[Paleopsych] Science: Women's Health
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Science: Women's Health
5.6.10 (Special section)
[I am including only the news articles, not the reports.]
Many a song and poem celebrates the splendid differences between men and women.
But obvious physical variation aside, in what ways do we differ mentally,
physiologically, and socially? This special issue on Womens Health highlights
many points of divergence. However, the title of this issue should not prompt
the male reader to put down this copy and wait for a subsequent one. The issue
covers many topics that concern men and women equally, such as the HIV/AIDS
pandemic, cardiovascular disease, sexuality, and personalized medicine, as well
as matters specific to women.
Much of our understanding of sex variation stems from the Womens Health
Initiative, an effort launched in the late 1980s to probe gender questions and
to increase the number of women in clinical trials. Without doubt, more women
are now included in trials, and more studies focus on diseases that especially
afflict women, but much improvement is needed; see the Editorial on p. 1517 and
News story on p. 1570. Uterine fibroids, a major indication of hysterectomy,
have received less attention. See Walker and Stewart on p. 1589. Likewise,
mechanistic insight is needed to define preeclampsia, a circulatory disturbance
between mother and fetus (see Redman and Sargent, p. 1592). In contrast,
Berkley and colleagues (p. 1587) note that substantial progress has been made
in understanding endometriosis, particularly the pain associated with it.
The understanding of male/female differences in disease manifestation and drug
response has also lagged behind (see News story on p. 1572). For instance,
investigators are beginning to probe the differences in brain chemistry and
anatomy that contribute to the different patterns of mental illness in men and
women (see News story on p. 1574). In a related story (p. 1576), Miller
describes how HIV/AIDS and other factors seem to increase risks to mental
health for women in developing countries. Greater awareness about gender
variation also reveals an increasing feminization of the HIV/AIDS pandemic,
due in part to the heightened social and biological vulnerability of women, as
Quinn and Overbaugh describe on p. 1582.
In dealing with topics that differentiate the sexes, the heart emerges as
central. Mendelsohn and Karas (p. 1583) review how the molecular and cellular
physiology of the heart and blood vessels differ between males and females
during development and in cardiovascular disease. And a News story on p. 1580
reports on gender differences in bone quality and fracture risk, an issue of
increasing importance to both sexes in an aging population. Finally, touching
on a hot-button topic, Enserink (p. 1578) explores what some call the
medicalization of female sexuality and whether, in the age of Viagra, lack of
desire is a disease requiring drug therapy.
Related materials include Policy Forums in which Greenberger and Vogelstein (p.
1557) and Manasse (p. 1558) debate some pharmacists refusal to dispense
prescriptions for contraception, a Book Review by Aplin on pregnancy loss (p.
1555), and multiple online articles in the Signal Transduction and Science of
Aging Knowledge Environments on topics such as cervical cancer and the role of
estrogen in diseases of aging.
In all, this issue contains ample fodder for the ongoing debate about what men
and women share and how they are uniquela différence.
BEVERLY PURNELL, LESLIE ROBERTS,ORLA SMITH Vive la Différence
T I T L E O F S P E C I A L S E C T I O N
1570 From Dearth to Deluge
Clinical Trials:Keeping Score on the Sexes
1572 Gender in the Pharmacy: Does It Matter?
1574 Sex and the Suffering Brain Poor Countries, Added Perils for Women
1578 Lets Talk About Sexand Drugs
1580 Bone Quality Fills Holes in Fracture Risk
R E V I E W S
1582 HIV/AIDS in Women: An Expanding Epidemic
T. C. Quinn and J.Overbaugh
1583 Molecular and Cellular Basis of Cardiovascular Gender Differences
M. E. Mendelsohn and R. H. Karas
1587 The Pains of Endometriosis
K. J. Berkley,A. J. Rapkin, R. E. Papka
1589 Uterine Fibroids: The Elephant in the Room
C. L.Walker and E.A. Stewart
1592 Latest Advances in Understanding Preeclampsia
C.W. Redman and I. L. Sargent
See also the Editorial on p.1517;the Book Review on p.1555;the Policy Forums on
pp.1557 and 1558;SAGE KE material on p.1511;STKE material on p.1511; and
www.sciencemag.org/sciext/womenshealth for related online material.
From Dearth to Deluge
The charge that women were being excluded from clinical studies led to the
Women's Health Initiative; it produced a flood of data and controversy At a
congressional hearing 15 years ago, male leaders of the U.S. biomedical world
endured a grilling about sex and science. Specifically, on 18 June 1990,
Representative Henry Waxman (D-CA) asked the heads of the various National
Institutes of Health (NIH) what they were doing to enforce a 3-year-old mandate
to include women in clinical trials. (The NIH director's job was vacant at the
time.) One by one, the witnesses acknowledged that they didn't have much to
report. It was a pivotal moment, say advocates for women's health studies. It
attracted the media and reduced an arcane debate about disease prevention and
sex differences into a simple theme: Women were being excluded.
The drama had been carefully choreographed, recalls Phyllis Greenberger,
executive director of the Society for Women's Health Research (SWHR) in
Washington, D.C. In 1989, its leaders discovered that a government panel
co-chaired by NIH official Ruth Kirschstein had found that "there was a dearth
of women enrolled in clinical trials," as Kirschstein recalls. The panel had
also instructed U.S. health agencies to insist that grantees recruit more
women--or explain why they didn't intend to.
"That was the hook" on which to hang an indictment, says Greenberger: "Here was
a mandate that said they were supposed to be doing something--and they weren't
doing it." Meanwhile, SWHR's co-founder, NIH obstetrician-gynecologist Florence
Haseltine, says that she used her own money to hire the lobbying team of Marie
Bass and Joanne Howes to push the campaign, leading to a congressional audit
and the 1990 hearing.
Although women were not systematically excluded from trials, later analysts
have found (see sidebar ) that they were kept out of some famous studies of
heart disease in the 1980s. One of the male-only studies--with the acronym MR
FIT--examined the benefits of a careful diet and exercise. Another, the
Physicians' Health Study by Harvard Medical School in Boston, Massachusetts,
found that middle-aged doctors who took a small dose of aspirin every other day
had a significantly lower risk (44% less) of heart attack. For efficiency, it
had enrolled 22,071 men (who were more likely than women to have heart attacks
and yield data) but not one woman. Critics said the results were irrelevant for
half the population.
Because of such criticism, NIH launched a companion aspirin study in the 1990s
of 39,876 women. A decade later, in March 2005, this $30 million study reported
that women were different after all: Unlike men, the aspirin takers did not
have a significantly lower risk of heart attack, but they did have a somewhat
lower risk of stroke.
The government also made some administrative changes in 1990, creating an NIH
Office for Research on Women's Health, headed by Vivian Pinn, to see that sex
differences were investigated. And in a move that surprised many, President
George H. W. Bush chose Bernadine Healy--a cardiologist at the Cleveland Clinic
in Ohio--to be the first woman director of NIH. Almost immediately, in 1991,
Healy unveiled what she called "a moonwalk for women," the most ambitious trial
undertaken by NIH, the Women's Health Initiative (WHI). Some warned that the
project, designed to run for 15 years and recruit more than 160,000 women,
would cost $1 billion. By official reckoning, however, it will only reach the
$725 million mark in 2007.
From the start, WHI caught flak, Healy recalls. Critics said it wouldn't work
because it was too complex and poorly designed; they also feared that not
enough women would enroll. Healy battled "relentlessly" to get money for it,
she says, adding that she helped get it entrenched by committing money to 40
study centers before she left NIH. She also says she helped fend off a move to
end the trial in the Clinton Administration.
Getting results. The number of clinical studies on women's health has increased
dramatically since the 1980s.
Now in its 13th year, WHI has been extended to at least until 2010 so that it
can continue tracking women in a large observational study. In October, WHI
plans to deliver findings from two key diet studies, on the effects of calcium
supplements and vitamins. But by far the project's most dramatic moment came in
July 2002, when it produced a stunning and unexpected result. Hormone
replacement therapy, assumed to help avert heart disease and keep the brain
healthy, actually elevated risks in older women.
