What is compounded bioidentical hormone therapy? Botanicals for Menopausal Symptoms

1. Compounded Bioidentical
Hormone Therapy
Vandana Y. Bhide, MD
Instructor, Division of Hospital Internal Medicine
Board Certified, Internal Medicine, Pediatrics
Diplomate, American Board of Integrative and
Holistic Medicine (Non-ABMS)

2. Disclosures
• American Medical Seminars-CME lectures (No
pharmaceutical funding)
• Will discuss non-FDA approved compounded
estrogen, progesterone, testosterone
products, including estriol (investigational new
drug)
• Non-FDA approved dietary supplements and

3. Objectives
• Distinguish the risks and
benefits of bioidentical
hormones
• Analyze herbal agents and
dietary supplements used
for vasomotor and other
menopausal symptoms

4. 62 YO asymptomatic female
requests “bioidentical” hormones
as anti-aging treatment to
A. Conjugated equine estrogen alone to reduce risk of breast
cancer
B. Bi-est 3.0 and topical progesterone cream
C. Avoid bioidentical hormones
D. Tri-est and compounded oral micronized progesterone
E. Estradiol patch and micronized progesterone
Audience Response Question 1
promote rejuvenation, longevity, maintain mental
alertness, improve bone density. She does not
want “synthetic” hormones or patches. She has
intact uterus. You advise

5. 52 YO female with peanut allergy requests treatment
of vasomotor symptoms and genitourinary syndrome
of menopause. You recommend
Audience Response Question 2
A. Estradiol patch and conventional oral micronized
progesterone
B. Estradiol patch and compounded progesterone
cream
C. Estradiol patch and compounded oral micronized
progesterone
D. Avoid postmenopausal hormone replacement
E. Soy sauce, yam flavored frozen yogurt, reruns of
“Three’s Company”

6. Bioidentical Hormone Replacement
• Compounds that have the same chemical and
molecular structure as hormones that are
produced in the human body (National
Menopause Society, Endocrine Society)
• Extracted from plants
Santen, RJ et.al. Postmenopausal hormone therapy: an Endocrine Society scientific statement.
J Clin Endocrinol Metab. 2010 Jul; 95(7 Suppl 1):s1-s66.
• Bioidentical hormone therapy recognized by
FDA, Endocrine Society as a marketing term
• Not necessarily based on scientific evidence
Rosenthal MS. The Wiley Protocol: an analysis of ethical issues. Menopause 2008;15:1014–22.

7. Compounded Bioidentical
Hormone Therapy (CBHT)
• Up to 2.5 million women use CBHT
• In response to concerns about risks of PMHRT in
WHI/HERS/PEPI/Million Women studies
• Many women think CBHT safe because “natural”
• Bioidentical does not mean natural
Sood, Richa et.al. Counseling Postmenopausal Women about Bioidentical Hormones: Ten Discussion
Points for Practicing Physicians. J Am Board Fam Med 2011;24:202–210.
• Custom compounded by pharmacy health care
provider’s prescription

8. Recommend Against CBHT
•North American Menopause Society
•American Congress Obstetricians and Gynecologists
•American Society Reproductive Medicine
•Endocrine Society
•American Association of Clinical Endocrinologists
•Women's Health Practice and Research Network of the
American College of Clinical Pharmacy
•U.S. Food and Drug Administration

9. Human Estrogens
• Estrone (E1) -highest concentration in
menopause
• Adipose tissue-converts estrone to estradiol
• Adrenal hormone androstenedione converted to
estrone
• 17β-estradiol (E2)
• Most active biologically
• Ovarian follicle/corpus luteum
• Estriol (E3)-16α-hydroxylation of estrone and
estradiol
• Placenta
• Low levels outside of pregnancy
• Not converted to estradiol
• Short half life, least potent

10. Progesterone
• Formed as cholesterol is converted to
estrogen and androgens
• Secreted by ovary
• Production stops after menopause
Pattimakiel, Lynn and Thacker, Holly L. Bioidentical hormone therapy: Clarifying the
misconceptions. Cleve Clin J Med 2011 Dec;78(12):829-836.

