FAMILY MEDICINE GRAND ROUNDS

Shou Ling Leong, MD

Department of Family and
Community Medicine, Penn
State College of Medicine
Deborah R. Erickson, MD
Department of Surgery,
Division of Urology, Penn
State College of Medicine
Richard C. Pees, MD
Department of Obstetrics
and Gynecology, Division
of Women’s Health, Penn
State College of Medicine
Hormone replacement therapy:
The right choice for your patient?
Mrs JC, a 55-year-old woman, arrives for her annual gynecologic exam. Besides
wanting to update her Pap smear and mammogram, she would like to discuss
estrogen replacement. She reached menopause at age 52 and began taking estrogen
for hot flashes and night sweats. Her cholesterol levels have been elevated since
menopause. She read that estrogen can lower cholesterol levels and therefore may
possibly reduce her risk for heart disease.
She did very well with estrogen. Her hot flashes and night sweats disappeared and
she felt great. However, after hearing news reports about the danger of estrogen, she
discontinued the hormone pills a few months ago. She is now feeling poorly with hot
flashes, night sweats, vaginal dryness, and occasional stress incontinence. She has
many questions and concerns and eagerly seeks your advice about what to do.

Medical history Review of systems

• Borderline hypertension Negative except for hot flashes, night
• Hyperlipidemia sweats, vaginal dryness, and occasional
• Obesity: body-mass index of 32 stress incontinence.

Family history Physical examination

F E AT U R E E D I T O R S
Audrey Paulman, MD, MMM,
and Paul Paulman, MD,
University of Nebraska College
of Medicine, Omaha
CORRESPONDING AUTHOR
Shou Ling Leong, MD, Penn
State College of Medicine,
Penn State Milton S. Hershey
Medical Center, P.O. Box 850,
Hershey, PA 17033-0850.
E-mail: sleong@psu.edu
• Mother, age 75, has hyperlipidemia,
hypertension, myocardial infarction (MI)
at age 60, and osteoporosis
• Father, died at age 55 of MI; had
hypertension and diabetes
• Her grandparents also had history of
stroke and heart disease, but she doesn’t
know all the details about their health.
She believes her maternal grandmother
broke her hip when she was elderly.
Social history
• Married, 2 children, works as an
attorney with the local government.
Her job is fairly demanding
• Does not smoke, occasional alcohol
consumption
• Does not exercise on a regular basis
• Alert female in no distress. Blood pres-
sure, 145/90 mm Hg; weight, 165 lbs;
pulse, 82; respiration, 18; temperature,
98.1°F
• HEENT exam, normal
• Neck, heart, lung, abdomen, breast,
and pelvic exams are all normal except
for mild atrophic changes of the vagi-
nal and genital tracts.
You perform the gynecologic exam
and order a mammogram. Mrs JC has not
been seen for 2 years. Her lipid profile
done 2 years ago was elevated, but Mrs JC
did not repeat the tests as requested. You
explain that you would like to further
define her risk factors and would like to
order a few tests. Making a well-informed
decision on hormone replacement therapy

428 VOL 54, NO 5 / MAY 2005 THE JOURNAL OF FAMILY PRACTICE

 Hormone replacement therapy

▲
(HRT) is complex and requires more infor- TA B L E 1
mation and adequate time for a full discus- Absolute risks of HRT
sion. You would like to see her after her
laboratory tests and will reserve time to Differences between treatment and control
groups; cases per 10,000 person-years
address her concerns and questions.
CEE/MPA CEE

