Abstract
Vasomotor symptoms (hot flashes and night sweats) affect two-thirds of all women as they transition into menopause and often for years beyond that time, often severely diminishing the quality of their lives [1,2]. Other symptoms, such as menopause-related vaginal dryness, contribute to reduced sexual functioning. Traditional therapy with products manufactured by pharmaceutical companies containing estradiol, conjugated estrogens, progestins, progesterone and testosterone has been readily available for patients. Technically, pharmaceutical products containing estradiol, progesterone and testosterone are ‘bioidentical’ in that they contain compounds identical in structure to endogenous hormones. Since the publications of the Women's Health initiative and the Heart and Estrogen/Progestin Replacement Study (HERS) in the USA [3,4], and with the encouragement of celebrity self-help books and the internet, women have become skeptical of traditional pharmaceutical products prescribed by physicians and sought ‘natural’ or ‘bioidentical’ alternatives made by compounding pharmacies. Animal data suggested that estriol-containing compounds may be safer than those containing estradiol with respect to causing breast cancer, so compounds such as Biest (20% estradiol and 80% estriol) and Triest (10% estradiol, 10% estrone and 80% estriol), made by compounding pharmacies, have increased in popularity, despite no evidence for efficacy or side effects of this treatment for menopausal symptoms [5]. In addition, compounding pharmacies may add progesterone, testosterone and dehydroepiandrosterone (DHEA) to these regimens. We will review the evidence for the efficacy and safety of bioidentical hormones for menopausal symptoms, both those made by pharmaceutical companies and those made by compounding pharmacies, so that practicing clinicians can more easily counsel patients who ask about these regimens.
Relevance of compounded hormones in medicine
Compounding is defined as the mixing of a drug or device consistent with a licensed practitioner's prescription [6,7]. A compounding pharmacist can not prescribe but is authorized only to prepare the prescription in accordance with the physician's order. For many years, compounding was the only mechanism to make drugs available to the public. However in the 1900s, pharmaceutical companies assumed most of the duties of compounding, which reduced the need for compounding by individual pharmacists. Today, compounding fulfills a need for children and older patients for special preparations when the exact products needed are not commercially available. The expansion of compounding now includes requests for particular drugs for all age groups for reasons such as their derivation from a plant rather than an animal. The US FDA has stated that compounded prescriptions are both ethical and legal as long as they are prescribed by a physician for a particular patient in a ‘reasonable’ quantity and are compounded by a licensed pharmacy [7,101]. The FDA has estimated that compounded products account for 1% of all prescriptions in the USA, or approximately 30 million prescriptions per year [101]. Compounding pharmacies are also popular in Europe. Clearly this number of prescriptions translates into billions of US dollars or Euros per year for compounding pharmacies, for the laboratories associated with them that measure salivary hormone levels, and for hormone consultants who offer opinions regarding hormone dosing adjustments based on salivary hormone levels.
Despite the virtues of compounding for special groups of patients, there are unanswered questions about the practice. Compounded hormones have not been subject to reports of adverse events. Safety and efficacy of products have not been studied in large clinical trials. Owing to the need for greater scientific scrutiny of compounded hormones, The Endocrine Society published a position statement in October 2006, supporting the FDA regulation of all hormones, including compounded hormones, regardless of chemical structure or method of manufacture [102]. The position statement suggests that a registry of adverse events be established for hormone preparations and that uniform information about hormone side effects should be included in the packaging. Large, randomized, placebo-controlled trials of compounded hormones should provide much needed information with regard to efficacy and potential adverse events.
Foundation & claims of ‘bioidentical’ hormones
Bioidentical hormones are typically derived from plant extracts and chemically altered to be identical in structure to endogenous human hormones [5]. Sources for these hormones often include plants (soy or yams), although de novo synthesis of hormones in the laboratory is also possible. Bioidentical is not a medical definition but one that has become popular with the media and public [102,105]. Celebrity self-help books written by Suzanne Somers and Michael Platt, along with many internet websites, promote bioidentical hormones as safer alternatives to conventional hormones prescribed for women to get ‘the exact dose that they require’ to replace the body's estrogen and progesterone [8,9]. These books state that FDA-approved products are ‘drug hormones,’ which only treat symptoms, and that nothing is being replaced. Bioidentical hormones are further described as the ‘secret elixir’ and ‘fountain of youth’, which can reverse the aging process and keep people mentally sharp and fit, although none of these claims have been clinically tested. As a result of these unsupported claims, the FDA recently sent warning letters to seven compounding pharmacies that were making false claims regarding their products for menopausal women [105].