There was never any doubt, Kirschstein says: "WHI was Bernadine's baby." To
make it work smoothly, Healy summoned the heads of 10 NIH institutes to weekly
meetings. At the core of the project were three randomized clinical trials that
recruited roughly 68,000 women aged 50 to 79. The studies were linked so that
women could contribute data to more than one at once. One examined hormone use,
and the other two were designed to test popular ideas: that a low-fat diet
could reduce breast cancer, colon cancer, or heart disease; and that taking
daily supplements of vitamin D and calcium could prevent osteoporotic bone
WHI also paid for a series of community projects designed to instruct women in
healthy living. Funded by NIH, they were carried out by the Centers for Disease
Control and Prevention in Atlanta, Georgia.
WHI's largest component is an observational trial that enrolled 93,000 women
and continues to collect blood, urine, and DNA; it will go for another 5 years,
says Program Director Jacques Rossouw of the National Heart, Lung, and Blood
Institute (NHLBI). Participants have given consent to future genetic studies,
including possible commercial uses of the data. Healy says this part--modeled
on a famous 50-year study of doctors in Framingham, Massachusetts--may be WHI's
The best-known part of WHI, though, is the clinical trial of hormone
supplements. It had been planned for years at NHLBI, says Rossouw, because of
the booming use of female hormones. In 1990, Wyeth Pharmaceuticals of
Collegeville, Pennsylvania, manufacturer of the most popular pill--containing
conjugated equine estrogen with progestin--was seeking approval to market the
drug as a heart disease preventive. "We would have done the trial anyway," says
Rossouw, but "Healy was forceful, and the political climate was favorable; that
was why she could get it funded so rapidly."
The "medical culture at the time," Healy recalls, was "basically to put every
woman over the age of 50 on hormones until she stepped into the grave." She,
too, believed hormones were beneficial but felt the evidence "wasn't
sufficient." The trial had two arms. One gave placebo or therapy in the form of
a pill containing estrogen and progestin--a hormone added to reduce estrogen's
known risk of increasing uterine cancer. The other gave estrogen alone to women
who had had hysterectomies.
The project had "many skeptics," Rossouw recalls. For example, some doubted
that women would stay with the low-fat diet long enough to yield results. A
review by the Institute of Medicine (IOM) in 1992 suggested that this part of
the study should change its primary endpoint to look for heart disease
benefits, not cancer reduction. The chance of failure was so high, the IOM
group warned, that it would be "wrong" to invest so much money and "find after
14 years that little in the way of useful information had been learned." A
member of that panel, epidemiologist Lynn Rosenberg of the Slone Epidemiology
Unit at the Boston University School of Medicine, says today: "I will be very
surprised if the results [of the diet trial] ... show anything." The vitamin
D-calcium trial, she thinks, is more likely to come up with significant
results. Data from both are to be published in the fall.
One of the critics' biggest worries--as Rossouw recalls with irony--was that
giving women a placebo would deprive them of the benefits of hormone therapy,
possibly making the trial unethical. Indeed, the IOM panel predicted that WHI
was "likely to terminate early because of evidence demonstrating [hormones']
protection against" coronary heart disease.
It did end early, but not because hormone therapy was beneficial: WHI officials
reported in July 2002 that women who took the combination pill were more likely
than those on placebo to develop invasive breast cancer--38 in 10,000 compared
to 30 in 10,000. Risks for heart disease, stroke, and blood clotting were also
higher, whereas risks for hip fracture or colon cancer were lower.
The announcement made front-page news and sent a shock through the more than 6
million U.S. women who were taking hormones. Many quit (Science, 19 July 2002,
p. 325 and 1 November 2002, p. 942). Sales of the estrogen-progestin pill
plummeted about 40% and never regained the lost ground.
Because cancer risks for estrogen alone were deemed much lower, this part of
the WHI trial continued. In March 2004, a monitoring panel stopped it, too,
because women on this therapy had a higher risk for blood clots and strokes
than those on placebo. An analysis showed that estrogen gave no significant
protection against heart disease. Later in 2004, an analysis of women over 65
in the estrogen-only group found that they had a somewhat elevated risk for
dementia compared to those on placebo.
The adverse events were undeniable, but some experts criticized the way WHI
officials and authors described and released the findings. Wulf Utian, for
example, a reproductive endocrinologist at the Cleveland Clinic and executive
director of the North American Menopause Society, charges that the government
stressed negative results to "achieve maximal impact."
Rossouw acknowledges that the data were released in a dramatic way. He didn't
give advance warning to drug companies, doctors, or professional societies, but
he mailed the findings directly to study participants--to maintain
"confidentiality," he says. And he held a press conference because "the goal
was to change medical practice." WHI succeeded, Rossouw thinks: Before WHI,
people were trying to "get all older women on hormones," and afterward, the aim
was to "minimize exposure." That is a "180-degree turnaround in medicine,"
Rossouw says--and one "we can feel gratified about."
Critics object, however, that WHI's specific results were used to discredit all
hormone therapy. Utian suggests that the heart disease findings from women in
the WHI group (median age 63) and dementia findings (age 65 and older) might
not apply to younger women. For those just approaching menopause around age 50,
he says, the benefits of symptom relief from hormones may outweigh other risks.
Endocrinologist Judith Turgeon of the University of California, Davis, also
points out that alternative formulations may be less risky than the hormone
pills used in WHI, which contain equine estrogens that can adversely affect the
liver (Science, 28 May 2004, p. 1269). She notes that some researchers are
testing lower drug doses or transdermal rather than oral administration.
Although WHI is not ready to conduct a big study of younger women--mainly
because it would cost too much, says Rossouw--it is looking into a few
lingering questions. For example, the WHI program is supporting an imaging
study of women in the estrogen-only therapy group to look for reduced
calcification of the arteries, a sign that may indicate a lower risk for
coronary heart disease. WHI experts are watching the private Kronos Longevity
Research Institute in Phoenix, Arizona, which is enrolling 720 women younger
than the WHI profile in a trial that aims to test low-dose estrogen therapy and
administration of estradiol by skin patch in combination with oral
progesterone. If such studies are encouraging, Rossouw thinks, the government
might consider a larger trial.
Healy argues that WHI's payoff will be greater than the sum of its findings. It
proved that "big, strategic trials" of this kind can work, she claims, and that
the government should not shy away from them. Most important, she says, WHI
"absolutely blew open" the topic of women's health, which had been "terribly
Clinical Trials: Keeping Score on the Sexes
Biomedicine used to have a bias against including young women in clinical
trials, says Ruth Kirschstein, a former director of the National Institutes of
Health (NIH)--partly because of the thalidomide disaster. This drug, given to
pregnant women to stop nausea in the 1950s and early 1960s, caused thousands of
birth defects. After it was withdrawn, regulatory agencies directed that young
women should be kept out of clinical trials to protect fetuses they might be
carrying. That attitude lived on into the 1980s--long after new tests and
testing methods had made it easy to identify early pregnancy and avoid risks,
Kirschstein says. In 1987, a government panel she co-chaired found that U.S.
agencies were slighting women's health and ordered that more women be included
in research trials (see main text ). Some trials, particularly big ones looking
at heart disease, were designed to focus on male patients. Too often, and with
too little evidence, results based on males were extrapolated to females, the
Some independent analysts argue that, aside from the big heart studies, the
imbalance was never that great. But since the initial complaints, both sides
agree, NIH has tipped the balance to include more women. NIH's own evaluation
of grants found in 1987 that only 13.5% looked at diseases unique to women. But
then, only 6.5% were on diseases unique to men (Science, 11 August 1995, p.
