BioidenticalHormones:Just the Facts

Melissa McNeil, MD, MPHProfessor of Medicine and Obstetrics,

Gynecology and Reproductive SciencesChief, Section of Women’s Health

University of Pittsburgh

Disclosures

! I have no conflicts of interest or anyfinancial disclosures to report

What is Bioidentical Hormone Therapy?

! Approach to the management ofmenopausal symptoms in women usingnon-conventional hormonesupplementation

! Increased in popularity in response tothe safety concerns about conventionalhormone therapy raised by the resultsof the Women’s Health Initiative

What is Bioidentical Hormone Therapy?

! Fundamental principles include! Use of hormones that are identical chemically to

hormones naturally in the body! Often topical rather than oral preparations! Individualization of the hormone prescription to

the individual patient

! There is no agreement (even amongproponents of BHT) about which principlesare fundamental

Why Are BioidenticalHormones So Popular?

! I love being 60!And I’m not justsaying that!

! I love it becauseI’m hormonally inbalance.

! Without hormones,there is no qualityof life!

Proponents Claim That . . .

! By avoiding the combinationof drugs used in the WHI, abetter outcome can beachieved

! Advocates assert thatbioidentical hormones are:! Better tolerated! More efficacious! Safer than conventional HT

But MDS Are Also Advocates

Why Suffer Needlessly?

Menopausal Hot Flashes? NightSweats? Vaginal Dryness?

Relief Is Now Possible, Using OnlyWhat Mother Nature Gives Us In

The First Place!

Website: Women’s Health Institute of Texas, accessed 2/26/11

! ESTRO 500!!!! For vaginal and topical use! No prescription needed! Sold

as a cosmetic!!!!! Estriol and Estradiol in Estro500 are bio-

identical to human estrogens! Formulation contains 80% estriol, 20%

estradiol; Two pumps of Estro500 equivalentto .500 mg of Premarin

Website: Women’s Health Institute of Texas, accessed 2/26/11

You Too Can Buy . . .

And If You’re Lucky . . .

! You will be smartenough to orderprogesterone to gowith your estradiol

! But you will need toknow this . . .

! Because the WHI ofTexas does not nottreat individualpatients

And You Will Needto Be Smart BecauseThe Site Says:

Medical Myth #6: “It is not safe to takehormones if you have breast cancer inthe past”

So what’s the big deal about sex hormonereceptors? Ignore them. Of course, it is safeto take bio-identical hormones in the face ofa past breast cancer.

More AboutMedical Myth #6

Why don’t 19 - 25 year women orpregnant women get massive amountsof cancers when their sex hormonelevels are at all-time highs? They don’t.

The women who get cancers don’t haveenough sex hormones. Not the otherway around . . . This is intuitive.

And Don’t ForgetThe Oprah Effect!

"After one day on bioidentical estrogen,I feltthe veil lift," Winfrey writes. "After threedays, the sky was bluer, my brain was nolonger fuzzy, my memory was sharper. I wasliterally singing and had a skip in my step.”(WebMD: Oprah and Bioidentical Hormones)

Where Oprah goes, others follow. . .You will need to answer questions!

Objectives! To review the pharmacology of

estrogen and progesteronepreparations

! To discuss! The premise of bioidentical

hormone therapy (BHT)! The safety benefits of BHT! The therapeutic benefits of BHT

! To outline a rationaleapproach to using BHT inpractice

What are the Naturally OccurringHormones of Interest?

