Complementary and Alternative Medicine for Women

Complementary and Alternative Medicine for Women

Lisa G Soldat, MD, MS, FAAFP

Activity Disclaimer

The material presented here is being made available by the American Academy of Family Physicians for educational purposes only. Please note that medical information is constantly changing; the information contained in this activity was accurate at the time of publication. This material is not intended to represent the only, nor necessarily best, methods or procedures appropriate for the medical situations discussed. Rather, it is intended to present an approach, view, statement, or opinion of the faculty, which may be helpful to others who face similar situations.

The AAFP disclaims any and all liability for injury or other damages resulting to any individual using this material and for all claims that might arise out of the use of the techniques demonstrated therein by such individuals, whether these claims shall be asserted by a physician or any other person.

Physicians may care to check specific details such as drug doses and contraindications, etc., in standard sources prior to clinical application. This material might contain recommendations/guidelines developed by other organizations. Please note that although these guidelines might be included, this does not necessarily imply the endorsement by the AAFP.

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Disclosure Statement

It is the policy of the AAFP that all individuals in a position to control content disclose any relationships with commercial interests upon

nomination/invitation of participation. Disclosure documents are reviewed for potential conflicts of interest. If conflicts are identified, they are

resolved prior to confirmation of participation. Only participants who have no conflict of interest or who agree to an identified resolution process prior to their participation were involved in this CME activity.

All individuals in a position to control content for this session have indicated they have no relevant financial relationships to disclose.

Learning Objectives

1. Assess patients’ use of herbal or dietary supplements and provide counseling to encourage safe and effective use.

2. Identify the supplements commonly used by your patient population and when to monitor appropriate labs and therapeutic response.

3. Recommend patient-friendly, evidence-based online

resources about the risks and benefits of using supplements for women’s health concerns, including premenstrual

syndrome, altered menses, sleep disorders, hot flashes, anxiety and depression.

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CAM includes

Mind-body practices (hypnosis, CBT, relaxation, biofeedback, mediation, aromatherapy)

Whole-system approaches (TCM, reflexology, acupuncture, homeopathy)

 Natural products/dietary supplements (herbs, vitamins, minerals, amino acids, and enzymes)

Studies about most CAM modalities can be described as

Heterogeneous . . . “Low quality”… “Insufficient evidence”… “More studies needed”… “No better than placebo”…

and

“Appears safe” … “no harm if patient wants to take”

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What’s the evidence?

Efficacy and safety of most supplements is difficult to establish due to lack of well-designed, randomized, controlled trials

Limited studies looking at interactions between:

Herbs and drugs

Herbs and other micronutrients

Supplements taken together

Dennehy CE. The use of herbs and dietary supplements in gynecology: an evidence-based review. J Midwifery Womens Health. 2006 Nov-Dec;51(6):402-9.

Botanical supplements:

A difference in philosophy

Traditional Chinese Medicine Western Interpretation

https://c1.staticflickr.com/1/171/419584946_2f37026552_z.jpg?zz=1 https://upload.wikimedia.org/wikipedia/commons/8/87/Chinese_traditional_medicine.jpg

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Example: Dong quai

Angelica sinensis (root)

Used for 1000’s of years in Chinese medicine

GSM, dysmenorrhea, PMS, menstrual problems, etc

Unclear which part of the plant is pharmacologically active

May be effective only in combination with other herbs

Shown to affect estrogen levels in animals

Insufficient evidence to rate effectiveness

Safety concerns (interactions with other medications and herbs, photosensitization, anticoagulation, and possible carcinogenicity)

Assess patients’ use of herbal or dietary

supplements and provide counseling to encourage safe and effective use.

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Ask patients about supplement use

Not all patients disclose unless specifically asked by the provider

Supplements are pharmacologically active

Alerts provider to monitor for adverse effects and drug-supplement interactions

Promotes dialogue about patient’s underlying health concerns

Provide evidence-based information and correct misperceptions, especially if taken in place of prescription medications

Talking points for discussing supplements with patients

Any evidence that it works?

Is it okay to take with prescribed medications?

What’s the right dose?

How much do supplements cost?

Are there any side effects?

How does one pick the best brand?

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Who takes supplements?

52% of adults

59% women, 45% men

Use ↑ with age

 Older women 71+ are the highest consumers

Highest prevalence in:

Higher education and income

 Food secure, non SNAP-eligible and income > 350% of the poverty level

 82% were high income and > 71 yo

Private insurance, > 2 health care visits/year, healthy, exercise, nonsmokers

> 1 prescription med in past 30 days Cowan AE, et al. Dietary Supplement Use Differs by Socioeconomic and Health-Related Characteristics among U.S. Adults, NHANES 2011⁻2014. Nutrients. 2018 Aug 17;10(8):1114.