11. • Before menopause, made in ovary, adrenal
cortex
• Peripheral conversion androstenedione and
dehydroepiandrosterone (DHEA) to
testosterone
• Androgen levels decline over time,
unaffected by menopause
Pattimakiel, Lynn and Thacker, Holly L. Bioidentical hormone therapy: Clarifying the
misconceptions. Cleve Clin J Med 2011 Dec;78(12):829-836.
Testosterone

12. Hormone/Steroid Classes
• Class A- Found in nature
• Conjugated equine estrogens (sulfate
esters)
• 50% estrone sulfate
• 50% estrogens native only to horses
• Extracted from pregnant mare's urine
Bhavnani, Bhagu R. and Stanczyk, Frank Z., Misconception and Concerns about
Bioidentical Hormones Used for Custom-Compounded Hormone Therapy. The
Journal of Clinical Endocrinology and Metabolism. Dec 2011. 97 (3).

13. Hormone/Steroid Classes
• Class B-native to the body
• Chemically synthesized from plant sources
• Mexican yam (Dioscorea villosa), soybean
• Sterols diosgenin and stigmasterol
• Mexican yam converted to progesterone,
dehydroepiandrosterone, androstenedione,
testosterone
• Soy converted to estradiol, estrone, estriol,
synthetic conjugated estrogens
Bhavnani, Bhagu R. and Stanczyk, Frank Z., Misconception and Concerns about Bioidentical
Hormones Used for Custom-Compounded Hormone Therapy. The Journal of Clinical
Endocrinology and Metabolism. Dec 2011. 97 (3).

14. Hormone/Steroid Classes
• Class B-native to the body
• Humans lack enzymes to convert diosgenin
and stigmasterol to
estrogens/progestins/androgens
• No hormones are extracted intact from plant
source
• Chemical synthesis of 17β estradiol from
diosgenin requires at least 15 reactions
Bhavnani, Bhagu R. and Stanczyk, Frank Z., Misconception and Concerns about
Bioidentical Hormones Used for Custom-Compounded Hormone Therapy. The
Journal of Clinical Endocrinology and Metabolism. Dec 2011. 97 (3).

15. Compounded Bioidentical Hormones
• Amount of hormone extracted depends on
chemical process/alcohol used for
extraction
• Actual amount of hormone may be variable
• All compounded bioidentical hormones are
manmade

16. Non Bioidentical
Hormones
• Conjugated equine estrogen (CEE)
• Equilin sulfate (mares)
• Estrone sulfate
• Extracted from urine pregnant mares
• Ethinyl estradiol used in combined oral
contraceptives
• Medroxyprogesterone

17. FDA approved Bioidentical Hormones
• 17β-estradiol
• Oral
• Transdermal patch
• Transdermal bypasses hepatic metabolism
• Results in estrone:estradiol ratio of 1:1
• Similar to pre-menopausal levels
• Vaginal ring
• Creams and gels
• Progesterone (oral)
• Brand name progesterone is micronized in peanut oil
Files, Julia A. et.al. Bioidentical Hormone Therapy Mayo Clin Proc. 2011 Jul; 86(7): 673–680.

18. Advantages of Compounded Hormones
• FDA-approved progesterone micronized in
peanut oil.
• Compounded progesterone can eliminate peanut oil
• Cellulose or olive oil
• Dosage and component flexibility
• Low-dose formulations
• Possible reduced cost
• Separate co-pays for estrogen patch/micronized
progesterone
• Highly individualized prescriptions
Committee on Gynecologic Practice and the American Society for Reproductive Medicine Practice
Committee, Compounded Bioidentical Menopausal Hormone Therapy. No 532, August 2012
(Reaffirmed 2014). Obstet Gynecol 2012;120:411–5.

19. Compounded Hormones
• Estrogens
• 17β-estradiol, estrone, estriol
• Progesterone
• 100-200 mg/day
• Testosterone
• 2–10 mg once/day
• Dehydroepiandrosterone (DHEA)
• Pregnenolone

20. CBHT Delivery
• Troches (lozenges) for
buccal administration
• Vaginal suppositories
• Creams, gels, lotions
• Sublingual tablets
• Subdermal implants
ACOG Committee on Gynecologic Practice and the
American Society for Reproductive Medicine Practice
Committee. Number 532, August 2012. (Reaffirmed 2014).

