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(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
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 1200 individuals who had prior MI, revas-
the issue of when to use hormonal therapy. cularization procedures, stroke, DVT, and
The answer to your question lies in knowing PE. Excluded were those with severe
how the WHI risks were calculated. menopausal symptoms, prior fracture/low
The WHI authors described 2 confi- bone mineral density (BMD), and cognitive
dence indexes (CI). The first was calculated function deficits. Also, only 10% of the
as if looking at a single outcome variable, a group was in the 50- to 54-year-old group;
nominal CI; the second, an adjusted CI, 25% were in the 70- to 79-year-old group.
took into account multiple outcomes. The dropout rate was fairly high: 42% in
For the CEE/MPA arm, when the nom- the CEE/MPA arm, and 38% placebo arm;
inal CI is used, CHD and breast cancer only 25% of the CEE/MPA arm remained
risks barely reached clinical significance; at the study termination. Unblinding
colon cancer and fracture reduction occurred in 40% of the CEE/MPA arm and
reached clinical significance; DVT and 5.4% in the placebo arm.
FAST TRACK strokes were also clinically significant using It is worth noting that CHD increased
both CIs. When the adjusted CI is used, in the first year of the study but decreased
It is worth noting DVT/strokes, and to a lesser degree frac- in subsequent years. VTE/DVT and total
that coronary ture reduction, retain clinical significance. fractures were the only 2 items that
heart disease In the CEE-only arm (February 2004 achieved true clinical significance. Total
increased in the report), DVT/strokes were the only vari- fracture reduction was 1.6 times greater
able that reached clinical significance. than the increases in CHD and breast can-
first year of the CHD/breast cancer/colorectal cancer did cer; and the fact that breast cancers double
WHI study but not reach clinical significance, and fracture every 300 days and are present for 7 to 8
decreased in reduction only a slight decrease in risk. years before they are detected with current
The WHI study introduced a new diagnostic testing.
subsequent years term, the Global Index, which had not Despite the biases and limitations of
been tested for validity or significance of the data presented by the WHI report, the
assigning weights to various outcomes. study does add to our knowledge and it
Additionally, there were certain biases in should be included in our discussion with
the construct of the study. Included were patients when addressing HRT.
Q: Have the data from WHI altered your practice in treating conditions associated
with menopause? If so, in what ways?
A:
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Dr Pees: The WHI data have altered the TA B L E 2
way in which I counsel patients. I still pre- Possible tapering schedules
scribe hormone therapy within the for estrogen regimens
American College of Obstetricians and
Gynecologists (ACOG) guidelines, and, Current hormone CEE/MPA 0.625/2.5 mg daily
after a very thorough discussion, reference regimen
the WHI data. This is to ensure that Month 1 CEE/MPA 0.625/2.5 mg qod (x 1 mo)
patients make informed decisions about
continuing or starting hormone therapy. Month 2 CEE/MPA 0.3/1.5 mg daily (x 1 mo)
Following ACOG recommendations, I Month 3 CEE/MPA 0.3/1.5 mg qod (x 1 mo)
evaluate each patient’s risk profile. I start
Month 4 CEE 0.3/1.5 mg 2/wk (x 1 mo)
treatment with the lowest effective dose to
relieve symptoms. I discuss the use of alter- Month 5 Estrogen patch 0.025/wk if needed
native treatments for menopausal symp-
CEE/MPA, conjugated equine estrogen/medroxyprogesterone acetate;
toms and osteoporosis prevention, as well qod, every other day
as evaluation and treatment for quality of
life issues. Most importantly I encourage TA B L E 3
periodic re-evaluation for hormone use.
