FDA-Approved Alternatives to Premarin Derivatives – are they safer ?


Contrary to popular belief, the FDA has yet to approve any generic as a substitute for Premarin and its daughter products (i.e. Prempro, Premphase, Duavee).

Accordingly no prescription drugs used to treat menopausal symptoms, other than the Premarin family, contain pregnant mare’s urine.

Image from PMU farm in Manitoba showing the collection bag used to collect the urine from pregnant mares used in the making of the Premarin family of drugs.
Image from PMU farm in Manitoba showing the collection bag used to collect the urine from pregnant mares used in the making of the Premarin family of drugs.

However much confusion arises when the subject of HRT is broached, particularly in terms of the safety aspect of FDA-approved versions that are not derived from pregnant mare’s urine.

The vast majority of FDA-approved HRT prescription drugs are synthetic bioidenticals — hormones identical on a molecular level to endogenous hormones that are synthesized in the lab from natural plant sources.

These are not to be confused with the compounded bioidenticals, none of which are approved by the FDA.

Premarin and its derivatives are also synthetics but, of course, sourced from an animal by-product.

Apart from Brisdelle, the only non-hormonal FDA-approved HRT, the rest fall into three categories of hormone combinations as follows:

• Estrogen combinations (e.g. Estrace, Cenestin, Enjuvia, Menest)
• Estrogen/Progestin combinations (e.g. Activella)
• Estrogen/Androgen combinations (e.g. Menogen, Covaryx)

The estrogen combinations are intended as substitutes for Premarin and Duavee while the estrogen/progestin versions are proposed alternatives to Prempro and Premphase.

Estrogen/androgen replacement therapy primarily represents mainstay therapy for young women who have undergone a hysterectomy. See http://www.medscape.com/viewarticle/438357.

A good proportion of these drugs contain estradiol or esterified estrogens (non-equine) as the estrogen component (e.g. Estrace, Femtrace, Activella, Femhrt, Angeliq). However several have identical equine estrogens that are derived from plant-based sources versus pregnant mare’s urine.

That said, these drugs are not entirely identical nor are they exactly equivalent in constituents. Cenestin, Enjuvia, and Menest are three such HRTs included in this group.

Cenestin was originally developed as a generic for Premarin by Duramed/Barr but in 1997, the FDA refused to approve the abbreviated new drug applications from Duramed and Barr Laboratories for a generic version of Premarin.

The FDA’s rationale was quite straightforward. A synthetic generic version of Premarin could not be approved because the exact chemical composition of Premarin could not be fully identified. This has been a controversial topic for years, a topic The Horse Fund has visited in the past. See https://tuesdayshorse.wordpress.com/2014/11/14/the-quest-for-a-generic-premarin-a-bitter-pill-to-swallow/.

In any case, all three of these drugs – Cenestin, Enjuvia, and Menest – contain similar estrogen components that are found in Premarin and its derivatives.

Premarin however is a complex mixture of numerous hormonal components, of which only some of the estrogenic components are found in the plant-based synthetics.

The table below compares the ingredients of Premarin, Cenestin and Enjuvia. I was unable to locate the same information for Menest.

However the pharmacology is similar to the others and contains a mixture of esterified estrogenic substances, principally estrone, that are of the type excreted by pregnant mares (e.g. sodium estrone sulfate, sodium equilin sulfate).

sodium estrone sulfate Yes Yes Yes
sodium equilin sulfate Yes Yes Yes
sodium 17 alpha-dihydroequilin sulfate Yes Yes Yes
sodium 17 beta-dihydroequilin sulfate Yes Yes Yes
sodium 17 alpha-betahydroequilenin sulfate Yes Yes Yes
sodium 17 beta-betahydroequilenin sulfate Yes Yes Yes
sodium 17 alpha-estradiol sulfate Yes Yes Yes
sodium equilenin sulfate Yes Yes Yes
sodium 17 beta-estradiol sulfate Yes Yes Yes
sodium D8,9-dehydroestrone sulfate Yes No Yes
5,7,9 (10) estratrien-3beta, 17 beta-diol Yes No No
17 alpha-dihydro-delta, 8,9-dehydroestrone Yes No No
17 beta-dihydro-delta, 8,9-dehydroestrone Yes No No
5,7,9 (10) estratrien-3betal-ol-17-one Yes No No
2-hydroxy-estrone Yes No No
2-methoxy-estrone Yes No No

In addition to the extra estrogens contained in Premarin, it also contains six progestin and four androgen equine hormones. See http://surmeno.blogspot.com/2006/03/comparison-of-ingredients-premarin-and.html.

