of oligo‐ovulation.
Exclusion criteria: secondary aetiologies, including hyperprolactinaemia, thyroid dysfunction, Cushing’s syndrome, congenital adrenal hyperplasia, and virilising tumours, were actively ruled out in all the patients. None of the patients had a personal history of hypertension, diabetes mellitus, or cardiovascular events, or received treatment with oral contraceptives, antiandrogens, insulin sensitisers, or drugs that might interfere with blood pressure regulation, lipid profile, or carbohydrate metabolism for the previous 6 months.
Number of women randomised: 34
MET: 19
OCP: 15
Number of women analysed: 27
MET: 12
OCP: 15
Number of withdrawal and reasons:
MET: protocol violation: 3/ 15.8%
GI adverse events: 2/ 10.5%
Pregnancy: 1/ 5.3%
Lost F/U: 1/ 5.3%
OCP: 0
Summary characteristics: PCOS, hyperandrogenic (precised in an other study with same population)
Age (years):
MET mean (+ SD):

25.1 (6.6)

OCP mean (+ SD):

23.4 (5.6)
BMI (kg/m²):

MET mean (+ SD):

30.5 (6.9)

OCP mean (+ SD):

29.2 (5.7)

Interventions

Treatment: MET 425 mg twice a day 1 week then 850 mg twice a dayControl: OCP (Ethinyl estradiol 35 mcg Cyproterone acetate 2 mg) 21 days followed by 7 days placebo pillsDuration: 6 monthsCo‐intervention(s): all the patients were instructed to maintain a diet containing 25 to 30 kcal per kg of body weight per day and moderate physical activity throughout the trial, although these measures were not stressed thereafter.

Outcomes

Primary outcomes:

Hirsutism score

Adverse events: severe (requiring stopping of medication) and minorSecondary outcomes:

Menstrual cyclicity, initiation of menses or significant shortening of cycles

BMI (kg/m²)

Blood pressure (systolic) (mm Hg)

Blood pressure (diastolic) (mm Hg)

Free androgen index (FAI) (%)
Fasting insulin (mIU/L)
Fasting glucose (mmol/L)
Fasting total cholesterol (mmol/L)
Fasting HDL cholesterol (mmol/L)
Fasting LDL cholesterol (mmol/L)
Fasting triglycerides (mmol/L)

Subjective outcomes

(a) Clinical parameters

1. Hirsutism score

Objective outcomes

(a) Clinical parameters

1. Adverse events: severe (requiring stopping of medication) and minor

2. BMI (kg/m²)

(c) Metabolic parameters

1. Fasting insulin (mIU/L)
2. Fasting glucose (mmol/L)
3. Fasting total cholesterol (mmol/L)
4. Fasting HDL cholesterol (mmol/L)
5. Fasting LDL cholesterol (mmol/L)
6. Fasting triglycerides (mmol/L)

Notes

Authors contacted about: the results because it was presented as a graph.Power calculation: yes, a priori, on secondary outcome

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: “patients were randomized to receive an antiandrogenic low‐dose oral contraceptive pill or 850 mg of metformin twice daily for 24 wk”, “One investigator generated the randomization envelopes, whereas another enrolled and assigned the participants to their arm of treatment”, “Simple randomization was conducted using blocks of 10 sealed opaque envelopes assigning five patients to receive Diane 35 Diario and five patients to receive metformin”
Insufficient information about the sequence generation process available to permit a judgement of ‘low risk’ or ‘high risk’.

Allocation concealment (selection bias)

Low risk

Quote: “One investigator generated the randomization envelopes, whereas another enrolled and assigned the participants to their arm of treatment” and “sealed opaque envelopes”.

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Quote: “No masking method was used after randomization”.

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Quote: “No masking method was used after randomization”.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

7 patients in MET group did not complete the entire study/ 0 in OCP group.
Quote: "protocol violation and lost to F/U" unclear if related to intervention. Insufficient reporting of attrition /exclusions to permit a judgement of 'low risk' or 'high risk."

