Premarin Facts & Opinion
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Premarin—Facts & Opinions

1. What Is Premarin?
2. How Is Premarin Made?
3. Is A Generic Available?
4. Is Premarin for Me? What About Other Estrogen Supplements?
5. Premarin Pros and Cons: One Author's Opinion
6. Dr. David Zava Comment
7. What Other Websites Say About Premarin

 

1. WHAT IS PREMARIN?

Premarin is a patented drug made up of conjugated estrogens obtained from the urine of pregnant mares (PREgnant MARes' urINE, or PMU)

Manufactured exclusively by Wyeth-Ayerst at Ayerst Organics Ltd. In Brandon, Manitoba, Canada, Premarin is Canada's most lucrative pharmaceutical export to date. It is the most widely prescribed drug in the United States and holds 80% of the estrogen supplement market worldwide.

Premarin was first marketed for menopause in 1942. By 1972, Premarin tablets were certified by the FDA as effective for treating menopause, and in 1986, based on studies conducted by Wyeth, the FDA approved Premarin for treatment of osteoporosis.

Premarin has become the drug of choice for hormone replacement therapy in the '90s. Some estimates claim that close to nine million women are currently taking Premarin (about a third of the thirty million plus post menopausal women in the United States are on estrogen replacement therapy, and of them, about 80% use Premarin). Wyeth's revenues from Premarin are currently $1billion a year and rising.

2. HOW IS PREMARIN MADE?

Urine extracted from the mares on the PMU farms (both in Canada and the United States) is shipped to the processing plant in Brandon, Manitoba for manufacture and marketing. There are roughly 490 PMU farms at this time, and there has been much controversy over the living conditions of the mares that are kept at these farms, as well as their foals. For more information please see http://www.premarin.org/

3. IS A GENERIC (LESS EXPENSIVE) VERSION OF PREMARIN AVAILABLE?

A generic version of Premarin would save female consumers approximately $300 million a year, not to mention a generic version would not involve horses or harvesting the horse's urine.

Several smaller pharmaceuticals, including Duramed Pharmaceuticals, did develop generic versions of Premarin in the '70s and '80s, as Premarin's patent expired. In 1990, however, Wyeth-Ayerst told the FDA that the generic products on the market released estrogens more quickly into the blood stream than Premarin. Relying on the Waxman-Hatch Act's requirement that a generic have the same rate (how fast the drug enters the blood) and extent (how much total drug enters the blood) of absorption as the listed drug product, Wyeth-Ayerst has (so far) successfully waged a campaign to keep these generics off the market. As a result, although the generics have been developed, none are currently on the market or available to women. For more details about the controversy regarding manufacture of the generics, please see http://www.cagw.org/site/PageServer?pagename=reports_premarin

4. IS PREMARIN FOR ME? WHAT ABOUT OTHER ESTROGEN SUPPLEMENTS?

There are many natural and synthetic estrogen supplements available as alternatives to Premarin. Please see our typical hormone products page. Whether as a woman you choose to take HRT, or include Premarin or other types of estrogen in that regimen, is something which should be discussed with your doctor.

5. PREMARIN PROS AND CONS

One author's opinion, and Dr. David Zava's comment

BEYOND PREMARIN by Ivy Greenwell, MA, an author who writes about women's health issues.

Over nine million American women take Premarin. Most appear to be satisfied with it. Some brave pioneers have been taking it for more than thirty years now, and appear to be thriving, with little if any bone loss, less heart disease and Alzheimer's disease, less diabetes, less arthritis, less colon cancer, fewer cataracts, and so on.

On the other hand, some women have ended up with headaches, gallbladder problems, and elevated blood pressure. Blood clots are also a possible side effect (these problems are seen with oral estrogens, including oral contraceptives, rather than Premarin per se).

Premarin seems to be one of those love-it-or-hate-it products: women either say that Premarin is wonderful, or else they launch into stories of terrible headaches and other side effects (sadly, those women are often unaware that they would probably do well on either triestrogen oil caps or on transdermal estrogens, not necessarily the patch, which irritates the skin and, some argue, delivers too much breast-stimulating estradiol, but rather the various mixed-estrogen hormone creams and gels from compounding pharmacies; also, a confounding factor here is that some of those women may actually be having a bad reaction to Provera, not Premarin).

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Premarin is obviously not politically correct due to the cruelty issue, but let us not get into that for a while. Let us only examine the scientific data on the main estrogens in Premarin. Let us consider the heretical question: for those women who do not experience side effects, who so often call Premarin "wonderful," could it be a physiologically correct blend of estrogens? Or, given the double-edged, good news/bad news nature of hormones, is it nevertheless possible that Premarin offers some unique benefits not provided by other estrogen products?

