Premarin Mares and Foals: Aprela, the Lesser Evil?

Written by JANE ALLIN
Research Analyst | Int’l Fund for Horses

Despite the tainted history of Premarin® and its acknowledged contribution to a plethora of cancers and other maladies in women who trustingly relied upon it for the relief of menopausal symptoms, Wyeth, and now Pfizer, shamelessly continue to promote the use of conjugated equine estrogens (CEEs) in their soon to be released Aprela® – the new panacea for postmenopausal women and men!

With the ever-growing aging population, the health and financial impact of osteoporosis in the United States and Canada may prove to be overwhelming without a concerted effort by the medical community to prevent and treat this debilitating disease.

Enter Aprela®

Designed as an alternative to combination estrogen/progestin therapy (i.e. Prempro®, Premphase®), Aprela® is a composite drug that claims to lessen menopausal symptoms while at the same time prevent or reduce the prevalence of bone loss in postmenopausal women reportedly without the elevated risk of estrogen-related cancers. A novel paradigm no less!

So what exactly is Aprela® and how does it differ from the Premarin® family of drugs, or for that matter, bona fide human estrogens?

Estrogen, Fuel for Feminine Survival: A Short Primer

The three major naturally occurring estrogens in women are estradiol (~10-20%), estriol (~60-80%) and estrone (~10-20%) all steroidal hormones produced in the body and derived from cholesterol through the actions of enzymes.[1] Note that these percentages are expressed as the amount typically circulating in the bloodstream and not within various tissues and organs in the body which can vary depending on numerous and complex biological processes.

Furthermore, the levels of human estrogens vary according to the state of the female body wherein estradiol is the strongest and principle estrogen present during reproductive years, estriol is the weakest and is found in large quantities during pregnancy and estrone tends to become elevated during postmenopausal years.[2] Unfortunately, the amount of estrone present after menopause is inadequate in superseding the operative loss of estradiol as one ages hence the symptoms of menopause develop. Here is where Big Pharma intervenes to exploit their market share monopoly and shameful profits without consequence to the survival of women and horses alike.

The principal dogma of the HRT industry is founded on the concept that the tissues of a postmenopausal woman are devoid of estrogen. This is simply not true. The concentration of a hormone in the blood is not directly correlated to the concentration in various organs.[3] It has been shown that when the concentration of progesterone (the pregnancy hormone) in the blood is high, the amount of estrogen in tissues declines and when there is a shortage of progesterone, the tissues retain estrogen, even when there is only a small amount of estrogen circulating in the blood.[4] In other words, it is the monthly cycling of progesterone levels during the reproductive years that helps regulate the amount of estrogen in various body tissues making sure that the concentration in the tissues is optimum during ovulation to enable conception. More importantly, when women reach menopause, a considerable reduction in progesterone levels occurs meaning that the tissues retain large amounts of estrogen on a continuous basis.[5]

Since estrogens are hormones, they function as signaling molecules. Estrogen signaling molecules circulate within the bloodstream and interact with a variety of “target” tissues such as the breast and uterus, the two main targets, but also the brain, liver, bone and heart.[6] Located within these target cells reside what are called estrogen receptors. It is here that the estrogen molecule attaches itself to the cell and eventually activates specific genes within the cell’s DNA to produce proteins that will influence the cell behavior in different ways. Normally, these proteins are beneficial to the tissues they affect. For example:

1. programming the breast and uterus for sexual reproduction,
2. controlling cholesterol production in ways that limit the buildup of plaque in the coronary arteries, and
3. preserving bone strength by helping to maintain the proper balance between bone buildup and breakdown[7].

However, too much of a good thing can be harmful. Estrogen also has the ability to stimulate cell proliferation, typically in the breast or uterus, which although a normal role for estrogen, can increase a woman’s chance of developing cancer. The reason for this is directly related to the presence of, or evolution of (spontaneous), mutations in the cell’s DNA. The mere presence of excess estrogen can in fact increase the incidence of spontaneous mutations. As cells continuously divide and proliferate, the number of mutated cells will also increase which can ultimately lead to the development of cancer.

The question then is how much and what kinds of estrogen do we really need or want in our postmenopausal body tissues considering that they will be exposed to estrogen all of the time rather than just some of the time.