Selective reporting (reporting bias)

Low risk

The study protocol is not available but it is clear that the published reports include all expected outcomes, including those that were prespecified.

Other bias

Low risk

The study appears to be free of other sources of bias.

Study characteristics

Methods

Randomised controlled trial

Same population as Luque‐Ramirez 2007a
Location of the trial: quote: Madrid, SpainMethod of randomisation: quote: “Simple randomization was conducted using blocks of 10 sealed opaque envelopes assigning five patients to receive Diane35 Diario and five patients to receive metformin”Method of allocation concealment: “One investigator generated the randomization envelopes, whereas another enrolled and assigned the participants to their arm of treatment”, “sealed opaque envelopes”
Source of funding: "This study was supported by the Spanish Ministry of Health and Consumer Affairs, Instituto de Investigacion Carlos III Grants Fondo de Investigacion Sanitaria and Red de Diabetes Enfermedades Metabolicas Asociadas; Ministry of Education and Science Grant; and by economic aid from Hospital Ramon y Cajal."

Participants

Inclusion criteria: the diagnosis of PCOS was based on the presence of clinical and/or biochemical hyperandrogenism, oligo‐ovulation, and exclusion of secondary aetiologies. Hirsutism was defined by a modified Ferriman‐Gallwey score above 7 and oligomenorrhoea (more than six cycles longer than 36 days in the previous year) or amenorrhoea (absence of menstruation for three consecutive months), or luteal phase progesterone measurements less than 4 ng/ml (12.72 nmo/L) in women with regular menstrual cycles were considered indicative of oligo‐ovulation.
Exclusion criteria:secondary aetiologies, including hyperprolactinaemia, thyroid dysfunction, Cushing’s syndrome, congenital adrenal hyperplasia, and virilising tumours, were actively ruled out in all the patients. None of the patients had a personal history of hypertension, diabetes mellitus, or cardiovascular events, or received treatment with oral contraceptives, antiandrogens, insulin sensitisers, or drugs that might interfere with blood pressure regulation, lipid profile, or carbohydrate metabolism for the previous 6 months.
Number of women randomised: 34
MET: 19
OCP: 15
Number of women analysed: 27
MET: 12
OCP: 15
Number of withdrawal and reasons:
MET: protocol violation: 3/ 15.8%
GI adverse events: 2/ 10.5%
Pregnancy: 1/ 5.3%
Lost F/U: 1/ 5.3%
OCP: 0
Summary characteristics: PCOS, hyperandrogenic (precised in an other study with same population)
Age (years):
MET mean (+SD):

25.1 (6.6)

OCP mean (+ SD):

23.4 (5.6)
BMI (kg/m²):

MET mean (+ SD):

30.5 (6.9)

OCP mean (+ SD):

29.2 (5.7)

Interventions

Treatment:
MET 425 mg twice a day 1 week then 850 mg twice a day
Control:
OCP (Ethinyl estradiol 35 mcg Cyproterone acetate 2 mg) 21 days followed by 7 days placebo pills
Duration:
6 months
Co‐intervention(s): All the patients were instructed to maintain a diet containing 25 to 30 kcal per kg of body weight per day and moderate physical activity throughout the trial, although these measures were not stressed thereafter.

Outcomes

Primary outcomes: None
Secondary outcomes: Menstrual cyclicity, initiation of menses or significant shortening of cycles

Subjective outcomes

None

Objective outcomes

(a) Clinical parameters:

1. Menstrual cyclicity, initiation of menses or significant shortening of cycles

Notes

Authors contacted about: the results because it was presented as a graph.
Power calculation: yes, a priori, on secondary outcome

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: “patients were randomized to receive an antiandrogenic low‐dose oral contraceptive pill or 850 mg of metformin twice daily for 24 wk”, “One investigator generated the randomization envelopes, whereas another enrolled and assigned the participants to their arm of treatment”, “Simple randomization was conducted using blocks of 10 sealed opaque envelopes assigning five patients to receive Diane 35 Diario and five patients to receive metformin”
Insufficient information about the sequence generation process available to permit a judgement of ‘low risk’ or ‘high risk’

Allocation concealment (selection bias)

Low risk

Quote: “One investigator generated the randomization envelopes, whereas another enrolled and assigned the participants to their arm of treatment” and “sealed opaque envelopes”

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Quote: “open label RCT”.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Insufficient information available to permit a judgement of ‘low risk’ or ‘high risk’.