After the WHI study was terminated, HRT dosing options
the North American Menopause Society
MEDICATION DOSAGE
(NAMS) convened an expert Hormone
Therapy Advisory Panel to examine the Conjugated estrogens 0.3 mg, 0.45 mg, 0.625 mg,
data and prepare a report. A position (Premarin) 0.9 mg
statement on the recommendations for
Estradiol (Estrace) 0.5 mg, 1 mg, 2 mg
clinical practice was released in September
(scored tablets)
2003.2 The expert panel reached consensus
on the following areas: Estradiol patches 0.025 mg/d, 0.0375, 0.05 mg/d
• The primary indication for systemic (Climara/Vivelle)
hormone therapy is moderate and severe
menopausal symptoms: Hot flashes, with long-term use of EPT, the risks
night sweats/insomnia, mood swings. and benefits of each option should be
• When treating moderate and severe discussed with the patient.
urogenital atrophy (vaginal dryness, • EPT is not recommended for primary
dyspareunia, urinary frequency, and prevention of dementia.
incontinence), local estrogen prepara- • Hormone therapy should be limited
tions are preferred. to the shortest duration to achieve
• The primary indication for progesto- treatment goals, taking into considera-
gen is endometrial protection for all tion the impact on quality of life.
women with an intact uterus using sys- • Lower-than-standard doses of EPT
temic estrogen therapy (ET). and ET should be considered (including
• Hormone therapy should not be used for 0.3 mg conjugated estrogen, 0.25–0.5
primary or secondary prevention of CHD. mg oral micronized 17 B-estradiol and
• Breast cancer risk is increased with 0.025 mg 17 B-estradiol patches).
ET and, to a greater extent, with estro- However, the long-term risk-benefit
gen progestogen therapy (EPT) used ratio has not been demonstrated.
beyond 5 years. • Extended use of ET/EPT is acceptable
• There is definitive evidence for EPT if the woman feels the benefits of symp-
efficacy in reducing the risk of fracture. tom relief outweigh the risks, an attempt
However, other effective alternate to withdraw ET has failed, or to prevent
forms of therapy are readily available. osteoporotic fracture when alternative
Because of potential risk associated therapies are not appropriate or usable.
■ 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 Clonidine (Catapres) was effective at
effective treatment for menopausal symp- reducing hot flushes in some, but not all,
toms, Mrs JC may yet consider taking it on clinical trials.6 Gabapentin (Neurontin)
a short-term basis, if her symptoms are and megestrol acetate (Megace) are other
debilitating. We should use the lowest dose possible choices.
required to control symptoms. She has Complementary and alternative ther-
already stopped her therapy, of course. But apies have been very popular among
had she still been taking ET and told you some postmenopausal women as they
she wished to discontinue it, you could look for symptom relief. There are mixed
have advised her that, often times, tapering data on soy compounds (phytoestrogen
estrogen over several months results in and isoflavone), with only 3 of 8 trials
fewer symptoms than when quitting “cold demonstrating a beneficial effect.7–9 Black
turkey” (TABLES 2 AND 3 ). cohosh showed modest benefits, but
If Mrs JC is absolutely against taking ginseng, dong quai, red clover, evening
estrogen, several other drugs have been primrose oil, vitamin E, acupuncture,
shown to reduce hot flashes. The selective wild yam, and progesterone cream were
serotonin reuptake inhibitors (SSRIs) were ineffective. The main cautions with these
effective in several randomized trials using products are that safety and efficacy are
venlafaxine (Effexor),4 paroxetine (Paxil), not well established and quality control
and, less effectively, fluoxetine (Prozac).5 of the products is often lacking.
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- endometrial growth.10 Thus, a topical
on a short-term monly associated with menopause are estrogen could provide the urologic bene-
basis incontinence and recurrent urinary tract fits without the risks of systemic treatment.
infections. Fortunately, both of these prob- If she wants to avoid estrogen altogether,
lems can be reduced with topical estrogen, she has other options.
which has minimal systemic absorption Stress incontinence. For stress inconti-
(TABLE 4 ). For example, a recent study of nence, pelvic floor muscle exercises are
intravaginal estradiol (25 µg) vs placebo helpful. These can be done without any
showed that the estrogen-treated group assistance if the patient is able to do the
had significant reduction in symptoms exercises and is motivated. For patients
(including dysuria, frequent voiding, and with marginal ability or motivation,
incontinence) and urodynamic findings, options include biofeedback training,
but no increase in serum estradiol levels or vaginal weights, electric stimulation, or
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magnetic stimulation. TA B L E 4
Alpha-adrenergic agonists have also Vaginal products
been used,11 although treatment of stress for genitourinary atrophy
incontinence is an off-label use for these
drugs and they have risks including hyper- PRODUCT DOSAGE
tension and tachycardia. Phenylpropa- Low-dose estrogen vaginal cream 0.3 mg 2x/wk
nolamine (eg, Entex LA) is the alpha-
adrenergic agent with the most reported Vaginal ring
studies for stress incontinence, but it was Estring 6–9 µg of estrogen/d
for 3 mo
withdrawn from the market due to
increased risk of cerebrovascular acci- Femring 50 to 100 µg/d for
dent.12 The alternative now contains pseu- vasomotor symptoms
doephedrine (eg, Entex PSE) but there are Vaginal tablet (Vagifem) 25 µg of estradiol 2x/wk or 10
no published trials of pseudoephedrine for µg 2x/wk may be effective for
genitourinary atrophy
stress incontinence.
