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Tiny Matters
'A cage of ovulating females': The development and testing of the oral birth control pill
The 1940s were a pivotal time for the world. In the United States, as men went to fight in World War II, women became essential additions to the US workforce. And when the war ended, many of those women wanted to continue working. But having more children than they wanted or could care for was a huge barrier to making that a reality. When the oral birth control pill became available in 1960, it was a massive deal because it gave women control over when and if they wanted to have children. Today the pill is widely accepted, comes in a number of formulations, and is considered so safe that now you can buy it over the counter. But setting the groundwork for what we have available today took time, and experimentation. The history of the pill was also shaped by racism in an era where discrimination was not just state-sanctioned, but backed by many scientific institutions. In this episode of Tiny Matters, we cover the science and development of the oral birth control pill and, importantly, the lack of ethics in its testing, particularly in the trials that began in Puerto Rico in 1955.
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The 1940s were a pivotal time for the world. In the United States, as men went to fight in World War II, women became essential additions to the US workforce, and when the war ended, many of those women wanted to continue working. But having more children than they wanted or could care for was a huge barrier to making that a reality, and at the time contraception options were less than ideal.
Speaker 2:Condoms leaked, diaphragms didn't fit and you had to go to a doctor to get them fit If you miscalculated your cycle. Rhythm method was very unreliable and the desire for like a simple, straightforward, reliable form of birth control had been around for a very long time and people saw they began to see hormones as a potential source of birth control.
Speaker 1:When the oral birth control pill became available in 1960, it was a huge deal. I feel like I can't overstate how big of a deal it was. It gave women control over when and if they wanted to have children. We now know that women who have access to the pill are more likely to pursue higher education and have increased employment options. Access also decreases their chances of living in poverty later in life. But back in 1960, the approval of the pill faced substantial backlash for being a quote lifestyle drug.
Speaker 3:Today, the pill is far more widely accepted, comes in a number of formulations and is considered so safe that you can now buy it over the counter. But setting the groundwork for what we have available today took time and experimentation. The history of the pill was also shaped by racism, in an era where discrimination was not just state-sanctioned but backed by many scientific institutions. Welcome to Tiny Matters, a science podcast about the little things that have a big impact on our society, past and present. I'm Sam Jones and I'm joined by my co-host, deboki Chakravarti.
Speaker 1:Today on the show, sam and I will be talking about the oral birth control pill, the science behind how it works, how it was developed and by who, and the dark history of its testing that's not often discussed. We'll start with the name you've likely heard at some point Margaret Sanger. It was.
Speaker 2:Margaret Sanger, who was the intrepid birth control advocate.
Speaker 1:That's Suzanne Janod, a retired FDA historian, who you heard at the top of the episode. In her time at the FDA, suzanne often focused on the history of women's health, including the first oral contraceptive. Focused on the history of women's health, including the first oral contraceptive. Margaret Sanger was an obstetrical nurse in New York City and saw horrific abortions done on desperate women. She became a champion for birth control and female autonomy and opened the US's first birth control clinic in 1916, which became the first Planned Parenthood.
Speaker 3:Sanger did a lot of good in her time, but this is Tiny Matters and you know we always provide context, so here's some that is very important. Sanger was a known eugenicist. Eugenics is the racist, ableist, unscientific theory that humanity can be improved through selective breeding. The theory of eugenics has helped fuel atrocities like the Holocaust. Some of the people Sanger worked alongside during her life include infamous Klansman and Nazi sympathizer Lothrop Stoddard, author of the book the Rising Tide of Color Against White World Supremacy. In 1926, sanger spoke to the women's branch of the Ku Klux Klan at a rally in New Jersey to generate support for birth control, and she endorsed the Supreme Court's 1927 decision in Buck v Bell, which upheld a law that people deemed quote mentally defective could be sterilized without their consent for the protection and health of the state. This led to more than 70,000 people being forcibly sterilized in the 1900s.
Speaker 1:It's not always clear how much Singer was motivated by her own racist beliefs. So while we're going to talk about how much Singer was motivated by her own racist beliefs, so while we're going to talk about how important she was in the development of the pill, we do want to add the caveat that the good she did also ran parallel to a legacy that includes things like the KKK and forced sterilization. In 1917, singer gave a lecture in Boston that a young woman named Catherine McCormick attended. Mccormick was a young widow and suffragist, and she and Singer grew close, fighting for a woman's right to vote. Mccormick also championed Singer's fight for women's reproductive freedom, but it wasn't until the early 1950s, when both women were in their 70s, that McCormick finally had access to her long-deceased husband's wealth, and that was a huge turning point for the development of the oral contraceptive pill.
