Download Click here for handout

3/31/2011
DISCLAIMER
NEITHER THE PUBLISHER NOR THE
AUTHORS ASSUME ANY LIABILITY FOR
ANY INJURY AND OR DAMAGE TO
PERSONS OR PROPERTY ARISING
FROM THIS WEBSITE AND ITS
CONTENT.

T. Watson Jernigan
T
Jernigan, MD MA NCMP
Professor and Interim Chairman
Department of Ob/Gyn
March 16, 2011

“I turned own a proposal for marriage. He
lives in Alabama. If it have been Alaska, I
would have said yes.”
“My husband now sleeps in the living room,
but at least I have my hot flashes to keep me
warm.”
1
3/31/2011




The participant should be able to discuss the
impact of Vasomotor Instability on patients
The participant should be able to discuss the
p
pathogenesis
g
of Vasomotor Instability
y
The participant should be able to document the
present evidence-based literature for use of
alternative medicines
The participant should demonstrate an
understanding of side effects of alternative
medicines







The speaker does not now or has had any
economic interest in the alternative therapies to
be discussed today
The speaker
p
is not now a member of any
y
speaker’s bureau for the mentioned products
The speaker will endeavor to use generic
names whenever possible….and whenever his
brain allows him to remember not to say
branded names
Baby Boomers (1946-1964) are “coming of age”
at this time
6,000 Baby Boomer women reach Menopause
g ((51)) each and every
y day
y
Ag
By 2020, the number of women who will be
older than 55 is estimated to be 46 million
Given a life expectancy of 83, US women live
nearly 40% of their lives without estrogen
2
3/31/2011





Symptoms of Menopause can start upwards of
Five (5) years before cessation of menses
Among most common symptoms of
p
are: Vaginal
g
Dryness,
y
Mood
menopause
Swings, Hair and Skin Changes, and
Vasomotor Instability (Hot Flashes, Night
Sweats)
Of those patients who are perimenopausal, it is
estimated 75% will experience Vasomotor
Symptoms (VMS)

The symptoms of Vasomotor Instability are
related directly to declining levels of estrogen
specifically 17-B Estradiol
 THEREFORE,
TREATMENT
FOR VASOMOTOR
INSTABILITY SHOULD BE
ESTROGEN
According to records of prescriptions, there
were 129 million prescriptions for Hormonal
Therapy (HT) including estrogen in the year
2000
In 2001, a Women’s Health Initiative (WHI)
study was undertaken to evaluate the efficacy
of Estrogen and Progestin as well as Estrogen
alone in preventing heart disease in
postmenopausal women
3
3/31/2011



After the 2002 WHI study was published
approximately 65% of women on HT stopped
therapy
In 2003, there were jjust over 76 million HT
prescriptions dispensed
By 2008, this number had dropped to
approximately 42 million prescriptions for HT
in USA (29 million were for estrogen only RXs)
4
3/31/2011



In 2004, among the TOP 10-selling herbal
products in the US at least 4 of the 10 had been
used for menopausal symptoms
These 4 were: soy
y supplements,
pp
black cohosh,
St. John’s Wort, and ginseng.
In one population based survey: 12% of
women had used Complementary Therapies to
manage Menopausal Symptoms






In the literature after the W.H.I., results varied
as to the use of Complementary/Alternative
Therapies for treatment of Menopausal
Symptoms
National Health Interview Survey: 40%
Study of Women Across the Nation (SWAN);
50% to 80%
Though 75% of peri-/postmenopausal patients
complain of vasomotor instability, historically,
the symptoms were considered “all in the
head” of patients
In 1975,
1975 GW Molnar published a paper in
Journal of Applied Physiology on “Body
Temperatures during Menopausal Hot
Flashes”
He demonstrated objective peripheral
temperature changes during several hot flashes
of a single postmenopausal patient
5
3/31/2011






The pattern of Vasomotor Instability in patients
is exceptionally inconsistent
The timing, duration, intensity, and
p
psychological
y
g
effect on the individual p
patient is
variable
There is no hormonal level or objective testing
to predict the length of time a patient will
suffer from these episodes
Perspiration and vasodilatation associated with
these episodes appear to be controlled by the
thermoregulatory nucleus, which is located in
the preoptic area of the hypothalamus
The thermoregulatory nucleus regulates core
body temperature and works to keep it within
a range called the Thermoregulatory Zone
Women who suffer from vasomotor instability
appear to have a narrower Thermoregulatory
Zone than others and thus small increases in
core body temperature can trigger episodes.






