Sex matters: Drugs can affect sexes differently

The following is a script from "Sex Matters" which originally aired on Feb. 9, 2014, and was rebroadcast on May 25, 2014. Lesley Stahl is the correspondent. Shari Finkelstein, producer.

Early last year the Food and Drug Administration made an unusual and surprising announcement -- it cut the recommended dose of the most popular sleep drug in the country, Ambien, in half -- for women. It turns out men and women metabolize Ambien, known generically as Zolpidem, very differently, leaving women with more of the drug in their bodies the next morning, and therefore at a greater risk of impaired driving.

60 Minutes helps pave way for change at NIH, FDA

Ambien, Zolpidem, is now the only prescription drug in the country with a different suggested dose for men and women. But as we first reported in February, it is far from an isolated example of differences between the sexes we never imagined. More and more, scientists are realizing that the differences are dangerously understudied and that, pervasively and fundamentally, sex matters.

Take aspirin. Low-dose aspirin lowers the risk of heart attacks in healthy men; but in healthy women, turns out it doesn't though it does protect women against stroke. And drugs are just the beginning. Sex differences have been found in pain receptors, liver enzymes, even the wiring of the brain.

Resources

For more information on the biology of sex differences visit:

The Society for Women's Health Research

Women's Health Research Institute at Northwestern University

Mary Horrigan Connors Center for Women's Health & Gender Biology

Laura Bush Institute for Women's Health

Larry Cahill: We have generated just a ton of information that suggests that there're sex differences everywhere.

Larry Cahill, a neuroscientist at the University of California Irvine, used to share his field's assumption that males and females outside the reproductive system were fundamentally the same. But he's changed his outlook 180 degrees. Ambien, he says, is a case in point.

Lesley Stahl: Ambien, prescribed 40 million times just last year, approved 20 years ago. We're only now finding out that women have been prescribed-- a dose that's twice as high as they need.

Larry Cahill: That is a textbook example of what's wrong. How did it happen that for 20 some years, women, millions of them, were essentially overdosing on Ambien?

The FDA says it made the change after new driving simulation studies established what amount of Ambien or Zolpidem in the blood the next morning could be dangerous for driving.

Dr. Sandra Kweder, deputy director of the FDA's office of new drugs, says only then did they realize women could be taking too much, since women metabolize the drug differently than men.

"How did it happen that for 20 some years, women, millions of them, were essentially overdosing on Ambien?"

Dr. Sandra Kweder: So if I took Zolpidem, and my brother took same dose, probably the maximum level of drug in my blood would be 45 percent higher than his maximum blood level.

Lesley Stahl: Now that sounds substantial--

Dr. Sandra Kweder: It is substantial.

But we discovered that that 45 percent difference between men and women had been known to the FDA all along. In the original FDA review of Ambien back in 1992, there was a page called "Effect of Gender," where the FDA reviewer noted that two key measures of how much drug is in the bloodstream "were approximately 45 percent higher in females than in males."

Larry Cahill: 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.

Lesley Stahl: I'm gonna hand you that page, "Effect of Gender."

Dr. Sandra Kweder: OK.

Lesley Stahl: The FDA reviewer went on to write, "The results suggest a gender-related difference. However, the lack of specific details such as study design and individual data make it difficult to draw a definite conclusion--"

Dr. Sandra Kweder: Exactly.

Lesley Stahl: So when you see that they didn't give you enough data, did you go back, or should you have gone back, and said, "OK, what was the study design? What was the data?"

Dr. Sandra Kweder: If I saw this today, in light of today's science, I think we would go back and try to tease this out a little bit further. But I think at the time, this was generally consis-- this was sort of business as usual for what you saw in clinical pharmacology studies.

That's because, she says, there was no evidence at the time that the difference mattered. That was 20 years ago, when if someone said "women's health," it usually meant what they call "bikini medicine" -- breast and ovarian cancer, pregnancy, menstrual cycles. But for parts of the body men and women share -- hearts, kidneys, the brain -- most of the studies were done predominantly on men.