Most common supplements taken by adults

39% multivitamins

 Especially vitamins B-6, B-12, C, D, or K

 75% include Vitamin D

 Calcium, iron, zinc, magnesium, selenium, or folate

 71% contain calcium

26% vitamin D only

22% omega-3 only

9% botanicals

 Ginkgo biloba, garlic, ginseng, St John’s wort, Echinacea, saw palmetto, evening primrose oil and ginger

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Why are supplements taken?

Top 4 reasons (older adults):

1. Improve health (41%) 2. For bone health 3. Maintain health

4. To supplement the diet

Why was a particular product/brand chosen?

Family or friend endorsement

Direct-to-consumer advertising

Gahche JJ, Bailey RL, Potischman N, Dwyer JT. Dietary Supplement Use Was Very High among Older Adults in the United States in 2011-2014. J Nutr. 2017;147(10):1968-1976

Know which supplements are typically used by your patients

Follow labs if indicated

Monitor supplements for therapeutic response

Expected response time for any particular supplement

Examples:

 Isoflavones:

 Several weeks before improvement expected

 Black cohosh

 Treatment for 4 weeks before significant improvement in sx

 Recommend no longer than one year of use 15

Drug-supplement interactions

Warfarin: most frequently implicated drug

St. John’s wort: the most drug-herb interactions

Cytochrome P450: most frequent mechanism herb-induced alteration

> 1 possible interactions found in 31%

Serious interactions seem to be uncommon

Loya AM, González-Stuart A, Rivera JO. Prevalence of polypharmacy, polyherbacy, nutritional supplement use and potential product interactions among older adults living on the United States- Mexico border: a descriptive, questionnaire-based study. Drugs Aging. 2009;26(5):423-36.

AES Question

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Question 1

Your 68 year old patient has been treated for many years with hydrochlorothiazide for hypertension. She mentions in passing that she’s been taking a calcium + vitamin D pill twice a day, along with a daily MVI, for “bone health” and general well-being. What drug- supplement adverse reaction is she at risk for?

A. Metabolic alkalosis B. Metabolic acidosis C. Photosensitivity D. Hypotension

Prescription medications and supplement use in older adults

Number of supplements taken

70% took > 1

54% took 1-2

29% took > 4

73% take > 3 prescription medications

8% taking >3 Rx’s were also taking >1 botanical supplement

Gahche JJ, Bailey RL, Potischman N, Dwyer JT. Dietary Supplement Use Was Very High among Older Adults in the United States in 2011-2014. J Nutr. 2017;147(10):1968-1976

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AES Question

Question 2

Taking more than the upper tolerable intake level (UL) of which of the following could potentially be harmful in pregnancy?

A. Iron

B. Vitamin A C. Folic acid D. Iodine

E. All of the above

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When is it too much of a good thing?

Taking more than recommended on the label

Taking different supplements together that have the same ingredients

Adding to a diet already fortified with same ingredients

Adults > 71 yo: UL was exceeded for folic acid (7%), vit A (3%) and vit B-6 (4%)

Bailey RL, Pac SG, Fulgoni VL, Reidy KC, Catalano PM. Estimation of Total Usual Dietary Intakes of Pregnant Women in the United States. JAMA Netw Open. 2019;2(6):e195967. doi:10.1001/jamanetworkopen.2019.5967

Fortified foods + PNV

33% of pregnant women get too much folic acid

28% of pregnant women get too much iron

36% get too little iron

45% get too little vitamins D, E and magnesium

Gernand AD. The upper level: examining the risk of excess micronutrient intake in pregnancy from antenatal supplements. Ann N Y Acad Sci. 2019 May;1444(1):22-34.

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Supplements are marketed as safe, natural and health-promoting . . . .

National surveys

81% believed premarketing proof of safety should be required

> 50% believe such regulations already existed

72% of patients would still use even if a negative government study exists

Blendon RJ, DesRoches CM, Benson JM, et al. Americans' views on the use and regulation of dietary supplements. Arch Intern Med 2001; 161:805.

. . . . But are they as safe as claimed?

Study of ER visits for supplement-related adverse events

Extrapolated 23,000 ER visits/year

Average age 32 years, women > men

9% hospitalized (16% were > 65 year-olds)

32% due to micronutrients (top 3: MVI, iron, calcium)

66% due to botanicals

 25% Weight loss supplements (women > men)

 10% Energy/bodybuilding (men > women)

 3% each sexual enhancement, cardiovascular, sleep/sedation

Geller AI, et al. Emergency Department Visits for Adverse Events Related to Dietary Supplements. N Engl J Med. 2015 Oct 15;373(16):1531-40.

