[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 Women’s 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 Women’s 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 unique—la 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

INTRODUCTION

CONTENTS
NEWS
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 Let’s Talk About Sex—and 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.

------------------

News
From Dearth to Deluge
Eliot Marshall

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.

[Figure 1]
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.

Clinical bombshell

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 
breaks.

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 
main legacy.

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 
neglected."

-----------------

Clinical Trials: Keeping Score on the Sexes
Eliot Marshall

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 
review found.

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?
Jocelyn Kaiser

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 problem.

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.

[Figure 1]

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, 
D.C.

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.

[Figure 2]

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 
(www.qtdrugs.org).

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 
before menopause.

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, 
however.

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 
yet.

------------------

Sex and the Suffering Brain
Constance Holden

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 
successful.

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, 
D.C.

[Figure 1]

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 
Park.

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 
about humans.

Affective disorders

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.

[Figure 2]

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 
substrate."

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 
disorder (ASP).

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.

Thought disorder

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 
centered.

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
Greg Miller

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 
tsunami survivors.

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 
depression.

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.

[Figure 1]

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 
birth.

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 
puberty.

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
Martin Enserink

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."

[Figure 1]
Not tonight. Waning desire is the most important sexual problem in women, 
clinicians say.

"Our turn"

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 
problem.

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.

[Figure 2]

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, 
were limited.

[Figure 3]

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
Erik Stokstad

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 
lot.

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 
fractures.

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.

Strong bones

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 
do.

[Figure 1]

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.

[Figure 2]
Virtual biopsy. An osteoporotic radius (right) and a healthy tibia, seen with 
MRI.

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. 
www.surgeongeneral.gov/library/bonehealth/content.html