Laboratory tests Coronary heart disease +7 –5

Complete blood count, normal
Cholesterol, 250 mg/dL (LDL, 130 mg/dL;
HDL, 45 mg/dL)
Triglyceride, 220 mg/dL
Electrolytes, blood urea nitrogen/creatine
(BUN/Cr) ratio, normal; glucose, 85 mg/dL
Mrs JC has many symptoms of
menopause:
• Vasomotor instability
• Urogenital symptoms
She also has risk factors:
• Cardiac: hypertension, hyperlipidemia,
obesity
• Osteoporosis: family history, sedentary
lifestyle
Before addressing Mrs JC’s specific
concerns, you review the findings of the
Women’s Health Initiative (WHI) study,1,2
which probably prompted her concerns.
You also have been asked to lead an
upcoming geriatric grand round presenta-
tion on HRT, and you further prepare for
both encounters by meeting with col-
leagues Dr Richard Pees, a gynecologist,
and Dr Deborah Erickson, a urologist, to
discuss practical applications of the WHI
findings.
■ Findings of the WHI
WHI, sponsored by the National Institute
of Health, comprised 2 multicentered
clinical trials to determine if conjugated
equine estrogen (CEE) given alone for
women who had a hysterectomy or in
combination with progestin (MPA,
medroxyprogesterone acetate) would
reduce the risk of cardiovascular events.
The study also assessed the long-term
risks and benefits of postmenopausal
hormone therapy in other chronic disease
prevention.
Exclusion criteria for the study includ-
ed competing risks with survival <3 years,
Breast cancer +8 –7
Stroke +8 +12
Venous thromboembolic +18 +7
disease
Colorectal cancer –6 +1
Hip fracture –5 –6
CEE/MPA, conjugated equine estrogen/medroxyprog-
esterone acetate; CEE, conjugated equine estrogen.
prior breast cancer, low hematocrit or
platelets, severe menopausal symptoms,
alcoholism, mental illness, and dementia.
In this study, 27,000 women aged 50 to 79
years (mean age, 63) were randomized to
take hormone or placebo.
The combined CEE/MPA (Prempro)
trial, with 16,000 women enrolled, was
discontinued at 5.2 years, on July 2002. FAST TRACK
The unopposed CEE (Premarin) trial, with
11,000 women, was discontinued at 6.8
The estrogen-
years, on February 2004. The study was progestin arm
stopped earlier than planned (2005) of the WHI had
because of increased adverse events in the more cases of
group taking hormone.
TABLE 1 summarizes the absolute
coronary heart
risks—number of events per 10,000 as com- disease, breast
pared with the control group—for both arms cancer, stroke,
of the study. In the CEE/MPA arm, there were
more cases per 10,000 of coronary heart dis-
and venous
ease (+7), breast cancer (+8), stroke (+8), and thromboembolism
venous thromboembolic disease (VTE)
including deep vein thrombosis/pulmonary
embolism (DVT/PE) (+18). However, there
were fewer cases per 10,000 of colorectal can-
cer (–6) and hip fracture (–5).
Recently published data2 on the unop-
posed estrogen arm showed an increase in
stroke (+12) and VTE (+7). No significant
increase was noted for coronary heart dis-
ease (CHD) (–5) or breast cancer (–7).

w w w. j f p o n l i n e . c o m VOL 54, NO 5 / MAY 2005 429

 FAMILY MEDICINE GRAND ROUNDS
While there is a reduction in osteoporotic
fracture (–6) in the hormone arm, there is
no significant difference in colorectal cancer
(+1). The CEE arm demonstrated that CEE
does not significantly affect the incidence of
CHD, a difference compared with the
Q: This study seems to have added more confusion to the issue of estrogen
replacement therapy. How would you interpret the data?
A:
Dr Pees: The WHI data do seem to confuse
the issue of when to use hormonal therapy.
The answer to your question lies in knowing
how the WHI risks were calculated.
The WHI authors described 2 confi-
dence indexes (CI). The first was calculated
as if looking at a single outcome variable, a
nominal CI; the second, an adjusted CI,
took into account multiple outcomes.
For the CEE/MPA arm, when the nom-
inal CI is used, CHD and breast cancer
risks barely reached clinical significance;
colon cancer and fracture reduction
reached clinical significance; DVT and
FAST TRACK strokes were also clinically significant using
both CIs. When the adjusted CI is used,
It is worth noting DVT/strokes, and to a lesser degree frac-
that coronary ture reduction, retain clinical significance.
heart disease In the CEE-only arm (February 2004
increased in the report), DVT/strokes were the only vari-
able that reached clinical significance.
first year of the CHD/breast cancer/colorectal cancer did
WHI study but not reach clinical significance, and fracture
decreased in reduction only a slight decrease in risk.
The WHI study introduced a new
subsequent years term, the Global Index, which had not
been tested for validity or significance of
assigning weights to various outcomes.
Additionally, there were certain biases in
the construct of the study. Included were
Q: Have the data from WHI altered your practice in treating conditions associated
with menopause? If so, in what ways?
A:
430 VOL 54, NO 5 / MAY 2005 THE JOURNAL OF FAMILY PRACTICE
CEE/MPA arm. Potential explanations for
this include the role of progestin, differ-
ences in the study populations, and the role
of chance. The reduction of breast cancer
incidence was unanticipated and required
further investigation.
1200 individuals who had prior MI, revas-
cularization procedures, stroke, DVT, and
PE. Excluded were those with severe
menopausal symptoms, prior fracture/low
bone mineral density (BMD), and cognitive
function deficits. Also, only 10% of the
group was in the 50- to 54-year-old group;
25% were in the 70- to 79-year-old group.
The dropout rate was fairly high: 42% in
the CEE/MPA arm, and 38% placebo arm;
only 25% of the CEE/MPA arm remained
at the study termination. Unblinding
occurred in 40% of the CEE/MPA arm and
5.4% in the placebo arm.
It is worth noting that CHD increased
in the first year of the study but decreased
in subsequent years. VTE/DVT and total
fractures were the only 2 items that
achieved true clinical significance. Total
fracture reduction was 1.6 times greater
than the increases in CHD and breast can-
cer; and the fact that breast cancers double
every 300 days and are present for 7 to 8
years before they are detected with current
diagnostic testing.
Despite the biases and limitations of
the data presented by the WHI report, the
study does add to our knowledge and it
should be included in our discussion with
patients when addressing HRT.