Blinding not stated.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

7 patients in MET group did not complete the entire study/ 0 in OCP group
Quote: "protocol violation and lost to F/U" unclear if related to intervention. Insufficient reporting of attrition /exclusions to permit a judgement of 'low risk' or 'high risk.".

Selective reporting (reporting bias)

High risk

Menstrual cyclicity is the only outcome of interest in this study and was not described in the methods. One or more primary outcomes have been reported using measurements, analysis, methods or subset of the data THAT WERE NOT PRE‐SPECIFIED

Other bias

Low risk

The study appears to be free of other sources of bias.

Study characteristics

Methods

Randomised controlled trial

Same population as Luque‐Ramirez 2007a
Location of the trial: quote: Madrid, SpainMethod of randomisation: quote: “Simple randomization was conducted using blocks of 10 sealed opaque envelopes assigning five patients to receive Diane35 Diario and five patients to receive metformin”Method of allocation concealment: “One investigator generated the randomization envelopes, whereas another enrolled and assigned the participants to their arm of treatment”, “sealed opaque envelopes”
Source of funding: "This study was supported by the Spanish Ministry of Health and Consumer Affairs, Instituto de Investigacion Carlos III Grants Fondo de Investigacion Sanitaria and Red de Diabetes Enfermedades Metabolicas Asociadas; Ministry of Education and Science Grant; and by economic aid from Hospital Ramon y Cajal."

Participants

Inclusion criteria: the diagnosis of PCOS was based on the presence of clinical and/or biochemical hyperandrogenism, oligo‐ovulation, and exclusion of secondary aetiologies. Hirsutism was defined by a modified Ferriman‐Gallwey score above 7 and oligomenorrhoea (more than six cycles longer than 36 days in the previous year) or amenorrhoea (absence of menstruation for 3 consecutive months), or luteal phase progesterone measurements less than 4 ng/ml (12.72 nmol/L) in women with regular menstrual cycles were considered indicative of oligo‐ovulation.
Exclusion criteria: secondary aetiologies, including hyperprolactinaemia, thyroid dysfunction, Cushing’s syndrome, congenital adrenal hyperplasia, and virilizing tumours, were actively ruled out in all the patients. None of the patients had a personal history of hypertension, diabetes mellitus, or cardiovascular events, or received treatment with oral contraceptives, antiandrogens, insulin sensitisers, or drugs that might interfere with blood pressure regulation, lipid profile, or carbohydrate metabolism for the previous 6 months.
Number of women randomised: 34
MET: 19
OCP: 15
Number of women analysed: 27
MET: 12
OCP: 15
Number of withdrawal and reasons:
MET: protocol violation: 3/ 15.8%
GI adverse events: 2/ 10.5%
Pregnancy: 1/ 5.3%
Lost F/U: 1/ 5.3%
OCP: 0
Summary characteristics: PCOS, hyperandrogenic (precised in an other study with same population)
Age (years):
MET mean (+ SD):

25.1 (6.6)

OCP mean (+ SD):

23.4 (5.6)
BMI (kg/m²):

MET mean (+ SD):

30.5 (6.9)

OCP mean (+ SD):

29.2 (5.7)

Interventions

Treatment:
MET 425 mg twice a day 1 week then 850 mg twice a day
Control:
OCP (Ethinyl estradiol 35 mcg Cyproterone acetate 2 mg) 21 days followed by 7 days placebo pills
Duration:
6 months
Co‐intervention(s): all the patients were instructed to maintain a diet containing 25 to 30 kcal per kg of body weight per day and moderate physical activity throughout the trial, although these measures were not stressed thereafter.