21. Bi-est Estriol: Estradiol
80%:20% or 90%:10%
• Bi-est 2.0
• 1.6 mg estriol and 0.4 mg estradiol
• Bi-est 2.5
• 2.0 mg estriol and 0.5 mg estradiol
• Bi-est 3.0
• 2.4 mg estriol and 0.6 mg estradiol
• Absorption of Bi-est not as consistent as
estradiol patch
Sood R, Warndahl RA, et al. Bioidentical compounded hormones: A pharmacokinetic evaluation
in a randomized clinical trial. Maturitas 2013;74:375.–382.

22. Tri-est
• Estriol:Estrone:Estradiol
• 80%:10%:10% (8:1:1 ratio)
• 1.25-2.5 mg/day
Davis, Ruth et.al. Risks and Effectiveness of Compounded Bioidentical Hormone
Therapy: A Case Series. J of Women’s Health. 23 (8) 2014.

23. Estrogen Receptors
• α receptor activation responsible for
proliferative effects of estrogens
• Ovary, endometrium, breast cancer cells
• β receptor activation balances α-
receptor effects
• Endothelial cells, bone, kidney, lung
Files, Julia A. et.al. Bioidentical Hormone Therapy Mayo Clin Proc. 2011 Jul;
86(7): 673–680.

24. Estrogen Receptors
• Estrone –mostly binds to to estrogen
receptor α
• 17β-estradiol -binds to estrogen α and β
receptors
• Estriol -weak binding to estrogen receptor α
and β

25. Estriol
• Safety of estriol unknown
• Estriol may stimulate breast cancer cells
Lippert C, Seeger H, Mueck AO.The effect of endogenous estradiol metabolites on the
proliferation of human breast cancer cells. Life Sci. 2003 Jan 10;72(8):877-83.
• Protection against breast cancer unproven
McBane, Sarah E. et.al. Use of Compounded Bioidentical Hormone Therapy in Menopausal
Women: An Opinion Statement of the Women's Health Practice and Research Network of
the American College of Clinical Pharmacy. 34 (4); 410–423, April 2014.
• Estriol not approved by FDA
• FDA: “Pharmacies should not compound drugs
containing estriol unless the prescriber has a valid
investigational new drug (IND) application.”
US Department of Health & Human Services, Food and Drug Administration. Transcript of FDA press
conference on FDA actions on bio-identical hormones.
http://www.fda.gov/downloads/NewsEvents/Newsroom/MediaTranscripts/ucm122174

26. Estrogen-Testosterone Therapy &
Breast Cancer Risk in Natural
Menopause
• 2.5 X in current users of estrogen plus
testosterone vs women who never used HT
• Significantly higher compared to estrogen-only
therapy (P=0.007)
• Slightly more than estrogen and progesterone
therapy (P = 0.11)
• HT with testosterone-17.2% increased risk of
breast cancer per year of use
Tamimi, RM, et al . Combined Estrogen and Testosterone Use and Risk of Breast Cancer in
Postmenopausal Women. Archives of Internal Medicine 2006,166:1483-1489.

27. Salivary Hormone Levels
• Anti-Aging doctors-urine/serum hormone
levels unreliable because measure protein
bound, biologically inactive hormone
• Free hormone moves freely into salivary
glands and represents ultrafiltrate of serum
• Salivary levels are not reliable Schmidt, Peter. The 2012 Hormone
Therapy Position Statement of The North American Menopause Society. Menopause.
2012 Mar; 19(3): 257–271.
• Saliva samples do not remain stable in storage
• Interassay test results can be variable
• Affected by diet, time of day
Hodis HN, Mack WJ. Postmenopausal hormone therapy in clinical
perspective. Menopause 2007; 14:944–957.
• Dose on symptom relief rather than
estrogen/ progesterone/testosterone levels

28. Controversial-Progesterone
Transdermal creams and gels
• Salivary and capillary levels high but serum levels
remain low
• Do serum or salivary levels represent tissue
levels?
• Progesterone cream does not achieve serum
levels to prevent endometrial proliferation
Du, J.Y., Sanchez, P., Kim, L., Azen, C.G., Zava, D.T., and Stanczyk, F.Z.Percutaneous progesterone
delivery via cream or gel application in postmenopausal women: a randomized cross-over study of
progesterone levels in serum whole blood saliva capillary blood. Menopause. 2013; 20: 1107–1226.

