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Sunday, April 9, 2017

The XX Factor

When gender differences are ignored in health studies, it’s women who pay the price




Claire Lehmann

The insistence that gender differences were and are immaterial to the proper functioning of a free society has been a feature of our common conversation since the 1970s. It was the key to “second-wave feminism,” the political and social movement that took women’s liberation beyond issues of suffrage and wages and employment to the question of how a just society orders itself.
By the close of the 20th century, however, the insistence that gender differences be treated as inconsequential had ossified into orthodoxy precisely at the moment when the biological sciences were uncovering differences between the sexes that had hitherto been unknown. An ongoing tug-of-war has resulted between scientists who investigate sex differences and activists who oppose such research. This battle over theory has had horrific real-world consequences. The minimizing of sex differences in areas of health and medicine in particular has led to sweepingly harmful and often fatal results, especially for women.
Consider the following fiasco. In 2013, the Food and Drug Administration announced it was slashing the recommended dosage of the sleeping pill Ambien in half—but only for women. The FDA had known for 20 years that women metabolized the active ingredient, zolpidem, more slowly than men, but the dosage for men and women had been exactly the same since the drug had been on the market. In 2014, neuroscientist Larry Cahill told 60 Minutes:
It appears to say that they found a significant difference in how this drug is being processed in the body. And then the question is, “What did they do with that?” and the answer appears to be, “Eh.” They rationalized it away.
Over time, this “rationalization” slowly frayed at the edges before completely coming apart. How did this rationalization affect the rest of us? In the early 2000s, studies began to show that people who took zolpidem late at night had impaired driving ability the next morning. And in 2011, researchers at Scripps Health in San Diego found that people who took Ambien (along with another popular sleeping pill, Restoril) had a fivefold increased risk of early death compared with people who didn’t. While a cohort study can never definitively prove causation, the researchers estimated that in the year 2010, these sleeping pills may have contributed to up to 500,000 of “excess deaths” in the United States alone. Heavy users of the pills were not the only ones at risk—even people who took fewer than two pills monthly were found to have a threefold increased risk of early death. These “early deaths” came in the form of accidental overdoses, car crashes, and falls.
Unfortunately for women, the necessity of taking account of
biological sex differences in early- stage pharmaceutical research has routinely been neglected, avoided, and rationalized away. Most early-stage research, which is done on animals, is conducted on male animals.