More recent studies have shown
duloxetine (Cymbalta) to be effective,13,14 Long-term success depends on the sling
although incontinence is currently an off- material used. The risks and duration of
label use for it. hospitalization depend on the specific
Fem-Soft urethral inserts are used by materials and techniques, but most slings
some patients and are covered by are inserted either as outpatient surgery or
Medicare. These soft inserts are held in with overnight hospitalization.
place by a unique balloon, which expands Urge incontinence. For urge inconti-
automatically after insertion and compress- nence, pelvic floor muscle exercises are
es when the patient pulls on the insert to beneficial because contraction of the
remove it (ie, the balloon does not need to pelvic floor inhibits the detrusor by a
be inflated or deflated in the office). They reflex. This is well described in a book for
are similar in width to Foley catheters (16 lay people.16
or 18 Fr) but are shorter, extending only Anticholinergic drugs are commonly FAST TRACK
about 1 cm out from the urethral meatus. used and are more effective than place-
Surgical options for stress inconti- bo.11,17 Side effects include dry mouth,
Topical estrogen
nence include periurethral injections and constipation, and mental status changes. could provide
sling operations. The former involves Ways to reduce side effects: urologic benefits
injecting a bulking material (such as 1. Sustained-release formulations of oxy- without the risks
collagen paste) around the urethra to butynin (Ditropan XL) or tolterodine
increase its coaptation (urethral closure). (Detrol LA) of systemic
It is a simple, almost painless, outpatient 2. Anticholinergics that are more selective treatment
procedure with minimal risks, but results for the bladder, such as tolterodine
vary. Several procedures may be required (Detrol)
to achieve continence, and most patients 3. Transdermal oxybutynin (Oxytrol),
have recurrent incontinence within which decreases the first-pass liver
5 years. metabolism and minimizes production
In contrast, sling operations have a of metabolites that have side effects of
better success rate. Slings can be made their own
from various materials including the 4. Trospium chloride (Sanctura), which
patient’s own fascia, cadaveric fascia, ani- does not cross the blood-brain barrier
mal materials such as porcine intestinal and therefore has less effect on the cen-
submucosa, or synthetic mesh. Most mate- tral nervous system.18
rials have good short-term results, with Interestingly, magnesium supplementa-
stress incontinence cured or significantly tion (MgOH, 350 mg twice daily) was
improved for over 90% of patients.15 effective for urge incontinence in a placebo-
Dr Leong: Mrs JC’s risk factors for heart her blood pressure, antihypertensive med-
FAST TRACK disease include hypertension, hyperlipi- ication would be indicated.
demia, obesity, and family history of For prevention of osteoporosis, Mrs
For osteoporosis CHD. While hormone therapy should not JC should be advised to start weight-
prevention, advise be used to prevent heart disease, there are bearing exercise and to include adequate
the patient to start well-established treatments for hyperlipi- calcium and vitamin D in her diet.
weight-bearing demia including diet, exercise, and lipid Besides estrogen, bisphosphonates,
lowering medications, such as the statins. raloxifene, and calcitonin are effective
exercise and She should be advised to lose weight. If medication for osteoporosis treatment
include adequate healthy lifestyle changes do not control and prevention.
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 strongly urged to begin an exercise pro-
does not contraindicate hormonal thera- gram, diet modifications, and possibly
py. But neither is hormonal therapy indi- the use of statins. Studies support exercise
cated to prevent CHD. Mrs JC should be as a significant factor in reducing the risk
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Family physician commentary