Dr Pees: The WHI data have altered the
way in which I counsel patients. I still pre-
scribe hormone therapy within the
American College of Obstetricians and
Gynecologists (ACOG) guidelines, and,
after a very thorough discussion, reference
the WHI data. This is to ensure that
patients make informed decisions about
continuing or starting hormone therapy.
Following ACOG recommendations, I
evaluate each patient’s risk profile. I start
treatment with the lowest effective dose to
relieve symptoms. I discuss the use of alter-
native treatments for menopausal symp-
toms and osteoporosis prevention, as well
as evaluation and treatment for quality of
life issues. Most importantly I encourage
periodic re-evaluation for hormone use.
After the WHI study was terminated,
the North American Menopause Society
(NAMS) convened an expert Hormone
Therapy Advisory Panel to examine the
data and prepare a report. A position
statement on the recommendations for
clinical practice was released in September
2003.2 The expert panel reached consensus
on the following areas:
• The primary indication for systemic
hormone therapy is moderate and severe
menopausal symptoms: Hot flashes,
night sweats/insomnia, mood swings.
• When treating moderate and severe
urogenital atrophy (vaginal dryness,
dyspareunia, urinary frequency, and
incontinence), local estrogen prepara-
tions are preferred.
• The primary indication for progesto-
gen is endometrial protection for all
women with an intact uterus using sys-
temic estrogen therapy (ET).
• Hormone therapy should not be used for
primary or secondary prevention of CHD.
• Breast cancer risk is increased with
ET and, to a greater extent, with estro-
gen progestogen therapy (EPT) used
beyond 5 years.
• There is definitive evidence for EPT
efficacy in reducing the risk of fracture.
However, other effective alternate
forms of therapy are readily available.
Because of potential risk associated
w w w. j f p o n l i n e . c o m
Hormone replacement therapy
▲
TA B L E 2
Possible tapering schedules
for estrogen regimens
Current hormone CEE/MPA 0.625/2.5 mg daily
regimen
Month 1 CEE/MPA 0.625/2.5 mg qod (x 1 mo)
Month 2 CEE/MPA 0.3/1.5 mg daily (x 1 mo)
Month 3 CEE/MPA 0.3/1.5 mg qod (x 1 mo)
Month 4 CEE 0.3/1.5 mg 2/wk (x 1 mo)
Month 5 Estrogen patch 0.025/wk if needed
CEE/MPA, conjugated equine estrogen/medroxyprogesterone acetate;
qod, every other day
TA B L E 3
HRT dosing options
MEDICATION DOSAGE
Conjugated estrogens 0.3 mg, 0.45 mg, 0.625 mg,
(Premarin) 0.9 mg
Estradiol (Estrace) 0.5 mg, 1 mg, 2 mg
(scored tablets)
Estradiol patches 0.025 mg/d, 0.0375, 0.05 mg/d
(Climara/Vivelle)
with long-term use of EPT, the risks
and benefits of each option should be
discussed with the patient.
• EPT is not recommended for primary
prevention of dementia.
• Hormone therapy should be limited
to the shortest duration to achieve
treatment goals, taking into considera-
tion the impact on quality of life.
• Lower-than-standard doses of EPT
and ET should be considered (including
0.3 mg conjugated estrogen, 0.25–0.5
mg oral micronized 17 B-estradiol and
0.025 mg 17 B-estradiol patches).
However, the long-term risk-benefit
ratio has not been demonstrated.
• Extended use of ET/EPT is acceptable
if the woman feels the benefits of symp-
tom relief outweigh the risks, an attempt
