Update in Women’s Health
Judith M. E. Walsh, MD, MPH1,3, Mary S. Beattie, MD, MAS1, and Pamela Charney, MD2
1Division of General Internal Medicine, Women’s Health Clinical Research Center, University of California, San Francisco, CA, USA;2Cornell
University School of Medicine, Ithaca, NY, USA;3UCSF Women’s Health Clinical Research Center, San Francisco, CA, USA.
J Gen Intern Med 25(4):363–8
© Society of General Internal Medicine 2009
The aim of this clinical update is summarize articles and
guidelines published in the last year that are scientifically
rigorous and have the potential to impact women’s health
Methods. We used two independent search strategies to
identify potentially relevant articles published between March
1, 2008 and February 28, 2009. We reviewed journal indices
from the New England Journal of Medicine, Journal of the
American Medical Association, Annals of Internal Medicine,
Archives of Internal Medicine, Journal of General Internal
Medicine, British Medical Journal, Lancet, Circulation,
Diabetes and Obstetrics and Gynecology. We also reviewed
Journal Watch, Journal Watch Women’s Health, and the ACP
Journal Club and the Cochrane database of systematic
reviews. Second, we did a MEDLINE search using the medical
subject heading, “sex factors.” All three authors, reviewed all
article titles, abstracts and when indicated, full text
publications. We focused on articles relevant to general
internists and excluded articles focusing on obstetric
medicine. We also identified new and or updated women’s
health guidelines that were released during the same time
period. Using a process of individual ratings and discussion,
we reached consensus about the most important articles.
We identified 122 articles with potential relevance to women’s
health; 34 articles were selected for presentation as part of the
clinical update and 14 for detailed discussion in this paper.
Ridker P, et al. Rosuvastatin to prevent vascular events in men
and women with elevated C-reactive protein (CRP). NEJM
2008: 359; 2195–2207.
What is already known. When national guidelines (ATP III) for
cholesterol lowering were applied to the NHANES population,
58% of women over 60 and men over 50 qualified for statin
treatment. However, only 24% of those eligible in NHANES
reported current statin use.1Inflammation has also been linked
to CHD risk. High sensitivity CRP, blood pressure as well as
CHD and stroke events decrease with a DASH-style diet.2
What does this study add?. This double-blind, placebo
controlled, multi-center international clinical trial, JUPITER,
provided rosuvastatin treatment to individuals with a high
sensitivity CRP values ≥2 mg/L and LDL cholesterols >130.
This industry-sponsored trial demonstrated significant benefit
after an average 1.9 years treatment with the primary endpoint
of non-fatal myocardial infarction or stroke, admission for
angioplasty or unstable angina, or confirmed cardiovascular
death. Over a 5-year period, 25 patients like the ones in this
trial would need treatment to prevent one event. Subgroup
analysis by gender, race and age documented benefit for all
sub-groups. There were no increased rates of myopathy,
rhabdomylosis or intracranial bleeding during follow up.
While more treatment participants were newly diagnosed by
their physicians with diabetes, there were no significant
differences in glucose or glycosuria levels. Further study is
required to know whether similar results would be achieved
with other statins.
How should I change my clinical practice?. Since statins have
become available for hyperlipidemia treatment, prescribing
indications have steadily expanded. If the JUPITER criteria
were applied to the general population, an additional 19% of
the population could benefit from statin treatment. If these
findings are confirmed in other studies, the indications for
statin use may further expand beyond current ATP III
guidelines to include most middle age Americans.
Fox CS, et al. Lifetime risk of cardiovascular disease among
individuals with and without diabetes stratified by obesity
status in the Framingham Heart Study. Diabetes Care 2008:
Charlton J, et al. Explaining the decline in early mortality in
men and women with Type 2 Diabetes: a population-based
cohort study. Diabetes Care 2008: 31; 1761–1766.
What is already known. Women with diabetes have not
experienced the decrease in all-cause and cardiovascular
Received July 30, 2009
Revised October 6, 2009
Accepted November 11, 2009
Published online December 18, 2009
mortality documented in diabetic men over the last several
decades.3For diabetics with known cardiovascular disease the
risk of dying is also greater for women (hazard ratio 2.2 for
women, 1.7 for men).4Diabetic women also receive less aspirin
and statins than diabetic men.5,6
What do these studies add?. Over 30 years, in the original
Framingham cohort, the risk of developing CVD was 67% in
women with diabetes compared to 38% in women without
diabetes. In the Framingham offspring cohort, CVD rates were
lower: 48% of women with diabetes and 26% of women without
diabetes developed CVD. Furthermore, among diabetic women
in the original cohort, over thirty years, CVD would occur in
79% of the obese diabetic women compared with 55% of the
A retrospective exploration of mortality within two years of
the diagnosis of type 2 diabetes from 1996–2006 was complet-
ed from The United Kingdom General Practice Research
Database.7Overall incidence of diabetes increased. In women
the relative decline of mortality within two years of diabetes
diagnosis was 26% compared with a 47% decrease among
men. Also noted were gender differences in medications at time
of diabetes diagnosis- more men than women were on renin-
angiotensin system drugs, and statins. More women than men
were taking metformin.