766). In 1990, a General Accounting Office (GAO) study ordered by Congress
found that NIH was being "very slow" in carrying out its own goals of
recruiting more women and investigating physiological differences between the
sexes. A sample of 50 grant submissions on diseases that affect both sexes, GAO
found, included 20% that didn't mention the subjects' sex, and "some" that
excluded women but didn't explain why. In a 2000 audit, GAO found that NIH had
made "significant progress." Peer reviewers reported that 94% of grant
proposals in 1997 met the standards for including women, and "more than 50% of
the participants in clinical research studies that NIH funded" were women.
As it became clear that women were not being excluded from the new crop of
trials, critics shifted ground. For example, in a paper released on 10 May, the
Society for Women's Health Research (SWHR) in Washington, D.C., said that NIH
is not doing enough to get researchers to run clinical trials in a way that
will bring to light physiological differences between men and women. The report
by Viviana Simon, Sherry Marts, and other members of the SWHR staff found that
"a very small percentage" of all indexed NIH grants between 2000 and 2003
(about 3%) were awarded to study sex differences. It also found that the
richest institutes--such as those dedicated to cancer, heart disease, and
infectious diseases--scored low in the study's index of funding research on sex
differences. Now that women are being included in trials, SWHR argues,
researchers should be doing more to learn how they differ from men.
Gender in the Pharmacy: Does It Matter?
Studies of how women's and men's bodies process drugs have turned up mostly
minor differences. But some drugs may be less or more effective in women or
cause more side effects, and other variations may await discovery In 1989, a
39-year-old woman blacked out while she and her husband were eating dinner. He
rushed her to the Naval Medical Center in Bethesda, Maryland, where tests
showed that her heart had a dangerous irregular rhythm that can lead to cardiac
arrest. Doctors were puzzled: The woman was taking a popular antihistamine,
Seldane, overdoses of which had caused abnormal heart rhythm, yet she was
taking the recommended dose. The doctors consulted Louis Cantilena, a clinical
pharmacologist at the hospital, who in turn called a colleague at the U.S. Food
and Drug Administration (FDA). Looking through FDA's adverse events database,
FDA staffers found two dozen cases of arrhythmias from Seldane, or
terfenadine--the majority in women. It was one of the first red flags that
researchers might have been missing sex differences in responses to drugs.
Combing through data on other medications, FDA and researchers realized that at
least nine drugs could cause potentially fatal heart arrhythmias in women,
especially when prescribed with certain antibiotics. By 2001, FDA had pulled
four of these drugs off the market, including Seldane. "There's no way to know
how many, but there were deaths," says Raymond Woosley, then a pharmacologist
at Georgetown University Medical Center in Washington, D.C., who began studying
The drug withdrawals fueled an argument made by advocates for women's health:
Sex differences in responses to drugs had been missed because women were not
always included in clinical trials, or if they were, the data were not broken
down by sex. That has changed considerably in the past dozen years, after the
National Institutes of Health brought more women into clinical trials and FDA
rescinded a 1977 rule that excluded women of childbearing age from early trials
(see p. 1570)--with positive results, advocates say. Earlier this year, for
example, researchers reported in the New England Journal of Medicine (NEJM)
that aspirin--which protects men against heart attack but not stroke--has
exactly the opposite effect in women.
Yet sex differences in drug responses remain controversial. Concerns center on
two aspects: how quickly drugs are metabolized and absorbed, and how they
affect the body once they're in the bloodstream. Although studies have found
many differences in how women and men process drugs, these changes are less
worrisome than expected. Differences in how safe and effective a given blood
level of a drug is for a man or woman are probably bigger issues, many experts
agree. This is harder to study, however, and so far only a few clear-cut
examples have emerged. That leaves some experts skeptical that sex will matter
much in the long run; genetic variation among individuals, especially of
different ethnicity, may dominate, they say. "Gender is not the major concern
that we thought it would be," says Leslie Benet, a pharmacologist at the
University of California, San Francisco (UCSF).
But others counter that drug researchers have barely scratched the surface.
Despite prodding, clinicians still don't always analyze data on women
separately, and more research--and better research tools--may yet reveal more
serious gender differences, they say. Even subtle sex differences may be
important in an era of personalized medicine. "When it's all done, we still
find sex is a factor that keeps coming out," says clinical pharmacologist and
cardiologist Janice Schwartz of UCSF.
Less than expected
As far back as 1932, researchers noticed that female rats could be knocked out
with half the dose of barbiturates needed for male rats of the same size. But
such differences were largely ignored until 1993, when FDA reversed course on
including women in trials. Until then, trial results were dominated by "the
cult of the typical 70-kilogram male," says Sherry Marts, vice president of
scientific affairs for the Society for Women's Health Research in Washington,
That began to change, slowly. The 1993 FDA guideline explicitly urged drug
companies to look for sex differences in drug processing, or pharmacokinetics.
Researchers examined old animal data and new human evidence suggesting that
males and females differ in the activity of liver enzymes that metabolize
drugs, particularly the cytochrome P450 enzymes, whose ex-pression is
mod-ulated by sex hormones. One such enzyme, CYP3A4, is involved in
metabolizing more than half of all therapeutic drugs; women clear some CYP3A4
enzyme drugs more quickly than men do and thus may need a higher dose to get
the same effect. (The difference probably also involves women's lower liver
levels of a protein called P-glycoprotein that shunts the drug out of cells in
which CYP3A4 processes it.)
Women are also smaller on average than men are, they may absorb drugs more
slowly, and their kidneys filter excreted drugs out more slowly. Because women
tend to have more body fat, fat-soluble drugs stay in their bodies longer. All
this means a woman who swallows the same number of pills as a man may end up
with a larger or smaller level in her blood.
In many trials, however, differences in women's responses to a drug disappear
if the dose data are simply adjusted for body weight or surface area. The
gender differences in processing drugs that remain appear to be relatively
minor, says pharmacologist Bernd Meibohm of the University of Tennessee,
Memphis. The best evidence is an FDA study of the 300 new drugs reviewed from
1995 to 2000, more than half of which provided sex data. Only for 11 drugs were
pharmacokinetic differences greater than 40%, and none resulted in separate
dosing instructions for women--indicating the difference wasn't important to
the clinical outcome, notes Margaret Miller, science program manager for FDA's
Office of Women's Health. Pharmacologist Gail Anderson of the University of
Washington, Seattle, is not convinced, pointing out that in negotiating labels
with FDA, companies would resist dosing for subpopulations--or even for body
weight--because it makes it harder to market the drug.
Metabolism differences in women do matter for drugs that must be given in very
precise doses, such as the blood thinner warfarin and cancer drugs and
immunosuppressive drugs. But doctors already carefully tailor doses of those
drugs to the individual, notes Benet. "The bottom line is, [sex differences in
pharmacokinetics] doesn't seem to make a major difference," agrees Meibohm.
The female heart
A potentially much bigger problem is the difference in how men's and women's
bodies react to the drug once it's reached the bloodstream. Known as
pharmacodynamics, this property of drugs is harder to measure: Gauging
improvement in depression, for example, is trickier than detecting the blood
level of a chemical. But disparities for some classes of drugs have emerged.
Probably best-established are differences in responses to medications that can
affect the heart's rhythm, such as terfenadine. These include some
antihistamines, antibiotics, antiarrhythmics, and antipsychotics. Woosley and
others showed that these drugs share the ability to block potassium channels in
the heart, which in turn can affect the heart's rhythm. Two-thirds of reported
arrhythmias from these drugs occur in women; they are especially vulnerable
because the female heart has a longer "QT interval," the time it takes to
recharge between beats. More than 30 marketed drugs are known to cause
arrhythmias, notes Woosley, president of the C-Path Institute in Tucson,
Arizona. The University of Arizona lists these drugs on a Web site
Women also appear to respond differently to drugs for treating or preventing
cardiovascular disease. The latest example is the study of aspirin reported in
the 31 March issue of NEJM of results from the Women's Health Study, which was
launched in 1993 after protests that a previous study had included only men.