to withdraw ET has failed, or to prevent
osteoporotic fracture when alternative
therapies are not appropriate or usable.
VOL 54, NO 5 / MAY 2005 431
 FAMILY MEDICINE GRAND ROUNDS
■ Menopausal symptoms
Q: If Mrs JC does not wish to take hormone, what advice can you give to minimize
menopausal symptoms? Are herbal products safe?
A:
Dr. Leong: Because estrogen is the most
effective treatment for menopausal symp-
toms, Mrs JC may yet consider taking it on
a short-term basis, if her symptoms are
debilitating. We should use the lowest dose
required to control symptoms. She has
already stopped her therapy, of course. But
had she still been taking ET and told you
she wished to discontinue it, you could
have advised her that, often times, tapering
estrogen over several months results in
fewer symptoms than when quitting “cold
turkey” (TABLES 2 AND 3 ).
If Mrs JC is absolutely against taking
estrogen, several other drugs have been
shown to reduce hot flashes. The selective
serotonin reuptake inhibitors (SSRIs) were
effective in several randomized trials using
venlafaxine (Effexor),4 paroxetine (Paxil),
and, less effectively, fluoxetine (Prozac).5
FAST TRACK
Because estrogen ■ Urinary tract symptoms
is the most Q: If the patient does not want to go back on estrogen, what can be done
effective treatment about her urinary symptoms?
for menopausal A:
symptoms, the
patient may yet
consider taking it
Dr Erickson: Urinary problems most com-
on a short-term monly associated with menopause are
basis incontinence and recurrent urinary tract
infections. Fortunately, both of these prob-
lems can be reduced with topical estrogen,
which has minimal systemic absorption
(TABLE 4 ). For example, a recent study of
intravaginal estradiol (25 µg) vs placebo
showed that the estrogen-treated group
had significant reduction in symptoms
(including dysuria, frequent voiding, and
incontinence) and urodynamic findings,
but no increase in serum estradiol levels or
432 VOL 54, NO 5 / MAY 2005 THE JOURNAL OF FAMILY PRACTICE
Clonidine (Catapres) was effective at
reducing hot flushes in some, but not all,
clinical trials.6 Gabapentin (Neurontin)
and megestrol acetate (Megace) are other
possible choices.
Complementary and alternative ther-
apies have been very popular among
some postmenopausal women as they
look for symptom relief. There are mixed
data on soy compounds (phytoestrogen
and isoflavone), with only 3 of 8 trials
demonstrating a beneficial effect.7–9 Black
cohosh showed modest benefits, but
ginseng, dong quai, red clover, evening
primrose oil, vitamin E, acupuncture,
wild yam, and progesterone cream were
ineffective. The main cautions with these
products are that safety and efficacy are
not well established and quality control
of the products is often lacking.
endometrial growth.10 Thus, a topical
estrogen could provide the urologic bene-
fits without the risks of systemic treatment.
If she wants to avoid estrogen altogether,
she has other options.
Stress incontinence. For stress inconti-
nence, pelvic floor muscle exercises are
helpful. These can be done without any
assistance if the patient is able to do the
exercises and is motivated. For patients
with marginal ability or motivation,
options include biofeedback training,
vaginal weights, electric stimulation, or