Speaker 2:When McCormick decided that she wanted to devote the rest of her fortune to working on this pill, Sanger suggested that she look to Pincus.
Speaker 1:Gregory Pincus was a biologist and world-renowned, although somewhat controversial, expert in mammalian reproduction.
Speaker 3:Sanger approached 47-year-old Pincus and somewhat controversial expert in mammalian reproduction, sanger, approached 47-year-old Pincus and explained that women were in dire need of an inexpensive, effective, straightforward method of contraception ideally a pill. Pincus was intrigued by the early 1900s. There had been a number of advances in biology that had led to various sex hormones being used for medical as well as non-medical needs, like cosmetic creams and fattening up livestock. The hormone Pincus soon fixated on was progesterone.
Speaker 3:Progesterone is a hormone secreted by the corpus luteum, a temporary gland in the uterus that develops when an egg is released from an ovary. During the first 10 weeks of pregnancy that progesterone stops ovulation and it helps build the uterine lining so that the fetus can grow. So Pincus' idea was that providing external progesterone would stop ovulation, something he'd already seen in rabbits. In January 1952, pincus filed a report to Planned Parenthood stating that In an experiment using rabbits, 10 mg doses of progesterone given orally suppressed ovulation in 90% of the animals. It was time, at least according to Pincus, to test the pill on women, but he needed a physician who could provide legitimacy both for the patients receiving the drug and for the companies supplying it. That physician was John Rock, an obstetrician-gynecologist and clinical professor of obstetrics at Harvard Medical School.
Speaker 1:Rock and Pincus began testing the pill on small groups of women to evaluate its safety and physical effects. Some of those women were patients at Worcester State Hospital, a Massachusetts state mental hospital. And you might be thinking how was this possible? Could these patients sign off on being part of this trial? Well, they didn't, and they didn't need to. At the time, there was no law in place that required informed consent, meaning scientists didn't need to tell the patients exactly what they were being exposed to or what the side effects may be. Informed consent didn't come about until 1962, following a disaster related to another drug called thalidomide.
Speaker 1:We've talked about thalidomide before in episode 48, our episode about phenylephrine and how the FDA drug approval process works. Thalidomide, which went by the brand name Kevidon, was a drug used in the late 1950s into the early 60s to treat pregnancy nausea and help with sleep. While it was used in a number of countries around the world, a medical officer at the FDA named Francis Oldham Kelsey saw a number of red flags and asked for more data, halting its approval in the US. Data soon began to surface in Europe showing that thalidomide caused severe birth defects, particularly limb defects. In the US, kelsey is still known today as the hero that saved the country from tragedy.
Speaker 3:In response to the thalidomide disaster in 1962, the Kefauver-Harris amendments were passed, establishing new FDA requirements for the safety and effectiveness of drugs. It formalized manufacturing practices, required the reporting of adverse events during trials and ensured that new drugs were not just safe but effective, because before then you only had to show that a drug was safe which I know sounds ridiculous now, but that was the deal back then. And, very importantly, these amendments required informed consent from human study subjects. But again, none of that happened until 1962. We're still in the 50s, specifically 1954, and Pincus has set eyes on the island of Puerto Rico as the next testing ground for the pill. Unlike many parts of the United States at the time, including Massachusetts where the researchers worked, there were no laws in Puerto Rico making it illegal to provide medication that could prevent pregnancy, so it would be much easier to set up a trial there.
Speaker 4:Before I got interested in this I wrote a book on. It was a history of the development of health services in Puerto Rico. In the course of doing that research with another colleague, we found a lot of references to contraception, to women's services, to birth control, to experimentation in general to experimentation in general.
Speaker 1:That's Annette Ramirez de Arellano, a retired researcher and professor whose career's focus has been public health planning and policy.
Speaker 4:And I thought, gee, this is a whole new topic that seems to have had a major impact in terms of what contraceptives were eventually accepted. But it turned out that Puerto Rico had served as a testing ground for a lot of other contraceptives as well.
Speaker 1:One of those was sterilization, which became the main option on the island for preventing pregnancy. So Annette and a colleague received a grant to look into the contraceptive trials in Puerto Rico and gain access to the Margaret Singer archives, the Pincus archives, the Harvard archives and others.