On the surface, it would seem that the answer should be a plain no, since horse estrogens are different from human estrogens and do not naturally occur in the human body. You know the "menopausal horse" jokes. But the undesirability of equine (horse) estrogens in the human body is merely a plausible-sounding argument, and not a proven fact. Using jokes about menopausal horses as an argument is somewhat similar to my endocrinologist's trying to discourage me from Armour Thyroid by calling it "a slaughterhouse product." In fact it's only now that the unique nature of equine estrogens is being seriously researched. And the studies of what horse estrogens do in the human body have already yielded some interesting results.

Premarin is 50% estrone sulfate, 25% equilin, 15% eqilenin. The rest consists of numerous metabolites, some very biologically active. There may be trace amounts of hormones other than estrogens. Thus Premarin is a very complex blend of hormones. It also provides certain metabolites that are metabolized relatively slowlyΡin contrast to Estrace, for instance, which has a half-life of less than three hours. This persistence can be an advantage if the result is a steady level of energy and good sleep, or a disadvantage if a woman happens to have side effects.

One of the earliest such studies dealt with the antioxidant properties of human and horse estrogens (Subbiah 1993). Horse estrogens, equilin and equilenin and their numerous metabolites, have a unique structure: these are the so-called RING-B UNSATURATED ESTROGENS, which gives them some special properties and makes for a different metabolism—they are not converted to the arguably dangerous 16-hydroxyestrone, the precursor of estriol (women at higher risk of breast cancer, such as obese and/or hypothyroid women, produce more 16-hydroxyestrone, while high-thyroid women or regular exercisers produce less).

Can we thus conclude that Premarin is safer? Not so fast. Other studies have shown that certain metabolites of equilin release free radicals that can damage the DNA. And it's possible (though not proven) that these metabolites are potentially more dangerous than certain metabolites of estradiol.

And then there is the plausible argument (based on massive Harvard Nurses and Iowa studies) that Premarin slightly increases the risk of breast cancer only in women who consume alcohol (Zumoff 1998).

Still others point out that Premarin is 50% estrone sulfate, and estrone is weaker by far than estradiol in its ability to stimulate breast tissue.

Some women who have tried both Estrace and Premarin, or the patch and Premarin, decide that they like Premarin better because there is less breast tenderness, whereas pure estradiol feels "too strong." Can we conclude that estrone is better? It's not that simple.

The defenders of Premarin cite studies that show its remarkable safety, while its attackers cite studies to the contrary. For every point, there seems to be a counterpoint. For instance, Premarin lowers the insulin-like growth factor 1 (IGF-1). This is cited as an anti-carcinogenic effect. Others point out that by lowering IGF-1, Premarin eventually leads to some loss of muscle mass, always an undesirable, pro-aging phenomenon (it can be prevented by simultaneous use of androgens such as DHEA). In common with other oral estrogens, Premarin also raises triglycerides; it's been argued, however, that this rise is harmless, and anyway it can be prevented with correct doses of progesterone and androgens, or even with exercise.

But it is Premarin's supposed superiority when it comes to protection against cardiovascular disease and Alzheimer's disease that is the central issue here. Serum lipid peroxide levels go up after menopause, and this is one of the main mechanisms of accelerated postmenopausal aging (atherosclerosis is strongly implicated in Alzheimer's disease). It has been suggested that horse estrogens are more potent antioxidants when it comes to protecting cholesterol.

Subbiah and colleagues (1993) looked at how well various types of estrogens protected LDL cholesterol against oxidation, using the formation of a compound known as malonaldehyde (MDA), a lipid peroxidation product, as a measure of antioxidant capacity—the less MDA formed, the better the antioxidant protection. Here are some figures:

Control 21 (units of MDA) Estrone 14.74 Estradiol 10.40 Equilenin 8.22 Equilin 7.08

The researchers then checked for the oxidation of cholesterol as expressed in the percentage of oxysterol, a very harmful (cytotoxic) form of oxidized cholesterol. Here the results were also quite dramatic:

Control - 8.87% estradiol - 3.77% equilin - 1.37%

They also checked the formation of MDA in macrophages, immune cells that can be involved in plaque formation. Here the results were startling: compared to control (22.7) both estrone and estradiol INCREASED lipid peroxidation in macrophages (25.3 and 25.7); equilenin and especially equilin considerably reduced lipid peroxidation in macrophages (17.2 and 14.3). Hurray for equilin? Not so fast. More recent studies, using different ways of measuring peroxidation, have reached different conclusions. One study found that the order of antioxidant potency is as follows: estradiol is more powerful than estrone, which in turn is more powerful than equilin, which is more powerful than estriol (McManus 1996).