29. Regulation Compounded Hormones
• Dietary Supplement Health and Education
Act of 1994 (DSHEA)
• Compounded hormones considered to be
supplements
• Dietary supplements are not required to
prove safety or efficacy
• Cannot claim treatment or curative
properties
• Compounded pharmacies regulated by
state boards of pharmacy

30. Labeling Hormones
• FDA requires Black Box warning on
conventional hormones based on WHI
concerns
• Compounded preparations are not regulated
by FDA and have no official package insert
• Exempt from Black Box warning that hormones
may lead to serious injury or death
• Pharmacies are not required to report adverse
events

31. FDA Testing Internet Bioidentical Hormones
• 29 compounded drugs from 12 compounding
pharmacies
• 10 products (34%) failed quality test
• 9 products (one of which was progesterone)
contained less active ingredient than indicated
U.S. Food and Drug Administration. Report: limited FDA survey of compounded drug products.
Silver Spring (MD): FDA; 2009.
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/PharmacyCompoundin
g/ucm155725.htm

32. Summary Compounded HRT
• Not FDA approved
• Treat symptomatic menopausal women
• Use lowest possible dose for shortest duration
Goodman NF, Cobin RH, Ginzburg SB, Katz IA, Woode DE. American Association of Clinical
Endocrinologists Medical Guidelines for Clinical Practice for the diagnosis and treatment of
menopause: executive summary of recommendations. Endocr Pract 2011;17:1–25.
• FDA approved bioidentical estradiol and
progesterone available
• Longterm safety estriol unknown
• Avoid progesterone cream and testosterone
• Compounded micronized progesterone for
peanut allergic patients

33. 62 YO asymptomatic female
requests “bioidentical” hormones
as “anti-aging” treatment to
A. Conjugated equine estrogen alone to reduce risk of breast
cancer
B. Bi-est 3.0 and topical progesterone cream
C. Avoid bioidentical hormones
D. Tri-est and compounded oral micronized progesterone
E. Estradiol patch and micronized progesterone
Audience Response Question 1
promote rejuvenation, longevity, maintain mental
alertness, improve bone density. She does not want
“synthetic” hormones or patches. She has intact
uterus. You advise

34. 62 YO asymptomatic female
requests “bioidentical” hormones
as “anti-aging” treatment to
A. Conjugated equine estrogen alone to reduce risk of breast
cancer
B. Bi-est 3.0 and topical progesterone cream
C. Avoid bioidentical hormones
D. Tri-est and compounded oral micronized progesterone
E. Estradiol patch and micronized progesterone
Audience Response Question 1
promote rejuvenation, longevity, maintain mental
alertness, improve bone density. She does not want
“synthetic” hormones or patches. She has intact
uterus. You advise

35. 52 YO female with peanut allergy requests treatment
of vasomotor symptoms and genitourinary syndrome
of menopause. You recommend
Audience Response Question 2
A. Estradiol patch and conventional oral micronized
progesterone
B. Estradiol patch and compounded progesterone
cream
C. Estradiol patch and compounded oral micronized
progesterone
D. Avoid postmenopausal hormone replacement
E. Soy sauce, yam flavored frozen yogurt, reruns of
“Three’s Company”

36. 52 YO female with peanut allergy requests treatment
of vasomotor symptoms and genitourinary syndrome
of menopause. You recommend
Audience Response Question 2
A. Estradiol patch and conventional oral micronized
progesterone
B. Estradiol patch and compounded progesterone
cream
C. Estradiol patch and compounded oral micronized
progesterone
D. Avoid postmenopausal hormone replacement
E. Soy sauce, yam flavored frozen yogurt, reruns of
“Three’s Company”

37. Vandana Y. Bhide, M.D.
Beyond Hot Flashes:
Botanicals for
Menopausal Symptoms

38. 52 YO female with hypertension requests
“herbal” non-hormonal approach to menopausal
symptoms including vasomotor symptoms, mood
changes, anxiety, and insomnia. What evidence
based regimen could you suggest?
A. Trial of meditation, Black Cohosh, valerian
B. Avoid soy isoflavanes in patient with history
of breast cancer
C. Inform patient of the risk of hepatotoxicity
with kava kava
D. Inform patient of medication interactions
with St. John’s Wort
F. All of the above

