This slide deck is for informational purposes and is not medical advice. It was created for a school presentation in 2017. Please see your personal clinician for recommendations or to discuss any health conditions.

1. Phytoestrogens
and
Menopausal Symptoms
Melinda Jones, PA-S2
Northern Arizona University
June 2017

2. Clinical Case
Mrs. Smith is a 52 y.o. female who presents for her well woman exam.
LMP 6/8/2016. She reports that she has had increasing vaginal dryness,
hot flashes, and sweating. She is not sure she wants to use HRT and
reports that when she eats “lots of” edamame these symptoms seem
to improve. She wants to know if eating more soy will help her
symptoms.
https://www.flickr.com/photos/tinfoilraccoon/30157230132

3. Clinical Question
• P: Perimonopasal, menopausal or postmenopausal women
• I: Phytoestrogens
• C: Placebo or no treatment
• O: Decrease severity of hot flashes, vaginal dryness and night sweats
Do phytoestrogens decrease symptoms of hot flashes, vaginal dryness,
and night sweats in perimenopausal, menopausal, or postmenopausal
women compared to placebo or no treatment?

4. Menopause Background
• DX: 12 mo of amenorrhea without other cause in women > 45 y.o.
• Perimenopause ~ 4 yrs before menopause
• Average age of menopausal onset: 51.4 y.o.
• Symptoms: hot flashes, night sweats, vaginal dryness, sleep disturbance,
mood changes(depression), joint pain, memory changes, breast pain
• Up to 80% of women experience hot flashes1
• Medical treatments:
• Hormone therapy (next slide)
• non-hormonal therapies: SSRI/SNRI, gabapentin/pregabalin
• 40-50% of women in western countries report using complementary
therapies to manage these sx2

5. Menopausal Hormone Therapy
• Goal: decrease sx of hot flashes, vaginal atrophy, mood changes
• Safe option in women if:
• within 10 years of menopause or younger than 60 y.o.
• no contraindications
• hx of breast cancer, coronary heart disease, previous thromboembolic event or stroke,
active liver disease, high risk of endometrial cancer, known thrombophilia
• Endocrine society suggests calculating ASCVD and breast cancer risk
• <10% 10-year ASCVD risk
• <5% five-year breast cancer risk
• 17-beta estradiol PO or transdermal +/- progestin (uterus or not)
• Lowest effective dose
• Transdermal estradiol + micronized progesterone preferred
• PO safe in young, otherwise health women3

6. Phytoestrogens
• Polyphenol substances in plants
• Structure similar to 17-beta estradiol
• Binds to estrogen receptors
• Can be an antagonist or agonist
• 3 major classes:
• Lignans: linseed oil, sunflower seeds, garlic, cherries, beer, red wine
• Stilbene: resveratrol e.g. wine, grapes
• Flavanoids: isoflavones, isoflavanones, isoflavanes, and coumestans
• Isoflavones: soy, beans, spinach, red clover
• Coumestans: red clover, sun flower seed, soy sprouts4,5

7. Phytoestrogen dose
• Cultures with higher soy intake: 15-50 mg isoflavones daily
• Western diet: 2 mg
• Available supplements: 20-80 mg4
• Generally minimally processed soy products have the largest amount
of isoflavones (tofu, edamame, soy milk, tempeh, miso)
• Isoflavones per cup6
• Edamame: 28 mg
• Low fat soy milk: 5 mg
• Tofu: 77 mg

8. Phytoestrogens: Adverse Effects?
• Mechanism of action could increase risk of endometrial hyperplasia,
endometrial cancer, and breast cancer
• Conflicting evidence on breast cancer risk
• Reduced risk vs. stimulation of malignant growth
• Not currently recommended for breast cancer survivors
• Theoretical impact on endometrial thickness
• Studies have demonstrated no change or thinning with red clover or soy extracts
• High soy diet poorly tolerated: bloating, GI distress
• Can weaken antineoplastic action of tamoxifen4,5

9. Search Strategy
16 results: 2 articles answered my PICO
Use of Plant-based Therapies and Menopausal Symptoms:
A Systematic Review and Meta-analysis. JAMA. 2016
Efficacy of phytoestrogens for menopausal symptoms: meta-analysis and
systematic review. Climacteric 2015
86 articles
5 years Systematic reviews or Meta-analysis
Pub Med
Phytoestrogens and menopause symptoms

10. Article 1: Franco OH, Chowdhury R, Troup J, et al.
Use of Plant-based Therapies and Menopausal Symptoms: A Systematic
Review and Meta-analysis.
By Franco OH, Chowdhury R, Troup J, et al.
JAMA 2016
Objective: Systematic search for RCTs that assessed plant based tx and
the presence of hot flashes, night sweats, and vaginal dryness in
perimenopausal, menopausal or postmenopausal women compared to
placebo or no treatment.

