Bioidentical Hormones: Just the Facts

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1 Bioidentical Hormones: Just the Facts Melissa McNeil, MD, MPH Professor of Medicine and Obstetrics, Gynecology and Reproductive Sciences Chief, Section of Women s Health University of Pittsburgh Disclosures! I have no conflicts of interest or any financial disclosures to report

2 What is Bioidentical Hormone Therapy?! Approach to the management of menopausal symptoms in women using non-conventional hormone supplementation! Increased in popularity in response to the safety concerns about conventional hormone therapy raised by the results of 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 among proponents of BHT) about which principles are fundamental

3 Why Are Bioidentical Hormones So Popular?! I love being 60! And I m not just saying that!! I love it because I m hormonally in balance.! Without hormones, there is no quality of life! Proponents Claim That...! By avoiding the combination of drugs used in the WHI, a better outcome can be achieved! Advocates assert that bioidentical hormones are:! Better tolerated! More efficacious! Safer than conventional HT

But MDS Are Also Advocates Why Suffer Needlessly? Menopausal Hot Flashes? Night Sweats? Vaginal Dryness? Relief Is Now Possible, Using Only What Mother Nature Gives Us In The First Place!

4 But MDS Are Also Advocates Why Suffer Needlessly? Menopausal Hot Flashes? Night Sweats? Vaginal Dryness? Relief Is Now Possible, Using Only What Mother Nature Gives Us In The First Place! Website: Women s Health Institute of Texas, accessed 2/26/11 You Too Can Buy...! ESTRO 500!!!! For vaginal and topical use! No prescription needed! Sold as a cosmetic!!!!! Estriol and Estradiol in Estro500 are bioidentical to human estrogens! Formulation contains 80% estriol, 20% estradiol; Two pumps of Estro500 equivalent to.500 mg of Premarin Website: Women s Health Institute of Texas, accessed 2/26/11

5 And If You re Lucky...! You will be smart enough to order progesterone to go with your estradiol! But you will need to know this...! Because the WHI of Texas does not not treat individual patients And You Will Need to Be Smart Because The Site Says: Medical Myth #6: It is not safe to take hormones if you have breast cancer in the past So what s the big deal about sex hormone receptors? Ignore them. Of course, it is safe to take bio-identical hormones in the face of a past breast cancer.

More About Medical Myth #6 Why don t 19-25 year women or pregnant women get massive amounts of cancers when their sex hormone levels are at all-time highs? They don t.

6 More About Medical Myth #6 Why don t year women or pregnant women get massive amounts of cancers when their sex hormone levels are at all-time highs? They don t. The women who get cancers don t have enough sex hormones. Not the other way around... This is intuitive. And Don t Forget The Oprah Effect! "After one day on bioidentical estrogen,i felt the veil lift," Winfrey writes. "After three days, the sky was bluer, my brain was no longer fuzzy, my memory was sharper. I was literally singing and had a skip in my step. (WebMD: Oprah and Bioidentical Hormones) Where Oprah goes, others follow... You will need to answer questions!

To outline a rationale approach to using BHT in practice What are the Naturally Occurring Hormones of Interest?

7 Objectives! To review the pharmacology of estrogen and progesterone preparations! To discuss! The premise of bioidentical hormone therapy (BHT)! The safety benefits of BHT! The therapeutic benefits of BHT! To outline a rationale approach to using BHT in practice What are the Naturally Occurring Hormones of Interest?! Estrogens! Estrone (E1)! Estradiol (E2)! Estriol (E3)! Androgens! Dehydroepiandrosterone (DHEA)! Testosterone! Progesterones! Progesterone! Pregnenolone

Estrogen and progesterone hormones are steroid hormones that are biosynthesized from cholesterol!

