Premarin is Extracted from Horse Urine, and that's Okay

Here's everything about the practice

Conjugated equine estrogens (CEE), also known as Premarin, named because it comes from pregnant mares urine, was the industry standard for menopause hormone therapy for years until all estrogens took a hit with the Women’s Health Initiative (WHI). Once the dust settled, the recommended first-line therapy for symptoms of menopause became transdermal estradiol due to the lower risk of blood clots. However, there has been a renewed interest in Premarin due to the fact that it is associated with a lower long-term risk of breast cancer (when used without a progestin), and it is available in combination with bazedoxifene as another option for menopause hormone therapy without progesterone or a progestin (read more about that option here). 

Along with the renewed interest are renewed questions about the process used to collect conjugated equine estrogens and an increase in the propagation of myths. So, I thought it was time to set the record straight. 

The Origin of Premarin

A hundred or so years ago, in the early days of hormone research and clinical use, estrogens were extracted from animal ovaries, human placenta, and urine from pregnant women. As you might imagine, extracting the hormone was cumbersome, and the cost of getting enough raw material and manufacturing was slow and expensive. It takes A LOT of hog ovaries or human urine to make a small amount of hormone. Urine was appealing because it’s a waste product, but getting pregnant women to collect enough (as in jugs of the stuff) wasn’t easy. Also, they had to be close to the end of their pregnancy for enough of the estrogens to spill into their urine.

The first oral estrogens, Emmenin and Progynon, were extracted from human urine. Before that, it was capsules of ground-up cow ovaries or injections. As an aside, the first time I heard of Eminem, the rapper, I thought of Emmenin, the oral estrogen. 

In the late 1930s, the pharmaceutical company Ayerst successfully extracted estrogens from pregnant mares’ urine. Obviously, it was easier to get a stable supply of urine from pregnant horses than from pregnant people, and the conjugated estrogens in horse urine proved to be more potent than those in human urine. In addition, the estrogens in horse urine were very stable when taken orally, which is not the case with all hormones. By 1941, Premarin was approved in Canada and later in the United States in 1943.

Along the way, Ayerst merged with Wyeth, so Premarin became a Wyeth product. And then Wyeth was acquired by Pfizer, so now it’s a Pfizer product. 

Initially, the farms where the urine was collected were in the province of Quebec and several U.S. states. Ayerst wanted to build a plant to handle extracting the estrogens and apparently wanted it to be where land was cheap so that it would be more cost-effective. In addition, according to Norm Luba, the executive director of the North American Equine Ranching Information Council (NAERIC), the urine must be kept cold when transported. The Canadian prairies fit the bill, so the plant to extract the estrogens from the urine was built in Brandon, Manitoba (my home province).

The Care of the Horses and the Collection of Urine

Mr. Luba told me the ranchers involved in equine farming are second and third-generation horse breeders. The primary purpose of their ranches is breeding. Collecting urine from the pregnant mares is an add-on business. I also confirmed this from an article in the Brandon Sun. 

Urine collection only happens during a specific point in the mares’ pregnancy, in the mid to early late part of gestation, when there is enough estrogen in the urine, and it is present in the right ratio for Premarin. As hormone production drops significantly in the last six weeks of a horse’s gestation, collection stops weeks before they foal. 

The timing of cold weather in the Canadian prairies matches the best time to collect urine. When it is cold, the horses are moved into heated barns. For those who don’t know, Manitoba can reach -40 C (which is -40 F) in the winter, and being outdoors in -40 degree weather sucks. The duration of urine collection varies based on analysis of the estrogens in the urine. The maximum collection duration is about three months, typically the end of November to the end of February, but in some seasons, it may be as short as 6-8 weeks. 

In the late winter, when urine collection stops, the horses may still be in barns due to the extremely cold weather. In spring, when foaling happens, the horses are out in the pasture. They are running around living life like horses live. During summer, which is breeding season, a group of mares are in a pasture with one stallion, and they breed naturally. The foal stays with its mother during this time (when she is pregnant again), and weaning is not allowed before four months. 

Each horse has a stall wide enough to turn around and lie down during urine collection season. The collection device is a flexible pouch-like apparatus attached by pulleys to the ceiling that is positioned under the horse’s vulva (see image below). The horse can lie down while wearing the collection system. Horse behavior inside the stall during the winter while hooked up to the collection system has been evaluated and found to be normal. The horses are also regularly inspected to ensure the device isn't chafing. 