A characteristic of bioidentical estrogen compounds is the frequent inclusion of estriol in the product. The metabolism of estradiol includes its reversible metabolism to estrone, with further irreversible conversion to estriol [10]. After menopause, estradiol is no longer produced by the ovaries, but estrone is produced in fat through the conversion of androstendione. Estriol is the end product of estrone and estradiol metabolism [10]. The reason for the inclusion of estriol, a weak estrogen, which is an end product of metabolism in bioidentical estrogen formulations, is largely based on animal data suggesting that estriol may be safer with regard to the development of breast cancer. In studies by Lemon, virgin Sprague–Dawley rats premedicated with estriol were exposed to a known carcinogen [11–14]. In the animals pretreated with estriol, rats had reduced tumor induction. Furthermore, when estriol was implanted after exposure to the carcinogen, tumors tended to regress. However, other experiments suggested that ethinyl estradiol had the same effects in these rats. Unfortunately, when older women with breast cancer were treated with estriol, 25% had increased growth of metastases [15]. Overall, his experiments led him to conclude that continuous estriol was not an effective therapy for breast cancer in women. Thus, the ‘safer’ theory of estriol therapy over estradiol and estrone with regard to breast cancer prevention in postmenopausal women has not been established.
Patient beliefs regarding bioidentical hormone therapy for menopause
Few surveys exist to determine patients' beliefs regarding compounded hormones and the types of compounded hormones in use. In one report, a survey at a local compounding pharmacy among 82 women discovered that approximately half of the patients believed the term ‘natural’ meant plant-derived and not synthesized. Furthermore, most believed bioidentical hormone therapy had fewer or no risks and adverse effects and was equally or more effective than conventional hormone therapy for menopause symptom relief [5]. This survey is interesting in that it occurred before the results of the Women's Health Initiative were published. However, it is likely biased because it was conduced at a compounding pharmacy. Further studies are needed to assess beliefs about compounded hormones for menopause symptoms since the Women's Health Initiative findings were published.
Types & formulations of bioidentical estrogens
Compounded estrogen formulations for menopause contain estradiol, estrone and/or estriol [5,16,17]. Currently, products such as Biest (biestrogen) containing 20% estradiol and 80% estriol, and Triest (triestrogen) containing 10% estradiol, 10% estrone and 80% estriol, expressed on a mg per mg basis, are prepared by compounding pharmacies for patients. It appears that Biest, available as capsules, sublingual compounds and transdermal cream or gel is clearly the most common preparation used [5,16,17]. It is important to understand that although the percentage of estrogens defines the compound, pharmacies vary in the total mg dose of Biest they dispense. For example, one pharmacy may prepare a 1.25 mg preparation of Biest (which contains 0.25 mg estradiol with 1.0 mg estriol), while another prepares a 2.5 mg preparation of Biest (which contains 0.5 mg estradiol and 2.0 mg estriol) [16]. Thus, the total weight in mg of the preparation dispensed by a particular pharmacy is the most important factor in understanding the doses of estrogens used by patients. In an informal telephone survey of four local US compounding pharmacies and three large national compounding pharmacies in Colorado, Texas and Wisconsin, identified through the internet, the 2.5 mg dose of Biest is the common transdermal estrogen preparation recognized by all seven compounding pharmacies at the time of writing.
The potency of estriol ranges from 1/10 to 1/100 that of estradiol, with 1/80 most often cited [18], leading one to believe that any benefits of Biest for menopausal symptoms may be more related to the estradiol component rather than to the estriol component. Estriol as the sole estrogen in any preparation is not commercially available in the USA, but is available commercially in Europe, mostly as vaginal preparations. Some practitioners in Europe may not consider vaginal estriol to be a bioidentical hormone, despite the fact that it has a structure like endogenous estriol. In a randomized, placebo-controlled trial of 88 women, 2 mg estriol alone as a daily dose vaginally in the absence of estradiol was reported to have beneficial effects on urogenital outcomes, including vaginal dryness, dysparunia, urogenital atrophy and in urodynamic testing variables, including maximum urethral pressure, mean maximum urethral closure and abdominal pressure transmission ratio [19]. This study of estriol demonstrates that it may have beneficial effects as a single hormone for urogenital symptoms.