Despite the fact that these alternatives contain several of the Premarin estrogenic components, a study comparing the pharmacokinetics and relative bioavailabilities of key estrogen components of Premarin with those of synthetic plant-based equivalents concluded that these are not in fact bioequivalent to Premarin and therefore cannot be assumed to be therapeutically equivalent. See http://www.ncbi.nlm.nih.gov/pubmed/10865186.

But does this mean that these and other FDA-approved synthetics are safe?

Unfortunately these alternative synthetics carry with them the same or similar warnings associated with their use.

However it is often cited in scientific literature that estrogens derived from pregnant mares urine pose a greater risk due to the complexity and concentrations of the combined hormones together with the unmistakable fact that equine estrogens are foreign to humans.

Given that alternatives such as Cenestin and Enjuvia assimilate the equine equivalents in Premarin, despite the fact they are derived from plants, it is perplexing why anyone would elect to choose these to alleviate menopausal symptoms – purely from the aspect of being equine-related and extrinsic to the human endocrine system. More likely it is a case where they are unaware of what they contain.

And what about the rest that contain estradiol (e.g. Estrace) and other esterified non-equine estrogens, or those that contain progestins and androgens extracted from plant sources?

Here are some examples of the risks associated with these so-called “safer” alternatives compared to the Premarin derivatives. Source: http://www.rxlist.com/script/main/hp.asp.

Estrogen-only HRT

Premarin (Conjugated Equine Estrogens – CEEs) http://www.rxlist.com/premarin-drug.htm
• Endometrial cancer, cardiovascular disorders, breast cancer and probable dementia (> 65 yrs).

Enjuvia (plant –derived equine estrogens) http://www.rxlist.com/enjuvia-drug.htm
• Endometrial cancer, cardiovascular disorders, breast cancer and probable dementia (> 65 yrs).

Estrace (estradiol – plant based) http://www.rxlist.com/estrace-drug.htm
• Endometrial cancer, cardiovascular disorders, breast cancer and probable dementia (> 65 yrs).

Estrogen –Progestin HRT

Prempro/Premphase (CEEs/progestin) http://www.rxlist.com/prempro-drug.htm
• Invasive breast cancer, cardiovascular disorders, and probable dementia (> 65 yrs).

Activella (estradiol/progesterone – plant based) http://www.rxlist.com/activella-drug.htm
• Invasive breast cancer, cardiovascular disorders, and probable dementia (> 65 yrs).

And let’s not forget the newest addition to the Premarin family.

Duavee (CEES/bazedozifene(SERM) http://www.rxlist.com/duavee-drug.htm
• Endometrial cancer, cardiovascular disorders, and probable dementia (> 65 yrs).
• The SERM bazedoxifene is believed to inhibit the formation of breast cancer cells by binding to the estrogen receptor thus interfering with its activity.

Premstoppers Campaign. Warning, Premarin Contains Horse Urine.

The picture is clear.

In effect the FDA-approved hormone-containing alternatives carry with them the same risks and warnings associated with drugs derived from conjugate estrogen estrogens, whether that be estrogen alone or combinations. Albeit the risks may not be of the same significance as those associated with drugs manufactured from pregnant mare’s urine.

Nonetheless they still exist, and potentially more so for susceptible individuals.

Although the hormonal ingredients are similar or equivalent, they may or may not function identically for any single given woman. This applies to the Premarin derivatives as well.

And so, as much as it may seem that these hormones are safer than the Premarin family of drugs, there is no solid evidence to prove this.

It is important to note that some of these drugs have been approved by the FDA because data collected from trials has proven their effectiveness in relieving menopausal symptoms and reducing the risk of osteoporosis.

