Table 1.

Phytoestrogens and Urinary Incontinence Studies

Study	Design	Intervention	Comparitor (as applicable)	Duration	Outcomes	Results
Tomaszewski (2003)[23]	In vitro, pubocervical fascia (PCF) from n=8 peri-menopausal women with SUI	PCF fibroblast cells serially exposed to 17 beta-estradiol (E2) or daidzein	Human skin fibroblast cells	96 hours	Proliferation ability of fibroblasts from PCF after exposure to E2 or daidzein	PCF fibroblasts from women with SUI exhibited increased proliferation after E2 > daidzein > skin fibroblasts.
Abstract in English						No objective analytic results in abstract.
Full text in Polish						Summary: Estradiol and daidzein increased PCF fibroblast proliferation from peri-menopausal women with SUI.
Gratzke (2008)[24]	Animal, ovariectomized (ovx) cynomolgus monkeys	Soy diet (1.88 mg total isoflavones per gram protein), n=9	Casein lactalbumin diet, n=9	32 months	Contractile responses in vitro were assessed in mid-bladder (BS) and urethral segments, proximal (S1), mid- (S2), and distal (S3) via electrical (EFS) and pharmacological (Carbachol, Phenylephrine, Endothelin-1) stimulation	Soy diet group resulted in higher contractile responses to EFS in BS and S1 (intergroup difference: 53% and 38%, p<0.005 and p<0.05, respectively). No difference noted in S2 (p>0.05). Carbachol stimulation resulted in higher contractile responses in BS and S1 among soy diet group (intergroup difference: 19% and 204%, p<0.05 and p<0.001, respectively) whereas S2 and S3 did not reach significance. Phenylephrine and Endothelin-1 produced significantly higher responses in S1among soy diet group (intergroup differences: 28% and 55%, respectively, both p<0.05) whereas S2 and S3 did not differ.
Full text					Proximal (S1), mid- (S2), distal (S3) urethral segments tested for urothelial thickness and mucosal area	Dietary soy resulted in higher thickness in all three segments in control vs. soy diet; S1: 24.1 ± .4 vs. 36.6 ± 1.5 μm (difference 52%, p <0.01), S2: 20.7 ± 2.0 vs. 29.6 ± 3.6 μm (difference 43%, p ≤0.001), S3: 22.4 ± 3.4 to 35.3 ± 1.1 μm (difference 57%, p ≤0.01). Soy diet resulted in larger mucosal area, S1: 4.3 ± 0.2 vs. 7.3 ± 0.6 mm2 (difference 71%, p ≤0.01), S2: 3.6 ± 0.1 to 5.5 ± 0.2 mm2 (difference: 52 %, p ≤0.001), S3: 5.3 ± 0.1 vs. 6.5 ± 0.3 mm2 (difference 22%, p ≤0.01).
						Summary: A soy diet resulted in higher contractile responses to EFS and pharmacological stimulation as well as increased mucosal thickness and surface area in certain areas of the bladder and urethra.
Thielemann (2010)[25]	Animal, ovx, Sprague Dawley mice	Oral E2 vs. phytoestrogen equol, genistein and puerarin	Ovx, untreated mice	3 months	Mice were catheterized with a biluminal catheter with one outlet in the bladder and another in the urethra. Urethral and bladder pressures were recorded during a 240s period of retrograde bladder filling	Bladder and urethra pressures were highest in the E2> puerarin > genistein treated mice, p<0.05. Mean differences in pressures (urethra minus bladder) were higher in the phytoestrogen and E2 treatment groups compared to controls during the filling period and in the filled status, p<0.05.
Full text						Results shown in figures, no actual values provided.
						Summary: Dietary estradiol and phytoestrogens improved urethral closure pressure.
Owen (2011)[26]	Animal, female Wistar rats	Ovx rats fed soy chow (soy/ovx), n=24	Sham-operated rat fed non-soy chow (non-soy/sham), n=24	Bladders dissected at 12, 24, and 52 weeks of age	Detrusor contractile response to carbachol	Contractile response to carbachol did not change with phytoestrogen diet or ovariectomy compared to non-soy/sham at 12 weeks; Soy/sham: 4.22 ± 0.39, non-soy/ovx: 5.56 ± 0.52, soy/ovx 4.53 ± 0.55 vs. non-soy/sham: 6.01 ± 0.58 gram tension (g), all p>0.05.
Full text		Ovx rats fed non-soy chow (non-soy/ovx), n=24				At 52 weeks, only soy-fed/sham resulted in significantly higher detrusor contraction to carbachol compared to non-soy/sham (6.28 ± 1.08 vs. 4.37 ± 0.76 (g), p<0.01).
		Sham-operated rats fed soy chow (soy/sham), n=24				Summary: A soy diet was associated with increased bladder detrusor muscle contractile response in aged (52 week old) rats.
Waetjen (2013)[27]	Prospective cohort study, women on entry age 42-52 yrs, n=1,459 at baseline, n=981 at 5 yrs, and n=883 at 9 yrs	SWAN Phytoestrogen Study created a phytonutrient database to estimate the usual daily intakes of four isoflavones, four lignans, and coumestrol via a food frequency questionnaire (FFQ)	Not applicable	10 yrs, follow up visits at 5 and 9 yrs	Development of UI: participants reported frequency and type of UI via an annual, non-validated, self-administered questionnaire	Mean intakes of isoflavones were 10 fold lower in non-Asian compared to Asian group. For Asian group, incidence of UI vs remaining continent based on isoflavones intake in mcg (median, quartile range): (111,512.17, 24,748.64) vs (9,717.91, 15,265.30), p=0.137. For Black/White: (292.01, 614.30) vs (315.60, 707.26), p=0.559. For both unadjusted and multivariable models, no significant association was noted between developing any UI or subtypes of UI and reported daily intake of phytoestrogen (p<0.05).