magnetic stimulation.
Alpha-adrenergic agonists have also
been used,11 although treatment of stress
incontinence is an off-label use for these
drugs and they have risks including hyper-
tension and tachycardia. Phenylpropa-
nolamine (eg, Entex LA) is the alpha-
adrenergic agent with the most reported
studies for stress incontinence, but it was
withdrawn from the market due to
increased risk of cerebrovascular acci-
dent.12 The alternative now contains pseu-
doephedrine (eg, Entex PSE) but there are
no published trials of pseudoephedrine for
stress incontinence.
More recent studies have shown
duloxetine (Cymbalta) to be effective,13,14
although incontinence is currently an off-
label use for it.
Fem-Soft urethral inserts are used by
some patients and are covered by
Medicare. These soft inserts are held in
place by a unique balloon, which expands
automatically after insertion and compress-
es when the patient pulls on the insert to
remove it (ie, the balloon does not need to
be inflated or deflated in the office). They
are similar in width to Foley catheters (16
or 18 Fr) but are shorter, extending only
about 1 cm out from the urethral meatus.
Surgical options for stress inconti-
nence include periurethral injections and
sling operations. The former involves
injecting a bulking material (such as
collagen paste) around the urethra to
increase its coaptation (urethral closure).
It is a simple, almost painless, outpatient
procedure with minimal risks, but results
vary. Several procedures may be required
to achieve continence, and most patients
have recurrent incontinence within
5 years.
In contrast, sling operations have a
better success rate. Slings can be made
from various materials including the
patient’s own fascia, cadaveric fascia, ani-
mal materials such as porcine intestinal
submucosa, or synthetic mesh. Most mate-
rials have good short-term results, with
stress incontinence cured or significantly
improved for over 90% of patients.15
w w w. j f p o n l i n e . c o m
Hormone replacement therapy
▲
TA B L E 4
Vaginal products
for genitourinary atrophy
PRODUCT DOSAGE
Low-dose estrogen vaginal cream 0.3 mg 2x/wk
Vaginal ring
Estring 6–9 µg of estrogen/d
for 3 mo
Femring 50 to 100 µg/d for
vasomotor symptoms
Vaginal tablet (Vagifem) 25 µg of estradiol 2x/wk or 10
µg 2x/wk may be effective for
genitourinary atrophy
Long-term success depends on the sling
material used. The risks and duration of
hospitalization depend on the specific
materials and techniques, but most slings
are inserted either as outpatient surgery or
with overnight hospitalization.
Urge incontinence. For urge inconti-
nence, pelvic floor muscle exercises are
beneficial because contraction of the
pelvic floor inhibits the detrusor by a
reflex. This is well described in a book for
lay people.16
Anticholinergic drugs are commonly FAST TRACK
used and are more effective than place-
bo.11,17 Side effects include dry mouth,
Topical estrogen
constipation, and mental status changes. could provide
Ways to reduce side effects: urologic benefits
1. Sustained-release formulations of oxy- without the risks
butynin (Ditropan XL) or tolterodine
(Detrol LA) of systemic
2. Anticholinergics that are more selective treatment
for the bladder, such as tolterodine
(Detrol)
3. Transdermal oxybutynin (Oxytrol),
which decreases the first-pass liver
metabolism and minimizes production
of metabolites that have side effects of
