The big freeze, p.26
The Big Freeze, page 26
Long story short: Ultimately, a man named Giulio Pacelli, an Italian aristocrat and nephew of Pope Pius XII, convinced Serono’s board of directors to make enough Pergonal to run a clinical trial. Doing so would require obtaining thousands of gallons of urine from menopausal women, which, in a speech to the board, Prince Pacelli assured wouldn’t be a problem, explaining that his uncle, Pope Pius, was prepared to ask nuns living in convents to collect urine daily for a sacred cause. The board hurried to commit money and resources. (As it happened, the Vatican owned 25 percent of Serono.) Tanker trucks began hauling the urine of hundreds of nuns from nearby retirement homes to Serono’s headquarters in Rome.[*2] Then, in 1962, a woman treated with Pergonal in Tel Aviv gave birth to a baby girl, the first child born from the treatment. “Within two years, another twenty pregnancies had been achieved with Pergonal,” the Quartz piece explains, “and by the mid-1980s, demand had grown so much that Serono needed 30,000 liters of urine a day to produce sufficient quantities of the drug.”
The company began to synthesize the hormones in labs, and the resulting treatment, Gonal-f, was first approved in 1995. The active ingredient in Pergonal equivalents used as fertility medications today, such as Menopur, is still obtained from the urine of postmenopausal women. Also, the modern method of producing FSH for fertility treatment comes from—equally bizarre, perhaps—cells derived from Chinese hamsters, whose ovaries are injected with the DNA for FSH, which tricks them into producing human FSH.[*3] Millions of cells are cultured in huge vats, enabling more FSH to be produced than can practically be derived from urine.
So, one of the most important advancements in infertility treatment was the ability to put the ovaries into overdrive. That’s not a technical term, of course, but it’s an easy way to conceptualize the act of stimulating a woman’s ovaries to produce a bounty of eggs by way of medications she takes, which are made in labs and/or through genetic recombination. Brief recap: During egg freezing, a woman’s ovaries are artificially prodded with hormone medications to prepare her body for treatment and to increase the probability that a plethora of viable eggs will be extracted from her ovaries. The cocktail of medicines involves drugs to stimulate the ovaries, drugs to prevent premature ovulation, and finally the trigger shot—usually hCG, the pregnancy hormone we discussed earlier—which causes the follicles to rupture, allowing the doctor to collect the eggs during the retrieval.[*4]
It’s remarkable, really, how scientists discovered and how doctors use synthetic hormones to manipulate the reproductive system. Ovaries in overdrive can yield an arguably invaluable return—a baby—but the powerful rewards go hand in hand with alarming risks, which aren’t talked about nearly as much as they ought to be. Lauren’s story made that clear, and her saga took me down an unsettling new side road of research.
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Much of the concern around egg freezing stems from these self-injected hormones. The medical risks associated with egg freezing fall into two categories: short-term knowns and longer-term unknowns. Hyperstimulation is the common short-term risk most egg freezers are warned about. Other short-term knowns include pelvic infection and bladder and bowel damage. Less serious but still unpleasant side effects of the hormonal fluctuations caused by fertility drugs are similar to PMS symptoms and include headaches, insomnia, mood swings, breast tenderness, and bloating. Some women have a pretty awful time during the several days of hormone shots—their abdomens feel like bricks; the emotional volatility is overwhelming—while others experience mild discomfort. It’s uncommon to experience issues during the egg retrieval itself; the chances of pelvic infection, significant bleeding, or serious anesthesia complications are quite low.