Speaker 4:And I was based in Puerto Rico at the time, so I also could interview a lot of the people who were participants in this, both as designers of the program but also as subjects of the program.
Speaker 1:As Annette began looking back at what was happening leading up to the Puerto Rico pill trials that began in 1955, she told us that public health concerns couldn't be separated from what was going on with the economy.
Speaker 4:Puerto Rico was, you know, in the 40s and certainly in the 50s was in the throes of a major push towards industrialization, and more and more people were leaving their agricultural communities, going to the cities and finding jobs in the new industries.
Speaker 1:Many of the companies that came to Puerto Rico were in the garment industry. Annette told us that Puerto Rico became known as the bra capital of the world because so many companies that produced undergarments for women were there, and those companies largely employed women. So all of a sudden, women were major wage earners in their families.
Speaker 4:It also meant that women were interacting with each other on a daily basis. In a work situation where people discuss each other's problems, certainly anything related to health and reproduction would have been a subject that would interest these particular women and because they were working, they wanted to control their fertility. You know most of them already had the number of children they wanted. So this was just a major concern, both individually for these women and for the island as a whole, because the feeling of the time was that Puerto Rico had a lot of potential in terms of industry, but in order for the island to progress, you had to control the population. But in order for the island to progress, you had to control the population because otherwise too much money was going just to supporting schools and health care and there wasn't enough to support major developments that would bring people up from poverty.
Speaker 3:Based on your research. Why was Puerto Rico chosen and what demographic or demographics of women were involved?
Speaker 4:Well, puerto Rico had a family planning association, so there was always some movement going on there and the people who were involved with research contraceptions knew about what was going on in terms of organizations like Planned Parenthood in the States and the equivalent in Puerto Rico, which is the Puerto Rico Family Planning Association. So there was an interaction among professionals you know, mostly physicians who were involved in these organizations. At the same time, because Puerto Rico was trying to get out of poverty and the government was very interested in industrialization as opposed to agriculture, there was a real change in terms of the economic basis of the society. So it was just a combination of factors. And then when the scientists in the United States began developing the pill you know Gregory Pincus, but John Rock was also instrumental in getting this set up they were looking for what they called a cage of ovulating females.
Speaker 1:These are cited as the words of rich widow Catherine McCormick, who was frustrated by how hard it was to recruit quote a cage of ovulating females to test the new oral contraceptive.
Speaker 3:At this point. The pill tested consisted of high amounts of progesterone along with estrogen. Estrogen was added to prevent menstrual bleeding and to block the development of fluid-filled sacs in the ovaries, called follicles that contain immature eggs.
Speaker 4:The word experimental was not used. The word was new and that was seen as something exciting that they were going to be part of this sort of discovery that was going to make women's lives easier and better and give them a greater sense of control over the reproduction. The local people and the health professionals on the island who were also interested in this and who felt that this could be a game changer for Puerto Rican development in general Desperation was a huge motivator for many of the women who enrolled I did interview several women who had been part of the experiments and I asked them you know what?
Speaker 4:had you been told? And they said you know, I didn't care that this was high risk. I had six kids and I didn't want number seven and eight because there was no way I could bring them up adequately and I was willing to do whatever it took. So these were women who were fairly desperate.
Speaker 3:A large percentage of the women who enrolled in the trial ended up dropping out due to side effects, some of which were severe and they were often dismissed as just being psychological.
Speaker 2:The problems with the pill came early because the dose was too large. That's Suzanne Janot again. Had they done these studies and listened to at least one of the female researchers who was on the ground in Puerto Rico, she was already reporting. Almost 25% of the women had severe side effects that mimicked pregnancy, which is one reason why the male researchers aren't taking it quite as seriously. Literally, within the first, I would say six months, certainly within a year, the dose had already been cut in half with no loss of efficacy.
Speaker 4:There were a number of people who dropped out of the experiments because they had side effects and whatever and they just didn't want to go through with it and they weren't followed up. So that was another flaw. You know that those who dropped out because they kept saying, oh well, there are others sort of that are in the queue, willing to participate, to fill in whatever is needed. And of course the data was in aggregated. But it's not the same thing to have somebody who's followed up for three years as opposed to three people that are followed up for one year. It's not the same thing scientifically or in any other way, but once the data were aggregated, these nuances were lost, unfortunately.