8 Non Bioidentical Hormones! Estrogens! Esterified estrogens! Ethinyl estradiol! Conjugated equine estrogens! Progesterones! Medroxyprogesterone! Norethindrone Hormone Biochemistry! Estrogen and progesterone hormones are steroid hormones that are biosynthesized from cholesterol! Produced in the adrenal gland, ovaries, and placenta in women! Different steps in the enzymatic pathways create different hormones each with differing physiologic functions

9 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 appropriate enzymes are present! Aromatase, 17B hydroxysteroid dehydrogenase, and estrone sulfatase! Thus, amount of hormone at the target tissues is heavily influenced by local estrogen production Hormone Biochemistry! Activity also depends on the types of receptors present in different cells! Two distinct receptor subtypes: alpha and beta! The interaction of drugs with different estrogen receptors is complex; some act as agonists at some tissues and as antagonists at other tissues

10 Hormonal Status in the Reproductive Years! Estradiol (E2) is the primary source of estrogen in women during their reproductive years! Secreted by the granulosa cells of maturing ovarian follicles! With menopause, plasma levels of estradiol fall from ng/ml during the menstrual cycle to 5-20 ng/ml Hormonal Status in the Menopausal Years! Estrone (E3) is the primary source of estrogen in post menopausal women! Comes from the peripheral conversion of adrenal androstenedione! Often the levels present are insufficient to prevent menopausal symptoms and bone loss

11 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 (native to 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 to Bioidentical Hormone Therapy?! Primary goal of BHT is to replace hormones with natural supplements! Biochemically similar to native hormones?! Plant derived?

12 How Does This Relate to Bioidentical Hormone Therapy?! Primary goal of BHT is to replace hormones with natural supplements! Biochemically similar to native hormones?! Plant derived?! Made without chemical synthesis?! Secondary goal is to replace the hormones with the type of hormone most gentle to menopausal women (ie: estriol (E3) What About Estriol (E3)?! Weakest of the three naturally occuring estrogens! Not commercially marketed for oral use in the US (although widely available in Europe and Japan)! It is the metabolic end product of both estradiol and estrone! Proponents claim that there is a decreased risk of both breast and endometrial cancer

13 Why Would Estriol be Safer?! Estriol is a less potent estrogen than either estradiol or estrone! It is also the byproduct of both estradiol and estrone! 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 the neoplastic effects of estradiol and estrone by blocking their binding to estrogen receptors Just the Facts: Estriol and Cancer Risk! Based on studies by Lemon from the 1970 s and early 1980 s! Animal models suggested that rats premedicated with estriol were protected from cancer development when exposed to a known carcinogen! HOWEVER, both estradiol and ethinyl estradiol were equally effective in this model suggesting no unique benefit from estriol Lemon HM. Oestriol and prevention of breast cancer. Lancet 1973 Lemon HM. Antimammary carcinogenic activity of 17 alpha ethinyl estriol, Cancer 1987.

14 Just the Facts: Estriol and the Endometrium! 1981 report by Whitehead in the NEJM established that estriol, when used in doses comparable to estradiol, causes endometrial hyperplasia! 1986 study comparing endometrial effects of estriol, estradiol, and the two in combination! Showed similar dose dependent histological proliferative and hyperplastic changes Whitehead et al. Effects of estrogen and progestins on the biochemistry and morphology of the menopausal endometrium. NEJM 1981 Padwick et al. Oestriol with estradiol versus estradiol alone: a comparison of endometrial, symptomatic, and psychological effects. Br J Obstet Gynaecol 1986 Just the Facts: What About Efficacy of Estriol?! Yang et al reported (although in Chinese!) that estriol is effective in alleviating the symptoms of menopause: 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 for climacteric women (in Chinese). Chung Hua I Hsueh Tsa Chih Head KA. Estriol safety and efficacy. Altern Med Review 1998.

There are no natural estrogens that mimic the chemical structure of native estrogens!

15 What is the Difference Between a Natural and a Synthetic Hormone! Natural is often equated with coming from a plant rather than being chemically synthesized! There are no natural estrogens that mimic the chemical structure of native estrogens! Thus, all bioidentical hormones are synthesized What are Bioidentical Estrogen Preparations?! Most common preparations! Biestrogen (Biest): 20% E2 /80% E3! Triestrogen (Triest): 10%E1/10%E2/80%E3! Only available by prescription from compounding pharmacies! If E3 is effective and the safest hormone, a formulation with only E3 would presumably be the safest supplement available