Estrogen-receptor subtypes & bioidentical estrogens
Estrogenic activity within a tissue is influenced by the type of estrogen and the subtype of estrogen receptor found within that tissue [20], as well as by the distribution of cofactors and corepressors of the estrogen-receptor complex within the tissue [21]. With estradiol as the standard, binding affinity for both estrogen receptor (ER)-α and -β is equal at 100 [20]. Estrone has a binding affinity for ER-α of 60 and for ER-β of 37. Estriol binds to ER-α with an affinity of 14 and to ERβ with an affinity of 21. Therefore, estradiol has the strongest binding affinity for both ER-α and -β.
Estrogen binding affinity alone does not predict estrogenic activity within a tissue. Compounds containing larger amounts of estradiol compared with estrone and estriol would be expected to have great effects on all estrogen-responsive tissues. However, ER-α receptors are found primarily in the endometrium, ovary and in breast cancer cells [20]. By contrast, ER-β receptors are found in the kidney, intestinal mucosa, lung, bone and bone marrow, brain and endothelial cells. Thus, Biest, containing estradiol and estriol, is likely to act on all the tissues above that contain ER-α and -β receptors, with a slight preference for tissues that are ER-β dominant because of the estriol component. As binding of the estrogen with the estrogen receptor allows for the recruitment of different coactivators and corepressors, it is possible that estriol acts somewhat differently than estradiol in tissues.
Evidence for relief of hot flashes & vaginal dryness with very low-dose estradiol
Since the findings of the Women's Health Initiative and HERS were published, patients and pharmaceutical companies have worked to find alternatives for menopause symptom relief. With the recommendation to use the smallest dose of estrogen for the shortest amount of time needed to relieve hot flashes and vaginal dryness [22], various formulations of transdermal estradiol therapy have emerged. The first generation of transdermal estradiol skin patches (reservoir or imbedded types) deliver estradiol in a constant fashion with application once or twice weekly, but 15% of patients note skin irritation caused by the adhesive [23]. Several new estradiol gel products have been developed and are approved by the US FDA for hot flash symptoms, including Divigel®, Estrogel® and Elestrin™. Gels have an advantage over patches in that there is no adhesive necessary, which markedly reduces skin sensitivity side effects.
With gels, estradiol is stored in the skin as a reservoir rather than in a pouch or matrix reservoir of a patch. It appears that the skin releases estradiol in a consistent fashion, with the pharmacokinetics of Estrogel and Elestrin both reporting that steady state is reached after 3 days of a once-daily application on the upper outer arm [23,24]. Pharmacokinetics for Elestrin, Estrogel and Divigel [103] are noted in the table below based on information submitted to the FDA.
Elestrin and Divigel are currently the lowest dose transdermal estradiol gels approved for the relief of hot flashes. The lowest dose of Elestrin tested in the Phase III clinical trial, 0.87 g delivering 0.52 mg estradiol per day, was effective in significantly relieving both the frequency and severity of hot flashes significantly by 50% at 4 and 12 weeks of treatment compared with placebo. Blood estradiol levels and safety profiles on this lowest dose of Elestrin were similar to placebo, with effectiveness noted at 12.5 μg/day of estradiol. Similarly, for Divigel, 0.5 mg estradiol per day delivered by gel significantly relieved hot flashes by 4 and 12 weeks [103]. A recent randomized, controlled trial also reported that a transdermal patch releasing 14 μg/day of estradiol significantly relieved hot flashes in 41% of participants, confirming the efficacy of transdermal microdose preparations [25]. Thus, FDA-approved transdermal gel preparations delivering approximately 0.5 mg/day estradiol, producing mean serum estradiol levels of 15.4–21 pg/ml, are adequate to significantly reduce the frequency and severity of hot flashes in postmenopausal women.