11. Methods: Franco OH, Chowdhury R, Troup J, et al.
• Authors search: MEDLINE, EMBASE and Cochrane Central March 27,2016
• Randomized clinical trials
• Any trial length of follow-up, any language
• Population: perimenopausal, menopausal, or post-menopausal women
• Interventions:
• Biological based therapies: phytoestrogens (dietary, supplements or extracts), black cohosh, flax seed
• Medicinal herbs (non-phytoestrogen based therapies)
• Outcomes:
• Difference in number of hot flashes and night sweats in 24 hours
• Difference in vaginal dryness score based on 4-point scale of severity
• 0=none, 1=mild, 2=moderate, 3=severe
• Comparison: placebo or no treatment
• Analysis:
• Pooled data with similar measures for meta-analysis, between study heterogeneity, and sensitivity analysis
• Narrative synthesis for studies that could not be quantitatively pooled
• Assessed risk of publication bias

12. Results: Franco OH, Chowdhury R, Troup J, et al.
• 36 studies on phytoestrogens
• 21 included in meta-analysis
• 3762 total participants (51-157)
• Median Age 53.5 (53-54)
• Average duration of follow-up was 12 weeks (12-16)
• Dosage
• Dietary Soy: 42-90 mg
• Supplements and extracts of soy isoflavones: 17-100 mg
• Red clover: 40-160 mg
• Pooled mean differences
• Hot flashes: -1.31 [95% CI, -0.52 to -0.61],
• Vaginal dryness: -0.31 [95% CI, -0.51 to -0.10]
• Night sweats: -2.14 [95% CI, -5.57 to 1.29]
• The narrative summary of the 15 studies not included in meta-analysis generally supported these results

14. Limitations: Franco OH, Chowdhury R, Troup J, et al.
• High heterogeneity of population and of study results
• Few studies available assessing night sweats (5)
• Quality and composition of supplements vary
• Variable dosage
• Self-reported measures of symptoms
• Short duration (12 week average)
• 15 of the studies were not included in the meta-analysis due to
differences in outcome measures

15. Conclusions: Franco OH, Chowdhury R, Troup J, et al.
• Modest reduction in frequency of hot flashes and vaginal dryness in
12-16 week interventions
• No significant reduction in night sweats

16. Article 2: Chen MN, Lin CC, Lin CF
Efficacy of phytoestrogens for menopausal symptoms: a meta-analysis
and systematic review.
By Chen MN, Lin CC, Lin CF
Climacteric 2015
Objective: To perform a meta-analysis examining the efficacy of
phytoestrogens for relief of menopausal symptoms

17. Study design and Methods: Chen MN, Lin CC, Lin CF
• Authors search: Medline, EMBASE, Google Scholar September 30, 2013
• Randomized clinical trials
• Population: perimenopausal, menopausal, or postmenopausal women
• Intervention: phytoestrogens (isoflavone, gesistein, soy extract)
• Outcomes: number of hot flashes in 24 hours, kupperman index (KI) difference, side-
effects
• KI: 11 menopausal symptoms rates from 0-3
• hot flashes, paresthesia, insomnia, nervousness, melancholia, vertigo, weakness, arthralgia or myalgia,
headache, palpitations, formication
• Comparison: Placebo or no treatment
• Excluded studies with only an active control group (e.g. HRT)
• Analysis:
• Pooled estimates, homogeneity test and sensitivity analysis via meta-analysis software
• Assessed for publication bias