However there have been no long-term studies like the WHI performed to assess their safety profile.

In the absence of comparable data, the risks are generally assumed to be similar to CEEs and other forms of estrogens.

Moreover, regardless of the source and type of hormones, it is always recommended that estrogens, with or without progestins, should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment.

Brisdelle as an alternative?

Brisdelle approved.
Brisdelle becomes first non-hormonal replacement therapy drug for the treatment of menopausal symptoms in NA.

As mentioned there is only one FDA-approved non-hormonal HRT. In early June of 2013 the U.S. Food and Drug Administration approved the drug “Brisdelle” (paroxetine – Paxil) manufactured by Noven Pharmaceuticals for the treatment of hot flashes due to menopause.
Brisdelle contains the selective serotonin reuptake inhibitor paroxetine mesylate, making it unique from all other FDA-approved treatment for hot flashes which contain the hormones estrogen or progestin. 

Brisdelle poses none of the risks associated with estrogens or estrogen combination therapies.

However it is a selective serotonin reuptake inhibitor (SSRIs) (antidepressant), which has been shown to increase the risk of suicidal thoughts and behavior in pediatric and young adult patients when used to treat major depressive disorder and other psychiatric disorders. See http://www.rxlist.com/brisdelle-drug.htm.

Whether this risk applies to menopausal women is unclear.

As with any drugs and medications there are inherent risks, the nature of which can range from mild to life-threatening. Always consult your doctor to help decide what is best for your particular situation.

Please visit our Alternatives to Premarin page to learn more about options other than drugs containing conjugated equine estrogens. See http://www.horsefund.org/pmu-alternatives-to-cee-drugs.php.

Comparing the cost of FDA-approved HRT

Pharmaceutical Industry: A prescription for money.
Pharmaceutical Industry: A prescription for making huge profits.

As an aside and for interest’s sake here is a list of some of the more common HRTs available and the costs associated with them. The list is by no means comprehensive and includes the tablet form of the drug only.

This information was taken from http://www.goodrx.com and pertains only to the U.S. Prices are per tablet and converted to monthly costs based on a 30-day interval.

For consistency, all of the costs were taken from Walgreen’s with the discount coupons applied. Obviously prices will vary depending on store, geographic location, available coupons, etc. and are only intended to provide a relative comparison using the same base source.

Prempro / Premphase CEEs / Progestin No Expired $5.77 $173
Brisdelle SSRI (paroxetine) No Apr 2029 $5.74 $172
Duavee CEEs / SERM (bazedoxifene) No Oct 2016 $4.77 $143
Premarin CEEs No Expired $4.33 $130
Angeliq Estrogen / Progestin No Oct 2017 $4.31 $129
Cenestin CEEs — plant based No Expired $3.97 $119
Prefest Estradiol / Progestin No March 2020 $3.37 $112
Enjuvia CEEs — plant based No Feb 2021 $2.75 $83
Femtrace Estradiol acetate No Dec 2021 $2.68 $80
Activella Estradiol / Progestin Yes Expired $2.06 $78
Menest CEEs — plant based No Expired $1.77 $53
Femhrt Estrogen / Progestin Yes Expired $1.32 $40
Ogen Estrogen (estrone) Yes Expired $0.28 $8
Estrace Estradiol Yes Expired $0.13 $4

Clearly, Pfizer is laughing all the way to the bank at the expense of women and horses alike.


© The Horse Fund

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The other side of the hormone therapy controversy

Most experts say women should take hormones for only a few years after menopause, and only if their symptoms are severe. Now, in a new book, biologist Winnifred Cutler claims that HT is safe for long-term use and highly beneficial — as long as you do it right. Here, she makes her case.

By Stephanie Young

A New Argument for Hormones

Could doctors have been wrong about hormones — again? In 2002, the authors of a large-scale study, the Women’s Health Initiative, set off panicky newspaper headlines by proclaiming that the risks incurred by women taking hormones outweighed the potential benefits. Many women and their doctors concluded that it was best to discontinue hormone therapy or use it only in the short term if menopausal symptoms were unbearable.