OHSS, one of the most common and potentially most severe complications, occurs when a woman’s ovaries receive more stimulation than her body can handle, and then the final trigger shot acts like a flame igniting a kerosene-soaked woodpile. OHSS typically hits within a week of the patient taking the trigger shot and undergoing the egg retrieval, as it did with Lauren. The condition is diagnosed by a physical exam, an ultrasound, and/or a blood test measuring hormone levels. OHSS symptoms can be anywhere from mild or moderate (nausea, bloating, diarrhea) to severe (extreme abdominal pain, persistent vomiting, blood clots, shortness of breath, and rapid weight gain of more than ten pounds in a few days), with acute cases of OHSS causing abnormal enlargement of the ovaries and sometimes ovarian cysts and torsion. As many as one in three women experience mild OHSS during IVF or egg freezing; fewer than 2 percent will develop a severe case. Women who freeze their eggs in their twenties or early thirties are at more risk for OHSS because larger egg supplies can cause hyperstimulation; the more eggs a woman has, the higher the chance that the medication she takes before her egg retrieval will stimulate a higher-than-desired number of ovarian follicles. For the same reason, women with PCOS are also more at risk for developing OHSS.
Determining how much medication an egg freezing patient needs to safely stimulate her ovaries isn’t an exact science. Monitoring the patient’s hormone levels throughout the days of self-injected shots allows the doctor to make necessary dose adjustments. The initial assessments and blood work help the doctor ascertain a baseline level of hormones and determine a treatment regime, as well as assess for any risk of OHSS at the outset while considering existing risk factors.[*5] Individualizing treatment regimens is typically the best way to prevent OHSS. If a doctor does this properly, severe OHSS shouldn’t develop. But if a doctor prescribes an overly aggressive medication protocol or insists on pressing forward with stimulation in the face of mild to moderate OHSS, that’s when things can get dangerous.[*6]
For all the colorful stories behind the development of several fertility drugs, troubling unknowns surround a few of the major ones. Take Lupron, a medication commonly prescribed during fertility treatment to prevent premature ovulation during the ovarian stimulation process.[*7] Except it’s not FDA-approved for that use; its use during egg freezing and IVF is considered off-label. Lupron is approved to treat prostate cancer; it’s also approved for and used to reduce the size of uterine fibroids, treat endometriosis symptoms, and block early puberty. For all the good it does, the drug has a dark side, too. Most drugs do, but Lupron, the use of which among women has been linked with bone density loss, severe joint and muscle pain, and memory loss, is particularly harrowing. The FDA has received thousands of adverse event reports for Lupron products in the past decade[*8] and people have petitioned Congress for further investigation into the drug’s side effects; there’s even a website called Lupron Victims Hub.
Why are Lupron and other off-label drugs permitted to be used in ways they were not intended to be used? Because while the FDA has the authority to punish drug companies for marketing a drug for a use that it has not approved, regulating the practice of medicine is outside its jurisdiction; the agency doesn’t oversee where and how off-label drugs are being used. Fertility doctors, like doctors in other fields of medicine, can only prescribe FDA-approved medications—but the purpose for prescribing isn’t tracked. So, unless a case clearly violates ethical guidelines and safety regulations, physicians can prescribe drugs like Lupron for off-label uses without fear of consequences. I remembered something Remy’s doctor said to her: “A lot of these drugs are not FDA-approved for what we do. The pharmaceutical companies don’t spend the money getting things approved for fertility. So a lot of times there’s a black box warning on the meds…but don’t worry about it.”
What I took away from my deep dive into hormone injections was this: Fertility medications are both powerful and somewhat frightening, and OHSS is clear evidence that bodies can respond badly when pumped too full of hormones. When undergoing fertility treatment, everyone’s baseline hormone cocktail is different. Every body is different, and a person’s reaction to the drugs falls across a wide spectrum. Reproductive endocrinologists have to find the sweet spot for their egg freezing patients as they try to successfully stimulate the ovaries to produce eggs. Not too many, but not too few. Dial up, dial down, get the most eggs possible without endangering a woman’s life or ovaries. Holy shit, this is complicated, I texted a friend one day while I was absorbed in my research. Avoiding overstimulating the ovaries and causing conditions such as OHSS was clearly a complex skill that involved an artful interpretation of the science. Egg freezing’s price tag, it now occurred to me, seemed a bit more justified. And the stakes? Much higher than I’d realized.
