Maturitas
Volume 64, Issue 2 , Pages 86-89, 20 October 2009

Bioidentical hormones for maturing women

Associate Clinical Professor of OB/GYN and Women's Health, Albert Einstein College of Medicine, Montefiore Medical Center, New York, United States

Received 10 June 2009; received in revised form 27 July 2009; accepted 9 August 2009. published online 28 August 2009.

Article Outline

Abstract 

Despite medical progress, climacteric symptoms still exist. With the coming of age of the baby boomers, more and more women will be experiencing these symptoms which may be adversely affecting their lives. Mistrust of the medical community and prescription drugs has led many to search for that perfect product which will ameliorate their symptoms, with less or no risk. They are turning to compounded bioidentical hormones. However, the term is somewhat nebulous and ill defined. In this review, the term will be explained and evidence regarding efficacy and safety discussed.

Keywords: Bio-identical hormones, Menopause, Estrogen, Progesterone, Salivary testing

 

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1. Introduction 

Today, women are living longer than ever. With the coming of age of the baby boomers, it is anticipated that the number of people ages 65–74 years will grow 74% while those under age 65 will only increase by about 24%. Also, over the last few decades, the US population, as a whole, has grown. The subgroup which is most rapidly rising is that of older women. Women greater than or equal to 45 years are expected to approximate 60 million in this decade [1], [2]. Since women are going to be living longer, they want to achieve not only longevity, but also maximum quality of life.

During the climacteric, the most common signs and symptoms are:

-Changes in menstruation.

-Vasomotor symptoms.

-Urogenital atrophy and its potential sequelae including dyspareunia and urinary symptoms.

-Changes in skin.

-Increased body weight and abdominal fat.

-Psychophysiologic changes like mood changes, irritability, insomnia, anxiety and sleep changes [1], [3].

These climacteric issues are extremely troublesome to many women, and affect their quality of life. Up to 85% of women complain of hot flushes during the perimenopause [4]. While hormone replacement therapy was commonly given to ameliorate these symptoms in the past, today, concerns regarding hormone therapy have led to fewer prescriptions. After the WHI trial released its findings in 2002 [5], there has been a decrease in the use of hormone therapy. The prevalence of use was greatest in 2002 at 11% in 50–54-year-old women and 10.1% of 55–59-year-old women. By 2007, its use had fallen by 89.1% in 50–54 year olds, 87.5% in 55–59 year olds, 84.6% in 60–64 year olds and 66% in 65–69 year olds. The number of new starts also fell [6].

So, women may have concerns about using standard hormone therapy, but still have their same signs and symptoms associated with the climacteric. Where do they turn?

They are looking for something safe which will ameliorate their symptoms, but will not have any associated risks. Does this magic cure exist? Unfortunately, no. Nothing is all good and without any associated risk. However, women have a misperception that there exists some risk free panacea due to advertisements, marketing strategies etc., that may be feeding into the symptomatic woman's fears and claiming that they have this magic potion, the “Bioidentical Hormone,” which they claim is safer than standard, prescribed hormone therapy.

The purpose of this review is to try to explain what it is when people refer to the term, “Bioidentical Hormones” so that we can better address patient's desires, questions and concerns.

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2. What exactly does the term Bioidentical Hormone mean? 

This is a somewhat nebulous term used to describe medications which are plant derived (like many of the Federal Drug Administration (FDA) approved hormone therapy drugs) and modified to be structurally identical to endogenous human hormones such as estrogen, progesterone, estrone, estriol, progesterone, testosterone and dehydroepiandrosterone. However, by the time that the laboratory is through processing the initially innocuous yam, it is nothing like the delicious treat we find on our thanksgiving tables.

The active estrogen made by a cycling woman's ovaries is 17 Beta-Estradiol. This is the form of estrogen most predominant in a cycling woman, and which is involved in maintaining vaginal tissue, bone and which, when in constant levels, helps to prevent vasomotor symptoms [3]. There is also a small amount of conversion of estrone and testosterone into estradiol. While most of a cycling woman's estrogen is derived from the ovary's production of estradiol, there also exists significant extraglandular conversion of androstenedione to estrone (1.3%), and estrone and testosterone to estradiol. However, only 0.15% of testosterone is converted to estradiol [7].

Estrone, estradiol and estriol levels fluctuate with life stage. While estradiol is the predominant estrogen in cycling women, estriol is predominant in pregnancy and estrone is the predominant postmenopausal estrogen.