Whereas men were protected from heart attacks but not stroke, women 45 years or
older who took low-dose aspirin for 10 years had no fewer heart attacks but a
17% lower rate of stroke. The results may involve differences in physiology in
women, such as smaller coronary arteries than men have and lower lipid levels
Sex differences also seem to come into play in the reaction to opiates. The
strongest evidence comes from a series of studies in the mid-1990s led by Jon
Levine's group at UCSF, which looked at how men and women respond to drugs
known as kappa-receptor opiates after wisdom tooth surgery. The drugs worked
much better on women and caused fewer side effects than opiates such as
morphine that have a different target, mu receptors. Male and female rodents
also respond differently to opiates.
But other groups haven't yet replicated the UCSF results, and in a controlled
lab setting--for example, with volunteers subjected to mild heat and muscle
pain--the same sex differences aren't always observed, cautions pain researcher
Roger Fillingim of the University of Florida, Gainesville. The discordant
studies may reflect factors such as the type of pain or opiate drug dose,
Fillingim says. "I just don't think we have enough data" to know which
conditions result in sex differences, he says.
The jury is still out on antidepressants as well. A fairly large study led by
psychiatrist Susan Kornstein of Virginia Commonwealth University in Richmond
and published in 2000 in the American Journal of Psychiatry reported that women
responded better to selective serotonin reuptake inhibitors (SSRIs); men got
more help from tricyclics, which target receptors for serotonin and other
neurotransmitters. Not all subsequent studies have found these differences,
Under the radar
Many agree that important sex differences are yet to be discovered. For
example, researchers noticed only in 2002 that an old drug for heart failure,
digoxin, raised the death rate in women by 4% in an earlier trial, possibly
because they received too high a dose, notes Schwartz. The painkillers known as
COX-2 inhibitors, one of which was withdrawn from the market last year because
of side effects, are also under the microscope. Concerns were raised after
Garrett FitzGerald's group at the University of Pennsylvania in Philadelphia
found that blocking the COX-2 enzyme in mice also hinders estrogen's protective
effects against cardiovascular disease, suggesting that giving COX-2 drugs to
young women could put them at higher risk for heart attacks and stroke
(Science, 19 November 2004, p. 1277).
Pinning down sex differences should become easier with new biomarkers--such as
brain imaging--that enable researchers to measure disease and other endpoints,
such as pain, more objectively. "My guess is we're going to find a lot more
gender differences," Woosley says.
Sex differences are also coming up in the context of pharmacogenomics: genetic
differences, often tied to a single polymorphism, or mutation, that affect an
individual's disease susceptibility, say, to heart disease or response to a
drug. Although these mutations are usually not carried on the X chromosome and
so are independent of sex, they can be modulated by sex hormones. For example,
researchers recently found a polymorphism that makes redheaded women--but not
men--more responsive to opiates, notes Fillingim, a co-author (Science, 16 July
2004, p. 328).
Even if most sex differences in drug responses aren't dramatic, they will feed
into the cost-benefit tradeoff for a drug--all part of the personalized
medicine equation, says Miller of FDA. "The most important message is to look
for differences in treatment response by gender," says Kornstein,
editor-in-chief of the Journal of Women's Health. She and others say their
colleagues in drug research are listening, but not everyone is on the same page
Sex and the Suffering Brain
Researchers are seeking biological reasons for the widespread gender
differences in the prevalence and symptomatology of mental disorders It's easy
to start a fight about whether there are gender differences when it comes to
mental skills, but there's little debate that patterns of mental illness and
disorders vary between the sexes. Women, for example, are more likely to get
depressed (see table). Men are more severely afflicted by schizophrenia.
Females have more anxiety. Males exhibit more antisocial behavior. Most
alcoholics and drug addicts are male; females have more eating disorders. Even
suicide has a gender bias. Females make more attempts; males are more
Although culture helps shape how the two sexes express mental problems, some
differences persist across cultures and across time, says psychiatrist Kenneth
Kendler of Virginia Commonwealth University in Richmond. And that suggests a
role for biology. In fact, says Thomas Insel, head of the National Institute of
Mental Health (NIMH) in Bethesda, Maryland, "it's pretty difficult to find any
single factor that's more predictive for some of these disorders than gender."
Talking about sex differences has long been taboo in some quarters--"People
hear 'sex differences' and think you're talking about individuals, not
populations," says Insel. "It's critical to remember there's a huge amount of
variation within a population and overlap between populations." But
neuroscience research, especially the explosion in brain imaging, has produced
data that are hard to ignore. "Every time you do a functional MRI on any test,
different parts of the brain light up in men and women," says Florence
Haseltine, a reproductive endocrinologist at the National Institute of Child
Health and Human Development (NICHD) in Bethesda, Maryland. "It's clear there
are big differences." Understanding them will have "tremendous implications"
for treatments of brain diseases and injuries, says Viviana Simon, director of
scientific programs for the Society for Women's Health Research in Washington,
Most mental disorders are complex and resist the hunt for specific genes, yet
family and twin studies have demonstrated significant heritability for them.
These disorders interact with brain differences between the sexes that arise
from genes on the X and Y chromosomes and from the bath of gonadal hormones
that soak fetal brains early in gestation. Sex hormones are far-reaching in
their powers, notes Insel. "They are sort of master transcription regulators;
they affect hundreds of downstream genes. ... There's no question these are big
players in mental disorders." Those sex-related changes are sort of early
filters, influencing the expression of underlying disorders in different ways,
says psychologist Elizabeth Susman of Pennsylvania State University, University
No one has managed to draw an unbroken line from prenatal development to adult
behavior. But some researchers are now trying to tease apart just what aspects
of brain anatomy and chemistry can help account for the gender skewing in
mental disorders. "We're just at the beginning of trying to examine these
differences," says Cornell University endocrinologist Margaret Altemus. Some
studies are contradictory, and there is still more known about animals than
Epidemiologic studies show that women are more vulnerable than are men to most
disorders that affect the emotions. These include major depression and a host
of anxiety-related conditions, such as generalized anxiety disorder, panic
disorder, posttraumatic stress disorder, and phobias.
Anxiety and depression are very closely related: Eye-blink tests reveal that a
strong "startle response" is a good predictor for both. Negative experiences
can trigger both anxiety and depression in vulnerable people. Those feelings
involve the activation of multiple neurotransmitter and hormonal systems,
including stress mechanisms that are heavily influenced by sex hormones.
The human stress response basically has two components: the autonomic nervous
system that causes raised heartbeat, sweaty hands, and gut churning; and the
slower-responding hypothalamic-pituitary-adrenal (HPA) axis. The HPA axis
involves a cascade of hormonal events that are normally counteracted by release
of the stress hormone cortisol.
Because female depression rates start to rise during puberty, notes
psychologist Laura Stroud of Brown University in Providence, Rhode Island,
researchers posit that hormones play a role in women's vulnerability to
affective disorders. Animal and human research has shown that sex hormones
affect stress responses in different ways. Just the right amount of estrogen is
required for emotional balance, says NICHD endocrinologist George Chrousos.
Some women go into "withdrawal" and hence depression when levels drop. But too
much estrogen can overactivate the HPA axis, also resulting in depression, he
says. Testosterone, on the other hand, may protect against stress and
depression through its damping effect on HPA reactivity. This is illustrated by
a study appearing last month in Neuropsychopharmacology. Psychiatrist David
Rubinow of NIMH and colleagues suppressed sex hormone production in 10 men and
stimulated their HPA axes with corticotropin-releasing hormone (CRH). They
found that testosterone replacement "significantly blunted" the cortisol
response to CRH.
Other research shows that fear, a powerful stressor, may activate stress
responses more in females than in males. Data from rats and mice
"overwhelmingly indicate that females show more intense fear responses than
males," says Jaak Panksepp of the Medical College of Ohio in Toledo.