Low-dose transdermal estradiol products have also been found to improve vulvovaginal atrophy symptoms in postmenopausal women, but may promote endometrial proliferation [26,27]. In a randomized, placebo-controlled trial, Estrogel 0.87 g/day was found to reduce the baseline severity in the most bothersome moderate-to-severe vulvovaginal atrophy symptoms significantly by week 12. Similarly, vaginal pH levels decreased and vaginal maturation index increased by week 12 [26]. In a 2-year randomized, double-blind, placebo-controlled trial of a transdermal patch releasing 14 μg estradiol per day in older postmenopausal women, vaginal epithelial cells showed a pattern of greater maturation in the estradiol group compared with the placebo group [27]. In addition, 2 years of ultralow-dose estradiol did not increase the rates of endometrial hyperplasia and was associated with minimal proliferative effect on the endometrium [27]. It is not known what effect long-term transdermal Biest will have on endometrial proliferation. If transdermal Biest is shown to increase endometrial proliferation, long-term studies should be performed to determine if bioidentical progesterone or commercial progestins reverse the proliferative changes caused by Biest. It is important to note that bioequivalence can not be claimed by ‘bioidentical’ compounded products that use different routes, carriers and doses of administration.
Use of bioidentical progesterone
Progesterone may be added to estrogen as part of menopausal hormone therapy. To increase oral availability, progesterone obtained from yams or soybeans is micronized. This compound, called Prometrium® in the USA, is approved by the FDA and has been reported to prevent endometrial hyperplasia at doses of 200 mg/day for 12 days monthly when conjugated estrogens were also prescribed [28]. The effect of Prometrium on menopausal hot flashes and vaginal dryness, alone or in combination with estradiol, has received little attention. It appears that Prometrium improves sleep quality in postmenopausal women better than synthetic medroxyprogesterone acetate when conjugated estrogens are also used [29].
Pharmacokinetics of US FDA-approved transdermal estradiol gels.
E2/E1: Estradiol/estrone.
Progesterone is also used in transdermal creams or gels compounded with transdermal estrogens by compounding pharmacies. One might think that progesterone is added to prevent endometrial hyperplasia when estrogens are also prescribed, but this is not the case with compounded progesterone because women with a hysterectomy may be prescribed this combined regimen, and natural progesterone, particularly when used as a skin cream, does not reliably prevent endometrial proliferation or endometrial hyperplasia [30–32]. In fact, three cases of endometrial cancer have been reported in Australia among women using bioidentical progesterone as troches or skin cream along with estrogen [33]. Advocates for bioidentical progesterone provide the following reasons for adding progesterone to their hormone regimen: beliefs that topical progesterone cream increases libido, effects on climacteric symptoms, prevention of osteoporosis, improvement in mood, effects on thyroid hormones, impact on blood clotting and serum glucose, as well as alteration in fat metabolism [34,35]. Popular books also claim that progesterone cream can eliminate ‘estrogen dominance secondary to relative insufficiency of progesterone’ that is characteristic of various medical conditions, such as breast cancer, uterine fibroids, fibrocystic breast disease, and premenstrual syndrome [36]. However, evidence for the efficacy of transdermal progesterone for these various medical conditions is largely lacking. There appears to be some efficacy for progesterone 40 mg daily plus estradiol 1 mg daily compounded as a transdermal cream for menopause symptoms, but further studies are needed to determine safety [31].
Role of testosterone in menopausal therapy
With reduced sexual desire occurring commonly in menopausal women, there has been increasing interest in testosterone as part of hormone therapy for ‘female androgen insufficiency’ [37]. Oral testosterone is delivered as methyltestosterone in the USA and as testosterone undecenoate in Europe. Some but not all studies suggest a potential negative effect on serum lipids and triglycerides with oral methyltestosterone in women [38–40]. Thus, transdermal routes of delivery of natural testosterone at 150–300 μg/day have been utilized in clinical trials [41]. This dosage appears to have minimal metabolic effects while increasing the number of satisfying sexual experiences per month in menopausal women [41]. There are currently no FDA-approved transdermal testosterone products available for women in the USA, so patients now rely on FDA-approved products for men or on compounded testosterone as part of hormonal therapy. In Europe, a new testosterone patch for women has been licensed for hypoactive sexual desire. The effect of testosterone on menopause symptoms may in part be related to the conversion of testosterone to estradiol or through effects on sex hormone-binding globulin and estrogen bioavailability. Further long-term studies are needed to examine the safety of transdermal testosterone alone or in combination with estradiol.
