1

Supplemental Table 1 Definitions for metabolic syndrome, hypertension and dyslipidemia in PCOS first-degree relatives and their controls

Author
(year) / Metabolic
syndrome / Hypertension / Dyslipidemia
Baillargeon and Carpentier, (2007) / NCEP–ATP III / - / -
Davies et al. (2011) / - / NA / NA
Hunter et al. (2007) / - / NA / NA
Yilmaz et al. (2005) / - / - / -
Dunaif and Legro (10 studies) * / AHA 2005 criteria / Subjects with systolic BP ≥ 140 mmHg or diastolic BP ≥ 90 mmHg, or on an antihypertensive medication / Being on a medication affecting lipids (includes statin) or triglycerides ≥ 150 mg/dL or HDL < 50 mg/dL for women or HDL < 40 mg/dL for men

NA, Not addressed

PCOS, polycystic ovary syndrome;

NCEP–ATP III; National Cholesterol Education Program Adult Treatment Panel III;

AHA, American Heart Association

Dunaif and Legro (10 studies)*: Legro et al. 1998, 2002a, 2002b, 2010; Sam et al. 2005, 2006, 2008a, 2008b; Coviello et al. 2009; Taylor et al. 2011(References 14-19, 68-71)

Supplemental Table 2 Data available for meta-analysis from each study regarding PCOS first-degree relatives and their controls

Author
(year) / PCOS
relative or control / Parameters available for meta-analysis
Baillargeon and Carpentier, (2007) / Brother / Prevalence of MetS and age, BMI, systolic BP, diastolic BP, LDL-C, HDL-C values
Davies et al. (2011) / Mother / Prevalence of hypertension, dyslipidemia
Father / Prevalence of hypertension, dyslipidemia
Hunter et al. (2007) / Father / Prevalence of hypertension, dyslipidemia
Yilmaz et al. (2005) / Mother / Prevalence of hypertension, dyslipidemia and age, BMI, systolic BP, diastolic BP, Total-C, LDL-C, HDL-C and triglyceride values
Father / Prevalence of hypertension, dyslipidemia and age, BMI, systolic BP, diastolic BP, Total-C, LDL-C, HDL-C and triglyceride values
Sister / Age, BMI, systolic BP, diastolic BP, Total-C, LDL-C, HDL-C and triglyceride values
Brother / Age, BMI, systolic BP, diastolic BP, Total-C, LDL-C, HDL-C and triglyceride values
Dunaif and Legro (10 studies)* / Mother / Prevalence of MetS, hypertension, dyslipidemia and age, BMI, systolic BP, diastolic BP, Total-C, LDL-C, HDL-C and triglyceride values
Father / Prevalence of MetS, hypertension, dyslipidemia and age, BMI, systolic BP, diastolic BP, Total-C, LDL-C, HDL-C and triglyceride values
Sister / Prevalence of MetS, hypertension, dyslipidemia and age, BMI, systolic BP, diastolic BP, Total-C, LDL-C, HDL-C and triglyceride values
Brother / Prevalence of MetS, hypertension, dyslipidemia and age, BMI, systolic BP, diastolic BP, Total-C, LDL-C, HDL-C and triglyceride values

PCOS, polycystic ovary syndrome; BMI, body mass index; MetS, metabolic syndrome; BP, blood pressure; Total-C, total cholesterol; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol

Dunaif and Legro (10 studies)*, Legro et al. 1998, 2002a, 2002b, 2010; Sam et al. 2005, 2006, 2008a, 2008b; Coviello et al. 2009; Taylor et al. 2011(References 14-19, 68-71)

Supplemental Table 3 Number of studies and patients for each parameter in four groups of first degree relatives of women with and without PCOS