Speaker 3:In addition to gender bias, the women faced in the hands of male doctors and researchers. The pill trials also came at a time when side effects were often a given. With the drugs on the market, Antibiotics including penicillin, tetracycline and streptomycin all had danger of side effects. Streptomycin could cause hearing loss, Tetracycline could negatively impact bone growth and for some people penicillin could cause a deadly allergic reaction. Today we have many, many more options to keep people safe, but back then the options were limited and the side effects were just kind of a risk you had to be willing to take.
Speaker 1:Even so, no one followed up with the women who reported side effects in the Puerto Rico trials, and three women actually died, yet no autopsies were done, so it's impossible to prove that their deaths were due to the pill. The trials continued in Puerto Rico into the 1960s, but in 1957, the pill was submitted for FDA approval, although not as a contraceptive.
Speaker 2:The company applied for it for amenorrhea, dysmenorrhea, menstrual irregularities in general, and they applied for it for endometriosis. And so that was what the agency was looking at, and only that. It had not been sought approval for it as an oral contraceptive, and in that case a lot of FDA's data came from just asking physicians did it work? A lot of it was relying on the ethical scruples of the manufacturers and the doctors, so sometimes just saying, oh, this worked for my patient. I gave it to eight of them.
Speaker 1:They seem to be doing fine by 1959, more than 500,000 women in the United States were taking the drug called Inovid for menstrual disorders, but it's unclear how many were also prescribed at off-label as a contraceptive.
Speaker 2:Once a drug is approved, the physician can prescribe it for any purpose they like. So we have absolutely no idea how many prescriptions for the oral contraceptive were written for women who had taken it either for menstrual irregularities or had gotten their doctors to let them try it for contraception.
Speaker 3:On May 9, 1960, inovid was approved by the FDA as the first oral contraceptive. Although it received some pushback, suzanne told us that in the end the benefits of the pill far outweighed the risks of childbirth, and that was used to defend the approval decision.
Speaker 2:The pill was safe precisely because it was so effective. Childbirth is very risky and because the pill was 100% effective when taken every day. That's what made it so safe, because pregnancy was unsafe.
Speaker 3:Having access to a pill that was nearly 100% effective at preventing pregnancy was life-changing for many women. In 1961, though, reports began to appear that in rare cases the pill could cause blood clotting. Since then, scientists have learned that the slightly increased risk of blood clots in women taking versions of the pill containing estrogen and progesterone is due to changes in coagulation and fibrinolysis, or the breakdown of blood clots. Over the years, the estrogen dose in combined oral contraceptives has been reduced significantly, and that has greatly decreased blood clotting risk. There are also progesterone-only options Today. In the United States, the pill is seen as very safe, so safe that in July 2023, an oral birth control pill called Opil was approved for non-prescription use by the FDA. Its only active ingredient is progestin, a synthetic hormone that mimics progesterone. It was available online and in stores starting in March of last year.
Speaker 1:So the pill has come a long, long way and it's changed the lives of so many women around the world for the better. But it's important to remember that its development didn't check all of the ethical boxes. Legal, sure, but legal and ethical are not always the same thing. When Annette began her research, she told us she was shocked by some of what she uncovered, but even more so by how few people knew about it.
Speaker 4:I remember when my work came out. You know it was big news to a lot of people. Even people who had been in the health field for 20, 30 years didn't know this had gone on and didn't know the intricacies of it. But it's amazing because there is such an abundance of material documenting everything. It's almost like a caricature of colonization at its worst in terms of not giving people adequate information and using them for purposes that are maybe not in add up in terms of FDA approval later on, and all that and certainly marketing it commercially as well. That doesn't mean that they weren't interested in the issue of birth control they were and giving women more options. They were interested in that, but it wasn't their major concern.
Speaker 3:I don't know who's going first.
Speaker 1:Yeah, I can actually go, because mine is like kind of half related, because I just saw this headline. I was like, oh right, this is, I think, kind of related to birth control pills at times, and it's about grapefruit. If you've been on birth controls, you might have seen this like that, some pills, if you're taking birth control, you can't have grapefruit without worrying about whether or not it's interacting with your pill. And there are other drugs as well where there's a warning that like, yeah, you shouldn't have grapefruit. I think they're like antibiotics. There's a cancer drug. Yeah, there are drugs out there that have this warning on there and you might see it and you might be like, how come? Like, why grapefruit in particular?