“There Are No Known Risks” and Other Half-Truths
I turned to the second category of egg freezing’s medical risks: longer-term unknowns. While the short-term effects of injecting lots of hormones to stimulate the release of multiple eggs at once are known, I discovered that there’s almost no information on potential long-term harm, because research is so sparse. Hormone therapy typically raises a patient’s estrogen levels, and estrogen can abet the growth of, specifically, ovarian and breast cancers. Studies examining the relationship between fertility drugs and the risk of hormone-sensitive cancers show mixed results. For the most part, they conclude that the medications used during fertility treatment don’t appear to increase a woman’s risk of cancer. That’s the good news. But as I dug into the limited data, I learned that the validity of these findings may be affected by confounding variables such as small subject numbers, as well as specific characteristics of the populations being studied: women who have been diagnosed with infertility versus women—typically younger—who have not. I also happened upon dark stories, many deep in Reddit threads, and read studies that do indicate that the high doses of hormones used during fertility treatments may increase a woman’s risk of cancer. What I found as I tumbled down rabbit holes on the internet was some of the most worrisome stuff I had encountered since first learning about egg freezing.
Around this time I listened to an episode on Reveal, an investigative reporting podcast, on egg donors. It was a short but shocking story about a young woman, Jessica Wing, who by age twenty-five had donated her eggs three times and who died from colon cancer when she was thirty-one. Jessica was an undergraduate at Stanford when she saw an ad recruiting students to donate their eggs. She called her mother, a doctor, to ask her about it. Her mother had only one question: Is it safe? Jessica said she was told it was, and decided to do it, using the money to help pay for her college education. The eggs she donated resulted in a pregnancy. According to Jessica’s mother, this made the fertility clinic deem Jessica a “proven” donor, and the clinic offered Jessica twice as much money to donate again. Through Jessica’s egg donations, five healthy children were born to three formerly childless families. Four years after her third donation, Jessica learned she had metastatic colon cancer. Doctors also found tumors in her ovaries. There was no history of any early cancer or colon cancer in her family, and twenty-nine is a young age for such a diagnosis, especially in a health-conscious woman like Jessica. To this day, her mother wonders if the extensive hormone treatments her daughter had undergone as an egg donor might have stimulated the growth of the cancer.
The reason Jessica’s story stuck with me—besides its objectively tragic nature—was because I knew how similar egg donation is to egg freezing. Egg donation, a multimillion-dollar and poorly regulated industry, has been around a lot longer than egg freezing. The processes of donating eggs and freezing one’s own eggs are exactly the same up until the last step: An egg donor is compensated for her eggs, which are used for research or to help another person or couple have a baby, while an egg freezer’s eggs go into a cryotank and remain hers. But egg freezers undergo the same hormone treatments as egg donors do. And like egg donors, egg freezers often cycle more than once if not enough viable eggs are obtained on a first attempt.[*9]
You would think that after more than forty years, we’d know more about long-term effects for women who use ART. But in fact large gaps in our knowledge persist. Part of the problem is a dearth of follow-up data, especially in our fragmented American health system, which lacks national medical records. While organ registries exist for many kinds of organ donation in the United States, there is no egg donor registry. Because of the anonymity of egg donors, there are no other databases from which to cull numbers. The rationale is that not having a registry protects egg donors’ privacy. But not monitoring an egg donor’s health after the fact means not knowing anything about the potential long-term risks of egg donation—which, in turn, means knowing little about the long-term risks of egg freezing. Egg banks have rules about women donating more than a few times, but because the government doesn’t maintain an egg donor registry, there isn’t any centralized tracking of who has donated eggs and where and when.[*10] It’s easy for a young woman to donate eggs at different clinics and be a repeat donor as many times as she wants; once she walks out of a facility’s door, she’s lost to medical history.