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Regulation of dietary supplements

 Federal Food, Drug and Cosmetics Act

1994 Dietary Supplement Health and Education Act (DSHEA)

 Dietary supplements regulated like foods

 Lower threshold of evidence for safety compared to drugs

2007: Good Manufacturing Practices (GMP)

Supplement manufacturers must be registered with the FDA to operate

FDA randomly audits manufacturers

Proper labeling

Adulterant- and contaminant-free

Manufactured using specific standards for personnel and equipment

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DSHEA labeling requirements

Labels must state: “this product is not intended to diagnose, treat, cure or prevent any disease”

Labels allowed to make health claims

“promotes colon health” or “supports brain function”

But not allowed to make specific health claims

AES Question

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Does this label meet DSHEA labeling requirements?

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Clinically proven to reduce symptoms of menopause:

 Night sweats/hot flashes*

 Occasional sleepiness*

 Dry skin*

 Mood swings/irritability*

 Vaginal dryness*

Naturally estrogen-free:

Ideal for women who choose not to take estrogen

Alternative to HRT:

Can replace HRT for menopause symptom relief*

Question 3

Does this label meet DSHEA labeling requirements?

A. Yes B. No C. Maybe

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FDA oversight is limited

Manufacturers not required:

To prove efficacy, safety quality prior to marketing

To report postmarketing adverse events to the FDA

FDA receives reports of < 1% of all serious adverse events

Encourages the public and health care providers to report any suspected cases of significant toxicity to the FDA MedWatch Adverse Event Reporting System

 https://www.fda.gov/safety/medwatch-fda-safety-information-and-adverse-event- reporting-program/reporting-serious-problems-fda

GMP compliance is monitored and certified by third party organizations

Audit and testing of product ingredients and quality

Product safety and efficacy not tested

Does not assure that the product is safe for the condition it treats or appropriate for all patients

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US Pharmacopeial Convention (USP)

www.Quality-supplements.org

National Sanitation Foundation (NSF) www.Info.nsf.org/certified/

dietary

ConsumerLab www.consumerlab.org

Not for profit Not for profit For profit

Function Sets the most widely accepted

standards for supplements (and also pharmaceuticals

Audits production sites to ensure GMPs are followed

Tests and rates dietary supplements, vitamins and other health products

U.S. law USP standards are included in

many federal laws

NSF/ANSI 173: Dietary Supplements Manufacturers, brands >100 supplements, 12

manufacturers:

Not all of a brand’s products are included

Many (>100) Many (>100)

Sample source Provided by the manufacturer Provided by the manufacturer

Purchased when a manufacturer requests testing

Cost to certify product or verify ingredients

Varies depending on ingredients;

$3000-$15,000 per product plus an additional audit fee of $15,000 and a label fee of 1 cent per bottle

$3000-$5000 per product, plus an audit fee of about

$13,000

$3000-$5000 per product

Minimum quality criteria

Ingredients match what is on the label

Free from:

Contaminants

Metals (arsenic, cadmium, chromium, mercury, lead)

Pesticides

Microbiological (yeast, mold, pathogens)

Industrial contaminants (PCBs, etc)

Known adulterants not present

Matches “free from” claims (like gluten)

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Example: Heavy metal contamination

Lead in prenatal vitamins

No amount of lead is thought to be safe

 Recommended limits

 FDA: 12.5 mcg/day

 CA Prop 65: 0.5 mcg/day

FDA (2008): lead found in all 75 products tested

2016 Canadian study: 26 common PNV tested had 0.1 - 4.0 mcg/day (average 0.535 mcg/d)

Schwalfenberg G, Rodushkin I, Genuis SJ. Heavy metal contamination of prenatal vitamins. Toxicol Rep. 2018;5:390-395. Published 2018 Mar 6.

ConsumerLab testing

Recent testing of 3 prenatal vitamins:

#1: Correct amounts, no heavy metals and disintegrated properly

#2: Too little vitamin A, too much iron and iodine, and took 80 min to disintegrate

#3: 17.4% of listed vitamin A and 188% of listed iodine

Vitamin B-12 ranged from 100 to 3500% in different brands

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DSHEA: Manufacturers are allowed to have non-GMP certifications

Less expensive than third-party independent testing

Should demonstrate adherence to good manufacturing practices, e.g.:

