Phytoestrogens and Thyroid Cancer Risk: A Population-Based Case–Control Study in Connecticut

Qian Wang; Huang Huang; Nan Zhao; Xin Ni; Robert Udelsman; Yawei Zhang

doi:10.1158/1055-9965.EPI-19-0456

DOI: 10.1158/1055-9965.EPI-19-0456 Published February 2020

Article Figures & Data

Tables

Additional Files

Table 1.

Selected characteristics among thyroid cancer cases and controls.

	Cases (n = 387)^a	Controls (n = 433)^a
	n (%)	n (%)	P
Age (years)			<0.01
Mean (SD)	51.7 (12.3)	54.8 (12.5)
<40	68 (17.6)	48 (11.1)
40–49	93 (24.0)	108 (24.9)
50–59	125 (32.3)	121 (27.9)
60–69	74 (19.1)	93 (21.5)
≥70	27 (7.0)	63 (14.6)
Gender			<0.01
Female	317 (81.9)	306 (70.7)
Male	70 (18.1)	127 (29.3)
Race			0.51
White	348 (89.9)	394 (91.2)
Black	16 (4.1)	20 (4.6)
Other	23 (5.9)	18 (4.2)
BMI (kg/m²)			<0.01
<25	126 (32.6)	176 (40.7)
25–29.99	116 (30.0)	146 (33.7)
≥30	143 (37.0)	106 (24.5)
Education			<0.01
High school or less	107 (27.7)	73 (16.9)
Some college	24 (6.2)	23 (5.3)
College graduate or more	243 (62.8)	323 (74.6)
Others	12 (3.1)	11 (2.5)
Family history of any cancer			0.33
None	112 (28.9)	139 (32.1)
Any cancer	275 (71.1)	294 (67.9)
Prior benign thyroid disease^b			<0.01
Yes	227 (58.7)	14 (3.2)
No	160 (41.3)	419 (96.8)
Previous radiation exposure^c			0.63
Yes	385 (99.7)	427 (99.5)
No	1 (0.3)	2 (0.5)
Alcohol consumption^d			<0.01
Never	223 (57.6)	193 (44.3)
Ever	163 (42.1)	238 (55.2)
Smoking^e			0.54
Never	270 (70.0)	293 (68.0)
Ever	116 (30.0)	138 (32.0)
Daily caloric intake (kcal/day)	2,399 ± 1,823	2,475 ± 966	0.45
% of calories from fat	36% ± 6%	35% ± 5%	0.12
Total carotenoid intake (μg/day)^f	7,338 ± 9,229	9,098 ± 12,750	0.03
Vitamin C intake (mg/day)^f	305 ± 313	321 ±273	0.45
Vitamin E intake (mg/day)^f	45 ± 99	42 ± 87	0.67
Fiber intake (g/day)	24 ± 20	26 ± 13	0.24

↵^aNumbers may not sum to total due to missing data.
↵^bBenign thyroid diseases included hyperthyroidism, hypothyroidism, goiter, thyroid nodules, and thyroid adenoma.
↵^cPrevious radiation exposure included previous diagnostic and therapeutic radiation exposure.
↵^dEver alcohol consumption was defined as ever had more than 12 drinks of alcoholic beverages, such as beer, wine, or liquor. 1 drink beer = 1 can or bottle; 1 drink wine = 14 oz. glass; 1 drunk liquor = 1 shot.
↵^eEver smoking was defined as ever smoked a total of 100 cigarettes or more.
↵^fBoth food sources and supplements.

Table 2.

Risk of thyroid cancer associated with PE intake among all cases and by histology subtypes.