Estrone is not produced directly by a cycling woman's ovaries. Instead, multiple sources contribute to circulating estrone levels. These sources include conversion of androstenedione to estrone and metabolism of estradiol and estrone sulfate into estrone. Thus, while the ovary indirectly contributes to estrone production by providing 40% of the substrate needed for androstenedione production (the other 60% comes from the adrenals), it is not a direct source of estradiol production [8]. Estrone is both a precursor and a metabolite of estradiol [9].

Estriol is an estrogen made by the placenta during pregnancy. It is produced in a unique process in which the fetus, placenta and mother all are interdependent [8].

It is popular belief that estrone and estriol and “weaker and safer” estrogens. This popular belief however has not yet been established in adequate well designed, unbiased trials which have the power to overcome their confounders. In a study of MCF7 human breast cancer cells, all three estrogens produced equivalent stimulation of nucleoside and amino acid incorporation. When saturating concentrations of all three estrogens were used, all three binded to an equivalent number of high affinity estrogen receptors. Despite common beliefs that estriol is safer than estradiol, especially at the level of the breast, the data do not support that estriol has an antiestrogenic role in human breast cancer [10], [23], [24].

At the level of the pituitary, both estrone and estriol were demonstrated to be strong, not weak, estrogens in functional responses and in the non-genomic signaling pathways [11].

In the mouse model, estriol had only a weak uterotrophic action when given daily, but when given more frequently, in small doses, it elicited as much growth in the vagina and uterus as did estradiol. But, the action of estriol has been shown to be short lived compared with estradiol [12]. In another study of the effects of estriol in the mouse model, estriol, at higher doses, had a comparable effect as estradiol on the mouse uterine luminal epithelium. The maximum response was on day one and by days two and three, mitotic activity was significantly decreased at all doses [13].

In pregnancy, estriol is produced continuously [14]. Studies suggest that at least in an animal model, estriol levels and effects vary with time. Since the goal of treatment for amelioration of vasomotor symptoms in women is to achieve constant and unfluctuating hormone levels, estriol would not be as good a choice as would estradiol.

If a cycling woman's ovaries produce 17 Beta-Estradiol, and fluctuations in levels are associated with vasomotor symptoms [3], and the sex steroid is available in low dose steady release form, then it seems logical that 17 Beta-Estradiol would be the choice over estrone or estriol for amelioration of symptoms which may last far longer than was previously thought. Recent evidence suggests that women suffer from climacteric symptoms for 5.2±3.8 years rather than the 2 years previously reported [15], [16], [17].

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3. Custom compounded formulations 

Custom compounded formulations of hormones have become quite popular and have received many media endorsements on various venues such as The Oprah Winfrey Show. The idea of customizing patient's medications is something that healthcare providers have always done. We choose the medication, dose and route of administration that is most appropriate for each patient. However, we traditionally use standard FDA approved prescription drugs. With these customized compounded formulations, there is no guarantee of efficacy, safety, or consistency. These products are individually created formulations, which have different dosages, and mixtures of products, some of which have not had the rigorous testing required by the government, as do prescription drugs. These products can vary in their ingredients and dosages from patient to patient. Since there is so much variation and potential for inconsistency, we do not have adequate testing of their safety and effectiveness based on randomized case control studies, which have the power to overcome the confounders. Also, the formulations can vary by batch and by pharmacist, and the patient may not be getting consistent and constant amounts of hormones. Routes of administration can also vary and absorption may not be consistent or achieve optimal blood levels [18]. Unfortunately, well designed large, randomized, placebo controlled trials with sufficient power have not been done of many of these non-FDA approved products, and their safety and efficacy is yet to be conclusively determined.

3.1. Salivary testing 

When topical preparations are used, it is sometimes recommended that patients themselves titrate their own doses depending on salivary levels, which they are using as an indirect marker of estrogen levels. As of May 2009, The North American Menopause Society did not advocate the use of salivary or blood testing of hormone levels. Steroid hormones, such as estrogen are secreted in pulses. This results in fluctuating levels. Since hormone levels fluctuate not only day-to-day but during the day itself, they are not good predictors for monitoring dosing. Salivary testing itself is not at this time considered the gold standard for monitoring hormone levels since there is a low correlation between salivary and serum estradiol, unless at least 5 salivary samples are taken daily [19], [20], [21].