! Estrogens! Estrone (E1)! Estradiol (E2)! Estriol (E3)

! Androgens! Dehydroepi-

androsterone (DHEA)! Testosterone

! Progesterones! Progesterone! Pregnenolone

Non Bioidentical Hormones

! Estrogens! Esterified estrogens! Ethinyl estradiol! Conjugated equine

estrogens

! Progesterones! Medroxy-

progesterone! Norethindrone

Hormone Biochemistry

! Estrogen and progesterone hormonesare steroid hormones that arebiosynthesized from cholesterol

! Produced in the adrenal gland, ovaries,and placenta in women

! Different steps in the enzymaticpathways create different hormoneseach with differing physiologic functions

Hormone Biochemistry! Hormones have differing effects on target

tissues based upon target tissue activity! Androgens are converted to estrogens

directly in target tissues if the appropriateenzymes are present! Aromatase, 17B hydroxysteroid dehydrogenase,

and estrone sulfatase! Thus, amount of hormone at the target

tissues is heavily influenced by local estrogenproduction

Hormone Biochemistry

! Activity also depends on the types ofreceptors present in different cells

! Two distinct receptor subtypes: alphaand beta

! The interaction of drugs with differentestrogen receptors is complex; someact as agonists at some tissues and asantagonists at other tissues

Hormonal Status in theReproductive Years

! Estradiol (E2) is the primary source ofestrogen in women during theirreproductive years

! Secreted by the granulosa cells ofmaturing ovarian follicles

! With menopause, plasma levels ofestradiol fall from 40-400 ng/ml duringthe menstrual cycle to 5-20 ng/ml

Hormonal Status in theMenopausal Years

! Estrone (E3) is the primary source ofestrogen in post menopausal women

! Comes from the peripheral conversionof adrenal androstenedione

! Often the levels present are insufficientto prevent menopausal symptoms andbone loss

Estrogen Preparations! Bioidentical Hormones (most derived from

plant sources)! Estradiol, estrone, estriol

! Natural Hormones! Conjugated equine estrogens (CEE) from pregnant

mare urine! Dominant estrogens: estrone sulfate (a human

bioidentical hormone) and equilin sulfate (nativeto horses)

! Synthetic Estrogens! Ethinyl estradiol

Progestin Preparations

! Bioidentical! Progesterone: available as creams, capusules,

trochees, suppositories! Poor GI absorption and short half life! Micronized progesterone: synthesized from

Mexican yams

! Synthetic! Medroxyprogesterone acetate, norethindrone:

synthesized from soy or Mexican yams

How Does This Relate toBioidentical Hormone Therapy?

! Primary goal of BHT is to replace hormoneswith “natural” supplements! Biochemically similar to native hormones?! Plant derived?! Made without chemical synthesis?

! Secondary goal is to replace the hormoneswith the type of hormone most “gentle” tomenopausal women (ie: estriol (E3)

What About Estriol (E3)?

! Weakest of the three naturally occuringestrogens

! Not commercially marketed for oral use in theUS (although widely available in Europe andJapan)

! It is the metabolic end product of bothestradiol and estrone

! Proponents claim that there is a decreasedrisk of both breast and endometrial cancer

Why Would Estriol be Safer?

! Estriol is a less potent estrogen than eitherestradiol or estrone

! It is also the byproduct of both estradiol andestrone! E2 has a plasma half life of 2 minutes and is

rapidly converted to E1! E1 is converted directly to E3

! Advocates claim that estriol prevents theneoplastic effects of estradiol and estrone byblocking their binding to estrogen receptors

Just the Facts:Estriol and Cancer Risk

! Based on studies by Lemon from the 1970’s and early1980’s

! Animal models suggested that rats premedicated withestriol were protected from cancer developmentwhen exposed to a known carcinogen

! HOWEVER, both estradiol and ethinyl estradiol wereequally effective in this model suggesting no uniquebenefit from estriol

Lemon HM. Oestriol and prevention of breast cancer. Lancet 1973Lemon HM. Antimammary carcinogenic activity of 17 alpha ethinyl estriol,

Cancer 1987.