39. 1994 Dietary Supplement Health and
Education Act (DSHEA)
• Products containing dietary ingredient,
including vitamins, minerals, amino
acids, animal extracts, probiotics,
enzymes, herbs or other botanicals
• Not required to undergo FDA review for
safety and effectiveness
• Cannot claim to diagnose, treat, cure or
prevent any disease

40. Difficult to Prove-Efficacy of Botanicals

41. Mind-Body Therapies Menopausal Symptoms
• 2010 – met-analysis 21 studies
• Meditation, yoga, tai chi
• Reduced frequency and intensity of hot
flashes, mood and sleep changes, stress
symptoms, muscle/joint pain
Innes KE, Selfe TK, Vishnu A. Mind-Body therapies for menopausal symptoms: a systematic
review. Maturitas. 2010;66(2):135–149.
NIH National Center for Complementary and Alternative Medicine.
https://nccih.nih.gov/health/menopause/menopausesymptoms?nav=gsa

42. Vasomotor Symptoms-
Potential Serotonergic Botanicals
• Black Cohosh
• Kudzu (vine-legume Pueraria labata)
• Kava Kava-hepatotoxicity
• Dong Quai-increased INR with warfarin
• Licorice-hypokalemia, interacts with
spironolactone
Bunchorntavakul, C. and Reddy, K. R. (2013), Review article: herbal and dietary
supplement hepatotoxicity. Alimentary Pharmacology & Therapeutics, 37: 3–17.

43. Vasomotor Symptoms-
Potential Phytoestrogens
• Soy
• Red clover
• Kudzu
• Mexican yam
• Chasteberry
• Licorice
• Rhubarb
• Hops
• Phytoestrogens-weak
estrogen agonists, partial
agonists, or antagonists to
endogenous estrogens
• Bind estrogen β receptor
• ? Add progesterone for
endometrial protection
• Avoid in women with or at
risk for breast, uterine, or
ovarian cancer
Hajirahimkhan,
Atieh et.al. Botanical Modulation of Menopausal Symptoms:
Mechanisms of Action? Planta Med 2013; 79(07): 538-553.

44. Vasomotor Symptoms-
Potential Progesterone-like
Herbs
• Red clover
• Chasteberry
• Mexican yam
• Hops

45. Black Cohosh
(Actaea racemosa
and Cimicifuga
racemosa)-
Buttercup family
• Roots and rhizomes (underground stems)
• Extracts are standardized to 26 deoxyactein
content (chemicals called saponins)
• Usual dose 20 mg tablet bid
• Vasomotor symptoms-conflicting results
• Rare reports liver damage/failure
• No known drug-drug interactions

46. Soy (pea plant)
• Soy protein 20-60 gm (34-80 mg isoflavones) daily
• Studes mixed results
• Modestly decreased frequency and severity of hot
flashes
• Moderate strength of evidence improved anxiety
symptoms: 7 trials, n=853
Grant MD, Marbella A, Wang AT, Pines E, Hoag J, Bonnell C, Ziegler KM, Aronson N. Menopausal
Symptoms: Comparative Effectiveness Review No. 147. (Prepared by Blue Cross and Blue Shield
Association Technology Evaluation Center Evidence-based Practice Center under Contract No.290-
2007-10058-I.) AHRQ Publication No. 15-EHC005-EF. Rockville, MD: Agency for Health care
Research and Quality; March 2015. www.effectivehealthcare.ahrq.gov/reports/final.cfm.

47. Soy Isoflavones-daidzein, genistein, glycitein
• Isoflavones bind estrogen receptor (ER) β- act as
selective estrogen receptor modulators (SERMs)
• Daidzein-isoflavone found in soy
• 75% of western women, 50% of Asians do not
have intestinal bacteria that convert daidzein into
the active metabolite S-(−)equol
• S-Equol, daidzein, genistein extracts may be
more beneficial than soy
• Soy intake prior to puberty may be protective of
breast cancer
Clarkson TB, Utian WH, Barnes S, et al. for the NAMS Isoflavone Translational Symposium Panel.
The role of soyisoflavones in menopausal health: report of The North American Menopause
Society/Wulf H. Utian Translational Science Symposium in Chicago, IL. (October, 2010).
Menopause 2011; 18: 732–753.

