Introduction
Materials and methods
Assays in PCOS OUH
The Danish health registries
Outcome
Secondary outcome
Exclusion criteria
Exposure
Statistical analyses
Ethics
Results
PCOS vs. controls (Additional file 1: Appendix Table S1)
Baseline clinical and biochemical data in PCOS OUH (Additional file 1: Appendix Table S2)
CVD event rates (Table 1)
PCOS OUH (N = 1159) | PCOS Denmark (N = 17,995) | Controls (N = 52,329) | Pa | Pb | ||||
---|---|---|---|---|---|---|---|---|
N (%) | IR | N (%) | IR | N (%) | IR | |||
CVD events | 264 (23) | 22.6 | 3970 (22) | 22.0 | 7344 (14) | 13.2 | < 0.001 | 0.54 |
CVD (HT and DL excluded) | 71 (6) | 5.4 | 1290 (7) | 6.4 | 2678 (5) | 4.5 | < 0.001 | 0.16 |
ICD10 CVD, total | 121 (10) | 9.5 | 1727 (10) | 8.7 | 3089 (6) | 5.2 | < 0.001 | 0.31 |
E 78 (dyslipidemia) | 33 (3) | 2.5 | 431 (2) | 2.1 | 653 (1) | 1.1 | < 0.001 | 0.30 |
G45–46, I63–66 (TCI, stroke) | 16 (1) | 1.2 | 206 (1) | 1.0 | 524 (1) | 0.9 | 0.102 | 0.44 |
I10–13 (hypertension) | 77 (7) | 5.9 | 1004 (6) | 4.9 | 1484 (3) | 2.5 | < 0.001 | 0.10 |
I20–25 (CVD) | 20 (2) | 1.5 | 364 (2) | 1.8 | 854 (2) | 1.4 | 0.001 | 0.46 |
I26 (VTE lung) | 4 (0.4) | 0.3 | 97 (0.5) | 0.5 | 151 (0.3) | 0.2 | < 0.001 | 0.35 |
I50 (incompensatio) | 0 | Na | 47 (0.3) | 0.2 | 200 (0.4) | 0.3 | 0.018 | 0.07 |
I80–82 (VTE extremities) | 17 (1) | 1.3 | 216 (1) | 1.0 | 451 (1) | 0.7 | < 0.001 | 0.39 |
Medical treatment | 247 (21) | 20.8 | 3643 (20) | 20.0 | 6656 (13) | 11.9 | < 0.001 | 0.35 |
Antithrombotics (B01) | 50 (4) | 3.8 | 940 (5) | 4.6 | 1887 (4) | 3.2 | < 0.001 | 0.15 |
Antihypertensive (C02, C07–09) | 189 (16) | 15.4 | 2744 (15) | 14.5 | 5087 (10) | 8.9 | < 0.001 | 0.30 |
Antilipids (C10) | 121 (10) | 9.4 | 1601 (9) | 8.1 | 2833 (5) | 4.8 | < 0.001 | 0.06 |
Baseline characteristics according to subsequent development of CVD in PCOS OUH (Table 2)
Development of CVD | P# | ||||
---|---|---|---|---|---|
Yes N = 264 | No N = 895 | ||||
Baseline characteristics | N (%) | Median (Q1–Q3) | N (%) | Median (Q1–Q3) | |
Age (years) | 230 (100) | 35 (28–39) | 935 (100) | 27 (21–33) | < 0.001 |
BMI (kg/m2) | 245 (93) | 30.2 (25.1–35,2) | 831 (93) | 26.1 (22.6–31.1) | < 0.001 |
Waist (cm) | 134 (51) | 100 (84–110) | 587 (66) | 87 (77–100) | < 0.001 |
Systolic BP (mmHg) | 148 (56) | 130 (120–140) | 624 (70) | 123 (114–131) | 0.002 |
Diastolic BP (mmHg) | 148 (56) | 85 (78–92) | 650 (70) | 80 (70–86) | < 0.001 |
LDL cholesterol (mmol/L) | 184 (70) | 3.2 (2.6–3.9) | 663 (74) | 2.6 (2.1–3.1) | 0.275 |
HDL cholesterol (mmol/L) | 186 (70) | 1.3 (1.1–1.6) | 663 (74) | 1.4 (1.1–1.6) | < 0.001 |
Cholesterol (mmol/L) | 186 (70) | 5.2 (4.5–5.9) | 674 (75) | 4.5 (4.0–5.1) | < 0.001 |