How should I change my clinical practice?. Diabetes remains
especially hazardous to women. For diabetic women, and for
all women at increased risk for CVD, aggressive CVD risk
factor management to treatment goals is essential and often
difficult to achieve.1Obese diabetic women are at especially
high risk for CVD.
Svetkey LP, et al. for the Weight Loss Maintenance Collabora-
tive Research Group. Comparison of strategies for sustaining
weight loss the weight loss maintenance randomized con-
trolled trial. JAMA 2008: 299(10):1139–1148.
What is already known. Obesity is associated with increases in:
overall mortality, CHD, stroke, deep venous thrombosis,
diabetes, hypertension, hyperlipidemia, obstructive sleep
apnea, asthma and multiple cancers including breast and
colorectal.8Clinical trials have facilitated weight loss with
group counseling interventions focused on increasing fruit
and vegetable consumption, keeping records of food
consumption and promoting physical activity.9
What does this study add?. After 1032 obese adults
successfully completed six months in a weight loss program
with at least 4 kg weight loss, they were randomized for thirty
months into the following: 1) Three monthly phone contacts
alternating with one monthly in person visit; 2) at least weekly
participation in an interactive web-site; or 3) “self-motivation”-
which provided written materials and follow-up at 12 months.
While the initial weight loss was on average 8.5 kg, after 30
months of follow-up most participants regained substantial
weight in all three groups.
How should I change my clinical practice?. This study found
that maintaining weight loss is difficult. Some studies have
shown that physical activity is key for sustained weight
MENOPAUSE AND HORMONE THERAPY
Duration of Vasomotor Symptoms During
Politi MC, Shlentz MD, Col NE et al. Revisiting the duration of
vasomotor symptoms of menopause: a meta-analysis. JGIM
2009: 23: 1507–13.
What is already known. Some clinical guidelines suggest that
the menopausalsymptomslast from6 monthstotwoyears.11,12
Hormone therapy is the most effective therapy for menopausal
symptoms. Guidelines recommend using the “lowest dose for
the shortest duration”
benefits of hormone therapy. However, data are limited
regarding the natural duration of menopause because many
13,14because of the known risks and
What does this study add?. This rigorous meta-analysis
included ten studies with over 35,000 participants. The
authors used a clear definition of vasomotor symptoms.
Overall, vasomotor symptoms increased in the two years
before the final menstrual period, peaked one year after the
final menstrual period and did not return to baseline levels
until 8 years after the final menstrual period. About half of
women had continued symptoms during the four years after
the final menstrual period and 10% continued to have
symptoms up to 12 years after the final menstrual period.
The prevalence of bothersome symptoms peaked about 1 year
after the final menstrual period and decreased 3–7 years after
the final menstrual period.
Recently published evidence based guidelines for the use of
hormone therapy (HT) focus on the use of HT for symptomatic
relief. Highlights of the guidelines include putting the absolute
level of risk with HT use in perspective, acknowledging that
there are no data to support any particular route of adminis-
tration, and advising greater caution in prescribing HT to
women over the age of 60, since the risk of CHD associated
with HT is greater in older than in younger women17
How should I change my clinical practice?. We should counsel
women that menopausal symptoms generally last about 4 years.
Women who are considering hormone therapy for symptomatic
treatment should consider the risks and benefits of hormone
therapy withinthe contextofthe longerdurationofuse,although
it is not known exactly what duration of use is safe.
Vitamin D Deficiency and Hip Fracture
Cauley JA, LaCroix AZ, Wu L et al. Serum 25-Hydroxyvitamin
D concentrations and risk for hip fracture. Ann Intern Med
2008: 149: 242–250.
Walsh and Charney: Women’s Health
What is already known about this topic?. Vitamin D deficiency
is common in older adults, homebound individuals and
women admitted with hip fracture. However a recent AHRQ
evidence report on vitamin D and bone health found that the
association between Vitamin D and fracture risk was
inconsistent.18This study was designed to answer the
following question: “What is the association between Vitamin
D level and fracture?” Additional questions include “When
should Vitamin D levels be checked?” and “When and how
should Vitamin D supplementation be given?”