Addition of DHEA to menopausal therapy
Owing to DHEA decreasing with age, DHEA has been added as a supplement to other hormones for menopausal women [42]. These supplements are not regulated by the FDA. Restoring youthful levels of DHEA has been reported to improve the sense of well being and increase libido, but these findings have been inconsistent [42]. In addition, there is little safety information available with regard to DHEA supplementation. High DHEA levels have been linked to breast cancer, possibly caused by the conversion of DHEA to estrogens [43]. More studies involving longer time periods of use and larger numbers of menopausal women are needed before DHEA can be recommended.
Relevance of salivary hormone measurements for menopause symptoms
Advocates of compounded hormones in the USA often recommend salivary hormone measurements of estradiol and progesterone for adjustment of hormone doses. Why saliva rather than blood tests? Proponents argue that saliva is similar to a blood ultrafiltrate, so saliva levels more accurately represent free hormone over total or bound hormone as measured in serum [44,45]. Unfortunately, this argument poses several problems. First, salivary hormones vary extensively depending on the collection technique, time of day and between and within individuals [46,47]. The correlation of salivary hormones with serum levels is poor [5,17]. Second, in an excellent review, Boothby argues that blood serum concentrations are more appropriate for monitoring drugs that undergo low hepatic extraction such as steroid hormones [17]. Lastly, adjustment of doses of menopausal hormones should be made based on symptoms (i.e., continuing bothersome hot flashes), not on serum or saliva levels [48]. It is therefore this author's opinion that salivary hormones are not useful in the management of women with menopausal symptoms receiving hormone therapy.
Conclusion
Compounded estrogen products have increased in popularity in recent years, possibly due in part to endorsements by celebrities and to health concerns regarding conjugated estrogens used in the Women's Health Initiative studies and HERS. However, no large trials have reported on the efficacy or adverse events of these products compared with placebo (including pills, sublinguals, transdermal creams or gels). FDA-approved trials of commercial patented low-dose gels or patches releasing estradiol can not be generalized to include compounded products, since the absorption of estradiol from the cream or gel formulation used by compounding pharmacies through the skin has not been tested. FDA-approved estradiol gels such as Elestrin use a patented hydroalcoholic base. It is completely unknown how estriol and estradiol are absorbed from compounded gels and creams, whether the various compounding bases used have an impact on absorption, and whether compounded hormones are more effective than placebo compounded gels or creams in relieving menopause symptoms.
Little information is available with regard to compounded progesterone, although it appears that in pharmacokinetic studies, area under the curve for serum progesterone is higher if progesterone is compounded in an emulsion-type base transdermal product compared with a lipophilic or hydrophilic base [48]. Transdermal delivery of progesterone for menopausal symptoms could be preferable to vaginal delivery, since the elimination half-life is 30–40 h with transdermal delivery regardless of type of base, compared with 9–14 h with vaginal suppositories [49,50]. Further information is needed to determine the effectiveness of compounded progesterone for menopausal symptoms and with regard to efficacy to induce secretory endometrial changes and prevent endometrial hyperplasia.
In the past, the FDA has not regulated compounded hormones because they are considered a ‘supplement’ since they are ‘metabolites’ [104]. The FDA has a great interest in regulating these products as their popularity has increased, but have been opposed by the American Pharmacy Association, who claims their right to compound. The Endocrine Society issued a position statement in October 2006 asking for greater oversight of all ‘bioidentical’ hormones, whether FDA-approved or compounded, to further understand the safety and efficacy of the products.