	Controls	All cases (n = 387)		Papillary (n = 328)		Well differentiated (n = 377)
PE intake	(n = 433)	Cases	OR^a (95% CI)	Cases	OR^a (95% CI)	Cases	OR^a (95% CI)
Genistein (μg/day)
<760	88	81	1.00 (—)	70	1.00 (—)	78	1.00 (—)
760–1,260	85	66	0.93 (0.51–1.68)	55	0.73 (0.39–1.37)	66	0.95 (0.52–1.72)
1,260–1,860	86	74	1.06 (0.60–1.88)	66	1.09 (0.61–1.96)	73	1.10 (0.62–1.94)
1,860–3,110	87	83	0.97 (0.54–1.71)	69	0.74 (0.40–1.36)	80	0.93 (0.52–1.67)
>3,110	87	83	1.21 (0.69–2.12)	68	0.98 (0.54–1.76)	80	1.18 (0.67–2.07)
P for linear trend			0.25		0.44		0.31
Daidzein (μg/day)
<530	88	73	1.00 (—)	62	1.00 (—)	70	1.00 (—)
530–910	85	72	1.31 (0.72–2.36)	62	1.08 (0.58–2.01)	72	1.35 (0.74–2.45)
910–1,310	86	76	1.30 (0.73–2.32)	69	1.35 (0.75–2.43)	75	1.34 (0.75–2.40)
1,310–2,240	87	86	1.26 (0.70–2.24)	71	0.98 (0.53–1.81)	82	1.20 (0.67–2.16)
>2,240	87	80	1.35 (0.76–2.39)	64	1.12 (0.61–2.05)	78	1.35 (0.75–2.41)
P for linear trend			0.26		0.45		0.32
Biochanin A (μg/day)
<30	108	136	1.00 (—)	105	1.00 (—)	126	1.00 (—)
30–50	81	70	0.74 (0.43–1.27)	63	0.78 (0.44–1.37)	70	0.81 (0.47–1.39)
50–70	77	62	0.79 (0.45–1.36)	53	0.84 (0.47–1.50)	62	0.86 (0.49–1.49)
70–120	91	67	0.70 (0.41–1.21)	61	0.83 (0.47–1.47)	67	0.76 (0.44–1.32)
>120	76	52	0.60 (0.33–1.08)	46	0.67 (0.36–1.25)	52	0.64 (0.35–1.15)
P for linear trend			0.64		0.97		0.74
Formononetin (μg/day)
0	93	101	1.00 (—)	82	1.00 (—)	96	1.00 (—)
0–10	153	133	1.05 (0.64–1.71)	118	1.21 (0.72–2.02)	129	1.09 (0.66–1.79)
10–20	81	50	0.80 (0.44–1.43)	39	0.87 (0.46–1.63)	50	0.85 (0.47–1.54)
20–30	27	33	0.87 (0.39–1.92)	30	1.11 (0.49–2.51)	33	0.93 (0.42–2.06)
>30	79	70	0.98 (0.55–1.73)	59	1.02 (0.56–1.89)	69	1.00 (0.56–1.79)
P for linear trend			0.79		0.77		0.85
Glycitein (μg/day)
<100	94	82	1.00 (—)	69	1.00 (—)	79	1.00 (—)
100–170	81	69	1.34 (0.75–2.39)	59	1.22 (0.66–2.25)	69	1.40 (0.78–2.50)
170–260	89	78	1.21 (0.69–2.14)	69	1.20 (0.67–2.16)	77	1.24 (0.70–2.20)
260–430	86	76	1.07 (0.60–1.92)	64	0.93 (0.50–1.72)	73	1.05 (0.58–1.89)
>430	83	82	1.45 (0.83–2.53)	67	1.26 (0.70–2.28)	79	1.41 (0.80–2.48)
P for linear trend			0.26		0.45		0.33
Total isoflavones (μg/day)
<1,410	88	81	1.00 (—)	69	1.00 (—)	78	1.00 (—)
1,410–2,240	85	62	0.90 (0.50–1.64)	53	0.71 (0.38–1.34)	62	0.92 (0.50–1.68)
2,240–3,280	89	82	1.16 (0.66–2.03)	74	1.21 (0.68–2.14)	81	1.19 (0.68–2.09)
3,280–5,440	84	79	1.00 (0.56–1.80)	65	0.76 (0.41–1.42)	76	0.97 (0.54–1.75)
>5,440	87	83	1.25 (0.72–2.18)	67	1.01 (0.56–1.83)	80	1.21 (0.69–2.13)
P for linear trend			0.25		0.44		0.31
Coumestrol (μg/day)
<40	94	76	1.00 (—)	63	1.00 (—)	71	1.00 (—)
40–80	85	117	2.48 (1.39–4.43)	103	2.80 (1.51–5.19)	115	2.53 (1.41–4.57)
80–130	88	74	2.41 (1.32–4.40)	59	2.50 (1.31–4.78)	73	2.49 (1.35–4.59)
130–200	88	54	1.45 (0.77–2.73)	48	1.60 (0.82–3.14)	54	1.53 (0.81–2.91)
>200	78	66	2.38 (1.26–4.50)	55	2.56 (1.30–5.06)	64	2.43 (1.27–4.65)
P for linear trend			0.25		0.18		0.26
Total PEs (μg/day)
<1,510	87	81	1.00 (—)	69	1.00 (—)	78	1.00 (—)
1,510–2,470	86	77	1.15 (0.64–2.05)	67	0.97 (0.53–1.77)	77	1.19 (0.66–2.13)
2,470–3,400	86	65	1.18 (0.67–2.10)	57	1.21 (0.67–2.19)	64	1.22 (0.68–2.18)
3,400–5,560	87	79	0.94 (0.52–1.70)	66	0.74 (0.40–1.39)	76	0.92 (0.50–1.66)
>5,560	87	85	1.36 (0.78–2.37)	69	1.13 (0.63–2.04)	82	1.32 (0.75–2.33)
P for linear trend			0.25		0.44		0.31

↵^aAdjusted for age, gender, race, family history of any cancer, education, BMI, history of benign thyroid disease, and previous alcohol consumption.