The horses are unhooked and moved into paddocks to exercise and socialize for at least an hour every two weeks, but some ranchers may take the horses outside more, and some have indoor arenas, which may be an option if the weather is very bad. The collection equipment must also be cleaned, which can only happen when the horse isn’t in the stall. The ranchers are required to log each time a horse goes out. Ultimately, the “required turnout frequency depends on the individual horse.” I suppose when it’s -40, and the wind is howling, some horses might be less inclined to go outside. 

When spring comes, and the horses are ready to foal, the cycle of living outside starts again. 

There are government regulations, as well as rules and inspections from Pfizer. The equine farming industry has also invited veterinarians and animal welfare experts to inspect farms. The equine industry has actively researched feeding, water supply, and stabling of horses, and this contributes to the general body of knowledge about how to best care for a horse. Vets visit three times a year, and the horses must all be vaccinated, have the right hoof care and feed, have computerized medical records, and have no contact with poultry. With privately owned horses, only 48% see a vet once or more a year, and there is no requirement for hoof care, medical care, feed quality, or exercise. 

Do All of the Conjugated Equine Estrogens Come from Canada?

Yes. It’s a Canadian product.

There is a rumor that some of the urine comes from equine farms in China, but there is no truth to that rumor, so it is misinformation. All estrogen extracted from urine that becomes Premarin comes from the plant in Brandon, Canada. Christina Antoniou from Pfizer Canada told me via email, “Pfizer’s equine ranching operations are limited to Canada” and “Pfizer does not operate any equine facilities in China.”

This image is on the Pfizer website. 

How many Horses are Involved?

In 2002, there were around 37,000 mares on 422 ranches. After the publication of the WHI, that number dropped significantly. By 2009, there were 5,500 mares at 49 farms in Manitoba, 13 in Saskatchewan, and two in North Dakota. According to Pfizer, there are now about 11 ranches that supply the plant in Brandon, Canada; according to NAERIC, there are about 1,300 mares. 

What Happens to the Foals?

There is a rumor that all the foals, except for a few that are kept to become mares, go to slaughter. This is untrue. Again, misinformation.

As mentioned previously, these ranchers breed horses for the reasons people breed horses. They collect pregnant mares’ urine to make extra money. Breeding horses for feedlots, and eventual slaughter is not any kind of business model, as the money for a horse sold to a feedlot is very low, maybe about $30 per foal. However, a quality foal can bring $ 3,000, so the economics clearly support breeding quality foals to sell for the reasons people buy horses, for pleasure riding, trail riding, competitive exhibitions, etc. Foals from these breeders are apparently quite desirable. Some foals are also kept for the purpose of ranching and improving the stock. Mr. Luba from NAERIC told me the number of foals going to feedlots and eventual slaughter is “minuscule” and that these are foals with obvious, severe malformations. 

It’s Not Vegan

If you are someone who won’t eat any product that is an animal or even an animal byproduct, for example, honey, then that’s your choice, and I can see how Premarin might not be for you. But for anyone who eats meat, eggs, or dairy, the care of the horses involved in producing equine estrogens seems far superior to other animal husbandry. For a maximum of three months a year, the worst months weather-wise, the pregnant horses urinate into a collection system that still allows them to move in their stall.

About 90% of these horses get pregnant once a year; for feral horses, this seems to be about 50%, although some of this lower rate among feral horses may be partly due to food scarcity and the general hardships of being a wild horse. Wild horses apparently reproduce a lot, and a herd can double in 4-5 years, which can harm the environment. (I went down a darting-wild-horses-with-contraceptives rabbit hole, which was interesting but slightly off-topic). 

Why Isn’t There a Generic?

It’s complicated. The TLDR is Premarin has so many estrogens, and no one knows which ones are important or if it is the sum of its parts, so replicating it in a lab is almost impossible. 

But if you want the full details (if you don’t want the full details, just skip down to the summary)…

Conjugated equine estrogens are many different estrogens. I’ve heard anywhere from 17 to 50. I don’t know how much of the 50 end of the spectrum is an exaggeration because Pfizer (and before them, Wyeth) was almost certainly invested in molecular complexity because that meant reproducing it in a lab from a plant source would be more challenging. 