Though the Ambien dosage adjustment took place in 2013, as far back as 2001, a U.S. Government Accountability Office study found that of the previous 10 drugs that had been removed from the market, women had experienced severe adverse reactions to eight. This is alarming because, despite the checks and balances that are in place, it is extremely difficult to prove that drugs cause harm once they are on the market.
Case in point: When thalidomide was released in the 1950s, it was not well known that certain substances might cross the placental barrier and harm a fetus. Even after women in Europe began giving birth to babies who had no limbs, or deformed flipper-like limbs, the drug continued to be aggressively marketed to women as a remedy for morning sickness. It was only when a determined scientist at the Food and Drug Administration in the United States named Frances Oldham Kelsey pushed for the systematic collection and analysis of data that thalidomide was finally proven to be the cause of these birth defects. But this process took years, and 2,000 European children were estimated to have died from thalidomide poisoning, and 10,000 children were estimated to have been born with serious birth defects in the interim. (The United States never approved its use, but it was tested here.)
The thalidomide horror story underscores just what is at stake—and how crucial it is to get the testing right in the earliest stages of research. Once a medicine is “approved,” it is extraordinarily difficult to demonstrate scientifically that it causes adverse outcomes. Only a prospective, longitudinal study of thousands of people (a sample large enough to show statistical significance) showing that a substance is directly causing harm will be accepted as proof by the scientific community and by the courts. Such studies are done at extraordinary expense before the drugs are approved. Who wishes to bear the cost of replicating them for the purposes of challenging their findings afterward, especially since in most cases the replication will simply validate the original decision to permit the drugs to come to market?
Unfortunately for women, the necessity of taking account of biological sex differences in early-stage pharmaceutical research has routinely been neglected, avoided, and rationalized away. Most early-stage research, which is done on animals, is conducted on male animals. In 2011, a study was published by Annaliese Beery and Irving Zuker showing that single-sex studies of male animals across eight fields of biomedicine outnumbered those of females by a ratio of 5.5 to 1. The authors of the study found that male bias had increased in the past 50 years and that studies of either sex often failed to acknowledge that only one sex was studied. The neuroscientist Larry Cahill has said he never even saw a female animal when he completed his Ph.D. and post-doctorate training in the late 1980s. And things have not improved since. In 2014, a surgeon named Melina Kibbe joined with five colleagues in a study of journal articles published in the field of surgery. What they found was shocking: Even for female-prevalent diseases, only 12 percent of reports had included female animals.
How did this happen? For a long time in the biomedical sciences it was thought that female animals were just too complex and variable to study, due to their fluctuating estrous cycles. Female sex was seen as a “nuisance variable”—it would provide extraneous data with no real meaning and would cloud and confound the carefully designed studies of academic scientists. And throughout the history of medicine, it has always been assumed that whatever was fundamental to human beings would be shared by both males and females, and that therefore studying the male would be sufficient. Yet while this assumption has been strongly held, it has been weakly supported.1 A 2014 meta-analysis on female mice (a synthesis of a large body of studies) found that female mice were not more “variable” than male mice in spite of their estrous cycles—meaning that scientists had been removing female animals from their studies for no good reason.
And what of drug studies involving humans? Most subjects are young healthy men. Until 1993, women of childbearing age were, for obvious reasons, explicitly excluded from drug trials, and for equally obvious reasons relating to possible childbearing, are still far less likely to volunteer for such studies. As a result, even drugs that are designed specifically for women are not tested on women. In 2015, when a female version of Viagra called Addyi was tested for potential side effects, it was tested on a sample of 25 subjects—only two of whom were female.
When it came to getting approval for Addyi, it was assumed that test results from male subjects could simply be extrapolated from, even when the side effects in men included low blood pressure, dizziness, and fainting. (As in the case of Ambien, one can easily imagine disastrous consequences when combined with driving.) After two rejected applications, Addyi was eventually approved by the FDA, which insisted on placing a black-box warning on the drug’s packaging, advising women not to drink any alcohol when taking the drug. But several doctors wondered why the drug was approved at all.
It was later reported in the New England Journal of Medicine that members of the FDA had actually been under pressure by advocacy groups to approve the drug under the auspices of “gender equality.” Addyi’s maker, Sprout Pharmaceuticals, had been funding those same advocates. The New England Journal claimed that Sprout Pharmaceuticals surreptitiously created an organization called Even the Score. Its ostensible purpose—to promote “women’s sexual health equity”—was a cover for the goal of securing FDA approval for this particular pill. That the pill’s marketing campaign was dedicated to equalityrather than women’s actual health or well-being—and that the company believed such a campaign would have an impact—speaks volumes about our current cultural obsessions. Gender equality has become a monomania that leaves us vulnerable to rather serious blind spots. All things must be “equal” between the sexes, no matter how superficial, while the truth goes by the wayside; not so much as an inconvenience but rather as an irrelevance.
Science, being science, is supposed to be immune from such ideological gamesmanship. So how could this all have happened? Theory may have outstripped empiricism because just as the idea that gender differences were meaningless gained cultural currency in the 1970s, there was precious little hard evidence to counteract it.
In the 1970s, the study of the brain was in its infancy. The first department of neuroscience was established at Harvard only in 1966. The fMRI scan, which allows scientists to watch the brain’s responses to stimuli in real time, was not invented until the 1990s. Only in the last 15 to 20 years has overwhelming evidence been amassed to show that sex differences, both large and small, exist at every level of analysis in the human animal. Neurobiologists have discovered that there are sex differences in how our brain hemispheres are wired, with women’s being more highly connected across the left and right hemispheres, and men having more connections from front to back. There are sex differences in the amygdala, hypothalamus, and hippocampus, in both size and activity. For example: Activation of the left side of the hippocampus is found to be more dominant in females, and activation on the right is found to be more dominant in males. There are fundamental sex differences in basic neurochemistry. Men and women have different baseline amounts of neurotransmitters such as serotonin and dopamine. They also differ in their abilities to synthesize these neurotransmitters. When neurons of male and female rats are placed under a microscope, the ways in which these cells die are different—a discovery with profound implications for the treatment of brain injuries, Alzheimer’s, and stroke.
