The origin story of estrogen therapy, with Alison Li

[00:00:00] This episode is sponsored by Tell Every Amazing Lady, an organization that does amazing work by elevating women's health through ovarian cancer resources and beyond. This is Overlooked, and I'm Golda Arthur. We talk about women's history once a year, every year. But women's medical history? Well, that's even more overlooked. And it doesn't even go that far back.

[00:00:28] Take, for example, the history of hormone replacement therapy. If you're like me, you're popping a little estrogen pill every day. But have you ever wondered, where did it come from? What is the origin story of estrogen therapy? Well, the story starts with a biochemist named James Bertram Collup at McGill University in Montreal.

[00:00:52] We're going to go back to Montreal, Canada in the 1930s. And to take us there is Alison Li. I'm a historian of science and medicine. And my special interest is the history of hormones. And in that history of hormones, James Bertram Collup is an important figure.

[00:01:16] He was already quite well known by that time because he participated in the discovery of two very important hormones. He was one of the co-discoverers of insulin in 1921 to 22. Frederick Banting and Charles Best, along with another scientist, John McLeod, discovered insulin. J.B. Collup worked with them and extracted and purified the insulin. This was one of the biggest breakthroughs in medical history.

[00:01:46] And of course, you will know that insulin is something that has saved the lives of hundreds of millions of people with diabetes since. So by the late 20s and early 1930s, he was already well known in this field.

[00:02:03] But during the 1920s and 30s, there was something called a gold rush in hormone research because there were so many groups around the world who were really invested in trying to isolate more and more hormones. Because it was clear that these were molecules of great influence and that could have important medical uses.

[00:02:30] What Collup did was he began working on trying to find a source of hormone that came from the ovaries that had been discovered by Edgar Allen and Edward Doisey in 1923 already. In 1923, a pair of scientists, Edgar Allen and Edward Doisey, made a breakthrough discovery. They extracted and isolated a hormone that would later be called estrogen.

[00:02:54] But the problem is they isolated it from painstaking work using the ovaries of hogs. Yes, that's right. Hogs. And of course, that works very well if you're looking at small quantities for the lab. But what happens if you want to produce this on a mass scale to make viable medicine for large numbers of people?

[00:03:18] So all these researchers were beginning to explore different sources of materials from which they could collect estrogens. And you have to understand that this required mountains of material.

[00:03:31] So, for example, in the case of insulin, to get eight ounces of insulin, the pharmaceutical companies that were working on this, Eli Lilly in particular, had to coordinate with meatpackers and teach the meatpackers, slaughterhouse workers, to collect the pancreas of cows and also later pigs. And it would take a mountain of pancreas.

[00:03:58] Can you even picture what a mountain of pancreas looks like? About two tons to make eight ounces of insulin. And similarly, with the ovarian hormones, the question was, how are they going to produce enough that it could be used to treat human beings for various uses? So one of the solutions that Collip came up with was to explore placentas.

[00:04:26] Placentas. Stay with me here. I know this is getting weird. And yes, the placenta is an organ that develops in the uterus during pregnancy. After the baby's developed, the placenta is also delivered or removed from the body. So yes, that is what J.B. Collip was exploring as a source of estrogen.

[00:04:45] And so what he did was he coordinated with gynecologists and obstetricians at a couple of different maternity hospitals in Montreal and collected all the placentas that would have been discarded. And they would arrive at his lab in Montreal in these big milk churns and I'm sure it looked pretty gruesome.

[00:05:06] But anyways, he would take these mountains of placenta and try to develop and isolate a product using different solvents to pull out the key ingredient. What he got in the 1930s was something that he called eminine, which was really significant because it was an estrogen that worked orally.

[00:05:30] That meant that people could take this medication by mouth with a pill rather than having to inject it. And so he worked on this product, Eminent, and he was approached by the director of this small pharmaceutical company in Montreal that was called Ayerst, McKenna & Harrison. Ayerst, McKenna & Harrison was a relatively young pharmaceutical company founded in Montreal in 1925.

[00:05:59] This small company really had a very tiny business making cod liver oil, but they worked with Colup during this period and they invested heavily in developing this project and manufacturing it successfully. I think the founders at the time decided that they really wanted to invest in scientific research to augment what they were able to produce.

[00:06:27] And they really put a lot of money. They hired staff to work on the science and the quality control of this. And because of the success of this product, they were able to expand into the U.S. They were eventually bought out by Wyeth. Okay, a little context here. Wyeth was another pharmaceutical company based in the U.S. The two companies merged in the early 40s to become Wyeth Ayerst Laboratories.

[00:06:55] And then that in turn was bought by Pfizer. In 2009. And you know what Pfizer is. But back to Ayerst, McKenna & Harrison. In the 1930s, it was still a small company, but ambitious. And in working with J.B. Colup to manufacture Eminen, the first orally active estrogen, they became pretty successful. They did so well that they ended up setting up a plant in New York as well.

