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CURRENT DRUG THERAPY CME EDUCATIONAL OBJECTIVE: Readers will discuss the risks and benefits of with their patients CREDIT LYNN PATTIMAKIEL, MD, NCMP HOLLY L. THACKER, MD, FACP, NCMP* Department of Internal Medicine, Center for Director, Center for Specialized Women’s Health, Specialized Women’s Health, Cleveland Clinic Department of Obstetrics and Gynecology, Cleveland Clinic

Bioidentical hormone therapy: Clarifying the misconceptions

■■ ABSTRACT ecent product endorsements from R celebrities on television have brought a Many women are turning to bioidentical hormone new term into the vocabulary of many Ameri- therapy on the basis of misconceptions and unfounded can women: bioidentical hormone therapy— claims, eg, that this therapy can reverse the aging pro- treatment with hormone products that are cess and that it is more natural and safe than approved identical in molecular structure to those in the hormone therapy. The aim of this article is to clarify some human body. of the misconceptions. Since 2002, when results of the Women’s Health Initiative1 raised questions about the ■■ KEY POINTS safety of hormone replacement therapy, wom- en have been inundated by commercials, talk Hormone therapy is indicated for relief of menopausal shows, and self-help books that promote bio- symptoms; claims of reversal of the aging process are identical hormone therapy as a safe and natural unsubstantiated. way to treat menopausal symptoms—and more. Although this publicity has helped promote Products that are custom-compounded are not regulated discussion about , it has also perpet- by the US Food and Drug Administration and therefore uated confusion and misinformation among the carry no assurance of purity, safety, or efficacy. lay public and the general medical community concerning menopausal hormone therapy. Many postmenopausal women suffering Transdermal progesterone creams do not achieve high from vasomotor symptoms, vaginal dryness, enough serum levels to protect the endometrium. and vaginal atrophy are apprehensive about seeking therapy, owing to concerns resulting Hormone therapy is titrated on the basis of symptom re- from misinterpreted information derived from sponse. Measuring hormone levels in saliva is not called the Women’s Health Initiative trial.1 (See for and is probably not reliable. “What are the known risks of FDA-approved hormone therapy,” page 830.2–8) Many oth- ers are told to suffer through their symptoms, which may eventually pass. It is not surpris- ing, then, that women turn to unconventional treatments that are claimed to be safer. This unfortunate situation has driven the business of many compounding pharmacies into the multibillion dollar level. In this paper, we hope to clarify some of

*Dr. Thacker has disclosed that she has taught and spoken for Bayer and Novogyne Pharmaceuticals, the misconceptions surrounding this issue. But makers of menopausal hormone therapies. first we need to define some terms in what has doi:10.3949/ccjm.78a.10114 become a confusing area.

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What are the known risks of FDA-approved hormone therapy?

The World Health Organization Council for Inter- of excess risk usually emerges within the first 1 or 2 national Organizations of Medical Sciences defines years of initiation and decreases over time.4 The risk a risk as “rare” if it occurs in 10 or fewer patients per is higher if hormone therapy is initiated after the 10,000 patients per year. A risk is considered “very age of 60. The risk is also higher in women with a rare” if it occurs in one or fewer patients per 10,000 body mass index greater than 30 kg/m2.4 The Estro- patients per year. The absolute risks associated with gen and Thromboembolism Risk (ESTHER) study hormone therapies approved by the US Food and showed a possible lower risk of venous thrombo- Drug Administration (FDA) fall into these catego- embolism with transdermal therapy than with oral ries. Moreover, the risks of FDA-regulated therapies therapy.3 Lower doses may also be safer than higher are known, whereas the risks associated with unregu- doses. lated products are unknown because there are no Cancer. Unopposed systemic therapy data. is associated with a risk of that Coronary heart disease. Women who start tak- is related to dose and duration of use. Therefore, ing hormone therapy decades after entering meno- women taking estrogen who have a uterus must pause may incur a higher risk of coronary heart still take an FDA-approved progestin or micronized disease.4 However, stratified data from the Women’s progesterone to prevent endometrial cancer. Health Initiative actually showed evidence of a There is a slightly higher risk of lower coronary risk in women who used hormone with concomitant estrogen-progestin treatment therapy for 5 years or more if they started when they beyond 5 years.2 In the Women’s Health Initiative, a were younger and more recently postmenopausal.5 randomized placebo-controlled trial, there were eight Stroke. Both estrogen therapy and combined additional cases per 10,000 women.2 In the estrogen- estrogen-progestin therapy appear to increase the only group, there was actually a lower risk of breast risk of ischemic stroke in women who are over the cancer in users of conjugated (0.625 age of 60, with no effect on the risk of hemorrhagic mg/day). A follow-up study of the Women’s Health stroke.5 No increase in stroke has been seen in Initiative found that women who were on com- younger women, nor in older women taking a lower bined estrogen-progestin therapy for more than 5 dose of conjugated equine (0.3 mg).6 years had a greater risk of developing more invasive Dementia. Hormone therapy seems to increase the breast cancers with node positivity.8 There were also risk of dementia if initiated at age 65 or older.7 more deaths attributable to breast cancer and more Venous thromboembolism. Oral hormone deaths from all causes after a breast cancer diagnosis therapy has been shown to pose a rare risk of venous in women on estrogen-progestin therapy compared thromboembolism in postmenopausal women when with placebo.8 The progestin used in this trial was initiated before the age of 60 years.4 The magnitude medroxyprogesterone acetate (2.5 mg/day).