Definition of Vasomotor Instability: Recurrent
periods of flushing, sweating, and intense heat that
begins on the face and upper chest. These
episodes can also be associated with a feeling of
anxiety,
anxiety palpitations,
palpitations and red blotching of the skin
Alternative definition: An exaggerated heat
dissipation response consisting of widespread
cutaneous vasodilatation, upper-body sweating
and modest tachycardia; preceded by a small
increase in core body temperature followed by a
rapid decline due to heat loss
Norepinephrine and Serotonin may be involved in
the complex neuroendocrine pathway controlling
the Thermoregulatory Zone
Hypothesis: Elevated brain norepinephrine
narrows the
th Thermoregulatory
Th
l t
Zone
Z
Hypothesis: Activation of specific Serotonin
receptors can cause hypothermia or hyperthermia
Estrogen withdrawal is associated with decreasing
levels of Serotonin and an increase in the Serotonin
receptors in the hypothalamus
6
3/31/2011






Model from Pachman, D/Jones, J/Loprubzi,C
(1) Estrogen withdrawal leads to a decrease in
endorphin and catecholestrogen levels
(2) In response, there is an increase in
Norepinephrine and Serotonin release
(3) This release lowers the set point in the
thermoregulatory nucleus….making the
Thermoregulatory Zone Narrower



Model works because it is the withdrawal of
Estrogen (not low levels of estrogen) that lead
to episodes
With surgical
g
menopause,
p
p
patients see rapid
p
onset of vasomotor instability
In patients with Gonadal Dysgenesis, those
with consistently low levels of estrogen have
no episodes; it is only seen with giving
hormone replacement therapy and then
stopping it that cause episodes
Two critical factors are noted: (1) in
symptomatic peri-/postmenopausal women
there is a reduced Thermoregulatory Zone and
(2) estrogen withdrawal (either gradually or
abruptly)
b
l ) leads
l d to a cascade
d off events which
h h
trigger an exaggerated response due to (1)
In other words: It’s all in a patient’s head!
7
3/31/2011





A Cochrane review by MacLennan, Broadbent,
Lester & Moore found that taking oral estrogen
or combined estrogen and progestin hormone
therapy greatly reduces the frequency and
severity off vasomotor instability
bl
Monotherapy to treat hot flashes with black
cohosh, dong quai, red clover,….soy
supplements cannot be recommended because
the totality of the evidence does not support
their use
Why the difference besides effectiveness of
estrogen?
Over past 10 years there have been a number of
g the
randomized, controlled trials evaluating
efficacy of single herbal supplements for
menopausal symptoms
Two reasons for conflicting results: (1) placebo
effect and (2) study design
8
3/31/2011





Geller et al published a randomized control
trial in 2009 in Menopause
This trial was a four-arm, double-blind clinical
trial of standardized black cohosh, red clover,
placebo, and 0.625 mgs CEE + 2.5 mgs MPA
The trial reviewed response by patients over a
12 month period of time




In the majority of randomized, clinical trials for
treatment of vasomotor instability, the placebo
effect is as great as 50%
Study designs include the herbal therapies with
behavioral modification to prevent hot flashes
including diet, exercise, layered clothing, and
smoking cessation
Primary endpoint outcome was reduction the
VMS by black cohosh/red clover vs. placebo
Results after one year: CEE/MPA had a 94%
reduction in VMS
For black cohosh (34%) and red clover (57%),
neither did as well as placebo (63%)
While not demonstrating effectiveness, the
study stated black cohosh and red clover were
safe during daily administration x 12 months
9
3/31/2011





2010 review and meta-analysis by Bolanos,
Castillo, and Francia in “Menopause”
This article reviewed thirty-four studies (34),
but only 19 were analyzed because of criteria of
published,
published randomized,
randomized placebo-controlled
placebo controlled and
with a 12-week duration of intervention
Conclusion: Although the overall combined
results showed a significant tendendcy in favor
of soy, it is still difficult to establish conclusive
results given the high heterogeneity found in
these studies
3. Analysis did not evaluate the influence of
the duration of the study on the results
4. Analyzed studies frequently used different
py
scores to measure the effect of the therapy.
There were nonhomogenous measurement
scales for the results which could add to the
heterogeneity factor