Another study followed the lead about strong antioxidant properties of the so-called "catechol estrogens," metabolites of estradiol, estrone, and estriol found in greater abundance in women who exercise, eat a lot of cabbage-family vegetables, and/or have high levels of thyroid hormones. One of these, 4-HYDROXYESTRONE, turned out to be "far more potent" as an antioxidant than equilin and its chief metabolite. At the same time, however, equilin and 17-alpha-dihydroequilin "strongly inhibited oxysterol formation, whereas 4-hydroxyestrone was ineffective." The authors come to the obvious conclusion that IT TAKES A WHOLE TEAM OF ESTROGENS to obtain the best antioxidant protection (Tang 1996).

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This conclusion seems to be further reinforced by the results of yet another study: while estrone had the best LDL-lowering action, equilin showed an outstanding ability to improve the action of insulin (Wilcox 1997). If estrogens could be bought over the counter, I have no doubt that we would have multiple estrogen blends being touted as superior to single-estrogen products, the way body builders are now urged to buy balanced mixed androgens (have you seen those "androgen symphony"ads?). Premarin, being a blend of more than twenty estrogens (more if we count those present only in trace amounts) does a pretty good job, but at least theoretically a better mix of estrogens could be designed specifically for cardiovascular protection. That mix would quite likely include equilin and its chief metabolites.

What about Premarin's protection against Alzheimer's disease? One study found that equilin was better than estradiol, estrone, or estriol in promoting the growth of nerve cells (Brinton 1997). Should we accept this as the final word on the subject? No. We must have more studies and test more types of estrogens, including perhaps designer estrogens not yet on the market, before we can draw any firm conclusions.

Besides, the release of nerve growth factor is not the only criterion that should be looked at. I suspect that just as different estrogens have different cardiovascular "talents," so it will also take a whole complex team of steroids to provide maximum protection against various degenerative brain disorders (a horrible way to die).

Women keep dreaming of the kind of estrogen replacement that will do it all—protect bones, heart, blood vessels, nerve cells, and more, but without stimulating the breast tissue and the uterine endometrium. Well, Premarin contains 17-alpha-dihydroequilenin, which has been shown to be as effective as estradiol in benefits for the brain; it also lowers insulin and has cardiovascular benefits without affecting breasts or uterus. In fact this particular estrogen can even be given to men, since it has no feminizing properties (Washburn 1996). But somehow there is not much interest in it, just as there is little interest in 2-hydroxyestrone, a metabolite of estradiol that is not only an excellent antioxidant, but, according to some studies, also seems to be anti-carcinogenic.

The point of my "good news/bad news" review of Premarin is to suggest that we do have the technology to do better. The use of horse urine is an absurd anachronism now that we can synthesize all types of estrogens and other steroids. Chemists also know how to modify the structure of various natural estrogens, horse or human, in order to enhance certain desired characteristics such as antioxidant power or bone-building ability, and/or diminish undesirable qualities, such as the ability to stimulate breast tissue.

But it's not likely that a single estrogen, whether natural or a designer estrogen, can truly do it all. It is probably going to take a whole team of estrogens to produce an optimal hormonal mix for various categories of menopausal women (those at high cardiovascular risk as opposed to those at a high breast cancer risk, for instance).

It is high time to go beyond Premarin, and toward trying to design better mixtures of estrogens according to various women's needs.

Note: Women who like the convenience of oral HRT, but object to Premarin and/or have not found Estrace to their liking, should consider getting the combined estrogens + progesterone oil capsules from a compounding pharmacy. Research indicates very good absorption, excellent (dose-dependent) effect on cholesterol, excellent uterine protection, and patient satisfaction. In fact I know one doctor who prescribes ONLY oil-capsule HRT because of high patient satisfaction.

For the references used by Ivy Greenwell, click here.

6. DR. DAVID ZAVA'S COMMENT ON PREMARIN

(Dr. David Zava, Ph.D., is a biochemist who has done a considerable amount of research in steroids, phytoestrogens, and breast cancer.)

"My opinion about Premarin is that it's a pretty good estrogen product with an extremely bad karma (horse torture). Premarin is made up of a mixture of conjugated estrogens, one of which is equilin. Of the three "natural" sister estrogens (estradiol, estrone, and estriol), equilin is structurally similar to estrone. The exception in its structure is that it has a double bond in the B-ring. What this means is that, like polyunsaturated fats (also have double bonds), the molecule is more easily oxidized than estrone.