■■ WHAT ARE BIOIDENTIcAL HORMONES? , and —as well as progesterone and .9 “Bioidentical” means identical in molecular 17-beta (E2) is the most bio- structure to endogenous hormones. Howev- active endogenous estrogen. It is primarily er, as we will see, a better distinction should produced by the dominant ovarian follicle be made between products that are approved and the corpus luteum and is synthesized in- and regulated by the US Food and Drug Ad- tracellularly through aromatase activity.10,11 ministration (FDA) and those that are not. The rest of the circulating estradiol is de- rived from peripheral conversion of estrone Endogenous reproductive hormones to estradiol, and this is the primary source Women produce various reproductive hor- in postmenopausal women not on hormone mones, including three estrogens—estradiol, therapy.11

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In postmenopausal women, serum estra- Other nonbioidentical products include diol levels are often below 15 pg/mL. Many ethinyl estradiol, which is used in most com- physiologic effects of the cellular compart- bined oral contraceptives. It is formed after mentalized estradiol contribute to an over- a minor chemical modification of estradiol riding force in certain tissues even after that makes it one of the most potent estro- menopause.10 With the loss of estradiol, gens. The ethinyl group at 17 of ring many tissues in postmenopausal women can D of the nucleus greatly slows the be affected, particularly resulting in genito- hepatic and enzymatic degradation of the urinary atrophy and bone loss. molecule and, thereby, makes oral ethinyl Estrone (E1), the second dominant hu- estradiol 15 to 20 times more active than man estrogen, is primarily derived from the oral estradiol. of estradiol and from the aro- is an inactive prodrug that is matization of in adipose converted in the body to ethinyl estradiol. tissue, with a small quantity being secret- While many women may find the idea of ed directly by the ovary and the adrenal natural bioidentical hormones derived from glands.9 In postmenopausal women, mean sweet potatoes or soybeans more acceptable estrone levels are about 30 pg/mL.11 than taking one made from horse’s urine, all Estriol (E3), the least active of the endog- the products undergo extensive chemical pro- enous estrogens, is very short-acting. cessing and modification. Progesterone is a 21-carbon steroid secret- ed by the human ovary.9 It is formed during Misconception: the transformation of cholesterol to estrogens FDA-regulated products are not bioidentical and and is no longer produced after Although many FDA-regulated hormone menopause.9 products contain nonbioidentical hormones, Testosterone. In premenopausal women, many other regulated, brand-name hormone the testosterone is synthesized by therapy products contain the bioidentical the ovary, the adrenal cortex, and the periph- hormone 17-beta-estradiol. Examples are eral conversion of circulating androstenedi- oral Estrace, the weekly Climara patch, and By relieving one and (DHEA).9 the twice-weekly Vivelle Dot.2 The makers moderate Over a woman’s life span, her androgen levels of Vivelle Dot have obtained approval from decline progressively.10 The rate of decline has the FDA to use the term “bioidentical.” Oral to severe not been shown to be appreciably affected by Prometrium is a government-approved bioi- menopausal 10 the onset of menopause. dentical progesterone product (TABLE 1). symptoms, All these hormone therapy products ■■ WHAT IS CUSTOMIZED COMPOUNDED hormone are synthesized HORMONAL THERAPY? therapy Many nonmedical women’s health books er- roneously classify the forms of estrogen used There is often confusion between the terms “bio- may improve in hormone therapy as either bioidentical or identical hormones” and “customized com- quality of life synthetic. In fact, they are all man-made. pounded therapy,” which are often used inter- Bioidentical hormones are synthesized by changeably. Compounded therapy combines chemically extracting from plants ratios of bioidentical hormones into a particular such as yams and soy.12 Diosgenin is chemi- recipe or mixture. Customized compounding cally modified to yield the precursor proges- can be done by local compounding pharmacies.2 terone, which is then used to synthesize bio- These customized compounds are often identical estrogens and androgens.10 promoted as more “natural” and “individu- Nonbioidentical estrogen products include alized” therapy for postmenopausal women. conjugated equine estrogens (CEE), which is These formulations, in fact, may have in- extracted from the urine of pregnant mares. gredients similar to those in FDA-approved The two predominant estrogens found in CEE products, but they are not regulated for safety, are sulfate (native to horses) and es- efficacy, and dosing consistency. There is no trone sulfate.10 proof that compounded hormones have fewer