Mother / Father / Sister / Brother
Study
(n) / PCOS
(n) / Control
(n) / Study
(n) / PCOS
(n) / Control
(n) / Study
(n) / PCOS
(n) / Control
(n) / Study
(n) / PCOS
(n) / Control
(n)
MetS,
n (%) / 1 / 559 / 225 / 1 / 522 / 187 / 1 / 518 / 511 / 2 / 289 / 345
Hypertension,
n (%) / 3 / 545 / 887 / 4 / 550 / 980 / 1 / 352 / 443 / 1 / 171 / 307
Systolic BP,
mmHg / 2 / 159 / 227 / 4 / 369 / 199 / 2 / 369 / 499 / 3 / 192 / 352
Diastolic BP,
mmHg / 2 / 113 / 227 / 2 / 369 / 199 / 2 / 368 / 499 / 3 / 192 / 352
Dyslipidemia,
n (%) / 3 / 464 / 879 / 4 / 634 / 956 / 1 / 476 / 345 / 1 / 258 / 255
Total-C,
mg/dL / 2 / 605 / 205 / 2 / 532 / 171 / 2 / 501 / 365 / 2 / 275 / 270
LDL-C,
mg/dL / 2 / 587 / 203 / 2 / 507 / 161 / 2 / 495 / 362 / 3 / 276 / 288
HDL-C,
mg/dL / 2 / 605 / 205 / 2 / 529 / 161 / 2 / 500 / 365 / 3 / 292 / 298
Triglyceride ,
mg/dL / 2 / 605 / 205 / 2 / 532 / 171 / 2 / 501 / 365 / 2 / 275 / 270

“Study (n)” means total number of included study for meta-analysis;

“PCOS (n)” means total number of first degree relative of PCOS proband in meta-analysis;

“Control (n)” means total number of control women in meta-analysis;

PCOS, polycystic ovary syndrome;

MetS, metabolic syndrome;

Supplemental Table 4 Comparison of results (PCOS Mother vs. Control Mother)

No. of trials / No. of participants / Statistical method / Effect size
PCOS
Mother / Control
Mother
MetS, n (%) / 1 / 241/599 / 51/225 / RR (M-H, fixed, 95 % CI) / 1.78 (1.37, 2.30) c
Hypertension, n (%) / 3 / 55/545 / 212/887 / RR (M-H, random, 95 % CI) / 1.02 (0.21, 4.88)
Systolic BP, mmHg / 2 / 159 / 227 / SMD (M-H, random, 95 % CI) / 0.54 (0.04, 1.04) a
Diastolic BP, mmHg / 2 / 113 / 227 / SMD (M-H, random, 95 % CI) / 0.55 (-0.24, 1.34)
Dyslipidemia, n (%) / 3 / 414/646 / 253/879 / RR (M-H, random, 95 % CI) / 1.16 (1.02, 1.31) a
Total-C, mg/dL / 2 / 605 / 205 / SMD (M-H, random, 95 % CI) / 0.85 (0.29, 1.42) b
LDL-C, mg/dL / 2 / 587 / 203 / SMD (M-H, random, 95 % CI) / 0.75 (-0.04, 1.55)
HDL-C, mg/dL / 2 / 605 / 205 / SMD (M-H, fixed, 95 % CI) / -0.01 (-0.17, 0.15)
Triglycerides, mg/dL / 2 / 605 / 205 / SMD (M-H, fixed, 95 % CI) / 0.48 (0.32, 0.64) d

PCOS, polycystic ovary syndrome

MetS, metabolic syndrome

BP, blood pressure

LDL-C, low-density lipoprotein cholesterol

HDL-C, high-density lipoprotein cholesterol

CI, confidence interval

RR, risk ratio

M-H, Mantel–Haenszel

SMD, standardized mean difference

a, P<0.05

b, P<0.01

c, P<0.0001

d, P<0.00001

Supplemental Table 5 Comparison of results (PCOS Father vs. Control Father)

No. of trials / No. of participants / Statistical method / Effect size
PCOS
Father / Control
Father
MetS, n (%) / 1 / 223/522 / 56/187 / RR (M-H, fixed, 95 % CI) / 1.43 (1.12, 1.81) a
Hypertension, n (%) / 4 / 315/550 / 275/980 / RR (M-H, fixed, 95 % CI) / 1.93 (1.58, 2.35) b
Systolic BP, mmHg / 2 / 369 / 199 / SMD (M-H, random, 95 % CI) / 0.52 (-0.04, 1.08)
Diastolic BP, mmHg / 2 / 369 / 199 / SMD (M-H, random, 95 % CI) / 0.36 (-0.25, 0.98)
Dyslipidemia, n (%) / 4 / 463/634 / 332/956 / RR (M-H, fixed, 95 % CI) / 1.29 (1.11, 1.50) a
Total-C, mg/dL / 2 / 532 / 171 / SMD (M-H, random, 95 % CI) / 0.78 (-0.52, 2.08)
LDL-C, mg/dL / 2 / 507 / 161 / SMD (M-H, random, 95 % CI) / 1.05 (-0.82, 2.92)
HDL-C, mg/dL / 2 / 529 / 171 / SMD (M-H, random, 95 % CI) / -0.67 (-1.56, 0.21)
Triglycerides, mg/dL / 2 / 532 / 171 / SMD (M-H, random, 95 % CI) / 0.50 (-0.26, 1.27)