Just the Facts:Estriol and the Endometrium! 1981 report by Whitehead in the NEJM

established that estriol, when used in dosescomparable to estradiol, causes endometrialhyperplasia

! 1986 study comparing endometrial effects ofestriol, estradiol, and the two in combination

! Showed similar dose dependent histologicalproliferative and hyperplastic changes

Whitehead et al. Effects of estrogen and progestins on the biochemistry and morphology of the menopausalendometrium. NEJM 1981

Padwick et al. Oestriol with estradiol versus estradiol alone: a comparison of endometrial, symptomatic, andpsychological effects. Br J Obstet Gynaecol 1986

Just the Facts:What About Efficacy of Estriol?

! Yang et al reported (although in Chinese!) thatestriol is effective in alleviating the symptoms ofmenopause: hot flashes, insomnia, vaginal dryness,and frequent urinary tract infections

! HOWEVER, it did not prevent bone loss! Similar conclusions were drawn in a 1998 article in

the Alternative Medicine Review

Yang et al. Efficacy and safety of estriol replacement therapy forclimacteric women (in Chinese). Chung Hua I Hsueh Tsa Chih1995.

Head KA. Estriol safety and efficacy. Altern Med Review 1998.

What is the Difference Between aNatural and a Synthetic Hormone

! Natural is often equatedwith coming from aplant rather than beingchemically synthesized

! There are no naturalestrogens that mimicthe chemical structureof native estrogens

! Thus, all “bioidenticalhormones” aresynthesized

What are BioidenticalEstrogen Preparations?

! Most common preparations! Biestrogen (Biest): 20% E2 /80% E3! Triestrogen (Triest): 10%E1/10%E2/80%E3

! Only available by prescription fromcompounding pharmacies

! If E3 is effective and the safest hormone, aformulation with only E3 would presumablybe the safest supplement available

What are BioidenticalEstrogen Preparations?

! The 80:20 ratio of E3:E2 in Biest impliesthat there is a significantly largerquantity of E3 in comparison with E2

! This suggestion is deceptive at best! The 80:20 ratio is not based on the

estrogenic potency, but rather on thedifferent milligram quantity of theagents combined

What are BioidenticalEstrogen Preparations?

! In 80:20 Biest: 2.0 mg of E3/ 0.5 mg of E2! BUT, the estrogenic potency of E3 ranges

from 1/10 to 1/100th of E2! This kind of potency calculation suggests that

most of the effect is from the E2 component! 0.5 mg of E2 (eg Estrace) is a standard dose

of conventional hormone therapy! Remember, estradiol is pharmaceutical

grade BHT

What About the Progestins?! Standard supplement is medroxyprogesterone

acetate (MPA)! MPA is a synthetic derivative of 17 alpha

hydroxyproesterone; the alterations in thechemical structure extend the half life to 12hours

! In contrast, “natural” progesterone issynthesized from yams or soybeans and thenconverted to oral micronized progesterone

! Micronized form has a half life of 1 hour! Micronized progesterone is a

pharmaceutical grade BHT

Just the Facts:Safety Issues

! Studies have determined that both MPA 5 mgand micronized progesterone 200 mg providesimilar protection for the endometrium

! The PEPI trail did not detect differences inefficacy or adverse effects, but did suggest abetter lipid profile with micronizedprogesterone

PEPI Writing Group. Effects of hormone replacement therapy onendometrial histology in postmenopausal women. JAMA 1996

Topical ProgesteroneAdministration

! Practitioners who prescribe BHT point tothe benefits of topical progesteronecreams

! According to supporters, these creamsare used to increase libido, normalizeblood clotting, promote bone building,manage hot flashes, and protect theuterus

Just the Facts: TopicalProgesterone Administration

! Example of such a product is Progest! Contains 200 mg progesterone/ounce! Percutaneous absorption is virtually

zero when Progest cream is applied! A typical dose is ! to 1 tsp daily! Randomized, double blind placebo

controlled trial determined theabsorption levels

Just the Facts:Topical ProgesteroneAdministration

! Randomized, double blind placebo controlledtrial of progesterone cream vs placebo inpostmenopausal women established:! Significant improvement in hot flashes (p=.03)! No decrease in bone loss as measured by DEXA

after 1 year

Leonetti et al. Transdermal progesterone cream for vasomotorsymptoms and postmenopausal bone loss. Obstet Gynecol 1999.