Lesley Stahl: If you want to understand me, they study you?

Larry Cahill: And here's why they do that. Because there's this assumption that you are me with pesky hormones.

Lesley Stahl: Oh...with pesky hormones.

Larry Cahill: I'm being only partially facetious. The idea is that the fundamental things are similar between you and me. So that ironically the best way to study you is to study me.

Lesley Stahl: Cause you don't have pesky hormones.

Larry Cahill: Right. We're studying all the fundamental things in you without this sort of nuisance stuff. That's literally an assumption on which all of biological medicine, especially neuroscience, which I know best, has been built.

But given what we now know, he says that assumption has to go. Look at heart disease, which is the leading killer of both men and women. Cardiologist Noel Bairey Merz from Cedars-Sinai Medical Center in Los Angeles says women, like her patient Pearl Grumet, can differ from men in the way they have heart attacks.

Pearl Grumet: I had this excruciating pain in between my shoulder blades. And then I got the nauseous feeling in my stomach...

Lesley Stahl: So the man comes in, he has chest pain, sometimes a radiating pain down the left arm. The woman comes in and she says--

Dr. Noel Bairey Merz: She might be having stomach upset, she might be feeling fatigue. She might just be short of breath.

Lesley Stahl: Why does she even go?

Dr. Noel Bairey Merz: 'Cause they don't feel right. And they know something's wrong.

Lesley Stahl: They know something's wrong.

Lesley Stahl: Did you ever have chest pain in this whole time?

Pearl Grumet: No.

Dr. Noel Bairey Merz: You can see, here's the constriction.

Typically men get clogs in major arteries that are easy to see on an angiogram. But many women get blockages in tiny microvessels inside the heart. So their heart disease is more often missed. Pearl had four minor heart attacks; five different hospitals couldn't find the problem.

Pearl Grumet: Doctor comes in and he says, "When you find out what's wrong with you, would you please let me know?"

Lesley Stahl: No, come on.

Pearl Grumet: "'Cause we don't have any idea what's wrong."

Dr. Bairey Merz says one of the reasons we haven't learned more about women goes all the way back to the beginning of the scientific pipeline, to research on animals. Dr. Melina Kibbe is a vascular surgeon who also runs a lab at Northwestern University Medical School, where she evaluates new therapies in mice and rats.

Lesley Stahl: If I walked into a lab anywhere in the country doing animal research, what are my chances of coming upon a study with only male animals?

Melina Kibbe: Very large.

Lesley Stahl: Today?

Melina Kibbe: Correct.

Turns out female rats also have those pesky hormones.

Melina Kibbe: So to control for that variable, most researchers study just males. I was also studying just males.

Lesley Stahl: So it made sense? Or you maybe didn't even think about it?

Melina Kibbe: I didn't even think about it.

And neither did Doris Taylor, a leading stem cell expert at Texas Heart Institute in Houston -- until she was designing an experiment in mice, to see if injections of stem cells could reverse plaque build-up in their arteries, and she needed a way to track the stem cells in the animals.

Doris Taylor: So what we decided to do is give female animals male stem cells, because we could track the Y chromosome. And we said, "Let's give male animals female cells."

Lesley Stahl: You only did it so you could track the cells.

Doris Taylor: So we could track the cells--

She was surprised to find that the results were not the same.

Doris Taylor: The male animals we gave female cells got better. And the female animals we gave male cells actually got a little worse.

Only the female stem cells got rid of the plaque.

Doris Taylor: And you can see all this fat here, the pink--

The male mouse artery on the left had not been treated; the one on the right got female stem cells.

Doris Taylor: And look at that.

Lesley Stahl: It's clean.

Doris Taylor: I am embarrassed to admit that, as a woman, it had never really occurred to me that doing the experiment in male versus female animals would give completely different results.

And that led to further discoveries. Taylor wanted to find out if human stem cells were different too, and she's found that. They are.

Lesley Stahl: My stem cells are actually different stem cells from a man's?