Premarin® et al

Premarin® and its CEE derivatives are complex steroidal mixtures containing as many as 20 equine estrogens, most not native to human beings, in which the blend is primarily composed of 50% estrone, 25% equilin and 15% equilenin. The remaining 10% harbors many metabolites, some extremely biologically active, as well as trace amounts of hormones other than estrogens. It is also recognized that certain metabolites (i.e. the intermediates and products of metabolism) of equilin release free radicals that can damage DNA, particularly in hormone sensitive cells.[8]

Sounds positively disgusting!

Conveniently, or perhaps not so conveniently, especially in the case of higher concentrations which are more ominously linked to elevated cancer risks, Premarin® is available in five dosages; 0.3 mg, 0.45 mg, 0.625 mg, 0.9 mg and 1.25 mg strengths of conjugated estrogens.[9] If you are wondering what a conjugated estrogen is, it simply means they are in the sulfate form (i.e. estrogen sodium sulfate salts) and the body subsequently de-sulfates these on ingestion to release the active form of the hormone.

Clearly the only component in common with human hormones is estrone. Unlike ingesting equine estrogens, there are no foreign hormones or metabolites present in natural hormones that have the capacity to incite extraneous reactions within various body tissues that may sensitize them to cell proliferation, a precursor to cancer – they are natural and hence act upon the tissues in a normal manner. Furthermore, studies have shown Premarin® to promote higher estrogen levels within the body as well as having a larger effect on the liver compared to non-equine hormones.[10] Premarin® is combined with progestin (medroxyprogesterone) in both Prempro® and Premphase®. Wyeth wants you to believe that both of these combination therapies are the sole culprits of the elevated cancer and cardiovascular risks associated with HRT and use this as the rationale for developing their new drug Aprela®. Hmmmm…what about the original Premarin® and all of those nasty CEEs?

That said, how can a dose of horse urine possibly be the universal remedy for postmenopausal symptoms. Moreover, apart from estrone, how compatible are these equine estrogens with human tissue? Without a doubt the answer is “not very” as the list of HRT related cancers and disorders continue to make headlines as time progresses. It is interesting to take a look at the chemical and structural formulas of equilin and equilenin and compare them to the human hormones, estradiol and estriol.

Yes, you might say they look similar but does this mean they are safe?

Consider another case of a seemingly innocuous molecule in which the outcome of its therapeutic use had sinister consequences. Marketed in 50 countries in the late 1950’s and early 1960’s, and sold as a sedative and anti-nausea medication to combat morning sickness in pregnant women, Thalidomide caused thousands of birth defects as well as deaths and was eventually taken off of the market in 1961. It was soon discovered that one particular conformation of the thalidomide molecule was responsible for the fetal deformities. These two different arrangements of the same molecule were in fact mirror images of one another but one was deadly and the other harmless. Yes, this is an extreme case, and no, it is not a steroidal hormone, but you get the drift.

Aprela ®

What a lovely sounding name.

According to Wyeth, Aprela® is a combination of CEEs (Premarin®) with a selective estrogen receptor modulator (SERM) called bazedoxifine (BZA), also known as Viviant®.[11] Aprela® is categorized as a tissue-selective estrogen complex (TSEC) and has been evaluated for the effects on menopausal symptoms, metabolic parameters and overall safety during a 2-year double-blind, placebo- and active-controlled trial involving healthy postmenopausal women (age 40-75 years).[12]

Dosages used in the study comprised BZA at 10, 20, or 40 mg in combination with CEEs of 0.625 or 0.45 mg – the mid-range dosages of Premarin®.

The overall strategy for the combination drug is a proven concept but not without issues. SERMs function to selectively stimulate or inhibit estrogen receptors in various tissues (e.g. breast tissue) in that they either stimulate cell proliferation (i.e. estrogen active) or inhibit it (i.e. estrogen inactive).[13]

Tamoxifin was the first SERM to be studied for its capacity to block the action of estrogen in breast cells effectively inhibiting cell proliferation and therefore useful in treating breast cancer. However, Tamoxifin has the serious side effect of increasing the risk of uterine cancer as it mimics the actions of estrogen and stimulates cell proliferation in the uterus.[14]

This concept was further explored with the combination estrogen-progestin therapies Prempro® and Premphase®. Studies in the 1980s suggested that the progesterone hormone tended to counteract the increased risk of uterine cancer. Oops! As the public well knows, this combined HRT resulted in increased risks of breast cancer, strokes, heart attacks and blood clots. Wyeth continues to battle thousands of lawsuits related to Prempro®.