Triglycerides (mmol/L) | 186 (70) | 1.3 (0.9–1.9) | 662 (74) | 1.0 (0.7–1.3) | 0.026 |
Prolactin (µg/L) | 223 (85) | 6 (5–9) | 731 (82) | 7 (5–10) | 0.010 |
HbA1c (mmol/mol) | 108 (41) | 37 (33–42) | 463 (52) | 33 (31–37) | 0.298 |
Fasting blood glucose (mmol/L) | 150 (57) | 4.7 (4.2–5.0) | 384 (43) | 4.6 (4.3–5.0) | 0.012 |
2 h blood glucose (mmol/L) | 149 (56) | 6.4 (5.3–7.6) | 373 (42) | 6.0 (5.2–6.9) | 0.001 |
Fasting insulin (pmol/L) | 157 (60) | 60 (40–114) | 410 (46) | 53 (36–82) | 0.002 |
HOMA-ir (pmol mmol/L2) | 152 (58) | 14.8 (9.1–25.9) | 388 (43) | 11.3 (7.6–17.1) | 0.330 |
Total testosterone (nmol/L) | 170 (64) | 1.7 (1.2–2.3) | 655 (73) | 1.8 (1.3–2.5) | 0.708 |
SHBG (nmol/L) | 244 (92) | 45 (30–64) | 829 (93) | 44 (31–67) | 0.367 |
Free testosterone (nmol/L) | 167 (63) | 0.032 (0.021–0.049) | 644 (72) | 0.033 (0.021–0.050) | 0.012 |
P¤ | |||||
BMI ≥ 25 kg/m2 | 186 (76) | 469 (56) | < 0.001 | ||
BMI < 25 kg/m2 | 59 (24) | 362 (44) | |||
Waist ≥ 88 cm | 94 (71) | 277 (47) | < 0.001 | ||
Waist < 88 cm | 40 (30) | 310 (53) | |||
Systolic BP ≥ 130 mmHg | 84 (57) | 205 (33) | < 0.001 | ||
Systolic BP < 130 mmHg | 64 (43) | 420 (67) | |||
Diastolic BP ≥ 85 mmHg | 77 (52) | 186 (30) | < 0.001 | ||
Diastolic BP < 85 mmHg | 71 (48) | 438 (70) | |||
Triglycerides ≥ 1.7 mmol/L | 63 (34) | 93 (15) | < 0.001 | ||
Triglycerides < 1.7 mmol/L | 123 (66) | 569 (86) |
Baseline characteristics according to development of CVD in PCOS Denmark and controls (Table 3): women with development of CVD including hypertension and dyslipidemia in PCOS Denmark vs. controls
Development of CVD in PCOS | Development of CVD in controls | PCOS vs. controls | P A vs. B | P A vs. C | |||||
---|---|---|---|---|---|---|---|---|---|
Total | Yes A | No B | Total | Yes C | No D | ||||
Development of CVD | 17,995 | 3970 | 14,025 | 52,329 | 7344 | 44,985 | |||
Age at diagnosis (years) Median (Q1, Q3) | 29 (23–35) | 35 (28–42) | 28 (22–33) | 29 (23–35) | 36 (30–43) | 28 (23–33) | 0.009 | < 0.001 | < 0.001 |
N (%) | N (%) | N (%) | N (%) | N (%) | N (%) | ||||
Age < 50 years | 17,331 (96) | 3591 (90) | 13,740 (98) | 50,718 (97) | 6496 (88) | 44,222 (98) | < 0.001 | < 0.001 | 0.001 |
Baseline characteristics | |||||||||
Obesity | 2005 (11) | 444 (11) | 1561 (11) | 648 (1) | 121 (2) | 527 (1) | < 0.001 | 0.924 | < 0.001 |
Diabetes | 448 (3) | 198 (5) | 250 (2) | 367 (1) | 163 (2) | 204 (1) | < 0.001 | < 0.001 | < 0.001 |
Infertility | 4158 (23) | 751 (19) | 3407 (24) | 2007 (4) | 259 (4) | 1748 (4) | < 0.001 | < 0.001 | < 0.001 |
Comorbidity | 796 (4) | 215 (5) | 581 (4) | 1646 (3) | 253 (3) | 1393 (3) | < 0.001 | 0.001 | < 0.001 |