[00:07:22] And they had to get special permits to export placentas from Canada into the U.S. to manufacture this product. Researchers around the world were starting to explore other materials, biological materials, from which you could get estrogens. One of them seemed to be the urine of pregnancy. So, of course, the urine of pregnant women would have been relatively difficult to gather.

[00:07:47] But what Ayerst and Colup hit upon was the idea of using pregnant mare urine. The estrogen extracted from the urine of pregnant mares turned out to be similar to human estrogen. And pregnant mare urine became Premarin. So, they could coordinate with ranchers, farmers, who bred horses and collect the urine from the mares during the last stage of pregnancy.

[00:08:17] This turned out to be a really rich source of estrogen. So, this new product, Premarin, was made available in Canada in 1941 and in the U.S. in 1943. Believe it or not, that is just the tip of the iceberg in this episode. I talked to Allison Lee not just about the origin story of Premarin and estrogen therapy,

[00:08:46] but how it was marketed to women by pharmaceutical companies. By understanding the origin story of estrogen therapy, you'll see menopause in a very different light. All of that is coming up in a minute. This episode is sponsored by Tell Every Amazing Lady.

[00:09:12] This nonprofit has a beautiful origin story, which we covered here on Overlooked in our very first season. Tell Every Amazing Lady elevates women's health through ovarian cancer resources and beyond. If you or someone you love has had an ovarian cancer diagnosis, or if you have a question about women's health, everything from your first visit to the OBGYN to menopause,

[00:09:39] Tell Every Amazing Lady is an amazing resource in itself and will help you navigate those questions. I know that when I went into surgical menopause or when I was dealing with trying to understand ovarian cancer, I found them incredibly supportive. We're so proud to have them as our sponsor in this season. Learn more about their work at telleveryamazinglady.org.

[00:10:10] Allison, thank you so much for joining me on Overlooked. Thank you for doing this interview. Thank you. It's great to be here. That is an insane story. We've not even been talking for like, that was your first answer to my first question. And I'm already like, I'm in. Let's talk about hormones. I mean, from hogs to placentas to horses. I think this is the draw in a way like science is wild. So let's start at the ground floor. Okay. So what is Premarin?

[00:10:39] Premarin is a family of drug products that are conjugated estrogens. They're a group of several different forms of estrogen that are derived ultimately from pregnant mare urine. And that's where the name comes from, Premarin. Right. I think that might have been the first thing that I learned about it that shocked me. But it was not the last. And we'll get to that. We'll get to the pregnant mare urine bit.

[00:11:08] Before we move on to the way Premarin kind of evolved and was developed, characterize for me J.B. Collip himself. What was he like? What kind of guy was he? He was someone who was quiet and shy on the outside, but actually extremely vigorous. He was someone who really was a very important figure in Canadian medical research. And he was well respected.

[00:11:33] And during this time, he created this really vibrant research environment at McGill. So he was known for this very restless personality. In this period in McGill, he would be known for walking around, testing one sample here and having a still running in a different room. And he would be on the phone with his stockbroker as well, you know, making calls. All the time he was doing this, he would have these large hand-rolled cigarettes that he'd be smoking.

[00:12:03] And the drug that he developed, Eminen, how did it work? What were its benefits to patients taking it? Well, initially, they thought of it as something that would be useful for people with menstrual disorders. So what the estrogen does is it does bring on menstruation. And so they thought it could be useful for that. They weren't all that sure of the range of problems it could address.

[00:12:28] But beginning in the 1930s, pharmaceutical companies, including one in the Netherlands called Organon, began to start large clinical trials of older women. Because they wanted to see if estrogen could be a treatment for the symptoms that were associated with menopause, including things like high blood pressure and heart rate, headaches and depression.

[00:12:58] And so they really began to push this particular angle. During the 1940s and 50s, probably most gynecologists would have considered menopause a normal phase of life. They didn't consider it something that most women needed treatment for. So I saw one gynecologist who said, you know, most women do fine.

[00:13:23] And maybe 35 to 40 percent have troubling symptoms. And these products can be of help to them for a few months or a year or two. Over time, as this hormone product became available, menopause began to be medicalized. It became reconceptualized as a disease, like something that was caused by a hormone deficiency.

[00:13:53] You can see the pharmaceutical companies really jumping into this in the 1960s and early 70s. So Airst began to promote premen not only to medical professionals, which was the way that prescription drugs were traditionally advertised, but they began to reach out to potential customers as well.

[00:14:14] So they did things like fund an information center that provided information on menopause to TV and radio and magazines and newspapers. And they also funded a gynecologist named Robert Wilson and his wife, who is a nurse, Thelma Wilson. And the two Wilsons published a very famous book in the 1960s called Feminine Forever.