Doris Taylor: Yes.

She told me men's are less powerful to begin with; and then they start to die off.

Doris Taylor: In men as they age, they decrease pretty dramatically. And in females, they stay relatively stable. Now, think about that--

Lesley Stahl: Wow.

Doris Taylor: Men develop heart disease much earlier than women. Why not look at the difference and see how to make men live longer without heart disease?

She speculates that ignoring this difference may be one reason stem cell treatments haven't lived up to their promise. And on a broader level, that not studying both male and female animals results in more problems for women down the road.

Larry Cahill: If the whole darn pipeline is male dominated and sex differences truly do matter, how can it not be the case that you're going to end up with, on average, a lot more negative side effects in women than in men? I mean it basically has to happen.

And it does. A GAO report found "8 of the 10 prescription drugs withdrawn" from the market from 1997 to 2001 "posed greater health risks for women than for men." Today when it comes to government-funded studies on humans, women must be included by law. But many researchers don't then take the next step and analyze the results by sex, which some argue defeats the whole purpose.

Lesley Stahl: We have come upon studies where they do use both male and female, but they then don't analyze how the two respond differently. So they have the two and no analysis of the difference.

Doris Taylor: If you do the two together and you really think females are here and males are here or vice versa, [gestures with hands] then you're gonna get results that are right here-

Lesley Stahl: And so they're almost useless--

Doris Taylor: And so they're almost not predictive of either males or females.

Larry Cahill: If you're clumping men and women together in your study and there truly is a sex difference, you're not just harming the women; you're harming the men. You're muddling up the understanding of what's going on, you're muddling up the path to clear treatment, not just for the women, but for the men as well.

The problem, he says, is that the scientific establishment hasn't caught up with its own discoveries.

Lesley Stahl: If science got Ambien so wrong, does that tell you that we really need to go back and review--

Larry Cahill: Yes.

Lesley Stahl: What? Everything?

Larry Cahill: Pretty much everything, yeah, 'cause once you see this difference and that difference and that difference and that difference and that difference and you see, "This thing's everywhere," you go, "Wait a minute. So the assumption we're making that it really doesn't matter, sex, is not a valid assumption." It may not matter. It may matter hugely. It may flip your results on their head and you don't know. So what happens is you start to realize, "Wow. The status quo is not OK. The way we're doing business has to change."

"If you're clumping men and women together in your study and there truly is a sex difference, you're not just harming the women; you're harming the men."

Lesley Stahl: There are scientists who say the Ambien situation is like a wakeup call. It's a tip of the iceberg. So, should the FDA go back and look at other drugs?

Dr. Sandra Kweder: Well, you know, to say every drug-- every drug, go back and look again?

Lesley Stahl: Yeah.

Dr. Sandra Kweder: That's an enormous undertaking.

Lesley Stahl: So can women feel secure that the dosages recommended on any of their medications is proper for them? Or should they now be a little worried?

Dr. Sandra Kweder: In medical practice, there is a general awareness that there may be individual differences among patients. And that every patient needs to have the right dose.

Lesley Stahl: How's a doctor supposed to know?

Dr. Sandra Kweder: You start at the lowest dose, and you see if it's enough.

Lesley Stahl: Yeah, but you're doing the studies. And they're gonna rely on your recommendation.

Dr. Sandra Kweder: Yup.

Lesley Stahl: It sounds like the FDA is being more reactive than aggressive about this.

Dr. Sandra Kweder: I think we're being very aggressive about bringing the most sophisticated science to new drugs and being aggressive about applying the science where we have reason to believe there is a concern to older drugs.

In the three months since our story first aired, a lot has happened. A bipartisan group of 15 women senators sent an open letter to the FDA commissioner, citing our report, and asking for better representation of women and analysis of sex differences in drug trials.

And just last week, the National Institutes of Health made a major announcement: It will now require scientists to include plans for balancing male and female animals and cells in all government-funded research. The announcement said, "Our goal is to transform how science is done."