This evidence has been a difficult pill for some to swallow. For the scientific establishment, there has been a slow and begrudging acceptance that its usual practices must change to carefully take into account the influences of sex. It was not until 2014 that the National Institutes of Health announced that female animals must be included in all animal and cell research. But for some academics whose political consciousness was formed in the era of second-wave feminism, this evidence has been angrily rejected on ideological grounds. The common argument put forward has been that this research will be used to justify the unequal treatment of women. In the closing paragraph of her chapter about “neurosexism” in Delusions of Gender (2010), Australian social psychologist Cordelia Fine wrote that neuroscientific findings “reinforce and legitimate the gender stereotypes that interact with our minds, helping to create the very gender inequalities that [they] seek to explain.” As a result of this widespread fear, scientists making discoveries about sex differences have been labeled “neurosexist,” accused of producing “neurotrash” and “populist science.” One result of the controversy may be that it has deterred many others from going into the field altogether.
In these and other instances, politics and ideology have dovetailed with convenience and a certain degree of parsimony. It’s easier and cheaper for the FDA to carry on as though everything is fine—because retesting drugs and adjusting dosage requirements for women might be seen as an admission of failure and liability. It has been easier and cheaper for scientific journals to maintain the status quo around early-stage research, because acknowledging that a great deal of published data is confounded by sex would mean that a great deal of it would need to be thrown out. And it’s also much easier for anti–sex difference academics to double down on their tactics of name-calling and avoiding the evidence rather than admit they have been wrong the whole time.
Of course, faulty theory and bad institutional practices can be fixed. Ideology is much more resistant to change, especially when individuals are afraid to speak out about it. And they have been. At the end of 2016, the Journal of Neuroscience Research released a special edition devoted entirely to sex differences in the human brain. Its subtitle was “an issue whose time has come.” In his foreword, the University of California biologist Larry Cahill writes:
I received strong advice to steer clear of studying sex differences from a senior colleague around the year 2000 when my research into brain mechanisms of emotional memory began drawing me into the issue of sex differences—or better yet, sex influences—on brain function. And in a way, he was right. For the vast majority of his long and distinguished neuroscience career, exploring sex influences was indeed a terrific way for a brain scientist not studying reproductive functions to lose credibility at best, and at worst, become a pariah in the eyes of the neuroscience mainstream.
It’s worth noting that historically, the hostility toward such research came not from the laboratory but from the humanities and social sciences. A 1986 paper in American Psychologist titled “Issues to Consider in Conducting Nonsexist Psychological Research” gives us a snapshot of the attitudes prevalent at the time. The authors state that “[sexist] bias need not be introduced into research intentionally or consciously” and that “even well-established findings can harbor unsuspected sexism.” They question whether objective scientific methods were even appropriate for use on women as women. Perhaps most troubling was their assertion that a male scientist studying female subjects is, by definition“sexist.” They write:
The inequality between the researcher and the research participants is especially clear and problematic when the experimenter is male and the participants are female. Here the research setting most clearly reflects and reinforces the imposition of male definitions of reality on females.
This assertion—that there is a different “definition of reality” for males and females—is a decidedly postmodern and anti-scientific statement. So it is perhaps surprising that such a philosophy would ever be accepted within the sciences. But cowed by politically minded colleagues, and acting out of a genuine fear of doing more harm than good to the world, many scientists simply steered clear of sex-differences research. And who can blame them? When accusations of sexism can be made so easily, and are so impossible to refute, is it any wonder?
In his 2016 foreword, Cahill writes:
Fortunately, times are changing. The past 15 to 20 years in particular witnessed an explosion of research (despite the prevailing biases against the topic) documenting sex influences at all levels of brain function. So overpowering is the wave of research that the standard ways of dismissing sex influences (e.g., “They are all small and unreliable,” “They are all due to circulating hormones,” “They are all due to human culture,” and “They don’t exist on the molecular level”) have all been swept away, at least for those cognizant of the research.
The question we must ask ourselves is: Why on earth would anyone wish to deny the self-evident truth that the biological differences between men and women from size and shape and bone structure down to the very XX-XY chromosomal separation would have second-order effects on health, the metabolization of medicines, and the way diseases work inside the body?
The answer is that we live in an age when politics and ideology override all.
In 2008, making her debut as an anti–sex difference academic, Fine coined the term “neurosexism.” She dubbed it the “ugly rush to cloak old-fashioned sexism in the respectable and authoritative language of neuroscience.” In 2010, she published the book Delusions of Gender, which purported to “demolish” the bad methodology underpinning the new science of sex differences. Fine’s book was celebrated with glittering reviews across the prestige media landscape—although in the scholarly literature, reviewers took a dim view. The Cambridge autism researcher Simon Baron-Cohen described it as “strident” and “extreme.” And the neuroscientists Margaret McCarthy and Gregory Ball described it as “insulting, “mean spirited,” and “inflammatory.” They went onto write that “nothing short of stopping research on the topic would seem to satisfy her”:
One of [Fine’s] frequent refrains is how little we know, suggesting that this is a flaw of the science as opposed to a natural consequence of the relatively slow pace of discovery resulting from only a small cadre of scientists being focused on and committed to the question at hand. . . . What is particularly frustrating to those of us who actively engage in the study of sex differences in the brain is how hard we are continuing to fight for sex or gender as a critical biological variable that must be considered in any study that purports to advance our understanding of the brain. . . . We fear that books such as the ones by Fine . . . will not hasten the pace of discovery, but instead threaten to severely hamper or even reverse the progress that is being made.
The frustration that McCarthy and Ball describe is understandable. In 2013, Fine collaborated with three others on an article in Frontiers in Human Neuroscience.They argued that sex should not be viewed as a “categorical variable,” but rather as a “dimensional trait-based variable.” Allow me to translate from the gibberish: Fine and her colleagues were saying that sex should simply not be viewed as biological fact arising from sex chromosomes, but should be evaluated as “stereotypes,” “gendered experience,” “gendered attitudes,” all of which needed to be measured and included as “dimensions” of gender.
Their article also read, in part, “unless [neuroscientists] have specific expertise or knowledge in gender scholarship, they too are laypeople with respect to gender research, and may also be susceptible to gender essentialist thinking.” They went on to argue that neuroscientists should be schooled in the theory of intersectionality—“the principle that important social identities like gender, ethnicity, and social class mutually constitute, reinforce, and naturalize one another.” 
The discovery of sex differences in the human brain and nervous system should not be seen as a blow to gender equality. Men are not the ‘gold standard’ version of the human species, and women should not be viewed as a deviation from the norm.







