Table 2.
Difference in average percent mammographic density [β (95% confidence interval)] by quartile of EM measure (pmol/mg creatinine) (n = 352).
| a) Total EM, parent estrogens, and estrogen hydroxylation pathways | ||||||
|---|---|---|---|---|---|---|
| Quartiles | ||||||
| Grouped EM | 1 | 2 | 3 | 4 | p-trend | |
| Total EM | cutpoints | <142.7 | 142.7–194.1 | 195.0–266.4 | >266.4 | |
| Model 1 | ref | 2.3 (−2.9, 7.6) | 2.5 (−2.8, 7.8) | 4.6 (−0.7, 10.0) | 0.11 | |
| Model 2 | ref | −1.2 (−5.6, 3.2) | −1.1 (−5.7, 3.5) | 3.4 (−1.1, 8.0) | 0.08 | |
| Parent estrogens | cutpoints | <27.4 | 27.4−42.7 | 42.9−61.4 | >61.4 | |
| Model 1 | ref | −0.1 (−5.2, 5.1) | −0.9 (−6.3, 4.5) | −1.9 (−7.2, 3.5) | 0.46 | |
| Model 2 | ref | −0.3 (−4.3, 3.8) | −1.0 (−5.3, 3.3) | 0.2 (−4.3, 4.7) | 0.96 | |
| Estrone | cutpoints | <17.8 | 17.8−27.7 | 28.1−40.9 | >40.9 | |
| Model 1 | ref | 2.8 (−2.0, 7.6) | 0.5 (−4.6, 5.7) | −0.4 (−5.7, 4.8) | 0.63 | |
| Model 2 | ref | 0.2 (−4.0, 4.4) | −1.1 (−5.2, 3.0) | 0.0 (−4.6, 4.5) | 0.90 | |
| Estradiol | cutpoints | <9.3 | 9.3−13.6 | 13.6−19.9 | >19.9 | |
| Model 1 | ref | −2.2 (−7.5, 3.1) | −0.2 (−6.1, 5.7) | −4.4 (−10.2, 1.3) | 0.16 | |
| Model 2 | ref | −2.3 (−6.5, 2.0) | −0.2 (−4.9, 4.6) | −0.7 (−5.7, 4.3) | 0.99 | |
| 2-Hydroxylation pathway | cutpoints | <44.5 | 44.5−67.4 | 67.7−106.2 | >106.2 | |
| Model 1 | ref | 2.8 (−2.8, 8.5) | 5.7 (0.4, 11.0) | 6.5 (1.3, 11.7) | 0.01 | |
| Model 2 | ref | 0.1 (−4.8, 5.1) | 0.3 (−4.2, 4.8) | 2.8 (−1.6, 7.1) | 0.18 | |
| 4-Hydroxylation pathway | cutpoints | <3.2 | 3.2−6.0 | 6.0−9.7 | >9.7 | |
| Model 1 | ref | −0.3 (−5.7, 5.2) | −2.8 (−7.9, 2.3) | 1.2 (−4.1, 6.5) | 0.65 | |
| Model 2 | ref | 0.1 (−4.3, 4.5) | −2.8 (−6.9, 1.4) | 0.8 (−3.5, 5.2) | 0.74 | |
| 16-Hydroxylation pathway | cutpoints | <42.7 | 42.7−71.0 | 71.6−106.4 | >106.4 | |
| Model 1 | ref | −5.8 (−10.9, −0.8) | −2.9 (−8.2, 2.5) | −1.3 (−6.1, 3.6) | 0.82 | |
| Model 2 | ref | −4.0 (−8.1, 0.1) | −1.6 (−6.3, 3.1) | 0.3 (−3.7, 4.3) | 0.39 | |
| b) Catechol estrogen metabolites | |||||||
|---|---|---|---|---|---|---|---|
| Quartiles | |||||||