[The WHI study did set off headlines, and with good reason. Whether or not they caused panic, women did sit up and take notice, causing the market for Premarin and Prempro to spiral downward and the closing of many “pee farms.” Numerous lawsuits were also filed, which Wyeth reportedly fended off, settled with closed judgments, or lost. The battles goes on. ~Editor, TH]

But that conclusion was wrong, insists biologist Winnifred Cutler, PhD. Like the study’s many other critics, she points out that the average age at enrollment in the WHI was 63; the study undersampled the younger women (ages 50 to 54), who, later analyses showed, may actually experience a lower risk of heart disease while on hormone therapy. Cutler also notes that the women in the study who still had their uteruses (some had undergone hysterectomy) given only one drug, Prempro, which combines conjugated equine estrogen (supplied by pregnant horses) and progestin (synthetic progesterone); other drugs, composed of different ingredients, may not present such risks.

[Premarin and Prempro are made with conjugated equine estrogen. There are many alternatives that do not carry the same risks according to many experts, with the added plus that thousands of horses need not be abused or slaughtered to manufacture them. Notice the phrase “other drugs . . . . may not present such risks. (emphasis added) ~Editor, TH]

In addition to her examination of the WHI, Cutler spent five years analyzing data from many other U.S. and international studies to parse out what’s really going on with HT. The controversial result, Hormones and Your Health: The Smart Woman’s Guide to Hormonal and Alternative Therapies for Menopause, out next month, argues that hormone therapy is not only good for you, it helps turn back the aging clock. Not every expert in her field agrees, but here she presents her reasoning.

Q. Tell us why you think hormones are so great.
A. Some are not! But combined with a healthy lifestyle, appropriately prescribed HT regimens can lengthen the span of your life, enhance your sexuality, build better bones, improve your posture, preserve your memory, help you sleep more soundly, sharpen your thinking and ability to learn, even out your moods, lower your odds of developing urinary tract infections, reduce your risk of colorectal cancer, and promote a healthier cardiovascular system.

Let’s consider heart health. Among the 120,000 women followed for 20 years in the Nurses’ Health Study, hormone users were 40 percent less likely to develop heart disease or to die. Or look at diabetes. A 2003 report from the HERS trial, conducted at 20 U.S. clinical centers, found that hormone users had a significantly lower risk of developing type 2 diabetes. What’s more, hormones can make you look younger. Estradiol or estriol [variants of human estrogen] in a face cream significantly reduced crow’s feet in six months in a University of Vienna study and similar research conducted at Yale University School of Medicine.

With demonstrated benefits like these, why take HT for only a few years after menopause? That advice does not withstand my scrutiny.

Q. One argument for limiting hormone therapy to short-term use is that it has been shown to increase the risk of breast cancer, right?
A. It is dangerously wrong to throw all hormone regimens into the same category when discussing breast cancer. For instance, the multicenter Women’s Contraceptive and Reproductive Experience study, which started in 2002, examined breast cancer risk in relation to specific hormone regimens, and reported that taking continuous-combined HT — the Prempro type — for five or more years was the only routine that increased the risk of developing breast cancer. The danger increased the longer women used that form of drug. No other hormone regimen showed increased risk.

[Note the use of Prempro “type” [drugs] was the only routine that increased the risk of developing breast cancer. ~Editor, TH]

In addition, some European studies support the safety of hormones that are chemically identical to human estradiol and progesterone in regimens where estradiol is taken every day and progesterone is added during the last half of the month.

Knowledge Over Fear

Q. But the Women’s Health Initiative study did find a connection between Prempro use and elevated breast cancer risk. In fact, the study was halted prematurely partly because it was feared that the women taking the hormones were increasing their risk.
A. Yes, but even in the WHI study, the risk of breast cancer on an individual basis was low. In the WHI, of the 8,506 women taking Prempro, 166 cases of invasive breast cancer occurred; in the 8,102 assigned to placebo, 124 cases were detected, that is, 1.95 percent versus 1.53 percent, or a difference of 0.42 percent. So 99 percent of women will not be at increased risk of breast cancer regardless of which hormones they take.