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TABLE 1 Examples of FDA-approved bioidentical hormones

Hormone ROUTE OF Brand name Dosage Effect ADMINISTRATION 17-beta estradiol Oral Estrace 0.5, 1.0, 2.0 mg/day Systemic Transdermal patch Alora 0.025, 0.05, 0.075, 0.1 mg/day, applied twice Systemic weekly Climara 0.025, 0.0375, 0.05, 0.075, 0.1 mg/day, applied Systemic once weekly Esclim 0.025, 0.0375, 0.05, 0.075, 0.1 mg/day, applied Systemic twice weekly Fempatch 0.025 mg/day, applied once weekly Systemic Menostar 0.014 mg/day, applied once weekly Systemic Vivelle 0.025, 0.0375, 0.05, 0.075, 0.1 mg/day, applied Systemic twice weekly Vivelle Dot 0.025, 0.0375, 0.05, 0.075, 0.1 mg/day, applied Systemic twice weekly Transdermal gel Estraderm 0.05, 0.1 mg/day, applied twice weekly Systemic EstroGel 0.06% 0.035 mg daily Systemic Elestrin 0.0375 mg daily Systemic Divigel 0.1% 0.003, 0.009, 0.027 mg daily Systemic Topical emulsion Estrasorb 2 packets daily Systemic (to deliver 0.05 mg/day absorbed dose) Transdermal spray Evamist 0.021 mg Systemic (1 spray, may increase to 2–3 sprays/day) Vaginal cream Estrace Initial: 2–4 g/day for 1–2 weeks Local Maintenance: 1 g/day Estring 7.5 µg/day (90 days continuous) Local

Estradiol acetate Oral Femtrace 0.45, 0.9, 1.8 mg/day Systemic Vaginal ring Femring 0.05, 0.10 mg/day (continuous)

Estradiol Vaginal Vagifem 0.010 mg/day (initially 1 tablet/day for 2 Local hemihydrate weeks, then 1 tablet twice a week)

Estropipate Oral Ortho-Est 0.625, 1.25, 2.5, 5.0 mg/day Systemic

Progesterone Oral (in peanut oil) Prometrium 100, 200 mg/day Systemic (continuous or cyclical regimens)

Adapted from information at www.menopause.org, with permission from the North American Menopause Society.

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TABLE 2 Bioidentical hormones: Regulated vs customized compounded

Prescription-regulated bioidentical hormones Customized compounded bioidentical hormones

Chemically identical to human hormones Chemically identical to human hormones US Food and Drug Administration oversight No US Food and Drug Administration oversight Published scientific research Minimal to no published scientific research Doses exactly reproducible Doses may be inexact and inconsistent Proven efficacy Efficacy and safety not proven in randomized controlled trials