| Grouped EM | Individual EM | 1 | 2 | 3 | 4 | p-trend | |
| Catechol EM | cutpoints | <40.0 | 40.0−62.4 | 62.5−94.8 | >94.8 | ||
| Model 1 | ref | 0.3 (−5.4, 6.1) | 3.9 (−1.2, 9.1) | 7.3 (2.6, 12.1) | <0.01 | ||
| Model 2 | ref | −0.9 (−5.9, 4.1) | −0.3 (−4.6, 4.0) | 3.4 (−0.9, 7.7) | 0.08 | ||
| 2-pathway catechol EM | cutpoints | <37.0 | 37.0−54.8 | 55.9−87.9 | >87.9 | ||
| Model 1 | ref | 2.2 (−3.4, 7.7) | 4.4 (−0.8, 9.6) | 8.0 (3.1, 13.0) | <0.01 | ||
| Model 2 | ref | 0.3 (−4.6, 5.2) | 0.0 (−4.4, 4.3) | 4.0 (−0.4, 8.4) | 0.06 | ||
| 2-Hydroxyestrone | cutpoints | <32.5 | 32.5−50.2 | 50.6−77.8 | >77.8 | ||
| Model 1 | ref | 3.2 (−2.3, 8.7) | 5.2 (0.1, 10.3) | 8.3 (3.4, 13.3) | <0.01 | ||
| Model 2 | ref | 0.8 (−4.0, 5.5) | 0.2 (−4.1, 4.5) | 4.2 (−0.1, 8.5) | 0.06 | ||
| 2-Hydroxyestradiol | cutpoints | <3.3 | 3.3−5.3 | 5.4−8.8 | >8.8 | ||
| Model 1 | ref | −0.7 (−5.9, 4.6) | 3.5 (−2.1, 9.0) | 4.6 (−0.4, 9.6) | 0.03 | ||
| Model 2 | ref | −2.0 (−6.4, 2.4) | 1.1 (−3.5, 5.7) | 2.2 (−2.4, 6.7) | 0.16 | ||
| 4-pathway catechol EM | 4-Hydroxyestrone | cutpoints | <2.9 | 2.9−5.7 | 5.7−9.4 | >9.4 | |
| Model 1 | ref | −0.9 (−6.4, 4.6) | −2.7 (−7.9, 2.5) | 0.6 (−4.7, 5.8) | 0.78 | ||
| Model 2 | ref | 0.5 (−3.9, 4.9) | −2.3 (−6.5, 2.0) | 0.6 (−3.7, 4.9) | 0.90 | ||
| c) Methylated catechol estrogen metabolites | |||||||
|---|---|---|---|---|---|---|---|
| Quartiles | |||||||
| Grouped EM | Individual EM | 1 | 2 | 3 | 4 | p-trend | |
| Methylated catechol EM | cutpoints | <7.4 | 7.4–10.8 | 10.9–15.6 | >15.6 | ||
| Model 1 | ref | 1.6 (−3.8, 7.0) | 4.9 (−0.4, 10.3) | 4.5 (−0.7, 9.6) | 0.07 | ||
| Model 2 | ref | −2.2 (−7.2, 2.8) | 0.1 (−4.6, 4.9) | 0.7 (−3.5, 4.8) | 0.51 | ||
| Methylated 2-pathway Catechol EM | cutpoints | <7.0 | 7.0–10.5 | 10.6–15.3 | >15.3 | ||
| Model 1 | ref | 3.3 (−1.9, 8.6) | 5.2 (−0.1, 10.6) | 5.6 (0.3, 10.8) | 0.04 | ||
| Model 2 | ref | −0.2 (−5.1, 4.8) | 0.9 (−3.8, 5.6) | 2.0 (−2.2, 6.2) | 0.28 | ||
| 2-Methoxyestrone | cutpoints | <5.7 | 5.7–8.5 | 8.5–12.2 | >12.2 | ||
| Model 1 | ref | 1.2 (−4.0, 6.5) | 6.9 (1.6, 12.3) | 3.8 (−1.7, 9.2) | 0.13 | ||
| Model 2 | ref | −1.4 (−6.2, 3.4) | 2.0 (−2.7, 6.7) | 1.2 (−3.0, 5.5) | 0.39 | ||