[00:14:39] And this was a popular book that argued that all menopausal women, except possibly those with breast cancer, should have estrogen and progestins for the rest of their lives. Airst really began to see the potential for marketing this, not only for a few months, but really potentially for the rest of a woman's life.

[00:15:06] Trying to promote this image of post-menopausal women as no longer fully women. And so it was partly about youthfulness, but it was also about being difficult. So you see that Premarin was also advertised to husbands saying, you know, don't you want your happy wife back rather than this sort of crotchety person who meets you at the door when you come home from work? Something along that line.

[00:15:33] And so between 1963 and 1973, as they really promoted this idea of being feminine forever, the sales of this product almost quadrupled. And it became one of the top five prescription drugs in the United States. And then come the 70s. So things start to change a little bit in the 70s, right? There was a bit of a turn and there was some research linking estrogen with endometrial and breast cancer. Tell me a little bit about that.

[00:16:01] So the other really important avenue was the contraceptive pill. In 1960, of course, this was made available. This was primarily progesterone, but sometimes with some estrogen connected with it. And there was concern that if the dose was too high and if someone was taking it for too long, that it could increase the risk of those cancers. Mm-hmm. Mm-hmm.

[00:16:26] The other interesting bit about this was that in 1976, the U.S. Food and Drug Administration said that manufacturers had to include a package warning of the risks. I was shocked when I read this because, to be honest, I forgot that there was a time when medication came without a package insert. So what impact did this have? And presumably the pharmaceutical company must have tried to fight this in some way, right? Yeah.

[00:16:53] As far as I know, it did definitely cause some decline in sales. But the companies actually then sort of moved in a different direction. In the 1980s, they really began a new kind of approach, which was sort of the living smart era.

[00:17:10] Because at the same time that those warnings came out, new studies were starting to suggest that estrogen therapy might actually have some protective advantages against preventing osteoporosis. And then also later by the 90s, some protective advantages in reducing heart disease and maybe even Alzheimer's.

[00:17:31] And so the companies then sort of turned the story around by arguing that this was part of what a healthy woman should be doing as part of her healthy lifestyle.

[00:17:44] And they began working with public relations companies and also advocacy groups and started these campaigns where they talked about the protective value that estrogens would have. And they began to focus these campaigns not only to women who were undergoing menopause, but to people who were as young as 35.

[00:18:13] The idea was that menopause begins silently. And if you could start early, you could prevent yourself from having osteoporosis later in life or maybe heart disease. There must be something you can do. Dr. Grant prescribed Premarin. But you eat right, exercise, do you even take calcium? He said it isn't always enough. I'm glad I found out while I still have a chance to help prevent osteoporosis. Premarin, conjugated estrogen tablets.

[00:18:41] At this time, in most countries, pharmaceutical firms are not allowed to advertise directly to the consumers. Here in Canada, pharmaceutical firms are not allowed to say what disease a drug is supposed to treat. They can just suggest that you talk to your doctor about it. Whereas in the U.S., starting in 1997, the Food and Drug Administration really eased the restrictions and allowed pharmaceutical firms to advertise to consumers.

[00:19:11] Night sweats? They go on, then off, then on. Hot flashes? Then something else comes off. If menopausal symptoms are disrupting your life, Premarin is approved to treat symptoms and prevent bone loss. With these restraints that were lifted, the ads for drug sales just boomed to something like $10 billion a year. I'm soaked. I'm dry. I'm cold. I'm hot. I'm not. My doctor prescribed Premarin. Premarin is not right for every woman. Discuss its use regularly with your doctor.

[00:19:38] In the U.S., the requirement is that the advertising has to be accurate and has to state all the medical risks. But they are also allowed to actually say what the conditions the product is used for. What every woman should know about estrogen. A seminar for women.

[00:20:06] Companies became ever more sophisticated in trying to set up medical seminars. My goal this morning is to help you understand the things our bodies go through during menopause, to recognize the symptoms of menopause, and to understand its management and treatment. Campaigns at workplaces and so forth that involve things like giving women a chance to win sessions with nutritionists and personal trainers and giving them free exercise videos.

[00:20:36] Look, we can't stop the aging process, but we sure can make the most of every stage of our lives. And that begins with taking care of our health. I look at estrogen as long-term health protection. And sort of promoting estrogen as something that you should start taking quite early on, even in perimenopause or even earlier, as a preventative. What did the doctor say?