 Precise equipment cleaning to avoid contamination

 Documenting ingredient identity and purity

 Additional quality testing

Certified Kosher vitamins and mushrooms

NSF Certified Gluten Free Vitamins made with

organic herbs and vegetables

Committed to non- GMO sourcing

“First-Party” seals do not prove safety or efficacy

Not required by FDA

Not based on testing or standards

Can be confusing

Created by manufacturers

To improve perception of high quality

To imitate legitimate third-party seals

May degrade the trust and value of legitimate seals like NSF and USP

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Recommend patient-friendly, evidence-based online

resources about the risks and benefits of using supplements for women’s health concerns

Strategies to improve safety

Choose brands that have been independently tested, meet minimum quality criteria and have a seal of approval (verification mark)

“Verified” or “approved” are meaningless labels

This can be difficult and time-consuming for patients

One option: Since 2019, CVS only sells supplements that have had 3^rdparty testing

 USP, NSF, UL and Eurofins 41

Be skeptical of direct-to-consumer advertising

Promises of a quick fix, for example, "lose 10 pounds in one week.”

Use of the words "guaranteed" or "scientific breakthrough.”

Advertising on social media

Products marketed as herbal alternatives to an FDA-approved drug or as having effects similar to prescription drugs.

Popular marketing terms

(not recognized by FDA)

Nutraceuticals

 Any substance that may be considered a food or part of a food and provides medicinal or health benefits including the prevention and treatment of disease

Functional foods

 Foods with added ingredients that may provide a health benefit beyond the traditional nutrients it contains

Phytochemicals/phytonutrients

 Health-protecting compounds from plant sources

Cosmeceuticals

 Cosmetics with ingredients marketed to provide medicinal or health benefits including the prevention and treatment of disease

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Patient (and physician)-friendly, credible online resources

NIH MedLinePlus

 www.MedlinePlus.gov

FDA

 https://www.fda.gov/food/dietarysupplements/default.htm

USDA

 https://www.nutrition.gov/

Federal Trade Commission

 https://www.consumer.ftc.gov/articles/0261-dietary-supplements

Additional physician resources

NIH National Center for Complementary and Alternative Medicine https://nccih.nih.gov

Herblist App (free, lists >50 common herbs)

 https://www.nccih.nih.gov/health/herblist-app

Drugs and Lactation Database

https://www.ncbi.nlm.nih.gov/books/NBK547435/

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NIH Office of Dietary Supplements (ODS)

www.ods.od.nih.gov

Evidence-based, current information for health professionals

https://ods.od.nih.gov/HealthInformation/healthprofessional.aspx

List of dietary supplement fact sheets

https://ods.od.nih.gov/factsheets/list-all/

Overview addressing effectiveness, safety and quality

https://ods.od.nih.gov/HealthInformation/DS_WhatYouNeedToKnow.aspx

 Dietary supplement label

 Physician-patient communication prior to starting a supplement

 Government’s role in regulating dietary supplements

Your patient knows the brand of supplement she takes but not the dose or what is in it.

Your EMR does not recognize the brand.

Where can you find more information?

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Dietary Supplement Label Database

Full label information as provided by manufacturer

Not verified to be accurate or compliant with FDA regulations

Not an endorsement or guarantee of accuracy by NIH

https://ods.od.nih.gov/

Finding Valid Information:

Example: Evening Primrose Oil

Several of your patients have told you that they have used evening primrose oil for hot flashes. Their opinions are mixed about whether it is helpful.

What’s your opinion?

Is there evidence that it works?

Is one brand superior to another?

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National Center for Complementary and Integrative Health

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Two internet subscription databases (there are more)

Natural Medicines

https://naturalmedicines.com

Institutional and personal subscriptions available

 $182/yr

Consumer Lab

www.consumerlab.com

Subscription

 $47/yr

Home page

Uses Safety and

Effectiveness

Insufficient evidence to

rate

Drug Interactions

Interactions Lab

Natural Medicines

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ConsumerLab

Product testing for quality concerns

Product ingredients

Test results: approved or not approved

Encyclopedia articles

Description, indications, adverse effects, literature review

What to consider when buying/using any particular product

ConsumerLab: Results of product testing

Product name, serving size, and suggested daily dose

Amount claimed for specific ingredients per label’s daily serving

Test results Cost for daily suggested serving dose on label Other comments Overall results:

APPROVED or NOT APPROVED

Contained label amounts

Did not exceed contamination limits for lead, cadmium and

arsenic

Product A EPO: 1300 mg

GLA: 110-130 mg Linoleic acid: 850-900 mg Oleic acid: 80-130 mg

APPROVED Yes Yes $0.24 (per 200 mg GLA)

$21.50 (softgels)