48. SE5-OH- Soy Isoflavane (Phytoestrogen)
• 126 equol non-producing postmenopausal
Japanese women 10mg/day S-(−)equol or
placebo for 12 weeks
• Soy germ with a strain of equol-producing Lactococcus
bacteria (generally recognized as safe) (GRAS).
• Soy Isoflavane daidzein broken down into S-(−)equol
• Only 30% to 50% Western women have lactic acid
secreting bacteria to convert daidzein to equol
• p=0.009 reduction in hot flashes and neck or
shoulder muscle stiffness
• Avoid soy/daidzein supplements in breast cancer
Takeshi Aso, Shigeto Uchiyama, Yasuhiro Matsumura, Makoto Taguchi, Masahiro Nozaki, Kiyoshi
Takamatsu, Bunpei Ishizuka, Toshiro Kubota, Hideki Mizunuma, and Hiroaki Ohta. Journal of
Women's Health. January 2012, 21(1): 92-100.

49. • Isoflavones require P450-metabolism to form
active phytoestrogens daidzein and genistein
• NCCAM RCT-black cohosh vs red clover vs
HRT vs placebo
• No better than placebo, not as effective as
HRT
Geller SE, Shulman LP, van Breemen RB, et al. Safety and efficacy of black cohosh and red
clover for the management of vasomotor symptoms: a randomized controlled trial.
Menopause. 2009;16(6):1156–1166
• Cochrane Review- no improvement with
Promensil (red clover extract) but extracts with
high (> 30 mg/d) levels of genistein
consistently reduced hot flashes
Lethaby Anne et.al. Phytoestrogens for menopausal vasomotor symptoms. The Cochrane
Library. 10 Dec. 2013.
Red clover (Trifolium pretense)-legume

50. Diascorea alata
(Purple Yam)
• 50 Taiwanese menopausal women two sachets
Diascorea extracts or placebo X 12 months
• Improvement in all Greene Climacteric Scale
symptoms except sexual function
• Most improvement in “insomnia,” “feeling tense or
nervous,” “excitable,” “musculoskeletal pain”
Hsu, CC et.al. The assessment of efficacy of Diascorea alata for menopausal symptom treatment in
Taiwanese women. Climacteric. 2011 Feb;14(1):132-9.
Grant MD, et.al. Menopausal Symptoms: Comparative Effectiveness Review No. 147. (Prepared by Blue
Cross and Blue Shield Association Technology Evaluation Center Evidence-based Practice Center
under Contract No.290-2007-10058-I.) AHRQ Publication No. 15-EHC005-EF. Rockville, MD: Agency
for Health care Research and Quality; March 2015. www.effectivehealthcare.ahrq.gov/reports/final.cfm.

51. St. John’s Wort
• Effective short term treatment mild to
moderate depression
• Interacts with multiple medications via P450
system in liver
• 301 German menopausal women vs placebo
X 16 wks
• St. John's wort and black cohosh
combination effective for hot flashes and
psychological symptoms
Uebelhack, Ralf et. al. Black Cohosh and St. John’s Wort for Climacteric Complaints: A
Randomized Trial. Obstetrics & Gynecology. Feb. 2006. 107 (2) 247-255

52. French Maritime Pine (Pinus pinaster)
• Polyphenols (antioxidants found in vegetables)
• 155 menopausal Taiwanese women
• 100 mg Pycnogenol or placebo BID X 6 months
• Women’s Health Questionnaire (somatic, depressed,
vasomotor, memory, attractiveness, anxiety, sexual,
sleep, menstrual problems)
• Superior to placebo p<0.01 to p<0.001 for each
• HDL increased/LDL decreased significantly
Yang, Han-Ming et.al. A randomised, double-blind, placebo-controlled trial on the effect of Pycnogenol on
the climacteric syndrome in peri-menopausal women. Acta Obstetricia et Gynecologica. 2007; 86: 978-
985)
Grant MD, Marbella A, Wang AT, Pines E, Hoag J, Bonnell C, Ziegler KM, Aronson N. Menopausal
Symptoms: Comparative Effectiveness Review No. 147. (Prepared by Blue Cross and Blue Shield
Association Technology Evaluation Center Evidence-based Practice Center under Contract No.290-2007-
10058-I.) AHRQ Publication No. 15-EHC005-EF. Rockville, MD: Agency for Health care Research and
Quality; March 2015. www.effectivehealthcare.ahrq.gov/reports/final.cfm.

