Effect of Dietary Flaxseed Intake on Circulating Sex Hormone Levels among Postmenopausal Women: A Randomized Controlled Intervention Trial

Figures & data

Figure 1. Flow diagram of the enrollment, randomization, and retention of participants in the Women’s Flaxseed and Health Study, Toronto, Canada, 2015–2016.

Table 1. Baseline characteristics and serum enterolignan and sex hormone levels of postmenopausal women participants in the Women’s Flaxseed and Health Study, Toronto, Canada, 2015–2016.

Characteristic	Intervention (n = 48)	Control (n = 51)	P
	Mean (SD)
Age, years (range: 57–64)	60 (2)	60 (2)	0.53
Age at menopause, years (range: 40–60)	52 (4)	51 (4)	0.20
Body mass index, kg/m^2 (range: 19–40)	26 (5)	25 (4)	0.10
	n (%)
Ethnicity			0.21
White	47 (98)	46 (90)
Non-white	1 (2)	5 (10)
Highest level of education			0.50
High school graduate or less	3 (6)	4 (8)
Some college or university	11 (23)	6 (12)
College or university graduate	27 (56)	31 (61)
Post-graduate degree	7 (15)	10 (20)
Current smoking			0.25
No	46 (96)	47 (92)
Yes	2 (4)	4 (8)
Alcohol consumption			0.88
<once/week	15 (31)	18 (35)
1–6 times/week	20 (42)	19 (37)
Daily	13 (27)	14 (27)
	Median (IQR)
Serum enterolignan concentration
Enterodiol, ng/ml	0.6 (0.3–1.5)	0.6 (0.3–1.5)
Enterolactone, ng/ml	12.7 (4.0–20.0)	9.4 (5.5–19.3)
Total enterolignan^a, ng/ml	13.2 (4.9–22.0)	10.6 (5.8–20.7)
Serum sex hormone concentration
Estradiol, pg/ml	3.7 (2.0–5.7)	2.7 (0.5–4.3)
Free estradiol^b, pg/ml	0.04 (0.02–0.08)	0.03 (0.02–0.08)
Estrone, pg/ml	95.9 (56.4–175.4)	84.3 (57.7–114.5)
Estrone sulfate^c, ng/ml	3.4 (2.2–4.7)	3.9 (2.4–6.3)
Estriol, pg/ml	12.6 (8.8–28.2)	14.5 (7.7–19.9)
2-Methoxyestrone, pg/ml	3.2 (0.5–4.1)	2.1 (0.5–4.0)
2-Hydroxyestrone, pg/ml	147.2 (96.3–209.1)	116.8 (69.9–170.8)
16α-Hydroxyestrone, pg/ml	230.5 (191.0–274.0)	230.0 (188.0–284.0)
2:16α-Hydroxyestrone ratio	0.7 (0.3–1.1)	0.5 (0.3–0.9)
Androstenedione^c, ng/dl	104.0 (71.0–132.5)	108.0 (87.0–131.0)
DHEAS, µg/dl	75.5 (51.6–119.7)	81.1 (47.9–129.0)
Testosterone, ng/dl	10.1 (5.8–17.3)	8.6 (2.9–14.4)
Prolactin, ng/ml	7.5 (6.0–9.0)	8.0 (7.0–12.0)
SHBG, nmol/l	61.3 (42.4–84.2)	73.3 (46.6–83.5)

a Sum of enterodiol and enterolactone concentrations.

b Non-albumin- and non-SHBG-bound estradiol, calculated from estradiol and SHBG concentrations.

c Data missing for 2 participants in the control arm.

Table 2. Changes in serum enterolignan concentrations from baseline to week 7, by study arm.

Enterolignan	n	Baseline geometric mean (95% CI)	Week 7 geometric mean (95% CI)	Change from baseline
				Absolute change^a	Percent change^b	P^c
Enterodiol, ng/ml
Intervention	48	0.8 (0.6–1.2)	10.3 (6.8–15.8)	9.5	1,148%	<0.001
Control	51	0.7 (0.5–1.0)	0.6 (0.4–0.8)	–0.2	–21%
Enterolactone, ng/ml
Intervention	48	10.7 (7.3–15.7)	51.4 (37.4–70.5)	40.7	380%	<0.001
Control	51	9.3 (7.0–12.3)	6.1 (4.3–8.8)	–3.2	–34%
Total enterolignan^d, ng/ml
Intervention	48	12.1 (8.3–17.6)	74.4 (58.1–95.1)	62.3	516%	<0.001
Control	51	10.7 (8.1–14.0)	7.4 (5.3–10.3)	–3.3	–31%

a Absolute change = week 7 geometric mean – baseline geometric mean.

b Percent change =100% × (week 7 geometric mean – baseline geometric mean)/baseline geometric mean.

c P-value for between-group difference (intervention vs. control) in change in enterolignan level estimated using ANCOVA, adjusted for baseline enterolignan level.

d Sum of enterodiol and enterolactone concentrations.

Table 3. Effect of the dietary flaxseed intervention on changes in serum sex hormone concentrations from baseline to week 7.