Product B EPO: 130 mg

GLA: 130 mg Linoleic acid: 960 mg Oleic acid: 40 mg

NOT APPROVED Yes: GLA and linoleic acid No: > 110% of oleic acid than claimed

Yes $0.20 (per 200 mg GLA) Organic:

$11.80 (softgels)

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Identify the supplements commonly used by your

patient population and when to monitor appropriate labs and therapeutic response

Dietary supplements marketed for many conditions

General

Anti-aging

Immune support

Fertility

Pregnancy and breastfeeding

Hair, skin and nails

Sexual problems

Specific

Menopause

Genitourinary

Bacterial vaginosis

Vulvovaginal candidiasis

Urinary tract infection

Dysmenorrhea

PMS/PMDD

Osteoporosis

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Premenstrual Syndrome (mild symptoms)

Most studied, all with low quality evidence

Cognitive behavioral therapy

Calcium (no more than 1200 mg total)

Chasteberry (Vitex agnus castus )

 20-40 mg extract daily

Mixed evidence

Vitamins D, B-6, Evening primrose oil

Likely no better than placebo

 Evening primrose oil

 St. John’s Wort Hofmeister S, Bodden S. Premenstrual Syndrome and Premenstrual Dysphoric Disorder.

Am Fam Physician. 2016 Aug 1;94(3):236-40. PMID: 27479626.

Premenstrual Dysphoric Disorder

Cognitive behavioral therapy

Meta-analysis, low quality data: decreased symptoms of anxiety, depression; improved coping skills compared to other interventions

May be a useful adjunct to pharmacologic treatment

Acupuncture

Many heterogeneous studies, insufficient evidence

Busse JW, et al. Psychological intervention for premenstrual syndrome: a meta-analysis of randomized controlled trials. Psychother Psychosom. 2009;78(1):6-15.

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Cyclic mastalgia

Low quality evidence

Chasteberry

Probably no better than placebo

Evening primrose oil, vitamin E

Insufficient evidence

Phytoestrogens

 Soy milk improved symptoms compared to cow’s milk

Ooi SL, Watts S, McClean R, Pak SC. Vitex Agnus-Castus for the Treatment of Cyclic Mastalgia: A Systematic Review and Meta-Analysis. J Womens Health (Larchmt). 2020 Feb;29(2):262-278.

Dysmenorrhea

No evidence of benefit or harm for any modality

Very limited evidence of benefit for

 Vitamins E, B-1, B-6, D-3, fish oil supplements, ginger, magnesium

Insufficient evidence:

Aromatherapy

 Lavender, clary sage and rose traditionally used for dysmenorrhea

Acupuncture

Pattanittum P, et al. Dietary supplements for dysmenorrhoea. Cochrane Database of Systematic Reviews 2016, Issue 3. Art. No.: CD002124.

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Breastfeeding

Galactagogues: few studies, insufficient evidence

Banana flower, fennel, fenugreek, ginger, ixbut, levant cotton, moringa, palm dates, pork knuckle, shatavari, silymarin, torbangun leaves or other natural mixtures)

Foong SC, Tan ML, Foong WC, Marasco LA, Ho JJ, Ong JH. Oral galactagogues (natural therapies or drugs) for increasing breast milk production in mothers of non-hospitalised term infants. Cochrane Database Syst Rev.

2020 May 18;5(5):CD011505.

Osteoporosis

Good evidence

Calcium and vitamin D:

 Modest improvement in slowing bone loss in postmenopausal women

 No effect on reducing fracture risk

Mixed results of benefit

Isoflavones

Weak evidence for many others

Vitamin K, strontium, magnesium, boron, DHEA, black cohosh 63

Soy isoflavones and bone density

Osteoporosis Prevention Using Soy (OPUS) study

50% less effective than risedronate

Higher amounts of isoflavones (120 mg) were needed to maintain and/or increase bone density in postmenopausal women

 1-2 years of treatment

 Bone density in lower back and hip were not increased

Pawlowski JW, et al. Impact of equol-producing capacity and soy-isoflavone profiles of supplements on bone calcium retention in postmenopausal women: a randomized crossover trial. Am J Clin Nutr. 2015 Sep;102(3):695-703.

