Sex matters Drugs can affect sexes differently - CBS News

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Sex matters Drugs can affect sexes differently - CBS News

Lesley Stahl: Now that sounds substantial.

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?

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

Dr. Sandra Kweder: It is substantial.

Lesley Stahl: No, come on.

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

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.

Lesley Stahl: They know something's wrong.

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.

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.

Lesley Stahl: Why does she even go?

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

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Lesley Stahl and Dr. Sandra Kweder CBS News 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: What? Everything?

Doris Taylor: And look at that.

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

Lesley Stahl: It's clean.

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

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.

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?

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

The FDA told us it is looking at other sleep drugs for possible sex differences, but not mounting an across the board review. As of today, Zolpidem remains the only drug on the market with different recommended doses for men and women.

Doris Taylor: So we could track the cells.

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 approximay 45 percent higher in females than in males.".

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.

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

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

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?".

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Only the female stem cells got rid of the plaque.

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

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

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

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.

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?

More and more, scientists are realizing that the differences between the sexes are dangerously understudied.

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.

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

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

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.

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Teresa Woodruff and Dr. Melina Kibbe, both of Northwestern University Medical School, describe how a simple chat and a few female rats led to a m.

Melina Kibbe: Very large. Lesley Stahl: Today? Melina Kibbe: Correct.

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

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

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.".

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--".

Women's Health Research Institute at Northwestern University.

Turns out female rats also have those pesky hormones.

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

Man or woman? What 60 Minutes' Lesley Stahl learned while reporting on the surprising medical differences between the sexes.

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

Lesley Stahl: My stem cells are actually different stem cells from a man's? Doris Taylor: Yes.

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.

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.

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

One of America's most recognized and experienced broadcast journalists, Lesley Stahl has been a 60 Minutes correspondent since 1991.

Earlier this 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.

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.

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.

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.

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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.

Lesley Stahl: And so they're almost useless.

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 compley different results.

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.

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.

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

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.

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.

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.

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

For more information on the biology of sex differences visit:

Dr. Sandra Kweder: OK.

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.

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

The Society for Women's Health Research.

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

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.".

Ambien CBS News Ambien, Zolpidem, is now the only prescription drug in the country with a different suggested dose for men and women. But we've discovered 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.

Dr. Sandra Kweder: Exactly.

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?

Lesley Stahl: If science got Ambien so wrong, does that l you that we really need to go back and review-- Larry Cahill: Yes.

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

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

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.

Dr. Sandra Kweder: Yup.

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.

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

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

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

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

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

Lesley Stahl: Did you ever have chest pain in this whole time? Pearl Grumet: No.

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

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Lesley Stahl: Oh...with pesky hormones.

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