"What we are learning about estrogens and cancer is that it's the oxidation of the estrogen that renders it dangerous as a carcinogen. Estrone is most easily oxidized to a 4-catechol estrogen (Ivy: that's 4-hydroxyestrone, which is also a potent antioxidant), and equilin is even more readily oxidized to the 4-catechol form. This may be why Premarin could be more dangerous than estradiol or estrone as regards cancer risk.

On the other side of the coin, keep in mind that Premarin is a mix of conjugated estrogens (Ivy: conjugated means they are in the sulfate form, a biologically inactive storage form; the body desulfates these hormones according to need), and apparently some progesterone and androgens also, which may counterbalance any increase in cancer caused by the equine estrogens.

I'm not aware of any epidemiologic evidence showing Premarin is any more or less dangerous than other estrogens as regards breast cancer risk. After 10 years of use the risk is anywhere from 1.3 to 2, depending on the study."

IVY RESPONDS:

I am thrilled to have this explanation by an authority in the field of steroids and breast cancer research. This is the kind of information you don't get from a typical book on menopause or a health newsletter, so I am very grateful that Dr. Zava has taken the time to write this.

I am also thrilled when I reflect on the fact that CH readers have joined a handful of biochemists in knowing that there exist saturated and unsaturated estrogens—like saturated and unsaturated fats—but please don't jump to the conclusion that one kind or another are therefore "bad estrogens." Each group has its pluses and minuses.

I especially wouldn't want anyone to conclude that catechol estrogens— 2-hydroxyestrone and 4-hydroxyestrone—are monstrously carcinogenic. These are above all wonderfully beneficial compounds. They inhibit the inflammatory prostaglandins of the E2 series. They also inhibit the synthesis of pain-producing leukotrienes. Possibly it is chiefly thanks to these metabolites that estrogen replacement has turned out to be such a godsend to arthritis victims.

With hormones it always seems to be the old "good news and bad news" story. But now that we know that even Vitamin C can under some circumstances damage DNA, and that a lot of antioxidants can turn into pro-oxidants, I think we are getting used to the idea. If easy oxidation of certain estrogens is possibly a risk factor, this points to the obvious steps women can take to protect themselves: use a lot of ANTIOXIDANTS, including the sulfur-containing N-acetyl-cysteine (NAC has been receiving more and more attention as a crucial antioxidant), and be sure to aid the methylation process by providing METHYLATING AGENTS (donors of the methyl group) such as folic acid and/or methylcobalamine (available from Life Extension Foundation, just discovered to have a powerful protective activity against breast cancer), and/or trimethylglycine.

As we grow older, neither our antioxidant defenses nor our methylation are as good as before, as thus is might be a good policy for all women on HRT to increase their intake of antioxidants and methylating agents. Since breast cancer is largely a disease of aging (80% of the cases are diagnosed after age 50, and the risk increases dramatically with advancing age), anything we do that helps the body preserve youthful physiology should also lower the cancer risk.

We also should pay attention to Zumoff 's suggestion that women taking oral estrogens should minimize their alcohol intake, and either eat a lot of cruciferous vegetables (cabbage family) or take indole-3-carbinol, the active ingredient which positively affects estrogen metabolism. One of our readers, Katie, has suggested that women on Premarin and other oral estrogens should be taking MILK THISTLE to insure liver health.

Finally, women taking oral estrogens in general, and Premarin in particular, should be encouraged to engage in regular daily exercise in order to prevent the rise in triglycerides, and to gain further protection against breast cancer.

Overall, it seems that some women do better on Premarin than on other forms of HRT. I would vastly prefer a product that does not involve horses, and one that is truly optimized for postmenopausal women's health needs. But until we have something "beyond Premarin," there seems to be a way to take Premarin with reasonable safety:

  • limit alcohol
  • take plenty of antioxidants and methylating agents such as folic acid
  • engage in regular exercise
  • eat those broccoli sprouts.

And, of course, be sure to balance the estrogens with progesterone (not Provera) and androgens.

7. PREMARIN: WHAT OTHER WEBSITES SAY

Premarin: A Prescription for Cruelty
http://www.peta.org/mc/factsheet_display.asp?ID=73

The truth about Premarin - What they don't tell you
http://my.athenet.net/~nrsprntg/stpindex.html

 

 

 

 
 
 

 

 

 

 

 

 

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Updated 09/29/2010