Table 3.

Risk of thyroid cancer associated with PE intake for thyroid cancer among papillary carcinomas by tumor size.

		Papillary carcinoma
		≤1 cm (n = 158)		>1 cm (n = 167)
PE intake	Controls (n = 433)	Cases	OR^a (95% CI)	Cases	OR^a (95% CI)
Genistein (μg/day)
<760	88	37	1.00 (—)	31	1.00 (—)
760–1,260	85	25	0.54 (0.24–1.24)	30	0.86 (0.39–1.91)
1,260–1,860	86	33	1.12 (0.55–2.30)	33	1.06 (0.49–2.29)
1,860–3,110	87	34	0.61 (0.28–1.33)	34	0.75 (0.34–1.68)
>3,110	87	29	0.78 (0.36–1.67)	39	1.19 (0.56–2.53)
P for linear trend			0.71		0.15
Daidzein (μg/day)
<530	88	32	1.00 (—)	28	1.00 (—)
530–910	85	31	0.93 (0.42–2.05)	31	1.07 (0.48–2.42)
910–1,310	86	33	1.38 (0.66–2.87)	36	1.39 (0.65–3.00)
1,310–2,240	87	35	0.84 (0.39–1.82)	35	0.87 (0.39–1.96)
>2,240	87	27	0.88 (0.40–1.94)	37	1.34 (0.61–2.92)
P for linear trend			0.70		0.15
Biochanin A (μg/day)
<30	108	49	1.00 (—)	55	1.00 (—)
30–50	81	37	1.04 (0.51–2.12)	26	0.67 (0.32–1.41)
50–70	77	25	0.90 (0.42–1.92)	27	0.84 (0.40–1.76)
70–120	91	30	1.00 (0.49–2.07)	31	0.65 (0.31–1.37)
>120	76	17	0.60 (0.25–1.41)	28	0.68 (0.32–1.49)
P for linear trend			0.61		0.34
Formononetin (μg/day)
0	93	41	1.00 (—)	41	1.00 (—)
0–10	153	54	1.11 (0.57–2.16)	63	1.13 (0.59–2.16)
10–20	81	22	0.89 (0.41–1.97)	17	0.74 (0.32–1.72)
20–30	27	15	1.22 (0.44–3.36)	14	0.96 (0.34–2.72)
>30	79	26	0.97 (0.45–2.11)	32	1.05 (0.48–2.28)
P for linear trend			0.76		0.59
Glycitein (μg/day)
<100	94	36	1.00 (—)	32	1.00 (—)
100–170	81	31	1.34 (0.63–2.87)	27	1.10 (0.48–2.50)
170–260	89	33	1.14 (0.54–2.39)	36	1.30 (0.61–2.74)
260–430	86	33	0.92 (0.42–2.00)	31	0.87 (0.38–1.96)
>430	83	25	1.01 (0.46–2.20)	41	1.54 (0.73–3.25)
P for linear trend			0.69		0.15
Total isoflavones (μg/day)
<1,410	88	36	1.00 (—)	31	1.00 (—)
1,410–2,240	85	24	0.69 (0.31–1.55)	29	0.64 (0.28–1.45)
2,240–3,280	89	37	1.25 (0.61–2.57)	37	1.15 (0.54–2.43)
3,280–5,440	84	33	0.73 (0.33–1.61)	31	0.65 (0.29–1.48)
>5,440	87	28	0.86 (0.40–1.87)	39	1.13 (0.53–2.38)
P for linear trend			0.70		0.15
Coumestrol (μg/day)
<40	94	24	1.00 (—)	39	1.00 (—)
40–80	85	56	4.33 (1.86–10.07)	47	2.31 (1.09–4.86)
80–130	88	31	4.38 (1.79–10.71)	27	1.46 (0.64–3.30)
130–200	88	23	2.29 (0.91–5.78)	24	1.32 (0.57–3.08)
>200	78	24	3.11 (1.22–7.91)	30	2.17 (0.94–5.02)
P for linear trend			0.34		0.50
Total PEs (μg/day)
<1,510	87	36	1.00 (—)	31	1.00 (—)
1,510–2,470	86	31	0.88 (0.40–1.92)	36	1.09 (0.50–2.37)
2,470–3,400	86	30	1.32 (0.63–2.76)	27	1.18 (0.54–2.59)
3,400–5,560	87	31	0.63 (0.28–1.42)	34	0.72 (0.32–1.65)
>5,560	87	30	1.00 (0.46–2.15)	39	1.30 (0.61–2.77)
P for linear trend			0.71		0.15

↵^aAdjusted for age, gender, race, family history of any cancer, education, BMI, history of benign thyroid disease, and previous alcohol consumption.