What does this study add?. This study addressed the question
of whether serum (25) OH D concentration is associated with
hip fracture in community dwelling older women. It was a
nested case-control study within the Women’s Health Initiative
Observational Study. None of the participants had a prior
history of hip fracture nor were on estrogen or other bone
resportive therapies. A total of 400 cases and 400 controls
were followed for 7.1 years. Mean 25-(OH) vitamin D levels
were lower in cases than in controls. Women with vitamin D
levels in the lowest quartile had an increased risk of fracture
compared with women in the highest quartile (OR 1.71; 95% C.
I. 1.05, 2.79). There was a significant trend across quartiles of
25-(OH) vitamin D (p=0.016), suggesting a dose-response
effect. The association was not affected by age, geographic
location, number of falls, frailty or renal function.
How should I change my clinical practice?. Low serum 25-
(OH) vitamin D levels can help identify women at high risk for
hip fracture. Perhaps we should consider vitamin D levels in
our decision making about anti-resportive therapies. This
study answers the question of whether or not vitamin D level
is a risk factor for fracture, but does not answer the other
important questions of whom we should test for vitamin D
deficiency and or how we should treat vitamin D deficiency or
Low-Trauma Fracture and Mortality
Bliuc D, Nguyen ND, Milch, VD, Nguyen TV, Eisman, JA,
Center JR. Mortality risk associated with low-trauma osteopo-
rotic fracture and subsequent fracture in men and women.
JAMA 2009: 301 (5): 513–521.
What is already known about this topic?. As the population
ages, osteoporotic fractures are increasing,19with concomitant
increases in morality among individuals with hip or vertebral
fractures.20,21However, it is less clear whether other fractures
are also associated with increased mortality. The goals of
this study were: 1) to assess mortality risk following an
osteoporotic fracture; 2) to determine whether the degree
of trauma and subsequent fracture affect this mortality
What does this study add?. This prospective cohort study from
the Dubbo Osteoporosis Epidemiology Study included all
individuals who had any fracture between 1989 and 2007.
Age and gender-specific standardized mortality ratios are
compared with the overall Dubbo population for major
(pelvis, distal femur, proximal tibia, proximal humerus, three
or more simultaneous ribs) and minor (all other ) osteoporotic
fractures. Age adjusted standardized mortality ratios in
women increased after a hip fracture (SMR 2.43; 95% C.I.
2.02, 2.93), after a vertebral fracture (SMR 1.82; 95% C.I. 1.52,
2.17), and after a major fracture (SMR 1.65; 95% C.I 1.31,
2.08). In addition, after a minor fracture, the age adjusted SMR
was also increased (1.42; 95% C.I.1.19, 1.70). Increased
mortality risk persisted for 5 years for all fractures and up to
10 years for hip fractures. In addition, a subsequent fracture
was associated with an increased risk of mortality in women
(HR 1.53; 95% CI 1.15, 2.04).
How should I change my clinical practice?. Although hip and
other major fractures have been associated with an increase in
mortality, the increased mortality following minor fractures is
important new information. Any fracture is associated with an
increased 5–10-year mortality risk. In addition, a subsequent
fracture is associated with an increased mortality risk for 5
more years. We should pay more attention to non-hip, non-
One potential tool clinicians can use to calculate the 10-year
probability of fractures is the FRAX tool, developed by the
World Health Organization. It has been suggested that treat-
ment is beneficial when there is a 10-year risk of hip fracture of
≥3% or a 10-year risk of a major osteoporosis related fracture
that is ≥20% based on the US adapted WHO algorithm.22
Sildenafil and Sexual Side Effects from Serotonin
Numberg HG, Hensley PL, Heiman JR, et al. Sildenafil
treatment of women with anti-depressant-associated sexual
dysfunction: a randomized controlled trial. JAMA 2008: 300
What is already known about this topic?. Sexual side effects of
serotonin reuptake inhibitors (SRIs), particularly delayed
orgasm, can affect 30–70% of women and men.23Although
sildenafil is FDA approved for treating sexual dysfunction in
men24–26, it is not FDA approved in women. Trials of sildenafil
for sexual arousal disorder in women have not show any
benefit.27However, case reports28, open-label studies29and
subgroup analyses30,31have suggested sildenafil’s efficacy for
specific groups of women with sexual dysfunction.