Oral contraceptives | 10,432 (58) | 1752 (44) | 8680 (62) | 16,005 (31) | 1652 (23) | 14,353 (32) | < 0.001 | < 0.001 | < 0.001 |
Development of CVD (HT and DL excluded) | 17,995 | 1290 | 16,705 | 52,329 | 2678 | 49,651 | |||
Age at diagnosis (years) Median (Q1, Q3) | 29 (23–35) | 36 (29–44) | 29 (23–35) | 29 (23–35) | 38 (31–46) | 28 (23–34) | 0.009 | < 0.001 | < 0.001 |
N (%) | N (%) | N (%) | N (%) | N (%) | N (%) | ||||
Age < 50 years | 17,331 (96) | 1098 (85) | 16,233 (97) | 50,718 (97) | 2235 (83) | 48,4834 (98) | < 0.001 | < 0.001 | 0.182 |
Baseline characteristics | |||||||||
Obesity | 2005 (11) | 128 (10) | 1877 (11) | 648 (1) | 39 (1) | 609 (1) | < 0.001 | 0.149 | < 0.001 |
Diabetes | 448 (3) | 60 (5) | 388 (2) | 367 (1) | 57 (2) | 310 (1) | < 0.001 | < 0.001 | < 0.001 |
Infertility | 4158 (23) | 217 (17) | 3941 (24) | 2007 (4) | 95 (4) | 1912 (4) | < 0.001 | < 0.001 | < 0.001 |
Comorbidity | 796 (4) | 98 (8) | 698 (4) | 1646 (3) | 105 (4) | 1541 (3) | < 0.001 | < 0.001 | < 0.001 |
Oral contraceptives | 10,432 (58) | 497 (39) | 9935 (60) | 16,005 (31) | 513 (19) | 15,492 (31) | < 0.001 | < 0.001 | < 0.001 |
PCOS Denmark and development of CVD yes vs. no
Proportional hazard regression analyses
Crude HR (95% CI) | Adjusted HR HR (95% CI) | Adjusted HR HR (95% CI) | Adjusted HR HR (95% CI) | Adjusted HR HR (95% CI) | Adjusted HR HR (95% CI) | Adjusted HR HR (95% CI) | |
---|---|---|---|---|---|---|---|
Outcome: CVD | |||||||
PCOS (yes/no) | 1.7 (1.7; 1.8) P < 0.001 | 1.6 (1.5; 1.7) P < 0.001 | 1.7 (1.6; 1.8) P < 0.001 | 1.7 (1.6; 1.8) P < 0.001 | 1.7 (1.6; 1.7) P < 0.001 | 1.7 (1.6; 1.8) P < 0.001 | 1.6 (1.5; 1.6) P < 0.001 |
Predictors | |||||||
Obesity | 2.7 (2.4; 3.1) P < 0.001 | 2.4 (2.1; 2.7) P < 0.001 | |||||
Diabetes (yes/no) | 4.9 (4.1; 5.9) P < 0.001 | 4.4 (3.6; 5.3) P < 0.001 | |||||
Infertility (yes/no) | 1.2 (1.1; 1.3) P = 0.001 | 1.0 (0.9; 1.1) P = 0.802 | |||||
Comorbidity | 1.6 (1.4; 1.8) P < 0.001 | ||||||
OCP (yes/no) | 1.1 (1.1; 1.2) P < 0.001 | 1.1 (1.1; 1.2) P < 0.001 | |||||
Outcome: CVD (HT and DL excluded) | |||||||
PCOS (yes/no) | 1.4 (1.3; 1.5) P < 0.001 | 1.3 (1.2; 1.4) P < 0.001 | 1.4 (1.3; 1.5) P < 0.001 | 1.4 (1.3; 1.5) P < 0.001 | 1.4 (1.3; 1.8) P < 0.001 | 1.4 (1.3; 1.5) P < 0.001 | 1.3 (1.2; 1.4) P < 0.001 |
Predictors | |||||||
Obesity | 2.4 (1.9; 3.1) P < 0.001 | 2.1 (1.7; 2.7) P < 0.001 | |||||
Diabetes (yes/no) | 2.9 (2.2; 3.8) P < 0.001 | 2.5 (1.9; 3.3) P < 0.001 | |||||
Infertility (yes/no) | 1.3 (1.1; 1.5) P = 0.001 | 1.2 (1.0; 1.4) P = 0.019 | |||||
Comorbidity | 1.8 (1.5; 2.1) P < 0.001 | ||||||