53. Proprietary combination of evening primrose
oil, damiana, ginseng, royal jelly (Lady 4)
• 120 Egyptian women
• Menopause Rating Scale II (MRS-II)
• 86.7% vs 56.7% “much or very much improved”
vs placebo p < 0.001
Yakoot, M, Salem A, Omar AM. Effectiveness of a herbal formula in women with menopausal syndrome.
Forsch Komplementmed. 2011;18(5):264-8. Epub 2011 Oct 10.
Natural Medicines Comprehensive Database. http://naturaldatabase.therapeuticresearch.com/
nd/Search.aspx?cs=MAYO&s=ND&pt=9&Product=menopause&btnSearch.x=6&btnSearch.y=9
• Avoid if highly bee allergic

54. Standardized extracts of black cohosh,
dong quai, milk thistle, red clover,
American ginseng, chaste-tree berry
• 50 Israeli women peri/menopausal
• Phyto-Female or placebo X 3 months
• 47% vs 19% placebo-eliminated hot flashes
• 73% decrease in hot flashes, 69% reduction of
night sweats, improved sleep quality
• No liver test or estradiol/FSH level changes
• No change transvaginal ultrasound
Rotem C, Kaplan B. Phyto-Female Complex for the relief of hot flushes, night sweats and quality of sleep:
randomized, controlled, double-blind pilot study. Gynecol Endocrinol 2007;23:117-22.

55. Vitamin E 400 IU daily vs placebo
• 51 Iranian women placebo X 4 wks,
Vitamin E X 4 wks
• Decrease in # (5) and severity of hot
flashes p < 0.0001
Ziaei S.,Kazemnejad A. ,Zareai M. The Effect of Vitamin E on Hot Flashes in
Menopausal Women. Gynecol Obstet Invest 2007;64:204–207.
Grant MD, Marbella A, Wang AT, Pines E, Hoag J, Bonnell C, Ziegler KM, Aronson N.
Menopausal Symptoms: Comparative Effectiveness Review No. 147. (Prepared by
Blue Cross and Blue Shield Association Technology Evaluation Center Evidence-
based Practice Center under Contract No.290-2007-10058-I.) AHRQ Publication
No.15-EHC005-EF. Rockville, MD: Agency for Health care Research and Quality;
March 2015. www.effectivehealthcare.ahrq.gov/reports/final.cfm.

56. Ethyl-eicosapentainoic Omega 3 fatty Acids
and Vasomotor symptoms
• E-EPA = 45; placebo = 46
• Average number hot flashes/day 2.8
• EPA:decreased by 1.58/day
• Placebo: decreased 0.5
• p=0.04
• No change QOL
Lucas M, Asselin G, Merette C, et al. Effects of ethyl-eicosapentaenoic acid omega-3
fatty acid supplementation on hot flashes and quality of life among middle-aged women:
a double-blind, placebo-controlled, randomized clinical trial. Menopause 2009;16:357-66.

57. Valerian (Valeriana officinalis)
• ? GABA inhibitor
Yurchesen,M. et.al. Evid Based Complement Alternat
Med. 2015.
• Extracted from root/rhizomes
• Randomized, triple-blind, controlled trial
• 100 postmenopausal women in Iran
• Pittsburgh Sleep Quality Index
• 530 mg concentrated valerian extract or placebo
twice daily X 4 weeks.
• 30% valerian group vs 4% placebo group with sleep
quality improvement (P < 0.001).
S. Taavoni et.al., Menopause 2011 Sept; 18(9): 951-5.

58. Valerian
• Cytochrome P450 3A4
• Lovastatin,
itraconazole,
fexofenadine
• Avoid with alcohol,
benzodiazepines,
anesthesia (stop 2 wks)
• 400-900 mg valerian
extract up to 2 hours
before bedtime for 28
days

59. Kava Kava-Helped Anxiety but
not Hot Flashes
• GABA, dopamine D2, benzodiazepine, opioid
(µ and δ), serotonin, histamine (H1 and H2)
receptor binding activity
• Hepatotoxicity
• Stems/leaves may be more toxic than roots
• Solvent used for extraction may contribute to
toxicity
Yurcheshen M, Seehuus M, Pigeon W. Updates on Nutraceutical Sleep Therapeutics and
Investigational Research. Evidence-based Complementary and Alternative Medicine :
eCAM. 2015;2015:105256. doi:10.1155/2015/105256.