Outcomes

Primary outcomes: none
Secondary outcomes:

Free androgen index (FAI) (%)

Subjective outcomes

None

Objective outcomes

(b) Hormonal parameters

1. Free androgen index (FAI) (%)

Notes

Authors contacted about: the results because it was presented as a graph.
Power calculation: yes, a priori, on secondary outcome

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: “patients were randomized to receive an antiandrogenic low‐dose oral contraceptive pill or 850 mg of metformin twice daily for 24 wk”, “One investigator generated the randomization envelopes, whereas another enrolled and assigned the participants to their arm of treatment”, “Simple randomization was conducted using blocks of 10 sealed opaque envelopes assigning five patients to receive Diane 35 Diario and five patients to receive metformin”
Insufficient information about the sequence generation process available to permit a judgement of ‘low risk’ or ‘high risk’

Allocation concealment (selection bias)

Low risk

Quote: “One investigator generated the randomization envelopes, whereas another enrolled and assigned the participants to their arm of treatment” and “sealed opaque envelopes”

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Quote: “open label RCT”.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Insufficient information available to permit a judgement of ‘low risk’ or ‘high risk’.

Blinding not stated.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

7 patients in MET group did not complete the entire study/ 0 in OCP group
Quote: "protocol violation and lost to F/U" unclear if related to intervention. Insufficient reporting of attrition /exclusions to permit a judgement of 'low risk' or 'high risk'.

Selective reporting (reporting bias)

High risk

FAI is the only outcome of interest in this study and was not described in the methods. One or more primary outcomes have been reported using measurements, analysis, methods or subset of the data THAT WERE NOT PRE‐SPECIFIED

Other bias

Low risk

The study appears to be free of other sources of bias.

Study characteristics

Methods

Randomised controlled trial

Same population as Luque‐Ramirez 2007a
Location of the trial: quote: Madrid, SpainMethod of randomisation: quote “Simple randomization was conducted using blocks of 10 sealed opaque envelopes assigning five patients to receive Diane35 Diario and five patients to receive metformin”Method of allocation concealment: “One investigator generated the randomization envelopes, whereas another enrolled and assigned the participants to their arm of treatment”, “sealed opaque envelopes”
Source of funding: "This study was supported by the Spanish Ministry of Health and Consumer Affairs, Instituto de Investigacion Carlos III Grants Fondo de Investigacion Sanitaria and Red de Diabetes Enfermedades Metabolicas Asociadas; Ministry of Education and Science Grant; and by economic aid from Hospital Ramon y Cajal."

Participants

Inclusion criteria: the diagnosis of PCOS was based on the presence of clinical and/or biochemical hyperandrogenism, oligo‐ovulation, and exclusion of secondary aetiologies. Hirsutism was defined by a modified Ferriman‐Gallwey score above 7 and oligomenorrhoea (more than six cycles longer than 36 d in the previous year) or amenorrhoea (absence of menstruation for 3 consecutive months), or luteal phase progesterone measurements less than 4 ng/ml (12.72 nmol/L) in women with regular menstrual cycles were considered indicative of oligo‐ovulation.
Exclusion criteria: secondary aetiologies, including hyperprolactinaemia, thyroid dysfunction, Cushing’s syndrome, congenital adrenal hyperplasia, and virilizing tumours, were actively ruled out in all the patients. None of the patients had a personal history of hypertension, diabetes mellitus, or cardiovascular events, or received treatment with oral contraceptives, antiandrogens, insulin sensitisers, or drugs that might interfere with blood pressure regulation, lipid profile, or carbohydrate metabolism for the previous 6 months.
Number of women randomised: 34
MET: 19
OCP: 15
Number of women analysed: 27
MET: 12
OCP: 15
Number of withdrawal and reasons:
MET: protocol violation: 3/ 15.8%
GI adverse events: 2/ 10.5%
Pregnancy: 1/ 5.3%
Lost F/U: 1/ 5.3%
OCP: 0
Summary characteristics: PCOS, hyperandrogenic (precised in an other study with same population)
Age (years):
MET mean (+ SD):