18. Results: Chen MN, Lin CC, Lin CF
• 15 studies included in the meta-analysis
• 7 assessed KI, 10 assessed hot flashes, 5 assessed side-effects
• Age 48-60.1 y.o.
• Participants: 1752 (30-252)
• Length: 3-12 mo
• No significant differences at baseline in symptoms
• Dosage 5 mg-100 mg
• Pooled mean difference
• KI: 6.44 [95% CI, -1.45 to 14.34], p=0.110
• Hot flashes: 0.89 [95% CI 0.26 to 1.52], p<0.05
• Side-effects:
• OR 0.62 [95% CI, 0.31 to 1.24], p=0.175
• no significant difference in side-effects between groups

19. Change in Kupperman Index
Change in hot flashes
Likelihood of side-effects

20. Limitations
• High heterogenicity of study populations and results
• Variable forms and dosage
• Quality not mentioned
• Did not do separate analysis for phytoestrogen source
• Side-effect not specified and only 5 studies included these results
• Only looked at KI overall and hot flashes
• Small number of studies included

21. Conclusions
• Phytoestrogens modestly reduce hot flashes over a 3 -12 mo
intervention
• Do not reduce all menopausal symptoms (KI)
• Well tolerated-no difference in side-effects between placebo and
control group.

22. Overall Conclusions
• Appear to modestly improve hot flashes and vaginal dryness
• Unclear if will improve night sweats or other sx
• Dosage not clear
• 5 mg to 160 mg used in studies
• Not all supplements are created equal
• Limited data on side-effects in these studies
• Theoretical increases in breast cancer, endometrial hyperplasia and
endometrial cancer risk due to structure similar to estrogen
• Research appears mixed or inconclusive on cancer risk in general
• More research and larger studies are needed on adverse effects of
phytoestrogens
https://well.blogs.nytimes.com/2015/02/12/107141/?_r=0

23. 15-50 mg of whole soy products appear to be possibly protective in epidemiological studies.
Safety is unclear in RCTs and case-control studies.
Following HRT guidelines at this time may be reasonable d/t similar structure and theoretical risks.
If she wants to use phytoestrogens instead of HRT, they appears to be effective.
However, they may only modestly reduce her symptoms.
Whole food options could potentially provide an adequate dose (1 c of edamame per day!)
What do we tell Mrs. Smith?
http://www.freestockphotos.biz/stockphoto/17229

24. References
1. Casper RF. Clinical manifestations and diagnosis of menopause. In: UpToDate, Post TW (Ed). Waltham, MA. https://www-
uptodate-com.libproxy.nau.edu/contents/clinical-manifestations-and-diagnosis-
ofmenopause?source=search_result&search=menopause&selectedTitle=1~150. Accessed June 8, 2017.
2. Franco OH, Chowdhury R, Troup J, et al. Use of Plant-Based Therapies and Menopause Symptoms: A Systematic Review and
Meta-Analysis. JAMA. 2016; 315(23):2552-2563.
3. Martin KA, Barbieri RL. Treatment of menopausal symptoms with hormone therapy. In: UpToDate, Post TW (Ed). Waltham, MA.
https://www-uptodate-com.libproxy.nau.edu/contents/treatment-of-menopausal-symptoms-with-hormone-
therapy/print?source= search_result&search=preperations%20for%20menopausal%20therapy&selectedTitle=1~150. Accessed
June 8, 2017.
4. Reitjens I, Louisse J, Beekmann K. The potential health effects of dietary phytoestrogens. British Journal of Pharmacology. 2017
(74):1263–1280. doi/10.1111/bph.v174.11/issuetoc
5. Czuczwat P, Paszkowski T, Lisiecki M, Wozniak S, Stepniak A. The safety and tolerance of phytoetherapies in menopausal
medicine-a review of the literature. Menopause Rev. 2017;16(suppl 1): 8-11 DOI: https://doi.org/10.5114/pm.2017.67365
6. Bhagwat S, Haytowitz DB, Holden JM. USDA Database for the Isoflavone Content of Selected foods. Beltsville, MD: U.S.
Department of Agriculture; 2008.
7. Chen MN, Lin CC, Lin CF. Efficacy of phytoestrogens for menopausal symptoms: a meta-analysis and systematic review.
Climacteric. 2015; 18:260-269
8. Becky Liugart-Stayner. Edamame [image]. Available at: http://www.cookinglight.com/eating-smart/smart-choices/healthy-
snacks/healthy-snack-edamame. Accessed June 8, 2017.