Full text					Discrete proportional hazards models to evaluate whether the estimated daily intake of each phytoestrogen class on the visit previous to the first report of UI was associated with development of monthly or more UI versus remaining continent	Summary: Neither low nor high levels of reported phytoestrogen intake were associated with development of UI in peri-menopausal women.
Kreydin (2015)[28]	Cross sectional, population-based cohort survey, National Health and Nutrition Examination Survey,(NHANES) of women ≥ 50 yrs, n=1,789	None	None	2001-2010 datasets	Urinary phytoestrogen levels: isoflavones (daidzein, equol, genistein, and O-desmethylangolensin) lignans (enterodiol and enterolactone)	Increasing urine concentrations of enterodiol associated with decreased odds of UUI (odds ratio [OR], 0.92; 95% confidence interval [CI], 0.85-0.99), mixed UI (OR, 0.90; 95% CI, 0.82-0.98), and other UI (OR, 0.90; 95% CI, 0.81-0.99) (p<0.05); increasing urine concentrations of enterolactone associated with decreased odds UUI (OR, 0.92; 95% CI, 0.86-0.99) and mixed UI (OR, 0.91; 95% CI, 0.84-0.99) (p<0.05). No association observed between any isoflavone phytoestrogens and types of UI (p>0.05).
Full text					Prevalence of self-reported SUI, UUI, other UI, or mixed UI via non-validated questions	Summary: Increasing concentrations of urinary lignans were associated with a decreased likelihood of UUI in postmenopausal women.
Juliato (2017)[29]	Cross-sectional, population-based household survey, n=749 women, ages 45-60 yrs (mean 52.5 ± 4.4)	None	None	Sept 2012 to June 2013	Reported UI and factors associated with UI based on the International Consultation on Incontinence Questionnaire short form (ICIQ-SF) and the Overactive Bladder (OAB) form	UI prevalence was 24%. Current or previous use of soy products to treat menopausal symptoms was associated with a lower prevalence of UI (PR: 0.43, 95 % CI, 0.24-0.78; p=0.006).
Full text						Summary: Current or previous use of soy products to treat menopausal symptoms was associated with a lower prevalence of UI.
Manonai (2006)[30]	Clinical, randomized, cross-over trial, n=36 women ages 40-59 yrs (mean 52.5 ± 5.1)	Soy-rich diet (25 g soy protein in various forms of soy food containing more than 50 mg/day of isoflavones substituted for an equivalent amount of animal protein)	Isocaloric soy-free diet	Two 12 week diets with two 4 week wash out periods	Effect on urogenital symptoms (SUI, UUI, urgency, frequency, vaginal dryness, dyspareunia) measured by non-validated questionnaire: no symptoms = score 0, mild= 1, moderate= 2, and severe= 3; vaginal health index (Robert Wood Johnson Medical school method); vaginal pH; and vaginal cytology	UUI and vaginal dryness symptoms increased after 12-week soy-free diet: from 0.14 ± 0.35 to 0.25 ± 0.50 and from 0.61 ± 0.84 to 0.92 ± 0.99, respectively (p<0.05). No symptom changes were observed in the soy-diet group (p>0.05). The vaginal health index (12.83 ± 4.20 vs 12.64 ± 4.18), vaginal pH (7.06 ± 0.72 vs 7.11 ± 0.88), and maturation value (38.68 ± 32.66 vs 30.83 ± 30.39) were not significantly changed after soy treatment (p>0.05).
Full text					Serum levels of daidzein and genistein	Good compliance to diet shown by elevation of serum levels of daidzein and genistein during soy-rich diet period; daidzein: pre- 21.3 ± 2.6 to post-treatment 71.0 ± 4.9 nmol/L and genistein: pre- 77.9 ± 9.1 to post-treatment 249.0 ± 18.6 nmol/L (p < 0.05).
						Summary: UUI and vaginal dryness increased after a 12-week soy-free diet.
Marañon (2017)[31]	Non-randomized, single-center, prospective, open label study, n=82 women aged 42-62 yrs (mean 52)	Dropsordry™, a compounded mixture containing phytoestrogens from SOLGEN™ isoflavones and pyrogallol from standarized pumpkin seed extract	None	8 weeks: two 500 mg Dropsordry ™ per day for the first 4 weeks, one tablet per day for an additional 4 weeks.	UI symptoms (voiding amount, time, urgency score, leakage episodes and types, number of liners per day) via bladder diary, non-validated urgency score (0-4), treatment satisfaction and improvement in quality of life (QOL) were compared at baseline and post-treatment.	Compared to baseline, mean urgency grade reduced by 24.7%, noctuira reduced by 69.4%, the use of daily panty liners by 66.3% (all p<0.05). No significant difference noted in reduction of SUI (no data provided). After 8-week treatment, 96% reported satisfaction with treatment, 92% reported improvement in QOL.
Full text						Summary: A compounded phytoestrogen mixture reduced mean urgency score, nocturia, and the use of daily panty liners in peri-menopausal women.