Testosterone appears to reduce males' reactions to pain, he adds. Human
evidence is beginning to accumulate. In a study in the journal Emotion in 2001,
researchers at the University of Florida (UF) observed the reactions of 50
women and 45 men to pictures of distressing things, such as car crashes and
mutilations. They found that women had more extreme autonomic reactions as
gauged by heart rate, skin conductance, and the startle response. "Women are
more reactive on average in everything involving negative stimuli," says UF
psychologist Margaret Bradley.
Brain-imaging studies are supplying a wealth of new data. A group at Westmead
Hospital in New South Wales, Australia, recently completed a study (in press at
Neuroimage) showing that females exhibited more widespread activation of the
amygdala, the seat of the fear response--corresponding with rapid heart rate
and sweating--than males did in reaction to pictures of people with fearful
facial express-ions. In another study, in press at Neuro-report, a team headed
by David Silbersweig of Cornell University's Weill Medical College in New York
City found that normal females show more reaction to stress--in this case,
anticipating a pain on the wrist--in the subgenual prefrontal cortex, a key
region linked with anxiety and depression.
Although the evidence is more ambiguous, gender differences have also been seen
in the HPA axis, the other component of the stress machinery. Observing 50
young volunteers, half of them women, Brown's Stroud found that in an
"achievement" test, in which subjects must make a speech and perform a
subtraction task in front of a panel of judges, men secreted higher levels of
cortisol. But in a "social rejection" test, in which trained confederates made
the subjects feel excluded in brief interactions, women's cortisol levels were
higher, her team reported in the journal Biological Psychiatry in 2002.
NICHD's Chrousos contends that the HPA axis is slightly more reactive in
females, as shown in a study in which young women responded with significantly
higher levels of cortisol to a CRH challenge. Chrousos speculates that a highly
tuned HPA axis, clearly evident in rodents and primates, is an evolutionary
adaptation to help mothers protect their young.
Aggression and impulsivity
Sex hormones are also implicated in aggression-related gender differences,
notes Kendler. There is abundant evidence, he says, that men are more prone to
expressing unhappiness through an "externalizing pathway" of physical behavior
that includes drinking, drug abuse, and violence, whereas women are more likely
to "internalize," leading to depression and disorders such as anorexia.
The pattern of male externalizing, like sex differences in general, becomes
more pronounced during puberty, when the hormones are flowing. "We know, from
primate studies, that testosterone is directly related to aggression," says
Kendler. "If you give females testosterone, they get more aggressive."
Addictions follow the pattern of male externalizing. Epidemiological studies
have shown, for example, that in families of women with bulimia, the men often
have alcoholism and other addictions. Studies have repeatedly shown that even
within the alcoholic population, females are more often diagnosed with
depression, whereas more males express antisocial behavior.
The sex-based tendency to act out versus internalize is evident in the
distribution of the personality disorders, which involve maladaptive patterns
of thinking and relating to the world. Some of these, such as dependent or
histrionic personality disorders, are hotly debated, and critics argue that
they only exemplify learned gender-typical behaviors. "Can it be that human
beings manifest certain symptoms in ways that are politically and socially
acceptable within certain historical times?" asks feminist therapist Arlene
Istar Lev of Albany, New York. But psychiatrist Larry Siever of Mount Sinai
School of Medicine in New York City says there's more to it. "It used to be a
non sequitur to link biology and personality," he says. "Now we see a very real
Take borderline personality disorder (BPD), which features extreme emotional
instability, impulsivity, and self-harming behavior and is most often seen in
post-adolescent girls. Although people with BPD frequently have a history of
childhood abuse, says Siever, brain scans of patients also show abnormalities.
In an unusual study now under review at Biological Psychiatry , Siever and
psychiatrist Antonia New also found sex differences. They compared the brains
of 17 males and 9 females with BPD and a history of impulsive aggression to
normal controls matched for sex. They report that the males with BPD showed
less neural activity in prefrontal areas involved in inhibition. This
"presumably suggests a brain mechanism" for this type of aggression, Siever
says. The fact that males with BPD are more prone than women with BPD to
impulsivity and aggression could partly explain why more women get the
diagnosis, he adds; the men may be seen as having antisocial personality
Researchers are also looking into the biological dimensions of ASP, in which
males outnumber females three to one. People with ASP (formerly known as
psychopaths) don't form deep attachments and feel little guilt. Psychologist
Adrian Raine of the University of Southern California in Los Angeles believes
he has hit upon a possible biological marker. He reported in 1997 in the
journal Child and Adolescent Psychiatry, from a longitudinal study of 1800
children in the Republic of Mauritius, a strong correlation between slow heart
rate among 3-year-old boys--suspected to reflect reduced autonomic
reactivity--and their subsequent antisocial behavior as adolescents. A high
threshold for reacting to physical or social threats can make for
"fearlessness," which in turn inhibits the learning of normal social
inhibitions, says Raine.
Susman of Penn State has similar findings. In a 1997 study she reported that
adolescents who had low cortisol levels prior to an anticipated physical
stressor exhibited raised antisocial behavior 1 year later. She believes these
individuals are unable to "anticipate" stresses. "They're not good at planning
or regulating," she says, so "they don't anticipate fear." It may be that males
are more prone to hypoarousal of the stress response system and females to
hyperarousal, speculates Susman.
Sex differences also extend to cognitive functions such as memory, attention,
and perception. Men's brains are more lateralized, which means that higher
cortical functions tend to be centered in the right or left side of the brain,
says genetic epidemiologist Kathleen Merikangas of NIMH, whereas in females
there's more "crosstalk" between the sides and therefore more redundancy.
Evidence for this comes from the fact that women are more likely than men are
to recover language from strokes in the left hemisphere, where language is
This redundancy may also be protective in girls, who have much lower rates than
do boys of childhood developmental and mental disorders, including attention
deficit hyperactivity disorder (ADHD) and autism, says psychiatrist Raquel Gur
of the University of Pennsylvania in Philadelphia. Estrogen, too, says Gur,
appears to have neuroprotective effects according to results of research on
brain injury, epilepsy, and cognitive decline in aging.
Gur says these differences also seem to work against men afflicted with
schizophrenia, the most complex and devastating mental illness of all. More
males than females have schizophrenia, and they have earlier, more severe
symptoms, says psychiatrist Jill Goldstein of Harvard University. In brain
scans comparing men and women with schizophrenia, Goldstein has found that men
tend to have greater deficits than women do in attention, language,
visual-spatial perception, and other areas ruled by the cortex, such as
olfaction and motor skills. These are also areas that she and others have found
to be sexually dimorphic in normal subjects. She believes these deficits all
begin prenatally during the period of sexual differentiation of the brain.
Researchers are still cautious about their conclusions. Despite evidence of a
"huge number of ... differences between men and women's brains," says Cornell's
Altemus, "it's hard to know which are functionally relevant." Nonetheless,
times have changed, observes Goldstein: "For many years we were not even
allowed to say there were sex differences in the brain."
Poor Countries, Added Perils for Women
When the Indian government disbursed the first round of financial aid to
families in Tamil Nadu state, hard hit by the 26 December 2004 tsunami, they
doled it out to men, the traditional household heads. That didn't work too
well, says K. Sekar, a psychiatrist with India's National Institute of Mental
Health and Neurosciences, who has coordinated mental health support for the
Many men have coped with the disaster by drinking, Sekar explains, and much of
the money intended for families flowed straight into state-run liquor stores.
The second round of aid, delivered to women, seems to be doing more good, he
says. Even though women--especially those who lost children in the
tsunami--appear to have suffered most in psychological terms, they've handled
it differently. Drinking is socially unacceptable for women, Sekar says, and
they have largely internalized their distress, showing signs of anxiety and
The psychological aftermath of the tsunami in Tamil Nadu reflects two of the
most robust trends in psychiatric epidemiology: Across the globe, anxiety
disorders and depression are more common in women, and substance abuse is more
common in men (see main text ). The situation there also hints at how social
factors and women's roles as childbearers influence the mental health of women
in developing countries, often for the worse.