| 2-Methoxyestradiol | cutpoints | <0.45 | 0.45−0.74 | 0.74−1.09 | >1.09 | ||
| Model 1 | ref | 3.0 (−2.5, 8.4) | 4.2 (−0.8, 9.2) | 2.8 (−2.6, 8.2) | 0.34 | ||
| Model 2 | ref | 0.1 (−4.6, 4.8) | −0.7 (−5.3, 3.8) | 1.4 (−3.0, 5.8) | 0.58 | ||
| 2-Hydroxyestrone-3-methyl ether |
cutpoints | <0.75 | 0.75−1.1 | 1.1−1.7 | >1.7 | ||
| Model 1 | ref | 7.3 (1.6, 13.0) | 4.8 (−0.6, 10.2) | 7.3 (2.1, 12.5) | 0.04 | ||
| Model 2 | ref | 1.3 (−4.0, 6.6) | 0.8 (−3.9, 5.6) | 3.6 (−1.0, 8.1) | 0.11 | ||
| Methylated 4-pathway Catechol EM | cutpoints | <0.11 | 0.11−0.20 | 0.20–0.41 | >0.41 | ||
| Model 1 | ref | 2.0 (−3.8, 7.8) | 0.8 (−4.4, 6.1) | 5.8 (0.2, 11.3) | 0.04 | ||
| Model 2 | ref | −0.1 (−4.7, 4.6) | −2.0 (−6.6, 2.7) | 0.8 (−3.7, 5.2) | 0.67 | ||
| 4-Methoxyestrone | cutpoints | <0.06 | 0.06–0.13 | 0.14–0.27 | >0.27 | ||
| Model 1 | ref | 1.1 (−5.1, 7.3) | 1.0 (−4.5, 6.5) | 5.6 (0.2, 10.9) | 0.02 | ||
| Model 2 | ref | −1.3 (−6.2, 3.6) | −4.0 (−8.8, 0.8) | −0.9 (−5.4, 3.5) | 0.99 | ||
| 4-Methoxyestradiol | cutpoints | <0.02 | 0.02−0.04 | 0.04−0.12 | >0.12 | ||
| Model 1 | ref | 3.3 (−2.1, 8.8) | 1.3 (−4.7, 7.3) | 5.8 (0.0, 11.6) | 0.06 | ||
| Model 2 | ref | 1.6 (−2.8, 6.1) | −0.7 (−5.5, 4.1) | 3.5 (−1.1, 8.1) | 0.12 | ||
| d) 16-hydroxylation pathway estrogen metabolites | ||||||
|---|---|---|---|---|---|---|
| Quartiles | ||||||
| Individual EM | 1 | 2 | 3 | 4 | p-trend | |
| 16α-Hydroxyestrone | cutpoints | <7.1 | 7.1–11.8 | 11.8–20.0 | >20.0 | |
| Model 1 | ref | −10.0 (−15.4, −4.6) | −6.5 (−11.8, −1.3) | −1.8 (−6.8, 3.3) | 0.34 | |
| Model 2 | ref | −7.2 (−11.8, −2.7) | −5.9 (−10.4, −1.4) | −2.1 (−6.6, 2.3) | 0.66 | |
| 17-Epiestriol | cutpoints | <0.74 | 0.74–1.5 | 1.5–2.8 | >2.8 | |
| Model 1 | ref | −5.2 (−10.3, −0.2) | −2.0 (−7.6, 3.7) | −4.8 (−10.0, 0.5) | 0.26 | |
| Model 2 | ref | −5.0 (−9.4, −0.5) | −1.7 (−6.8, 3.4) | −1.8 (−5.9, 2.2) | 1.00 | |
| Estriol | cutpoints | <18.4 | 18.4–30.3 | 30.5–46.8 | >46.8 | |
| Model 1 | ref | −1.7 (−6.7, 3.2) | −3.4 (−8.5, 1.8) | −4.8 (−10.1, 0.4) | 0.07 | |
| Model 2 | ref | −0.2 (−4.5, 4.1) | −1.9 (−6.4, 2.5) | −0.9 (−5.3, 3.5) | 0.61 | |