OCP (yes/no) | 1.0 (0.9; 1.1) P = 0.661 | 1.0 (0.9; 1.1) P = 0.687 |
CVD | CVD (HT and DL excluded) | |||||
---|---|---|---|---|---|---|
Crude HR (95% CI) | n | Age and BMI Adjusted HRa (95% CI) | Crude HR (95% CI) | n | Age and BMI Adjusted HRa (95% CI) | |
Age (years) | 1.1 (1.1; 1.1) P < 0.001 | 1076 | 1.1 (1.1; 1.1) P < 0.001 | 1.1 (1.1; 1.1) P < 0.001 | 1076 | 1.1 (1.1; 1.1) P < 0.001 |
BMI (kg/m2) | 1.1 (1.0; 1.1) P < 0.001 | 1076 | 1.1 (1.1; 1.1) P < 0.001 | 1.1 (1.0; 1.1) P < 0.001 | 1076 | 1.1 (1.1; 1.1) P < 0.001 |
Waist (cm) | 1.0 (1.0;1.0) P < 0.001 | 710 | 1.0 (1.0; 1.0) P = 0.02 | 1.0 (1.0;1.0) P = 0.004 | 710 | 1.0 (1.0; 1.1) P = 0.61 |
Systolic BP (mmHg) | 1.0 (1.0; 1.1) p < 0.001 | 730 | 1.0 (1.0; 1.0) p < 0.001 | 1.0 (1.0; 1.1) P = 0.001 | 730 | 1.0 (1.0; 1.0) P = 0.09 |
Diastolic BP (mmHg) | 1.1 (1.0; 1.1) P < 0.001 | 729 | 1.0 (1.0; 1.1) P < 0.001 | 1.1 (1.0; 1.1) P < 0.001 | 729 | 1.0 (1.0; 1.1) P = 0.06 |
LDL (mmol/l) | 1.8 (1.6; 2.1) P < 0.001 | 804 | 1.5 (1.2; 1.7) P < 0.001 | 1.3 (1.0; 1.8) P = 0.06 | 804 | 1.1 (0.7; 1.5) P = 0.78 |
Cholesterol (mmol/L) | 1.8 (1.6; 2.1) P < 0.001 | 815 | 1.5 (1.3; 1.7) P < 0.001 | 1.4 (1.0; 1.8) P < 0.02 | 815 | 1.1 (0.8; 1.5) P = 0.41 |
Triglycerides (mmol/L) | 1.7 (1.4; 2.0) P < 0.001 | 805 | 1.5 (1.2; 1.7) P < 0.001 | 1.3 (0.9; 1.8) P = 15 | 805 | 1.1 (0.7; 1.6) P = 0.63 |
Prolactin (µg/L) | 0.96 (0.9; 1.0) P = 0.02 | 891 | 0.99 (0.95; 1.02) P = 0.61 | 1.0 (0.9; 1.1) P = 0.89 | 891 | 1.0 (1.0; 1.1) P = 0.33 |
HbA1c (mmol/mol) | 1.0 (1.0; 1.0) P = 0.30 | 525 | 1.0 (1.0; 1.0) P = 0.73 | 1.0 (1.0; 1.0) P = 0.64 | 525 | 1.0 (1.0; 1.0) P = 0.81 |
Fasting blood glucose (mmol/L) | 1.5 (1.3; 1.8) P < 0.001 | 510 | 1.3 (1.1; 1.5) P = 0.001 | 1.5 (1.2; 2.0) P = 0.001 | 510 | 1.2 (1.0; 1.7) P = 0.15 |
2 h blood glucose (mmol/L) | 1.2 (1.1; 1.3) P < 0.001 | 497 | 1.1 (1.1; 1.2) P < 0.001 | 1.2 (1.1; 1.3) P = 0.003 | 497 | 1.1 (1.0; 1.2) P = 0.12 |
Fasting insulin (pmol/L) | 1.0 (1.0; 1.0) P < 0.001 | 533 | 1.0 (1.0; 1.0) P = 0.007 | 1.0 (1.0; 1.0) P = 0.32 | 533 | 1.0 (1.0; 1.0) P = 0.82 |
HOMA-ir (µg/L) | 1.0 (1.0; 1.0) P < 0.001 | 509 | 1.0 (1.0; 1.0) P = 0.001 | 1.0 (1.0; 1.0) P = 0.13 | 509 | 1.0 (1.0; 1.0) P = 0.81 |
Total testosterone (nmol/L) | 0.9 (0.8; 1.1) P = 0.25 | 772 | 1.0 (0.9; 1.2) P = 0.99 | 0.9 (0.7; 1.3) P = 0.72 | 772 | 1.0 (0.8; 1.4) P = 0.89 |
SHBG (nmol/L) | 1.0 (1.0; 1.0) P = 0.43 | 1000 | 1.0 (1.0; 1.0) P = 0.30 | 1.0 (1.0; 1.0) P = 0.77 | 1000 | 1.0 (1.0; 1.0) P = 0.23 |
Free testosterone (nmol/L) | 0.75 (0.01; 39.37) P = 0.89 | 759 | 1.9 (0.03; 112.8) P = 0.75 | 0.0 (0.0; 338.2) P = 0.26 | 759 | 0.0 (0.0; 1858.0) P = 0.36 |