their own
4. Trospium chloride (Sanctura), which
does not cross the blood-brain barrier
and therefore has less effect on the cen-
tral nervous system.18
Interestingly, magnesium supplementa-
tion (MgOH, 350 mg twice daily) was
effective for urge incontinence in a placebo-
VOL 54, NO 5 / MAY 2005 433
 FAMILY MEDICINE GRAND ROUNDS
controlled trial.19 If conservative treatments
fail, the surgical options include sacral nerve
stimulation or augmentation cystoplasty.
The latter has high morbidity and should be
considered only as a last resort for a person
with incapacitating incontinence.
Recurrent UTI. For recurrent urinary
tract infections, several options are avail-
able. Cranberries contain polymeric
proanthocyanidins, which inhibit the bind-
ing of Escherichia coli to uroepithelial
cells. Cranberry juice or cranberry extract
tablets were more effective than placebo in
the few studies available, but the optimum
preparation and dose are unknown.20 Also,
since the P fimbriae on E coli bind to man-
nose residues on uroepithelial cells, it is
expected that free mannose in the urine
■ Cardiac risk factors
Q: What should be done about Mrs JC’s cardiac risk factors? Osteoporosis prevention?
A:
Dr Leong: Mrs JC’s risk factors for heart
FAST TRACK disease include hypertension, hyperlipi-
demia, obesity, and family history of
For osteoporosis CHD. While hormone therapy should not
prevention, advise be used to prevent heart disease, there are
the patient to start well-established treatments for hyperlipi-
weight-bearing demia including diet, exercise, and lipid
lowering medications, such as the statins.
exercise and She should be advised to lose weight. If
include adequate healthy lifestyle changes do not control
calcium and
vitamin D in ■ Should the patient be treated with HRT?
her diet Q: With the patient’s family history of CHD and her personal risk factors,
is HRT contraindicated?
A:
Dr Pees: Mrs JC’s family history of CHD
does not contraindicate hormonal thera-
py. But neither is hormonal therapy indi-
cated to prevent CHD. Mrs JC should be
434 VOL 54, NO 5 / MAY 2005 THE JOURNAL OF FAMILY PRACTICE
might competitively inhibit this binding.
Mannose is sold over the counter as a
preventative for urinary tract infections.
No published literature supports its use,
but it appears harmless.
Another option is methenamine hippu-
rate, which is a urinary tract antiseptic.
Controlled trials to date have not proven its
efficacy, but adverse events are infrequent.21
Antibiotics can also be used as chronic
low-dose prophylaxis or intermittent self-
start therapy when infection symptoms
occur.22 Best for low-dose prophylaxis are
antibiotics with minimal adverse effects on
the fecal and vaginal flora, such as trimetho-
prim alone, trimethoprim/sulfamethoxa-
zole, nitrofurantoin, cephalexin (in minimal
doses), and fluoroquinolones.23
her blood pressure, antihypertensive med-
ication would be indicated.
For prevention of osteoporosis, Mrs
JC should be advised to start weight-
bearing exercise and to include adequate
calcium and vitamin D in her diet.
Besides estrogen, bisphosphonates,
raloxifene, and calcitonin are effective
medication for osteoporosis treatment
and prevention.
strongly urged to begin an exercise pro-
gram, diet modifications, and possibly
the use of statins. Studies support exercise
as a significant factor in reducing the risk