Libido

Many products, none with studies showing efficacy and safety

Botanical massage oils

“Warming” vaginal lubricants

Dietary supplements

 Avlimil

 Proprietary blend (Sage leaf, red raspberry leaf, kudzu root extract, red clover extract, capsicum pepper, licorice root, bayberry fruit, damiana leaf, valerian root, ginger root, black cohosh root)

 Likely has both estrogenic and antiestrogenic effects 65

The story of Avlimil

2003 marketed to “boost sex drive, regularize menstruation and relieve menopausal hot flashes”

 Advertised that one small study showed benefit for libido

 but product studied had different ingredients than the commercial blend product

2006 The FTC charged the manufacturer for making false and unsubstantiated claims

2008 owner convicted for mail fraud

2012 $24 million class action lawsuit

Company went bankrupt, bought by landlord and renamed

Avlimil is still on the market…just for menopause symptoms

Menopause

CAM used by 50 – 75% of postmenopausal women

89-100% of women find it be somewhat or very helpful

Women with history of breast cancer are 6x more likely to use soy-based products

Placebos reduce symptoms in 25 - 50% of patients

Nedrow A, Miller J, Walker M, Nygren P, Huffman LH, Nelson HD. Complementary and alternative therapies for the management of menopause-related symptoms: a systematic evidence review. Arch Intern Med. 2006 Jul 24;166(14):1453-65.

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Mind-body modalities for menopause

 Recommended by North American Menopause Society

Hypnosis

 Limited data acknowledged

 A few randomized trials suggested ↓ perception of hot flashes

CBT:

 Modestly effective for insomnia with or without hot flashes

 ↓ hot flash severity but not frequency

Johnson A, Roberts L, Elkins G. Complementary and Alternative Medicine for Menopause. J Evid Based Integr Med. 2019;24:2515690X19829380.

Biofeedback, MBSR, and relaxation techniques

 Limited evidence for stress reduction, improved quality of life with

Insufficient or no evidence:

Exercise, aromatherapy, reflexology, yoga

Acupuncture

 Popular for hot flashes

 Evidence so far suggests no better than sham acupuncture

 Both showed improvement at 6 months after treatment

Ee C, Xue C, Chondros P, Myers SP, French SD, Teede H, Pirotta M. Acupuncture for Menopausal Hot Flashes: A Randomized Trial. Ann Intern Med. 2016 Feb 2;164(3):146-54.

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Dietary supplements for menopause

Some/mixed evidence of benefit (compared to placebo)

Phytoestrogens, black cohosh, progesterone cream

Not better than placebo

Wild yam, dong quai, maca, pollen extract, evening primrose oil, vitamin E, flaxseed, ginseng

Insufficient evidence

St. John’s wort: (for associated depression)

 Drug/herb interactions (warfarin, antidepressants, BCPs, some cancer drugs)

Valerian (for associated insomnia, anxiety depression)

 No major safety concerns with short-term use; long-term use unknown

Phytoestrogens

Isoflavones

 Richest source: soybeans and soy products; also red clover and kudzu

 Soy best studied

 Common in Asian diets

 Most researched form of phytoestrogens

Lignans

 Richest source: flaxseed, unrefined grains, cereal brans and beans

 Most common phytoestrogen in Western diets

 Limited research, mixed evidence of efficacy

Coumestans

 Alfalfa and clover sprouts, split peas, pinto and lima beans 71

Soy isoflavones

Chen et al (2015) Meta-analysis and systematic review

 No treatment effect on menopausal symptoms compared to placebo

 Decreased frequency of hot flashes compared to placebo

Franco et al (2016) Meta-analysis of clinical trials

 Generally suboptimal, heterogeneous evidence

 Modest decrease in hot flashes and vaginal dryness but not night sweats

 Composite and specific phytoestrogen supplements

Franco OH, Chowdhury R, Troup J, Voortman T, Kunutsor S, Kavousi M, Oliver-Williams C, Muka T. Use of Plant-Based Therapies and Menopausal Symptoms: A Systematic Review and Meta-analysis. JAMA. 2016 Jun 21;315(23):2554-63..

Chen MN, Lin CC, Liu CF. Efficacy of phytoestrogens for menopausal symptoms: a meta-analysis and systematic review. Climacteric. 2015 Apr;18(2):260-9.

Isoflavone forms vary in potency

Glycosidic isoflavones in food

→ converted by gut microflora to metabolically active aglycone isoflavones

→ 1/3 absorbed as free aglycones

→ 2/3 converted by gut microflora to active metabolites and absorbed

→ Genistein (most abundant)

→ Daidzein

→ Converted by gut microflora to equol (may have highest estrogen-agonist potency)

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Not all people can metabolize dietary isoflavones

Only 30-60% of people have the specific gut bacteria to convert

Glycosidic isoflavones into aglycones, or

Aglycones into equol

Equol-containing supplements given to equol nonproducers appears to significantly lower the incidence and/or severity of hot flashes

Daily JW, Ko BS, Ryuk J, Liu M, Zhang W, Park S. Equol Decreases Hot Flashes in Postmenopausal Women: A Systematic Review and Meta-Analysis of Randomized Clinical Trials. J Med Food. 2019 Feb;22(2):127-139.