| 16-Ketoestradiol | cutpoints | <8.9 | 8.9–14.2 | 14.3–20.3 | >20.3 | |
| Model 1 | ref | −3.5 (−8.2, 1.2) | −2.6 (−8.1, 2.9) | −0.7 (−5.8, 4.4) | 0.87 | |
| Model 2 | ref | −2.6 (−6.5, 1.4) | −1.4 (−5.8, 3.0) | −1.1 (−5.4, 3.2) | 0.91 | |
| 16-Epiestriol | cutpoints | <4.2 | 4.2–6.3 | 6.4–9.0 | >9.0 | |
| Model 1 | ref | −6.9 (−12.0, −1.7) | −1.0 (−6.4, 4.4) | −6.5 (−11.8, −1.1) | 0.14 | |
| Model 2 | ref | −5.7 (−10.1, −1.4) | 0.4 (−4.4, 5.2) | −2.5 (−7.1, 2.0) | 0.94 | |
| e) Ratios of metabolic pathway groups | ||||||
|---|---|---|---|---|---|---|
| Quartiles | ||||||
| Ratios of EM | 1 | 2 | 3 | 4 | p-trend | |
| 4-pathway catechol/2-pathway catechols |
cutpoints | <0.06 | 0.06–0.10 | 0.10–0.15 | >0.15 | |
| Model 1 | ref | −4.0 (−9.5, 1.5) | −7.7 (−12.9, −2.5) | −5.6 (−10.7, −0.6) | 0.05 | |
| Model 2 | ref | −1.0 (−5.5, 3.5) | −3.6 (−7.9, 0.7) | −1.7 (−6.1, 2.6) | 0.45 | |
| Catechols/Methylated catechols | cutpoints | <4.0 | 4.0–5.6 | 5.6–7.7 | >7.7 | |
| Model 1 | ref | 2.5 (−3.0, 8.1) | 3.3 (−2.4, 9.1) | 1.2 (−3.5, 6.0) | 0.73 | |
| Model 2 | ref | 1.7 (−2.6, 6.0) | 1.5 (−3.5, 6.4) | 2.2 (−1.7, 6.1) | 0.34 | |
| 2-pathway catechols/Methylated 2- pathway catechols |
cutpoints | <3.75 | 3.75−5.2 | 5.2–7.0 | >7.0 | |
| Model 1 | ref | 5.0 (−0.5, 10.4) | 3.7 (−2.3, 9.7) | 4.2 (−0.7, 9.1) | 0.18 | |
| Model 2 | ref | 0.9 (−3.6, 5.4) | 0.5 (−4.4, 5.5) | 2.4 (−1.9, 6.6) | 0.29 | |
| 4-pathway catechol/Methylated 4- pathwhay catechols |
cutpoints | <11.5 | 11.5–26.6 | 26.7–59.4 | >59.4 | |
| Model 1 | ref | −0.8 (−6.2, 4.6) | −4.2 (−9.7, 1.4) | −3.1 (−8.2, 1.9) | 0.21 | |
| Model 2 | ref | 1.1 (−3.6, 5.8) | −1.0 (−5.4, 3.5) | 0.3 (−3.9, 4.5) | 0.98 | |
| Parent estrogens/Estrogen | cutpoints | <0.20 | 0.20–0.27 | 0.27–0.36 | >0.36 | |
| metabolites | Model 1 | ref | −1.7 (−7.2, 3.8) | −6.5 (−11.7, −1.2) | −6.0 (−11.3, −0.6) | 0.01 |
| Model 2 | ref | −1.2 (−5.8, 3.4) | −3.8 (−8.1, 0.5) | −1.3 (−5.5, 2.8) | 0.44 | |
| 2-pathway/Parent estrogens | cutpoints | <1.08 | 1.08–1.6 | 1.6–2.3 | >2.3 | |
| Model 1 | ref | 4.7 (−0.8, 10.1) | 8.3 (2.9, 13.6) | 9.1 (4.0, 14.2) | <0.01 | |