25.1 (6.6)

OCP mean (+ SD):

23.4 (5.6)
BMI (kg/m²):

MET mean (+ SD):

30.5 (6.9)

OCP mean (+ SD):

29.2 (5.7)

Interventions

Treatment:
MET 425 mg twice a day 1 week then 850 mg twice a day
Control:
OCP (Ethinyl estradiol 35 mcg Cyproterone acetate 2 mg) 21 days followed by 7 days placebo pills
Duration:
6 months
Co‐intervention(s): All the patients were instructed to maintain a diet containing 25 to 30 kcal per kg of body weight per day and moderate physical activity throughout the trial, although these measures were not stressed thereafter.

Outcomes

Primary outcomes: none
Secondary outcomes:

Blood pressure (systolic, diastolic) (mm Hg)

Subjective outcomes

None

Objective outcomes

(a) Clinical parameters

Blood pressure (systolic, diastolic) (mm Hg)

Notes

Authors contacted about: the results because it was presented as a graph.
Power calculation: yes, a priori, on secondary outcome

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: “patients were randomized to receive an antiandrogenic low‐dose oral contraceptive pill or 850 mg of metformin twice daily for 24 wk”, “One investigator generated the randomization envelopes, whereas another enrolled and assigned the participants to their arm of treatment”, “Simple randomization was conducted using blocks of 10 sealed opaque envelopes assigning five patients to receive Diane 35 Diario and five patients to receive metformin”
Insufficient information about the sequence generation process available to permit a judgement of ‘low risk’ or ‘high risk’

Allocation concealment (selection bias)

Low risk

Quote: “One investigator generated the randomization envelopes, whereas another enrolled and assigned the participants to their arm of treatment” and “sealed opaque envelopes”

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Quote: “No masking method was used after randomization”.

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Quote: “No masking method was used after randomization”.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

7 patients in MET group did not complete the entire study/ 0 in OCP group
Quote: "protocol violation and lost to F/U" unclear if related to intervention. Insufficient reporting of attrition /exclusions to permit a judgement of 'low risk' or 'high risk.".

Selective reporting (reporting bias)

Low risk

The study protocol is not available but it is clear that the published reports include all expected outcomes, including those that were prespecified.

Other bias

Low risk

The study appears to be free of other sources of bias.

Study characteristics

Methods

Randomised controlled trial
Location of the trial: quote: Huazhong, China
Method of randomisation: unclear, quote: “The subjects were randomized to either the CPA group (n=25) or to the CPA + metformin group (n=25).”
Method of allocation concealment: not stated
Source of funding: Not stated

Participants

Inclusion criteria: PCOS was defined as the presence of: (1) chronic anovulatory disorders such as oligomenorrhoea, anovulatory cycles, or secondary amenorrhoea; (2) the ratio of LH/FSH was > 2 and (or) the plasma testosterone (T) level was > 2.6 nmol/L; (3) 10 or more follicles (2 mm to 8 mm in diameter) in one or both ovaries by transvaginal ultrasound examination. All the women were euthyroid and had normal prolactin levels.
Exclusion criteria: women who had any other known endocrinological disease, and those taking drugs known to affect carbohydrate or lipid metabolism and OGTT results during the 6 months preceding the study were excluded.
Number of women randomised: 50

MET + OCP: 25

OCP: 25
Number of women analysed: not stated
Number of withdrawal and reasons: not stated
Summary characteristics: PCOS, aged 16 to 36 years, all women were either of normal weight or thin BMI (≤ 25 kg/m²).
Age (years):
OCP + MET mean (+ SD):

24.5 (5.6)
OCP mean (+ SD):
24.35 (5.11)
BMI (kg/m²):

OCP + MET mean (+ SD):

22.1 (2.46)

OCP mean (+ SD):

21.81 (1.37)