Tips for buying isoflavone supplements

Ideal dosage not known

Amounts/ratios of isoflavones in supplements based on:

Intakes in countries where soy is a staple

The development of clinical endocrine effects in premenopausal women

Total soy isoflavones: 40-70 mg/day; or red clover 40 mg/day

> 15 mg genistein, and/or

> 28 mg daidzein

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Soy in food

Food Serving mg isoflavones

Tofu yogurt ½ cup 21

Soy flour 100 g 150-200 mg

Soy protein concentrate 100 g 100 mg

Boiled soybeans ½ cup 56

Soy milk 1 cup 6.2

Soybean curd 3 oz 19

Meatless soy burger 1 patty 4.5

Miso ½ cup 57

Edamame ½ cup 16

Soy oils and soy lecithin are devoid of isoflavones

Soy isoflavones and breast cancer

Risk appears to depend on time of life when used, family history and estrogen receptor status

 Asian women have lower incidence of breast cancer

 Higher soy consumption early in life

2019 Cohort study, 76,000 French women > 50 yo

 Soy isoflavone use overall not associated with risk of breast cancer

 If current soy isoflavone use

 36% ↑ risk if family history of breast cancer

 50% ↓ risk of ER+ breast cancer in premenopausal/recently menopausal women

Touillaud M, et al.. Use of dietary supplements containing soy isoflavones and breast cancer risk among women aged >50 y: a prospective study. Am J Clin Nutr. 2019 Mar 1;109(3):597-605..

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Black cohosh

(Actaea racemosa or Cimicifuga racemosa)

 Used mostly for menopausal symptoms

 Historically used as a general “women’s” herb

ACOG (2015) clinical guidelines: “data do not show that” herbal dietary supplements like black cohosh “are efficacious for the treatment of vasomotor symptoms”

2016 systematic review and meta-analysis of RCTs

No reduction in VMS found in various formulations vs placebo

Black cohosh

 Unknown active ingredient(s) and mechanism of action

 Raises estrogen levels? LH? FSH?

 Brain-related action, eg, modulation of serotonergic pathways?

 Antioxidant, anti-inflammatory, or SERM?

No evidence of

↑ risk of recurrence of ER+ breast cancer

Liver toxicity

Lack of long-term safety data

Recommend avoiding use in pregnancy, breastfeeding, women at high risk for or currently have breast cancer

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Tips for buying black cohosh supplements

Make sure it is not BLUE cohosh

Available products vary considerably in chemical composition

Products often standardized to provide at least 1 mg triterpene glycosides per daily dose

 Exception: Remifemin currently standardized to be equivalent to 40 mg black cohosh root/rhizome per daily dose of 2 tablets

Progesterone cream

Synthesized from chemicals in soy and Mexican yam

aka “bioidentical” or “natural” progesterone

Mexican yam neither contains nor can directly provide progesterone

Humans don’t produce the needed enzyme

Mixed evidence of efficacy for hot flashes

Skin absorption is much lower than therapeutic dose

Does not prevent bone loss or improve bone density

Does not lower the risk of endometrial cancer 81

Tips for buying progesterone cream

Concentration should be about 16-25 mg/gram of cream

20 mg of progesterone from cream applied daily to the skin (vary site daily)

Should be used with physician supervision even though little is absorbed

Caution: Risk of containing manufacturing by-products like androstenedione or other steroids (but not enough to be banned from Olympics)

Probiotics

Nearly 2,000 clinical research studies have been published

Multiple types of interactions with gut microbiota theorized

 Affecting GI tract function

 Interactions with other microbiota outside GI tract

Most popular probiotics: natural gut-dwelling gram-positive bacteria

 Lactobacillus, Bifidobacterium, Streptococcus, Saccharomyces, Bacillus, and Enterococcus

Quality concerns:

Viability at time of purchase

Contamination

Ability to colonize the gut

Aponte M, Murru N, Shoukat M. Therapeutic, Prophylactic, and Functional Use of Probiotics:

A Current Perspective. Front Microbiol. 2020 Sep 11;11:562048.

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Probiotics for bacterial vaginosis

Used alone or in combination with antibiotics

To prevent recurrence or relapse

More research needed

Oral versus vaginal route, dose, duration

Lactobacillus strains

Senok AC, Verstraelen H, Temmerman M, Botta GA. Probiotics for the treatment of bacterial vaginosis. Cochrane Database Syst Rev 2009; :CD006289.

BV: what’s the latest?