3.2. How much estradiol are they actually getting? 

At present, there exists limited research regarding the compounded products and estradiol equivalency. The pharmacodynamics and pharmacokinetics of estrogen are complex and different for the different types of estrogen. For example, estradiol is 80 times more potent than estriol [22]. Estriol is present in many of the compounded products. While it is less potent, it can still carry some of the risks associated with other prescribed estrogens such as stimulation of MCF breast cancer cell lines and endometrial hyperplasia [10], [23], [24]. When given topically, estriol has been shown to reverse vaginal atrophy but has not demonstrated bone protective effects [22].

A concern regarding these custom compounded formulations is just how much estradiol are patients actually getting? Patients and some health care providers may think that they are giving less hormone with the compounded products than with standard hormone therapy, but in reality they may be taking more. Biest is a compounded formulation cream made up of estradiol and estriol. If someone takes a 2.5mg Biest (2mg estriol with 0.5mg estradiol), they are actually taking the equivalent of 0.525mg estradiol, which is more than a prescription of 0.5mg of estradiol [22]. Some women take Biest at a dosage of 2.5mg twice daily [25]. This gives them a dosage of 5mg Biest daily, which provides the estradiol equivalent of 1.05mg daily, which is higher than most prescribed estrogen therapy dosage [22], [26].

While conversion into estradiol equivalents is more difficult with Triest (a combination of estriol, estradiol and estrone), it too may provide more equivalent estradiol than would a FDA approved prescription drug. For example, if 2.5mg of Triest is given daily, this would provide more equivalent estradiol than is often recommended. If a lower dose of Triest (1.25mg) is given, it is often given twice a day and may provide more estradiol than would be regularly prescribed [26]. Since estriol's action may be shorter lived than estradiol [12], it is often given more frequently than once daily for efficacy in symptom relief.

Current Phase 1 studies, as of May 2009, are currently being recruited to better determine estradiol equivalents of the compounded hormonal products as compared to an FDA approved prescription estradiol transdermal product [27]. Hopefully, they will provide a better scientific understanding of these compounded products.

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4. Topical progesterone 

FDA approved bioidentical micronized progesterone products are available on prescription. We know that in nonhysterectomised women, estrogen must be given with a progestogen for endometrial protection. There are various ways established by supporting data, for providing progestogens in FDA approved prescription drugs [28]. However, many women are using over the counter topical progesterone products that are being sold in varied venues such as health food stores. A problem with these over the counter, topical progestogens is that absorption is poor. In an Australian study of the endometrial response to 14 days of transdermal micronized progesterone (16–64mg/d), no secretory endometrial changes were observed and plasma progesterone levels were low [29]. Another study was a double blind, placebo controlled study which looked at amelioration of vasomotor symptoms and osteoporosis prevention using a topical transdermal progestogen cream in recently postmenopausal women. There was no benefit regarding bone conservation in either group. However, while 19% of women on placebo had relief from vasomotor symptoms, 83% on active treatment had amelioration of symptoms (P<.001) [30].

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5. Summary 

Climacteric symptoms are not going away. Women are going to be living longer than ever and with the coming of age of the baby boomers, more and more women will be experiencing these symptoms as they traverse the menopause. Women are turning to alternative products, some of which are not FDA approved and have not been adequately tested for their safety and efficacy. They have concerns regarding standard hormonal therapy and may be experiencing mistrust of the medical community after the media's coverage of findings regarding studies such as the Women's Health Initiative [5]. In their quest for amelioration of lifestyle affecting symptoms, women may turn to non-standard therapies, in hopes of it being safer. It is our responsibility to listen to their questions and concerns and to educate them should they have misperceptions. In our cornucopia of FDA approved prescription drugs, we do have “Bioidentical” preparations available which may be safer and more efficacious. However, we need better designed, larger, placebo controlled, randomized studies to better define the safety and efficacy of the custom compounded bioidentical products.

For now, Utian provides a summary [31] regarding compounded bioidentical hormone Therapy versus manufactured, FDA approved, commercial hormone therapy products:

-Active and inactive ingredients in compounded products vary greatly.

-Prescription drugs are tested for efficacy, purity, safety and potency and are federally regulated, unlike compounded products.

-To date, there is no conclusive evidence that compounded bioidentical hormones are more efficacious of safer than conventional prescription estrogen products.

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Contributor 

Judi Chervenak—sole author.

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Competing interests 

None declared.

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Funding 

No funding.

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Provenance and peer review 

Commissioned, externally peer reviewed.

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PII: S0378-5122(09)00263-1

doi:10.1016/j.maturitas.2009.08.002

Maturitas
Volume 64, Issue 2 , Pages 86-89, 20 October 2009

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