In 1972, the Food and Drug Administration decided that estrone sulfate and equilin sulfate, two of the estrogens in Premarin, were mostly responsible for how the drug worked. This opened the door for generic companies to join in on the Premarin action. Two of them, Duramed and Barr, started the application process and were then shut down when the FDA later decided the complexity of Premarin meant that it wasn’t just two estrogens. 

There was a back and forth between the FDA upping the number of bioactive estrogens in Premarin, the generic companies trying to meet those needs, and Wyeth presenting research about additional bioactive estrogens to show the FDA that solving the Premarin puzzle (meaning what’s actually in it) was an impossible task. By 1997, the FDA made it clear that to get approved as a generic for Premarin, the product would have to be biologically equivalent to Premarin, with all its molecular complexity.

The end result of all of this is that there are semi-synthetic estrogens (meaning made from plant material, which is how ALL non-Premarin estrogen is produced) that are almost-Premarin versions, Cenestin and Enjuvia. Cenestin has nine estrogens found in Premarin, and Enjuvia has ten, making them similar but not identical. These medications did not get FDA approval as generics for Premarin; they were approved as stand-alone estrogens for menopause. Cenestin had a controlled release, which was supposed to produce more stable levels in an attempt to reduce side effects like breast tenderness.

While Cenestin or Enjuvia were fine for hot flashes when we are talking about the potential impact of Premarin on breast cancer, we don’t know which of the many estrogens produces that effect or if it is all of them together. As a result, we can’t say the outcomes with Cenestin or Enjuvia would be the same as Premarin, just like we can’t say estradiol will be the same. Nevertheless, both Cenestin and Enjuvia were later withdrawn from the market in the United States, almost certainly because Premarin sales plummeted post-WHI. 

Summary

Premarin is an important drug for many people. It’s also not the right medication, medically speaking, for many people. But claims about how the horses are mistreated seem to be just that–claims, not facts. It is ranching, and it’s well-regulated. 

After doing all this research and reading a lot of literature on the care of horses, I was left wondering how many personally owned horses receive the same level of care as the pregnant mares on these 11 ranches. Some might, but I suspect a lot don’t. So if the idea of Premarin bothers you, then you should probably complain first about all the horses owned by the non-ranching public that don’t get enough exercise for extended periods and don’t get the right hoof care or veterinarian care. 

If the idea of a farmed product bothers you, well, you get to make choices that work for you, and that’s okay. I respect that.  

Urine collection happens for a maximum of three months a year, during the coldest part of the winter when it’s preferable for the horses to be indoors. The ranching is run by ranchers who are breeding these horses for sale and who collect urine from horses as a way to enhance income from a by-product. If you were thinking about Premarin or Duavee and were turned off because of what you’d previously heard, hopefully, this eases your mind.

References

McDonnell DA, Freeman SM, Cymbaluk NF, et al. Behavior of stabled horses provided continuous, intermittent access to drinking water. Am J Vet Res 1999;60:1451-1456

Management of mares used in the pregnant mare urine (PMU) collection industry. American Veterinary Medical Association

Veterinary, equine community dispel accusations against the pregnant mare urine industry https://www.avma.org/javma-news/2002-04-15/veterinary-equine-community-dispel-accusations-against-pregnant-mare-urine#:~:text=The%20urine%20is%20collected%20over,that%20are%20weaned%20through%20September.

Arnason R. Business as usual for PMU industry: Pfizer. The Western Producer Oct, 2009. https://www.producer.com/livestock/business-as-usual-for-pmu-industry-pfizer/

Veterinary, equine community dispel accusations against the pregnant mare urine industry. American Veterinarian Medical Association. https://www.avma.org/javma-news/2002-04-15/veterinary-equine-community-dispel-accusations-against-pregnant-mare-urine#:~:text=The%20urine%20is%20collected%20over,that%20are%20weaned%20through%20September.

Cenestin Package Insert https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/020992s034lbl.pdf

Drew May, Mare urine demand decrease hits producers. Brandon Sun, accessed October 20. 2023 https://www.brandonsun.com/local/2019/04/10/mare-urine-demand-decrease-hits-producers