60. Kava Kava (Piper methysticum)
• Meta-analysis Cochrane Review
• 700 patients in 12 randomized,
controlled studies
• “The data available…suggest that
kava is relatively safe for short-
term treatment (1 to 24 weeks)…”
Pittler M. H., Ernst E. Kava extract versus placebo for treating
anxiety. Cochrane Database of Systematic Reviews. 2003
(Republished 2010 including additional studies).

61. Dehydroepiandrosterone (DHEA)
• 12 weeks intravaginal DHEA daily vs placebo
• Vaginal suppository 0.25% (3.25 mg) or 0.50%
(6.5 mg) DHEA
• Helped vaginal atrophy, burning, itching, libido,
dyspareunia
• Must be converted to estrogen to be effective
• No increase in serum estradiol levels
• Dietary Supplement in US
Archer, David. Dehydroepiandrosterone intra vaginal administration for the
management of postmenopausal vulvovaginal atrophy. Journal Steroid Biochemistry
and Molecular Biology. 145. Jan 2015,139–143
Labrie F, Archer D, Bouchard C, et al. Intravaginal dehydroepiandrosterone
(Prasterone), a highly effective efficient treatment of dyspareunia. Climacteric.
2011;14(2):282–288.

62. Homeopathic Vaginal Gel for GSM
• 186 women received daily oral isoflavones and
Lactobacillus sporogenes
• 103 women also used vaginal gel containing
isoflavones
• Calendula officinalis extract 1X
• Lactobacillus sporogenes
• Lactic acid
• Vaginal dryness, itching, burning, erythema,
dyspareunia significantly reduced with gel
• Calendula-drowsiness when taken with
benzodiazepines, phenobarbital, or zolpidem
Tedeschi, Christina et.al. Comparison of vaginal gel isoflavones versus no topical treatment in
vaginal dystrophy: results of a preliminary prospective study. Gyn Endo 2012. 28 (8).

63. Skin
• Argan oil (oral or topical)
• 30 patients, 30 controls (dietary olive oil)
• Dietary or topical argan oil improved skin
elasticity in postmenopausal women
Boucetta, KQ et.al. The effect of dietary and/or cosmetic argan oil on postmenopausal
skin elasticity. Clin Interv Aging. 2015 Jan 30;10:339-49.
©2010 MFMER | slide-63

64. Weight Loss Agents-No Benefit Proven Saper, Robert
B. et.al. Common Dietary Supplements for Weight Loss American Family Physician. 2004. 70 (9); 1731-8.
• Apple cider vinegar
• Acai Berries (Avoid prior
to MRI)
• Cascara
• Chitosan
• Chromium
• Conjugated linoleic acid
• Dandelion
• Ephedra (Withdrawn)
• Ginseng
• Glucomannan
• Green tea
• Guar gum
• Guggul
• Hydroxycitric acid
• Laminaria
• L-carnitine
• Licorice
• Psyllium
• Pyruvate
• Spirulina
• St. John’s Wort
• Vitamin B5

65. 52 YO female with hypertension requests
“herbal” non-hormonal approach to menopausal
symptoms including vasomotor symptoms, mood
changes, anxiety, and insomnia. What evidence
based regimen could you suggest?
A. Trial of meditation, Black Cohosh, valerian
B. Avoid soy isoflavanes in patient with history
of breast cancer
C. Discuss risk of hepatotoxicity with kava
kava
D. Discuss medication interactions with St.
John’s Wort
F. All of the above

66. 52 YO female with hypertension requests
“herbal” non-hormonal approach to menopausal
symptoms including vasomotor symptoms, mood
changes, anxiety, and insomnia. What evidence
based regimen could you suggest?
A. Trial of meditation, Black Cohosh, valerian
B. Avoid soy isoflavanes in patient with history
of breast cancer
C. Discuss risk of hepatotoxicity with kava
kava
D. Discuss medication interactions with St.
John’s Wort
F. All of the above

67. Bhide.Vandana@Mayo.edu
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