Speaker 1:So scientists have been looking into it and so the compound that's responsible for this warning are called furanocamorins, and apparently if you have a lot of it, it interferes with liver enzymes, and so that is one of the reasons why you have to be on the lookout with certain drugs.
Speaker 1:So scientists wanted to look and see if they could help identify the enzyme responsible for making these compounds, and I thought this was interesting.
Speaker 1:What they did is they crossed grapefruits with mandarins, because mandarins are low in the compound, and so they created these crosses that if you look at the different like fruits that are made as a result of this, you can find the ones that have that still have furinicumarins and then see if you can find the genes associated with that.
Speaker 1:And so, based on that, they were able to identify an enzyme called 2-oxoglutarate-dependent-dioxygenase or 2-OGD, and it turns out mandarins do have this gene, but it's mutated so the enzyme doesn't work. So I just thought this was really neat overall. I thought just like the design itself was really cool, like this idea of crossing the fruits to be able to find the gene responsible For some reason, like I think about this like with animals and like it makes sense there, and I just don't think of it with fruits, even though it's probably where all of our knowledge of how to create different crosses to find genes was kind of stemming from. But I just thought it was really neat and also maybe it'll help us with being able to eat grapefruit if you're on a medication that before like was denying you grapefruit.
Speaker 3:Right, yeah, that's really interesting. Okay, so they identified a gene that codes for an enzyme that's really important for the activity of these furanukumaris. Yeah, I think with like making them, okay, that's really cool and it is true, it's like going back to like Mendelian genetics or something where you're like crossing peas. Right yeah, that's great. So I am going to tell you about something that has absolutely nothing to do with this episode which is that researchers have made a battery using fungi.
Speaker 3:So researchers in Switzerland have developed a functioning fungal battery using 3D printing methods and combining two types of fungi. So they used soft biobased materials, namely cellulose, and also simple sugars were added to the battery cells, because fungi love eating sugar. And in terms of electrical conduction, what they did was they had on the anode side of the battery there was this yeast fungus whose metabolism, I guess, releases electrons, and then on the cathode side there was this white rot fungus, which sounds lovely, and that fungus produces an enzyme that allows the electrons to be captured and then conducted out of the cell, which I thought was really interesting. And so, yeah, I mean that's the battery. It's totally biodegradable. So you have sugar and cellulose, which is essentially just a really complex sugar.
Speaker 3:The fungi will eat both of them, and so now the researchers want to make a fungal battery that's more powerful and have it last longer, which probably means looking for different species of fungi, so probably doing like similar things, but to a greater degree, I guess. So at this point, you know the cells. They don't produce a lot of electricity, they produce enough to power. They gave an example of a temperature sensor for a few days, which I think is still like pretty cool. And I guess temperature sensors they're used a lot in agriculture and in different types of environmental research, so even that could be kind of useful, but if it only lasts for a few days, like there's only so much you can do. So essentially they figured out on a really small scale how to do it and now they're trying to scale up. So I just thought that was really fun.
Speaker 1:Yeah, that's really neat, that's so cool. I always forget that conducting a battery in some ways is kind of simple. Yeah, I mean, it makes you think of like a potato battery or something Right. Yeah, but in my head I'm just like no battery sounds hard, that sounds complicated, but I mean it is like. I'm not saying that like what they did was easy, but it's like it takes clever thinking to also make something that kind of just like logically ends up sort of making sense when you describe it like that.
Speaker 3:Yeah, no, I thought it was very cool and I think these efforts to create a biodegradable version of something like a battery, where we have just excessive amounts of waste with traditional batteries, that kind of stuff I think is really really interesting Because, even though this is super small scale, you can imagine that they'll find ways of scaling it up and that could be really beneficial For sure of scaling it up and that could be really beneficial For sure.
Speaker 1:Thanks for tuning in to this week's episode of Tiny Matters, a podcast brought to you by the American Chemical Society and produced by Multitude. This week's script was written by Sam, who is also our exec producer, and was edited by me and by Michael David. It was fact-checked by Michelle Boucher. The Tiny Matters theme and episode sound design is by Michael Simonelli and the Charts and Leisure team.
Speaker 3:Thanks so much to Annette Ramirez de Arellano and Suzanne Janod for joining us. A reminder that we have a newsletter Sign up for updates on new Tiny Matters episodes, video clips from interviews, maybe a sneak peek at upcoming episodes and other science content that we really think you'll like. We'll see, you'll like. We'll see you next time.