At first glance, this is a peculiar demand. Intersectionality, a theory developed by the law professor KimberlĂ© Crenshaw in the early 1990s, derives not from the biological but the social sciences. Crenshaw argued that feminism as an enterprise had neglected issues of race, and that feminism should recognize intersecting social identities. So to practice intersectionality, one must privilege the voices of black women over white women, and the voices of women over men, for example. The least privileged deserve the most sympathy; the straight white male deserves the least. The relevance of Crenshaw’s work for neuroscience is unclear at best. But its utility as an ideological weapon has made it popular among academics hoping to politicize scholarship and silence their enemies.
Fine’s 2013 call for neuroscientists to incorporate intersectionality is just one of the more recent attempts by anti–sex difference academics to dilute the objective methods of the natural sciences with theories emanating from the humanities. This is bad news. The Ambien and Addyi fiascos make clear that women would benefit from more rigor in science, not less. Instead of injecting subjectivity into scientific methods, feminist advocates should be demanding that the influences of biological sex differences be investigated and accounted for systematically, as a matter of routine practice.
Most disturbing, Fine and her fellow travellers are often held up by the uninformed press as fearless advocates for women; “a pinnacle piece of feminist literature” is how one reviewer in the Huffington Post described Fine’s Delusions of Gender. In reality, their contributions amount to little more than obscurantism. That women have many more adverse drug reactions than men and that male subjects are consistently overrepresented in the early stages of clinical research at women’s expense seem not to register with them as legitimate issues to care about. These realities are merely mentioned in passing, or in glib disclaimers about why they are not prima facie opposed to studying sex differences (just as long as they don’t show that male and female brains are actually different).
The discovery of sex differences in the human brain and nervous system should not be seen as a blow to gender equality. Men are not the “gold standard” version of the human species, and women should not be viewed as a deviation from the norm. In stoking fears about difference, these political activists dressed in scholars’ clothing unwittingly imply that female-typical traits are something to be ashamed of and are by default inferior. Why would the discovery of differences be so ominous if one didn’t secretly harbor the view that female-typical traits were unsatisfactory? Whether such attitudes will ultimately be remembered as sexist or feminist is something only history can decide.
When the aims of political zealots converge with institutional inertia and profit-hungry industry, significant harms can result. And while it might be fun and games to the humanities scholars who spend their time waxing lyrical about the social construction of gender, for clinicians and their patients, ignoring the reality of sex can be fatal. Long impugned for being a “neurosexist,” Larry Cahill now has the beleaguered appearance of a man who has carried the weight of a heavy and inconvenient truth for years. Meanwhile, Cordelia Fine has just recently been celebrated in the New York Times and the Guardian with hagiographic reviews of her latest pop-science book
Anti-sex difference academics are not personally responsible for women overdosing on sleeping pills and not being able to access medical treatments tailored specifically to their sex. But it is becoming increasingly clear that the ideology they have pushed for years—that biological sex differences are trivial—almost certainly is. The scientific enterprise and its quest for truth will win in the long run. But how many casualties will this battle eventually claim?
1 The history of sex-difference research is one in which scientists have had to overturn their faulty assumptions from the get-go. In the 1950s, when pioneers in the field of behavioral endocrinology starting researching the role of sex differences, they began from the assumption that sexual behavior was somatic—that the brain simply directed actions dictated to the animal by its body. Then some female guinea pigs were tested whose mothers were given testosterone during pregnancy. They went around mounting other guinea pigs like males would, despite not having penises. This was a breakthrough discovery, which taught us that the prenatal period was a critical period in which male and female brains “differentiated.”

Source>https://www.commentarymagazine.com/articles/the-xx-factor/

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