| Model 2 | ref | −0.2 (−5.1, 4.7) | 1.1 (−3.7, 5.8) | 1.4 (−3.1, 5.9) | 0.44 | |
| 4-pathway/Parent estrogens | cutpoints | <0.08 | 0.08–0.13 | 0.13–0.21 | >0.21 | |
| Model 1 | ref | 2.2 (−3.0, 7.5) | 4.3 (−1.3, 9.9) | 3.5 (−1.4, 8.3) | 0.22 | |
| Model 2 | ref | −1.1 (−5.4, 3.3) | 2.4 (−2.1, 6.9) | −0.7 (−4.6, 3.2) | 0.85 | |
| 16-pathway/Parent estrogens | cutpoints | <1.13 | 1.13−1.57 | 1.58−2.3 | >2.3 | |
| Model 1 | ref | 2.0 (−3.5, 7.5) | −0.9 (−6.4, 4.5) | 1.3 (−3.9, 6.6) | 0.79 | |
| Model 2 | ref | 1.4 (−3.5, 6.3) | −1.6 (−6.4, 3.1) | 1.8 (−2.6, 6.2) | 0.49 | |
| 4-pathway/2-pathway | cutpoints | <0.06 | 0.06−0.09 | 0.09–0.13 | >0.13 | |
| Model 1 | ref | −3.1 (−8.3, 2.2) | −8.0 (−13.1, −2.9) | −6.1 (−11.3, −1.0) | 0.02 | |
| Model 2 | ref | −0.4 (−4.8, 4.0) | −4.6 (−9.0, −0.2) | −1.3 (−5.4, 2.8) | 0.48 | |
| 2-pathway/16-pathway | cutpoints | <0.61 | 0.61–1.0 | 1.0–1.67 | >1.67 | |
| Model 1 | ref | 1.0 (−4.8, 6.8) | 9.5 (4.1, 15.0) | 5.9 (0.9, 10.9) | <0.01 | |
| Model 2 | ref | −2.0 (−6.6, 2.7) | 4.9 (0.3, 9.5) | 1.1 (−3.3, 5.4) | 0.23 | |
| 4-pathway/16-pathway | cutpoints | <0.05 | 0.05–0.09 | 0.09–0.15 | >0.15 | |
| Model 1 | ref | 0.6 (−5.0, 6.1) | 2.1 (−3.8, 7.9) | 3.3 (−2.1, 8.6) | 0.17 | |
| Model 2 | ref | −1.2 (−5.6, 3.3) | −1.2 (−5.9, 3.5) | 0.2 (−4.5, 4.9) | 0.75 | |
| 2-hydroxyestrone/16a- hydroxyestrone |
cutpoints | <2.4 | 2.4−4.3 | 4.3−7.0 | >7.0 | |
| Model 1 | ref | 1.7 (−4.1, 7.4) | 5.8 (0.3, 11.2) | 3.8 (−1.3, 8.9) | 0.09 | |
| Model 2 | ref | −0.2 (−5.2, 4.8) | 1.4 (−3.4, 6.1) | 0.8 (−3.8, 5.4) | 0.62 | |
EM; estrogens and estrogen metabolites
Model 1: Adjusted for age at urine collection, age at mammogram, first morning urine sample (yes, no), age at menarche (<12, 12, 13, ≥14), parity & age at first birth (nulliparous, 1–2 children & <25 yrs, 1–2 children & 25–29 yrs, 1–2 children & ≥30 yrs, 3+ children & <25 yrs, 3+ children & ≥25 yrs, missing), family history of breast cancer (yes, no), alcohol intake (0 g/d, 0.1–4.9 g/d, 5–14.9 g/d, 15+g/d, missing)
Model 2: Additionally adjusted for body mass index at urine collection (continuous, kg/m2)