Future perspective
Compounded hormones provide a unique method for patients to acquire the exact drug they need in the exact dose when it is not commercially available. When produced by pharmacies producing a large volume and using good compounding practice, these drugs may be safe and effective. Currently, for menopausal symptoms, FDA-approved products containing estradiol and progesterone are available in a variety of doses and utilize various routes of administration. Owing to increased quality control of FDA-approved bioidentical hormones, these should be favored over compounded hormones for menopause symptoms if available in the dose required. In the future, FDA-approved transdermal testosterone may be available in the USA similar to its current availability in Europe for menopausal women with a reduced sexual desire. This author believes that new FDA-approved products delivering bioidentical hormones as transdermal gels and creams will become popular in the future, reducing the need for compounded products. These products will produce constant, low levels of natural hormones required to reduce menopausal symptoms, with proven endometrial safety profiles.
Executive summary
Compounding is defined as the mixing of a drug or device consistent with a licensed practitioner's prescription; it is distinguished from manufacturing because it is a compound made for one individual patient's needs.
Compounded prescriptions may account for 1% of all prescriptions per year in the USA.
Compounded hormones have been defined as metabolites, therefore they are regulated as supplements rather than drugs. Because of this definition, they have not been subject to reports of efficacy and adverse events compared with US FDA-approved hormones.
The Endocrine Society, FDA and other organizations are now demanding greater scrutiny of compounded hormones, along with inclusion of package inserts stating similar risks as noncompounded hormones.
Bioidentical hormones are typically made from soy or yams.
Self-help books and the internet promote that bioidentical hormones allow menopausal women to get the exact dose they require.
Compounded bioidentical hormones in the USA typically contain a large quantity of estriol, a weak estrogen. The rationale for this is that rats pretreated with estriol developed less breast cancer; yet humans had more breast cancer when treated with estriol.
Patients may believe that bioidentical hormones are safer because they are natural, without the risks of FDA-approved hormones.
Studies are needed since publication of the Women's Health Initiative to determine current thinking about bioidentical hormones.
Biest, containing 80% estriol with 20% estradiol by weight, is one of the most popular bioidentical estrogen compounds in the USA.
Although estradiol in this compound is more potent and believed to offer the most benefit for menopausal symptoms, 2 mg of estriol alone administered vaginally has beneficial effects on urogenital symptoms in menopause.
Estrogen-receptor subtypes may influence how various estrogens act in different tissues.
Estradiol binds equally to estrogen receptors α and β; and with slightly greater affinity to estrogen receptor β compared with α.
Skin patches (reservoir or imbedded types) deliver constant, low doses of estradiol that reduce hot flashes and vaginal dryness, although some women have skin sensitivity to the adhesive of the patch.
New transdermal gels that deliver estradiol are applied daily and reduce menopause symptoms with minimal skin reaction.
Low-dose transdermal patches and gels delivering estradiol may promote endometrial proliferation, so a progestin or progesterone should be considered if the patient has her uterus, to prevent endometrial hyperplasia.
Prometrium® (oral estrogen, available in the USA) is effective in reducing endometrial hyperplasia when estrogens are also prescribed.
Prometrium improves sleep quality in menopause.
Compounded progesterone in transdermal creams does not reliably prevent endometrial hyperplasia.
Oral testosterone must be methylated as part of hormone therapy for women with reduced sexual desire, and may have negative metabolic effects compared with transdermal bioidentical testosterone.
There are currently no FDA-approved testosterone patches for women in the USA, so patients use compounded products or lower doses of FDA-approved testosterone gels approved for men.
Long-term studies are needed to examine the safety of transdermal testosterone alone or in combination with estrogens.
DHEA levels decrease with age in women and men; and although DHEA may be added to menopausal therapy to improve libido and the sense of well being, the data supporting this practice is inconsistent, and safety data are lacking.
Salivary hormone measurements are extremely variable, with no standards to indicate how hormone doses should be adjusted in menopausal women based on an improvement or lack of improvement in menopause symptoms.
Compounded hormones are available for menopause symptoms and could be considered if the exact doses of hormones are not commercially available for a patient. A wide variety of FDA-approved bioidentical hormones are currently available.
New transdermal biodentical estradiol gels have been approved by the FDA for menopausal symptoms. In the future, new gels delivering small amounts of other hormones for menopause may reduce the need for compounded hormones for menopause symptoms without inducing endometrial hyperplasia.
Footnotes
Cynthia K Sites has received grant NIH K24 RR019705 (Soy Phytoestrogen Supplementation and Menopause). The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.