Although there are no reliable figures on the prevalence of mental disorders
for many parts of the world, there are signs that women in poor countries are
more vulnerable than women in richer parts of the world, says Ricardo Araya, a
Chilean-trained psychiatrist at the University of Bristol, U.K. A recent study
by Araya and colleagues is the first to attempt a direct comparison of the
gender gap in the prevalence of depression and anxiety disorders between
developing and developed countries. The researchers interviewed more than
10,000 men and women in urban areas of Chile and the United Kingdom about their
mental health and reported in the April issue of Social Science and Medicine
that the gender gap is greater in Chile.
For women in sub-Saharan Africa, especially, HIV is a major risk factor for
depression, says Sylvia Kaaya, a psychiatrist at Muhimbili University College
of Health Sciences in Dar es Salaam, Tanzania. Although little research has
been done to examine HIV's toll on women's mental health in particular, Kaaya
suspects that women experience extra stress that ups their risk of depression.
Women have little say in negotiating condom use and other protective measures
and are generally expected to care for infected relatives, Kaaya says.
Much of the research on women's mental health overall in developing countries
has investigated its links to reproductive health. Women in poorer countries
are more likely to have miscarriages or lose young children, and such events,
especially when they occur more than once, take a heavy toll on a woman's
psychological well-being, says Veena Das, an anthropologist at Johns Hopkins
University in Baltimore, Maryland. Das has just completed a study in poor
communities in Delhi, India, that documents sharply elevated rates of
depression in women who have lost multiple pregnancies.
Women who give birth to healthy babies aren't immune either. Rates of postnatal
depression run high in some developing countries. In India and Pakistan, for
example, a handful of studies in the past few years have found that 20% to 30%
of women suffer postnatal depression, about twice the prevalence in wealthy
countries. That's not just bad for moms. A study published last September in
the Archives of General Psychiatry found that Pakistani infants born to
depressed moms were four times more likely to be underweight 6 months after
Socioeconomic factors work against women in many societies, says Jill Astbury,
a psychologist at Victoria University in Melbourne, Australia. Even in
developed countries, she says, the most disadvantaged women--for example,
single moms with low incomes, insecure work, inadequate housing, and lack of
child care--have rates of depression two to three times higher than those of
women in more favorable circumstances.
Unemployment and low income, aside from being bad for mental health in their
own right, have been linked to high rates of another risk factor: domestic
violence. "Factors in many developing countries such as low levels of education
for women ... [and a] lack of legal redress and property rights in divorce make
it more likely that women living with violent partners will be forced to stay
with them to survive economically," Astbury says.
Such factors might help explain why some of the highest suicide rates in the
world are found among women in developing countries. More than half of all
female suicides worldwide take place in China, one of the few countries where
more women than men die by suicide. A paper published last year in The Lancet
reported a startling suicide rate of 148 per 100,000 among young women in
Vellore, an inland city in Tamil Nadu, India. In the United States, roughly 4
women per 100,000 commit suicide each year.
Rising economies don't necessarily relieve the risk factors for poor mental
health, however. A 1999 paper published in Social Science and Medicine
suggested that growing income disparities created by rapid economic development
in India, Chile, Brazil, and Zimbabwe may have increased the risk of anxiety
and depression for women there. Development can add to the stress of everyday
life for women, says Araya, one of the study's authors. As jobs become
available, women are often expected to work outside the home in addition to
their household duties. "They go and work in a sweatshop, and then they have to
go home and cook," he says.
A more comprehensive view of women's mental health around the world should come
from a massive international survey now under way in 28 countries. Ronald
Kessler, an epidemiologist at Harvard Medical School in Boston who is directing
the project for the World Health Organization, says it will examine a variety
of potential influences on women's mental health, such as access to birth
control, property rights, education, and reproductive history, including age of
Some researchers have proposed that sex hormones are responsible for the higher
incidence of depression and anxiety in women, but the main evidence for that
hypothesis is that these disorders appear in midpuberty in the United States,
Kessler says. In developing countries, puberty is often delayed by several
years as a result of malnutrition, even though girls marry and are thrust into
adult roles earlier. Says Kessler: "This creates a natural experiment to tease
out the relative effects of biology and social roles on female mental illness."
Let's Talk About Sex--and Drugs
Seven years after Viagra was launched, many drugs are on the horizon to treat
women's sexual problems. But several questions remain: Are they safe? And are
they needed? Laura was miserable. She had once enjoyed a healthy sex life, but
any desire for sexual activity had vanished after her hysterectomy. Her 9-year
marriage was on the rocks, and her husband was becoming emotionally abusive.
Her real-life story, told by marriage and sex therapist Jean Koehler to a panel
of experts gathered by the U.S. Food and Drug Administration (FDA) in December,
was meant to help persuade the committee to approve the first drug developed to
treat women's sexual problems. Koehler had traveled from Louisville, Kentucky,
to suburban Maryland to deliver 3 minutes of testimony on behalf of a
testosterone patch called Intrinsa. Once her client started taking
testosterone, Koehler said, her life changed for the better: She enjoyed sex
again, her relationship improved, "and two little children were spared the
trauma of impending divorce."
Intrinsa, developed by Procter and Gamble (P&G), is part of a wave of new drugs
stirring controversy before a single one has hit the market. Advocates for
these drugs, including some prominent researchers of women's sexuality, say
they have the potential to help tens of millions of suffering women; not just
those who have had their ovaries removed, which often happens as part of a
hysterectomy, but "naturally menopausal" women as well. Even if the drugs don't
promise to save a marriage, market analysts see them as potential blockbusters.
But the FDA panel was not convinced. At the end of its daylong session, the
group unanimously rejected the drug. Panelists decided that there weren't
enough data to show that long-term hormone treatment--patients have to wear the
patch continuously--does not cause serious side effects. The decision, decried
as overly cautious by proponents of the patch, was a setback not just to P&G
but to several other companies whose products contain testosterone.
But safety isn't the only issue. Some researchers also worry that the new
pills, patches, gels, and nasal sprays will lead women to take drugs for what
are really social or psychological problems that can be treated more
effectively with education or psychological intervention. "Most of women's
sexual complaints have to do with self-respect, self-image, and the quality of
the relationship," says clinical psychologist Leonore Tiefer of the New York
University (NYU) School of Medicine, a leading critic of what she calls the
"medicalization" of female sexuality. "They're things a pill can't treat."
Not tonight. Waning desire is the most important sexual problem in women,
It's no surprise that the drug industry has turned its attention to women.
Sildenafil, or Viagra--discovered when a candidate angina drug had surprising
side effects--has grossed billions of dollars for Pfizer since its launch in
1998; copycats tadalafil (Cialis) and vardenafil (Levitra)--which also block
the PD5 receptor, resulting in increased blood flow to the penis--have become
successes in their own right. Meanwhile, interest in women's sexuality is
growing; to wit, the adventures of four Manhattan women in the HBO smash hit
series Sex and the City . "Women started asking: What's there for us?" says
Harvard reproductive endocrinologist Jan Shifren, who directs the Vincent
Menopause Program at Massachusetts General Hospital in Boston.
But exactly what sex drugs should do in women is much less obvious than in men.
When the FDA put together "draft guidelines" in 2000 for companies interested
in producing drugs to treat female sexual dysfunction (FSD), it followed the
4th edition of the Diagnostic and Statistical Manual of Mental Disorders. DSM-4
says that FSD has four major components: decreased desire to have sex;
decreased arousal (such as blood flow to the genitals and lubrication); pain
during intercourse; and difficulty or failure to have orgasms. Companies must
choose which component their drug affects and show efficacy in women with that
Not everyone subscribes to that delineation, based on the classic model of the
"human sexual response cycle" proposed by William Masters and Virginia Johnson
in the 1960s. The distinction between desire and arousal, for instance, doesn't
make much sense, says Ellen Laan, a sex researcher at the University of
Amsterdam in the Netherlands. How to measure a drug's effect on people's sex
lives is controversial, too. Because of those debates, the final version of
FDA's guidelines has yet to appear.