Family physician commentary
H ormone replacement therapy (HRT) has gener-
ated fear and confusion among many women.
While the absolute risk for diseases associated with
hormone use is low, the diseases are devastating.
Breast cancer and stroke are 2 of the most feared
illnesses, yet research studies often provided con-
flicting results on the risk of hormone replacement
associated with these conditions.
Individualize every decision
The calculation of risks/benefits ratio has changed
with the WHI data. All patients on HRT must be
counseled on the new data, ideally in a face-to-face
visit. Phone calls for medication refill, annual exam,
and regular office visits are opportunities to revisit
the subject of hormone therapy (HT). Given the
mixed benefits and risks associated with HT, every
decision should be individualized. A patient-cen-
tered counseling approach would allow a shared
decision: the patient expresses her needs, goals,
and preferences, and the physician applies medical
knowledge to his and her values. In this dynamic
approach, the physician can shift from a directive
to a nondirective posture, taking the lead vs giving
the patient full autonomy. The point in the continu-
um where the physician chooses to participate is
determined by the patient, the physician, and the
medical evidence.
The patient’s personal and family histories
(breast/colon cancer, stroke, MI, osteoporosis) and
risk factors (lipid profile, diet, exercise, body-mass
index) play major roles in the decision. However,
the patient’s philosophical approach to health often
is the determining factor. The physician must pro-
vide the facts and ensure a patient is not taking
HRT for reasons no longer valid. Questions such as,
“What benefits do you hope to gain from HRT?”
and “What are your major fears of HRT?” can help
facilitate the discussion.
The patient’s philosophy
Patients often will select treatments most consis-
tent with their philosophical approach to health.
Patients with a holistic view of healthcare and an
uneasiness with HRT are unlikely to have many
questions. The patients who could benefit from
w w w. j f p o n l i n e . c o m
Hormone replacement therapy
▲
your counsel are those who stopped HRT due to
the findings of the WHI studies and those still on
HRT who would like to continue. A recalculation of
their individual risk/benefit ratio will help determine
if HRT is still the right decision for them.
Considering symptoms
Menopausal symptoms are common and
bothersome, often adversely impacting patients’
quality of life. Symptoms should be considered in
calculating the risks/benefits ratio, but unfortunate-
ly, they are seldom included in research studies. In
a UK qualitative study using a “time trade-off”
method, participants were asked to make trade-offs
between a shorter life span in “perfect health”
compared with a longer life span with the condition
under study.23 Women reported they might give
up 3 months of their life to live the rest of the year
without menopausal symptoms, underscoring the
importance of menopausal symptoms.
Unanswered questions remain
Though national organizations such as ACOG,
NAMS (The North American Menopause Society),
and USPSTF (US Preventive Services Task Force)
generally agree that estrogen and progestin should
not be used routinely to prevent chronic conditions
of menopause, such as CHD, there remain many
unanswered questions. What are the risks associat-
ed with progestin? Is topical estrogen truly safe?
Does the type of estrogen and delivery system
have an impact on the safety profile? A recent sys-
tematic review and meta-analysis of the commonly
used estrogen preparations showed that CEE and
oral and transdermal 17 B-estradiol have consis-
tent and comparable efficacy in the treatment of
hot flashes and may have similar short-term
adverse effects.24 But current clinical trials have
many limitations, and further testing is needed to
answer many remaining questions. Until clear
strategies become available for HRT, the role of the
physician continues to be that of a medical advisor
helping patients make well-informed, personal,
and thoughtful decisions.
—Shou Ling Leong, MD
VOL 54, NO 5 / MAY 2005 435
FAMILY MEDICINE GRAND ROUNDS
of CHD and, to a lesser degree, the risk
of breast cancer. If, after thorough coun-
seling with reference to WHI risk find-
ings, Mrs JC wishes to remain on or start
hormone therapy, she should start on the
lowest effective dosage to relieve her
vasomotor symptoms. She should also
be reevaluated periodically and be kept
appraised of new data as they become
available. ■
REFERENCES
1. Rossouw JE, Anderson GL, Prentice RL, et al; Writing
Group for the Women's Health Initiative Investigators.
Risks and benefits of estrogen and progestin in healthy
postmenopausal women: principal results from the
Women’s Health Initiative randomized controlled trial.
JAMA 2002; 288:321–333.
2. Anderson GL, Limacher M, Assaf AR, et al; Women's