2019 meta-analysis:

 Combo treatment probiotics + antibiotics more effective than either alone

 Unclear efficacy due to quality and heterogeneity of the trials

Vaginal microbiome transplantation

 To reconstitute vaginal flora towards a Lactobacillus-dominated vaginal microbiome

 For intractable recurrent BV or UTIs

Li C, Wang et al. Probiotics for the treatment of women with bacterial vaginosis: A systematic review and meta-analysis of randomized clinical trials. Eur J Pharmacol. 2019 Dec 1;864:172660

Lev-Sagie A, et al. Vaginal microbiome transplantation in women with intractable bacterial vaginosis.

Nat Med. 2019 Oct;25(10):1500-1504.

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Probiotics for UTIs

Vagina may serve as a reservoir in transfer of intestinal uropathogens to the intestinal tract

Vaginal probiotics: ↓ UTI recurrence compared to placebo

Oral probiotics:

 Lactobacillus group compared to antibiotic group:

 Shorter interval/more frequent recurrences

 Lower development of antibiotic resistance

Beerepoot MA,et al. Lactobacilli vs antibiotics to prevent urinary tract infections: a randomized, double-blind, noninferiority trial in postmenopausal women. Arch Intern Med. 2012 May 14;172(9):704-12.

Stapleton AE, et al. . Randomized, placebo-controlled phase 2 trial of a Lactobacillus crispatus probiotic given intravaginally for prevention of recurrent urinary tract infection. Clin Infect Dis. 2011 May;52(10):1212-7.

Probiotics for vulvovaginal candidiasis

FPIN Clinical Inquiries (2020)

 Short-term cure rates ↑ 14%

 One-month relapse rates ↓ 66%

 Long term recurrent VVC rates may improve over 3-6 months

2019 RCT: Recurrent VVC, new acute episode

 Induction phase:

 Topical clotrimazole + oral probiotic (Lactobacillus + lactoferrin),

 Probiotic continued 8 days beyond antifungal

 Maintenance phase:

 2 caps/day probiotics x 5 days, then 1 cap/day x 10 days monthly

Conclusion: ↓ symptoms and recurrence rates

Russo R, Superti F, Karadja E, De Seta F. Randomised clinical trial in women with Recurrent Vulvovaginal Candidiasis: Efficacy of probiotics and lactoferrin as maintenance treatment. Mycoses. 2019 Apr;62(4):328-335.

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Cranberry for UTIs

In vitro findings not reproduced in vivo

Insufficient evidence for prevention of recurrent simple cystitis

Ineffective for treatment of existing UTI

Optimal dose/duration/formulation not known

Probably no harm other than increased calorie and glucose intake

Jepson RG, Williams G, Craig JC. Cranberries for preventing urinary tract infections. Cochrane Database Syst Rev 2012; 10:CD001321.

July 2020: FDA allowed qualified health claims for certain cranberry juice products and UTIs

Qualified Health Claims (QHCs): scientific evidence supporting a claim is

“limited and inconsistent” but doesn’t meet standards for “significant scientific agreement”.

“Consuming one serving (8 oz) each day of a cranberry juice beverage may help reduce the risk of recurrent urinary tract infection (UTI) in healthy women. FDA has concluded that there is limited

scientific evidence supporting this claim.”

“Consuming 500 mg each day of cranberry dietary supplement may help reduce the risk of recurrent urinary tract infection (UTI) in healthy women. FDA has concluded that there is limited scientific

evidence supporting this claim.”

https://www.fda.gov/food/cfsan-constituent-updates/fda-announces-qualified-health-claim-certain-cranberry-products-and-urinary-tract-infections

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“Estrogen Dominance” (ED):

a new diagnosis, or a new marketing concept?

Too much estrogen compared to progesterone due to inadequate estrogen elimination and/or too much exogenous estrogens

Symptoms

 Hot flashes, night sweats, mood swings, irritability, insomnia, foggy thinking, fatigue, weight gain, decreased libido, PMS, irregular periods, hair loss, bloating, tender lumpy breasts, endometriosis, thyroid nodules, cellulite, infertility, anovulation, estrogenic cancers . . .

Treatment: diet and supplements

 DIM (diindolylmethane): Claimed to balance estrogen metabolites

 Very limited studies with low quality evidence: alters estrogen urinary metabolite profiles in women and has androgen-antagonistic effects

Best Practice Recommendations

1. Just ask.

2. Educate your patients about the potential for harm from excessive micronutrient intake, considering the total amount from combined diet and supplements.

3. Know when to monitor labs and therapeutic response for the supplements commonly used by your patient population.

4. Educate yourself and your patients about how to access reliable on-line resources to assess the risks and benefits of using supplements.

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Answers

1. A 2. E 3. B

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