What does this study add?. This 8-week, 7-site, randomized,
double-blind, placebo-controlled trial included 98 sexually
active premenopausal women whose major depression was
remitted by serotonin uptake inhibitors, but who were also
experiencing sexual dysfunction. These women were
randomized to sildenafil, 50–100 mg before sex, versus
placebo. The primary outcome of the study was based on the
7-point, anchored, clinician-rated Clinical Global Impression
scale, adapted for sexual function.32Multiple other
measurements of desire, arousal, and orgasm were examined.
For the primary outcome, both the sildenafil and placebo
groups reported an improvement in sexual function, with a
Walsh and Charney: Women’s Health
larger mean improvement in sildenafil users. In the intent to
treat analysis, the mean difference between groups on this 7-
point scale was 0.8 (p=0.001). A more conservative analysis
assumed that women who did not return for the final visit at
8 weeks returned to baseline sexual function, and these
results showed a mean difference between groups of 0.6 (p=
0.03). Most secondary outcomes were not statistically
significant; however those that measured orgasm tended to
demonstrate statistical significance. Side effects of sildenafil
included headache, visual disturbances, dyspepsia, flushing,
and nasal congestion.
How should I change my clinical practice?. The clinical
significance of a mean change of 0.8 on a 7-point sexual
satisfaction scale is unclear, and sildenafil is not without side
effects. Sildenafil is also not FDA approved or covered by most
insurance companies for women. So, in practical terms, it is
not likely that sildenafil use will substantially increase for
women with SRI-associated sexual side effects. However, this
study reminds us of the importance of taking a sexual history
before and after initiation of SRIs.
Weight-Reduction and Urinary Incontinence
Subak LL et al. Weight loss to treat urinary incontinence in
overweight and obese women. NEJM 2009: 360 (5): 481–490.
What is already known about this topic?. Observational studies
have suggested that obesity is a strong risk factor for urinary
incontinence.33–36For obese women, weight loss, including
that from bariatric surgery37–39may have a beneficial effect on
37–41, particularly for stress urinary
What does this study add?. This two-site, 6-month, randomized
clinical trial enrolled 338 overweight and obese women with at
least 10 urinary incontinence episodes per week. 226 women
who received diet, exercise, and behavior modification lost an
average of 7.8 kg; 112 women who received a structured
education program lost an average of 1.5 kg (p<0.001).
Incontinent episodes decreased from 24/week (in both groups)
to 13/week in the weightloss group (47% reduction versus 28%
in the control group, p=0.01). Stress incontinence was reduced
more than urge incontinence in the intervention group.
How should I change my clinical practice?. In overweight and
obese women, moderate weight reduction has multiple benefits,
including the potential for decreasing incontinent episodes,
particularly stress incontinence episodes. The intervention was
modeled after weight-reduction programs used in large diabetes
trials, and it required 1-hour weekly meetings for 6 months.
Although the 8% weight loss observed in the intervention group
may be difficult to replicate over 6 months in practice, weight
reduction is generally without side effects and has other health
benefits. This study provides evidence for yet another benefit of a
rigorous weight-reduction program.
Behavioral and Drug Therapy for Urge Urinary
Burgio KL et al. Behavioral therapy to enable women with urge
incontinence to discontinue drug treatment. Annals of Internal
Medicine 2008; 149 (3): 161–169.
What is already known about this topic?. For women with urge-
predominant urinary incontinence, antimuscarinic
medications and behavioral treatments are both considered
safe and effective first-line treatments.42–44Many women,
however, discontinue these medications. Furthermore, few
studies have examined the effectiveness of either therapy
alone compared to combination therapy.45–47
What does this study add?. This randomized clinical trial of 307
women with urge-predominant incontinence studied 10 weeks
of tolterodine alone versus 10 weeks of tolterodine plus
behavioral training, examining outcomes at 8 months. The
primary outcome was the proportion of women at 8 months who
were not taking medications AND had achieved a 70% orgreater
reduction in the frequency of incontinence episodes. In both
groups, this proportion was 41%, and therefore not statistically
significant. At 10 weeks, there was a modest, nonsignificant
improvement in the frequency of incontinence in the
combination group. Combination therapy had a statistically
significant benefit for patient satisfaction, perceived
improvement, and reduction of other bladder symptoms.
How should I change my clinical practice?. Although
combination therapy for urge incontinence improved several
secondary outcomes of this study, it did not augment drug
therapy in improving urge incontinence at 8 months, nor did it
enhance the ability to discontinue medications at 8 months. In
clinical practice, therefore, behavioral treatments may have
beneficial effects on satisfaction and other secondary
outcomes; but many women with urge incontinence will
require long-term medication for maintenance.