So how will Aprela® (BZA + CEEs) compare and is it safer? It certainly does nothing for the suffering and cruelty the horses must endure.

BZA (Viviant®) is a novel selective estrogen receptor modulator (SERM) specifically developed to help prevent postmenopausal osteoporosis. In combination with CEEs, it is anticipated that it will alleviate the symptoms of menopause as well as increase bone mass density (BMD) without causing stimulation of breast and uterine tissues – the ideal solution? At least that is the conjecture.

While it is true that a 2-year clinical phase III trial has taken place and appears to have been effective for menopausal vasomotor symptoms, while at the same time increasing BMD, available data are very limited, optimal dosages are unclear and detailed information on long-term efficacy or side effects are unknown. Moreover, it is well known that cancers are insidious and can typically take 10 years or more to develop. Isn’t that what happened with ALL of the Premarin® family of drugs – not just the combination Prempro® therapy? As far back as the 1970’s there was damaging evidence about the risk of cancers and cardiovascular disorders using CEEs, long before the arrival of Prempro® in 1995 and finally the WHI which undisputedly linked HRT with increased cancer and cardio risks among others.

And bazedoxifene itself is not without issues. Clinical trials have indicated a higher incidence of deep vein thrombosis, retinal thrombosis, hot flushes and leg cramps compared with placebo-treated subjects. In fact, bazedoxifene has garnered two approvable letters from the FDA, but concerns about the increased risk of stroke and thromboembolic events have contributed to a delay for this drug.[15] Initially to be released in 2009, it still awaits approval from the FDA as does Aprela®, slated to be launched in 2011.

Conclusion

Isn’t it time for a change given the serious risks of CEEs and the unknown risks of Aprela®? Will we have to wait for another decade or more to realize yet again, we have been duped by Big Pharma while in the interim thousands of women and horses suffer at the hands of these insipid gluttons?

Why not genetic engineering? Yes, perhaps a frightening word to some, but these techniques afford the promise of liberating our dependence on many animal-derived products and advance the ethical objective of humane animal treatment.

Examples of recombinant DNA products include the production of synthetic human insulin using modified bacteria and the thyroid stimulating hormone (TSH) both of which were once derived from animal sources only. The human gene that codes for either the insulin or thyroid hormone is inserted into the genetic material of bacteria (RNA) and the bacteria grow and manufacture the hormone which can then be purified and used medically. The advantage of these techniques is that the cloned material is an exact replica of the human component hence perfectly compatible with human tissue without risks of serious contraindications.

Imagine now if human estrogens could be produced in the same manner; I believe they can be. All the suffering of the mares and foals would be resolved, postmenopausal women would have fewer uncertainties about the risks of HRT and Big Pharma would still be raking in the big bucks albeit not at the expense of the innocent.

Perhaps the future will beget good fortune but in the mean time we need to be vigilant about the introduction of this new CEE toxin with the pretty name – Aprela®. No doubt Wyeth’s marketing strategy will be a clever disguise to underplay any uncertainties associated with the estrogen derivatives of PMU, while promoting the benefits of the osteoporosis therapy component. Business ethics seemingly do not apply to Big Pharma as we have seen time and time again.

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SOURCES

[1] http://www.holisticonline.com/Remedies/hrt/hrt_estrogen.htm
[2] http://rx4u.com/natural%20hormones.htm#ESTRIOL%20%28E3%29
[3] http://raypeat.com/articles/articles/tissue-bound-estrogen.shtml
[4] See 3.
[5] See 3.
[6] http://www.cancer.gov/cancertopics/understandingcancer/estrogenreceptors/allpages/print
[7] See 6.
[8] http://www.project-aware.org/Managing/Hrt/PremarinFacts_Opinion.shtml
[9] http://www.rxlist.com/premarin-drug.htm
[10] http://www.goodpharma.com/estrogen.htm
[11] http://www.ncbi.nlm.nih.gov/pubmed/20336595?dopt=Abstract
[12] http://www.ncbi.nlm.nih.gov/pubmed/19635615
[13] See 6.
[14] See 6.
[15] medco.mediaroom.com/file…/2009+DRUG+TREND+REPORT.pdf

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