In the meantime, about two dozen companies now have products in development for
FSD (see table). Viagra, once considered a candidate to treat arousal problems,
is no longer among them; Pfizer gave up last year after disappointing trials.
But other companies have products that would do the same: Vivus in Mountain
View, California, for instance, is in phase III trials with alprostadil, a
vasodilating agent that women apply directly to their genitalia.
Most candidate drugs, however, focus on what clinicians say is by far the most
common disorder: decreased interest in sex, also known as hypoactive sexual
desire disorder (HSDD). Some of these compounds act on the central nervous
system. One is flibanserin, a pill previously studied and rejected as an
antidepressant, from German pharma giant Boehringer Ingelheim. Another, PT 141
from Palatin Technologies in Cranbury, New Jersey, is a nasal spray that
stimulates melanocortin receptors in the brain.
Plain old testosterone is the basis for most of the desire-enhancing products.
It usually comes in the form of skin gels, sprays, or patches, because the
hormone is broken down quickly by the liver when taken orally. Women naturally
produce testosterone, although at much lower levels than men, and production
declines after menopause. Levels also drop on average by 50% after a woman's
ovaries are removed, a condition called "surgical menopause." Several small
trials suggested that testosterone enhances sexual desire in women, and U.S.
doctors widely prescribe the hormone "off-label"--without being specifically
approved--to women with HSDD. (European women are generally more reluctant to
take hormones, Laan says.)
Because no specific product has been approved for women, doctors prescribe male
testosterone drugs at about one-tenth of the dose or order pharmacists to
produce special formulations that contain smaller amounts. A product aimed at
and approved for women would be more convenient and safer, says Shifren, as
well as opening a huge new market.
Those hopes were dealt a blow by the FDA panel in December. P&G had asked for
approval of Intrinsa in surgically menopausal women first. The panel concluded
that the results of two trials in this group were "clinically significant" if
not exactly mind-blowing. (Roughly, patients who took placebo went from 3 to 4
"satisfying sexual episodes" per month, whereas those who got testosterone went
from 3 to 5-5.5.) Side effects, such as increased facial hair growth and acne,
But the panel balked at the long-term safety data. The two trials together had
enrolled 1095 women for 24 weeks--not nearly enough time to detect subtle risks
resulting from long-term use, says panel member Steven Nissen, a cardiologist
at the Cleveland Clinic in Ohio. Fresh on the panel's mind, he says, were the
disturbing results of the Women's Health Initiative (WHI), a huge study funded
by the U.S. government, which discovered in 2002 that long-term use of
estrogen, alone or in combination with progestin, can increase women's risk of
cardiovascular disease (see p. 1570). "We have a bad history with manipulating
hormones in women," says Nissen, and the decision "wasn't even close."
Some critics say the vote smacks of a double standard, because drugs like
Viagra, or even testosterone treatments in men, were never subjected to the
long-term safety trials that the panel wished to see. "Be as conservative for
men as you are for women," says Shifren. Clinical psychologist Sheryl Kingsberg
of Case Western Reserve University in Cleveland, Ohio, calls the panel "very,
very overconservative" and says it's "paternalistic" to deny women the choice
to use testosterone.
The fate of Intrinsa and similar drugs is unclear. P&G withdrew its application
after the panel meeting; a spokesperson says the company "is working with the
FDA" to design new trials. "The key questions are going to be: How long does a
trial have to be, and how many patients?" says Stephen Simes, president of
BioSante Pharmaceuticals in Lincolnshire, Illinois, a company developing a
testosterone gel. Companies will abandon their efforts if the agency requires
studies like the WHI, which enrolled more than 16,000 women for 5 years in its
main trial, Simes predicts. But Nissen says a trial of a few thousand women for
2 years, plus thorough postmarketing surveillance, might allay the worries.
Defining what's normal
But proving the safety of Intrinsa and its slew of competitors won't solve
women's sexual problems, says NYU's Tiefer, who also gave a 3-minute
presentation at the December meeting. Tiefer worries that women will feel
compelled to start taking drugs, even if they're comfortable with their
decreasing sex drives, once they become available. "I'm pro-sex," she says.
"I'm pro-porn, I'm pro-vibrators. ... But sex is a hobby. It's fine not to do
it if you're not interested." (And certainly, an abusive husband like Laura's
isn't a reason to put a woman on drugs, she adds.) Tiefer has founded a group,
FSD Alert, that takes a feminist view of female sexual problems and puts more
emphasis on sociocultural, political, and psychological factors.
There are other foes of FSD as a medical problem. In a series of articles over
the past few years in the British Medical Journal , Ray Moynihan, a freelance
journalist based in Sydney, Australia, called it the "corporate-sponsored
creation of a new disease." He implicates the media for what he says are
titillating but sloppy stories.
Those who favor the new drugs--even while admitting that they receive corporate
support--dismiss this idea as absurd and slightly conspirational. Women had
sexual problems long before drug companies started paying attention, says
Shifren. And counseling or a getaway weekend with their partners, she notes,
are some of many other options before medication. For some of her clients, lack
of desire really is a source of misery, Shifren says.
Irwin Goldstein of Boston University adds that the critics are now telling
women what men heard in the pre-Viagra era: that it's all in their heads. "They
talk about medicalization. I call what they do psycholization," Goldstein says.
But even experts who believe that some women might benefit from medical
treatment don't like the idea of large numbers of healthy women, nudged by
wall-to-wall advertising on U.S. television, on FSD drugs. Already, the extent
of the problem is being blown far out of proportion, says John Bancroft, a
former director of the Kinsey Institute at Indiana University, who is now
retired in England.
For instance, a 1999 study by Edward Laumann and his colleagues at the
University of Chicago found that a staggering 43% of women between 18 and 55
suffer from sexual dysfunction--a number often repeated in scientific
literature and the press that Bancroft calls "extreme." A recent British study
suggests that many problems are transient, he adds: Although 40% of women
reported having a problem with sexual function that lasted at least 1 month,
the study found, only 10% had complaints that lasted longer than 6 months.
Laan, at the University of Amsterdam, also believes that there's nothing
medically wrong with most of the women who have arousal or desire problems.
Instead, she says they just need more sexual stimulation. A recent German study
among college students, for instance, showed that a woman's desire dropped with
the duration of the relationship. "It's a huge taboo to say so, but many women
who have lost interest in their partner still feel like having sex with the guy
next door," Laan says. But desire can be stimulated, she adds, by anything from
romantic dinners to fantasizing: "It's just something that takes some work."
Ironically, the drug trials themselves suggest that some women may not need
desire-boosting drugs. Most show a considerable placebo effect; in the Intrinsa
studies, for instance, some 36% of patients on placebo wanted to continue after
the study closed. Maybe P&G should just market the placebo, Nissen quipped
during the panel meeting. Talking about a sexual problem and deciding to tackle
it might have a therapeutic effect by itself, say researchers.
Even with all the questions about FSD drugs, Bancroft believes that the
increased attention will benefit the field. "We're having a very healthy
debate," he says. "The good thing is that we'll come out of this with a much
better understanding of women's sexuality."
Bone Quality Fills Holes in Fracture Risk
Osteoporosis isn't the only factor behind broken bones. A better understanding
of bone quality, coming from biochemical markers and refined imaging
techniques, will help predict who is most at risk of debilitating fractures
When a woman is tested for osteoporosis, technicians shoot low-dose x-rays
through her hip to get a picture of the bone and a measure of its density. The
less bone, the higher the overall risk of breaks, including debilitating hip
fractures. But over the last decade, researchers have come to a greater
awareness that it's not just quantity that matters: Bone quality counts for a
The importance of bone quality--a term covering aspects such as the
organization of the tiny struts that make up the inner tissue--became obvious
during clinical trials of drugs for osteoporosis. These drugs prevent the loss
of bone, but it turned out that, statistically, bone mineral density (BMD)
couldn't explain all of the reduction in fracture risk. That fit with
observations by clinicians: Some women with osteoporotic bones don't suffer
breaks, whereas many women with apparently healthy bones still end up with
Identifying women at risk before they fracture is "the most challenging public
health question" facing osteoporosis researchers, says Ego Seeman of Austin
Hospital in Melbourne, Australia. And it's not just an issue for women.