Though there was a tendency towards favoring
use of soy, the study identified four
weaknesses
1. Current regulatory framework has not
established final dose for soy dietary
supplements….making it difficult to compare
the studies without adequate standardization
2. Evidence suggests that the intestinal
metabolic character could have significant
influence on bioavailability….most studies doe
not evaluate participants metabolic pattern
Burke, GL, et al in 2003 study published in
“Menopause” investigated the efficacy of
dietary soy proteins containing differing
amounts of isoflavones on the number and
severity off vasomotor symptoms
Study had 241 women randomized to three
groups…(a) isoflavone extracted soy protein
(control); (b) soy protein with medium dose of
isoflavones (42 mgs/day); and (c) soy protein
with higher dose of isoflavones (58 mgs/day)
10
3/31/2011





While a reduction in number and severity of
vasomotor symptoms was observed in all three
treatment groups, no significant decreases were
observed in the three groups
Conclusion: The data suggested that soy
protein with additional isoflavones was no
more effective than isoflavone-extracted soy
protein
Three trials reported reduced hot flash
frequency with soy isoflavones compared to
placebo
Three other fair-qualified
q
trials found no
differences in hot flash frequency compared
with placebo using similar preparations
Five other trials (4 trials of women with breast
cancer) found no difference in severity scores
with soy isoflavones compared with placebo






In 2006, Nelson, H et al published a systematic
review and meta-analysis in “JAMA” looking
at eleven (11) placebo-controlled soy isoflavone
trials
Of the 11 trials, three were graded POOR and
eight were graded FAIR
Reductions of vasomotor symptoms with use
of placebo ranged from 21% to 69 %
In the same article as above, Nelson also did a
meta-analysis of the use of Red Clover
Isoflavones
He analyzed
y
six ((6)) studies with one ((1)) being
g
deemed Good; three (3) Fair; and two (2) Poor
Duration of study was from 12 weeks (3) to 16
weeks (1) to 12 months (1)….one study had
crossover phase with 12 weeks in each
crossover
11
3/31/2011




Red clover isoflavones are not a monotherapy
as they contain genistein, daidzein,
formononetin, and biochanin
In the trials evaluated by
y Nelson, Promensil
was chiefly used by patients
Promensil contains a higher proportion of
biochanin and genistein
Only two of the trials used a placebo control



Nelson noted “The trials do not support the
efficacy of red clover isoflavone extracts….”
He further noted “hot flash frequency was not
reduced when all trials of red clover isoflavone
extracts were combined….”
His conclusion: “Despite increasing interest in
therapies for menopausal hot flashes that avoid
use of estrogen, the efficacy and safety of other
options currently are not well supported.”
12
3/31/2011






Upon review, the USP assigned the cases as
“possible causality”
USP determined that black cohosh must
g statement that in rare cases,
include a labeling
it can “affect the liver”
This label would be required only if a black
cohosh product goes through the rigorous
process to qualify for a USP label



2007 Black Cohosh was the 7th “top-selling
herbal dietary supplement” in the US with
sales of $8.6 million
2008 Regulatory
g
y Agencies
g
from Australia,
Canada, and the EU released statements
regarding the “potential association” between
black cohosh and hepatoxicity
United States Pharmacopeia (USP) reviewed 30
cases of liver damage associated with black
cohosh exposure
In 2009, Teschke et al published in Menopause
an analysis of nine (9) suspected cases of
hepatotoxicity by black cohosh
Of the nine cases, the report
p
indicated 4 cases
were excluded; 4 cases were unlikely; and only
in 1 case was causality possible
The authors concluded: “the present study
shows, little, if any hepatotoxic risks by the use
of black cohosh”
13
3/31/2011






By 2010, Teschke published a review article in
Menopause reviewing now 69 initially
suspected cases of black cohosh-induced liver
disease
His report indicated that the presented data
did not support the concept of hepatotoxicity
He did urge that going forward use of a
structured, quantitative, and hepatotoxicityspecific causality assessment method be done
At present, the treatment for symptomatic
vasomotor symptoms should be estradiol if not
contraindicated (lowest dose…shortest time)
Alternative Medications have not
demonstrated statistically significant
improvement of symptoms (placebo effect)
Newer alternative medications are coming to
the market place (eg. Nutrafem)



Remember there is no FDA or for that matter
no USP labeling for these drugs
Remember also your patients are going to hear
g non-medical sources
about them through
Just because the product notes a “natural
source” does not mean that it is safe….short
term or especially long term without
information regarding long term safety
14
3/31/2011



Finally, there is another treatment for
discussion for another day----ACUPUNTURE
Remember to Individualize
As in the past, stay tuned for more
developments as the need for non-hormonal
therapies for severe vasomotor symptoms is
still present and will increase over the next few
years
15