Interventions

Treatment: OCP (Ethinyl estradiol 35 mcg Cyproterone acetate 2mg) 21 days stop 7 days + MET 500 mg/day
Control: OCP (Ethinyl estradiol 35 mcg Cyproterone acetate 2 mg) 21 days stop 7 days
Duration: 6 months
Co‐intervention(s): Medroxyprogesterone for amenorrhoeic patients

Outcomes

Primary outcomes: noneSecondary outcomes:

BMI (kg/m²)

Serum total testosterone (nmol/L)

Fasting insulin (mIU/L)
Fasting glucose (mmol/L)
Fasting total cholesterol (mmol/L)
Fasting HDL cholesterol (mmol/L)
Fasting LDL cholesterol (mmol/L)
Fasting triglycerides (mmol/L)

Subjective outcomes

None

Objective outcomes

(a) Clinical parameters

1. BMI (kg/m²)

(b) Hormonal parameters

1. Serum total testosterone (nmol/L)

(c) Metabolic parameters

1. Fasting insulin (mIU/L)
2. Fasting glucose (mmol/L)
3. Fasting total cholesterol (mmol/L)
4. Fasting HDL cholesterol (mmol/L)
5. Fasting LDL cholesterol (mmol/L)
6. Fasting triglycerides (mmol/L)

Notes

Authors contacted about: the number of patient randomised in each group and number of withdrawal.Power calculation: unclear

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: “The subjects were randomized to either the CPA group (n=25) or to the CPA + metformin group (n=25).”
Insufficient information about the sequence generation process available to permit a judgement of ‘low risk’ or ‘high risk’.

Allocation concealment (selection bias)

Unclear risk

Method of allocation concealment not stated.
Insufficient information available to permit a judgement of ‘low risk’ or ‘high risk’

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Insufficient information available to permit a judgement of ‘low risk’ or ‘high risk’.

Blinding not stated.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Insufficient information available to permit a judgement of ‘low risk’ or ‘high risk’.

Blinding not stated.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Paper does not provide any information on participant after randomisation.

Selective reporting (reporting bias)

Low risk

The study protocol is not available but it is clear that the published reports include all expected outcomes, including those that were prespecified.

Other bias

Low risk

The study appears to be free of other sources of bias.

Study characteristics

Methods

Randomised controlled trial
Location of the trial: quote: "Melbourne, Australia"Method of randomisation: quote: "computer‐generated random numbers"Method of allocation concealment: not statedSource of funding: pharmaceutical, quote: "This work was an investigator‐initiated trial funded by a competitive CVL grant sponsored by Pfizer Australia and through internal department funds. Pfizer Australia provided the aldactone, and Douglas Pharmaceuticals Australia provided the metformin. H.J.T is an National Health and MedicalResearch Council and National Heart
Foundation Fellow. C.M. is an National Health and Medical Research Council PhD Scholar."

Participants

Inclusion criteria: PCOS diagnosis was based on perimenarchal onset of irregular cycles ( < 21 days or > 35 days) and clinical manifestations of hyperandrogenism (hirsutism or acne) or biochemical hyperandrogenism with elevation of at least one circulating ovarian androgen (according to 1990 National Institutes of Health criteria).
Exclusion criteria: secondary causes of amenorrhoea and hyperandrogenism were excluded with clinical screening and early follicular 17‐hydroxyprogesterone levels. Diabetes was excluded on OGTTs. Pregnancy tests were negative before enrolment.
Number of women randomised: 72:

MET : 37
OCP: 35
Number of women analysed: 67

MET: 36
OCP: 31
Number of withdrawal and reasons:

MET:
Personal reason: 1/ 2.7%
OCP:
Personal reason: 3/ 9.7%
Swinging mood: 1/ 3.2%
Summary characteristics: PCOS, Overweight BMI > 27 kg/m², Mean age 31 years.
BMI (kg/m²):

MET mean:
BMI (kg/m²): 36.3
OCP mean:
BMI (kg/m²): 36.5

Interventions