side effects or are more effective than FDA- in the FDA-regulated oral product Prometri- 12 approved hormone preparations (TABLE 2). um). Customized compounded formulations have also been used when prescribing hor- Compounded bioidentical mones currently not FDA-approved for wom- estrogen products en, such as testosterone and DHEA.12 Before There are several commonly marketed com- oral micronized progesterone was marketed in pounded products. the United States as Prometrium, it was fre- Tri-estrogen (tri-est) is a compounded quently prescribed as a compounded hormone. hormone preparation made up of a mixture of 80% estriol, 10% estrone, and 10% estradiol.12 ■■ HORMONE THERAPY COMES IN Bi-estrogen (bi-est) contains estriol and VARIOUS FORMS estradiol in a ratio of 8:1 or 9:1. 17-beta Although both tri-est and bi-est are largely Both FDA-regulated hormone therapy and estradiol composed of estriol, given the low potency of unregulated compounded hormone therapy estriol, the effects of these products may be come in various doses and dosage forms ad- is the most solely mediated by their major bioactive com- ministered by different routes, allowing for bioactive 10,12 ponent, estradiol. No large prospective, individualization for each woman’s specificof the well-controlled clinical trial has investigated characteristics. the compounded ratios of these mixtures of endogenous estrogens.10 Estrogens: Oral, transdermal, others estrogens Tri-est and bi-est are frequently promoted Estrogen therapy can be given orally, trans- as posing less risk of breast or endometrial vaginally (as creams, tablets, and rings), cancer than FDA-approved agents, although transdermally (as patches, gels, and creams), there is no research to back up this claim.12 In subcutaneously in pellets, intranasally (in Eu- fact, estriol may have a stimulatory effect on rope), and by injection.11 the breast and endometrium.9 Most oral contraceptives contain the syn- In addition to these “standard” compound- thetic estrogen ethinyl estradiol. Ethinyl es- ed preparations, women can receive more cus- tradiol is more potent than human estrogens,11 tomized compounds. specifically in increasing the production of hepatic proteins (sex-hormone-binding glob- Valid uses for customized compounded ulin, renin substrate, corticosteroid-binding formulations globulin, and thyroid-binding globulin).11 Some clinical providers use customized com- Bioidentical estradiol, taken orally in tab- pounded formulations when prescribing hor- let form, is first processed through the liver mone therapy to women who have allergies to and converted into estrone.12 This stimulates certain ingredients, such as peanut oil (found proteins such as C-reactive protein, activated

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TABLE 3 Formulations of systemically acting

Progestogen Brand Route of Dosage (mg/day) name administration

Progesterone Prometrium Oral 100, 200 (cyclic or continuous regimens) Medroxyprogesterone acetate Provera Oral 2.5, 5, 10 (cyclic or continuous regimens) Norethindrone acetate Aygestin Oral 5 Norethindrone Micronor Oral 0.35 Nor-QD Megace Oral 20, 40 Norgestrel Ovrette Oral 0.075 Levonorgestrel Mirena Intrauterine 0.020 (5 years continuous)

Adapted from information at www.menopause.org, with permission from the North American Menopause Society.

protein C, and clotting factors, which may widely in dosage and formulation. Over-the- increase the risk of clotting.12 Estradiol given counter progesterone creams vary in concen- transdermally by patch or gel or vaginally by- tration from no active ingredient to 450 mg passes the liver and enters the bloodstream as or more of progesterone per ounce. Applica- 17-beta estradiol, therefore avoiding stimula- tion sites for progesterone cream include the tion of these proteins.12 Case-control data have inner arm, chest, and inner thigh. No trans- shown an associated lower risk of deep venous dermal hormone should be applied to areas of Many FDA- thromboembolism with transdermal therapy.3 the body that may allow possible contact and approved Subcutaneous pellet therapy is a less com- transference to others. mon, non-FDA-approved method of hormone products therapy to relieve postmenopausal symp- products are in fact toms.10 In an outpatient procedure, the pellet Progestogen products include “natural” pro- bioidentical is inserted into the subcutaneous fat of the ab- gesterone and synthetic progestins. They domen.10 The crystalline pellet is biodegrad- should be given concurrently with estrogen able and contains a mixture of testosterone therapy in women who have an intact uterus and 17-beta estradiol.10 It is important to re- to prevent endometrial hyperplasia.9 member that endometrial stimulation may be Bioidentical progesterone is micronized in prolonged with this form of therapy and levels the laboratory for better absorption in the gut.2 may be supraphysiologic. Nonbioidentical progestins significantly differ from endogenous progesterone in both Progestogens can also be given their molecular structure and function.10 Pro- by different routes gestins include oral medroxyprogesterone ac- Oral progesterone has poor gastrointestinal ab- etate, norethindrone acetate, drospirenone, 10 sorption and a short half-life. Therefore, it is and levonorgestrel (TABLE 3). micronized with oil for better absorption. Re- ported side effects include sedative and anes- Misconception: Transdermal progesterone thetic effects; therefore, it is recommended that protects the endometrium oral progesterone be taken at bedtime.9 Me- In general, transdermal progesterone should droxyprogesterone acetate may interfere more be avoided, as it does not protect against en- with estrogen’s positive effects on cholesterol dometrial cancer. than micronized progesterone does.13 Many forms of progesterone are available Topical progesterone preparations vary by prescription at compounding pharmacies