Health Initiative Steering Committee. Effects of conju-
gated equine estrogen in postmenopausal women with
hysterectomy, the women’s health initiative random-
ized control trial. The Women’s Health Initiative Steering
Committee. JAMA 2004; 291:1701–1712.
3. The Hormone Therapy Advisory Panel of the North
American Menopause Society position statement on
hormone therapy. Available at: www.menopause.org.
Accessed on April 1, 2005.
4. Loprinzi CL, Kugler JW, Sloan JA, et al. Venlafaxine in
management of hot flashes in survivors of breast can-
cer: a randomised controlled trial. Lancet 2000;
356:2059–2063.
5. Stearns V, Beebe KL, Iyengar M, Dube E. Paroxetine
controlled release in the treatment of menopausal hot
flashes: a randomized controlled trial. JAMA 2003;
289:2827–2834.
6. Nagamani M, Kelver ME, Smith ER. Treatment of
menopausal hot flashes with transdermal administra-
tion of clonidine. Am J Obstet Gynecol 1987;
156:561–565.
7. Upmalis DH, Lobo R, Bradley L, Warren M, Cone FL,
Lamia CA. Vasomotor symptom relief by soy isoflavone
extract tablets in postmenopausal women: a multicen-
ter, double-blind, randomized, placebo-controlled
study. Menopause 2000; 7:236–242.
8. Tice JA, Ettinger B, Ensrud K, Wallace R, Blackwell T,
Cummings SR. Phytoestrogen supplements for the
treatment of hot flashes: the isoflavone clover extract
(ICE) study: a randomized controlled trial. JAMA 2003;
290:207–214.
9. Kronenberg F, Fugh-Berman A. Complementary and
alternative medicine for menopausal symptoms: a
review of randomized, controlled trials. Ann Intern Med
2002; 137:805–813.
10. Simunic V, Banovic I, Ciglar S, Jeren L, Pavicic Baldani
D, Sprem M. Local estrogen treatment in patients with
urogenital symptoms. Int J Gynecol Obstet 2003;
82:187–197.
11. Fantl JA, Newman DK, Colling J, et al. Urinary
Incontinence in Adults: Acute and Chronic
Management. Clinical Practice Guideline, No. 2; 1996
update. AHCPR Publication No. 96-0682. Rockville, Md:
US Department of Health and Human Services, Public
Health Services, Agency for Health Care Policy and
Research; 1996.
436 VOL 54, NO 5 / MAY 2005 THE JOURNAL OF FAMILY PRACTICE
12. Kernan WN, Viscoli CM, Brass LM, et al.
Phenylpropanolamine and the risk of hemorrhagic
stroke. N Engl J Med 2000; 343:1826–1832.
13. Millard RJ, Moore K, Rencken R, Yalcin I, Bump RC;
Duloxetine UI Study Group. Duloxetine vs. placebo in
the treatment of stress urinary incontinence: a four-con-
tinent randomized clinical trial. BJU International 2004;
93:311–318.
14. Dmochowski RR, Miklos JR, Norton PA, Zinner NR,
Yalcin I, Bump RC; Duloxetine UI Study Group:
Duloxetine versus placebo for the treatment of North
American women with stress urinary incontinence.
J Urol 2003; 170:1259–1263.
15. Leach GE, Dmochowski RR, Appell RA, et al. Female
stress urinary incontinence clinical guidelines panel
summary report on surgical management of female
stress urinary incontinence. J Urol 1997; 158:875–880.
16. Burgio KL, Pearce KL, Lucco AJ. Staying Dry: A Practical
Guide to Bladder Control. Baltimore, Md: Johns
Hopkins University Press; 1989.
17. Hay-Smith J, Herbison P, Ellis G, Moore K.
Anticholinergic drugs versus placebo for overactive
bladder syndrome in adults. Cochrane Database Syst
Rev 2002; (3) CD003781.
18. Halaska M, Ralph G, Weidemann A, et al. Controlled,
double-blind, multicentre clinical trial to investigate
long-term tolerability and efficacy of trospium chloride
in patients with detrusor instability. World J Urol 2003;
29:392–399.
19. Gordon D, Groutz A, Ascher-Landsberg J, Lessing JB,
David MP, Razz O. Double-blind, placebo-controlled
study of magnesium hydroxide for treatment of senso-
ry urgency and detrusor instability: preliminary results.
Br J Obstet Gynaecol 1998; 105:667–669.
20. Jepson RG, Mihaljevic L, Craig J. Cranberries for pre-
venting urinary tract infections. Cochrane Database
Syst Rev 2004; (1) CD001321.
21. Lee B, Bhuta T, Craig J, Simpson J. Methenamine hip-
purate for preventing urinary tract infections. Cochrane
Database Syst Rev 2002;(1):CD003265.
22. Schaeffer AJ. Infections of the urinary tract. In: Walsh
PC, Retik AB, Vaughan ED, Wein AJ, eds. Campbell’s
Urology. 8th ed. Philadelphia, Pa: Saunders;
2002:515–602.
23. Minelli C, Abrams KR, Sutton AJ, Cooper NJ. Benefits
and harms associated with hormone replacement ther-
apy: clinical decision analysis. BMJ 2004; 328:371.
24. Nelson H. Commonly used types of postmenopausal
estrogen for treatment of hot flashes: Scientific Review.
JAMA 2004; 292:1610–1619.
DRUG BRAND NAMES
Calcitonin • Calcimar, Cibacalcin, Miacalcin
Cephalexin • Biocef, Keflex, Keftab
Clonidine • Catapres
Duloxetine • Cymbalta
Fluoxetine • Prozac
Gabapentin • Neurontin
Megestrol acetate • Megace
Nitrofurantoin • Furadantin, Macrobid, Macrodantin
Oxybutynin • Ditropan, Oxytrol
Paroxetine • Paxil
Raloxifene • Evista
Tolterodine • Detrol
Trospium chloride • Sanctura
Venlafaxine • Effexor