Just the Facts: TopicalProgesterone Administration

! Bigger concern is the ability of progesterone creamsto provide adequate endometrial protection

! One small randomized study of 27 women studiedthe impact of progesterone cream (16 mg and 64 mgdaily) with transdermal estradiol

! At doses studied, no changes in the proliferativeendometrium were noted

Wren et al. Effect of sequential transdermal progesterone cream onendometrium, bleeding pattern, and plasma progesterone and salivaryprogesterone levels in postmenopausal women. Climacteric. 2000.

Just the Facts:Quality of theAvailable Products

! Limited FDA survey examining 12compounding pharmacies during June toDecember of 2001 was completed

! 29/37 products identified were obtained andsubjected to repeated analysis of indentity,potency, uniformity, and tests ofcontamination

! Study was published by the Center for DrugEvaluation and Research

Just the Facts: Quality of theAvailable Products

! 10/29 sampled products (34%) failed one ormore standard quality tests

! 9/10 products failed potency testing with only59%-89% of promised hormone present asindicated in the product’s label

! Progestins were most suspect! Compared to pharmaceutical products where

only 0.13% of products failed potency tests

Salivary Testing

! One of the foundations of BHT is the beliefthat treatment should be individualized foreach patient based on hormonal levels

! Recommend the use of saliva testing toidentify which hormones are deficient and inneed of supplementation

! Believe that:! Saliva measures “bioavailable” over “protein

bound” hormones! This is more accurate than serum measurements

Just the Facts:Salivary Testing

! Boothby et al, in a review of the topic,concluded the following:! Levels vary on the time of day! On the diet of the individual! And the particular hormone being tested

! Thus poor reproducibility and largerinterassay variability undermine the precisionof salivary hormone testing

Boothby et al. Bioidentical Hormone Therapy: A review. Menopause, 2004.

Costs of Therapy

! Costs taken from the Physio AgeMedical Group Website

! Following are estimates:! $800 for initial 2 hour consultation fee! Initial lab tests $600; follow up tests 2-3

times per year are $200-300! Medications range from $125-$200 per

month

Physio Age Medical Group Web Site, 2007

Costs of Therapy! Medications include:

! $72 for estradiol, progesterone, andtestosterone transdermal cream

! $28 DHEA and pregnenolone compoundedinto capsules

! $462 for Human Growth Hormone! $95 for nutritional supplements! $6 for melatonin

Physio Age Group Web Site, 2007

Take Home Messages:The Bottom Line! Appreciate that there is NO EVIDENCE that BHT is

any safer or more efficacious than conventional HT! ACOG and NAMS both assert that the risk of estrogen

supplementation is a class effect; to that effect,there is no reason to suspect that BHTpreparations are any more hazardous thanconvention HT

! There are in fact some concerns that topicalprogesterone may not in fact provide adequateendometrial protection

! Available evidence also suggests that salivaryhormone testing is unreliable and uninterpretable

So What’s an Evidence BasedPractitioner to Do?

! Patients will want these preparations! Discuss the issue with your patients; you

should be involved in their decision making! Remember that bioidentical estrogen

hormones are commercially available both inoral and in transdermal preparations

! Micronized progesterone is also availablecommercially and is a bioidentical hormone

An Evidenced Based Strategy

! I refuse salivary testing! I explain that there is no data to suggest that

BHT is any safer! And when I have patients who requests BHT

therapy I suggest pharmaceutical BHT:! Transdermal estrogen! Biest or Triest if the patient insists! Oral micronized progesterone

! And I promise to individualize therapy--bytitrating to symptoms not by matchinghormone levels!

For More Information

! Understanding the Controversy:Hormone Testing and BioidenticalHormones. Proceedings from thePostgraduate Course Presented atNAMS, October 2006

! Position Statement: The EndocrineSociety, October 2006

Questions?