What does the Zolpidem case teach us about gender pharmacology?

by Rosie Audino, expert in philosophy and science and health communication

In the episode Waiting for Guide of the third season of Dr. House, we finally discover the origin of the iconic catchphrase: “It’s never Lupus.” House needs more Vicodin (a powerful opioid painkiller based on hydrocodone and paracetamol, widely used in the United States but not marketed in Italy and the rest of Europe) but James Wilson, concerned about his addiction, refuses to give him more drugs. At this point, his stratagem is revealed: House was hiding the pills (his Vicodin) in a manual about lupus. He was convinced that no one would ever open it, because that diagnosis, in his experience, was never confirmed in patients. Precisely for this reason, the volume represented an ideal hiding place, a book destined to remain closed, ignored. If that manual were dedicated to gender pharmacology, a fundamental subject but still too often ignored in clinical practice, we wouldn't have been surprised if House had still chosen it as an ideal hiding place: a text destined, unfortunately, to remain untouched and ignored as much as the one on lupus. Dear Dr. House, it's not lupus, it's a lack of data!

What is gender pharmacology

The WHO defines gender medicine as the study of the influence of biological differences related to sex and socio-cultural differences related to gender on the health and disease status of each person. Gender pharmacology falls within this approach, analyzing how, based on gender, people absorb, metabolize, and react to drugs differently, with consequences for efficacy, safety, and the risk of adverse reactions.

Gender pharmacology emerged as an evolution of biomedical research between the 1980s and 1990s, when it began to be recognized that men and women can respond differently to drugs. A pivotal figure in this journey is Bernadine Healy, an American cardiologist who in 1991 became the first woman to direct the National Institutes of Health (NIH). During her tenure, she realized there was a significant bias: cardiology was built almost entirely on male data. Women were less frequently enrolled in clinical trials, underwent fewer diagnostic tests, and, in some cases, were treated later than men.

Healy coined the term Yentl syndrome to describe this disparity. 

The name comes from Yentl, a film directed by and starring Barbra Streisand, based on a story by Isaac Bashevis Singer. In the film, Yentl is a young Jewish woman who, in order to study the Talmud (one of Judaism's sacred and fundamental texts), an activity forbidden to women in her community, is forced to disguise herself as a man. Only by pretending to be male can she access education and intellectual recognition. Healy used this metaphor to describe what happened to women with heart disease: they were taken seriously, underwent angiographies, or were treated with the same intensity as men only when their symptoms mimicked those considered “classic” male symptoms, such as typical chest pain or certain diagnostic patterns. If, however, they presented different symptoms, more frequent in women, such as dyspnea, fatigue, or atypical pain, the risk was that they would be underestimated or treated less promptly. In other words, to receive the same care, women had to “resemble” men, just as Yentl had to pretend to be a man to study. 

Obviously, this is not pure theory; the consequences are tangible. 

Did you know that approximately 60% of hospital admissions for adverse drug reactions involve women?
Watson S et al. Reported adverse drug reactions in women and men: Aggregated evidence from globally collected individual case reports during half a century. EClinicalMedicine. 2019;17:100188. doi:10.1016/j.eclinm.2019.10.001.

Based on a true story

The story of Zolpidem, one of the most prescribed insomnia drugs in the world since the 1990s, is emblematic. It was initially approved with the same dosage for men and women, at a time when biological sex differences were little considered in clinical research. Subsequent post-marketing studies, however, showed that women metabolize Zolpidem more slowly, maintaining higher blood concentrations until the next morning, with possible effects on alertness and safety, particularly when driving. 

Only in 2013 did the FDA recommend reducing the initial dosage for women. The Zolpidem story is reminiscent of the Thalidomide case: drugs tested only on men or on restricted populations, with devastating consequences for female bodies (we discuss this in the article Trust Me, It Works!). As early as 1932, some researchers observed that barbiturates produced different effects in males and females in animal experiments. 

Despite this early evidence, the first concrete steps towards clinical research reform only came in 1993, when the FDA introduced guidelines that mandated the recruitment of both sexes in clinical trials – until then, the reference was the young, white male, around 70 kg, the standard model for clinical research.

From Yentl Syndrome to Today 

According to a study by Daitch et al. (2022) published in Trials the overall percentage of women enrolled in randomized clinical trials included in the analysis was approximately 41%, significantly lower than the expected 50% considering the female prevalence in the studied populations. In cardiovascular trials, female participation was particularly low, with averages often below 35%, despite cardiovascular diseases affecting men and women similarly. In the areas of oncology and autoimmune diseases, female representation was closer to 50%, but still lower than the actual impact of these pathologies on women. 

Since the 1990s, when cardiologist Healy used the metaphor of the film Yentl to highlight that women were only diagnosed with cardiovascular diseases if they simulated male symptoms, such as chest pain, things have not changed much to this day, as shown by the data from the 2022 study. Behind this scientific gap lies the legacy of a cultural bias, which for decades considered men as the standard model in medicine. The female body, on the contrary, has often been perceived as a variant or a more complex subject, due to hormonal variations, and thus to be excluded from clinical trials for reasons of convenience or alleged additional risks. 

But women are not just men without a menstrual cycle

The menstrual cycle is a fundamental variable: many drugs can have different effects depending on the phase of the cycle. Some antidepressants, for example, can be too potent or insufficient depending on the hormonal phase, while some therapies for heart rhythm can be dangerous, sometimes fatal, in the first 14 days of the cycle. Unfortunately, when women are included in trials, the test is often administered at the beginning of the follicular phase, when hormone levels are minimal, ignoring the entire physiological variability.

In addition to hormonal variability, the male and female bodies present significant differences: organ size, composition and distribution of fat and lean mass, body fluid content, enzymatic expression for drug metabolism, and different immune response. These factors influence the pharmacokinetics and pharmacodynamics of medicines, meaning how the drug is absorbed by the body and its effects on the organism. A 2007 study on male and female mice showed that the tested drugs had different effects between sexes in 54% of cases (Beery & Zucker, 2007, Sex does matter: comments on the prevalence of male-only investigations of drug effects on rodent behaviour). Despite this, most clinical trials still primarily describe data from men, even for drugs predominantly intended for women. But … 

Women, and all bodies that do not conform to the “neutral” or “standard” model, are not simply smaller versions of men.

Continuing to prescribe drugs based on efficacy in the adult white male model exposes women and all bodies different from the neutral model to risks of overdose and adverse effects. This also applies to transgender people, the elderly, and children, categories still heavily underrepresented in clinical studies. 

This systematic exclusion has not been without consequences: it has led to a serious lack of data on the effects of drugs, therapies, and diagnoses on a significant portion of the population. When data is missing, treatments become less precise, dosages less safe, and diagnoses later or incorrect. The result is medicine that works better for some bodies and worse for others, transforming biological difference into health inequality. 

It is from this understanding that Geen was founded, with the aim of bridging the data gap that has excluded entire categories from scientific knowledge. Geen is based on the idea that every body should be represented, and that only by collecting data on this diversity can truly adequate solutions be built. Because medicine that ignores differences is not neutral: it is simply incomplete.

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