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as lotions, gels, creams, capsules, trochees, However, many physiologic effects of estro- and suppositories.9 Transdermal progesterone gens are determined intracellularly at the level creams are also available over the counter at of tissues.10 Therefore, although levels during health stores. Some of these creams contain therapy with bioidentical estrogens can be only diosgenin, a progesterone precursor de- monitored more precisely, the FDA states that rived from wild yams.10 Diosgenin cannot be hormone therapy should be guided by symptom converted into progesterone within the body response and findings on physical examination and thus does not provide an adequate amount and not by hormone levels alone.2,12 It may be of absorbable progesterone.9 Therefore, pro- reasonable to order serum levels of estradiol in gesterone cream that contains only diosgenin women being treated with therapeutic doses is not effective in preventing endometrial hy- of bioidentical estrogen but still not achiev- perplasia and cancer. ing symptom relief. If women are being treated To achieve a physiologic response, proges- with conjugated equine estrogens, serum levels terone levels must be at least in the nanogram cannot be monitored. Total estrogen can be range.10 Transdermal progesterone cream has monitored as a send-out laboratory test. not been shown to reach this level and may not significantly improve vasomotor symp- ■■ MISCONCEPTION: HORMONE THERAPY toms.12 Some practitioners prescribe cream IS A FOUNTAIN OF YOUTH that contains more than 400 mg progesterone per ounce. This may achieve physiologic lev- Customized compounded hormonal therapy is els of progesterone, but no improvement has marketed as being able to help with rejuvena- been proven for bone mineral density or endo- tion, improve memory, sexual function, and metrial protection. In general, no transdermal reverse the aging process, essentially promis- progesterone cream can be assumed to protect ing to be an elixir or fountain of youth. the endometrium against the stimulatory ef- These claims are not substantiated. How- fects of estrogen. ever, the actual benefits of hormone therapy in women who have menopausal symptoms ■■ CUSTOM COMPOUNDING AND SALIVA include alleviation of moderate to severe vaso- There is no TESTING TO INDIVIDUALIZE THERAPY motor symptoms and vaginal atrophy that proof that can result in dyspareunia. By alleviating their Some clinicians who prescribe compounded symptoms, hormone therapy improves wom- compounded hormones order saliva tests. They argue the en’s quality of life. It also reduces the incidence hormones tests help them to establish which hormones of postmenopausal osteoporotic fractures. are deficient and therefore to customize ther- A research finding that is often overlooked have fewer apy.12 The basis for this is that saliva is similar is that postmenopausal women younger than side effects to an ultrafiltrate of blood and, theoretically, 60 years who started estrogen or estrogen- or are more hormone levels in saliva should represent the progestin therapy soon after menopause had bioavailable hormone in serum.10 a 30% lower rate of death from all causes.2,14 effective Unfortunately, this testing is often unreli- This difference was statistically significant able due to poor stability of samples in storage when the estrogen and estrogen-progestin and large interassay variability.10 Many factors therapy groups were combined. No reduction may alter hormone levels in saliva and make in the mortality rate was seen if therapy was test results unreproducible, including the time started after age 60. of day the sample is collected and dietary hab- its.10 The FDA states that there is no scientific ■■ MISCONCEPTION: basis for using salivary testing to adjust hor- COMPOUNDED THERAPY IS SAFER mone levels.2 Levels of drugs with clearance that varies Compounded hormone therapy is often mar- depending on hepatic enzyme activity and keted as a safer or more effective alternative to plasma binding (capacity-limited metabolism) government-regulated and approved therapy. such as estradiol and testosterone can be moni- Unfortunately, these claims are often false tored with total blood serum concentrations.10 and misleading, and safety information is not

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consistently provided to patients as is required are considered experimental. Therefore, they with FDA-regulated hormone therapy.2 are often not covered by insurance, and many Since these compounds have not been women must pay for them out of pocket.11 approved by the FDA, there is no guarantee The North American Menopause So- that the ingredients have been tested for pu- ciety does not recommend custom-mixed rity, potency, and efficacy. There is no batch products over well-tested, government-ap- standardization. These unregulated therapies proved commercial products for most wom- may use unapproved ingredients, routes of ad- en.2 All bioidentical hormone prescriptions ministration, and mixtures with contaminants should include a patient package insert,11 such as dyes and preservatives.2 identical to that required of FDA-approved Also, custom-compounded prescriptions products.2 ■

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