PCOS, polycystic ovary syndrome

MetS, metabolic syndrome

BP, blood pressure

LDL-C, low-density lipoprotein cholesterol

HDL-C, high-density lipoprotein cholesterol

CI, confidence interval

RR, risk ratio

M-H, Mantel–Haenszel

SMD, standardized mean difference

a, P<0.01

b, P<0.0001

Supplemental Table 6 Comparison of results (PCOS Sister vs. Control Sister)

No. of trials / No. of participants / Statistical method / Effect size
PCOS
Sister / Control
Sister
MetS, n (%) / 1 / 97/518 / 64/511 / RR (M-H, fixed, 95 % CI) / 1.50 (1.12, 2.00) a
Hypertension, n (%) / 1 / 65/352 / 28/443 / RR (M-H, fixed, 95 % CI) / 2.92 (1.92, 4.45) b
Systolic BP, mmHg / 2 / 369 / 499 / SMD (M-H, fixed, 95 % CI) / 0.21 (0.07, 0.34) a
Diastolic BP, mmHg / 2 / 368 / 499 / SMD (M-H, fixed , 95 % CI) / 0.09 (-0.04, 0.23)
Dyslipidemia, n (%) / 1 / 313/476 / 220/345 / RR (M-H, fixed, 95 % CI) / 1.03 (0.93, 1.14)
Total-C, mg/dL / 2 / 501 / 365 / SMD (M-H, fixed, 95 % CI) / 0.35 (0.21, 0.48) b
LDL-C, mg/dL / 2 / 495 / 362 / SMD (M-H, fixed, 95 % CI) / 0.28 (0.14, 0.42) b
HDL-C, mg/dL / 2 / 500 / 365 / SMD (M-H, fixed, 95 % CI) / -0.00 (-0.14, 0.13)
Triglycerides, mg/dL / 2 / 501 / 365 / SMD (M-H, fixed, 95 % CI) / 0.27 (0.14, 0.41) b

PCOS, polycystic ovary syndrome

MetS, metabolic syndrome

BP, blood pressure

LDL-C, low-density lipoprotein cholesterol

HDL-C, high-density lipoprotein cholesterol

CI, confidence interval

RR, risk ratio

M-H, Mantel–Haenszel

SMD, standardized mean difference

a, P<0.01

b, P<0.0001

Supplemental Table 7 Comparison of results (PCOS Brother vs. Control Brother)

No. of trials / No. of participants / Statistical method / Effect size
PCOS
Brother / Control
Brother
MetS, n (%) / 2 / 56/289 / 63/345 / RR (M-H, fixed, 95 % CI) / 1.05 (0.76, 1.45)
Hypertension, n (%) / 1 / 58/171 / 27/307 / RR (M-H, fixed, 95 % CI) / 3.86 (2.54, 5.85) b
Systolic BP, mmHg / 3 / 192 / 352 / SMD (M-H, fixed, 95 % CI) / 0.21 (0.03, 0.39) a
Diastolic BP, mmHg / 3 / 192 / 352 / SMD (M-H, fixed, 95 % CI) / 0.13 (-0.04, 0.31)
Dyslipidemia, n (%) / 1 / 148/258 / 137/255 / RR (M-H, fixed, 95 % CI) / 1.07 (0.91, 1.25)
Total-C, mg/dL / 2 / 275 / 270 / SMD (M-H, random, 95 % CI) / 0.78 (-0.42, 1.99)
LDL-C, mg/dL / 3 / 276 / 288 / SMD (M-H, random, 95 % CI) / 0.34 (-0.14, 0.82)
HDL-C, mg/dL / 3 / 292 / 298 / SMD (M-H, fixed, 95 % CI) / -0.02 (-0.19, 0.14)
Triglycerides, mg/dL / 2 / 275 / 270 / SMD (M-H, random, 95 % CI) / 0.69 (-0.40, 1.78)