Screening Breast Ultrasound and Mammography
Berg WA, et al. for the ACRIN 6666 Investigators. Combined
screening with ultrasound and mammography vs. mammog-
raphy alone in women at elevated risk of breast cancer. JAMA
2008; 299 (18): 2151–2163.
What is already known about this topic?. Mammography in
women with dense breasts is associated with increases in both
false positive and false negative readings.48In some studies,
particularly studies of women with dense breasts, the addition
of a screening ultrasound has been shown to improve
sensitivity.49–51The number of cancers detected in the
literature from screening breast ultrasounds is still quite
small, at less than 200, in over 48,000 exams reported.49–51
What does this study add?. This study was designed to examine
the diagnostic yield (the proportion of women with positive
Walsh and Charney: Women’s Health
screen test results and positive reference standard) when
screening ultrasound is added to mammography. It included
2809 women with dense breasts who received both screening
mammogram and physician-preformed breast ultrasound at 21
sites. Forty women were diagnosed with breast cancer during
the study: 8 cancers were found by both mammography and
ultrasound; 12 with ultrasound alone; 12 with mammography
alone; and 8 with neither modality. The diagnostic yield was 7.6
per 1000 women screened with mammography alone, and 11.8
per 1000 women screened with combined mammography plus
ultrasound. The difference of 4/1000 cancers detected,
however, was associated with a substantial increase in false
positives. Of the 84 abnormal mammograms that led to biopsy,
77% were not related to cancer; of the 235 abnormal
ultrasounds that led to biopsy, 91% were not related to cancer.
Per screen, about 5% of all screening mammograms required
further study versus about 10% of all screening ultrasounds.
How should I change my clinical practice?. Although the
primary outcome of this study (diagnostic yield) improved
when ultrasound was added to mammography, it was at a
substantial clinical cost. The increased sensitivity of adding
ultrasound to mammography was associated with a decrease
in specificity from over 95% to about 90%. This resulted in an
approximately threefold increase in biopsies to work-up false
positive screens. Women at high risk of breast cancer who
might be candidates for enhanced screening, as well as their
providers, should be aware of the substantial risk of false
positive screens that could lead to biopsy.
Menopausal Hormone Therapy, Breast Screening,
and Breast Cancer
Chlebowski RT, Anerson G, Pettinger M, et al. Estrogen plus
progestin and breast cancer detection by means of mammog-
raphy and breast biopsy. Archives of Internal Medicine 2008;
Chlebowski RTet al. Breast cancer after use of estrogen plus
progestin in postmenopausal women. NEJM 2009; 360 (6):
What is already known about this topic?. Combined menopausal
hormone therapy (HT) increased the risk of breast cancer in the
Women’s Health Initiative (WHI) study.52Observational studies
have suggested that HT also increases the false positive rate of
screening mammography.53–55Prior to these studies, the effects
of HT on breast cancer detection in a large randomized
controlled trial had not been examined, nor had the time
course for these effects been carefully examined. Additionally,
the link between the observed decrease in breast cancer
incidence and the decrease in HT use
examined in the WHI population.
56,57had not been
What do these studies add?. In the WHI HT trial, the cumulative
rates of abnormal mammograms and breast biopsies in women
randomized to HT were significantly higher than these rates in
women randomized to placebo (P<0.001 for both comparisons).
Although breast cancers were significantly increased and
were diagnosed at higher stages in the HT group, biopsies in
the HT group less frequently diagnosed cancer. After stopping
HT, its adverse effects on mammograms persisted for at least
12 months. Additionally, by examining trends in breast
cancer diagnosis in the WHI setting, where mammography
rates and HT use were carefully monitored, investigators
could rigorously examine the potential cause-effect
relationship between stopping HT and decreasing breast
How should I change my clinical practice?. Women on long-
term HT should be counseled not only of the increased risk of
breast cancer, but also about the increased risk for false positive
mammograms that could lead to breast biopsies. After 5 years,
over 10% of HT users would be expected to experience an
otherwise avoidable false positive mammogram; and over 4% of
HT users are predicted to require an otherwise avoidable breast
biopsy. After stopping HT use, breast cancer risk decreases
rapidly, as does the risk of abnormal mammography. It may take
several years for these risks to return to the baseline risk of a
Corresponding Author: Judith M. E. Walsh, MD, MPH; UCSF
Women’s Health Clinical Research Center, 1635 Divisadero Suite
600, San Francisco, CA 94115, USA (e-mail: Judith.walsh@ucsf.
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Walsh and Charney: Women’s Health