[Risk of breast cancer taking Prempro “low?” ~Editor, TH]

And remarkably, most studies show that postmenopausal women who develop breast cancer when they are on hormones are less likely to die from it than postmenopausal women who have breast cancer and are not on hormone therapy. This points to the complexity of the relationship between hormones and breast health.

Q. Cardiovascular risks were another reason the WHI was halted prematurely. Can you shed some light on this?
A. WHI researchers tested the drug too late in the lives of women who already showed evidence of heart disease in the form of atherosclerotic plaques in their arteries. However, if you’re in the early stages of atherogenesis, some studies say that HT regimens may prevent or inhibit up to 70 percent of the progression of this disease.

Q. If the science shows that hormones are so beneficial, why do many doctors still seem leery of them? Why are we being told to take them in the lowest dose for the shortest possible time?
A. Many doctors understood the early termination of the WHI to mean categorically that the risks of taking combination hormone therapy outweighed the benefits. Since then it has become clear that is simply not the case. In a sense, the WHI was helpful in disclosing that the drug it tested, Prempro, was more harmful than helpful to a group of older women who started hormone therapy years after experiencing menopause. However, this major study’s findings about that one drug were then erroneously and unfortunately applied across the board to all types of hormones and all women.

[WHI study disclosing Prempro was more harmful than helpful, helpful? ~Editor, TH]

Suggesting that the best course of action for HT is the “lowest dose for the shortest time” is a standard medical practice guideline. [Editor’s note: This is the position of the Food and Drug Administration, which regulates pharmaceuticals, as well as of the North American Menopause Society.] That advice is designed to serve the needs of the medical establishment rather than the individual. It’s a recommendation that is generated to protect doctors from the damaging costs of malpractice lawsuits. A doctor is relatively invulnerable to a lawsuit if his or her treatment follows practice guidelines, because they are the accepted standard of care.

Q. Given that other experts disagree, why should we believe your analysis of the various studies?
A. Well, I do favor skepticism! But my credentials are on the public record. This is my eighth book on women’s health; I have also published two respected medical textbooks on hormones. As a scientist, I have the training to analyze scientific findings. My agenda is not influenced by malpractice fears, nor have I ever received consultant fees, funding, or stipends from any pharmaceutical company. Also, I am not employed by a university whose funding may depend on the goodwill of a pharmaceutical company.

Q. So what would you recommend to women who are interested in hormone therapy?
A. Bearing in mind that new studies keep refining our understanding and that women taking hormones tend to live longer, I favor daily use of an estrogen, 17 beta-estradiol, generally through a nonoral route [like a patch, suppository cream, or lozenge]. This would be coupled, for about 12 days in a row each month, with progesterone, not synthetic progestins. The progesterone should be taken in a non-cream form — via a pill that is swallowed or absorbed under the tongue.

Q. What if you or your doctor panicked about the news coming from the WHI, and you stopped taking hormones? Can you get back on them and still reap some of these benefits?
A. That is something you should decide with your doctor; I always encourage a respectful patient-physician partnership. You would need some careful monitoring during the first few months to make sure markers associated with increased cardiovascular risk (such as triglyceride and C-reactive protein levels in your blood) or breast cancer (increased density) do not occur. Hormone therapy cannot erase any existing damage, such as blood vessel blockage due to plaque from atherosclerosis.

In your time off from hormones, if your health status has changed — you’ve become overweight, for example — some or all types of hormone therapy may no longer be appropriate. Being overweight is not good for your health, and in conjunction with hormones it may slightly raise your risk of stroke. But certainly, if you can follow a good hormonal regimen, then other body systems, such as your bones, will benefit.

Q. Hormones may be anti-agers, but they’re not a panacea. How else do you advise women to stay healthy?
A. Hormones work best in conjunction with a healthy lifestyle: regular exercise; a diet rich in low-fat dairy, fruits, vegetables, and whole grains; and stress management. I also favor a rich spiritual life. Replace fear of hormones with knowledge — and enjoy the best years of your life!

Originally published in MORE magazine, April 2009.

© Copyright 2009 Meredith Corporation. All Rights Reserved. 20092009