Sex hormone	n	Baseline geometric mean (95% CI)	Week 7 geometric mean (95% CI)	Change from baseline		Treatment effect
				Absolute change^a	Percent change^b	TER^c (95% CI)	P
Estradiol, pg/ml
Intervention	48	3.1 (2.4–4.0)	2.7 (2.0–3.7)	–0.4	–12%	0.84 (0.59–1.19)	0.325
Control	51	2.1 (1.6–2.8)	2.5 (1.9–3.4)	0.4	20%
Free estradiol^d, pg/ml
Intervention	48	0.04 (0.03–0.05)	0.04 (0.03–0.05)	0.0	–6%	0.96 (0.75–1.23)	0.756
Control	51	0.04 (0.03–0.05)	0.04 (0.03–0.05)	0.0	–2%
Estrone, pg/ml
Intervention	48	96.7 (76.6–121.9)	101.7 (81.3–127.2)	5.0	5%	1.15 (0.90–1.46)	0.259
Control	51	89.8 (74.8–107.9)	83.5 (65.1–107.2)	–6.3	–7%
Estrone sulfate, ng/ml
Intervention	48	3.6 (2.9–4.4)	4.7 (3.9–5.7)	1.1	32%	1.00 (0.84–1.19)	0.983
Control	49	3.8 (3.0–5.0)	5.0 (3.9–6.5)	1.2	30%
Estriol, pg/ml
Intervention	48	14.4 (11.3–18.4)	13.4 (10.2–17.7)	–1.0	–7%	0.98 (0.76–1.26)	0.846
Control	51	13.8 (11.0–17.3)	13.2 (10.2–17.1)	–0.6	–4%
2-Methoxyestrone, pg/ml
Intervention	48	2.3 (1.7–3.1)	1.7 (1.2–2.4)	–0.6	–25%	0.94 (0.61–1.42)	0.753
Control	51	1.6 (1.2–2.2)	1.5 (1.0–2.1)	–0.2	–9%
2-Hydroxyestrone, pg/ml
Intervention	48	110.1 (80.1–151.4)	183.7 (158.9–212.3)	73.6	67%	1.54 (1.18–2.00)	0.002
Control	51	78.1 (55.6–109.7)	104.0 (78.6–137.6)	25.9	33%
16α-Hydroxyestrone, pg/ml
Intervention	48	215.7 (184.5–252.3)	228.7 (210.0–249.1)	13.0	6%	0.98 (0.83–1.15)	0.806
Control	51	185.3 (144.0–238.5)	216.9 (178.2–263.9)	31.5	17%
2:16α-Hydroxyestrone ratio
Intervention	48	0.5 (0.4–0.7)	0.8 (0.7–0.9)	0.3	57%	1.54 (1.15–2.06)	0.004
Control	51	0.4 (0.3–0.6)	0.5 (0.3–0.7)	0.1	14%
Androstenedione, ng/dl
Intervention	48	102.5 (87.2–120.6)	92.7 (74.2–115.9)	–9.8	–10%	0.98 (0.84–1.16)	0.842
Control	49	105.3 (91.6–121.0)	96.6 (85.0–109.8)	–8.7	–8%
DHEAS, µg/dl
Intervention	48	76.4 (64.2–91.0)	77.3 (65.4–91.3)	0.9	1%	1.01 (0.92–1.11)	0.766
Control	51	76.2 (63.7–91.3)	76.0 (64.1–90.2)	–0.2	0%
Testosterone, ng/dl
Intervention	48	7.3 (5.4–9.9)	7.4 (5.5–10.0)	0.1	1%	0.98 (0.80–1.20)	0.852
Control	51	6.2 (4.6–8.4)	6.5 (4.7–9.0)	0.3	5%
Prolactin, ng/ml
Intervention	48	7.2 (6.6–7.9)	7.3 (6.7–7.9)	0.1	1%	0.91 (0.80–1.03)	0.146
Control	51	8.1 (7.2–9.2)	8.3 (7.5–9.2)	0.2	2%
SHBG, nmol/l
Intervention	48	59.5 (51.5–68.8)	59.2 (50.9–68.9)	–0.3	–1%	0.93 (0.81–1.07)	0.307
Control	51	60.7 (49.3–74.8)	64.3 (56.1–73.7)	3.6	6%

a Absolute change = week 7 geometric mean – baseline geometric mean.

b Percent change =100% × (week 7 geometric mean – baseline geometric mean)/baseline geometric mean.

c Treatment effect ratio (TER) represents the effect of the flaxseed intervention on change in sex hormone level, adjusted for baseline hormone level using ANCOVA; it is the intervention:control ratio of geometric means at week 7 relative to baseline. A TER <1 indicates a reduction in hormone level in the intervention relative to the control arm, whereas a TER >1 indicates an increase in hormone level in the intervention relative to the control arm.

d Non-albumin- and non-SHBG-bound estradiol, calculated from estradiol and SHBG concentrations.

Table 4. Spearman correlation coefficients between changes in serum enterolignan concentrations and changes in sex hormone concentrations among women in the intervention arm (n = 48).

Sex hormone	Enterolignan
	Δ Enterodiol	Δ Enterolactone	Δ Total enterolignan^a
Δ Estradiol	0.25	0.20	0.26
Δ Free estradiol^b	0.15	0.08	0.14
Δ Estrone	–0.09	–0.22	–0.18
Δ Estrone sulfate	0.10	0.01	0.07
Δ Estriol	–0.09	0.09	0.06
Δ 2-Methoxyestrone	0.00	0.22	0.23
Δ 2-Hydroxyestrone	0.15	0.40*	0.33*
Δ 16α-Hydroxyestrone	–0.06	0.03	0.01
Δ 2:16α-Hydroxyestrone ratio	0.25	0.41*	0.37*
Δ Androstenedione	0.18	–0.09	0.05
Δ DHEAS	0.07	–0.15	–0.06
Δ Testosterone	–0.09	–0.12	–0.06
Δ Prolactin	–0.37*	–0.22	–0.32*
Δ SHBG	–0.11	0.10	0.07

*P < 0.05.

Δ: Change, defined as week 7 concentration minus baseline concentration (untransformed) for each enterolignan or sex hormone.

^aSum of enterodiol and enterolactone concentrations.

^bNon-albumin- and non-SHBG-bound estradiol, calculated from estradiol and SHBG concentrations.