Another difficulty arises when subsets of patients are treated alike even when they’re not. Most of the research conducted on egg retrievals has focused on women undergoing IVF—the first half of which, you’ll recall, involves ovarian stimulation, as do egg donation and egg freezing. And so, similar to how much of the limited data that exists on egg freezing success rates relies partially on data extrapolated from IVF (discussed in chapter 8), the health risks to women who freeze or donate their eggs have been extrapolated from research on IVF patients—but the populations are different. Most women undergo IVF because they are struggling with infertility, which can be a symptom of other health problems. Egg donors, by contrast, are chosen precisely because they have zero health problems (or at least, very few and not serious ones) and are not infertile. They’re almost always younger, unlike most women undergoing IVF, who tend to be a good deal older. Egg donors are also typically given higher amounts of hormones to stimulate the production of eggs, and many undergo the procedure several times. So, OHSS rates among egg donors differ from those of IVF patients, too. The point is, using IVF patients to draw conclusions about ovarian stimulation’s risks to egg donors and egg freezers is about as helpful as using kindergartners to draw conclusions about car seats for infants.
I read several cases about people who donated eggs and then developed cancer while relatively young. None of these egg donors had an apparent genetic risk for the disease. (Of course, cancer also develops in young people who haven’t donated their eggs.)[*11] In most of the reports, women hadn’t been given any information about the long-term risks of egg donation—in part because no such information exists. More studies on egg donors in the United States, which a national egg donor registry would help to facilitate, would give us more to rely on than anecdotal evidence of women who served as egg donors and later developed cancer, struggled with infertility, or experienced other health issues. Without such long-term follow-up data, it’s impossible to gather information to estimate the prevalence of cancer in egg donors or draw conclusions about the possibility of an increased risk compared to the general population. In a statement to Reveal, the CDC said, “Better understanding the long-term outcomes of fertility treatments for donors…is a priority within the field.” Is it, though? The CDC collects data on IVF. It or the Department of Health and Human Services could also collect data on egg donors that would help shed light on the potential link between hormone treatments and increased risk of cancer and other health issues in patients donating or freezing eggs.
The pessimistic take is that there isn’t any incentive for anyone to study the health risks to egg donors because the system as it stands now seems like a win-win-win: Fertility clinics get business, egg donors are well compensated, and infertile couples have a better chance to conceive a baby. An embryologist[*12] I spoke with who manages the lab of a well-known fertility clinic on the East Coast told me: “In the early days of IVF, everybody talked about the concerns of the drugs putting women at risk for certain cancers. Now, it’s just so swept under the rug. And before the question even comes out of people’s mouths, REIs [reproductive endocrinologists] say, ‘There’s absolutely no clinical evidence to suggest it,’ ” the embryologist continued, referring to the potential long-term health risks associated with fertility medications. “The question isn’t even allowed in the room anymore.”
The bottom line is this: The absence of information on egg donors has led to inadequate attention to potential health risks in egg freezers. And both groups aren’t appropriately counseled about the nature of that absence of information. Which brings us to the issue of informed consent. In the United States, the informed consent agreements that fertility clinics give to egg donors include minimal information on long-term risks. And the information they do provide is based on studies of infertile women rather than egg donors—and doesn’t include the crucial fact that this is a different group.
There are no known risks. That’s how most fertility clinics characterize the possible association between fertility drugs and health concerns, particularly cancers.[*13] The problem is with the word “known”: Can we really say there aren’t any long-term adverse effects associated with hyperstimulating ovaries unless such effects have been systematically researched? A 2020 New York Times article titled “What We Don’t Know About I.V.F.” summed up the issue well with a quote from an NYU School of Medicine professor: “We have no idea what this level of hormonal stimulation at this time in a woman’s life might be doing to her body.” All women who take fertility medications and undergo ovarian stimulation, especially more than once, should be told that such risks amount to a big fat question mark. But they’re not. Instead, patients are told there is no evidence proving harm, when in fact there remains considerable uncertainty about the true extent and severity of ovarian stimulation’s potential long-term health risks—especially to egg donors and egg freezers.