16 What are Bioidentical Estrogen Preparations?! The 80:20 ratio of E3:E2 in Biest implies that there is a significantly larger quantity 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 the different milligram quantity of the agents combined What are Bioidentical Estrogen 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 1/100 th 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

17 What About the Progestins?! Standard supplement is medroxyprogesterone acetate (MPA)! MPA is a synthetic derivative of 17 alpha hydroxyproesterone; the alterations in the chemical structure extend the half life to 12 hours! In contrast, natural progesterone is synthesized from yams or soybeans and then converted 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 mg and micronized progesterone 200 mg provide similar protection for the endometrium! The PEPI trail did not detect differences in efficacy or adverse effects, but did suggest a better lipid profile with micronized progesterone PEPI Writing Group. Effects of hormone replacement therapy on endometrial histology in postmenopausal women. JAMA 1996

18 Topical Progesterone Administration! Practitioners who prescribe BHT point to the benefits of topical progesterone creams! According to supporters, these creams are used to increase libido, normalize blood clotting, promote bone building, manage hot flashes, and protect the uterus Just the Facts: Topical Progesterone 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 the absorption levels

Just the Facts: Topical Progesterone Administration! Randomized, double blind placebo controlled trial of progesterone cream vs placebo in postmenopausal women established:!

19 Just the Facts: Topical Progesterone Administration! Randomized, double blind placebo controlled trial of progesterone cream vs placebo in postmenopausal 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 vasomotor symptoms and postmenopausal bone loss. Obstet Gynecol Just the Facts: Topical Progesterone Administration! Bigger concern is the ability of progesterone creams to provide adequate endometrial protection! One small randomized study of 27 women studied the impact of progesterone cream (16 mg and 64 mg daily) with transdermal estradiol! At doses studied, no changes in the proliferative endometrium were noted Wren et al. Effect of sequential transdermal progesterone cream on endometrium, bleeding pattern, and plasma progesterone and salivary progesterone levels in postmenopausal women. Climacteric

20 Just the Facts: Quality of the Available Products! Limited FDA survey examining 12 compounding pharmacies during June to December of 2001 was completed! 29/37 products identified were obtained and subjected to repeated analysis of indentity, potency, uniformity, and tests of contamination! Study was published by the Center for Drug Evaluation and Research Just the Facts: Quality of the Available Products! 10/29 sampled products (34%) failed one or more standard quality tests! 9/10 products failed potency testing with only 59%-89% of promised hormone present as indicated 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 belief that treatment should be individualized for each patient based on hormonal levels!

21 Salivary Testing! One of the foundations of BHT is the belief that treatment should be individualized for each patient based on hormonal levels! Recommend the use of saliva testing to identify which hormones are deficient and in need 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 larger interassay variability undermine the precision of salivary hormone testing Boothby et al. Bioidentical Hormone Therapy: A review. Menopause, 2004.

22 Costs of Therapy! Costs taken from the Physio Age Medical 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 $ ! Medications range from $125-$200 per month Physio Age Medical Group Web Site, 2007 Costs of Therapy! Medications include:! $72 for estradiol, progesterone, and testosterone transdermal cream! $28 DHEA and pregnenolone compounded into capsules! $462 for Human Growth Hormone! $95 for nutritional supplements! $6 for melatonin Physio Age Group Web Site, 2007

23 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 BHT preparations are any more hazardous than convention HT! There are in fact some concerns that topical progesterone may not in fact provide adequate endometrial protection! Available evidence also suggests that salivary hormone testing is unreliable and uninterpretable So What s an Evidence Based Practitioner 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 in oral and in transdermal preparations! Micronized progesterone is also available commercially and is a bioidentical hormone

24 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--by titrating to symptoms not by matching hormone levels! For More Information! Understanding the Controversy: Hormone Testing and Bioidentical Hormones. Proceedings from the Postgraduate Course Presented at NAMS, October 2006! Position Statement: The Endocrine Society, October 2006

25 Questions?

Appendix: Reference Table of HT Brand Names

Appendix: Reference Table of HT Brand Names This is a full reference table in alphabetical order, of Brand Name drugs used in HT. It is the basis for prescription advice throughout this handbook. Drug