[00:21:03] Well, he thinks I could develop osteoporosis. Osteoporosis? He said I'm at risk. And since I already have symptoms of menopause, now's the time to do something about it. You know, I went into a bit of a rabbit hole when I was preparing for this interview with you. And the 1990s were an especially fruitful time for these ads. If your patients are at risk for osteoporosis, estrogen replacement therapy is an important option to consider

[00:21:28] because 50% of the bone mass women lose occurs in the first seven years after menopause begins. I think in the 2000s, Premarin was still the single best-selling drug in the U.S. Where are we now with Premarin? As you said, Premarin was so successful at the turn of the century. That all changed dramatically around 2002 with the release of information from the Women's Health Initiative,

[00:21:56] which was this large-scale clinical study that was conducted by the National Institutes of Health. And it was a clinical trial of 160,000 women that many different issues related to women's health. And among the things that they examined was the effect of long-term use of estrogen and also progesterone in preventing illnesses.

[00:22:19] And what they had to do was they had to actually halt the studies because it became apparent that there were risks, increased risks for heart attacks and blood clots and breast cancer gained a huge amount of media attention. And it really caused a large reduction in the number of hormone therapies that were prescribed for women in menopause.

[00:22:47] And so there was a significant decline. I think the sales were cut in about half. So this created a lot of fear among women who were taking menopause hormone therapy. But in subsequent years, as follow-ups have been done and further studies have been done, what is clear is that the study was concerned with long-term use of these hormones.

[00:23:12] And the question that was being asked was whether or not these had a preventative effect in preventing heart disease and breast cancer. These studies called that into a doubt. These studies did not say anything about whether these hormones would be useful on the short term for women who actually had menopausal symptoms. And so what has happened now is I think we're starting to get some balance back.

[00:23:40] The Menopause Society and the College of Obstetricians and Gynecologists and the Endocrine Society all recommend it for short-term treatment of menopausal symptoms. If women have symptoms that are really difficult for them, hormone therapy might be the right thing for them in consultation with their doctors, of course. And that brings us up to the current moment.

[00:24:04] And this is where my skin in the game is particularly relevant because I went into surgical menopause in December of 23 and had a really rough 2024. And then in December of 2024, after a year of dealing with borderline debilitating symptoms, I started taking a drug that contains Premarin. And I'd heard about Premarin before from another interview and I just put it to the back of my mind.

[00:24:32] But now suddenly I pulled out the little piece of paper that comes with the drug and I started to read it. And I was like, Premarin? OK. And immediately, of course, my mind went to horses. But that's just me. But it has been fascinating for me to take a moment and just look into this wild history. I think if you're not sort of seeped in science, this does come across as a wild history of one particular drug.

[00:24:57] And it is incredibly fascinating because not just of the development of the drug, but the evolution of how we have thought about how to treat women, how to regard menopause. And I'm curious if you think that we've medicalized menopause now. I think especially early in the 20th century, there was this excitement about discovering different hormones and understanding them as useful to treat deficiency diseases.

[00:25:27] When the body was not able to produce enough of that hormone, you could use a pharmaceutical product to correct that. And the classic example would be insulin for diabetes, right? Where it's actually saving lives every single day. Menopause began to be interpreted in that model as well. Though I think it is something that is now increasingly resisted.

[00:25:53] I think we're getting many good sources of information from very reputable gynecologists and scientists who understand that menopause is a natural stage of life and that some women can sail through it with no symptoms at all. And some people could benefit from medical help.

[00:26:28] The last question that I want to ask you is the question I ask all my guests on this show. What is the most overlooked aspect of the topic that we've been talking about today, Premarin? And where do you think that inequality is felt most deeply? The real challenge for us as individuals is to really try to make sense of all the information that we're getting from so many different sources.

[00:26:55] So when we get prescribed something from our doctors, you know, how many of us take time to actually read all the small print? And yet at the same time, once we're diagnosed with something, we may jump into the online world of information and have to sort of swim through so much disinformation as well to get through to what is reliable.

[00:27:20] And so I think that's the real challenge for us now is to try to figure out what the good sources and reliable sources of information are and how to make those key decisions for our own lives and our own health. Yeah. Yeah. This has been a truly fascinating conversation, Alison. Thank you so much for joining me on Overlooked. You're welcome. We're building a community around women's health so that no one is overlooked.

[00:27:50] If you'd like to be part of it, hit the follow button on this podcast wherever you're listening to it. Overlooked is written and created by me, Golda Arthur. Jessica Martinez-Lios is the show's producer. Overlooked is an independent show and we would love your support. You can support us on Patreon or you can show us some love by writing us a review and sharing this episode with someone. Stay up to date with the show by signing up for the newsletter or following us on Instagram and LinkedIn.

[00:28:19] We read every review and email. So write to us. Hello at overlookedpod.com. Thanks for listening. This episode is sponsored by Tell Every Amazing Lady. Tell Every Amazing Lady elevates women's health through ovarian cancer resources and beyond. If you or someone you love has had an ovarian cancer diagnosis or if you have a question

[00:28:49] about women's health, Tell Every Amazing Lady will help you navigate those questions. Learn more about their work at telleveryamazinglady.org. Thank you.