Table 4.

Risk of thyroid cancer associated with PE intake among female subjects.

PE intake	Controls (n = 306)	Cases (n = 317)	OR^a (95% CI)
Genistein (μg/day)
<760	64	71	1.00 (—)
760–1,260	62	55	0.59 (0.28–1.23)
1,260–1,860	66	63	0.95 (0.48–1.90)
1,860–3,110	55	65	0.88 (0.43–1.81)
>3,110	59	63	0.82 (0.40–1.68)
P for linear trend			0.37
Daidzein (μg/day)
<530	65	64	1.00 (—)
530–910	60	60	1.09 (0.53–2.25)
910–1,310	64	62	1.36 (0.67–2.77)
1,310–2,240	58	71	1.16 (0.57–2.35)
>2,240	59	60	1.03 (0.50–2.12)
P for linear trend			0.38
Biochanin A (μg/day)
<30	86	123	1.00 (—)
30–50	62	59	0.68 (0.34–1.35)
50–70	59	52	0.71 (0.35–1.43)
70–120	57	52	0.59 (0.29–1.21)
>120	42	31	0.56 (0.27–1.28)
P for linear trend			0.82
Formononetin (μg/day)
0	61	82	1.00 (—)
0–10	101	106	1.09 (0.57–2.07)
10–20	62	43	0.77 (0.37–1.58)
20–30	20	29	0.62 (0.22–1.75)
>30	62	57	0.82 (0.39–1.72)
P for linear trend			0.38
Glycitein (μg/day)
<100	68	71	1.00 (—)
100–170	62	60	0.89 (0.44–1.79)
170–260	66	66	1.17 (0.58–2.35)
260–430	52	60	0.96 (0.46–2.01)
>430	58	60	0.94 (0.46–1.89)
P for linear trend			0.42
Total isoflavones (μg/day)
<1,410	65	70	1.00 (—)
1,410–2,240	63	53	0.74 (0.36–1.52)
2,240–3,280	66	68	1.15 (0.57–2.30)
3,280–5,440	54	63	1.01 (0.49–2.09)
>5,440	58	63	0.94 (0.46–1.92)
P for linear trend			0.37
Coumestrol (μg/day)
<40	67	65	1.00 (—)
40–80	62	104	2.08 (1.01–4.29)
80–130	60	59	1.56 (0.73–3.35)
130–200	68	48	1.35 (0.63–2.88)
>200	49	41	1.50 (0.64–3.54)
P for linear trend			0.94
Total PEs (μg/day)
<1,510	63	69	1.00 (—)
1,510–2,470	65	67	0.94 (0.47–1.91)
2,470–3,400	64	54	1.21 (0.59–2.49)
3,400–5,560	56	63	0.89 (0.42–1.87)
>5,560	58	64	1.04 (0.51–2.12)
P for linear trend			0.37

↵^aAdjusted for age, race, family history of any cancer, education, BMI, history of benign thyroid disease, age at menarche, use of oral contraceptives, age at first full-term pregnancy, menopausal status, estrogen use, and previous alcohol consumption.

Table 5.

Risk of thyroid cancer associated with PE intake for thyroid cancer among papillary carcinomas by tumor size among female subjects.