PCOS, polycystic ovary syndrome

MetS, metabolic syndrome

BP, blood pressure

LDL-C, low-density lipoprotein cholesterol

HDL-C, high-density lipoprotein cholesterol

CI, confidence interval

RR, risk ratio

M-H, Mantel–Haenszel

SMD, standardized mean difference

a, P<0.05

b, P<0.00001

Supplemental Table 8 Risk of Bias Assessment for included studies

Davies 2011 / Legro 2002a / Baillargeon 2007 / Yilmaz 2005 / Sam 2008a / Sam 2005 / Sam 2006 / Sam 2008b / Hunter 2007 / Legro 1998 / Legro 2002b / Legro 2010 / Coviello 2009 / Taylor 2011
1. Was the research question or objective in this paper clearly stated? / Yes / Yes / Yes / Yes / Yes / Yes / Yes / Yes / Yes / Yes / Yes / Yes / Yes / Yes
2. Was the study population clearly specified and defined? / Yes / Yes / Yes / Yes / Yes / Yes / Yes / Yes / Yes / Yes / Yes / Yes / Yes / Yes
3. Was the participation rate of eligible persons at least 50%? / No / Yes / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR
4. Were all the subjects selected or recruited from the same or similar populations (including the same time period)? Were inclusion and exclusion criteria for being in the study prespecified and applied uniformly to all participants? / Yes / Yes / Yes / Yes / Yes / Yes / Yes / Yes / No / Yes / Yes / Yes / Yes / No
5. Was a sample size justification, power description, or variance and effect estimates provided? / Yes / No / Yes / No / Yes / No / Yes / No / No / No / No / No / No / No
6. For the analyses in this paper, were the exposure(s) of interest measured prior to the outcome(s) being measured? / Yes / Yes / Yes / Yes / Yes / Yes / Yes / Yes / Yes / Yes / Yes / Yes / Yes / Yes
7. Was the timeframe sufficient so that one could reasonably expect to see an association between exposure and outcome if it existed? / Yes / Yes / Yes / Yes / Yes / Yes / Yes / Yes / Yes / Yes / Yes / Yes / Yes / Yes
8. For exposures that can vary in amount or level, did the study examine different levels of the exposure as related to the outcome (e.g., categories of exposure, or exposure measured as continuous variable)? / N/A / N/A / N/A / N/A / N/A / N/A / N/A / N/A / N/A / N/A / N/A / N/A / N/A / N/A
9. Were the exposure measures (independent variables) clearly defined, valid, reliable, and implemented consistently across all study participants? / Yes / Yes / Yes / Yes / Yes / Yes / Yes / Yes / Yes / Yes / Yes / Yes / Yes / Yes
10. Was the exposure(s) assessed more than once over time? / N/A / N/A / N/A / N/A / N/A / N/A / N/A / N/A / N/A / N/A / N/A / N/A / N/A / N/A
11. Were the outcome measures (dependent variables) clearly defined, valid, reliable, and implemented consistently across all study participants? / Yes / Yes / Yes / Yes / Yes / Yes / Yes / Yes / Yes / Yes / Yes / Yes / Yes / Yes
12.Were the outcome assessors blinded to the exposure status of participants? / No / No / No / No / No / No / No / No / No / No / No / No / No / No
13. Was loss to follow-up after baseline 20% or less? / N/A / N/A / N/A / N/A / N/A / N/A / N/A / N/A / N/A / N/A / N/A / N/A / N/A / N/A
14. Were key potential confounding variables measured and adjusted statistically for their impact on the relationship between exposure(s) and outcome(s)? / Yes / Yes / Yes / Yes / Yes / Yes / Yes / Yes / Yes / Yes / Yes / Yes / Yes / Yes
Overall Rating / POOR (history recall) / GOOD / GOOD / GOOD / GOOD / GOOD / GOOD / GOOD / POOR (controls have other pathologies) / GOOD / GOOD / GOOD / GOOD / POOR (controls from other population)