Osteoporosis is becoming more common in men, and more commonly diagnosed,
especially as they live longer.
Researchers are trying to get a better handle on bone quality in several ways.
They're searching for new and better biochemical markers of bone change, to add
to the handful already used in the clinic to assess the effects of drugs.
Higher resolution imaging with computed tomography (CT) and magnetic resonance
imaging (MRI) is beginning to probe the inner architecture of bones without the
need for direct sampling.
The hope is that these advances may one day better identify patients in need of
treatment, as well as provide a way to chart their progress on drugs, but the
newer imaging techniques are still being developed and won't be widely
available for several years. In the meantime, some researchers are trying to
integrate proven risk factors to predict a woman's chance of fracture.
Osteoporosis is a factor in more than 1.5 million fractures each year in the
United States alone. Costs have been estimated at more than $17 billion a year,
particularly from hip fractures, more than 75% of them in women. Part of the
reason is that women who are not in nursing homes are twice as likely as men to
fall, perhaps because they lose muscle strength faster with age. But another
major factor is that their bones tend to become much weaker with age than men's
Strength comes from two features of bones. The outer shell of dense material,
called cortical bone, is like the metal tubing of a bicycle that makes a
strong, light frame. Inside this cortex is a porous network of tiny support
struts and rods, called trabeculae. Trabecular bone makes up just 20% of bone
mass but most of its surface area.
Sex differences appear relatively early in life. Growing girls tend to add more
mass to the inner side of the bone cortex, beefing up the trabeculae to create
a storehouse of calcium for pregnancy and lactation. Boys, in contrast, tend to
add more material to the outside of the cortex. The greater the diameter, the
stronger the bone. The effect, as seen in cross-sectional studies, is
"absolutely huge," says Heather McKay of the University of British Columbia in
Vancouver. In addition, girls tend to be less active than boys, she says, so
many don't get the bone-building benefits of exercise.
The big kicker comes at menopause. Estrogen is a key regulating signal for the
cells that are constantly remodeling bone, thus repairing damage and allowing
bones to bulk up to the loads placed on them. When estrogen levels decline
during menopause, the bone-building cells known as osteoblasts slacken their
activity. But the bone-resorbing osteoclasts continue to remove bone mineral
and break down collagen. That means women typically lose 1% to 2% of their bone
per year around menopause, more of it from trabecular bone.
Several risk factors influence the likelihood that a woman will lose more bone
than normal and eventually suffer a fracture. A previous fracture ups the odds
substantially, as does a family history of fracture, although genetic factors
remain fairly murky. Race matters, too. The incidence of hip fractures is 25%
lower in Asian than in white women, for example, even for women with similar
bone densities. Behaviors--poor diet and lack of exercise, especially in
youth--are also negative influences on bone health, as discussed in a massive
report from the Surgeon General last year.*
These risk factors are fairly weak predictors of an individual's absolute risk,
however. Up until the 1980s, clinicians basically waited until a fracture
occurred before treating patients for osteoporosis. Diagnosis--and
research--got a considerable boost in the 1990s with the advent of dual x-ray
absorptiometry (DXA). "It just revolutionized the field," says B. Lawrence
Riggs of the Mayo Clinic in Rochester, Minnesota. DXA enabled clinicians and
researchers to follow patients over a long time and assess their responses to
medications, helping bring the current crop of drugs to market, Riggs says
(Science, 3 September 2004, p. 1420 ). In the United States, the National
Osteoporosis Foundation recommends that women over the age of 65, or younger
women who have one or more risk factors, be tested with DXA for osteoporosis.
Virtual biopsy. An osteoporotic radius (right) and a healthy tibia, seen with
But DXA's usefulness for making predictions is limited. "The number one
clinical goal is to be able to sit down with a patient and give a numerical
indicator of fracture risk," says Lawrence Raisz of the University of
Connecticut Health Center in Farmington. DXA doesn't do that well, although
many researchers point out that it's a better predictor than is cholesterol
level for heart disease. By factoring in bone quality as well, researchers and
doctors eventually hope to do better.
Sharpening the picture
One of the main approaches to gleaning details about the quality of bones is to
measure the activity of osteoclasts and osteoblasts, the cells that remodel
bone and thus influence its structural properties. The first cell activity
marker approved by the U.S. Food and Drug Administration, in 1995, measures the
products of bone breakdown and can pick out women with extremely high rates of
bone loss. In general, however, markers are not currently useful for diagnosis
of osteoporosis, because levels overlap between those who have and don't have
the disorder. Researchers are trying to explain the variability and
investigating new markers that might be more specific.
The main clinical use of markers at the moment is to help chart how patients
respond to drugs. That kind of information may also encourage patients to keep
taking their medicine, as Pierre Delmas of Claude Bernard University in Lyon,
France, explained last month at a meeting on bone quality run by the National
Institutes of Health and the American Society of Bone and Mineral Research in
Bethesda, Maryland. His unpublished data showed that providing patients with
progress reports from biomarkers could increase the numbers who stay on their
medications by 20%. Biochemical markers may also help refine the assessment of
fracture risk, but the results of large studies so far have been inconsistent.
Another way of getting new information about bone quality is by looking at bone
architecture directly. A time-tested research method is to study actual bone
from biopsies, cadavers, or hip replacement operations. CT and electron
microscopy can resolve individual rods and struts, the crucial support elements
inside trabecular bone. But direct sampling is too invasive and expensive to be
used to track individual patients' health.
Researchers have been trying to get similar and more clinically useful
information using imaging tools. One benchmark in the field is a 2001 paper in
the Journal of Bone and Mineral Research (JBMR ) by Felix Wehrli's group at the
University of Pennsylvania, Philadelphia. The researchers showed in a study of
79 women with various bone densities and vertebral deformities that a souped-up
MRI machine can reveal microscopic bone structure noninvasively. In April, a
group led by Charles Chesnut of the University of Washington, Seattle,
published online in JBMR the first such longitudinal study of bone
microarchitecture with MRI.
The other main imaging techniques use quantitative CT, mainly to study
peripheral bones, such as the forearm. Aspects of bone quality are then
extrapolated to hip and spine. Given the small size of studies so far, CT and
MRI haven't been used to assess fracture risk. Researchers say those results
should come in the next few years: Larger trials are incorporating CT and MRI
in subsets of patients.
One attempt to get at fracture risk is already under way. Tony Keaveny, a
biomechanical engineer at the University of California, Berkeley, is using a
technique called finite element analysis. Keaveny and colleagues take CT images
of human vertebrae, including information about the trabecular architecture,
and model how they respond to stress. In a paper published in Bone in 2003, he
and his former student R. Paul Crawford showed that their analysis of CT images
of cadaver bones predicted 85% of the variation in bone strength in experiments
with actual loadings of the bones--"better than BMD did," he says. Ultimately,
Keaveny says, the method should be able to provide a personalized fracture risk
assessment for patients, adjusted for their height and weight and other
factors. Clinicians say the approach is exciting but might be prohibitively
expensive for screening patients.
In the meantime, clinicians and researchers say much can be done to get more
women checked for osteoporosis and give patients a better idea of their
fracture risk. In one high-profile effort, a center at the University of
Sheffield, U.K., sponsored by the World Health Organization has been designing
a method to express a person's absolute risk of fracture during the next 10
years. "This will allow us to have a standard of care," comments Ethel Siris of
Columbia University College of Physicians and Surgeons. "It will give us a
better threshold for determining treatment."
* Bone Health and Osteoporosis: A Report of the Surgeon General (2004), HHS.
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