		Papillary carcinoma
		≤1 cm (n = 142)		>1 cm (n = 126)
PE intake	Controls (n = 306)	Cases	OR^a (95% CI)	Cases	OR^a (95% CI)
Genistein (μg/day)
<760	64	33	1.00 (—)	28	1.00 (—)
760–1,260	62	24	0.40 (0.15–1.07)	23	0.34 (0.12–0.98)
1,260–1,860	66	32	1.19 (0.51–2.75)	26	0.54 (0.19–1.51)
1,860–3,110	55	27	0.60 (0.24–1.53)	25	0.26 (0.08–0.85)
>3,110	59	26	0.48 (0.18–1.26)	24	0.53 (0.19–1.49)
P for linear trend			0.60		0.31
Daidzein (μg/day)
<530	65	29	1.00 (—)	25	1.00 (—)
530–910	60	29	0.77 (0.30–1.97)	24	0.85 (0.30–2.42)
910–1,310	64	31	1.80 (0.76–4.27)	27	0.94 (0.33–2.64)
1,310–2,240	58	28	0.67 (0.26–1.74)	27	0.42 (0.13–1.33)
>2,240	59	25	0.63 (0.24–1.69)	23	0.84 (0.29–2.39)
P for linear trend			0.60		0.31
Biochanin A (μg/day)
<30	86	48	1.00 (—)	46	1.00 (—)
30–50	62	35	0.77 (0.33–1.83)	20	0.86 (0.32–2.32)
50–70	59	22	0.79 (0.32–1.95)	22	0.81 (0.29–2.25)
70–120	57	27	0.79 (0.33–1.89)	21	0.41 (0.14–1.25)
>120	42	10	0.38 (0.12–1.18)	17	0.91 (0.30–2.71)
P for linear trend			0.59		0.63
Formononetin (μg/day)
0	61	40	1.00 (—)	29	1.00 (—)
0–10	101	49	1.28 (0.57–2.86)	45	0.87 (0.34–2.24)
10–20	62	19	0.77 (0.30–1.93)	15	0.74 (0.25–2.19)
20–30	20	13	0.86 (0.24–3.04)	12	0.57 (0.13–2.47)
>30	62	21	0.59 (0.22–1.59)	25	0.76 (0.26–2.19)
P for linear trend			0.26		0.50
Glycitein (μg/day)
<100	68	32	1.00 (—)	28	1.00 (—)
100–170	62	30	1.05 (0.43–2.55)	23	0.56 (0.20–1.60)
170–260	66	31	1.31 (0.55–3.11)	28	0.79 (0.29–2.16)
260–430	52	26	0.83 (0.32–2.17)	23	0.44 (0.14–1.40)
>430	58	23	0.66 (0.25–1.73)	24	0.68 (0.25–1.88)
P for linear trend			0.54		0.35
Total isoflavones (μg/day)
<1,410	65	32	1.00 (—)	28	1.00 (—)
1,410–2,240	63	23	0.62 (0.24–1.62)	23	0.32 (0.11–0.95)
2,240–3,280	66	36	1.53 (0.66–3.57)	27	0.66 (0.24–1.83)
3,280–5,440	54	25	0.75 (0.29–1.92)	24	0.25 (0.07–0.83)
>5,440	58	26	0.61 (0.23–1.59)	24	0.56 (0.20–1.58)
P for linear trend			0.60		0.31
Coumestrol (μg/day)
<40	67	22	1.00 (—)	32	1.00 (—)
40–80	62	55	2.94 (1.12–7.73)	38	2.16 (0.80–5.86)
80–130	60	29	2.55 (0.91–7.14)	18	0.65 (0.19–2.20)
130–200	68	21	1.57 (0.56–4.38)	22	1.28 (0.43–3.79)
>200	49	15	1.41 (0.44–4.56)	16	1.02 (0.29–3.68)
P for linear trend			0.93		0.41
Total PEs (μg/day)
<1,510	63	32	1.00 (—)	27	1.00 (—)
1,510–2,470	65	30	0.85 (0.34–2.13)	30	0.65 (0.24–1.78)
2,470–3,400	64	29	1.60 (0.66–3.85)	19	0.72 (0.25–2.12)
3,400–5,560	56	24	0.64 (0.24–1.70)	26	0.27 (0.08–0.91)
>5,560	58	27	0.72 (0.28–1.88)	24	0.69 (0.24–1.97)
P for linear trend			0.60		0.31

↵^aAdjusted for age, race, family history of any cancer, education, BMI, history of benign thyroid disease, age at menarche, use of oral contraceptives, age at first full-term pregnancy, menopausal status, estrogen use, and previous alcohol consumption.

Additional Files

Tables

Supplementary Data

Supplementary tables 1-6 - Supplementary Table S1. Risk of thyroid cancer associated with phytoestrogen-rich foods intake among all subjects. Supplementary Table S2. Risk of thyroid cancer associated with phytoestrogen-rich foods intake by histology subtypes. Supplementary Table S3. Risk of thyroid cancer associated with phytoestrogen-rich foods intake among papillary carcinomas by tumor size. Supplementary Table S4. Risk of thyroid cancer associated with phytoestrogen-rich foods intake among female subjects. Supplementary Table S5. Risk of thyroid cancer associated with phytoestrogen-rich foods intake among papillary carcinomas by tumor size among female subjects. Supplementary Table S6. Risk of thyroid cancer associated with phytoestrogen intake by histological subtypes among females.